1.1
1.2
1.3
1.4
1.5
2.1
2.1.1
2.1.2
2.1.3
2.1.4
2.1.5
2.1.6
2.1.7
2.1.8
2.1.9
2.1.10
2.1.11
2.1.12
2.2
2.2.1
2.2.1.1
2.2.1.2
2.2.2
2.2.2.1
2.2.2.2
2.2.2.3
2.2.2.4
2.2.2.5
2.2.2.6
2.2.2.7
2.2.2.8
2.2.2.9
2.2.3
2.2.3.1
TableofContentsAboutPartOne
DownloadPartOne
HowtoPass
TheSAQ
TheViva
Curriculum
ResearchMethodsandStatistics
Evidence-BasedMedicine
StudyTypes
ClinicalTrialDesign
DataTypes
BiasandConfounding
FrequencyDistributions
SampleSizeCalculation
StatisticalTests
StatisticalTerms
RiskandOdds
SignificanceTesting
DrugDevelopment
Pharmacology
Pharmaceutics
Additives
Isomerism
Pharmacokinetics
Modeling
Absorption
Distribution
MetabolismandClearance
Elimination
BolusandInfusionKinetics
DrugMonitoring
EpiduralandIntrathecal
TIVAandTCI
Pharmacodynamics
ReceptorTheory
2
2.2.3.2
2.2.3.3
2.2.3.4
2.2.4
2.2.4.1
2.2.4.2
2.2.4.3
2.2.4.4
2.2.4.5
2.2.5
2.2.5.1
2.2.5.2
2.2.5.3
2.3
2.3.1
2.3.2
2.3.3
2.3.4
2.3.5
2.3.6
2.4
2.4.1
2.4.1.1
2.4.1.2
2.4.1.3
2.4.2
2.4.3
2.4.3.1
2.4.3.2
2.4.3.3
2.4.3.4
2.4.3.5
2.4.3.6
2.4.3.7
2.4.3.8
2.4.4
2.4.4.1
2.4.4.2
2.4.5
2.4.5.1
ReceptorTypes
Dose-ResponseCurves
MechanismsofAction
VariabilityinDrugResponse
AdverseEffects
DrugInteractions
AlterationstoResponse
Pharmacogenetics
DrugsinPregnancy
Toxicology
GeneralManagement
TCAOverdose
Organophosphates
CellularPhysiology
TheCellMembrane
Organelles
ExcitableCells
TransportAcrossMembranes
FluidCompartments
CellHomeostasis
RespiratorySystem
RespiratoryAnatomy
AirwayandAlveolus
ChestWallandDiaphragm
VariationsinAnatomy
ControlofBreathing
MechanicsofBreathing
Respiration
Compliance
Time-Constants
Resistance
Surfactant
VolumesandCapacities
Spirometry
WorkofBreathing
DiffusionofGases
OxygenCascade
DiffusingCapacityandLimitation
V\QRelationships
West'sZones
3
2.4.5.2
2.4.5.3
2.4.5.4
2.4.6
2.4.6.1
2.4.6.2
2.4.7
2.4.7.1
2.4.7.2
2.4.7.3
2.4.7.4
2.4.7.5
2.4.7.6
2.4.7.7
2.4.7.8
2.4.7.9
2.4.7.10
2.4.8
2.4.8.1
2.5
2.5.1
2.5.1.1
2.5.1.2
2.5.1.3
2.5.2
2.5.2.1
2.5.3
2.5.3.1
2.5.3.2
2.5.3.3
2.5.3.4
2.5.3.5
2.5.4
2.5.4.1
2.5.4.2
2.5.4.3
2.5.4.4
2.5.4.5
2.5.5
2.5.5.1
BasicsofV\QMatching
DeadSpace
Shunt
GasTransport
OxygenStorage
CarbonDioxide
AppliedRespiratoryPhysiology
PositivePressureVentilation
Hypoxia
HypoandHypercapnea
PositionandVentilation
Humidification
CoughReflex
Non-RespiratoryFunctions
AltitudePhysiology
RespiratoryChangeswithObesity
NeonatesandChildren
RespiratoryPharmacology
Anti-AsthmaDrugs
CardiovascularSystem
StructureandFunction
CardiacAnatomy
CoronaryCirculation
CardiacCycle
ElectricalProperties
CardiacActionPotential
CardiacOutput
DeterminantsofCardiacOutput
VenousReturn
MyocardialOxygenSupplyandDemand
Pressure-VolumeRelationships
CardiacReflexes
PeripheralCirculation
StarlingForces
VariationsinBloodPressure
PulmonaryCirculation
CerebralBloodFlow
HepaticBloodFlow
CirculatoryControl
Baroreceptors
4
2.5.5.2
2.5.5.3
2.5.5.4
2.5.6
2.5.6.1
2.5.6.2
2.5.6.3
2.6
2.6.1
2.6.1.1
2.6.1.2
2.6.1.3
2.6.1.4
2.6.1.5
2.6.1.6
2.6.1.7
2.6.2
2.6.2.1
2.6.2.2
2.7
2.7.1
2.7.2
2.7.3
2.8
2.8.1
2.8.2
2.8.3
2.8.4
2.8.5
2.8.6
2.8.7
2.8.8
2.8.9
2.8.9.1
2.8.9.2
2.8.9.3
2.8.9.4
2.8.9.5
2.8.9.6
2.8.9.7
ValsalvaManoeuvre
CVSChangeswithObesity
CVSEffectsofAgeing
CardiovascularPharmacology
Inotropes
Adrenoreceptors
Antiarrhythmics
RenalSystem
RenalPhysiology
FunctionalAnatomyandControlofBloodFlow
GlomerularFiltrationandTubularFunction
HandlingofOrganicSubstances
MeasurementofGFR
EndocrineFunctionsoftheKidney
Acid-BaseBalance
Dialysis
FluidsandElectrolytes
SodiumandWater
Potassium
Acid-BasePhysiology
PrinciplesofAcid-BasePhysiology
Compensation
Buffers
NervousSystem
Blood-BrainBarrier
CSF
SpinalCordAnatomy
IntracranialPressure
IntraocularPressure
Sleep
Pain
AutonomicNervousSystem
Neuropharmacology
Neurotransmitters
Anticonvulsants
LocalAnaesthetics
NeuraxialBlockade
AcetylcholineReceptors
Opioids
InhalationalAnaesthetics
5
2.9
2.9.1
2.9.2
2.9.3
2.9.4
2.9.5
2.9.6
2.9.7
2.9.8
2.9.9
2.10
2.10.1
2.10.2
2.10.3
2.11
2.11.1
2.11.2
2.11.3
2.11.4
2.11.5
2.11.6
2.12
2.12.1
2.13
2.13.1
2.13.2
2.13.3
2.13.4
2.14
2.14.1
2.14.2
2.14.3
2.15
2.15.1
2.15.2
2.15.3
2.15.4
2.16
2.16.1
2.16.2
Endocrine
ABriefOverviewofHormones
Insulin,Glucagon,andSomatostatin
ControlofBloodGlucose
HypothalamusandPituitary
Thyroid
AdrenalHormones
CalciumHomeostasis
Histamine
Prostanoids
MusculoskeletalSystem
SkeletalMuscleStructure
SkeletalMuscleInnervation
NeuromuscularBlockers
Nutrition&Metabolism
BasalMetabolicRate
FatMetabolism
CarbohydrateMetabolism
ProteinMetabolism
RequirementsandStarvation
AnaerobicMetabolism
Thermoregulation
RegulationofBodyTemperature
Immunology
Inflammation
InnateImmunity
AdaptiveImmunity
Hypersensitivity
Microbiology
ClassificationofMicroorganisms
AntimicrobialResistance
Antiseptics
Obstetrics&Neonates
RespiratoryChanges
CardiovascularChanges
FoetalCirculation
ThePlacenta
GastrointestinalSystem
Oesophagus
GastricSecretions
6
2.16.3
2.16.4
2.16.5
2.16.6
2.16.6.1
2.16.6.2
2.16.6.3
2.17
2.17.1
2.17.2
2.17.3
2.17.4
2.17.5
2.17.6
2.17.7
2.18
2.18.1
2.18.2
2.18.3
2.18.4
2.18.5
2.18.6
2.18.7
2.18.8
2.18.9
2.18.10
2.18.11
2.18.12
2.18.13
2.18.14
2.18.15
2.18.16
2.18.17
2.18.18
2.18.19
2.18.20
2.18.21
2.18.22
2.18.23
2.18.24
ControlofGastricEmptying
Swallowing
PhysiologyofVomiting
LiverPhysiology
FunctionsoftheLiver
LaboratoryAssessmentofLiverFunction
Bile
Haematology
Erythrocytes
IronHomeostasis
Platelets
Transfusion
Haemostasis
HaemostaticRegulation
CoagulopathyTesting
EquipmentandMeasurement
SIUnits
ElectricalSafety
WheatstoneBridge
NeuromuscularMonitoring
PressureTransduction
PressureWaveformAnalysis
Non-InvasiveBloodPressure
CardiacOutputMeasurement
PulseOximetry
OxygenAnalysis
End-TidalGasAnalysis
BloodGasAnalysis
GasFlow
PrinciplesofUltrasound
TemperatureandHumidity
Electrocardiography
Humidifiers
SupplementalOxygen
BispectralIndex
MedicalGasSupply
Vapourisers
BreathingSystems
CircleSystem
Scavenging
7
2.18.25
2.18.26
2.19
2.19.1
2.19.2
2.19.3
2.19.4
2.19.5
3.1
3.1.1
3.1.1.1
3.1.2
3.1.2.1
3.1.2.2
3.2
3.2.1
3.2.2
3.2.3
3.2.3.1
3.2.3.2
3.2.3.3
3.2.3.4
3.2.4
3.2.5
3.3
3.3.1
3.3.2
3.3.3
3.3.3.1
3.3.3.2
3.3.3.3
3.3.3.4
3.3.3.5
3.3.3.6
3.3.3.7
3.3.4
3.3.4.1
Diathermy
Lasers
ProceduralAnatomy
SubclavianVein
InternalJugularVein
IntercostalCatheter
AntecubitalFossa
Tracheostomy
Pharmacopoeia
Toxicology
RecreationalDrugs
ToxicAlcohols
Antidotes
Naloxone
Flumazenil
Respiratory
Oxygen
Helium
Bronchodilators
BetaAgonists
Antimuscarinics
PhosphodiesteraseInhibitors
LeukotrieneAntagonists
Corticosteroids
PulmonaryVasodilators
CardiovascularPharmacology
AdrenergicVasoactives
Non-adrenergicVasoactives
Antihypertensives
CentrallyActingAgents
CalciumChannelBlockers
DirectVasodilators
ACEInhibitors
AngiotensinReceptorBlockers
NeprilysinInhibitors
PotassiumChannelActivators
Antiarrhythmics
SodiumChannelBlockers
8
3.3.4.2
3.3.4.3
3.3.4.4
3.3.4.5
3.3.4.6
3.3.4.7
3.3.4.8
3.4
3.4.1
3.4.2
3.5
3.5.1
3.5.2
3.5.3
3.5.4
3.5.5
3.5.6
3.5.7
3.5.8
3.5.9
3.5.10
3.5.11
3.5.12
3.6
3.6.1
3.6.2
3.6.3
3.6.4
3.7
3.7.1
3.7.2
3.8
3.8.1
3.8.2
3.8.3
3.8.4
3.9
3.9.1
3.9.2
3.9.3
Beta-Blockers
Amiodarone
Sotalol
Digoxin
Adenosine
Magnesium
Atropine
Renal
Diuretics
IntravenousFluids
Neuropharmacology
Propofol
Barbiturates
Ketamine
Dexmedetomidine
LocalAnaesthetics
Benzodiazepines
Antidepressants
Antipsychotics
Anticonvulsants
GABAAnalogues
InhalationalAnaestheticAgents
NitrousOxide
Analgesics
Opioids
COXInhibitors
Tramadol
Paracetamol
Autonomic
Anticholinesterases
Antimuscarinics
Neuromuscular
DepolarisingNMBs
Non-DepolarisingNMBs
Dantrolene
Sugammadex
Haematological
Anticoagulants
DirectThrombinInhibitors
Antifibrinolytics
9
3.9.4
3.10
3.10.1
3.10.2
3.10.3
3.10.4
3.10.5
3.10.6
3.11
3.11.1
3.11.1.1
3.11.1.2
3.12
3.12.1
3.12.2
3.13
3.13.1
3.13.2
3.14
3.14.1
4.1
4.2
4.3
4.4
Antiplatelets
Antimicrobials
Penicillins
Glycopeptides
Aminoglycosides
Lincosamides
Metronidazole
Antifungals
Endocrine
Hypoglycaemics
Insulin
OralHypoglycaemics
Obstetric
Oxytocics
Tocolytics
Gastrointestinal
AcidSuppression
Antiemetics
OtherDrugs
IVContrast
Appendices
Definitions
KeyGraphs
LawsandEquations
StructuresforSAQs
10
PartOnePartOneisareferencefortraineespreparingfortheCICMandANZCAPrimaryExams.
PartOneis:DesignedtocovertheassessedsectionsoftheCICMandANZCAcurriculainenoughdetailtopassAroughguidefortheexpecteddepthofknowledgerequiredonatopicAtooltocorrectyourwrittenanswersAsourceofinformationyoumightfinddifficulttofindelsewhere
PartOneisnot:AtextbookThedefinitiveguidetotheprimaryexamAcompletereferenceTherewillbebothomissionsanderrors.Ifyoufindany,pleaseletmeknow.
Layout
Thebookisdividedintothreesections:
CurriculumCoversstatistics,physiology,equipmentandmeasurement,andanatomy.
Pagesarelaidoutusingthesectiontitle,topictitles,andorderfromtheCICMcurriculumAgreyblockindicatesatopicisfromtheCICMcurriculumORbothcurricula
WhenatopicisonlyexaminableintheANZCAcurriculum,ithasbeenslottedinsomewheresensibleApurpleblockindicatesatopicisONLYfromtheANZCAcurriculum
Topicscoveredbythepagearelistedatthebeginningofeachpage
PharmacopoeiaCoversdrugs.
Forthesakeofconsistency,thegeneralprinciplesofpharmacologyarecoveredinthecurriculum,whilstthespecificsofdifferentagentswillbefoundinthepharmacopoeia.Iflost,usethesearchbox.
AppendicesIncludesthekeydefinitions,graphs,andequationsyoushouldknow,aswellassamplestructuresforSAQs.
Acknowledgements+TechnicalStuff
PartOneisbuiltwithanumberofopen-sourcetools:
WritteninJohnGruber'selegantMarkdownBuiltandmadeprettybytheGitBooktoolchainWithpluginsfrom:
BenLauforautomatictimestampsMichaelJergerforcollapsiblechaptersRishabhGargfortopnavigation
EquationswritteninLATEXGraphshavebeen:
WritteninPGF/Tikzusingtexworks
AboutPartOne
11
ConvertedtovectorgraphicswithdvisvgmRefinedwithsvgo(Somegraphshavebeentakenfromopen-sourcesitessuchasWikimediaCommons.Thesehavebeencreditedwhereused.)
Additionally,chemicalstructureshavebeenbuiltinMarvinSketch
AbouttheAuthor
JakeBarlowisanAnaestheticandIntensiveCareRegistrarfromMelbourne,Australia.Interestedinallthingscriticalcare(withaparticularfascinationforphysiology),aswellasbiotech,physicalcomputing,teaching,analytics,andoutcomepredictioninintensivecare.Sendallcomments,criticism,andcomplaintsaboutPartOnetohimhere.
Copyright+Legal
Copyright©2015-2019C.JakeBarlow
ThisworkislicensedunderaCreativeCommonsAttribution-NonCommercial-ShareAlike4.0InternationalLicense.
Lastupdated2019-11-09
AboutPartOne
12
DownloadPartOne
PartOneisalsoprovidedwith:
APDFversionforofflineuseNotethat:
TheimagequalityofgraphsisreducedinthePDFversionThePDFversionisautomaticallybuiltwheneverthesiteisupdatedTherefore:
ThedownloadlinkwillalwayslinktothemostrecentversionThispagewillappearinthePDFversion
Acompanionsetofflashcards,madeinAnki
Lastupdated2018-07-16
DownloadPartOne
13
HowtoPassThefirstpartexamis:
PainfulTheknowledgedemandedishuge,andcannotbeavoided.EminentlyachievableRemember,itisnotimpossible-everybodybeforeyouhascompletedit.
PlanforSuccess
Thisisnotanexamyouwanttohavetositmorethanonce-trytogiveyourselfthebestchanceofsuccessthefirsttimeround:
CommityourselfearlyDecidewhenyouaregoingtosit:
Pickadate~9monthsinadvance6monthsisprobablypushingit9monthsisachievable12monthsisalmosttoolong-youwilllosemotivationandknowledgewillfade.
AcceptthatthetimebetweennowandtheexamisnotgoingtobethebesttimeofyourlifeConsiderpayingthemoneyassoonaspossible-lockyourselfinYourfamilyandfriendswillforgiveyou,eventually
Don'tlosefaithTherewillbetimesthatyouquestionwhyyouhavetolearnthisThoseareverylegitimatefeelingsAcceptthatpartofthisexamisanacademichazingyoumustpassthroughonyourpathtofellowship
BeStrategicThecurriculumprovidedisoverwhelming,andprobablynotachievableformostofus.Haveaplanabouthowyouwillapproachit:
HaveatimetableContenttocovereachweek
Ifoundsettingaweeklygoalwouldallowmetoplanaroundday-to-dayvariations(finishinglate,gooddays,baddays,etc)Adailytimetablewasoftenmangledbylife,creatingunnecessarystress
TimetostartvivapracticeAimtostartbeforethewritten.
Topicsthatyoucan'texplain,youprobablydon'tunderstandfullyThismaynotbeapparentuntilyoutryandexplainit.
KnowtheenemySyllabusReadthroughitsoyouappreciatethebreadthofknowledgerequired.KnowthestyleThisallowsyoutogiveanswersefficiently-thekeymetricforboththevivasandtheSAQsismarksperunittime.
StyleofexamquestionsIncludingthestyleofanswers-seetheSAQ.
HowtoPass
14
StyleofvivasDopracticevivas
Recordyourself,soyouknowyourticsDoadressrehearsalMakesureyoursuitstillfitsbeforetheday.
GraphsBeabletodrawthemwhiletalkingaboutthem.
DopastquestionsIcannotstressthisenough.Thisisthekeytopreparingforthisexam.
Pastquestions:TeachyouappropriatestructureTeachyoutowritetotimeEnsureyoulearnthecontentinthewayitwillberecalledEnsureyoudon'twastetimelearningthingsthatareunlikelytobeexaminedWhenIsattheCICMexam,Ihaddonealmostallthepastquestions,whichcovered~60%ofthecurriculum.Therewas1(outof24)oftheSAQsonatopicIhadnotansweredanSAQonbefore.
DoquestionstotimeKeepingtotimeisvital.
Itisalmostimpossibletowriteaperfectanswerin10minutesInmanycasesyouwillneedtomoveontothenextquestiondespitestillhavingthingstosayRememberthatthemarkingfollowsasigmoiddistribution
Thefirst30%ofmarksforaquestionareeasytogetThelast30%ofmarksareverydifficulttogetTherefore,themostefficientuseofyourtimeistoaimtoget~60-70%ofmarksforeachquestion.
Rememberthepassmarkis50%YouarenotexpectedtoknoweverythingBreadthtendstoberewardedoverdepthItisnormaltosittheexamandhaveaquestionyouhavenotthoughtaboutbefore
SuggestedApproach
Therearemanyequallyvalidwaystoapproachtheseexams.ThisishowIwoulddoit,ifIhadtodoitagain:
1. ReadageneralphysiologyandpharmacologytextbookThiswillhelpyouunderstandthescopeoftheundertaking.Iwouldrecommendspending2-3weeksreading:
ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.Inmyopinion,thisisthegeneralphysiologytext.Ibelievethatifyoukneweverythinginthisbook,youwouldpassthephysiologycomponentofbothexams.PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.Thefirstfewchaptersareagoodintroductiontopharmaceuticsandpharmacokinetics,whichwillhelpyouputlaterinformationfrommorecompletetextsintocontext.
2. Startdoingpracticequestions:Thisisthekeytotheexam.Isuggest:
StartdoingonequestionatatimeInthebeginning,youwillnotknowenoughtowritefor10minutes.
Afterdoingthequestion,checkyouransweragainstavailablepastanswersThisforcesactivelearning,andisfarmoreefficientthanreading.Lookat:
StructureHowdidyoustructureyouranswer?Whatwastheexamplestructure?
HowtoPass
15
ContentWhatdidyoumiss?Arethenumbers/graphsyouusedcorrect?
Thenstudythecurriculumareasthatquestioncovered,andmakenotesThiswouldtakeme~1-2hoursforanewcurriculumarea.
Onceyoustartdoingquestionswhichyouknowsomethingabout(havingansweredonesimilarpreviously),moveuptothreequestionsin24minutes.Thisteachesyoutokeeptime,whichisvitalforsuccessintheSAQ.
Stillcheckeachanswerafterwards,lookoverthatareaofthecurriculum,andreviseandrefineyournotesWhenyoufindyourselfrunningoutoftimebeforeyourunoutofthingstowrite,giveyourself9minutesperquestionIwouldsuggestnotgoingbeyondthis-youneedtoallocateyourtimestrategicallyontheday,andwritingtotimeiscritical.Asthisgetseasier,startdoing6ormorequestionsatatimetotrainyourwritinghandDooneortwofullexamstotimebeforegameday
3. DoalotofflashcardsFlashcardsarelessdemandingthandoingquestions,andasimpleformofrevision.
Theyaretheabsolutebestwayofrotelearningfacts(inmyopinion)Iusedanki,butusewhateverworksforyouMyankideckisavailablehere
4. DopracticevivasStartbeforethewritten.Thereisalotofcrossoverofskillsbetweenthevivaandthewritten.Bothrequireastructuredapproach,andgoodcontentknowledge.
Remembertotakeabreakafterthewrittenexams,itisexhausting
TheBottomLine
Pickadate,andcommittoitWorkoutwhichtimesworkbestforyouwithrespecttostudyDifferenttimeswillbebetterfordifferentthings.Ifound:
Daysoff(includingweekends)werebestforlearningnewcontentWorkdayswereforrevisingPostnightshiftwasawrite-off
MaintainapositiveattitudeStudygroupsaregoodforthis-sharethesuffering!SplitlargetopicsintomanageablechunksDon'tloseyourheadSetasidetimeforrelaxation,anddon'tfeelguiltyaboutit.Youdon'thavetoknoweverythingThepassmarkis50%
ReferencesThisisbasedonatalkIgaveatthe2016VPECCCourse,stillrawfromtheCICMprimary
Lastupdated2019-08-01
HowtoPass
16
HowtoPass
17
TheSAQAgoodresponsetoashort-answerquestionisconstructedfromtwothings:
StructureDevelopingastructuredapproachtoansweringSAQsisessentialtosucceedinginthissectionoftheexam.Astructuredapproach:
IseasilydigestedbytheexaminerReducestheamountoffilleryouneedtowrite,meaningyoucanwritemorefactsTypicallylendsitselftobulletpointsratherthanparagraphsAllowsyoutorecallmoreinformationthanyouwouldotherwiseEspeciallyifyoulearntitinthesameformat.Thisisparticularlyimportantforpharmacology.
KnowledgeObviously.
Additionally,agoodresponsewill:
AnswerthequestionThisisstatedrepeatedlyinexaminerreports.Ifthequestionasksforadiscussionoftherespiratorychangesofpregnancy,nomarkswillbeawardedforcardiovascularchanges.BelegibleNotbeperfectThisisoften-overlooked.
Examinerreports(andsomemodelanswers),assumeaperfectresponseThisnotfeasiblegiventhetimeallowedItisalsonotactuallyexpected-rememberthatthepassmarkis50%
Thebottomline:
AgoodresponsewillcoverthemajorpointsinreasonabledetailWillgenerallyfocusonprinciplesratherthanspecificsMarksbecomeprogressivelyhardertoacquire:
ThefirstoneortwomarksonaquestionshouldbeeasyGoingfroman8/10toa10/10willrequiretimewhichyoulikelycannotspare
AnsweringtheQuestion
Youhaveexactly10minutesperSAQYoushouldpracticeto8-9minutesperSAQInmanycases,thelastquestion(orquestions)goesunanswered.Thisdemonstratespoortimemanagement,aseasymarkswerethrownawaybycandidatesreachingforhardermarksonearlierquestions.
Duringreadingtime,youshouldevaluateeachquestionto:
DecidewhatpartofthecurriculumitisassessingWorkoutthecontext,ifanyDecidewhatstructurewouldbemostappropriate
Lastupdated2017-08-14
TheSAQ
18
TheSAQ
19
TheVivaThevivaisthepartoftheexammostcandidatesseemmoststressedabout.However:
Ifyoumakeitthroughthewritten,youwillmostlikelypassVeryfewpeoplesucceedinthewrittenexamstofailattheviva.
TheknowledgeisthereExaminerswantyoutopassTheywillredirectyouifyou'reofftrack.
Thismakesiteasiertomakeupmarksthanonthewritten,whereyoucaneasilygooffdowntherabbithole,haemorrhagingtimeandmarks
UnderstandingtheViva
Todowellattheviva:
UnderstandthevivaisaperformancepieceThevivaisaritualisedconversation.Successrequiresyoutoknowandunderstandthelanguageandstructureused,justliketheSAQ.StructureyouranswerAswiththeSAQ,categoriseyouranswer.
HaveagoodopeningstatementDon'tanswermorethanisasked.StartbroadOftenthevivawillgointodepthononlyoneortwoareasofatopic.Ifyoustartgoingintodetailononlypartsofatopic,itmakesithardfortheexaminertoredirectyouandscoresyounomarks.
BeconfidentEnjoyitifyoucan.LearntothinkonyourfeetThevivaassessesknowledgeinadifferentwaytotheSAQs.
Theknowledgewillbethere,butitmayrequireadifferentapproachtoaccessitThisrequirespractice.Thisisalsoimportantfordeliveringasoundanswerbasedonincompleteknowledge
It'sokaytosay"Idon'tknow"Butprobablynotonthefirstquestion.
Ifyoudon'tknowimmediately,canyouworkitoutfromfirstprinciples?Don'tgetangry
WithyourselfWiththeexaminerDon'targue.
Don'tapologiseApologies:
MakeyouloseconfidenceDon'tgetyoumarksRemember,marksperunit-time.
Don'ttalkovertheexaminerTheyareinterruptingyoubecausewhatyouaresayingisgainingnomarks.Ifyoukeeptalking,youwill:
NotbegettingmarksIrritatethem
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Potentiallylosingfuturemarks.
Lastupdated2019-11-02
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Evidence-BasedMedicineDescribethefeaturesofevidence-basedmedicine,includinglevelsofevidence(e.g.NHMRC),meta-analysis,andsystematicreview
WhatisEvidence-BasedMedicine?
Evidence-basedmedicine(EBM)is"theconscientious,explicit,andjudicioususeandappraisalofcurrentbestevidenceinmakingdecisionsaboutthecareofindividualpatients."ThepurposeofEBMistoprovideaframeworkforacquiringknowledgeandmakingoptimaldecisionsaroundmedicalcare.Itmeansintegratingindividualclinicalexpertisewiththebestavailableexternalclinicalevidencefromsystematicresearch."
TherearefivestagesofEBM:
1. Askananswerablequestion2. Search3. Criticallyappraisetheevidence4. Integratetheevidencewiththepatientsuniquecircumstancesandvalues5. Evaluatetheresult
LevelsofEvidence
Levelsofevidencegradestudiesonlikelihoodofbiasandinternalvalidity.TheNHMRCdefines6levelsofevidence,gradedfromI-IV(withthreelevelIIIsubtypes).
Ingeneral:
LevelIisevidencefromasystematicreviewofRCTsLevelIIisevidencefromatleastonegoodRCTLevelIII-1isevidencefromapseudo-RCTLevelIII-2isevidencefromacomparativestudywithconcurrentcontrols,suchasacohortorcase-controlstudyLevelIII-3isevidencefromacomparativestudywithoutconcurrentcontrols,suchasacohortstudywithhistoricalcontrolsLevelIVisevidencefromacase-series
NotethatexpertopinionisnotpartofNHMRClevelsofevidence,thoughitisincludedontheOxfordCentreforEvidenceBasedMedicinesystem,usedbytheNHS.
Level Intervention DiagnosticAccuracy Prognostic Aetiology Screening
IAsystematicreviewoflevelIIstudies
AsystematicreviewoflevelIIstudies
AsystematicreviewoflevelIIstudies
AsystematicreviewoflevelIIstudies
AsystematicreviewoflevelIIstudies
II Arandomisedcontrolledtrial
Astudyoftestaccuracywith:anindependent,blindedcomparisonwithavalidreferencestandard,amongconsecutivepersonswithadefinedclinicalpresentation
Aprospectivecohortstudy
Aprospectivecohortstudy
Arandomisedcontrolledtrial
Astudyoftestaccuracy
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III-1Apseudorandomisedcontrolledtrial
with:anindependent,blindedcomparisonwithavalidreferencestandard,amongnon-consecutivepersonswithadefinedclinicalpresentation
Allornone AllornoneApseudorandomisedcontrolledtrial
III-2
Acomparativestudywithconcurrentcontrols
AcomparisonwithreferencestandardthatdoesnotmeetthecriteriarequiredforLevelIIandIII-1evidence
Analysisofprognosticfactorsamongstpersonsinasinglearmofarandomisedcontrolledtrial
Aretrospectivecohortstudy
Acomparativestudywithconcurrentcontrols
III-3
Acomparativestudywithoutconcurrentcontrols
Diagnosticcase-controlstudy
Aretrospectivecohortstudy
Acase-controlstudy
Acomparativestudywithoutconcurrentcontrols
IV
Caseserieswitheitherpost-testorpre-test/post-testoutcomes
Studyofdiagnosticyield(noreferencestandard)
Caseseries,orcohortstudyofpersonsatdifferentstagesofdisease
Across-sectionalstudyorcaseseries
Caseseries
Gradesofevidence
Evidenceisgradedto"indicatethestrengthofthebodyofevidenceunderpinningarecommendation"(e.g.inaclinicalguideline).TheNHMRCgradesrecommendationsfromAtoDasfollows:
A:BodyofevidencecanbetrustedtoguidepracticeB:Bodyofevidencecanbetrustedtoguidepractice,inmostsituationsC:Bodyofevidenceprovidessomesupport,butcareshouldbetakeninitsapplicationD:Bodyofevidenceisweakandrecommendationmustbeappliedwithcaution
Studytypes:SystematicReviewsandMeta-analyses
SystematicReview
Processofevaluatingallofthe(quality)literaturetoansweraspecificclinicalquestion.Doesnotnecessarilyinvolvestatisticalanalysis.Ifitinvolvesquantitativeanalysisofmultipletrials,itisknownasameta-analysis.
Meta-analysis
Mathematicaltechniqueofcombiningtheresultsofdifferenttrialstoderiveasinglepooledestimateofeffect.Canbedoneby:
PoolingtheresultsofeachtrialPoolingalloftherawdataandconductingareanalysis
Meta-analysesusuallyuserandom-effectsmodels,whichassumestherewillbeavarietyofsimilartreatmenteffectsIndividualtrialsaresummarisedwithanoddsratio,andweighted,usuallybysamplesize
Stagesofa[meta-analysis]andsystematicreview:
1. Inclusionandexclusioncriteriaarepredefined2. Search:includingonlinedatabases,referencelists,citations,andexperts3. Validationofpotentiallyeligibletrials(critiqueofintervalvalidity,i.e.trialquality)
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4. [HeterogeneityAnalysis]5. [Meta-analysis]6. Reliabilityofresultdetermined
i.e.Consistencyacrossstudies,statisticalsignificance,largeeffectsize,biologicalplausibility.7. Sensitivityanalysis
Repeatingtheanalysiswithanalternativemodel,excludingborderlinetrialsoroutliers.Iftheresultisunchanged,thenthefindingsarerobust.
Heterogeneity
Forthepoolingofresultstobevalid,thetrialsneedtobesimilar.Differencesbetweentrialsiscalledheterogeneity,andisimportantbecause:
Heterogeneityanalysisaffectsthetypeofmodelthatcanbeused(fixedormixedeffects)Highlyheterogenousdataisnotappropriateformeta-analysis.
Heterogeneityisdividedinto:
StatisticalHeterogeneityTheeffectsoftheinterventionaremoredifferentthanwouldbeexpectedtooccurthroughchancealone.ClinicalHeterogeneityDuetotrialdesignitwouldbeinappropriatetopooltheresults.
E.g.,conductingameta-analysisontheeffectsofthesamedruginapaediatricandadultpopulationmaybeinappropriate,asthesetwotrialshaddifferentinclusioncriteria.
MethodologicalHetreogeneityWherethemethodsusedindifferenttrialsaretoodifferenttoallowpoolingofthedata.
ForestPlots
Resultsofmeta-analysesarepresentedinablobbogram,ormoreboringly,aForestPlot.
Where:
Thex-axisplotstheoddsratio,rememberingthatanORof1indicatesnodifferenceThey-axisliststhestudiesincluded,andtheoverallsummarystatisticThedot(orsquare)indicatesthepointestimate(fromitsx-location)andtheweightgiventothestudy(byitssize)ThehorizontallineindicatestheupperandlowerboundsoftheconfidenceintervalThediamondindicatestheoverallpointestimateand(byitswidth)theconfidenceintervalforthepointestimateTheresultoftheheterogeneitytestshouldalsobedisplayedP<0.1indicatessignificantheterogeneity.
FunnelPlots
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Funnelplotsareagraphicaltooltodetectpublicationbias.
Duetostatisticalpower,largerstudiesshouldbeacloserrepresentationofthetrueeffectTherefore,whenevaluatingannumberofstudies,onewouldexpectthatlargestudiesclusteraroundthe'trueeffect',andsmallerstudiestoscatterfurtherAgraphisthenplottedofORonthex-axis,andstandarderroronthey-axis
PublicationbiasissuggestedwhenresultsclusterononesideofthefunnelplotNoevidenceofpublicationbiaswouldhavestudiesclusteredaroundthetrueeffect
Strengthsandweaknessesofmeta-analyses
Strengths Weaknesses
Enhancedprecisionofestimatesofeffect Publicationbias
Usefulwhenlargetrialshavenotbeendoneorarenotfeasible Duplicatepublication
Generateclinicallyrelevantmeasures(NNT,NNH) Heterogeneity
Inclusionofoutdatedstudies
Becauseoftheseweaknesses:
Positivemeta-analysesshouldbeconsideredlargelyhypothesis-generating,andshouldbeconfirmedby(alarge)RCTNegativemeta-analysescanprobablybeaccepted
References
1. SacketDL,RichardsonWS,RosenbergW,HaynesRB.Evidence-basedMedicine:HowtopracticeandteachEBM.ChurchillLivingstone,London1997.
2. SackettDavidL,RosenbergWilliamMC,GrayJAMuir,HaynesRBrian,RichardsonWScott.Evidencebasedmedicine:whatitisandwhatitisn'tBMJ1996;312:71.
3. NHMRC.NHMRCadditionallevelsofevidenceandgradesforrecommendationsfordevelopersofguidelines.NationalHealth&MedicalResearchCouncil.2009.
4. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.5. LalkhenAG,McCluskeyA.StatisticsV:Introductiontoclinicaltrialsandsystematicreviews.CEACP2008.
Lastupdated2019-07-18
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StudyTypesDescribethefeaturesofevidence-basedmedicine,includinglevelsofevidence(e.g.NHMRC),meta-analysis,andsystematicreview
RandomisedControlTrial
Aprospectiverandomisedcontrolledtrialisthegoldstandardofexperimentalresearch.
Itinvolvesallocatingpatientsrandomlytoeitheraninterventionorareference(control)group,andmeasuringtheoutcomeofinterest.Allocationcanbeperformedinthreeways:
SimpleIndividualsallocatedrandomly.Thismayleadtounevengroupsizes.BlockAllocationisperformedwithinblockssuchthatgroupsizeswillremaincloseinsizeStratifiedGroupsarerandomisedwithinacategory(i.e.menandwomenarerandomisedseparately).
Strengths
OnlystudydesignwhichcanestablishcausationEliminatesconfoundingRandomisationcontrolsforbothknownandunknownconfoundingfactors,astheseshouldberandomlyallocatedbetweengroups.BlindingcanbeperformedinastandardisedfashionDecreasesselectionbias
Weaknesses
CostlyTime-consumingNotappropriateforallstudydesigns
Ethicalconcernse.g.AdrenalineinALSPracticalconcernsSmallpatientpopulationoruncommondiseasemaycauserecruitmentdifficulties
SystematicReviewTheprocessofevaluatingallofthe(quality)literaturetoansweraspecificclinicalquestion.This:
DoesnotnecessarilyinvolvestatisticalanalysisIfitinvolvesstatisticalanalysisofmultipletrialstogenerateacombinedestimateofeffect,itisknownasameta-analysis.
Meta-analysis
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Mathematicaltechniqueofcombiningtheresultsofdifferenttrialstoderiveasinglepooledestimateofeffect.Canbeperformedby:
PoolingtheresultsofeachtrialCombiningalloftherawdataandconductingareanalysis
Meta-analysesusuallyuserandom-effectsmodels,whichassumestherewillbeavarietyofsimilartreatmenteffectsIndividualtrialsaresummarisedwithanoddsratio,andweighted,usuallypredominantlybysamplesize
Stagesofa[meta-analysis]andsystematicreview:
1. Inclusionandexclusioncriteriaarepredefined2. Search:includingonlinedatabases,referencelists,citations,andexperts3. Validationofpotentiallyeligibletrials(critiqueofintervalvalidity,i.e.trialquality)4. [HeterogeneityAnalysis]5. [Meta-analysis]6. Reliabilityofresultdetermined
i.e.Consistencyacrossstudies,statisticalsignificance,largeeffectsize,biologicalplausibility.7. Sensitivityanalysis
Repeatingtheanalysiswithanalternativemodel,excludingborderlinetrialsoroutliers.Iftheresultisunchanged,thenthefindingsarerobust.
Heterogeneity
Forthepoolingofresultstobevalid,thetrialsneedtobesimilar.Differencesbetweentrialsisknownasheterogeneity.Heterogeneitycanbeeither:
Statistical;wheretheeffectsoftheinterventionaremoredifferentthanwouldbeexpectedtooccurthroughchancealone.Heterogeneityanalysisaffectsthetypeofmodelthatcanbeused(fixedormixedeffects)andhighlyheterogenousdataisnotappropriateformeta-analysis.Clinical;where,duetotrialdesign,itwouldbeinappropriatetopooltheresults.Forexample,conductingameta-analysisontheeffectsofthesamedruginapaediatricandadultpopulationwouldbeinappropriate,asthesearetwodifferentpopulations.Methodological;Wherethemethodsusedindifferenttrialsaretoodifferenttoallowpoolingofthedata.
ForestPlots
Resultsofmeta-analysesarepresentedinablobbogram,ormoreboringly,aForestPlot.
Where:
Thex-axisplotstheoddsratio,rememberingthatanORof1indicatesnodifferenceThey-axisliststhestudiesincluded,andtheoverallsummarystatistic
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Thesquareindicatesthepointestimate(fromitsx-location)andtheweightgiventothestudy(byitssize)ThehorizontallineindicatestheupperandlowerboundsoftheconfidenceintervalThediamondindicatestheoverallpointestimateand(byitswidth)theconfidenceintervalforthepointestimateTheresultoftheheterogeneitytestshouldalsobedisplayed.P<0.1indicatessignificantheterogeneity.
FunnelPlots
Agraphicaltooltodetectpublicationbias.Duetostatisticalpower,largerstudiesshouldbeacloserrepresentationofthetrueeffect.Whenevaluatingannumberofstudies,onewouldexpectthatlargestudiesclusteraroundthe'trueeffect'andsmallerstudiestohavemorescatter.
Strengthsandweaknessesofmeta-analyses
Strengths Weaknesses
Enhancedprecisionofestimatesofeffect Publicationbias
Usefulwhenlargetrialshavenotbeendoneorarenotfeasible Duplicatepublication
Generateclinicallyrelevantmeasures(NNT,NNH) Heterogeneity
Inclusionofoutdatedstudies
Becauseoftheseweaknesses,positivemeta-analysesshouldbeconsideredlargelyhypothesis-generating,andshouldbeconfirmedby(alarge)RCT.Negativemeta-analysescanprobablybeaccepted.
References
1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.
Lastupdated2019-07-18
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ClinicalTrialDesignDescribethestagesindesignofaclinicaltrial
1. Determineresearchquestion2. Determinetargetpopulation3. Specifyoutcomes4. Determinerequirementforcontrolgroup5. Samplesizeestimation6. Controlforconfounding7. Controlforbias8. Datahandling9. Statisticalanalysisplan(pre-specified)
References
1. PSMyles,TGin.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.
Lastupdated2017-09-12
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DataTypesDescribethedifferenttypesofdata
Dataareaseriesofobservationsormeasurements.Canbeeitherqualitativeorquantitative.
QualitativeData
Usingwordsasdataratherthannumbers,evaluatingmeaningandprocess.Commoninthesocialsciences.
QuantitativeData
Usesnumbers,orcanbecodednumerically.Dividedintomultipletypes,eachwithmultiplesubtypes.
CategoricalDataexistindiscretecategorieswithoutintrinsicorder.
e.g.Medicalspecialty(intensivecare,emergencymedicine,orthopaedics,cardiology)Descriptivestatisticsforcategoricaldatacanbereportedusingtheabsolutenumberforeachcategory,percentages,orproportions
OrdinalDataexistsindiscretecategorieswithanintrinsicorder,e.g.agegroups(0-5,6-10,11-15...)
Descriptivestatisticsforordinaldataarethesameforcategoricaldata,buttheycanalsobesummarisedbythemedianandtherange(e.g.medianagegroup,agegrouprange).
NumericalDataisanactualnumber.Canbesubdividedintodiscreteorcontinuous:
DiscreteCanonlyberecordedasaninteger(wholenumber),e.g.numberofhospitaladmissions.
Dichotomousorbinarydata,whichoccurswhenthereareonlytwocategoriesContinuousWheredatacanassumeanyvalue(includingfractions),e.g.whitecellcount.
Continuousdatacanbefurthersubdividedintointervalorratiodata:RatiodataAreexpressedwithreferencetoarationalzero,whichiswherezeromeansnomeasurement.
e.g.Temperaturein°Kisaratiovariable,whilsttemperaturein°CisnotThisisbecause0°Kmeansnotemperature,whilst0°Cdoesnot;e.g.50°Kishalfthetemperatureof100°K,but50°Cisnothalfthetemperatureof100°C.Ratiovariablescan(unsurprisingly)beexpressedasratios,whilstintervalvariablescannot
IntervaldataDonothavearational0-thisisjustanotherpointontheline(e.g.temperaturein°C).
References
1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.
Lastupdated2019-07-18
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BiasandConfoundingDescribebias,typesoferror,confoundingfactorsandsamplesizecalculations,andthefactorsthatinfluencethem
Bias
Biasisasystematicdeviationfromtruth,andcausesastudytolackinternalvalidity.
Inaresearchstudy,anobserveddifferencebetweengroupsmaybedueto:
AtruedifferencebetweengroupsAnerrorErrorcanbedueto:
Normalrandomvariation,i.e.chanceAsystematicdifference,i.e.biasUnlikeerrorduetochance,theeffectofbiascannotbereducedbyincreasingthesamplesize.
TypesofBias
Typeofbias Description Prevention
Selection Wheresubjectallocationresultsintreatmentgroupsthataresystematicallydifferent,apartfromintheinterventionbeingstudied Randomisation
Detection Wheremeasurementsaretakendifferentlybetweentreatmentgroups Blinding
Observer Wherethedatacollectorisabletobesubjectiveabouttheoutcome Blinding,Hardoutcomes
Publication Whennegativestudiesarelesslikelytobesubmittedorpublishedthanpositiveones Clinicaltrialregistries
Recall Alteredreportingofsymptomsbypatientsdependingonwhichgrouptheyhavebeenallocatedto Blinding
Response Whenpatientswhoenrollforatrialdifferfromthepopulation,limitinggeneralisability Randomsampling
Hawthorneeffect Whentheprocessofactuallydoingthestudyimprovestheoutcome
Controlgroup,maskingstudyintentfrompatientsandobservers
ConfounderAconfounderis"avariablethat,ifremoved,resultsinachangeintheoutcomevariablebyaclinicallysignificantamount."Itisatypeofbiaswhichwillresultinadistortionofthemeasuredeffect.
Aconfoundingfactormustbe:
AssociatedwiththeexposurebutnotaconsequenceofitAconfoundingfactorcannotbeonthecausalpathwaybetweenexposureanddiseaseItmustbepresentunevenlybetweengroupstocausedistortionofthemeasuredeffect
AnindependentpredictorofoutcomeTheconfoundingfactormustalsobeariskfactorforthedisease,butindependentlyfromexposure.
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Controllingforconfounding
ByDesign
RandomisationAllconfounders(knownandunknown)aredistributedevenlybetweengroups.RestrictionRestrictsparticipantstoremoveconfounders.
ResultsinreducedgeneralisabilityanddoesnotcontrolallfactorsMatchingPairingofsimilarsubjectsbetweengroups.
Mayintroduceadditionalconfounding,andmatchingbymultiplecharacteristicsisdifficult
ByAnalysis
StandardisationAdjustfordifferencesbytransformingdata.StratificationAnalysethedatainsubgroupsforeachpotentialconfoundingfactor.
References1. Sackett,D.L.(1979).Biasinanalyticresearch.JournalofChronicDiseases32(1–2):51–63.2. PSMyles,TGin.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.3. StatsnotesfrommyMPh(UniversityofSydney).ProbablyaTimothySchlublecture,circa2014.
Lastupdated2019-07-18
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FrequencyDistributionsandMeasuresofCentralTendencyDescribefrequencydistributionsandmeasuresofcentraltendencyanddispersion
FrequencyDistributions
Frequencydistributionsareamethodoftabulatingorgraphicallydisplayinganumberofobservations.
TheNormalDistribution
Thenormaldistributionisagaussiandistribution,wherethemajorityofvaluesclusteraroundthemean,andwhilstmoreextremevaluesbecomeprogressivelylessfrequent.
Thenormaldistributioniscommoninmedicinefortworeasons.
MuchofthevariationinbiologyfollowsanormaldistributionWhenmultiplerandomsamplesaretakenfromapopulation,themeanofthesesamplesfollowsanormaldistribution,evenifthecharacteristicbeingmeasuredisnotnormallydistributedThisisknownasthecentrallimittheorem.
Itisusefulbecausemanystatisticaltestsareonlyvalidwhenthedatafollowanormaldistribution
Theformulaforthenormaldistributionisgivenby:
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Fromthis,itcanbetseenthetwovariableswhichwilldeterminetheshapeofthenormaldistributionare:
μ(mu):Themeanσ(sigma):Thestandarddeviation
TheStandardNormalDistribution
Thestandardnormaldistributionisanormaldistributionwithameanof0andastandarddeviationof1.Theequationforthestandardnormaldistributionismuchsimpler,whichiswhyitisused.
Anynormaldistributioncanbetransformedtofitastandardnormaldistributionusingaztransformation:
Thevalueofzthengivesastandardisedscore,i.e.thenumberofstandarddeviationsformthemeaninastandardisedcurve.Thiscanthenbeusedtodetermineprobability.
Binomialdistribution
Whereobservationsbelongtooneoftwomutuallyexclusivecategories,i.e.:
If then
Ifthenumberofobservationsisverylargeandtheprobabilityofaneventissmall,aPoissondistributioncanbeusedtoapproximateabinomialdistribution.
MeasuresofCentralTendencyAsnotedaboveinthenormaldistribution,resultstendtoclusteraroundacentralvalue.Quantificationofthedegreeofclusteringcanbedoneusingmeasuresofcentraltendency,ofwhichtherearethree:
ModeThemostcommonvalueinthesample.MedianThemiddlevaluewhenthesampleisrankedfromlowesttohighest.
ThemedianisthebestmeasureofcentraltendencywhenthedataisskewedArithmeticmean
Theaverage,i.e:Themeaniscommonandreliable,thoughinaccurateifthedistributionisskewed.
MeasuresofDispersion
Measuresofvariabilitydescribethedegreeofdispersionaroundthecentralvalue.
BasicMeasuresofDeviation
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Range:ThelowestandhighestvaluesinthesampleHighlyinfluencedbyoutliersPercentiles:Rankobservationsinto100equalparts,sothatthemedianbecomesthe50%percentile.Bettermeasureofspreadthanrange.Interquartilerange:The25thto75thcentileAbox-and-whiskerplotgraphicallydemonstratesthemean,25thcentile,75thcentile,and(usually),the10thand90thcentiles.
OutliersarerepresentedbydotsOccasionallytherangeisplottedbythewhiskers,andtherearenooutliersplotted
VarianceandStandardDeviation
Varianceisabettermeasureofvariabilitythantheabovemethods.Variance:
Evaluateshowfareachobservationisfromthemean,andpenalisesobservationsmorethefurthertheyliefromthemeanSumsthesquaresofeachdifferenceanddividesbythenumberofobservationsi.e:
isused(insteadof )becausethemeanofthesampleisknownandthereforethelastobservationcalculatedmusttakenonaknownquantity
Thisisknownasadegreesoffreedom,whichisamathematicalrestrictionusedwhenusingonestatisticaltestinordertoestimateanotherItisaconfusingtopicbestillustratedwithanexample:
Youhavebeengivenasampleoftwoobservations(say,agesoftwoindividuals),andyouknownothingaboutthemThedegreesoffreedomistwo,sincethoseobservationscantakeonanyvalue.Alternatively,imagineyouhavebeengiventhesamesample,butthistimeItellyouthatthemeanageofthesampleis20Thedegreesoffreedomisone,sinceifItellyouthevalueofoneoftheobservationsis30,youknowthattheothermustbe10Therefore,onlyoneoftheobservationsisfreetovary-assoonasitsvalueisknownthenthevalueoftheotherobservationisknownaswell.
Differentstatisticaltestsmayresultinadditionallossesindegreesoffreedom.
StandardDeviation
Thestandarddeviationisthepositivesquarerootofthevariance.
Inasampleofnormaldistribution:
1SDeithersideofthemeanshouldinclude~68%ofresults2SDeithersideofthemeanshouldinclude~95%ofresults3SDeithersideofthemeanshouldinclude~99.7%ofresults
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StandarderrorandConfidenceIntervals
Standarderrorofthemeanis:
AmeasureoftheprecisionoftheestimateofthemeanCalculatedfromthestandarddeviationandthesamplesizeAsthesamplesizegrows,theSEMdecreases(astheestimatebecomesmoreprecise).Givenbytheformula:
Usedtocalculatetheconfidenceinterval
ConfidenceInterval
Theconfidenceinterval:
GivesarangeinwhichthetruepopulationparameterislikelytolieThewidthoftheintervalisrelatedtothestandarderror,andthedegreeofconfidence(typically95%):
Isafunctionofthesamplestatistic(inthiscasethemean),ratherthantheactualobservationsHasseveralbenefitsoverthep-value:
IndicatesmagnitudeofthedifferenceinameaningfulwayIndicatestheprecisionoftheestimateThesmallertheconfidenceinterval,themoreprecisetheestimate.AllowsstatisticalsignificancetobecalculatedIftheconfidenceintervalcrosses1,thentheresultisinsignificant.
References
1. "Normaldistribution".LicensedunderAttribution3.0Unported(CCBY3.0)viaSubSurfWiki.2. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,20013. Coursenotesfrom"IntroductiontoBiostats",UniversityofSydney,SchoolofPublicHealth,circa2013.
Lastupdated2019-07-18
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SampleSizeCalculationDescribebias,typesoferror,confoundingfactorsandsamplesizecalculations,andthefactorsthatinfluencethem
Samples
Asampleisasubsetofapopulationthatwewishtoinvestigate.Wetakemeasurementsonoursamplewiththeaimtomakeinferencesonthegeneralpopulation.Anoptimalsample(inquantitativeresearch)willberepresentative,thatis,ithasthesamecharacteristicsofthepopulationitisdrawnfrom.
SamplingError
Duetochance,thesamplemeanwillnotequalthepopulationmean.Thisiscalledsamplingerror,andisaformofrandomerror.Alargersamplewillmorecloselyapproximatethepopulationmean,reducingrandomerrorleadingtomoreaccuratepointestimatesandnarrowerconfidenceintervals.
Thisiswhylargesamplesizesaredesirableinresearch.However,largerstudiesarealsomorecostlyandtimeconsumingtorun.Sample-sizecalculationsareperformedtofindahappymedium.
SampleSizeCalculation
Allsamplesizecalculationsdependon:
AcceptableriskofTypeIerror(α),typicallysetat0.05Asmallerα(lowerfalsepositiverisk)requiresalargersamplesize.AcceptableriskofTypeIIerror(β),typicallysetat0.20Asmallerβ(lowerfalsenegativerisk)requiresalargersamplesize.ExpectedeffectsizeAsmallereffectsizerequiresalargersamplesize,asthedifferencebetweengroupswillbesmallerandhardertodetect.PopulationvarianceAlargerpopulationvariancerequiresalargersamplesize,asthereismore'noise'inthesample.StudydesignCertaintrialdesigns(e.g.multiplearms)requirealargersamplesizeforagiveneffectsizeandpower.Practicalconsiderations
CostIncreasingsamplesizeincreasesthecostofastudy.ParticipantavailabilitySamplesizeislimitedwhenthenumberofeligibleparticipantsforastudyissmall(e.g.rarediseases)
Differentformulasforsamplesizecalculationsexistfordifferentstudies,andcanbeadjustedforparticularstudydesigns,suchasmultipleorunequalgroups.
References
1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.2. Coursenotesfrom"IntroductiontoBiostats",UniversityofSydney,SchoolofPublicHealth,circa2013.
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Lastupdated2017-09-22
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StatisticalTestsDescribetheappropriateselectionofnon-parametricandparametrictestsandteststhatexaminerelationships(e.g.correlation,regression)
ParametricTests
Parametrictestsareusedwhendatais:
ContinuousandnumericalNormallydistributed
Rememberthatduetothecentrallimittheorem-largedatasets(n>100)aretypicallyamenabletoparametricanalysis,assamplemeanswillfollowanormaldistributionNon-normaldatacanbetransformedsothattheyfollowanormaldistribution
SamplesaretakenrandomlySampleshavethesamevarianceObservationswithinthegroupareindependentIndependentresultsarethosewhenonevalueisnotexpectedtoinfluenceanothervalue.
Acommonexampleisrepeatedmeasures:whenserialmeasuresaretakenfromapatientorahospital,theresultscannotbetreatedasindependentPairedtestsareusedwhentwodependentsamplesarecomparedUnpairedtestareusedwhentwoindependentsamplesarecompared
Testsmaybeone-tailedortwo-tailed:
Atwo-tailedtestevaluateswhetherthesamplemeanissignificantlygreaterorlessthanthepopulationmeanAone-tailedtestonlyevaluatestherelationshipinonedirectionThisdoublesthepowerofthetesttodetectadifference,butshouldonlybeperformedifthereisaverygoodreasonthattheeffectcouldonlyoccurinonedirection.
Commonparametrictestsinclude:
Ztest
Usedtotestwhetherthemeanofaparticularsample(x̄)differsfromthepopulationmean(μ)byrandomvariation.
Assumptions:
Largesamplen>100.DataisnormallydistributedPopulationstandarddeviationisknown
Student'sTTest
ThisisavariantoftheZtest,usedwhenthepopulationstandarddeviationisnotknown.
TheresultsfromTtestapproximatetheresultsoftheZtestwhenn>100
FTest
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Comparestheratioofvariances( )fortwosamples.IfFdeviatessignificantlyfrom1,thenthereisasignificantdifferenceingroupvariances.
AnalysisofVariance(ANOVA)
ANOVAtestsforsignificantdifferencesbetweenmeansofmultiplegroups,inamoreefficientmannerthanmultiplecomparisons(doinglotsofTtests).
ThereareseveraltypesofANOVAtestsusedindifferentsituations.
Non-ParametricTests
Non-parametrictestsareusedwhentheassumptionsforparametrictestsarenotmet.Non-parametrictests:
DonotassumethedatafollowsanyparticulardistributionThisisrequiredwhen:
Non-normalityisobviouse.g.Multipleobservationsof0Possiblenon-normalityTypicallysmallsamplesizes.Dataisordinal
Arenotaspowerfulasparametrictests(alargersamplesizeisrequiredtoachievethesameerrorrate)Aremorebroadlyapplicablethanparametrictestsastheydonotrequirethesameassumptions
Non-parametrictestsstillrequirethatdata:
IscontinuousorordinalWithin-groupobservationsareindependentSamplesaretakenrandomly
Ingeneral,non-parametrictests;
TakeeachresultandrankthemCalculationsarethenperformedoneachranktofindtheteststatistic
Commonnon-parametrictestsinclude:
Mann-WhitneyUTest/WilcoxonRankSumTest
AlternativetotheunpairedT-testfornon-parametricdata.
Process:
Datafrombothgroupsarecombined,ordered,andgivenranksTieddataaregivenidenticalranks,wherethatrankisequaltotheaveragerankofthetiedobservations
ThedataarethenseparatedintotheiroriginalgroupRanksineachgroupareaddedtogiveateststatisticforeachgroupAstatisticaltestisperformedtoseeifthesumofranksinonegroupisdifferenttoanother
WilcoxonSignedRanksTest
AlternativetothepairedT-testfornon-parametricdata.
Process:
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Asabove(fortheWilcoxonRankSumTest),exceptabsolutedifferencebetweenpairedobservationsarerankedThesign(i.e.positiveornegative)ispreserved.ThesumofpositiveranksisthencomparedwiththesumofnegativeranksIfthereisnodifferencebetweengroups,wewouldexpectthenetvaluetobe0
References1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.
Lastupdated2017-09-22
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StatisticaltermsUnderstandthetermssensitivity,specificity,positiveandnegativepredictivevalueandhowtheseareaffectedbytheprevalenceofthediseaseinquestion
Describebias,typesoferror,confoundingfactorsandsamplesizecalculations,andthefactorsthatinfluencethem
Allthesetermsrefertocharacteristicsofdiagnostictests.Theeasiestwaytoapproachthisisviaa2x2table,andhasbeenrecommendedinpreviousexamsasanapproachtoquestionsonthistopic.
TypesofErrorDrawa2x2tableofdiseasestateversustestoutcome:
DiseasePositive DiseaseNegative Total
TestPositive TruePositives FalsePositives AllTestPositives
TestNegative FalseNegatives TrueNegatives AllTestNegatives
Total AllDiseasePositives AllDiseaseNegatives
TrueorfalsereferstowhetherthetestwascorrectPositiveornegativereferstothetestresult
ATypeIerrorisafalsepositive,whenweincorrectlyrejectthenullhypothesisThetypeIerrorratecanbedecreasedbydecreasingα
ATypeIIerrorisafalsenegative,whenweincorrectlyacceptthenullhypothesisThetypeIIerrorratecanbedecreasedbydecreasingβ,usuallyexpressedasincreasingpowerPoweristhechanceofdetectingadifferenceifitexists.Powerisequalto1-β.
SensitivityandSpecificity
Sensitivity
Sensitivityistheprobabilitythosewiththediseasetestpositive,i.e.thetruepositiverate,andexpressedmathematicallyas:
ItreferstotheabilityofatesttodetecttheconditionAhighlysensitivetestwilllikelybepositiveiftheconditionispresentTherefore,anegativeresultonasensitivetestgivesahighlikelihoodthediseaseisnotpresent
ThemnemonicforthisisSNOUT-Sensitive,Negative,ruleOUT
Specificity
Specificityistheprobabilitythosewithoutthediseasetestnegative,i.e.thetruenegativerate,andexpressedmathematicallyas:
ItreferstotheabilityofatesttodetectabsenceoftheconditionAhighlyspecifictestwilllikelybenegativeiftheconditionisnotpresent
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ThereforeapositiveresultonaspecifictestgivesahighlikelihoodthediseaseispresentThemnemonicforthisisSPIN-Sensitive,Positive,ruleIN
PositiveandNegativePredictiveValues
PositiveandnegativepredictivevaluesdescribetheproportionoftestresultswhicharetrueAhighvalueindicatesaccuracyofthetestBecauseofhowtheyarederived,theyaredependentonpopulationprevalenceofthedisease
PositivePredictiveValue(PPV)istheprobabilitythatthediseaseispresentwhenthetestispositive:
NegativePredictiveValue(NPV)istheprobabilitythatthediseaseisabsentwhenthetestisnegative:
RememberingtheDifference
RotelearningtheseformulasishardRememberthat:
SensitivityandspecificityarethesameforanygivenprevalenceofdiseaseThereforetheylookatcolumns(diseasepositiveordiseasenegative).PPVandNPVarenotThereforetheylookatrows(testpositiveortestnegative).
LikelihoodRatiosTheweaknessofPPVandNPVastoolsofevaluatingtheutilityofatestinclinicalpracticeisthattheydonottakeintoaccountthepopulationprevalence,i.e.thepriorprobability,ofacondition.
AclassicexampleistheurinebHCG,whichhasahighpositivepredictivevalueforpregnancy.Testedonanexclusivelymalegrouphowever,thetruepositiveratewillbe0(sincetherearenopregnancies),andsoalltestpositiveswillbefalsepositives.
Therefore:
TheactualutilityofatestindecisionmakingisdependentuponthepriorprobabilityofthediseasebeingpresentLikelihoodRatiosrelatethepre-testoddstothepost-testoddsTheyareusefulbecause(unliketheabovevalues)theydonotassumethatthepatientyouareapplyingthemtoisidenticaltothesamplefromwhichthestatisticwasderived.Thelikelihoodratiomultipliedbythepre-testoddsgivesthepost-testoddsofthediseasebeingpresent
Apositivelikelihoodratioisusedwhenthetestispositive:
Anegativelikelihoodratioisusedwhenthetestisnegative:
References
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1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.2. Coursenotesfrom"IntroductiontoBiostats",UniversityofSydney,SchoolofPublicHealth,circa2013.
Lastupdated2019-11-02
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RiskandOddsUnderstandtheconceptsofriskandOddsRatio
Risk
AbsoluteRiskistheriskofaneventoccurringintheexposedgroupRelativeRisk(orriskratio)istheriskofaneventoccurringintheexposedgrouprelativetotheunexposedgroup.
AbsoluteRiskReductionisthedecreaseinriskprovidedbyanexposure:
Isaclinicalusefulmeasureofthevalueofanintervention,howeverisbetterexpressedas:NumberNeededtoTreat(NNT)isthenumberofindividualswhomustreceiveatreatmenttopreventoneevent:
RelativeRiskReductionisthedecreaseinincidenceprovidedbytreatment.Itisnotasusefulameasureofthevalueofanintervention,butdrugcompanieslikeitbecausethenumbersarebiggerthanabsoluteriskreduction.
Odds
Oddsaretheprobabilityofaneventhappeningcomparedtotheprobabilityofitnothappening,usuallyexpressedasafractionTheOddsRatioistheratiooftheoddsoftheoutcomeoccurringintheexposedcomparedtotheoddsofitoccurringintheunexposed
AnOR<1suggeststheriskislowerintheexposedgroupAnOR>1suggeststheriskishigherintheexposedgroupAnOR=1suggeststhatthegroupsareequivalent
Ingeneral,theORoverstatesriskcomparedtotheRR.ItisapproximatelyequaltotheRRwhentheoutcomeisrare(<10%)Itisusedwhen:
Thedenominatorisuncertain,i.e.:Inretrospectivedesigns,suchascase-controlstudieswhenpatientswiththediseasewereidentified,andthenexposuresascertained
Whenitstatisticallyappropriate(ORsaremucheasiertouseinstatisticaltests),i.e.:MultivariateregressionSystematicReviews
RiskversusOdds
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RelativeRiskandOddsRatiosarebothmethodsofcomparingthelikelihoodofanoutcomeoccurringbetweentwogroups.Thedifference,andparticularlytheconceptofoddsratios,arecommonlyconfused.Relativerisktendsbemuchmoreintuitivethanoddsratios.Imagineatrialhasbeenperformed,wheregroupAwasexposedgroup:
IngroupA,themortalitywas50%IngroupB,themortalitywas25%
Therelativeriskisintuitive:
Theoddsratioisnot:
ARRof2isintuitive,buttheORof3isnot.Now,imagineanothertrialwhere:
IngroupA,themortalitywas90%IngroupB,themortalitywas10%
Therelativeriskis9,buttheORis81!
Sowhyuseoddsratiosatall?Oddsratiosare:
RequiredwhenresearchsubjectsareselectedonthebasisofoutcomeratherthanthebasisofexposureUsedbymanystatisticaltestsbecausethelogoddsratioisnormallydistributed,whichisamathematicallyusefulproperty
RelativeRiskhasaweaknessaswell-itisdependentonhowthequestionisframed.Usingthefirsttrialabove,wecalculatedthatRRfordeathwas2andtheORwas3.Ratherthancalculatingmortality,analternativemethodcouldbetolookatsurvival:
IngroupA,thesurvivalwas50%IngroupB,thesurvivalwas75%
Notethattherelativeriskisnot0.5(asyoumayinitiallyassume),howevertheoddsratioisjusttheinverseofthepreviousvalue.
References
1. MylesPS,GinT.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.2. Coursenotesfrom"IntroductiontoBiostats",UniversityofSydney,SchoolofPublicHealth,circa2013.3. SimonS.Oddsratiovs.relativerisk."Steve'sAttempttoTeachStatistics(StATS)".Children'sMercyHospital,2006.4. BlandJM,AltmanD.BlandJMartin,AltmanDouglasG.Theoddsratio.BMJ2000;320:1468.
Lastupdated2019-07-18
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RiskandOdds
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SignificanceTesting'Understandconceptofsignificanceandtestingofsignificance
Significancetestingis:
Theprocessofdeterminingwhetheradifferencebetweengroupsinastudyisduetoarealdifference,orchancealonePerformedusingp-valuesDoesnotimplyclinicalsignificanceForaresulttobestatisticallysignificant,theremustbea'real'differencebetweengroups.
Thisdifferencedoesnothavetobeclinicallymeaningfule.g.Adrugmayreliablycausea5mmHgdecreaseinSBP-thisisunlikelytocauseameaningfuldropincardiovascularmortalitybutmaybestatisticallysignificant
PValuesThep-valueistheprobabilityofobtainingasummarystatistic(e.g.amean)equaltoormoreextremethantheobservedresult,providedthenullhypothesisistrue.
Thep-valueiscommonly(mis)usedinfrequentistsignificancetesting.
Priortoperforminganexperiment,asignificancethreshold(α)isselectedTraditionally0.05(5%)or0.01(1%)Thesevaluesdefinethe"false-positiverate".
Whenmultipletestsarebeingperformedononesetofdata,thechanceofafalse-positivewillincreaseToreducethechanceofafalsepositiveoccurring,thesignificancethresholdforeachtestcanbereduced.OnemethodofthisistheBonferronicorrection,whereαisdividedbythenumberoftestsbeingperformed.
Thentheexperimentisperformed,andavalueforpiscalculatedIfp<α,itsuggeststhattheresultsareinconsistentwiththenullhypothesis(atthatsignificancelevel),anditshouldberejected.
ProblemswithP-values
P-valuesare,whenemployedcorrectly,areuseful.However,theydohaveseveralweaknesses:
AssumethenullhypothesisistrueThep-valueassumesthatthereisnorealdifferencebetweengroups.
ThismaynotbethecaseNotallhypothesesarecreatedequalTheremaybesignificantpriorevidencesupporting(orrefuting)H -thiswillbeignoredwheninterpretingap-value.
Anystudywithsignificantresultsmustthereforebeinterpretedinthecontextof:BiologicalplausibilityofthoseresultsThepreviousevidenceonthetopic
Itisacommonmisconceptionthatthep-valueestimatesthechancethattheresultistrueThisisnotthecase.Thep-valuemeasureshowinconsistenttheobservedresultsarewiththenullhypothesis.
Athresholdof0.05isnotalwaysappropriateThecostofbeingwrongmustbeincludedwheninterpretingap-value.Ifthisisatrueresult,whatarethepotentialbenefits?Ifthisisafalsepositive,whatarethepotentialharms?
VulnerabletomultiplecomparisonsConductingrepeatedanalyseswilleventuallyfinda'significant'result.Atanαof0.05,wewouldexpect1/20analysestobe
A
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afalsepositive.Conducting20analyseswouldthereforegenerateonefalsepositiveresult.
DoesnotquantifyeffectsizeAsignificantp-valuesimplysuggestsadifferenceexists,itdoesnotmeasurehowbigthisdifferenceis.
Aresultmaybestatisticallysignificantbutclinicallyunimportant,e.g.anantihypertensivemedicationcausingadecreaseinSBPby2mmHgmaybestatisticallysignificant,butclinicallyunimportant.
Relatedtosamplesizep-valuesareaffectedbysamplesize:Alargeeffectsizemaybehiddenbyaninsignificantp-valueifsamplesizeissmallSimilarly,atinyeffectsizemaybedetected(i.e.asignificantp-value)ifsamplesizeislarge
DoesnotaccountforbiasLikeotherstatisticaltest,thep-valuecannotaccountforbiasorconfounding.
References
1. WassersteinRL,LazarNA.TheASA'sStatementonp-Values:Context,Process,andPurpose.TheAmericanStatistician.2016vol:70(2)pp:129-133.
Lastupdated2019-07-18
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DrugApprovalandDevelopmentDescribetheprocessesbywhichnewdrugsareapprovedforresearchandclinicaluseinAustralia,andtooutlinethephasesofhumandrugtrials(PhaseI-IV)
DrugApproval
TheTherapeuticGoodsAdministration(TGA)approvesmedicineforbothresearchandclinicaluseinAustralia.
Research
Drugtrialsareapprovedforresearchpurposesundertwoschemes:
1. ClinicalTrialsExemptionDrugsmustbeevaluatedbyanexpertcommitteetoevaluateallaspectsofpharmacology,toxicology,mutagenicity,teratogenicity,organdysfunction,andotherside-effects.
2. ClinicalTrialsNotificationAdrugwhichhasbeenapprovedinanothernationwithsimilarlystringentrequirements(NewZealand,Netherlands,UK,Sweden,US)maybeusedinatrialwithoversightbyalocalethicscommittee.
ClinicalUse
TheTGAclassifiesmedicinesinto:
RegisteredMedicinesAssessedbytheTGAforquality,safety,andefficacy.
Allprescription(high-risk)medicines.Assessedon:Quality
CompositionofdrugsubstanceBatchconsistencyStabilitydataSterilitydata(ifapplicable)Impurities
Non-clinicalPharmacologydataToxicologydata
ClinicalEfficacy:resultsofclinicaltrials
MostOTC(low-risk)medicinesSomecomplementarymedicines
ListedMedicinesAssessedbytheTGAforquality,safety,butnotefficacy.
SomeOTCmedicinesMostcomplementarymedicines
PhasesofDrugDevelopment"Phase0"
Pre-clinicalR&D
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InvitroandanimaltestingPhaseI
FirstadministrationinhumansBasicpharmacokineticandtoxicologydata20-100humansubjects
PhaseIIAdministrationtoselectpatientgroupsAimtoestablishdose-responsecurveEvidenceofefficacy
PhaseIIIFull-scaleevaluationofbenefits,potentialrisksandcostsanalysis2000-3000patients,usuallytreatedingroupsofseveralhundredforrelativelyshortdurations(3-6months),regardlessofthelengthoftimethedrugwillbeusedinpracticeMaynotrevealuncommonorlong-termrisks
PhaseIVPost-marketingsurveillance
References1. PSMyles,TGin.Statisticalmethodsforanaesthesiaandintensivecare.1sted.Oxford:Butterworth-Heinemann,2001.2. MedicinesandTGAclassifications.TherapeuticGoodsAdministration.Availableat:https://www.tga.gov.au/medicines-and-
tga-classifications3. ChrisAnderson.PharmaceuticalAspectsandDrugDevelopment.ICUPrimaryPrep.
Lastupdated2017-09-16
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AdditivesDescribethemechanismsofactionandpotentialadverseeffectsofbuffers,anti-oxidants,anti-microbialandsolubilizingagentsaddedtodrugs
Additivesarecomponentsofadrugpreparationwhichdonotexertthepharmacologicaleffect.
Additivesinclude:
PreservativesBenzylalcohol
Antimicrobialwhen>2%Canbeusedasasolventwhen>5%Toxic
AntioxidantsSulfites
HypersensitivityNeurotoxicifgivenintrathecally
SolventsWaterAppropriatefordissolvingpolarmolecules.Non-aqueoussolventsUsedtodissolvenon-polarmolecules,ortoproducemorestablepreparationsofsemi-polarmolecules.Examplesinclude:
PropyleneglycolHypotensionArrhythmiaWithrapidinjection.PainoninjectionThrombophlebitis
MannitolDiuresis
SoybeanoilPainoninjectionAllergy
EmulsionFormedwhendropsofaliquidaredispersedthroughoutanotherliquidinwhichitisimmiscible.Emulsionsare:
UnstableEmulsifiersareusedtoenhancestability.PronetocontaminationDuetothewatercomponent.PronetorancidityDuetotheoilcomponent.
BuffersMaintainpHinaparticularrangeinorderto:
MaximisestabilityPreserveshelflife.Maintainsolubility
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Maximisepreservativefunction
References1. MacPhersonRD.Pharmaceuticsfortheanaesthetist.Anaesthesia.2001Oct;56(10):965-79.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2019-07-18
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IsomerismDescribeisomerismandprovideexamples
Isomerismdescribesgroupsofcompoundswhichhavethesamechemicalformulabutdifferentchemicalstructures.Isomerismisrelevantbecausedifferentisomersmayhavedifferentenzymaticandreceptoraffinities,alteringtheirpharmacokineticandpharmacodynamicproperties.
TypesofIsomerism
Isomerscanbedividedinto:
StructuralIsomersIdenticalchemicalformulabutdifferentarrangementofatoms.Structuralisomerismissubdividedinto:
StaticFurthersubdividedinto:
ChainisomerThecarbonskeletonvaries,butpositionoffunctionalgroupsisstatic.PositionisomerThecarbonskeletonisstatic,butthepositionoffunctionalgroupsvaries.
e.g.Isofluranevs.enfluraneDynamic(alsoknownastautomer)Themoleculeexistsinadifferentmolecularstructuresdependingontheenvironment.
e.g.MidazolamhaspHdependentimidazoleringopening.WhenthepHislessthan4theringremainsopen,maintainingwatersolubility.MidazolamissuppliedatpHof3.5,andsoiswatersolubleoninjectionbut(duetoitspKaof6.5)becomes89%unionisedatphysiologicalpHthereforeabletocrosslipidmembranes.
StereoisomersAtomsareconnectedinthesameorderineachisomer,butdifferentorientationoffunctionalgroups.Stereoisomersarenotsuper-imposable,meaningthedifferentisomerscan'tberotatedsothattheylookthesame.Stereoisomersaredividedinto:
GeometricIsomersHaveachemicalstructure(e.g.acarbon-carbondouble-bond)preventsfreerotationofgroups,sodifferentlocationsofchemicalgroupswillcreateanisomer.Geometricisomersareknownascis-ortrans-dependingonwhetherthesubgroupsareonthesameoroppositesides(respectively)ofthechemicalstructure.
e.g.AtracuriumOpticalIsomersOpticalisomersarechiral.Thismeanstheyhavenoplaneofsymmetry.Opticalisomers:
Wereinitiallynamedbasedonhowtheyrotatedunderpolarisedlight:(NotethisisdifferentfromD-andL-molecules,wheretheD-isomerreferstothemoleculesynthesisedfrom(+)glyceraldehyde).
Dextrorotatory(d-or(+)isomers)moleculesrotateclockwiseunderpolarisedlight.Levorotatory(l-or(-)isomers)moleculesrotatecounter-clockwiseunderpolarisedlight.
Unfortunately,differentmoleculeswerefoundtorotateindifferentdirectionsdependingonthetemperature.Therefore,adifferentclassificationscheme(R/S)isalsoused:
Basedonchemicalstructure"Priority"isassignedtoeachatominthestructureHighestpriorityisusuallythosewiththehighestmolecularweight,butotherrulesexistforambiguousorvery
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largemoleculesThemoleculeisarrangedinspacesuchthatthelowestpriorityatomisfacing"away"Anarrowisthendrawnfromthehighestprioritytothelowerpriorityatoms:
IfthisarrowtravelsclockwiseitistheR(Rectus)isomerIfthisarrowtravelscounter-clockwiseitistheS(Sinister)isomer
Opticalisomersaredividedinto:EnantiomersPossessonechiralcentre.
e.g.levobupivacaineislesscardiotoxicthanracemicbupivacaine.DiastereoisomersPossessmultiplechiralcentres,andmayhavemultiplestereoisomers.Sincenotallaremirrorimages,thesearenotenantiomers.
Foramoleculewithnchiralcentresupton isomersarepossible,thoughsomeofthesemaybeduplicates.
Preparations
Drugscanbeprovidedas:
RacemicsolutionsAracemicsolutionisonewhichwherethedifferentenantiomersarepresentinequalproportions.
EnantiopurepreparationsAdrugproducedwithasingleisomer,whichmaybemoreefficaciousorlesstoxic(anddefinitelymoreexpensive)thantheracemicpreparation.
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. CICM.TheMockExam.3. ChemGuide.Geometricisomerism4. ChEBI.Misoprostol.EuropeanMolecularBiologyLaboratory.5. ANZCAJuly/August20006. DayJ,ThomsonA,McAllisterT.GetThroughPrimaryFRCA:MTFs.2014.Taylor&FrancisLtd.
Lastupdated2019-07-18
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ModelingExplaintheconceptofpharmacokineticmodelingofsingleandmultiplecompartmentmodels.
Pharmacokineticsdescribeswhatthebodydoestoadrug.Pharmacokineticmodelsaremathematicalconceptsusedtopredictplasmaconcentrationsofdrugsatdifferenttimepoints.
BasicPharmacokineticTerms
Keyconceptsinpharmacokineticsinclude:
Volumeofdistribution,VThevolumeofdistributionisdefinedasthetheoreticalvolumeintowhichanamountofdrugwouldbedistributetoproducetheobservedplasmaconcentration.
Unitsareml.kg
Itisawaytodescribewhatproportionofadrugisconfinedtoplasma,andwhatproportiondistributestoothertissuesItdoesnotcorrespondtoanyparticularvolume,howeveraV of:
Lessthan40ml.kg indicatesadrugisconfinedtoplasmaUpto200ml.kg indicatesadrugisconfinedtotheECFUpto600ml.kg indicatesadrugisdissolvedintotheTBWGreaterthan1L.kg indicatesadrugishighlyproteinboundorlipophilicAgentswhichcrossthebloodbrainbarriertypicallyhaveaV of1-2L.kg .
SubtypesofthevolumeofdistributionareusedtodescribedrugdistributionatdifferenttimesorwithdifferentmodelsTheseinclude:
VVolumeofcentralcompartment.V ssVolumeofdistributionatsteadystate.V peVolumeofdistributionatpeakeffect.
Whichvolumetousedependsonthepharmacologicalquestione.g.IntubatingdoseforopioidshoulduseavolumebetweenV (verysmall)andV ss(verylarge)-V peisidealasitwillallowatargetconcentrationtobeselectedforthetimeatwhichintubationwilloccurrelativetodrugadministration
Half-life(t )Thetimeittakesforaprocesstobe50%complete.Withrespecttodrugclearance,itisthetimeittakesforconcentration(typicallyinplasma)tofallby50%.
Aprocessisconsideredtobecompleteafter4-5half-livesConcentrationwilldecreaseby50%aftereachhalf-life,soafter5half-livesconcentrationwillbe3.125%ofitsstartingvalue.
Thisalsoappliestowashin-itwilltake~4-5eliminationhalf-livesofadrugforaconstant-rateinfusiontoreachitsfinalconcentration
Half-lifeismathematicallyrelatedtomanyotherkeypharmacokineticterms:
,where:isthetimeconstant
D
-1
D-1
-1-1
-1
D-1
1
D
D
1 D D
1/2
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istherateconstantforelimination
isthevolumeofdistribution
istheclearanceVarioustypesofhalf-lifearedescribed:
t αdescribestherapidityofthedistributionphasefollowingdrugadministrationt βdescribestherapidityoftheeliminationphaseoccurringafterdrugdistributionequilibriumThisonlyevaluatesclearancefromplasma,andsoisacompositeofbothexcretionfromthebody(e.g.renalandhepaticclearance)andongoingdistributiontoperipheraltissues.
Theeliminationhalf-lifeisgenerallynotusefultopredictdrugoffset,asthisisaffectedbymanyfactorsHowever,itdoessetanupperlimitonhowlongitwilltakeplasmaconcentrationtofallby50%.
Time-constant( )Thetimetakenforaprocesstocompleteifitcontinuedatitsinitialrateofchange.Timeconstantsarerelatedtohalf-life,butarebettersuitedwhenmodelingchangeinexponentialprocesses.
TimeconstantsarediscussedinmoredetailunderrespiratorytimeconstantsEliminationwillbevirtuallycompleteafterthreetimeconstants
Atimeconstantistheinverseoftherateconstantforelimination,i.e.Illustrationoftherelationshipbetweenhalf-lifeandtimeconstant:
ClearanceTheclearanceisvolumeofplasmacompletelyclearedofadrugperunittime.
Inaonecompartmentmodel,thiscanbeexpressedas: inml.min .
Asthetimeconstantistheinverseofk,clearancecanalsobeexpressedas:
Since and areconstants,clearanceisalsoaconstantTotalclearanceisasumoftheclearanceofeachindividualclearanceorgan
RateofeliminationAmountofdrugremovedbythebodyperunittime.
Rateofeliminationistheproductoftheclearanceandthecurrentconcentration:
,inmg.minThisisnottherateconstantforelimination
CompartmentalModeling
Thesimplestmodelimaginesthebodyasingle,well-stirredcompartment.
1/21/2
-1
-1
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Inaonecompartmentmodel,theconcentrationofadrug( )attime isgivenbytheequation:
Where:
istheconcentrationattime0Asdrugcanonlybeeliminatedfromthecompartment,thisisalsothepeakconcentration.kistherateconstantforeliminationThisisthefractionoftheVdfromwhichthedrugisremovedperunittime.Therateconstantdeterminestheslopeofthecurve.
Ahighrateconstantforeliminationresultsinasteepcurveandthereforeashorttimeconstant
Steadystate
Atsteadystate,inputisequaltooutput.Thereforeconcentrationatsteadystateis:
ProportionaltotheconcentrationoftheinfusionandinfusionrateInverselyproportionaltotheclearance:
ConcentrationofdrugcanthereforebedeterminedbytheamountinfusedandtheclearanceNotesteadystaterequiresperipheralcompartmentstobesaturated,andsowillonlyoccurafteraninfusionofmanyhours
MultipleCompartmentModels
ModelswithmultiplecompartmentshaveabetterfitwithexperimentaldatathansinglecompartmentmodelsThree-compartmentmodelsaretypicallyused,asadditionalcompartmentstypicallyoffernoextrafidelitybutaremathematicallymorecomplexAthree-compartmentmodelcanbeconceptualisedasaplasma(orcentral)compartment,awell-perfusedcompartment,andapoorly-perfusedcompartmentThisdoesn'tmeanthattheyshouldbethoughtofinthisway-theyareamathematicaltechniqueusedtocalculateplasmaconcentrationatagiventime.
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Plasmaconcentrationinmulti-compartmentmodelsis:
PredictedthroughtheneteffectofseveralnegativeexponentialequationsxThisiscoveredundertwo-compartmentmodelsbelow.Dependentontheeffectsof:
DistributionDistributiondescribesthemovementofdrugfromthecentralcompartment(V )totheperipheralcompartment(s).
RapidfallinplasmaconcentrationofadrugafteradministrationisgenerallyduetodistributionDistributionisanimportantmethodfordrugoffsetinshort-actingdrugs.
RedistributionRedistributionreferstothemovementofdrugfromtheperipheralcompartment(s)backintoplasma.
DrugswhichhavealargeV inaperipheralcompartmenttendtodistributequicklyalongthisconcentrationgradient,andredistributeslowlybackintoplasmaDrugswhichtendtodistributeslowlytendtoredistributequicklyonceadministrationhasceased
ExcretionExcretionistheremovalofdrugfromthebody.
ClearanceinTwo-CompartmentModels
Removalofdrugintwo-compartmentmodelsisvia:
DistributionfromthecentraltotheperipheralcompartmentEliminationfromthecentralcompartmentThisproducesabi-exponentialfallinplasmaconcentrationConsistsoftwophases:
PhaseαDistributionphase:Arapiddeclineinplasmaconcentrationduetodistributiontoperipheraltissues.PhaseβEliminationphase:Slowdeclineinplasmaconcentrationdueto:
EliminationfromthebodyRedistributionintoplasma
1
D
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Thiscurveisgivenbytheequation ,where:
istheconcentrationofdruginplasma
isthey-interceptofthedistributionexponentUsedtocalculatedistributionhalf-life.
isthey-interceptoftheeliminationexponentUsedtocalculateeliminationhalf-life.istherateconstantfordistribution
Thevalueof isdependentontheratioofrateconstantsfordistributionandredistribution(i.e. ).Ifdistributiongreatlyexceedsredistribution,thegradientof willbeverysteepandplasmaconcentrationwillfallrapidlyafteradministration
istherateconstantforelimination
Notethatthedistributionandeliminationcurvesappearstraightbecausethey-axisislog-transformedIfplasmaconcentrationwasplottedonthey-axis,theneachofthesecurveswouldbeanegativeexponential(wash-outcurve)
EffectSite
Pharmacokineticmodelstypicallydisplaytheplasmaconcentration.
Clinicallyhowever,weareinterestedindrugconcentrationsatthesiteofaction(e.g.thebrain)Concentrationattheeffectsite(alsoknownasbiophase)isgivenbyCe
Thiscannotbemeasured,andsoisacalculatedvalueEffectsiteconcentrationbedifferentfromplasmaconcentration(Cp)priortoreachingsteadystateThedelaybetweenplasmaandeffectsiteconcentrationsisanexampleofhysteresis.
Theeffectsitecanbemodeledasanadditionalcompartmentinthree-compartmentmodelsTheeffectsiteismodeledasacompartmentofnegligiblevolumecontainedwithinV ,butdoeshaverateconstants
EffectsitevolumechangesasV changesThek istherateconstantfordrugdiffusionfromplasmaintotheeffectsiteThek istherateconstantforeliminationofdrugfromtheeffectsiteThisisatheoreticaleliminationpathway-drugisnotusuallymetabolisedattheeffectsite.
Thet ke0describestheeffect-siteequilibrationtimeItdescribeshowrapidlytheeffectsitereachesequilibriumwithplasma.
Alargeke0(rapiddrugflow)givesashortt ke0Afteronet ke0,50%ofthefinaleffectsiteconcentrationwillbereachedprovidedplasmaconcentrationremainsconstant
Ashortert ke0indicatesthatthattheeffectsiteconcentrationwillreachequilibriumwithplasmamorerapidly,andthereforeamorerapidclinicaleffectfollowingadministrationisseenNotethat:
Thet ke0isnotthetimetopeakeffectNeitherisk
Foraninfusionrunatconstantplasmaconcentrationthepeakeffectwillbeseenat3-5xthet ke0Thetimetopeakeffectisafunctionofbothplasmakineticsandthet ke0
e.g.adenosinehassuchashorteliminationt
11
e1e0
1/2
1/21/2
1/2
1/2e0
1/21/2
1/2theeffectsiteconcentrationwillreachitspeakrapidlyregardlessoftheke0
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Non-CompartmentalModels
Compartmentmodelsarenotappropriatefordescribingthebehavioursofalldrugs.Non-compartmentalmodelsareusedwhendrug:
Clearanceisorgan-independentEliminationdoesnotoccursolelyfromthecentralcompartment
ThesemodelsuseAUC,whichiscalculatedbymeasuringtheplasmaconcentrationofadrugatdifferenttimeintervals,andplottingtheareaunderthecurve(AUC).Thiscanbeusedto:
Determineclearance
DetermineBioavailabilityDifferencebetweentheAUCofthesamedoseofdrugadministeredIVandviaanotherroute.
Footnotes
Theformulaforhalf-lifecanbederivedfromtheequationforawash-inexponentialasfollows:
Washinexponentialisgivenby:
canthenbesubstitutedandtheequationsolvedfor asfollows:
References
Pharmacokinetics
62
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PlasmaVolume.Mosby'sMedicalDictionary,8thedition.2009.3. StanskiRD,ShaferSL.TheBiophaseConceptandIntravenousAnesthesia.4. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2019-07-18
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AbsorptionDescribeabsorptionandfactorsthatwillinfluenceit.
Absorptionisdependentontherouteofadministration.Routesofadministrationareselectedbasedon:
EffectsiteofthedrugDrugfactors
BioavailabilityAvailablepreparations
PatientfactorsAbilitytotakeorabsorboralmedicationsPreference
KeyConceptsBioavailabilityistheproportionofdruggivenwhichreachesthesystemiccirculationunchanged,comparedtotheIVform.Itisaffectedby:
FormulationPhysicochemicalInteractionsInteractionswithotherdrugsandfood.PatientFactors
MalabsorptionsyndromeGastricstasis
First-passmetabolism
First-pass(pre-systemic)metabolismistheextenttowhichdrugconcentrationisreducedafteritsfirstpassagethroughanorgan,priortoreachingthesystemiccirculation.Firstpassmetabolismis:
Typicallyusedwhenreferringtopassageoforally-administereddrugsthroughtheliverMayalsorefertometabolismbythe:
LungsFirstpassofintravenouslyinjecteddrugspriortoenteringthearterialsideofthecirculation,e.g.fentanyl.Vascularendothelium
Relevantin:UnderstandingdifferencesbetweenPOandIVdosing
AlternativeroutesofadministrationfordrugswithlowPObioavailabilityDeliveryofprodrugsviaPOmechanismsIncreasesactivedrugconcentration.UnderstandingenzymeinteractionsUnderstandingtheeffectsofhepaticdisease
Porto-systemicshuntsdecreasefirstpassmetabolismAlteredbioavailabilityofdrugswithhighhepaticextractionratios
Routesofadministration
Intravenous
RapidOnset
Absorption
64
100%bioavailabilitySomedrugsmaystillundergometabolisminthepulmonarycirculation,suchasfentanyl,lignocaine,propofol,andcatecholamines.
Oral
Absorptionisthroughgutmucosa,througheither:TransportmechanismsUnionised(lipidsoluble)
AcidicdrugsareabsorbedmorerapidlyinthestomachThesmallbowelabsorbsbothacid(despitebeingionised)andalkalinedrugsduetohighsurfacearea
Lowestbioavailabilityofanyroutedueto:First-passmetabolismGutmetabolismofdrugsBacterialmetabolismofdrugs
Drugsmustbelipidsolubleenoughtocrosscell-membranesandwatersolubleenoughtocrossinterstitium
FactorsaffectingGITAbsorption
DrugFactorsMolecularWeightConcentrationGradientLipidSolubility
pHandpKaPharmaceuticalPreparationPhysiochemicalInteractions
FoodOtherdrugs
PatientFactorsGITbloodflowSurfaceArea
SmallbowelhasthelargestsurfaceareaofanyGITorganpHMotilityDigestiveEnzymesGITbacteriaandsubsequentmetabolismDisease
CriticalIllnessBowelObstructionEmesis/Diarrhoea
Epidural
MaybeviabolusorinfusionOnsetdeterminedbyproportionofunioniseddrugavailableLignocainehasamorerapidepiduralonsetthanbupivacaineasithasapKaof7.9(comparedto8.4)andthereforeagreaterunionisedportionatphysiologicpH.
Additionalfactorsincludeadditivesandintrinsicvasoactivepropertiesofthedelivereddrug
Subarachnoid/Intrathecal
Absorption
65
VerysmalldosingMinimalsystemicspreadExtentofsubarachnoidspreadisdependentonvolumeandtypeofsolutionAppropriatepositioningofthepatient,withhigher-specificgravitysolutions,isrequiredtoavoidsuperiorspreadoftheblockAdditionalfactorsincludeadditivesandintrinsicvasoactivepropertiesofthedelivereddrug
Inhalation
SystemicabsorptiondependentonparticlesizeLargeparticlesreachthebronchioles<1microndiameterparticlesmayreachthealveolus
Rapiddiffusiontocirculationduetohighsurfaceareaandnofirst-passmetabolism
Transdermal
Systemicabsorptiondependenton:Doserequirement
LargedoserequirementscannotbeeffectivelygiventransdermallyFickPrinciple
AmountofdruggivenAmountofdruginskin
RegionalbloodflowHistaminerelease
SurfaceAreaSkinthicknessLipidsolubility
pHofskinandemulsionpKaofdrug
MolecularweightAdvantages
ConvenientPainlessNofirstpassmetabolismSteadyplasmaconcentrationonceestablished
DisadvantagesSlowonsetVariableplasmaconcentrationinitiallyOverdoseandabusepotentials
Subcutaneous
Absorptiondependentonregionalbloodflow
Sublingual
RapidonsetBypassportalcirculation(drainsintoSVC)
Rectal
Variableabsorption
Absorption
66
DistalrectalabsorptionbypassesportalcirculationProximalrectalabsorptiondoesnotandmayresultinhepaticfirstpassmetabolismSmallsurfaceareaforabsorption
Intramuscular
Bioavailabilitycloseto1AbsorptiondependentonregionalbloodflowPotentiallocalcomplications:
AbscessHaematoma
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. ChongCA,DennyNM.Localanaestheticandadditivedrugs.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2019-07-18
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DistributionDescribefactorsinfluencingthedistributionofdrugs.
Drugdistributionisdependentonmanyfactors,allofwhichcanberelatedtoFick'sLawofDiffusion:
Concentrationgradient
Tissuemass
MolecularWeightLargermoleculesarelessabletocrosscellmembranes,andsoagreaterportionwillremaininthecompartmenttheyaredeliveredto.
LipidSolubility
IonisationIoniseddrugsarepolar,andsoarelesslipidsoluble.
Ionisationisafunctionof:pKaThepKaisthepHatwhichaweakacidorweakbasewillbe50%ionised.
AssolventpHchanges,theproportionofionisedvs.unioniseddrugwilldifferHowdependsonwhetherthedrugisanacidorbase:
BasesareionisedBelowtheirpKaAcidsareionisedAbovetheirpKa
pHIncombinationwithpKa,affectstheionisedportion.
Unioniseddrugs:CrosscellmembranesmorereadilythantheionisedformAretypicallyhepaticmetabolisedAretypicallynotrenallyeliminated
Ioniseddrugs:AretypicallyrenallyexcretedwithoutundergoingmetabolismArepoorlylipidsolubleanddonotcrosscellmembranesreadilyMaybeiontrappedThisoccurswhenanunioniseddrugmovesacrossamembraneandbecomesionisedduetoachangeinpH.Thenow-insolubledrugistrappedinthenewcompartment.Thisisrelevantin:
PlacentaFoetalpHislowerthanmaternalpH,whichcantrapbasicdrugs(e.g.LA,opioids)infoetus.
ThisbecomesmoresignificantwithagreaterdivergenceofpH(e.g.placentalinsufficiency)RenaleliminationUrinaryalkalinisationisusedtoaccelerateeliminationofacidicdrugs,astheybecomeionisedandtrappedinurine.
Distribution
68
ProteinbindingProteinsanddrugsmaybeboundtogetherbyweakbonds.Theseincludeionicbonds,vanderWaal'sforces,andhydrogenbonds.
Drugsmaybindtoproteinsin:Plasma
AlbuminBindsacidandneutraldrugs.
HighcapacityTwomajorbindingsites(sixtotal)
SiteI(warfarin)SiteII(diazepam)
α1-acidglycoproteinBindsbasicdrugs.
SinglebindingsiteLowcapacityTypicallyresultsinlowertotalbinding(comparedtoalbumin)ofalkalinedrugs,despiteitsincreasedaffinity.
LipoproteinForlipidsolubledrugs.
TissueReceptor
Proteinbindingisimportantas:Onlyunbounddrugsareableto:
CrosscellmembranesInteractwithreceptorsUndergometabolismReducedproteinbindingincreasesclearanceofdrugswithlowextractionratios.Befilteredbythekidney
Highlytissuebounddrugs:HavealongdurationofactionHaveahighvolumeofdistribution,prolongingtheireliminationMaybuildupintissues,leadingtoadverseeffectse.g.Cornealdeposition,lungfibrosis.
Proteinbindingisaffectedby:Affinityofdrugforprotein
IoniseddrugsdonotbindtoproteinpH.Competitionbetweendrugsforbindingsites
AmountofproteinDisease
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69
Dueto:HypoalbuminaemiaNegativeacutephasereactant.Increasedα1-acidglycoproteinAcutephasereactant.
CompetitionSourceofpharmacokineticinteractions.
Proteinbindingtypically:CorrelateswithlipidsolubilityIsimportantonlywhenitisveryhighResultsinadecreasedV whenplasmabindingishighResultsinanincreasedV whentissuebindingishighIsimportantindurationofactionasitalsorelatestoaffinityfortissueproteins
RegionalbloodflowAffectsconcentrationgradientsbetweenbloodandtissue,andisaffectedbycardiacoutput.Regionsinclude:
VesselRichGroupBrainHeartLiverKidneys
VesselPoorGroupConnectivetissue
BonesLigamentTeethHair
MusclegroupsFat
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2019-07-18
DssDss
Distribution
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MetabolismDescribethemechanismsofdrugclearanceandmetabolism.
Removalofdrugfromthebodyrequireseither:
MetabolismofactivedrugtoaninactivesubstanceTypicallybytheliver,butotherorgans(kidney,lungs)alsometabolisesomesubstances.ExcretionofactivedrugOftenbythekidneys,butmayalsobeinbile,orexhaled.
Removalofdrugsfromthebodyisachievedpredominantlythroughrenalexcretionofwater-solublecompoundsAsmanydrugsarelipophilic,metabolismtowatersolublecompoundsisrequiredtocleardrugsfromthebody
ClearanceClearancedescribestheeliminationofdrugfromthebody.Clearanceis:
ThevolumeofplasmacompletelyclearedofadrugperunittimeMeasuredinml.min .
DiscussedfurtherinmodelingDoesnotincluderedistributionIscalculatedfromtheareaundertheconcentrationtimecurve:
Totalclearanceisthesumofclearancesfromindividualorgans,e.g.:
,where:
,where:
isurineconcentrationinmmol.LFunctionofglomerularfiltration,reabsorption,andsecretion.
istheurineflowinml.min
istheplasmaconcentrationinmmol.L
,where:
isthehepaticbloodflowinml.min
istheextractionratio
Kinetics
Drugclearancecanfolloweitherfirstorderorzero-orderkinetics:
First-orderKineticsAconstantproportionofthedruginthebodyiseliminatedperunittime.
Mostdrugsareeliminatedbyfirstorderkinetics,asthecapacityoftheeliminationsystemexceedstheconcentrationofdrug
-1
-1
-1
-1
-1
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Zero-orderkineticsAconstantamountofdrugiseliminatedperunittime,independentofhowmuchdrugisinthebody.
OccurswhenthereissaturationofenzymesystemsItisalsoknownassaturationkineticsforthisreason.
e.g.Phenytoinfollowsfirstorderkineticsatlowerdoses,butzero-orderkineticsatdoseswithinthetherapeuticrangeThisisclinicallyrelevantasthenarrowtherapeuticindexmeansthattoxiclevelsmayoccurrapidlywithasmallincreaseindose.e.g.Ethanolalsofollowszero-orderkineticswithinthe"therapeuticrange",asitisaveryweak(dosesareingrams)positiveallostericmodulatoroftheGABA receptor
Zero-orderkineticsisconcerningas:PlasmaconcentrationswillrapidlyincreasewithonlymodestdoseincreaseThereisessentiallynosteadystate:ifdruginputexceedsoutput,plasmalevelswillcontinuetorise
Michaelis-Menten
TheMichaelis-Mentenequationdescribesthetransitionfromfirstordertozeroorderkineticsasdrugconcentrationincreases:
Metabolismincreasesproportionallywithconcentrationaslongastheconcentrationofdrugleavingtheorganofmetabolism(e.g.inthehepaticvein)islessthanhalfofthemaximalconcentrationofdrugthatorgancanmetabolise
A
rd
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Thisis~1/3 ofthemaximalrateofmetabolism
HepaticMetabolism
Theprincipleorganofdrugmetabolismistheliver.Hepaticmetabolism:
Usuallydecreasesthefunctionofadrug,though:ProdrugshaveincreasedpharmacologicallyactivityafterlivermetabolismSomedrugshaveactiveortoxicmetabolites
Canbedividedintotwophases
PhaseI
Phaseonereactions:
OccurintheendoplasmicreticulumImprovewatersolubilitybyexposingafunctionalchemicalgroupTypicallyoccurpriortophaseIIreactionsformostdrugsInclude:
OxidationLossofelectrons.
MainphaseIreactionCYP450driven
ReductionGainofelectrons.
CYP450drivenHydrolysisAdditionofawatermolecule,whichmayresultintwonewcompounds.
EsterasedrivenThereforerapid,highcapacity,organ-independentelimination.
ButylcholinesteraseNon-specificplasmacholinesteraseRBCesterase
CYP450System
CYP450enzymesare:
AsuperfamilyofenzymesvitalindrugmetabolismNamedafterthewavelengthoflighttheyabsorbwhen:
ReducedCombinedwithCO
Locatedin:LiverEndoplasmicreticulumofhepatocytes.LungsKidneyGutBrain
Over1000enzymes,with~50functionallyactiveClassifiedbythedegreeofsharedamino-acidsequenceinto:
Families
rd
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CYP1,CYP2,CYP3...SubfamiliesCYP1A,CYP1B...IsoformsCYP1A1,CYP1A2...
CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP2E1 CYP3A4 CYP3A5
PropofolPropofol,Parecoxib,Warfarin
Diazepam,Omeprazole,Clopidogrel,Phenytoin
Codeine,Metoprolol,Flecainide
Volatileanaestheticagents,paracetamol
Commonbenzodiazepines,Fentanyl,Alfentanil,Lignocaine,Vecuronium
Diazepam
KeyCYPenzymesinclude:
CYP2E1Metabolisesvolatilesandparacetamol.CYP3A4Responsiblefor60%ofmetabolicactivity.CYP2D6
Importantbecausegeneticpolymorphismleadstosignificantinter-patientvariabilityMayresultinsignificantover-orunder-metabolismofdrugs,andthereforesignificantinter-individualvariabilityinresponse.
5-10%ofthepopulationarepoormetabolisers2-10%areintermediatemetabolisers1-2%areultra-rapidmetabolisersBulkofthepopulation(70-90%)areextensivemetabolisers
ClinicaleffectwilldependonthetypeofdrugPro-drugs
Extensive/ultra-rapidmetaboliserswillconvertmoredrugtotheactiveform,andseeagreatereffectMayleadtooverdose.Poormetaboliserswillexcretemorepro-drugpriortometabolism,andseeareducedclinicaleffect
ActivedrugExtensive/ultra-rapidmetaboliserswillinactivatemoredrug,andseeareducedeffectPoormetaboliserswillseeaprolongedclinicaleffect
Clinicaleffectmaybealteredbyenzymeinteractionse.g.Oxycodoneusebyanultra-fastmetaboliser,incombinationwithaCYP3A4inhibitor(e.g.diltiazem)willresultinasignificantincreaseintheclinicaleffectofoxycodone
DrugsmetabolisedbyCYP2D6include:Analgesics
Codeine(prodrug)Oxycodone(metabolisedtothesignificantlymorepotentoxymorphone)MethadoneTramadol(metabolisedtoformwithgreaterMOPselectivity)
PsychiatricdrugsSSRIsTCAsHaloperidol
CardiovasculardrugsAmiodaroneFlecainideMexiletine
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PhaseII
PhaseIIreactions:
Involveconjugationwithanothercompound,producingahighlypolarmetaboliteThisincreaseswatersolubilityandthereforerenalelimination.TypicallyoccurinthehepaticendoplasmicreticulumInclude:
GlucuronidationAdditionofglucuronicacid.SulfationAdditionofasulfagroup.AcetylationAdditionofanacetylgroup.
Alsooccursinthelungandspleen.MethylationAdditionofamethylgroup.
ExtractionRatio
Extractionratioistheproportionofadrugthatisclearedfromcirculationduringeachpassthroughtheorgan,typicallytheliver:
Extractionratioisdependenton:
BloodflowHepatocyteuptakeEnzymecapacityDescribedbytheMichaelisConstant:Theconcentrationofasubstratewhichcausesanenzymetoworkat50%ofitsmaximumcapacity.
Drugscanhaveeitherahighorlowextractionratio:
HighextractionratioThesedrugshavearapiduptakeandhighcapacity,soeliminationisperfusiondependent.
Freedrugisrapidlyremovedfromplasma,bounddrugisreleasedfromplasmaproteinsandaconcentrationgradientismaintainedMetabolismofdrugswithahighextractionratiois:
IndependentofproteinbindingDependentonliverflowTypicallydoublingliverbloodflowwilldoublehepaticclearance.
ThereisahighvariabilityinplasmaconcentrationbetweenindividualsduetothevariationinliverbloodflowDrugswithhighextractionratiosaregenerallyindependentofenzymeactivity-decreasingenzymeactivityfrom99%to95%hasaminimaleffectonhepaticclearance
Thekeyexceptionisfirstpassmetabolism,astheabovechangewillresultinafive-folddifferenceindosereachingthesystemiccirculationThereforedrugswithahighextractionratiohavelowPObioavailability.
LowextractionratioEliminationiscapacity-dependent.
AmountoffreedrugavailableformetabolismisgreatlyaffectedbythedegreeofproteinbindingMetabolismis:
Largelyindependentofflow
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DrugshavegoodPObioavailability.Dependentonhepatocytefunctionandproteinbinding
FactorsAffectingHepaticMetabolism
DrugFactors PatientFactors
Lipidsolubility Age
Ionisation Obesity
Proteinbinding Pregnancy
Enzymecompetition Genetics:Slowvs.fastacetylators
Hepaticflow/ExtractionRatio
EnzymeInhibition/Induction
Hepaticdisease
Smoking,ETOH
OrganIndependentMetabolism
Mechanismsoforganindependentmetabolisminclude:
HofmannDegradationSpontaneousdegradationormetabolismofsubstancesoccurringinplasma.
e.g.CisatracuriumundergoesHofmanndegradationPlasmaEsterasesPlasmaesterasesarenon-microsomalenzymeswhichhydrolyseesterbonds.They:
AretypicallysynthesisedintheliveranderythrocytesHaveahighcapacityThis,combinedwiththeorgan-independentelimination,meansdrugsmetabolisedbyplasmaesteraseshaveareliableoffset.e.g.Suxamethoniumishydrolysedbyplasmaesterases
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. EssentialpharmacologyfortheANZCAprimaryexam3. Birkett,DJ.Pharmacokineticsmadeeasy9:Non-linearpharmacokinetics.1994.AustralianPrescriber.
Lastupdated2019-07-18
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EliminationDescribethemechanismsofdrugclearanceandmetabolism.
Drugscanbeeliminatedin:
UrineBileSweatBreastmilkTearsExhaledgas
RenalEliminationDrugscanbe:
FilteredattheglomerulusFiltereddrugsare:
NotproteinboundOnlyfreedrugpresentinfilteredplasmawillbeexcreted.
ConcentrationoffiltereddrugwillbethesameasinunfilteredplasmaHighlyproteinbounddrugsarepoorlyfilteredThereisonlyaweakconcentrationgradientfavouringdissociationfromplasmaproteins.
SmallSubstanceslessthan7,000DaarefreelyfilteredSubstancesgreaterthan70,000Daareessentiallyimpermeable
Hydrophilic/lipophobicLipophilicdrugsmaybefilteredattheglomerulusbutwillbefreelyreabsorbedduringtheirpassagedownthetubule,suchthatonlytrivialamountsareeliminatedinurine.
SecretedinthetubulesActiveprocessallowssecretionagainstconcentrationgradientsSeparatemechanismsforacidicandalkalinedrugs
SaturatableprocessSaturationmayoccurofabasictransporterwhilststillallowingexcretionofacidicdrugs,andviceversa.
ReabsorbedinthetubulesPassivediffusiondownaconcentrationgradient.
HydrophilicmoleculescanonlybereabsorbedbyaspecialisedtransportmechanismAcidicdrugswillbebecomeionisedinanalkalineurine(andviceversa),reducingtheirsolubilityThisisthephysiologicaljustificationforurinaryalkalinisation.
HepaticElimination
Biliaryeliminationoccursfordrugsunabletobefilteredbytheglomerulus.Thesearetypically:
LargeGreaterthan30,000dalton.Lipidsoluble
Elimination
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Enterohepaticrecirculation
Drugsexcretedinbilemay:
BehydrolysedinthesmallbowelbybacteriaandthenreabsorbedThenpassthroughtheportalcirculationandgetmetabolisedagainThisprocessmayoccurmanytimes
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-07-18
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BolusandInfusionKineticsExplaintheconceptsofintravenousbolusandinfusionkinetics.Todescribetheconceptsofeffect-siteandcontextsensitivehalftime.
ContinuousInfusions
PlasmaconcentrationsofanIVinfusionareinfluencedby:
DistributionMetabolismElimination
OnsetofContinuousRateInfusions
Withoutaloadingdose,theconcentrationofdruginfusedataconstantincreasesinanegativeexponentialfashion:
PlasmaconcentrationinitiallyrisesrapidlyDistributionintoperipheralcompartmentsisthemainmethodfordrugstoleaveplasmaThisisbecauseatthestartofaninfusionthereisalargeconcentrationgradientbetweenplasmaandperipheralcompartments.EliminationbecomesmoreimportantinprolongedinfusionsAsperipheralcompartmentsfilltheconcentrationgradientbetweenplasmaandcompartmentsfalls,andredistributionbecomesrelativelylessimportant.Steadystateisachievedwhenconcentrationsincompartmentsareequal,andinputisequivalenttoclearance
Concentrationatsteadystateisdeterminedbytheratioofinfusionratetoclearance:Therefore,atsteadystatewithdrugswith100%bioavailability:
Fordrugsgivenbyaroutewithlessthan100%bioavailability:
Ifthedosingisgivenintermittently,then:
VolumeofdistributionatsteadystateistermedV ssandistheapparentvolumeintowhichadrugwilldisperseduringaprolongedinfusion,andisthesumofallcompartmentvolumesinthemodel.
ContinuousRateInfusionswithBolusDosing
Asseen,abovestartinganinfusionattheraterequiredtomaintainsteadystateisinefficient:
Foranydesiredplasmaconcentration,itwilltakethreetimeconstants(4-5half-lives)foracontinuousinfusiontoreachthisconcentration
Ifthehalf-lifeislong,thenachievingatherapeuticlevelwilltakesometimeAbolusdoseaimedtofilltheV willallowsteady-statetobereachedimmediately:
D
D
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79
StoppinganInfusion
Forabi-exponentialmodel(i.e.onlyoneperipheralcompartment),declineinplasmaconcentrationcanbemodeledbythe
equation .Inthismodel:
isthetime-constantforredistribution
isthetime-constantforterminalelimination(Providedtheinfusionhasreachedsteady-state).
Neither or correspondtoanyindividualrateconstant
Factorsaffectingrateofoffsetofaninfusioncanbeclassifiedintopharmacokinetic,pharmacodynamic,andotherdrugfactors:
PharmacokineticfactorsDistribution
VHighV willdecreaseclearancefromcentralcompartment.FactorsaffectingV include:
IonisationIontrappingcancausedrugtobesequestered.ProteinbindingLipidsolubilityAffectedbybodyfat.
SpeedofdistributionCOAffectsorganbloodflow.
RedistributionDuringaninfusion,peripheralcompartmentsbecomesaturatedwithdrug.Whenaninfusionceases,drugisredistributedcentralcompartment.
Thisisrelatedtocontext-sensitivehalftime(seebelow)Metabolism
RouteofclearanceOrgan-dependent
OrganfailuresExtractionratioOrganbloodflow
Organ-independentSaturatablekineticsZero-orderkinetics.
PresenceofactivemetabolitesEliminationRouteofexcretionofactivedrugoractivemetabolites.
DD D
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OrganfailuresPharmacodynamicFactors
AgeSensitivityDoserequiredforeffectanddoserequiredforrecovery.
OrganfailuresPregnancy
OtherdrugfactorsPharmacokineticinteractions
Enzymeinhibition/inductionPharmacodynamicinteraction
DrugtolerancesTachyphylaxis
DrugactionDrugswhichaltergeneorreceptorexpression,orbindirreversibly(e.g.clopidogrel)mayshowongoingeffectsevenafterthedrughasleftthesystem.
Context-SensitiveHalf-Time
Context-sensitivehalftimeis:
DefinedasthetimeforplasmaconcentrationtofalltohalfofitsvalueatthetimeofstoppinganinfusionAmethodtodescribethevariabilityinplasmaconcentrationsafterceasinganinfusionThe"context"isthedurationofinfusion.Usedbecauseterminaleliminationhalf-lifehaslittleclinicalutilityforpredictingdrugoffsetHalf-livesareoftenmisleadingwhendiscussingdruginfusions.Dependenton:
DurationofinfusionDuringaninfusion,drugsdistributeoutofplasmaintotissues.Whentheinfusionceases,drugisclearedfromplasmaandtissuedrugredistributesbackintoplasma.
Thelongeraninfusion,themoredrughasdistributedoutoftissues,andthelongertheredistributionphaseThelongestcontext-sensitivehalftimeoccurswhenaninfusionisatsteady-state
RedistributionThemaximalCSHTreacheddependsonthe:
V ssDrugswithalargerV sshavealongerCSHT,asonlyasmallproportionofthedruginthebodywillbeinplasmaandabletobecleared.RateconstantforeliminationDrugswithasmallerrateconstantforeliminationhavealongerCSHT.
Drugswithlongercontext-sensitivehalf-timeswillwearofflesspredictably.
DD
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RemifentanilhaslittleredistributionandasmallVd,andsohasaveryshortcontext-insensitivehalftimeItwearsoffreliablyandquicklyfollowingcessationofinfusion.
Context-SensitiveDecrementTime
DescribethetimeittakesforadrugleveltofalltoaparticularpercentageofitsstartingvaluefollowingcessationofaninfusionTheyareusedbecausethehalf-timesdonotdescribemono-exponentialdecayi.e.Thetimetakenfordrugconcentrationtoreach25%ofitsstartingvalueisnottwicethecontextsensitivehalf-time.Thecontext-sensitivehalf-timecouldalsobedescribedasthe50%context-sensitivedecrementtime
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. HillSA.PharmacokineticsofDrugInfusions.ContinEducAnaesthCritCarePain(2004)4(3):76-80.
Lastupdated2019-07-18
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DrugMonitoringExplainclinicaldrugmonitoringwithregardtopeakandtroughconcentrations,minimumtherapeuticconcentrationandtoxicity
Drugmonitoring:
DescribestheindividualisationofdosingbymaintainingplasmadruglevelswithinatargetrangeIsimportantinadjustingdosetoaccountforinter-patientvariabilityinresponseVariabilitycanbe:
PharmacokineticAdjustingdrugdosebymonitoringplasmalevelsreducespharmacokineticvariability.PharmacodynamicDrugdoseisadjustedbyevaluatingtheclinicaleffect.
Druglevelsaremeasuredtoensuretheconcentrationisabovetheminimumtherapeuticconcentrationbutbelowtoxiclevels:
MinimumtherapeuticconcentrationTheED ,i.e.thedoserequiredtohaveaneffectin50%ofthepopulation.
DeterminesdesiredtroughlevelsMinimumtoxicconcentrationTheLD ,orthedosewhichislethalin50%ofthepopulation.
Determinestheacceptablepeaklevels
Fromtheselevelstworelatedtermsarederived:
Therapeuticrange(alsoknownasthetherapeuticwindow)Differencebetweentheselevels.TherapeuticindexRatiobetweentheselevels,i.e.
Ahighertherapeuticindexgivesagreatermarginforsafety
IndicationsDrugsaremonitoredinorderto:
AvoidtoxicityAdjustdosingforefficacyMonitorcomplianceordeterminefailureoftherapy
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Drugsthattypicallyrequiremonitoringhavea:
NarrowtargetrangeSignificantpharmacokineticvariabilityRelationshipbetweentheconcentrationinplasmaandclinicaleffectsDeterminedconcentrationrangeValidatedmonitoringassay
Drugswheretheeffectcanbemeasuredclinically(e.g.antihypertensives)tendtobeadjustedbasedonobservedeffects.Thisisnotpossiblewhen:
Theclinicalresponseistheabsenceofacondition,e.g.antiepilepticsThedrughasanarrowtherapeuticrange
DrugscommonlymonitoredintheICUsettinginclude:
Drug TherapeuticRange
Digoxin 0.8-2microgram/L
Vancomycin 10-20mg/L*
Tacrolimus 5-20microgram/L
Serolimus 5-15microgram/L
Phenytoin 10-20mg/L
*Trough
Timingofsamples
SamplingfortoxicityshouldoccurattimesofpeakconcentrationThisrequiresaccountingforabsorptionanddistribution
e.g.Digoxinlevelsshouldbeperformed>6hoursfollowingadosetoallowtimefordistributiontooccurIfsymptomatic,samplestakenatthistimemaydemonstratetoxicconcentrations
Samplingformonitoringshouldideallyoccuratsteadystatei.e.after4-5eliminationhalf-livesFordrugswithverylonghalf-lives(suchasamiodarone),samplingtendstooccurearliertoensuretoxiclevelshavenotbeenreached,assteadystatemaytakemonthstoachieve
Fordrugswithshorthalf-lives,troughlevels(i.e.pre-doselevels)shouldbetakenThisistheleastvariablepointinthedosinginterval.Fordrugswithlonghalflives,timingofsamplingislessimportant
InterpretationInterpretationofdruglevelsisdependenton:
TimingofsampleDurationoftreatmentatthecurrentdoseanddosingscheduleIndividualcharacteristicsthatmayaffectthepharmacokinetics
AgePhysiologyComorbidities(hepatic,renal,cardiac)
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DruginteractionsGeneticsEnvironmental
ProteinbindingAssaysmeasureboundandunbounddrugOnlyunbounddrugispharmacologicallyactive.Ifbindingischangedbydiseaseordisplacementbyotherdrug,theproportionofunbounddrugmaychangeandtargetedlevelsmayneedtobeadjustedaccordingly
ActivemetabolitesActivemetabolitesarenotmeasuredbutwillcontributetotheresponse.
References1. BirkettDJ.Therapeuticdrugmonitoring.AustPrescr1997;20:9-11.2. GhiculescuRA.Therapeuticdrugmonitoring,whichdrugs,why,when,andhowtodoit.AustPrescr2008;31:42-4.
Lastupdated2018-09-21
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EpiduralandIntrathecalDescribethepharmacokineticsofdrugsintheepiduralandsubarachnoidspace
Inbothspaces,speedofonsetisdeterminedbyFick'sLaw.
EpiduralSpace
Factorsimportanttoepiduraladministration:
DosegivenVolumegivenIncreasedvolumeincreasesareaofsubarachnoidthatthedrugisincontactwith,increasingrateofdiffusion.SolubilityAffectedby:
pKaandpHDeterminesunionisedportionavailabletocrossintoCSF.ProteinbindingDeterminesfreedrugportionabletocrossintoCSF.Lipidsolubility
CSFflowAltersconcentrationgradientbetweenepiduralandsubarachnoidspace.
IntrathecalFactorsimportanttointrathecaladministration:
DoseMuchsmallerdosesrequired.VolumeAffectsextentofspread.BaricityAffectsdirectionofspread:
Hyperbaricsolutionswillsinkwithgravitye.g.Heavybupivacaine(0.5%bupivacainewith8%dextrose)Hypobaricsolutionswillriseagainstgravity
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. ANZCAFebruary/April20073. Factorsinfluencingdistributionofbupivacaineafterepiduralinjection-DiazNotes.
Lastupdated2017-09-17
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EpiduralandIntrathecal
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TotalIntravenousAnaesthesiaandTarget-ControlledInfusion
Describethepharmacologicalprinciplesofandsourcesoferrorwithtargetcontrolledinfusion
TotalintravenousanaesthesiainvolvesusingIVagentsalonetoachievehypnosis,analgesia,andmusclerelaxation.TIVA:
AdvantagesAvoidsadverseeffectsofanaestheticagents
Nausea/vomitingPollutionIncreasedcerebralbloodflow
DisadvantagesDrugmustbemetabolisedPotentialincreasedlikelihoodofawareness
LikelyrelatedtopoorapplicationoftechniqueratherthanthetechniqueitselfMostlyrelatedtodisconnectionofinfusionwithoutEEGmonitoring
Variableplasmaconcentration
TargetControlledInfusionTCIistheuseofpharmacokineticmodels(typicallycombinedwithmicroprocessor-controlledinfusionpumps)toachieveatargetconcentrationofdruginaparticularbodycompartment.
TCI-systems:
Areopen-loopEffectsofdrugarenotmeasured(unlikewithend-tidalgasmonitoring),whichintroducesavulnerabilitythatcanleadtoawareness.
e.g.Comparedtoinhalationalanaesthetics,wheretheloopisclosedbyusingend-tidaldrugmonitoringFollowstheBET(Bolus,Elimination,Transfer)principle:Aloadingdoseisgiventosaturatethevolumeofdistributiontoachievetargetconcentration
Infusionrateisthensettomaintainatargetplasmaconcentration:
Ratecompensatesfor:DrugeliminationDrugdistribution(transfer)
Target canbeadjusted:Forahigherconcentration:
AsmallbolusisgivenInfusionrateisincreased
Foralowerconcentration:InfusionispauseduntildesiredlevelisreachedInfusionraterestartsatalowerrate
Modelscantargeteither:
Plasmaconcentration,
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Willnotapproximate untilsteadstateisreached.Therefore:
Increase duringinduction,sothat willrisemorequickly
shouldbeadjustedtothelevelofthesurgicalstimulus
Effect-siteconcentration,Over-pressureoccursautomatically,sothereisnorequirementtoincreasetargetduringinduction.
TCIModelsforPropofol
TheBristolModel:
FirstpharmacokineticmodelBasedonthree-compartmentmodelofhealthpatientsAssumes:
PremedicationwithtemazepamFentanyl3μg.kg oninductionInhaledN O
Atargetplasmaconcentration( )of3μg.mlThemodel:
1mg.kg inductionbolus10-8-6maintenance:
10mg.kg .hr for10minutes8mg.kg .hr for10minutes6mg.kg .hr thereafter
MarshandSchniderModels:
ThesearecomputercontrolledmodelsBothwerederivedonverysmallgroupsofpatients(18and24respectively)Themodelsdiffermostlyinthefirst10minutesafterinduction,andprogressivelyconverge
-1
2-1
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Theinitialbehaviourofthemodeliskeyindecidingwhichmodeltoapplytoanyparticularpatient.
Property Marsh Schnider
Targets
Typicallytargetplasmaconcentration,butcantargeteffectsite.
EffectsitetargetingisusuallydonewiththemodifiedMarshmodel,duetothelargebolusdosinggivenbythestandardMarshmodel.
Typicallyeffectsite,butcantargetplasmaconcentration.
Plasmatargetinggivesinconsistentresults,asthefixedsizeofV meansanyincreaseindesiredplasmaconcentrationresultsinthesamesizebolusbeinggiven,irrespectiveofpatientparameters.
Requiredvariables
TBW(overestimatesinduction(butnotmaintenance)inobesepatients,considerusingIBW),Age(butnotusedincalculation)
Age,height(tocalculateleanbodymass),TBW
Values VariablecompartmentsizesbutbiggerV FixedV (4.27L)andV ,variableV andK
Other
The'modifiedMarsh'modelusesak of1.2L.min
insteadof0.26L.min ,whichdecreasesthe
requiredtoachievethetarget quickly.ThemodifiedMarshisthereforepreferableinpatientsathigherriskofoverdose.
LimitsBMIto<42formalesand<35forfemales,topreventabsurdcompartmentsizesbeingcalculatedfromthemethodusedtocalculateleanbodymass
Overall FasterinductionduetolargerV ,whichresultsinalargerloadingdose
Reducedrateofadverseevents.Overalllesspropofolused.
References
1. AbsalomAR,ManiV,DeSmetT,StruysMM.Pharmacokineticmodelsforpropofol--definingandilluminatingthedevilinthedetail.BrJAnaesth.2009Jul;103(1):26-37.
2. NaidooD.TargetControlledInfusions.DepartmentofAnaesthetics,UniversityofKwazulu-Natal.2011.3. EngbersFH,SutcliffeN,KennyG,SchraagS.Pharmacokineticmodelsforpropofol:Definingandilluminatingthedevilin
thedetail.BrJAnaesth.2010Feb;104(2):261-2;authorreply262-4.4. FRCA-TargetControlledInfusionsinAnaestheticPractice
Lastupdated2019-07-20
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ReceptortheoryToexplaintheconceptofdrugactionwithrespectto:receptortheory
Todefineandexplaindose-effectrelationshipsofdrugs,includingdose-responsecurveswithreferenceto:therapeuticindex,potencyandefficacy,competitiveandnon-competitiveantagonists,partialagonists,mixedagonist-antagonistsandinverseagonists
ToexplaintheLawofMassActionanddescribeaffinityanddissociationconstants
Areceptorisacomponentofacellwhichinteractswithadrugandinitiatesasequenceofeventsleadingtoanobservedchangeinfunction.
Existenceofreceptorsisinferredfromtheresponseoftissuestodrugs,genomesequencing,andmolecularbiology.Adrugbindstoareceptorformingareceptor-drugcomplex,whichinitiatesacascadeofeventstoexertapharmacologicaleffect.
DissociationConstantsInteractionbetweenareceptorandadrugisbaseduponthelawofmassaction,whichstatestherateofachemicalreactionisproportionaltothemassesofreactingsubstances.Thiscanbeexpressedas:
Theratiooftherateconstantfortheforwardsreaction(K )andthebackwardsreaction(K )isthedissociationconstant.Thisistheconcentrationofdrugwhen50%ofreceptorsareoccupied:
AlowK valueindicatesthatalowerconcentrationofdrugisrequiredtooccupy50%ofthereceptor,indicatingthatthedrughasahighaffinityforthereceptor.
PhysiologicalfactorswhichaffectthedissociationconstantaredeterminedbytheArrheniusequation:
,where:
isaconstant
istemperatureinkelvin
istheactivationenergyrequired,whichmaybeloweredbyacatalyst
isthegasconstant
PropertiesofDrugs
Keypropertiesofdrugsinclude:
PotencyTheamountofdrugrequiredtohaveaneffect.
Givenbythe(typicallytheE 50)ThisrelatestoBowman'sprinciple,whichstatesthattheleastpotentanaestheticagentshavethequickestonsetThisisbecausetheyareadministeredinhigherdoses(astheyarelesspotent,moreisrequiredtogetaneffect),which
association dissociation
D
D
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resultsinahighconcentrationgradientandarapiddistributionintotissues.
EfficacyThemaximaleffectthatadrugcangenerate.
IntrinsicactivityThesizeofeffectadrughaswhenbound,whichisgradedfrom0to1.
Thisisalsoknownasactivity
Drug-ReceptorInteractionsDrugscanbeclassifiedbythewaytheyinteractwithreceptorsinto:
AgonistsPartialagonistsInverseagonists
AntagonistsIndirectantagonists
AllostericModulatorsMixedAgonist-Antagonists
Agonists
Anagonistwillgenerateamaximalresponseatthereceptorsite.Anagonisthashighaffinityandanactivityof1.Agonistscanbecomparedby:
Relativepotencyimpliesthatiftwoagonistsareequallyefficacious,asmallerdoseofoneisrequiredtogetaneffectRelativeefficacyimpliesthatthemaximaleffectofoneagonistisgreaterthantheother
Partialagonist
Apartialagonistgeneratesasubmaximalresponseatthereceptor.Apartialagonisthasahighaffinityandanactivitybetween0and1.Apartialagonistcanactasaneffectiveantagonistinthepresenceofafullagonist,asitwillpreventmaximalbindingatareceptor,evenwithahighagonistconcentration.
Inverseagonist
Adrugwhichhasanegativeactivity(between0and-1)producingtheoppositeresponse(comparedtotheendogenousagonist)atreceptor.
Occursduetolossofconstitutiveactivityatthatreceptor
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Antagonist
Anantagonistproducesnoresponseatthereceptorsite,andpreventsotherligandsbinding.Antagonistshavehighaffinityandanactivityof0.
Antagonistswiththesepropertiesarealsoknownasdirectantagonists,whichcanbeeither:
CompetitiveantagonistsDisplaceotherligandsfromabindingsite.Competitiveantagonistscanbe:
ReversibleTheeffectcanbeoverriddenbyincreasingthedoseofagonist.IrreversibleDrugcannotbeoverriddenbyincreasingdoseofagonist.Dose-responsecurveappearssimilartothatofthenon-competitiveantagonist.
Non-competitiveantagonistsCreateaconformationalchangeinthereceptor.Theycannotbeoverriddenbyincreasingthedoseofagonist.
IndirectAntagonist
Indirectantagonistsreducetheclinicaleffectofadrug,butdosoviameansotherthanreceptorinteraction.Theyinclude:
ChemicalantagonistsWherethedrugbindsdirectlytoanother.Examplesincludeprotamineandheparin,andsugammadexandrocuronium.PhysiologicantagonistsAcounteringeffectisproducedbyagonismofotherpathways.
AllostericModulator
Adrugwhichbindstoanallostericsiteonthereceptorandproducesconformationalchangethatalterstheaffinityofthereceptorfortheendogenousagonist.
Allostericmodulatorscanbe:
PositiveIncreasesaffinityforendogenousagonist.
e.g.BenzodiazepinesarepositiveallostericmodulatorsattheGABA receptorNegativeDecreasesaffinityforendogenousagonist.
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MixedAgonist-Antagonist
Adrugwhichhasdifferenteffectsondifferentreceptors.
References
1. PinnockC,LinT,SmithT.FundamentalsofAnaesthesia.2ndEd.CambridgeUniversiyPress.2003.2. EncyclopaediaBritannica.Availableat:https://www.britannica.com/science/law-of-mass-action3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2019-07-20
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ReceptorTypesToexplaintheconceptofdrugactionwithrespectto:receptortheory,enzymeinteractions,andphysicochemicalinteractions.
Toexplainreceptoractivitywithregardto:ionicfluxes,secondmessengersandGproteins,nucleicacidsynthesis,evidenceforthepresenceofreceptors,regulationofreceptornumberandactivity,structuralrelationships.
ReceptorTypes
Areceptorisaprotein,usuallyinthecellularmembrane,towhichaligandmaybindtogeneratearesponse.
IntracellularreceptorsMaybeeithercytoplasmicorintra-nuclear.
Intranuclearreceptorsareactivatedbylipidsolublemolecules(suchassteroidsandthyroxine)toalterDNAandRNAexpressionThisresultsinanalterationofproductionofcellularproteins,sotheeffectstendtobeslowacting.
Enzyme-linkedreceptorsAreactivatedbyaligandandcauseenzymaticactivityontheintracellularside.Theycanbeeither:
MonomersDimersWheretwoproteinsjoin,ordiamerise,onbindingofaligand.
Ion-channelreceptors(inotropic)Createachannelthroughthemembranethatallowselectrolytestoflowdowntheirelectricalandconcentrationgradients.Theycanbeeither:
Ligand-gatedchannelsUndergoconformationalchangewhenaligandisbound.Therearethreeimportantfamiliesofligandchannels:
PentamericfamilyConsistoffivemembranespanningsubunits.Include:
NicotinicAChreceptorGABA receptor5-HT receptor
InotropicglutamatereceptorsBindglutamate,aCNSexcitatoryneurotransmitter.Include:NMDAreceptor
1
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HighCa permeabilityInotropicpurinergicreceptorsFormcationicchannelsthatarepermeabletoCa ,Na ,andKActivatedbyATP
Voltage-gatedchannelsOpenwhenthethresholdvoltageisreached,facilitatingelectricalconductioninexcitabletissues.
Intheirnormalphysiologicalstate,voltagegatedchannelsdonotgenerallybehaveasreceptorsforaligand,howeversomedrugs(e.g.localanaesthetics)willbindtovoltagegatedchannelstoexerttheireffectHaveacommon4-subunitstructure(eachwith6transmembranesegments)surroundingacentralporeThisporeisselectivefortheparticularion,whichinclude:
NaLocatedinmyocytesandneuronsImportantingeneratingandtransmittinganactionpotentialbypermittingsodiuminfluxintocellsInhibitedbylocalanaesthetics,anti-epileptics,andsomeanti-arrhythmics
CaDividedintosubtypes,including:
LMuscularcontraction.TCardiacpacemaker.N/P/QNeurotransmitterrelease.KLocatedinmyocytesandimportantinrepolarisationfollowinganactionpotential.
UndergoaconformationalchangewhenthethresholdpotentialisreachedThisissensedbytheS4helix,whichactstoopenandclosethechannel.Existinoneofthreefunctionalstates:
RestingPoreisclosed.ActivePoreisopen,andionscanpass.InactiveTransientrefractoryperiodwheretheporeisopen,butionscannotpass.Thiscreatestheabsoluterefractoryperiodofacell.
G-proteincoupled(metabotropic)receptors:G-proteinsareagroupofheterotrimeric(containingthreeunits;α,β,γ)proteinswhichbindGDP.Whenstimulated,theGDPisreplacedbyGTPandtheα-GTPsubunitdissociatestoactivateorinhibitaneffectorprotein.Theeffectdependsonthetypeofα-subunit:
G proteinsArestimulatorly.These
IncreasecAMP,leadingtoabiochemicaleffectG proteinsAreinhibitory.These:
Inhibitadenylylcyclase,reducingcAMPG proteinsHaveavariableeffect,dependingonthecell.These:
ActivatephospholipaseCThisaffectstheproductionof:
Inositoltriphosphate(IP )
2+
2+ + +
+
2+
+
s
i
q
3
2+
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StimulatesCa fromtheSR,affectingenzymaticfunctionorcausingmembranedepolarisation.Diacylglycerol(DAG)ActivatesproteinkinaseC,whichhascell-specificeffects.
ActivateintracellularsecondmessengerproteinswhenstimulatedSecondmessengersystems:
Resultinbothtransmissionandamplificationofastimulus,asasingleactivatedreceptorcanactivatemultipleproteinsandeachactivatedproteinmayactivateseveralotherintermediateproteins
ThisisknownasaG-proteincascade
Enzymeinteraction
Drugscaninteractwithenzymesbyantagonismorbybeingafalsesubstrate.
Enzymeantagonism
Mostdrugswhichinteractwithenzymesinhibittheiractivity.Thisresultsin:
IncreasedconcentrationofenzymaticsubstrateDecreasedconcentrationoftheproductofthereaction
Drugscanbecompetitive,non-competitive,orirreversibleinhibitorsofenzymaticactivity.Examplesinclude:
Ramiprilisacompetitiveinhibitorofangiotensin-convertingenzyme.Aspirinisanirreversibleinhibitorofcyclo-oxygenase.
Falsesubstrates
Falsesubstratescompetewiththeenzymaticbindingsite,andproduceaproduct.Examplesinclude:
Methyldopaisafalsesubstrateoftheenzymedopaminedecarboxylase.
PhysicochemicalDrugswhosemechanismofactionisduetotheirphysicochemicalproperties.Examplesinclude:
MannitolreducesICPbecauseitincreasestonicityoftheextracellularcompartment(andisunabletocrosstheBBB),drawingfreewaterfromtheintracellularcompartmentasaconsequence.Aluminiumhydroxidereactswithstomachacidtoformaluminiumchlorideandwater,reducingstomachpH.
References
1. Anderson,C.Pharmacodynamics2.ICUPrimaryPrep.2. LawofMassAction.EncyclopaediaBritannica.3. ANZCAAugust/September20014. CatterallWA.StructureandFunctionofVoltage-GatedIonChannels.Annu.Rev.Biochem.1995.64:493-531.
Lastupdated2019-07-18
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Dose-ResponseCurvesTodefineandexplaindose-effectrelationshipsofdrugs,includingdose-responsecurveswithreferenceto:gradedandquantalresponse.
StandardDose-ResponseCurves
Adose-responsecurveisagraphofconcentrationagainstthefractionofreceptorsoccupiedbyadrug.
Log-DoseResponseCurves
Itisdifficulttocomparedrugsusingstandarddose-responsecurves.Therefore,doseiscommonlylog-transformedtoproducealog-doseresponsecurve.
Thiscurve:
Compareslog-doseversusclinicaleffectDemonstratesthatthebluedrughasgreaterpotencythanthereddrug,thoughbotharefullagonists
Responsescanbeeithergradedorquantal:
GradedresponsesdemonstrateacontinuousincreaseineffectwithdoseE.g.Bloodpressureandnoradrenalinedose
QuantalresponsesdemonstratearesponseonceacertainproportionofreceptorsareoccupiedExamplesinclude:
EDMediandoseofneuromuscularblockerrequiredtoproducea95%lossoftwitchheight.MACMeanalveolarconcentrationofagentrequiredtopreventmovementinresponsetoasurgicalstimulus.
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References
1. AndersonC.Pharmacodynamics1.ICUPrimaryPrep.Availableat:https://icuprimaryprep.files.wordpress.com/2012/05/pharmacodynamics-1.pdf
Lastupdated2017-10-04
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MechanismsofActionDrugscanactinfourways:
ReceptorsGPCRIntracellular
CytoplasmicIntranucleare.g.Steroids,whichalterRNAexpression.
IonChannelsBlockadeAllostericmodulation
EnzymeinteractionAnenzymeisabiologicalcatalyst,increasingthespeedofreaction.Enzymeinteractioncanbe:
Irreversibleinhibitione.g.Aspirin,whichirreversiblyinhibitsplateletthromboxaneproduction.
ReversibleinhibitionCompetitiveantagonism
e.g.ACE-I.Non-competitiveantagonism
PhysicochemicalOsmotic
e.g.mannitol.Acid-base
e.g.antacids.ChelationRedoxreactions
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2019-07-18
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AdverseeffectsClassifyanddescribeadversedrugeffects.
Anadverseeffectis:
Anoxiousorunintendedeffectassociatedwithadministrationofadrugatthenormaldosei.e.,notanoverdoseOccur:
Mainlyinyoungandmiddle-agedindividualsTwiceascommoninwomenMaybeexacerbatedbyasthmaandpregnancy.
Distinctfromanadverseevent,whichisanuntowardoccurrenceduringtreatmentthatdoesnotnecessarilyhaveacausalrelationshiptodrugadministration
Adverseeffectscanbeclassifiedbymechanismasfollows:
TypeAAdverseReactions
Thesearerelatedtothepharmacologicalactionofthedrug.Theyare:
CommonRelatedtodose(dose-responserelationship)TemporallyassociatedwithdrugadministrationReproduciblePharmacologicallypredictablebasedonunderstandingofthedruginquestion
e.ghypokalaemiasecondarytodiureticuse
Theytypicallyresultin:
Organ-selectiveinjuryMorepronouncedwithlong-termuseandinriskgroups:
ExtremesofagePregnancyRenalfailure
HighmorbiditybutlowmortalityTreatmentistodecreasedose.
TypeBAdverseReactions
Thesearepatient-specificoridiosyncraticreactions.Theyare:
RarePotentiallygenetic,butpoorlyunderstood.Independentofdose
OccurwithlowdosesDonothaveadose-responserelationship
NotpharmacologicallypredictableImportantcausesinclude:
AcetylatorstatusCYP450variants
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ReceptorabnormalitiesEnzymealterations/deficiencies
e.g.SuxamethoniumapnoeaNotnecessarilyreproducible
Theytypicallyresultin:
Immuno-allergicreactionsPseudo-allergyIdiosyncraticreactionLowmorbiditybuthighmortality
e.g.Stevens-JohnsonSyndromeoranaphylaxisfollowingpenicillinadministration
Treatmentistoceasethemedication.
TypeCAdverseReactions
Theseare'statisticaleffects'associatedwithmonitoring.Theyare:
TypicallyanincreasedfrequencyofbackgrounddiseasethatisdetectedduetoincreasedscreeningAtypicalforadrugreactionandnotpharmacologicalpredictableNoidentifiabletemporalrelationshipNotreproducible
References
1. RHBMeyboom,MLindquist,ACGEgberts.AnABCofDrug-RelatedProblems.DrugSafety2000;22:415-23.2. PirmohamedM,BreckenridgeAM,KitteringhamNR,ParkBK.Adversedrugreactions.BMJ.1998Apr25;316(7140):1295-
8.OpenAccessReview.3. LazarouJ,PomeranzBH,CoreyPN.Incidenceofadversedrugreactionsinhospitalizedpatients—ameta-analysisof
prospectivestudies.JAMA1998;279:1200-5.
Lastupdated2019-07-18
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DrugInteractionsClassifyanddescribemechanismsofdruginteraction.
Druginteractionsoccur"whentheactionofonedrugmodifiesthatofanother".
MechanismsofDrugInteraction
Druginteractionsarebestclassifiedintothreecategories:
PhysicochemicalPharmacokineticPharmacodynamic
Physicochemical
Physicochemicalinteractionsoccurbecauseofanincompatibilitybetweenchemicalstructures.
e.g.Thiopentoneandsuxamethoniumprecipitateoutofsolutionifpreparedtogetherordeliveredtogetherinthesameline
Pharmacokinetic
Pharmacokineticinteractionscanbesub-classifiedintothoseaffectingabsorption,distribution,metabolism,orelimination.
Absorption
Fororalmedications,absorptionmaybeaffectedbydrugswhichalter:
GastricpHGastricemptyingtime
Metoclopramideresolvesgastricstasisandimprovesabsorptionoforallyadministereddrugs
Distribution
Distributionmaybeaffectedby:
CompetitionforplasmaproteinbindingLossofalbuminandα1-acidglycoproteinMedicationswhichaltercardiacoutputDisplacementfromtissuebindingsitesThistypicallyoccursduetoalterationofmetaboliccapacityofonedrugbytheother.ChelationofdrugfromtissuesChelatingagentsbindtoxicelementsandpreventtissuedamage
Phenytoinisusuallyhighly(90%)proteinbound.Areductioninproteinbindingto80%willdoublethefreephenytoinlevel.Fordrugswithfirst-orderkinetics,metabolismwillincreaseproportionallyhoweverphenytoinrapidlysaturatestheenzymesystem,leadingtozero-orderkineticsandahighplasmalevel.
β-blockersreducecardiacoutputandwillprolongthetimetofasciculationofsuxamethonium.
Metabolism
MetabolismmaybeaffectedbychangestotheCYP450enzymes:
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EnzymeinductionBarbituratesPhenytoinCarbamazepine
EnzymeinhibitionAmiodaroneAmiodaroneinhibitsmetabolismofS-warfarinbyCYP2C9,enhancingit'seffect.DiltiazemVerapamilCiprofloxacinMacrolidesMetronidazoleGrapefruitjuice
Elimination
Renaleliminationcanbeaffectedby:
ChangesinurinarypHCompetitionforactivetubulartransportmechanisms
SodiumbicarbonateincreasesurinarypHandenhancesexcretionofweakacidssuchasaspirin.
Pharmacodynamic
Pharmacodynamicinteractionscanbedirect,duetointeractiononthesamereceptorsystem;oraindirect,whentheyactondifferentreceptorsystem.Theseinteractionscanbeclassifiedaseither:
AdditiveWhentheeffectssummate.
e.g.Administeringmidazolamwithpropofolreducestheamountofpropofolrequiredtogenerateaneffect.AntagonisticWhentheeffectsopposeeachother.
e.g.NeostigmineindirectlyantagonisestheeffectofNDMRsbyincreasingthelevelofAChattheNMJ.SynergisticWhenthecombinedeffectisgreaterthanwouldbeexpectedfromsummationalone.
e.g.Co-administrationofremifentanilandpropofolhasasynergisticeffectinmaintenanceofanaesthesia.
Thesethreeinteractionscanbegraphicallydemonstratedusinganisobologram,whichdrawsalineofequalactivityversusconcentrationoftwodrugs.
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References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. KhanS,StannardN,GreijnJ.Precipitationofthiopentalwithmusclerelaxants:apotentialhazard.JRSMShortReports.
2011;2(7):58.
Lastupdated2019-07-18
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AlterationstoDrugResponseDefinetachyphylaxis,tolerance,addiction,dependenceandidiosyncrasy
Therearefourmechanismswhichresultinvariableresponsetodrug:
AlterationindrugthatreachesthereceptorThisistypicallyduetopharmacokineticfactors.RelativedifferenceinpresenceofexogenousandendogenousligandsAntagonistswillhaveagreatereffectinthepresenceofhighendogenousligandconcentration.VariationinreceptorfunctionandnumberUp-regulationanddown-regulationofreceptorsmayoccurasaconsequenceofprolongedstimulus.Alterationinfunctiondistaltothereceptor
KeyTermsTachyphylaxisistherapiddecreaseinresponsetorepeateddosingoverashorttimeperiod,usuallyduetodepletionoftransmitter
Desensitisationisthelossinresponseoveralongtimeperiod,usuallyduetochangeinreceptormorphologyorlossinreceptornumbers
Withdrawalisapathologicalresponsewhenadrugisceased
Duringadministrationreceptorsmaybe:Up-regulatedinthecontinuedpresenceofanantagonistDown-regulatedinthecontinuedpresenceofanagonist
LossofreceptornumbersmayprecipitatewithdrawalwhentheagonistorantagonistisceasedAddictionisabehaviouralpatterncharacterisedbycompulsiveuseandfixationonacquiringandusingadrug
IdiosyncrasyisanindividualpatientresponsetoadrugTypicallymediatedbyareactivemetaboliteratherthanthedrugitself.
Tolerance
Toleranceistherequirementforalargerdosetoachievethesameeffect,duetoalteredsensitivityofthereceptorstothestimulant.Mechanismscanbeclassifiedinto:
PharmacokineticAltereddrugmetabolismMetabolismmaybeincreasedordecreased:
EnzymaticinductionandincreaseddrugmetabolismIncreasedhepaticenzymepathwaycapacityincreasesmetabolismandlowersplasmaconcentration.DecreasedmetabolismDecreasedmetabolismofaprodrugcanresultinareducedeffect.
PharmacodynamicChangeinreceptormorphologyCanoccurwithion-channelreceptorsandGPCRs:
Ion-channelreceptorsbindtheligandbutdonotopenthechannelGPCRbecome'uncoupled'-phosphorylationofthereceptormakesitunabletoactivatesecondmessengercascade,thoughitcanstillbindtheligand.
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Receptordown-regulationProlongedexposuretoagonistscausestransmembrane(typicallyhormone)receptorstobecomeinternalised.Thisoccursmoreslowlythanuncoupling.Receptorup-regulationProlongedexposuretoantagonistscausesanup-regulationofreceptor.
Canleadtoreboundeffectswhenadrugisceased(e.g.hypertensionwithcessationofclonidine)ExhaustionofmediatorsSimilartotachyphylaxis-depletionofamediatingsubstancedecreasestheeffect.PhysiologicaladaptationActionsofadrugmaybecounteredbyacompensatoryhomeostaticresponse.Activeremovalofthedrugfromthecell
AlterationsinDrugResponse:PatientFactors
Pharmacokineticsandpharmacodynamicsareaffectedinpregnancyandatextremesofage.
Pregnancy
AbsorptionDecreasedgastricemptyingNauseaandvomitingIncreasedcardiacoutput
IncreasesIMandSCabsorptionVolatiles:
IncreasedonsetduetoincreasedMVandreducedFRCDecreasedonsetduetoincreasedCO
DistributionIncreasedV dueto:
IncreasedTBWIncreasedplasmavolumeIncreasedfatmass
Decreasedalbuminandα -glycoprotein
MetabolismNochangetoHBFProgesteroneinducesenzymesOestrogencompetesforenzymesDecreasedplasmacholinesteraseactivity
EliminationIncreasedRBFIncreasedGFR
PharmacodynamicDecreasedMACIncreasedLAsensitivityduetodecreasedα -glycoprotein
Foetus
Drugsthatcrosstheplacentacanbeteratogenictothefoetus,besidesexertingtheirusualpharmacologicaleffects.
Pharmacokineticfactorspredominantlyaffectplacentaltransfer,andinclude:
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LipidsolubilityLipidsolubledrugsdiffusemorerapidly.MolecularsizeDrugswithamolecularweight>1000daltoncrosstheplacentaslowly.ProteinbindingPlacentaltransportersSomemedicationsareactivelyremovedfromfoetalcirculation.PlacentalmetabolismTheplacentacanmetabolisesomemedications,althoughinsomecasesresultsintoxicmetabolites.
Maternalpharmacodynamicfactorspredominantlyaffecttheuterusandbreast,butmajororgansystemsarenotsignificantlyaffected.
Drugsthatcrosstheplacentacanhavedramaticeffectsinthefoetus.Theseinclude:
TeratogenesisAdrugwhichadverselyaffectsfoetaldevelopmentcausingapermanentabnormality.Multifactorialmechanismsthatarenotwellunderstood.
Neonates
At<1yearofage,pharmacokineticsaresignificantlyaltered:
AbsorptionDelayedgastricemptying,increasingabsorptionofdrugsmetabolisedinthestomachDecreasedsecretionofpancreaticenzymesandbilesaltsimpairsabsorptionoflipidsolublemedicationsSmallermusclemassandhigherrelativemusclebloodflowincreasesIMonsetIncreasedV :FRCratioincreasesonsetofvolatiles
DistributionTBWis70-75%(comparedto50-60%foranadult),andextracellularwateris40%(comparedto20%),whichtypicallyincreasesVPreterminfantshavereducedbodyfatGreaterproportionofcardiacoutputgoestohead,increasingonsetofcentrallyacting(e.g.anaesthetic)drugsDecreasedalbuminandα -glycoproteinImmatureBBBincreasesuptakeofpartiallyioniseddrugs
MetabolismEnzymaticcapacityofallpathwaysisreduced,whichprolongseliminationhalf-livesandreducesclearance.
HepaticallymetaboliseddrugsmustbedoseadjustedaccordinglyTheglucuronidepathwaymaynotmatureuntilage4
ExcretionGFRisproportionallyloweranddosenotreachadultequivalenceuntil6-12months
GFRisfurtherreducedinpre-terminfantsGFRisincreasedin1-3yearolds
PharmacodynamicSmallerAChreservesincreasesensitivitytoNMBsIncreasedMACbutmorerapidonsetNSAIDscauseclosuresofductusarteriosus
Geriatric
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Thoughthereisalineardecreaseinfunctionalcapacityofmajorsystemsbeginningat45,alterationsarepredominantlyaconsequenceofpolypharmacyanddruginteractions.
AbsorptionLaxativesandprokineticincreasegastricemptyingandreduceabsorptionoforalagents
DistributionThereisaproportionalincreaseinfatThereisaproportionaldecreasein:
LeanbodymassTotalbodywaterAlbumin
Metabolism↓Hepaticbloodflow↓EnzymaticactivityPhaseI>PhaseII.
EliminationLossofnephronnumberwithagereducesrenalclearance
PharmacodynamicIncreasedsensitivitytosedatives,opioids,andhypnoticsDecreasedsensitivitytoβ-agonistsandantagonistsDecreasedMACPolypharmacyincreasespotentialfordruginteractions
AlterationsinDrugResponse:DiseaseFactors
CardiacDisease
AbsorptionDecreasedcardiacoutputdecreasesPOabsorptionduetodecreasedgradient
DistributionDecreasedCOprolongsarm-braincirculationtimeIncreasedα -glycoproteinincreasingbindingofbasicdrugsDecreasedV
MetabolismLow-cardiacoutputstatesreducehepaticflowandwillreducemetabolismofdrugswithahighextractionratioHigh-outputstateshavetheoppositeeffect
EliminationDecreasedrenalbloodflow
HepaticDisease
AbsorptionPorto-cavalshuntingDecreasedfirstpassmetabolism.
DistributionImpairedsyntheticfunctionreducesplasmaproteinsandincreasesunboundfractionIncreasedV duetofluidretention
1D
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Metabolicacidosischangesionisedfraction
MetabolismImpairedphaseIandIIreactionsReducedplasmaesteraselevels
EliminationReducedbiliaryexcretion
PharmacodynamicsHepaticencephalopathyincreasessensitivitytosedativesandhypnotics
RenalDisease
AbsorptionUraemiaprolongsgastricemptying
DistributionIncreasedV duetofluidretentionMetabolicacidosisadjustsionisedfraction
MetabolismBuildupoftoxicmetabolitesmayinhibitdrugtransportersUraemictoxinsinhibitenzymesanddrugtransporters
EliminationReducedclearanceofactivemetabolites/activedrugclearedrenally
Obesity
Absorption:DelayedgastricemptyingDecreasedsubcutaneousbloodflowPracticaldifficultywithIMadministration
Distribution:IncreasedV oflipidsolubledrugs
Dosingoflipid-solubledrugsbyactualbodyweightDosingofwater-solubledrugsbyleanbodyweight
IncreasedCOIncreasedα -glycoproteinIncreasedbloodvolumeGreaterlipidbindingtoplasmaproteins,increasingfreedrugfractions
Metabolism:IncreasedplasmaandtissueesteraselevelsNormalorincreasedhepaticenzymes
EliminationIncreasedrenalclearanceduetoincreasedCO
Non-SpecificAlterationstoDrugResponse
Absorption:
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Drugsgivencentrallywillactfasterthanthosegivenintoperipheralveins.RateofadministrationFasterrateofadministrationwillincreaserateofonset.
Pharmacodynamic
DrugtoleranceIncreaserequirementofdrug.e.g.inductionanaestheticagentsinpatientstoleranttoCNSdepressants.
DruginteractionMaybe:SynergisticAdditiveAntagonistic
References
1. AndersonC.VariabilityinDrugResponse1.ICUPrimaryPrep.2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.SixthEdition.ChurchillLivingstone.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. CICMExaminerReport:Sep/Nov20125. AlfredAnaestheticDepartmentPrimaryExamTutorialSeries
Lastupdated2019-07-18
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PharmacogeneticsOutlinegeneticvariability.
Explainthemechanismsandsignificanceofpharmacogeneticdisorders(egmalignanthyperpyrexia,porphyria,atypicalcholinesteraseanddisturbanceofcytochromefunction).
Geneticpolymorphismoccurswhenseveralfunctionallydistinctgenesexistwithinapopulation.Geneticpolymorphismis:
CommonImportantindetermininganindividualssusceptibilitytoadversedrugreactionsAgoalofpersonalisedmedicineAimstoadjustdrugtherapiesforinterpatientvariability.
Pharmacogeneticdisorders
Pseudocholinesterase
Aconditionwhereplasmacholinesteraseisunabletobreakdownsuxamethonium,prolongingitsdurationofaction.Thisdisease:
MaybecongenitaloracquiredCongenitalisautosomalrecessiveHasfouralleles
UsualAtypical(dibucaine-resistant)Silent(absent)Fluoride-resistance
AcquiredisduetoalossofplasmacholinesterasePregnancyOrganfailure
HepaticRenalCardiac
MalnutritionHyperthyroidismBurnsMalignancyDrugs
OCPKetamineLignocaineandesterlocalanaestheticsMetoclopramideLithium
HasbeentraditionallymeasuredusingthedibucainenumberDibucaineis:
AnamidelocalanaestheticwhichinhibitsplasmacholinesteraseDifferentformsareinhibitedtodifferentextents,withgreaterinhibitionindicatingalessseveremutation.
Percentageinhibitioncorrelateswithdifferentgenotypes,e.g.:Normal(Eu:Eu)hasadibucainenumberof80(80%inhibited)
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Dibucaineresistant(Ea:Ea)hasadibucainenumberof20(20%inhibited)Notethatacquireddiseasewillhaveanormaldibucainenumber,astheenzymeitselfisworkingcorrectly,howeverdoesnotexistinalargeenoughquantitytometabolisesuxamethoniumrapidly
G6PD
Acommonx-linkedrecessiveconditionthatmaycausehaemolysisfollowingadministrationofoxidativedrugs.Theseinclude:
AspirinSulfonamidesSomeantibiotics
MalignantHyperthermia
Autosomaldominantdeficiencyintheskeletalmuscleryanodinereceptorgeneresultinginadefectofintracellularcalciumregulation.Thismutation:
Causesmassivecalciumreleasefromsarcoplasmicreticuluminthepresenceofvolatileanaestheticagents(andpotentiallysuxamethonium)Leadsto:
IncreasedmuscleactivityRapidincreaseinbodytemperatureandlacticacidosisHighmortalityfromhyperthermia,hyperkalaemia/rhabdomyolysis,leadingtoventriculararrhythmiaandcardiacarrest
Mutationpresentin1:5,000-1:50,000Presentswith:
Initially:TachycardiaMasseterspasmHypercapneaArrhythmia
Intermediate:HyperthermiaSweatingCombinedmetabolicandrespiratoryacidosisHyperkalaemiaMusclerigidity
Late:Rhabdomyolysis
MyoglobinuriaElevatedCK
CoagulopathyCardiacarrest
Managementconsistsof:Ceaseadministrationofvolatile
StartTIVAGivedantrolene
2.5mg.kg incrementsupto10mg.kg20mgvialsreconstitutedwith60mlsterilewater
3gmannitolasadditiveHighlyalkaline
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Damagingifextravasationoccurs.Treatcomplications:
HyperkalaemiaHyperthermiaAcidosisArrhythmiasRenalfailure
Porphyria
Autosomaldominantdeficiencyinthefirststepofhaemesynthesis.Thesemutations:
ResultinapartialdeficiencyofenzymesLeadtoaccumulationofporphyrinprecursorsMaybeprecipitatedbymanydrugs:
KetamineClonidineKetorolacDiclofenacPhenytoinErythromycinBarbiturates
References
1. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.SixthEdition.ChurchillLivingstone.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2019-07-18
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DrugsinPregnancyTheTherapeuticGoodsAdministrationclassifiesdrugsforsuitabilityinpregnancybasedonthepotentialofadrugtocause:
BirthdefectsDetrimentaleffectsatbirthProblemsinlaterlife
Theclassificationsystemis:
ValidonlyforthedoseandrouteofadministrationlistedDoesnotapplyinoverdose
Nothierarchical'B'drugsarenotsaferthan'C'drugs
Categories
CategoryATakenbylargenumberofwomenwithoutdetrimentaleffects.
CategoryBSubclassifiedinto:
CategoryB1TakenbyalimitednumberofwomenwithoutdetrimentaleffectAnimalstudiesshownoevidenceofdetrimentaleffecttothefoetus
CategoryB2TakenbyalimitednumberofwomenwithoutdetrimentaleffectAnimalstudiesareinadequateorlacking,butavailabledatashowsnoevidenceofdetrimentaleffecttothefoetus
CategoryB3TakenbyalimitednumberofwomenwithoutdetrimentaleffectAnimalstudiesshowevidenceoffoetaldamage,butthesignificanceofthisinhumansisunknown
CategoryCDrugswhichhavecaused(orasuspectedtocause)detrimentalfoetaleffects,butwithoutmalformationsTheseeffectsmaybereversible
CategoryD
Drugswhichhavecaused(oraresuspectedtocause)anincreasedincidenceoffoetalmalformationsordamageMayalsohavedetrimentaleffects
CategoryX
DrugswhichhaveahighriskofcausingpermanentdamageShouldnotbeusedinpregnancy,orwhenpregnancyispossible
References
1. Australiancategorisationsystemforprescribingmedicinesinpregnancy.TherapeuticGoodsAdministration.
Lastupdated2017-09-23
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GeneralManagementofPoisoningUnderstandingofthegeneralprinciplesofpoisoninganditsmanagement.
Principlesofmanagementofpoisoning:
"Recognition-Resus-RSI-DEAD"
RecognitionDegreeofemergencyGettingseniorhelpApplicationof100%oxygenearly
ResuscitationA:ControlinanypatientwithsignificantlyimpairedconsciousstateB:Oxygenifnotpreviouslyapplied.Mechanicalventilationifrequired.C:Intravenousaccessisalwaysrequired.Centralvenousaccessmayberequired.D:Glucoselevel.Controlseizures.E:Controlhypothermia
RiskassessmentHistoryincludingtiming,amount,co-administereddrugs,currentpatientstatus.
SupportivecareInvestigations
ECGInvasivemonitoringmayberequiredifhaemodynamicsareunstable.Druglevels
DecontaminationActivatedcharcoalmaybeappropriateifrecentingestion(<1hour)andtheairwayissecured
EnhancedEliminationUsedinseverepoisoningwhensupportivecareislikelytobeinadequate.Includes:
UrinaryalkalinisationFiltration
AntidotesE.g.naloxoneforopiates
Disposition
FootnotesLITFLhasafantasticsectionontheapproachtothepoisonedpatientifyouwantmoreinformation.
References1. Nickson,C.ApproachtotheAcutePoisoning.LITFL.2. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.
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TricyclicAntidepressantOverdoseTricyclicantidepressantsareweakbasestypicallyusedfordepressionandasanadjunctforanalgesia.Theyhaveacomplexmechanismofaction,competitivelyinhibitingnoradrenalineandserotoninreuptake,andalsoblockingmuscarinicreceptors,histaminergicreceptors,α-adrenoreceptors,GABA-areceptors,andfastsodiumchannels.
Toxicity
Inoverdose,toxicityispredominantlyduetocardiacandcentraleffects,thoughthereareeffectsonmostofthemajororgansystems.
Cardiactoxicity
Cardiactoxicityisduetoantagonismofα-adrenoreceptorsuse-dependentblockadeoffastsodiumchannels.
α-antagonismresultsinvasodilatationandsubsequenthypotension.Hypotensionmayalsobeduetomyocardialdepressionfromsodiumchannelblockade.
BlockadeoffastsodiumchannelsoccursintheHis-Purkinjesystem,aswellastheatrialandventricularmyocardium.Thisresultsindecreasedmyocardialimpulseconduction.Theyblockchannelsintheinactivatedstate,resultinginause-dependentblockadesuchthattheeffectisgreateratfasterheartrates.Thisresultsinanincreaseddepolarisationandrepolarisationtime.ECGfindingsareconsistentwiththisandareessentiallypathognomonic:
WidenedQRSRightaxisdeviationoftheterminalQRS⩾3mmterminalRwaveinaVR.
AdditionalECGfindingsinclude:
TachycardiaAnydegreeofheartblockVentriculararrhythmias
Centraltoxicity
Centraltoxicityispredominantlyduetoanticholinergiceffects,thoughantihistaminiceffectscontribute.
Anti-cholinergiceffectstendtooccurpriortocardiaceffects,andinclude:
ConfusionAgitationSeizuresPupillarydilatationandblurredvision
Antihistaminiceffectsincludeobtundation.
Management
Standardmanagementofpoisoningapplies.TCAsarenotdialysableandastheyareweakbasesarenotamenabletourinaryalkalinisation.
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Cardiactoxicity
NaHCO andhyperventilationtoapH>7.5isusedtomanagecardiactoxicity.Thereareanumberofproposedmechanismsofactionforthebenefitofalkalinisation:
PlasmaalkalosisresultsinlessioniseddrugandincreasesdistributionintotissuesPlasmaalkalosisincreasesproteinbindingofdrugIntracellularalkalosisresultsinlessboundintracellulardrug,favouringitsmovementoutofcellsExtracellularalkalosisresultsinreducedH /K exchange,increasingintracellularpotassiumandhypopolarisingthecell.
Inadditiontothealkalinisingeffects,sodiumloadfromtheNaHCO improvesthesodiumconcentrationgradientintocells
α-adrenoreceptorantagonismcanbecounteredwithuseofanα-agonistsuchasnoradrenaline.
Arrhythmiasshouldbemanagedwithdrugsthatdonotprolongtheactionpotential-soamiodaroneandbeta-blockersarecontraindicated.InitialmanagementshouldbeusingNaHCO ,thoughMgSO andlignocainecanbeconsideredinrefractorycases.
Centraltoxicity
Seizuresshouldbemanagedwithbenzodiazepines,phenytoin,propofol,andphenobarbital.AvoidagentswhichresultinQRSprolongation.
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.3. CICMJuly/September20074. SalhanickSD,TraubSJ,GrayzelJ.TricyclicAntidepressantPoisoning.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,
MA,2017.5. Nickson,C.ToxicologyConundrum22.LITFL.6. Nickson,C.TricyclicAntidepressantToxicity.LITFL.7. UpToDate.Tricyclicantidepressantpoisoning
Lastupdated2019-07-20
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OrganophosphatePoisoningOrganophosphatesaresubstancesbindirreversiblytoacetylcholinesterase,causingcholinergicexcess.Examplesincludefertilisersandsaringas.
Toxicity
Effects(asexpected)aresignsofmuscarinicandnicotinicover-activation.Thiscanberememberedby'BLUDGES'forthemuscariniceffects:
Bradycardia(andsubsequenthypotension)LacrimationUrinationDefecationGITupsetEmesisSweatingandSalivation
and'M'forthenicotiniceffects:
Muscularspasm
Management
ManagementisaimedatreducingAChburden:
AtropineCompetitiveantagonisesAChatthemuscarinicreceptor.
AtropineispreferredoverglycopyrrolateasitwillcrossthebloodbrainbarrierandtreatcentralAChtoxicityPralidoximeReactivatesacetylcholinesterasebyluringtheorganophosphateawayfromtheenzymewithatantalisingoximegroup.
PralidoximemustbeusedwithinthefirstfewhoursofpoisoningAfterwhichtheorganophosphate-enzymegroup'ages'andisnolongersusceptible.Doesnotcrosstheblood-brainbarrierandsocannottreatcentraleffects
References
1. CICMMarch/May20092. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.
Lastupdated2019-07-18
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TheCellMembraneDescribethecellmembraneandcellularorganellesandtheirproperties.
Cellmembranesare:
FormedbyaphospholipidbilayerSeparatestheintracellularandextracellularfluid.Semi-permeableLeadstodifferentionicconcentrations(andthereforeelectricalcharge)oneithersideofthemembrane.
Alterationinchargemeansthemembraneactsasacapacitor,withmostcellshavingarestingpotential70-80mVlowerthanextracellularfluid
IonPermeabilityAtrest,thecellis:
PermeabletopotassiumPotassiumflowsoutdownitsconcentrationgradientThismakestherestingpotentialbecomesmorenegative.
Thisnegativechargeopposesthefurthermovementofpotassiumandsoanequilibriumisestablishedbetweenopposingelectricalandchemicalgradients
ImpermeabletoothercationsThemembraneisnotperfectlyimpermeabletosodium,andNa willleakindownitsconcentrationgradient.
The3Na -2K ATPasepumpsthreesodiumionsoutsideinexchangefortwopotassiumionsinordertomaintainthesegradientsAsthereisanunequalexchangeofcharge,thispumpiselectrogenic.
Ion [Intracellular] [Extracellular]
Na 15 140
K 150 4.5
Cl 10 100
References
1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2018-06-25
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OrganellesDescribethecellmembraneandcellularorganellesandtheirproperties
Organellesarespecialisedfunctionalsubunitswithinacell,typicallycontainedwithintheirownlipidbilayer.
Keyorganellesinclude:
MitochondriaEndoplasmicreticulumGolgiapparatus
Mitochondria
Mitochondria:
ProduceATPviaaerobicmetabolismOnlymethodofaerobicmetabolisminthebody.
MitochondriaexistingreaternumbersinmoremetabolicallyactivecellsConsistoftwomembranes(outerandinner),whichcreatethreespaces,
CytoplasmOutsidetheoutermembrane.IntermembranespaceBetweenthemembranes.
Outermembraneseparatesmitochondriafromcytoplasm,butcontainsporesallowingsomesubstances(pyruvate,aminoacids,fattyacids)topassInnermembrane:
Isolatestheelectrontransportchainfromtheintermembrane(spacebetweeninnerandoutermembranes)space.ProteinsontheinnermembraneconducttheredoxreactionsimportantforATPproductionElectrontransportchainpumpshydrogenionsintotheintermembranespace
InnermitochondrialmatrixContentsimportantinmanymetabolicprocesses:
CitricacidcycleFattyacidmetabolismUreacycleHaemesynthesis
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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ExcitableCellsExplainthebasicelectro-physiologyofneuraltissue,includingconductionofnerveimpulsesandsynapticfunction.
MembranePotential
Atrest,membranesare:
PermeabletopotassiumImpermeabletoothercations
Generationofmembranepotential:
IntracellularpotassiumconcentrationismuchhigherthanextracellularpotassiumconcentrationDuetotheactionoftheNa -K pump.Asthemembraneispermeabletopotassium,potassiumwillattempttodiffusedownthisgradient,generatinganegativeintracellularchargewhichopposesfurtherdiffusionAtsomepoint,anelectrochemicalequilibriumisreachedbetween:
TheconcentrationgradientdraggingpotassiumoutofthecellNegativeelectricalchargepullingitin
ThisequilibriumistherestingmembranepotentialRMPisdeterminedby:
PermeabilityofthemembranetodifferentionsRelativeionicconcentrationsoneithersideofthemembrane
ImpermeableionsdonotcontributetotherestingmembranepotentialAlteringmembranepermeabilitycausesaflowofionsandachangeinvoltage.
NernstEquation
ThepotentialdifferencegeneratedbyapermeableioninelectrochemicalequilibriumwhentherearedifferentconcentrationsoneithersideofthecellcanbecalculatedviatheNernstEquation:
,where:
istheequilibriumpotentialfortheion
isthegasconstant(8.314J.deg .mol )
isthetemperatureinKelvin
isFaraday'sConstantistheionicvalency(e.g.+2forMg ,-1forCl )
Goldman-Hodgkin-KatzEquation
TheNernstequationdescribestheequilibriumpotentialforasingleion,andassumesthatthemembraneiscompletelypermeabletothation.
However,calculationofmembranepotentialrequiresexaminingtheeffectsofmanydifferentionswithdifferentpermeability.ThiscanbeperformedwiththeGoldman-Hodgkin-Katzequation:
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,where:
isthepermeabilityconstantfortheion,
Ifthemembraneisimpermeableto ,then .
Notethat:
ThismodeldoesnotconsidervalencyTheconcentrationsofnegativeionsarereversedrelativetopositiveions
ActionPotential
Excitablecellscanrespondtoastimulusbyachangingtheirmembranepotential.Thismaybemediated:
Chemicallye.g.AChreceptorscausingNa channelstoopen.PhysicallyPressurereceptorsphysicallydeformingandopeningNa channels.
StimulatinganexcitablecellincreasesNa permeabilityThisincreases(i.e.makeslessnegative)membranepotentialIfseveralstimuli,oralargeenoughstimuliraisesthemembranepotentialabovethethresholdpotential,thenanactionpotentialwillbegeneratedThisisduetofastNa channels
Alsoknownasvoltage-gatedNa channelsOpenwhenmembranepotentialexceedsthresholdpotentialThresholdpotentialistypically-55mV.Fastsodiumchannelsgeneratetheall-or-nothingresponse:
StimulibelowthethresholdpotentialdonotgenerateanactionpotentialStimuliabovethresholdpotentialgenerateanactionpotentialThesizeofthestimulusdoesnotaffectthemagnitudeoftheactionpotential,asthisisdeterminedbythefastsodiumchannels.
KeyPlayersintheActionPotential
FastNa channelsareresponsiblefordepolarisation.Theyexistinthreestates:
ClosedImpermeabletoNa .OpenPermeabletoNa .Occurswhenthemembranepotentialreachesthresholdpotential.
Differentvoltage-gatedchannelsmayhaveslightlydifferentopening(threshold)potentialsInactivatedImpermeabletoNa .Occursshortlyaftertheopenstate,andlastsuntilthemembranepotentialfallsbelow-50mV.
Voltage-gatedK channels:
ArevitalforrepolarisationOpenslowlywithdepolarisationThisincreasespotassiumpermeabilityandreducesmembranepotential.
PhasesoftheActionPotential
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Thisdescribestheperipheralnerveactionpotential.Theheartiscoveredunderthecardiacactionpotential.
1. RisingPhaseAstimuluswhichrisesabovethethresholdpotentialopensfastNa channels,increasingNa influx.
AdditionalNa hasapositivefeedbackeffect,causingadditionalNa channelstoopenandfurtherdepolarisationThisdrivesthemembranepotentialtowardstheNernstequilibriumforNa
2. PeakPhaseInactivationoffast-channelsanddelayedactivationofK channelsslowsdepolarisation.
Membranepotentialpeaksat30mV3. FallingPhase
Aspotassiumexitsthecell,membranepotentialcontinuestofall.Voltage-gatedK channelsstarttocloseat-50mVInactivationoffastsodiumchannelsdefinestheabsoluterefractoryperiodNoNa canbeconducted,regardlessoftheintensityofthestimulus,andsoanactionpotentialcannotbegenerated
Theabsoluterefractoryperiodlasts~1ms4. Hyperpolarisation
Aspotassiumchannelscloseslowly,themembranepotentialslightlyundershootsrestingpotential,causingslighthyperpolarisationofthecell.
ThisistherelativerefractoryperiodAlargeenoughstimulusmayovercometheadditionalhyperpolarisationandgenerateasecondactionpotential.
Therelativerefractoryperiodlasts10-15ms5. Resting
Cellisstableatrestingmembranepotential.
PropagationoftheActionPotential
AnincreaseinNa inoneregionwilldiffusedownthecell,raisingthemembranepotentialabovetherestingpotentialintheadjacentmembraneThiscauseslocalfastNa channelstoopen,andthecelldepolarisesThisresultsinapropagatingwaveofdepolarisationandrepolarisation
RegionsofanervecellcoveredbyamyelinsheathdonothaveionchannelsInthesecells,propagationissaltatoryThisdescribesthe"jumping"oftheactionpotentialbetweengapsinthemyelinsheath.
ThesegapsareknownasnodesofRanvierIonchannelsgenerateanactionpotentialatthenodesintheusualmanner.Betweennodes,conductionisvialocalelectricalcurrents
Myelination:IncreasesconductingvelocityReducesenergyexpenditureViareductionintotalionflux.
ClassificationofNerveFibres
Classifiedontheirdiameterandconductionvelocity:
TypeAMyelinated,12-20μmindiameter,conductat70-120m.s .Subdividedinto:
AαMotorfibres.AβTouchfibres.
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AγIntrafusal(proprioceptive)musclefibre.AδPainfibres.
TypeBMyelinated,<3μm,conductat4-30m.s .Innervatepre-ganglionicneurons.TypeCUnmyelinated,1μm,conductat0.5-2m.s .Painfibres.
References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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TransportAcrossCellMembranesExplainmechanismsoftransportofsubstancesacrosscellmembranes,includinganunderstandingoftheGibbs-Donnaneffect.
Substancescancrosscellmembranesbydiffusion,activetransport,andexo-orendocytosis.
Diffusion
Thereareseveraltypesofdiffusion:
SimplediffusionMoleculespassthroughthecellmembraneorviaachannel.Thisprocessispassive,andoccursdownaconcentrationgradient.
Onlylipidsolublemolecules(gases,steroids)canpassdirectlythroughthelipidbilayerwithoutaspecialisedchannelVoltage-gatedandligand-gatedchannelsfacilitatesimplediffusion
Facilitateddiffusion(uniporters)Moleculesbindtoacarrierprotein,andmovetogetherthroughthelipidbilayer,beforeseparatingontheotherside.Facilitateddiffusionisconcentrationgradient-dependent,andlimitedbytheamountofcarrierproteinavailable..
Therateandextentofdiffusionisaffectedby:
HydrostaticpressuregradientsConcentrationgradientsElectricalgradients
ActiveTransport
Substancesthataremovedagainstaconcentrationgradientrequireactivetransport,andrequiresenergyintheformofATP.Activetransportmechanismsmaybe:
PrimaryactivetransportThesubstanceitselfismoved.SecondaryactivetransportThesubstancemovesagainstaconcentrationgradientwithanothermoleculethathadagradientestablishedbyactivetransport.
Thismoleculeistypicallysodium
Co-transporters(symporters)Usescarrierproteinsandmovestwosubstances(e.g.sodiumandanaminoacid)acrossamembrane.
Thisprocesswillbepassiveiftheenergygainedmovingonesubstancedownitsconcentrationgradientisgreaterthantheenergyrequiredtomovetheothersubstanceupitsconcentrationgradient
Counter-transporters(antiporters)Usecarrierproteinsandmovestwosubstancesinoppositedirectionsacrossthemembrane.
Maybeactiveorpassive
Keytransportersinclude:
TheNa -K ATP-asepumpThismovesthreesodiumionsoutofacellandtwopotassiumionsin,cleavingoneATPintheprocess.Thispumphasmanyfunctions:
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Maintenanceofcellularvolume(whichwouldotherwiseburstfromtheinfluxofwaterwithchangingECFtonicities)bynetlossofosmolesMaintenanceofthepotentialdifferenceacrossthemembraneEstablishmentofchemicalgradientstobeusedinsecondaryactivetransportmechanism
e.g.ReabsorptionofglucoseinthekidneyviatheS-GLUTtransporter
Exo-andEndocytosis
Theseprocessesdescribetheformationofavesicle(typicallyfrommembranephospholipid)totransportsubstances:
ExocytosisVesiclecontainingasubstancetobesecretedfuseswiththecellmembranewhenactivatedbycalcium,depositingthesubstanceoutsidethecell.
EndocytosisThecellmembraneinvaginatesaroundthesubstance,absorbingthesubstanceintothecell.Avesicle(orvacuole)mayormaynotbecreated.Endocytosismaybesubdividedinto:
Phagocytosis,whereleukocytesengulfbacteriaintoavacuolePinocytosis,wheresubstancesareendocytosedbutnotintoavacuole
Gibbs-DonnanEffectDescribesthetendencyofdiffusableionstodistributethemselvessuchthattheratiosoftheconcentrationsareequalwhentheyareinthepresenceofnon-diffusableions.
TheGibbs-DonnanEffect:
Occurswhen:Asemi-permeablemembraneseparatestwosolutionsAtleastoneofthosesolutionscontainsanon-diffusableion
Thedistributionofpermeablechargedionswillbeinfluencedbyboththeirvalenceandthedistributionofnon-diffusableions,suchthatatequilibriumtheproductsoftheconcentrationsofpairedionsoneachsideofthemembranewillbeequal:
Alterstonicityoneithersideofthecellmembrane,causingmovementofwaterwhichthenupsetstheGibbs-DonnaneffectThisresultsinno'steady'stablestate.
ThetwomaincontributorstotheGibbs-Donnaneffectinthebodyaresodiumandprotein.Thisoccursbecausecellmembranes:
AreimpermeabletoproteinIntracellularproteinconcentrationishigh.EffectivelyimpermeabletosodiumDuetotheNa -K ATP-asepump.
ChangingGibbs-Donnanequilibriumsalsochangethetonicityoneachsideofthecellmembrane,causingmovementofwaterwhichthenupsetstheGibbs-Donnaneffect-thereforethereisnostablestate.
TheGibbs-DonnanEffectisimportantfor:
MaintenanceofcellvolumeNa actsasaneffectiveosmole,reducingcellularswelling.PlasmaoncoticpressureIncreasedplasmaionconcentrationincreasesoncoticpressure.
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RestingMembranePotential
References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. EatonDC,PoolerJP.Vander'sRenalPhysiology.6thEd(Revised).McGraw-HillEducation-Europe.2004.
Lastupdated2018-09-21
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FluidCompartmentsTodescribethecompositionandcontrolofintracellularfluid~andthemechanismsbywhichcellsmaintaintheirhomeostasisandintegrity~
Onaverage,thehumanbodyis~60%water.Distributionofwatercontentcanbedividedconceptuallyinto:
IntracellularfluidComposes2/3 oftotalbodywater.ICFis:
NotacontiguousfluidspaceUsefulasthecompositionofcellularcontentsisrelativelyuniform:
PotassiumisthedominantintracellularcationSodiumconcentrationsarelow.ThedominantanionisproteinChlorideconcentrationisrelativelylow.Lowinmagnesium
ExtracellularfluidComposestheremaining1/3 oftotalbodywater,andisfurtherdividedinto:
IntravascularfluidComposes~20%ofECF.Thisreferssolelytoplasmavolume(asthevolumeofbloodfromcellularcomponentsisICF).TheICFis:
Vitalfortransportingnutrients,waste,andchemicalmessengersbetweentheplasmaandcellsTranscellularfluidComposes~7%ofECF,anddescribesthevolumeofCSF,urine,synovialfluid,gastricsecretions,andaqueoushumor.InterstitialfluidComposesthebulkofECFvolume,anddescribesthefluidthatoccupiesthevolumebetweencells.
VariationsActualtotalbodywatercontentvariespredominantlywithfatcontent.Thisleadstodifferencesconcentrationsin:
Neonates~75-80%.Elderly~50%bytheageof60,duetoincreasedadiposity.WomenTypically~55%.
MeasuringVolumesofFluidCompartments
Allmethodsrelyontheindicator-dilutionmethod:
Aknownamount(i.e.knownvolumeofaknownconcentration)ofindicatorwithaffinitytoaparticularcompartmentisgivenandallowedtoequilibrateTheconcentrationoftheindicatoristhenmeasuredThedifferencebetweenthemeasuredconcentrationandtheinitialconcentrationisproportionaltothevolumeofthecompartment
Indicatorsusedforcalculationof:
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PlasmavolumeAcolloidthatwillberetainedinthevascularcompartment;e.g.radio-labeledalbumin.ECFvolumeAsubstancewhichcanentertheinterstitiumbutnotcells;e.g.thiosulfate.Totalbodywater
Asubstancewhichcanenterallcompartmentsfreely;e.g.heavywater( ).ICFvolumeCanbemeasuredbythedifferencebetweencalculatedECFvolumeandTVW.
References1. Brandis,K.FluidCompartments.AnaesthesiaMCQ.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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CellHomeostasisTodescribethe~compositionandcontrolofintracellularfluidandthe~mechanismsbywhichcellsmaintaintheirhomeostasisandintegrity
CellularrespirationdescribestheproductionofATPthroughaseriesofredoxreactions.Oxygenisusedastheoxidisingagent,whilstthecatabolicfuelmaybeglucose,fat,orprotein.
Cellularrespirationcanbebrokendowninto:
Glycolysis/Lipolysis/ProteolysisCitricAcidCycleElectronTransportChain
Glycolysis
Glycolysis,ortheEmbden-Meyerhofpathway,describestheproductionofpyruvatefromglucose.Glycolysis:
OccursinthecytoplasmBeginswiththephosphorylationofglucosetoglucose-6-phosphateProduces:
2ATP2Pyruvate2NADH
NotethatoxygenisnotconsumedandcarbondioxideisnotproducedInaerobicconditions:NADHexchangeselectronsacrossthemitochondrialwall,regeneratingNAD andallowingglycolysistocontinueInanaerobicconditions:NAD isregeneratedthroughtheproductionoflactate
Whenaerobicconditionsarerestored,lactatecanbeoxidisedbacktopyruvateandentertheCACTransportedtotheliverandconvertedbacktopyruvate(andentertheCAC),orproduceglucose(Coricycle)
CitricAcidCycle/Kreb'sCycle
TakesplaceinthemitochondriaComplicatedCantakemanyvarioussubstrates:
AcetylCoAProducedbyβ-oxidationoffattyacidsandpyruvate.PyruvateKetoacids
Doesnotconsumeoxygenbutalsodoesn'tfunctionunderanaerobicconditions,duetoitsrequirementonfreshNADfromtheETCProduces:
NADHFADHCO
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ElectronTransportChain
Finalstageofcarbohydrate,fat,andproteincatabolismETCconsistsoffiveproteincomplexesElectronsarepassedalongthechainandcombinewithoxygen,releasingenergywhichstimulatesthemovementofhydrogenionsEachtimeahydrogenioncrossesthemitochondrialmatrix,anATPisproduced
ThisiscalledcoupledphosphorylationUncoupledphosphorylationallowshydrogenionstotraveldowntheirgradientwithoutgeneratingATP,whichproducesexcessheatinstead
36-38ATPareproducedbyaerobicglycolysisSourcesdisagreeonexactlyhowmuchATPisproduced.
2fromtheEmbden-Meyerhofpathway34-36fromtheCACandETC
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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AirwayandAlveolarAnatomyDescribethefunctionandstructureoftheupper,lowerairwayandalveolus.
UpperAirway
Theupperairwayconsistsofthe:
MouthNasalcavity
HairsfilterlargeparticlesOlfactoryreceptorsdetectharmfulgasespriortoinhalation
PharynxLarynx
Breathingcanbeoralornasal.Nasalbreathingoffers:
Goodhumidificationandfiltrationofinhaledparticlesbecausetheseptumandturbinateshave:HighmucosalsurfaceareaHighmucosalbloodflowGenerateturbulentflow
HighresistancetoflowAtahighminuteventilation,oralbreathingisfavoured.
Structures
PharyngealdilatormusclesIncludinggenioglossusandlevatorpalati.Preventpharyngealcollapseduringnegative-pressureventilationandduringsleep.
LarynxImportantforairwayprotection,speech,andeffortclosure.
PreventsaspirationduringswallowingbyelevatingtheepiglottisandoccludingofthearyepiglotticfoldsPhonationisachievedbyadjustingtension(andthereforeresonance)ofthevocalcordsbyactionofthecricothyroidDuringinspiration,cricoarytenoidmusclesrotatethearytenoidcartilageandabductthevocalcordstoreduceresistancetoairflowDuringexpiration,thethyroarytenoidmusclesadductthecordsandincreaseresistance,providingintrinsicPEEP
3-4cmH OofPEEPisgeneratedMaintainspatencyofsmallairwaysPreventsalveolarcollapseandthereforemaintainsFRC.
Effortclosureistighterocclusionofthelaryngealinlet,inwhichthearyepiglotticmusclescontractstronglytoactasasphincter,allowingtheairwaytowithstandupto120cmH Oofpressure.
LowerAirwayThelowerairwayconsistsofthetracheobronchialtree:
Fromtracheatoalveolus,theairwaysofthelungsdivide23timesThetracheobronchialtreeisdividedintotwozones,basedonwhethertheycontainalveoliandthereforeareabletoparticipateingasexchange:
Theconductingzoneisthefirst16divisions
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Therespiratoryzoneisthelast7divisions
ConductingZone
Thefirst16divisionsconstitutetheconductingzone:
Anatomically,theconductingzoneconsistsof:Trachea
Meandiameterof1.8cmandalengthof11cmD-shapedcrosssectionCurvedcartilagesanteriorlyandlongitudinalmuscle(trachealis)posteriorly.Externalpressureof40cmH Oissufficienttooccludetheextrathoracictrachea.Flowistypicallyturbulentinthetracheaandlargeairways
BronchiComprisethefirstfourdivisionsofthetracheaRightmainbronchusiswideranddeviateslessfromtheaxisofthetrachea(theleftmainbronchushasatighterturnovertheheart),whichiswhyforeignbodieswilltendtotherightsideThetwomainbronchidivideintoatotalof5lobarbronchi,whichinturndivideintoatotalof18segmentalbronchi
Cross-sectionalareaoftherespiratorytractislowestatthethirddivisionThesebronchiwillcollapsewhenintrathoracicpressureexceedsintraluminalpressureby~5cmH O.SegmentalbronchitravelwithbranchesofthepulmonaryarteryandlymphaticsThesearethebronchithatdemonstrateperibronchialcuffingandperihilarhazeinearlypulmonaryoedema.Flowistypicallytransitionalinthesmallerbronchiandbronchioles
BronchiolesEmbeddedinthelungparenchymaDonothavecartilageintheirwallstomaintainpatency-areheldopenbylungvolumeResistancetoflowtendstobenegligibleduetolargecrosssectionalarea,unlessthereisspasmofhelicalmusclebandsinbronchialwall
TerminalbronchiolesFlowmaybecomelaminarinthesmallestbronchiolesasflowdecreases
FlowintheconductingzoneduringinspirationisfastandturbulentNogasexchangeoccursintheconductingzoneThevolumeoftheconductingzonethereforecontributestoanatomicdeadspace.Bloodsupplytotheconductingzoneisviathebronchialcirculation
MucousissecretedbygobletcellsinthebronchialwallstotrapinhaledparticlesCiliainthebronchialwallsmoverhythmicallytodrivethemucociliaryelevator,drivingmucousuptotheepiglottis,whereitisthenswallowedorexpectorated
RespiratoryZone
Theremaining7divisionsmakeuptherespiratoryzone.Thisregion:
MakesupthemajorityoflungvolumeAllnon-anatomicaldeadspacevolumeisintherespiratoryzone,andis~30ml.kg (FRC)atrestBloodsupplyisviathepulmonarycirculation
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Gasflowintheterminalrespiratoryzoneisslowduetotheexponentialincreaseincross-sectionalareawitheachairwaydivision
Diffusionisthepredominantmechanismofgasmovement
Alveolus
Thealveolusisoptimisedforgasexchange:
SphericalshapemaximisessurfaceareatovolumeratioTotalsurfaceareaoflungalveoliis50-100mAlveolarwallsareextremelythin(0.2-0.3μm)Consequently,theyarefragileandcanbedamagedbyincreasesincapillarypressureAlveolarwallscontainadensemeshofcapillaries7to10μmthick,whichisjustlargeenoughforanerythrocytetopassthroughThealveolar-capillarybarrierconsistsofthreelayers:
TypeIpneumocytesExtracellularmatrixPulmonarycapillaryendothelium
Alveoliarecomposedofthreetypesofcells:
TypeIpneumocytesThin-walledepithelialcellsoptimisedforgasexchange.
Form~90%ofthealveolarsurfacearea
TypeIIpneumocytesSpecialisedsecretorycells.
SecretesurfactantAlveoliareinherentlyunstable,andsurfacetensionofalveolarfluidfavourscollapseofthealveoli.Surfactantreducessurfacetension,allowingthealveolitoexpand.Form~10%ofalveolarsurfacearea
AlveolarmacrophagesAlveolihavenocilia-inhaledparticlesarephagocytosedbyalveolarmacrophagesinalveolarseptaandlunginterstitium.
References1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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ChestWallandDiaphragmDescribethestructureofthechestwallanddiaphragmandtorelatethesetorespiratorymechanics.
Thechestwallisformedbytheribsandintercostalmuscles:
RibsSlopeantero-inferiorly,andareconnectedbytheexternal,internal,andinnermostintercostalmuscles.Intercostalmuscles
Externalintercostalsslopeantero-inferiorlyInternalandinnermostintercostalsslopeinfero-posteriorly
DiaphragmComplexdome-shapedmembranousstructure,consistingofacentraltendonandperipheralmuscles
PerformsthemajorityofinspiratoryworkofbreathingAbletodramaticallyincreaseintraabdominalpressure,soisessentialin:
CoughingVomitingSneezing
RoleinmaintainingloweroesophagealsphinctertoneIthasthreeperforations:
T8forthevenacava(eightletters)T10fortheoesophagus(tenletters)T12fortheaorta,thoracicduct,andazygosvein
Inspiration
Duringinspiration,thediaphragmandexternalintercostalmusclescontractDiaphragmpushestheintraabdominalcontentsdown,increasingthoracicvolumeandgeneratinganegativeintrathoracicpressure
DiaphragmissuppliedbythephrenicnervesfromC3/4/5.Externalintercostalspulltheribsantero-superiorly,whichincreasesthecross-sectionalareaofthechest,furtherincreasingthoracicvolume(andnegativepressure)
IntercostalmusclesaresuppliedbyintercostalnervesfromthesamespinallevelParalysisoftheexternalintercostalsdoesnothaveadramaticeffectoninspiratoryfunctionprovidedthediaphragmisintact
Accessorymusclesincludesternocleidomastoidandthescalene,whichelevatethesternumandfirsttworibsrespectively.Theyareactiveinhyperventilation.
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Expiration
ExpirationispassiveduringquietbreathingaselasticrecoilofthelungwillreturnthemtoFRCWhenminuteventilationishigh,expirationbecomesananactiveprocess:
Abdominalwallmuscles(rectusabdominis,internaloblique,externaloblique,transversusabdominis)contract,raisingintraabdominalpressureandforcingthediaphragmupInternalandinnermostintercostalscontract,pullingtheribsdownwardsandinwards,furtherdecreasingthoracicvolume
RespiratoryMechanicsinSpinalInjury
Paralysisoftheabdominalwallmuscles(e.g.spinalinjury)hassignificantaffectonrespiratorymechanics:Intheinitialphasesofinjury,spinalshockresultsinaflaccidparalysisoftheabdominalwall
Intraabdominalpressureislow,andsothediaphragmmovesinferiorlyThisresultsinahigherFRCbutlimitstidalvolumes,ascontractionofthediaphragmonlyincreasethoracicvolumebyasmallfraction.Nursinginasupinepositioncausestheabdominalcontentstopushthediaphragmsuperiorly,causing:
LowerFRCGreaterproportionalexpansionwithrespiration,improvingtidalvolumes
Oncespasticparalysisensues,theabdominalwallisrigidandthepatientcanbesatup
References
1. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.
Lastupdated2019-07-18
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VariationsinUpperAirwayAnatomyUnderstandthedifferencesencounteredintheupperairwayforneonates,childrenandadults.
NeonatesandChildren
Changesaremostobviousbelow1yearofage.Theytypicallyresolveby~8yearsofage.
HeadandneckchangesObligatenosebreathersNasalobstructionmaysignificantlyimpairrespiration.ProportionallyenlargedheadandocciputOptimalintubatingpositionisneutralratherthanramped.ProportionallyshortneckFavoursairwayobstructionwhenflexed.
LaryngealchangesDisproportionatelylargetonguethatcomplicateslaryngoscopyEpiglottisisu-shaped,longer,andstifferLarynxliesatC4(ratherthanC6inadults)NarrowestpartoftheupperairwayisthetransversediameterofthevocalcordsNotatthecricoid.
IntrathoracicchangesIntrathoracictracheaisalsoshorterMaybeonly4cmlong,sothereislittlemarginforerrorintubeplacement.Leftandrightbronchiariseatsimilarangles,soendobronchialintubationmayoccuroneithersideAirwaysthemselvesarenarrower,andhaveahigherresistancetoflow.
References
1. Nickson,C.PaediatricAirway.LITFL.2. Anderson,C.AnatomyoftheRespiratorysystem..ICUPrimaryPrep.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.4. TobiasJD.Pediatricairwayanatomymaynotbewhatwethought:implicationsforclinicalpracticeandtheuseofcuffed
endotrachealtubes.PaediatrAnaesth.2015Jan;25(1):9-19.
Lastupdated2019-11-02
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ControlofBreathingDescribethecontrolofbreathing
Ventilationiscontrolledbyafeedbackloopinvolving:
InputsIntegrationandcontrolcentresEffectors
InputsInputstotherespiratorycentrecomesfromanumberofsensors:
ChemoreceptorsChemoreceptorsactsynergistically.Chemoreceptorsaredividedinto:
PeripheralCentral
MechanoreceptorsOthereffects
PeripheralChemoreceptors
Peripheralchemoreceptorsaredividedinto:
ThecarotidbodyLocatedatthebifurcationofthecommoncarotidartery,andareinnervatedbytheglossopharyngealnerve(CNIX).TheaorticbodyLocatedintheaorticarch,andinnervatedbythevagus(CNX).
Peripheralchemoreceptorsarestimulatedby:
LowPaOPeripheralchemoreceptorsarestimulatedbylowO tension
HighPaCOPeripheralreceptorshavearapid(~1-3s)butweaker(~20%ofresponse)tochangesinCO ,comparedtocentralchemoreceptors
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Acidaemia(Carotidbodiesonly)Hypotension
CentralChemoreceptors
Centralchemoreceptorsarelocatedontheventralmedulla,andarestimulatedbyafallinCSFpHH andHCO areionised,andcannotcrosstheBBBbydiffusionBecauseofthis,centralchemoreceptorsrespondindirectlytochangesinarterialPaCO
CarbondioxideislipidsolubleandfreelydiffusesintoCSFInCSF,carbondioxidecombineswithwater(catalysedbycarbonicanhydrase)toformH andHCO
Thisgivesthecentralchemoreceptorsanumberofspecialproperties:IncreasedsensitivityIncreasedrelativetoplasmaduetominimalbuffering(asthereislessproteininCSF)RespondtorespiratoryacidosisFixedaciddoesnotcrossthebloodbrainbarrierandsohaveaminimalresponseonCSFpH.CerebralhypoxiaincreasesCSFlactate,whichwillstimulaterespiration.
MechanismofCO Retention
Prolongedrespiratoryacidosis(i.e.prolongedCSFacidosis)stimulatesactivesecretionofbicarbonateintotheCSFWhenpHnormalises,thestimulationofcentralchemoreceptorsceases
Similarly,renalabsorptionofbicarbonateincreases,whichnormalisesarterialpHandreducesperipheralchemoreceptorstimulation
Mechanoreceptors
Stretchreceptorsinbronchialmusclearestimulatedbyoverinflation,andstimulatetheapneusticcentretoreduceinspiratoryvolumes.ThisistheHering-Breuerreflex.
OtherStimulants
Otherinputswhichstimulaterespirationinclude:
Juxtacapillaryreceptors(J-receptors)Receptorsinalveolarwalls,potentiallystimulatedbyoedemaandemboli.IrritantreceptorsInhalationofnoxiousgasesstimulatesrespiration.PainreceptorsThalamus
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Increasedcoretemperaturestimulatesrespiration.LimbicsystemEmotionalresponses.CerebralcortexConsciouscontrolofbreathing.MusclespindlesVentilatoryresponsetoexercise.
IntegrationandControl
Therespiratorycentreislocatedinthemedullaandthepons.Itconsistsoffourgroups:
DorsalRespiratoryGroup(DRG)Controlsthediaphragm,andissoonlyinvolvedwithinspiration.VentralRespiratoryGroup(VRG)Controlstheintercostalmuscles,andsoisinvolvedininspirationandexpiration.ApneusticCentreModulatesDRGfunctiontopreventover-expansion.Lossofthisareacausesapneusis-long,deepbreaths.PneumotaxicCentreAlsomodulatestheDRG,increasingRRanddecreasingV tomaintainMV.
References
1. CICMFebruary/April20152. CICMMarch/May20093. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.4. BrandisK.ThePhysiologyViva:Questions&Answers.2003.
Lastupdated2019-07-18
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RespirationDescribetheinspiratoryandexpiratoryprocessinvolvingthechestwall,diaphragm,pleuraandlungparenchyma
Explainthesignificanceoftheverticalgradientofpleuralpressureandtheeffectofpositioning
Changeinlungvolumeoccursduetochangeinintrapleuralpressures.Therefore,respirationreliesonthethoraciccavitybeingairtight,withthetracheabeingtheonlymethodgascanenterorexitthechest.
Intrapleuralpressure(P )Intrapleuralpressureisthepressureinthespacebetweenthevisceralandparietalpleura,or(physiologically)betweenthelungsandthechestwall.
Usuallynegative,typically-5cmH OatrestBalancebetweenthe:
OutwardsrecoilofthechestwallInwardsrecoilofthelungs(P )
VarieswithverticaldistanceinthelungGravitypullsthelungparenchymainferiorlyIntrapleuralpressureistherefore:
MorenegativeintheapexTypically-10cmH OatFRCLessnegativeinthebaseTypically-3cmH OatFRC
ThischangesthedegreeofinflationatFRCApicalalveoliaremaximallyinflatedBasalalveoliarerelativelydeflated
Duringinspiration,thepleuralpressurechangesevenlythroughoutthelung,howeverthebasalalveoliarebetterventilatedbecausetheircomplianceisincreased(duetolowerrestingvolume)
Inspiration
Diaphragmaticandexternalintercostal/accessorymusclecontractioncausesanincreaseinthevolumeofthethoraxIntrapleuralpressurebecomesmorenegative,typicallyto-8cmH OWhenP >P ,thelungsexpandsAlveolarpressure(P )becomessub-atmospheric,andinspirationoccursAtendinspiration:
P =PP =P
Expiration
MuscularrelaxationcausesthechestwalltopassivelyreturntotheirrestingpositionThoracicvolumefallsP fallsto-5cmH OTheelasticrecoilofthelungcausesittocollapseuntilP =P
Pl
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pl elA atmospheric
pl 2A atmospheric
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References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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ComplianceDefinecompliance(static,dynamicandspecific),itsmeasurement,andrelatethistotheelasticpropertiesoftherespiratorysystem.
ComplianceisthechangeinvolumeforagivenachangeinpressureComplianceismeasuredinml.cmH O .ItoccursduetothetendencyofatissuetoresumeitsoriginalpositionafterremovalofanappliedforceItistheinverseofelastance,whichistheforceatwhichthelungrecoilsforagivendistensionAdecreasedcompliancemeansthetranspulmonarypressuremustchangebyagreateramountforagivenvolume,whichincreaseselasticworkofbreathing
ComplianceoftheRespiratorySystem
Complianceoftherespiratorysystemisafunctionofbothlungandchestwallcompliance:
.
ThecurveisnotlinearascompliancevarieswithlungvolumeInthenormalrangehowever,(-5to-10cmH O)complianceofthelungandchestwallindependentlyistypicallystatedas~200ml.cmH O .
Complianceoftherespiratorysystemasawholeistherefore~100ml.cmH O
MeasurementofLungandChestWallCompliance
Lungcomplianceiscalculatedformthealveolar-intrapleuralpressuregradientChest-wallcomplianceiscalculatedfromtheintrapleural-ambientpressuregradientTotalcomplianceiscalculatedfromthealveolar-ambientgradient
Measuringambientandalveolarpressureisstraightforward,asiscalculatingcomplianceoftherespiratorysystemAlveolarpressureismeasuredbytakingaplateaupressure
SeparatinglungandchestwallcompliancerequiresmeasurementofintrapleuralpressureThisisperformedbymeasuringoesophagealpressure(usingaballoon)withanopenglottis,asoesophagealpressureapproximatesintrapleuralpressure.
Measurementofcomplianceofeachsystemindividuallydetermineswhatproportionofplateaupressureisdistributedtoeach
Ifthelungissignificantlylesscompliantthanthechestwall,agreaterpressureisrequiredtodistendthelungTherefore,thealveolar-intrapleuralgradientwillbemuchgreaterthantheintrapleural-ambientgradientThiscanbeexpressedbytheequation:
StaticCompliance
StaticcomplianceisthecomplianceofthesystematagivenvolumewhenthereisnoflowThereforethereisnopressurecomponentduetoresistanceAstaticcompliancecurveismadebymeasuringthepressureacrossarangeoflungvolumes,withpatienttakingincrementalbreathsStaticcomplianceisafunctionof:
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ElasticrecoilofthelungSurfacetensionofalveoli
DynamicCompliance
Dynamiccomplianceisthecompliancemeasuredduringrespiration,usingcontinuouspressureandvolumemeasurementsTherefore,dynamiccomplianceincludesthepressurerequiredtogenerateflowbyovercomingresistanceforces
ThismeansitisalsoabitofmisnomerDynamiccomplianceisalwayslessthanstaticcompliance,astherewillalwaysbeadegreeofairwayresistanceDynamiccomplianceisafunctionofrespiratoryrateInnormallungsatnormalrespiratoryratesitapproximatesstaticcompliance.Reducedininlungunitswithunequaltimeconstantsathighrespiratoryrates
Duetoincompletefillingofalveoli-theportionofpressurethatisusedtoovercomeairwaysresistanceisthereforeproportionallygreater
SpecificComplianceSpecificcomplianceisthecomplianceperunitvolumeoflung,expressedas:
Specificcomplianceisusedtocomparedifferentlungs
Hysteresis
Ingeneral,hysteresisreferstoanyprocesswherethefuturestateofasystemisdependentonitscurrentandpreviousstateSpecifictothelung,itmeansthecomplianceofthelungisdifferentininspirationandexpiration
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Thereishysteresisinbothstaticanddynamiccurves:Indynamiccompliancecurves:Airwaysresistanceisafunctionofflowrate.Flowrate(thereforeresistance)ismaximalatthebeginningofinspirationandend-expiration.Instaticcompliancecurves:Thereisnoresistivecomponent.Hysteresisisduetoviscousresistanceofsurfactantandthelung.
ChangesinCompliance
Respiratorysystemcompliancecanbeaffectedbychangestoeitherlungorchestwallcompliance,andcanbeincreasedordecreased.
IncreasedLungCompliance
NormalageingAsthmaattackEmphysema
DecreasedLungCompliance
AlterationsinlungvolumeandconsolidationComplianceisreducedatextremesoflungvolume.ItishighestatFRC.
ChildrenPneumonectomy/lobectomyAtelectasis/collapsePneumoniaARDS
Increasedpulmonarybloodvolume/venouscongestionAPO
IncreasedsurfacetensionReducedsurfactant
HyalineMembraneDiseaseImpairedparenchymalcompliance
Pulmonaryfibrosis
IncreasedChestWallCompliance
Collagendisorders
DecreasedChestWallCompliance
Chestwallrestriction/structuralabnormalitiesObesitySpasticparalysisofchestwallmusculatureOssificationofcostalcartilagesKyphosis/scoliosisScarring/constriction(e.g.circumferentialburns)
PositionProne(60%reducedcompliance)/supineThisisduetotheeffectofpositiononlungvolume.
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References1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. KennyJE.Heart-LungInteractionLectureSeries.Fromheart-lung.org.
Lastupdated2019-07-20
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Time-ConstantsExplaintheconceptsoftimeconstants
ARefresheronTimeConstants
Thetime-constantis:
ThetimethataprocesswouldtaketocompleteifitsinitialrateofchangeremainedconstantRelevantwhenmodelingaprocessusingexponentialfunctions
Rememberanexponentialfunctionisacurvewheretherateofchangeisproportionaltothecurrentvalue
Foraquantitythatdecreases overtime,thegeneralcaseis:
,where:
isthevalueof at
istherateconstant( plotsacurvethatgrows)
istime
Importantly:
isthereciprocalofthetimeconstant,
Inanegativeexponential,time-constantisthetimeitwouldtakefor toreach0iftheoriginalrateofchangewasmaintained.Otherfunfactsaboutthetimeconstant(foranexponentialdecay)include:
After1 , willbe37%( )ofitsinitialvalue
After2 , willbe13.5%( )ofitsinitialvalue
After3 , willbe5%( )ofitsinitialvalue
After5 , willbe1%( )ofitsinitialvalue
PhysiologicalSignificance
Thetime-constantisusedinrespiratoryphysiologyin:
TiminginspirationandexpirationEliminationofinhalationalanaestheticsThechangeinPaO andPaCO afterchangesinventilation
Inventilation:
Thetimeconstantisaffectedby:ComplianceResistanceInflationpressureAtaconstantinflationpressure,thetimeconstantisequaltotheproductofresistanceandcompliance,i.e.
1
2 2
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151
.
FortwolungunitsofequalcomplianceandresistanceInflationwilloccuraspertheexponentialgrowthfunctionTime-constantsofeachlungunitwillbeequalNoredistributionofgaswilloccuratend-inspirationasthepressureandvolumeofeachunitisthesame
Fortwolungunits,whereonehashalfthecompliancebuttwicetheresistanceThetimeconstantsareequal,thereforebothreachpeakfillingatthesametime
However,thepoorlycompliantunitwillonlyreachhalfthevolumeNoredistributionofgaswilloccuratend-inspirationasthepressureandvolumeofeachunitisthesame
Fortwolungunits,whereonehastwicetheresistanceoftheotherThetime-constantsareunequalTheresistantunitwillfillathalftherateoftheother
IfinspirationisprolongedbothwillreachthesamevolumeIfinspirationhishaltedearly,andexpirationprevented,therewillbeapressuregradientbetweentheunits(ascomplianceisthesame),andgaswillredistributefromthelow-resistantunittothehigh-resistantunit
FortwolungunitswhereonehashalfthecomplianceThetimeconstantsareunequalThepoorlycompliantunitwillfillathalftherateoftheother
IfinspirationisprolongedtheywillbothreachthesamepressureThevolumeinthepoorlycompliantunitwillbehalfthatofthemorecompliantunit.
Duringinspiration,thepressurerisesmorerapidlyinthepoorlycompliantunit,andifinspirationisstoppedandexpirationprevented,thiswillresultinredistributionintothemorecompliantunituntilpressuresareequal
Ingeneral:
RateoffillingisdeterminedbytimeconstantsHigh-resistancelungunitshavelongertimeconstantsandtakelongertofill
Finalvolume(assuminganindefiniteinspiration)isafunctionofcompliancePoorlycompliantunitswithemptyandfillrapidlyThiscreatestheconceptoffastandslowalveoli,dependingontheirtimeconstants.
Atasustainedinflationpressure:Alow-resistanceunitshowsinitialgreatervolumechangebutrapidlyapproachesequilibriumvolumeAhigh-complianceunittakesagreateroverallvolumeoveralongerperiod
Atend-inspiration:Pressureinunitswithashortertime-constantrisesmorerapidlyandifabreathisheldwillresultinredistributiontothoseunitswithalongertime-constant.
ClinicalSignificance
Iftime-constantsareequal:
ThepressureineachunitisidenticalthroughoutinspirationanddistributionTherefore,dynamiccompliancewillbeindependentofrespiratoryrate.
Iftime-constantsareunequal:
Long-timeconstantunitsmaystillbeinhalingwhilsttherestofthelunghasstopped,orbegunexhalationThisiscalledpendelluft.Inpendelluft,distributionofinspiredgasisdependentonrespiratoryrate
Asrespiratoryrateincreases,theproportionofthetidalvolumethatisdeliveredtotheregionwithalongtime-constantdecreasesFastalveoliarepreferentiallyinflated,causingV/Qscatterorshuntintheunventilatedslowalveoli.
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Dynamiccompliancewilldecreaseasrespiratoryraterisesandbemarkedlydifferentfromstaticcompliance
Footnotes
.Foracurvethatgrowsovertime,thetimeconstantisthetimeitwouldtakefor toreach63%ofitsfinalvalue,i.e.
.↩
References1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.
Lastupdated2019-07-18
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153
ResistanceExplaintherelationshipbetweenresistanceandrespiratorygasflow
Describethefactorsaffectingairwayresistance,anditsmeasurement
Resistance(measuredincmH O.L .sec )comprisestheenergylostasfrictionalandinertialimpedancetogasflow,whereenergyislostasheat.Flowisafunctionofpressuregradient,resistance,andtypeofflow.
TypesofFlowFlowcanbeeitherlaminarorturbulent.Inlaminarconditionsflowisproportionaltodrivingpressure,whilstinturbulentconditionsflowisproportionaltothesquarerootofdrivingpressure.
Reynolds'Number
TypeofflowcanbepredictedbyReynolds'sNumber,adimensionlessindexwhere:
,where:
=Radius
=Gasdensity=Velocity
=Gasviscosity
AReynolds'Numberof<2000ispredominantlylaminarflow,whilst>4000ispredominantlyturbulent.
LaminarFlow
Inlaminarflow:
GasmovesinaseriesofconcentriccylinderswhichslideoveroneanotherGasinthecentremovestwiceasfastcomparedtotheoutside,whereitisalmoststationary
Gasappearsincross-sectionasanadvancingconeGasmayreachtheendofthetubewhenthevolumeofflowislessthanthevolumeofthetube.
Thisisthemechanismofalveolarventilationwhentidalvolumesarelessthananatomicaldeadspacevolume
Inastraightunbranchedtube,flowcanbequantifiedbytheHagen-PoiseuilleEquation:
,where:
=Flow
=Drivingpressure=Radius
=Length
=Viscosity
However,asinlaminarconditionsflowisproportionaltothedrivingpressureandinverselyproportionaltoresistance,flowcanbesubstitutedandtheequationsolvedforresistance:
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Thiscanbeusedtodescribethefactorsaffectingresistance:
LengthFixedconstant.ViscosityVarieswiththeparticulargasmixturebeingused.RadiusMaindeterminant.Maybedividedinto:
ExtraluminalfactorsCompression:
Haemorrhage,tumour,dynamichyperinflation,atelectasiscompressingairways,etc.Lungvolume:
Airwayradiusincreaseswhenlungvolumeexpandsduetoradialtractiononairways(untildynamichyperinflationoccurs,atwhichpointairwaysarecompressedagain)
LuminalconstrictionBronchospasm,bronchoconstriction.IntraluminalobstructionSputumplugging,aspiration.
Notethatairwayresistance:
Peaksatthe5 generationRapidlydecreaseswitheachairwaydivisionthereafterThisisduetothetotalcross-sectionalareaincreasingdramatically.
Reduceswithincreasinglungvolume,asradialtensiondistendsairways,increasingtheircrosssectionalarea
TurbulentFlow
th
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Highflowratesandbranchingofairwaysdisruptdisciplinedlaminarflow.Turbulentflow:is:
Dominantintheupperairway(wherevelocityishigh)Dominantinearly-generationairwaysduetoregularbranching,changesindiameter,andsharpanglesReducesafterthe11thgenerationbronchiolesProportionaltothesquarerootofthedrivingpressureTherefore,resistanceishigherinturbulentflowthaninlaminarflow.
Drivingpressureisproportionaltogasdensity,andindependentofviscosity
Resistanceinturbulentflowismanagedbymakingflowlessturbulent:
AchievedbyreducingReynoldsnumberHeliummixturesreducegasdensityOfgreaterbenefitinupperairwaythanlowerairwaydisease.
TransitionalFlow
Transitionalflowoccursatbranchesandanglesintheairways,asoccurinmostofthebronchialtree.
References
1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.
Lastupdated2018-04-24
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SurfactantDescribetheproperties,productionandregulationof,surfactantandrelatethesetoitsroleininfluencingrespiratorymechanics
SurfaceTension
SurfacetensiondescribesthetendencyofafluidtominimiseitssurfaceareaItisrelatedtotheattractionbetweenparticlesinthefluidrelativetoparticlesoutsidethefluidSurfacetensioniswhy:
WaterscatteredonasurfaceformsroundeddropletsWhymultipledropletswilltendtocoalesceintoasinglelargerdroplet
ThisrelationshipisdescribedbyLaPlace'sLaw
,where:
ispressure
issurfacetensionisradius
AlveoliobeyLaplace'sLawHighsurfacetensioncausesthreeproblemswithalveoli
CompliancefallswhenthealveolusisemptyAstheradiusfalls,thepressurerequiredtoopenit(atagivensurfacetension)willbeincreased.Thisincreasesworkofbreathing.SmalleralveoliwillpreferentiallyemptyintobiggeralveoliSmalleralveolirequiregreatertransmuralpressurestoremaininflated.Thiscausessmalleralveolitoemptyintolargerones.FluidtransudationSurfacetensiondrawsfluidfrominterstitialspacesandcontributestopulmonaryoedema.
Overall,highsurfacetensionisdetrimentaltothelungs
Surfactant
SurfactantisasubstancewhichsubstantiallyreducesworkofbreathingbyreducingalveolarsurfacetensionSurfactantisproducedbytypeIIalveolarcellsinresponsetolunginflationandrespirationItiscomposedof:
85%phospholipid5%neutrallipid10%protein
SurfactantisamphipathicEachcomponenthasahydrophobicandhydrophilicend.
Thiscausesthemoleculestoorientthemselvesalongtheair-liquidinterface,disruptingtheattractivebondsbetweenwatermoleculesSurfacetensionisreducedinproportiontotheconcentrationofmolecules
TheconcentrationofsurfactantchangesthroughouttherespiratorycycleDuringexpirationalveolicollapseThedecreaseinalveolarradiusisoffsetbytheincreaseinsurfactantconcentration,sothefallinradiusismitigatedby
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157
thedropinsurfacetension.
References1. CICMSeptember/November20122. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.
Lastupdated2019-07-18
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VolumesandCapacitiesExplainthemeasurementoflungvolumesandcapacities,andfactorsthatinfluencethem
Statethenormalvaluesoflungvolumesandcapacities
Defineclosingcapacityanditsclinicalsignificanceandmeasurement
Thelunghasfourvolumesandfour(main)capacities:
AvolumeismeasureddirectlyAcapacityisasumofvolumes
Volumes
Tidalvolume(V )Volumeofairduringnormal,quietbreathing.
Normalis7ml.kg ,or500ml
Inspiratoryreservevolume(IRV)Volumeofairthatcanbeinspiredabovetidalvolume.
Normalis45ml.kg ,or2500ml
Expiratoryreservevolume(ERV)Volumeofairthatcanbeexpiredfollowingtidalexpiration.
Normalis15ml.kg ,or1500ml
Residualvolume(RV)Volumeofairinthelungsfollowingamaximalexpiration.
Normalis15-20ml.kg ,or1500ml
Capacities
FunctionalResidualCapacity(FRC)FRC=RV+ERV.
Normalis30ml.kg or3000mlFRCdecreases20%whensupine,andafurther20%undergeneralanaesthesia
VitalCapacity(VC)VC=ERV+V +IRV.
Normalis4500ml
T
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InspiratoryCapacity(IC)IC=V +IRV.
Normalis3000ml
TotalLungCapacity(TLC)TLC=RV+ERV+V +IRV.
Normalis6000ml
FunctionalResidualCapacity
TheFRChasmanyimportantphysiologicalfunctions:
GasexchangeTheFRCallowsbloodinthepulmonarycirculationtobecomeoxygenatedthroughouttherespiratorycycle(iftherewasnoFRC,thenatexpirationthelungswouldbeemptyandnooxygenationwouldoccur).
OxygenReserveFRCistheonlyclinicallymodifiableoxygenstoreinthebody,andallowscontinualoxygenationofbloodduringapneicperiods.
MinimiseWorkofBreathingWorkofbreathingisafunctionoflungresistanceandcompliance.
ThelungsitsonthesteepestpartofthecomplianceoccursatFRCComplianceisoptimisedas:
AlveoliareopenandminimallydistendedBelowFRC,somealveolicollapseandthevolumeoflungavailabletoreceivethetidalvolumedecreasesRe-expansionofcollapsedalveolirequiresmoreworkthanexpandingopenalveoli.AboveFRC,somealveoliwillbecomeoverdistendedandtheircompliancewillfall
Airwayresistancedecreasesasairwayradiusincreasesaslungvolumeincreases
MinimiseRVAfterloadPVRisminimalatFRC.
AboveFRC,compressionofintra-alveolarvesselsoccursandPVRincreasesBelowFRC,extra-alveolarvesselscollapseandPVRincreases
MaintainlungvolumeaboveclosingcapacityIfclosingcapacity(seebelow)exceedsFRC,thenshuntwilloccur.
FactorsaffectingFRC:
FRCisreducedby:SupinepositioningFallsby~20%.AnaesthesiaFallsby~20%.Raisedintra-abdominalpressureImpairedlungandchestwallcompliance
FRCisincreasedby:PEEP
ExtrinsicIntrinsic(gastrapping)
PEEPEmphysemaAcuteasthmaAge
T
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Mayincreaseslightly.
MeasurementofLungVolumesandCapacities
ERV,V ,andIRVcanallbemeasureddirectlyusingspirometryAspirometerisaflowmeter
ThepatientexhalesasfastaspossiblethroughtheflowmeterAflow-timecurveisproducedThiscurvecanbeintegratedtofindvolume
Anycapacitywhichisasumofthese(IC,VC)canthereforebecalculated
RVcannotbemeasuredbyspirometry,asitcan'tbeexhaledThereforeFRCandTLCcannotbecalculated
RVcanbemeasuredusing:GasdilutionBodyplethysmography
GasDilution
Gasdilutionreliesontwoprinciples:ConservationofMassHeliumhaspoorsolubilityandwillnotdiffuseintocirculation
Limitationsofgasdilution:Onlygascommunicatinggascanbemeasured-willunderestimateFRCingas-trapping
Method:Patienttakesseveralbreathsfromagasmixturecontainingaknownconcentrationofhelium(givingtimeforequilibration)TheconcentrationofexpiredheliumisthenmeasuredFromthelawofconservationofmass:
isequaltothevolumeofthegasmixturethepatientwasbreathingfrom( )andthepatientsFRCTherefore:
BodyPlethysmography
Bodyplethysmographyrelieson:Boyle'slaw
Pressureandvolumeareinverselyproportionalataconstanttemperature,i.e.( ).
Method:Patientisplacedinaclosedbox,withamouthpiecethatexitstheboxThepatientinhalesagainstaclosedmouthpiece:
Whenthepatientinhales,thevolumeofgasintheboxdecreases(thepatienttakesupmorespace)andthereforethepressureincreasesThechangeinvolumeoftheboxisgivenby:
T
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161
,where:
isthechangeinboxvolume,orTherefore:
As istheonlyunknownvalue,itcanbecalculated.
Thechangeinvolumeofthelungmustbethesameasthevolumeofthebox( )
Inthecaseofthelung,theinitialvolume( )isFRCTherefore:
ClosingCapacity
ClosingcapacityisvolumeatwhichsmallairwaysbegintocloseClosingcapacityisthesumofresidualvolumeandclosingvolume.
Becausedependentlungiscompressedbygravity,dependent(typicallybasal)airwaysareofsmallercalibrethannon-dependent(typicallyapical)airwaysDuringexpiration,theseairwaysarecompressedfirstAlveoliconnectedtotheseairwaysareisolated,andV/Qscatterorshuntoccurs.IfclosingcapacityexceedsFRC,thenairwayclosureoccursduringnormaltidalbreathingThisoccurswhen:
FRCisdecreasedCCisincreased
IncreaseswithageCCexceedsFRCinthesupinepatientat44CCexceedsFRCintheerectpatientat66
Thisisclinicallyrelevantduringpreoxygenation,asitwilllimitthedenitrogenationthatcanoccur
MeasurementofClosingCapacity
ClosingcapacityismeasuredusingFowler'sMethod,andiscoveredunderDeadSpace.
References
VolumesandCapacities
162
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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SpirometryDescribethepressureandflow-volumerelationshipsofthelung,chestwallandthetotalrespiratorysystem
Describethemeasurementandinterpretationofpulmonaryfunctiontests,includingdiffusioncapacity.
Pulmonaryfunctiontestsareperformedwithaspirometer,whichmeasureseithervolumeorflow(integratedfortime)toquantifylungfunction.
Basicspirometrycanbeusedtoquantify:
LungvolumesandcapacitiesAllexceptresidualvolume(andthereforeFRCandTLC).Dynamicmeasurements
FEVVolumeofairforciblyexhaledinonesecond.FVCForcedvitalcapacity.PEFRPeakexpiratoryflowrate.Flow-volumeloop
Additionaltestingcanbeperformedtomeasure:
ResidualvolumeFRCandTLCcanthereforebecalculated.Diffusioncapacity
BasicSpirometry
Basicspirometryincludes:
ForcedspirometryPatientforciblyexhalesavitalcapacitybreath,producingaexponential(wash-in)curve.Thiscalculates:
PEFRfromthegradientattime0(assumingmaximaleffort)FEV isthevolumeexpiredin1sNormalis>80%ofpredicted.FVCisthetotalvolumeexhaled.TheFEV /FVCratioNormalis>0.7.Thesevaluesalsoquantifydiseaseseverity:
Inobstructiveairwaysdisease:FEV <80%predictedFEV /FVCratio
Restrictivedisease:FEV <80%predictedFVCFEV/FVCratio>0.7TheratioisnormalastheFEV andFVCfallproportionally.
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Volume-TimeGraph(alsoknownasaspirographorspirogram)Quantifiesstaticlungvolumesbyhavingapatientperform:
NormaltidalbreathingVitalcapacitybreathVitalcapacityexhalation
Flow-VolumeLoopsNormal
Peakexpiratoryflowof~8L.sInitialflowishighestastheincreasedlungvolumeincreasesthecalibreoflungairways,reducingairwaysresistance.
ThisiscalledtheeffortdependentpartofthecurveFlowtailsofflaterinexpiration
Lungscollapse,andairwaycalibrefallsSmallairwaysarecompressedAnyincreaseinexpiratorypressurewillincreaseairwayresistanceproportionally.
Thisiscalleddynamicairwayscompression,andresultsinauniformflowratethatisindependentofexpiratoryeffort*Thisisthereforelabeledtheeffortindependent**partofthecurve.
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165
ObstructivelungdiseaseRVandTLCareincreasedduetogastrappingPeakflowislimitedEffort-independentportionbecomesconcave
RestrictivelungdiseaseTLCisreduced,butresidualvolumeisunchangedPeakflowmaybereduced(asseenhere)However,thisreductionisproportionaltothedecreaseinvolume,suchthattheFEV :FVCratioisnormal.Ifpeakflowispreserved,theFEV :FVCratiowillbeincreased.Effortindependentpartislinear
FixedupperairwayobstructionDescribesanupperairwayobstructionthatdoesnotchangecalibreduringtherespiratorycycle.
Peakinspiratoryandexpiratoryflowratesarelimitedbythestenosis
VariableextrathoracicobstructionVariableastheobstructionchangesduringtherespiratorycycle:
During(negativepressure)inspirationthelesionispulledintotrachea,reducinginspiratoryflowDuringexpirationthelesionispushedoutofthetracheaThewaytorememberthisisanextrathoracicobstructionimpedesinspirationThereverseeffectoccursinpositivepressureventilation
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VariableintrathoracicobstructionTheoppositetoextrathoracicobstruction.
DuringinspirationtheairwaycalibreincreasesandinspiratoryflowisunimpededDuringexpirationtheairwaycalibrefallsandexpiratoryflowisreduced
References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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WorkofBreathingDescribetheworkofbreathinganditscomponents
Workofbreathingistheenergyusedbythemusclesforrespiration.Itisdefinedas:
,measuredinJoules.
ThisgivestheworkforasinglerespiratorycycleEnergyexpenditureovertimeisbetterdescribedasthe"powerofbreathing".ItdoesnottakeintoaccountrespiratoryrateorflowrateThesefactorshaveasignificanteffectonenergyrequirement.
Thiswouldbegivenbytherateofwork,orpower,where:
,measuredinWatts.Tidalbreathingisefficientanduses<2%ofBMR
Theoxygenrequirementofbreathingatrestis~2-5%ofVO ,or~3ml.min
DeterminantsofWorkofBreathingWorkofbreathingisdividedinto:
ElasticworkAbout65%oftotalwork,andisstoredaselasticpotentialenergy.Energyrequiredtoovercomeelasticforces:
LungelasticrecoilSurfacetensionofalveoli
ResistiveworkAbout35%oftotalwork,andislostasheat.Thisisduetotheenergyrequiredtoovercomefrictionalforces:
BetweentissuesIncreasedwithincreasedinterstitiallungtissue
BetweengasmoleculesIncreasedathighflowratesIncreasedwithturbulentflow
HighrespiratoryratesUpperairwayobstructionIncreasedairwaydensity
HyperbaricDiving
IncreasedwithdecreasedairwayradiusLowlungvolume
InadequatePEEPDecreasedrespiratorymuscletone
BronchoconstrictionDynamicairwaycompressionEffort-independentexpiration.Apparatus
EndotrachealTubeHMEfilters
Airwayresistancevariesdependingonairwaydivision:Resistancepeaksatthe3rdairwaydivision(lobarbronchi)
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Fallswithincreasingairwaydivisionsduetoincreasedcross-sectionalarea
GraphingWorkofBreathing
Workofbreathingcanbeevaluatedwithadynamiclungcompliancecurve:
Iftherewerenoresistiveforces,thenthiscurvewouldbeastraightlineThetriangularareaistheelasticworkdone
Theresistiveworkofbreathingcausesthedeviationoftheinspiratoryandexpiratorylines:TheareabetweenthecompliancelineandtheinspiratorylineisadditionalresistiveinspiratoryworkdoneTheareabetweenthecompliancelineandexpiratorylineisadditionalresistiveexpiratoryworkdone
ThisworkistypicallydonebyelasticrecoilofthelungsIfthisareafallswithintheareaofelasticworkofbreathing,itisapurelypassiveprocess,usingthestoredelasticpotentialenergyofinspirationIfpartofthisareafallsoutsidetheareaofelasticworkofbreathing,itdemonstratesadditionalactiveworkofexpirationwhichmayoccurinobstructivelungdiseaseorwhenminuteventilationishigh
Activeexpiratorywork:
MinimisingWorkofBreathing
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Workofbreathingcanbeminimisedbyoptimisingthedeterminants:
ElasticworkPEEPKeeplungvolumeatFRCandmaximisenumberofventilatedalveoli.PositioningOptimiselungvolume.SurfactantMinimisingsurfacetension.OptimiserespiratoryrateElasticworkofbreathingtypicallydecreaseswithincreasedrespiratoryrate.
ResistiveworkDecreaserespiratoryrateRespiratoryrateisdirectlyproportionaltoresistivework.IncreaselaminarflowLaminarflowismoreefficientthanturbulentflow.Laminarflowcanbeincreasedby:
ReducinggasdensityHeliox.
IncreaseRadiusIncreaselungvolumeBronchodilators
Derivation
Workisdefinedas:
,where:
=WorkinJoules
=ForceinNewtons
=DistanceinMetres
Additionally,pressureisdefinedas:
,where:
=PressureinPascal
=AreainMeterssquared
Therefore:
Substituting:
,where:
=Volume
Therefore:
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170
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.
Lastupdated2019-07-18
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OxygenCascadeDescribeandexplaintheoxygencascade
Theoxygencascadedescribesthetransferofoxygenfromairtomitochondria.
IneachstepofthecascadethePaO fallsItdemonstratesthatoxygendeliverytotissuesreliesonthepassivetransferofgasdownpartialpressuregradients.Thestepsofthecascadeare:
DryatmosphericgasHumidifiedtrachealgasAlveolargasArterialbloodMitochondriaVenousblood
Remember:
PartialpressuredeterminesrateandextentofgastransferOxygencontentiswhatisimportantforcellularfunction
AtmosphericGas
AtmosphericpartialpressureofoxygenisafunctionofbarometricpressureandtheFiO :
,where:
is760mmHg
is0.21
Therefore, =160mmHg
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172
HumidifiedTrachealGas
GasishumidifiedduringinspirationGasintheproximaltracheaisheatedto37°Candhas100%relativehumidityThesaturatedvapourpressureofwaterat37°Cis47mmHgTherefore:
,where:
and areasabove
is149mmHg
AlveolarGas
IdealalveolarPO iscalculatedusingthealveolargasequation:
,where:
isthealveolarpartialpressureofoxygen
istheinspiredpartialpressureofoxygen
isthearterialpartialpressureofcarbondioxide
istherespiratoryquotient,whereRisusedinthealveolargasequationtocorrectforthechangeininspiredrelativetoexpiredvolumeAsgenerallylessCO isproducedthanO consumed,expiredvolumesaretypicallylessthaninspiredvolumesRisdependentonthemetabolicsubstratesusedformetabolism:
Purefat≈0.7Pureprotein≈0.9Purecarbohydrate≈1ThenormalvalueforaWesterndietisquotedas0.8
isacorrectionfactor,usuallyequalto~2mmHg,andisgivenby
Alveolaroxygenisthereforedependenton:
PiO ,whichisafunctionof:FiOAirpressure
Alveolarventilation
As .
ArterialBloodThedifferenceinpartialpressureofoxygenbetweenalveolarandarterialbloodiscalledtheA-agradient:
AnormalA-agradientis
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NormalarterialPO is100mmHgItoccursdueto:
Shunt/VQscatterAsmallshuntisnormalduetobloodfromthebronchialcirculationandthebesianveins.Diffusionabnormality
Mitochondria
PO varieswithmetabolicactivity,buttypicallyquotedas5mmHgThePasteurpointisthepartialpressureofoxygenatwhichoxidativephosphorylationceases,andis~1mmHg
VenousBlood
PO isgreaterthanmitochondrialPOMixedvenousbloodtypicallyquotedas40mmHg.Higherthanmitochondriaasnotallarterialbloodtravelsthroughcapillarybeds
References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. BrandisK.ThePhysiologyViva:Questions&Answers.2003.
Lastupdated2019-07-18
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DiffusingCapacityandLimitationExplainperfusion-limitedanddiffusion-limitedtransferofgases
Definediffusingcapacityanditsmeasurement
Describethephysiologicalfactorsthatalterdiffusingcapacity
RateofdiffusionofgasesisgivenbyFick'sLaw:
,where:
isthepressuregradientacrossthemembrane
istheareaofthemembraneisthesolubilityofthesubstance
isthethicknessofthemembrane
isthemolecularweightofthesubstance
Thesecanbedividedintopressure,lungfactors,andsubstancefactors:
PressuregradientInthelung,thisisafunctionof:
PartialpressureofthegasinthealveolusThisisaffectedby:
AtmosphericpressureVentilationAlveolarhypoventilationwill:
IncreasePACODecreasePAO
PartialpressureofthegasinbloodThisisaffectedby:
SolubilityofthegasinbloodCO is~20timesassolubleasO inblood.Bindingofgastoprotein:
ParticularlyhaemoglobinAffectstherateofuptakeofO andCO,andiswhycalculatedDL iscorrectedforhaemoglobin.
Theshapeoftheoxy-haemoglobindissociationcurveallowsalargevolumeofoxygentobeboundbeforePaO beginstorisesubstantially.
FormationofcarbaminocompoundsAnaestheticagentstoplasmacontentse.g.albumin,cholesterol.
LungfactorsSurfaceAreaAffectedby:
ParenchymavolumeBodysizePathologyManylungdiseaseswillreducesurfaceareaforgasexchange.
V/QmismatchBothshuntanddeadspacereducethesurfaceareaavailableforgasexchange.
22
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PulmonarybloodvolumeVasculardistensionandrecruitmentalsoaffectssurfacearea.Factorsaffectingpulmonarybloodvolumeinclude:
CardiacoutputIncreasedrecruitmentofvasculatureinhighoutputstatesDecreasedrecruitmentandincreasedV/Qmismatchinshockstates.
PostureIncreasedsurfaceareawhensupinerelativetosittingorstanding.
ThicknessIncreasingalveolar-capillarymembranethicknessimpedesgasexchange.Causesofthisinclude:
Pathologye.g.Pulmonaryoedemaandcardiacfailure.
SubstancefactorsSolubilityMoresolublesubstanceswilldiffusemorequickly.MolecularweightSmallersubstanceswilldiffusemorequickly.
DiffusionandPerfusionLimitation
Limitationreferstowhatprocesslimitsgasuptakeintoblood:
Gaseswhicharediffusionlimitedfailtoequilibrate,i.e.thepartialpressureofasubstanceinthealveolusdoesnotequalthatinthepulmonarycapillary
e.g.CarbonMonoxideGaseswhichareperfusionlimitedhaveequalalveolarandpulmonarycapillarypartialpressures,sotheamountofgascontenttransferredisdependentonbloodflow
e.g.Oxygen
Oxygen
Oxygendiffusiontakes~0.25sPulmonarycapillarytransittimeis0.75sTherefore,undernormalconditionsoxygenisaperfusionlimitedgasHowever,oxygenmaybecomediffusionlimitedincertaincircumstances:
Alveolar-capillarybarrierdiseaseDecreasestherateofdiffusion.
DecreasedsurfaceareaIncreasedthickness
Highcardiacoutput
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176
Decreasespulmonarytransittime.AltitudeDecreasesPAO .
CarbonDioxide
Carbondioxideisventilationlimited,ratherthandiffusionorperfusionlimitedThisisbecauseitis:
20xmoresolubleinbloodthanoxygenRapidlyproducedfrombicarbonateandcarbaminocompoundsPresentinfargreateramountsthanoxygen1.8L.kg existinthebody(though1.6L ofthisareinboneandotherrelativelyinaccessiblecompartments).
Impairmentofdiffusioncapacitycausestype1respiratoryfailureasoxygenisaffectedtoamuchgreaterextentthancarbondioxide
OtherGases
CarbonmonoxideDiffusionlimiteddueto:
HighaffinityforhaemoglobinContinualuptakeintoHbresultsinalowpartialpressuresinblood.
NitrousoxidePerfusionlimitedasequilibriumbetweenalveolusandbloodisrapidlyreachedasitis:NotboundtohaemoglobinRelativelyinsoluble
DiffusionCapacity
MeasurementoftheabilityofthelungtotransfergasesMeasuredasDL ordiffusingcapacityofthelungforcarbonmonoxideCarbonmonoxideisusedasitisadiffusionlimitedgas.Process:
Vitalcapacitybreathof0.3%COHeldfor10sandexhaledInspiredandexpiredCOaremeasuredDifferenceistheamountofCOwhichisnowboundtoHbDL iscorrectedfor:
AgeSexHb
DL isdecreasedin:Thickenedalveolar-capillarybarrier
InterstitiallungdiseaseReducedsurfacearea
EmphysemaPELobectomy/pneumonectomy
DL isincreasedin:ExerciseRecruitmentandcapillarydistension.Alveolarhaemorrhage
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HbpresentwithinthelungbindsCO.Asthma(maybenormal)Potentiallyduetoincreasedapicalbloodflow.Obesity(maybenormal)Potentiallyduetoincreasedcardiacoutput.
References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.3. ANZCAMarch/April19994. DerangedPhysiology-CarbonDioxideStorageandTransport
Lastupdated2017-10-04
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West'sZonesDescribeWest'szonesofthelungandexplainthemechanismsresponsibleforthem
West'sZonestakeintoaccounttheeffectofalveolarpressureonpulmonarybloodflow.Thelungisdividedintofourzones:
WestZone1:P >P >PAlveolarpressureexceedsarterialpressure.
Thealveoluscompressesthecapillary,andnobloodflowoccursAsthereisventilationbutnoperfusion,thiscanalsobethoughtofasdeadspaceThisoccurswhen:
AlveolarpressureishighPEEP
ArterialpressureislowShock
Hypovolaemia
WestZone2:P >P >PArterialpressureexceedsalveolarpressure,whichexceedsvenouspressure.
BloodflowoccursintermittentlyduringthecardiaccycleAlveolarpressureactsasaStarlingresistorFlowisproportionaltotheP -P gradient.
WhenP fallsbelowP (e.g.indiastole),thennobloodflowwilloccur
WestZone3:P >P >PArterialpressureexceedsvenouspressurewhichexceedsalveolarpressure.
BloodflowoccursthroughoutthecardiaccycleFlowisproportionaltotheP -P gradient.ForanaccuratemeasureofPCWP,aPACmustbeplacedinWestZone3(sothereisacontinualcolumnofblood)Thistendstohappennaturallyasthemajorityofpulmonaryflowistothisregion
WestZone4:P >P >P >PInterstitialpressureactsasaStarlingresistorforpulmonarybloodflow.
Itisseenwheninterstitialpressureishigh(e.gduetopulmonaryoedema).
References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2018-07-09
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BasicsofV/QMatchingOptimalgasexchangeoccurswhenregionsoflungareventilatedinproportiontotheirperfusion,i.e.V/Q=1
Unevendistributionofventilationandperfusioncausesinefficientgasexchange:ExcessiveventilationcausesexcessiveworkInadequateventilationcausesinadequategasexchange
DistributionofVentilation
TherightlungisslightlybetterventilatedthantheleftInanerectpatientthebasesofthelungarebetterventilatedTheweightoflungabovecompressesthelungbelow,improvingthecomplianceofdependentlungwhilststretchingthenon-dependentlung.
ThisisonlysignificantatlowinspiratoryflowratesTheV/Qratiointhebasesis~0.6TheV/Qratiointheapicesis>3
Inalateralposition:ThedependentlungisbetterventilatedinaspontaneouslybreathingpatientThenon-dependentlungisbetterventilatedinaventilatedpatient
DistributionofPerfusion
ThepulmonarycirculationisalowpressurecirculationGravitythereforehasasubstantialeffectonfluidpressureConsequently,thedistributionofbloodthroughoutthelungsisuneven:
ThebasesperfusedbetterthantheapicesThisisaffectedbylungvolume,withtheeffect:
BecomingmorepronouncedatTLC(withapicalperfusionfallingprecipitously)ReversingslightlyatRV
V/QRatios
TheglobalV/Qratiofornormalrestinglungis0.9TheglobalV/Qratioimprovesto1.0duringexercise
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V/QMismatchandEtymology
V/QmismatchoccurswhenV/Q≠1:V/Q>1(DeadSpace)Ventilationinexcessofperfusion.
However,pulmonarybloodispassingventilatedalveoliandPaO isnormal
V/Q0to1(V/Qscatter)Perfusioninexcessofventilation.
IncreasinginPAO willincreasePaOThisiscommonlyreferredtobythegeneraltermofV/Qmismatch
V/Q=0(Shunt)Mixedvenousbloodenteringthesystemiccirculationwithoutbeingoxygenatedviapassagethroughthelungs.PaOfalls.
References
1. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.2. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.
Lastupdated2017-10-04
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DeadSpaceDeadspaceistheproportionofminuteventilationwhichdoesnotparticipateingasexchange.
TypesofDeadSpace
Deadspacecanbedividedinto:
ApparatusdeadspaceDeadspacefromequipment,suchastubesventilatorcircuitry.Someapparatusdeadspacemayactuallyreducetotaldeadspace,asanETTbypassesthemajorityofanatomicaldeadspaceofthepatient(nasopharynx).
PhysiologicaldeadspaceDeadspacefromthepatient.Physiologicaldeadspaceisdividedinto:
AnatomicaldeadspaceThevolumeoftheconductingzoneofthelung.Anatomicaldeadspaceisaffectedby:
SizeandAge3.3ml.kg intheinfant,fallsto2.2ml.kg intheadultPostureDecreaseswhensupine.PositionoftheneckandjawIncreasedwithneckextension.LungvolumesIncreasesby~20mlperlitreofadditionallungvolume.AirwaycalibreBronchodilationincreasesairwaydiameterandthereforeV .
Pathological/AlveolarDeadSpaceDeadspacecausedbydisease.Causesofpathologicaldeadspaceinclude:
ErectpostureDecreasedpulmonaryarterypressure/impairedpulmonarybloodflow
HypovolaemiaRVfailure/IncreasedRVafterload:
HPVMI
PEIncreasedalveolarpressureIncreasesWestZone1physiology.
PEEPCOAD
CalculationofDeadSpaceTwomethodsexisttoallowdeadspacevolumestobecalculated:
PhysiologicaldeadspacemaybemeasuredwithBohr'smethodAnatomicaldeadspacemaybemeasuredbyFowler'smethodPathologicaldeadspacemaybecalculatedbysubtractinganatomicaldeadspace(Fowler'smethod)fromphysiologicaldeadspace(Bohr'sMethod)
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Fowler'sMethod
Fowler'sMethodisasingle-breathnitrogenwashouttest,usedtocalculateanatomicaldeadspaceandclosingcapacity.
Method:
Attheendofanormaltidalbreath(atFRC)avital-capacitybreathof100%oxygenistakenThepatientthenexhalestoRVExpirednitrogenconcentrationandvolumeismeasured.Aplotofexpirednitrogenconcentrationbyvolumeisgenerated,producingagraphwithfourphases:
Phase1(PureDeadSpace)Gasfromtheanatomicaldeadspaceisexpired.Thiscontains100%oxygen-nonitrogenispresent.Phase2Amixofanatomicaldeadspaceandalveolar(lungunitswithshorttimeconstants)isexpired.Themidpointofphase2(whenareaA=areaB)isthevolumeoftheanatomicaldeadspace.Phase3Expirednitrogenreachesaplateauasjustalveolargasisexhaled(lungunitswithvariabletimeconstants).Phase4Suddenincreaseinnitrogenconcentration,whichindicatesclosingcapacity.Thisincreaseoccursbecause:
BasalalveoliaremorecompliantthanapicalalveoliTherefore,duringinspirationbasalalveoliinflatemorethanapicalalveoliThesingle100%oxygenbreaththereforepreferentiallyinflatesthebasalalveoli.Attheendofthevitalcapacitybreath,theoxygenconcentrationinbasalalveoliisgreaterthanthatofapicalalveoli.Inexpiration,theprocessisreversed:
BasalalveolipreferentiallyexhaleAtclosingcapacity,smallbasalairwayscloseandnowonlyapicalalveoli(withahigherconcentrationofnitrogen)canexhaleMeasuredexpirednitrogenconcentrationincreases
Bohr'sMethod
PhysiologicaldeadspaceismeasuredusingtheBohrequation.Thiscalculatesdeadspaceasaratio,orproportionoftidalvolume:
TheBohrequationisbasedontheprinciplethatallCO exhaledmustcomefromventilatedalveoli.
Notethat:
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isthemixed-expiredcarbondioxidePartialpressureofCO inanexpiredtidalbreath.TheBohrequationrequiresalveolarPCO tobemeasuredAsthisisimpractical,theEnghoffmodificationistypicallyused,whichassumesthatPACO ≈PaCO .Theequationthenbecomes:
Anormalvalueforphysiologicaldeadspaceduringnormaltidalbreathingis0.2-0.35
PhysiologicalConsequencesofIncreasedDeadSpace
Indeadspace:
TheV/QratioapproachesinfinityasalveolarperfusionfallsThisresultsinariseinPaCOInaspontaneously-ventilatingindividual,thisstimulatestherespiratorycentretoincreaseminuteventilationtoreturnalveolarventilation(andthereforeCO )tonormalThereisminimaleffectonPaO ,asinpuredeadspaceallbloodispassingthroughventilatedalveoliandthereforeundergoesgasexchange
RelationshipbetweenAlveolarVentilationandPaCO
AtmosphericaircontainsnegligibleCO .AsMVincreases,PaCO willfall,aswillthegradientforfurtherCO diffusion.Thiscanbeexpressedbytheequation:
Notethatthisgraph:
DescribesthechangeinPaCO forachangeinalveolarventilationAdoublingofalveolarventilationwillhalvePaCO .DoesnotdescribethechangeinventilatorydriveforagivenchangeinPaCOThisiscoveredunderremovalofCO .
Footnotes
NotethatWestZone1(wherePA>Pa>Pv)physiologyisincreaseddeadspace.
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ThePaCO -ETCO differenceisaconsequenceofdeadspace,asdeadspacegasdilutesalveolargas.
References1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.
Lastupdated2019-07-18
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ShuntExplaintheconceptofshuntanditsmeasurement
Shuntisbloodreachingthesystemiccirculationwithoutbeingoxygenatedviapassagethroughthelungs.
FactorsContributingtoShunt
NormalshuntAnatomicalshunt
Thebesianveins,whichdraindirectlyintotheleftcardiacchambersBronchialcirculations,whichdrainintothepulmonaryveins
FunctionalshuntBlooddrainingthroughalveoliwithaV/Qbetween0and1.
Thismaynotbetrueshunt,asbloodmayhavesomeoxygencontentbutnotbemaximallyoxygenatedPathologicalshuntPathologicalshuntingcanbeanatomical(e.gcongenitalcardiacmalformations),orphysiological(e.g.pneumoniacausingalveolarconsolidation).
Intra-cardiace.g.VSDExtra-cardiace.g.PulmonaryAVM,PDA
CalculationofShunt
ShuntcannotbedirectlymeasuredThisisbecausewecannotseparatetrueshunt(V=0)fromV/Qscatter(V/Q<1)whensamplingbloodenteringtheleftheartVenousadmixtureisusedinsteadVenousadmixtureistheamountofmixedvenousbloodthatmustbeaddedtopulmonaryend-capillarybloodtogivetheobservedarterialoxygencontent.Venousadmixture:
Isacalculated,theoreticalvalueAssumesthatalveolihaveeithercompleteshunt(noventilationatall,i.e.V/Q=0)ornoshunt(V/Q=1)Isexpressedasaratio,orshuntfraction:
,where:
=Shuntbloodflow
=Cardiacoutput
=Pulmonaryend-capillaryoxygencontent,assumedtohaveanoxygentensionequaltoPAO (withthecorrespondingoxygensaturation)
=Arterialoxygencontent
=Mixedvenousoxygencontent
PhysiologicalConsequencesofShunt
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NoCO candiffusefromshuntedbloodThereforePaCO mightbeexpectedtorise,however:
InaspontaneouslybreathingpatienttheincreasedPaCO increasesrespiratorydrive,andalveolarventilationincreasesTherefore,shuntdoesnottendtoincreasePaCO unless:
TheshuntfractionislargeandThepatientisunabletoincreasetheiralveolarventilationtocompensate
Additionally,thesteepnessoftheCO dissociationcurveatthearterialpointmeansthatalthoughCO contentincreases,theincreaseinPaCO issmall
EffectonOxygen
PaO fallsproportionallytoshuntfractionAsshuntedalveoliareperfusedbutnotventilated,trueshuntissaidtobeunresponsivetoanincreaseinFiOThisiswheretechnicaldefinitionsbecomeimportanttoavoidconfusion.
ForanalveoliwithaV/Qbetween0-1(V/QmismatchorV/Qscatter,butnottrueshunt):Thereisperfusion,butrelativelylessventilationThereforebloodpassingthroughthisalveoliwillbepartiallyoxygenatedIncreasingPAO willimproveoxygenation(assumingnodiffusionlimitation):
AdministrationofsupplementaloxygenHyperventilationAsperthealveolargasequation
ForanalveoliwithaV/Qof0(trueshunt)Thereisnoventilation.RegardlessoftheincreaseinPAO ,PaO willnotimprove.
TheIsoshuntDiagram
IsoshuntdiagramplotstherelationshipbetweenFiO andPaO againstasetof'virtualshuntlines'These'shuntfractions'arecalculatedfromtheaboveequationandsoareactuallyV/Qadmixturefractions
References
1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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OxygenStorageDescribetheoxygenandcarbondioxidestoresinthebody
Thestandardtextbook70kgmalecontains~1.5Lofoxygen,splitbetween:
~850mlinbloodThereis20.4mlofoxygenper100mlofblood,dividedupas:
20.1mlboundtohaemoglobin0.3mldissolved
~250mlboundtomyoglobin~450mlcontainedinFRC(21%of2.4L)Thisiswhypreoxygenationincreasessafeapnoeatimes,asthenitrogenwashoutincreasesthevolumeofoxygenstored.
Oxygen-HaemoglobinDissociationCurveThesigmoidshapeoftheoxygen-haemoglobindissociationcurveoffersmanyphysiologicaladvantages:
BufferingincaseoflowPaOTheplateauallowsoxygencontenttoremainhigh,evenifthePaO fallsMaintenanceofdiffusiongradienttotissuesThesteepsectionallowsalargeamountofoxygentobedeliveredwithonlyasmalldropinPaO ,whichallowstherateofoxygendeliverytobemaintained(astheblood-tissuepartialpressuregradientissteep)withanincreaseinoxygendemand.
ThesigmoidshapeexistsduetocooperativebindingEachoxygenwhichbindstoHbcausesconformationalchangeswhichallowitbindadditionaloxygenmoleculesmoreeasily.
Whenthefourthoxygenmoleculehasbound,Hbissaidtobeintherelaxedconformation(Rstate)Whennooxygenisbound,Hbissaidtobeinthetensestate(Tstate)
Thecurvecanberightorleft-shiftedbychangesintemperature,pH,CO ,and2-3DPG
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Notethatthemixedvenouspointisnotonthearterialcurve(unlikehowitisdisplayedabove),asthevenousdissociationcurveisright-shiftedrelativetothearterialcurve
HaemoglobinSpecies
Haemoglobinisafour-tetramermolecule,anditsspeciescanbephysiologicalorpathological:
PhysiologicalHbA
Mostcommon2alphaand2betasubunits(α β )
HbALesscommon2alphaand2deltasubunits(α δ )
HbFFoetalHbHigheraffinityforoxygenduetolackof2,3-DPG2alphaand2gammasubunits(α γ )
PathologicalHbSSickle-celldisease.
AbnormalbetasubunitUnabletodeformastheypassthroughcapillaries
Increasesbloodviscosity,thrombus,andischaemiathroughcapillaryocclusionOftencausessplenicinfarction
Reducedredcelllifespanto10-20days
MetHbMethaemoglobinaemia.
Ferrousiron(Fe )isoxidisedtoferriciron(Fe )Cannotbindoxygen,andleft-shiftstheoxyHbcurvefornormalHbwhichreducesoxygenoffloadingattissuesNormallypreventedby:
GlutathioneinredcellreducesoxidisingagentsMethaemoglobinreductaseenzymeusesNADHtoreduceMetHb
Occursdueto:Oxidisingagentsoverwhelmcapacityofglutathionesystem,e.g.:
SNPNOAmidelocalanaesthetics
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SulfonamidesFailureofthemethaemoglobinaemiareductaseenzyme
G6PD
COHbCarboxyhaemoglobin.
Haemoglobinbindscarbonmonoxidewithgreateraffinitythanoxygen
CyanoHbHaemoglobinirreversiblybindscyanidemolecules,causingafunctionalanaemiaCyanideinhibitscytochromeoxidaseintheelectrontransportchain,preventingoxidativephosphorylationoccurring
OxygenSaturation
OxygenSaturationcanbedefinedintwoways:
FunctionalSaturation
However,additionalhaemoglobinspeciesexistinvaryingamounts,andthisdefinitionmaydeceptivelyimplygoodoxygendeliverywhenthisisnotthecase.
FractionalSaturation
Fractionalsaturationincludescarboxy-andmet-haemoglobin,andsoisamoreaccurateestimatorofoxygensaturation.
Notethatpulseoximetrydoesn'tmeasureeitheroftheseandisdependentonthecalibration,butwilltypicallymeasurefunctionalsaturation.
Myoglobin
MuscleishighlymetabolicallyactiveandhasalargeO demand.MyoglobinservesasanO storeformuscle.ItissimilartoHbinthatitisalargeO -bindingiron-containingproteinmyoglobin,andisdifferentbecauseit:
Containsoneglobinchainandonehaemegroup(bindingoneO molecule),andsodoesnotexhibitcooperativebindingThemyoglobindissociationcurvethereforehasarapidupstrokeandanearlyplateau.HasaP of2.7mmHgThisallowsittotakeupoxygenfromhaemoglobin(asthepartialpressuregradientfavoursdiffusionintothecell),andunloaditintothecell(soitcanactuallybeused).Isfoundinskeletalandcardiacmuscle
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. BrandisK.ThePhysiologyViva:Questions&Answers.2003.
Lastupdated2019-07-18
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CarbonDioxideDescribetheoxygenandcarbondioxidestoresinthebody
DescribethecarbondioxidecarriageinbloodincludingtheHaldaneeffectandthechlorideshift
Explainthecarbondioxidedissociationcurve
Describethemovementofcarbondioxidefrombloodtotheatmosphere
CO isproducedinthemitochondriaduringthecitric-acidcycleasaproductofmetabolism.
Thereis~120LofcarbondioxideinthebodyAtotalof1.8L.kg ,1.6L.kg ofwhichisinrelativelyinaccessiblecompartments.Normalelimination(and,atsteadystate,production)ofcarbondioxideis200ml.min
CarbonDioxideinBlood
Inblood,CO isstoredas:
Bicarbonate(90%)DissolvedgasCarbaminocompounds
Form ArterialBlood AdditionalCO invenousblood
Bicarbonate 90% 60%
Dissolved 5% 10%
Carbaminocompounds 5% 30%
Bicarbonate
CO diffusesfreelyintoerythrocytes,whereitcanbecatalysedbycarbonicanhydrasetoproducebicarbonate:
Tomaintainbicarbonateproduction,theproducts(H andHCO )arethenremoved:H ionsarebufferedtohaemoglobin
IntracellularHCO isthenexchangedwithextracellularCl-viatheBAND3membraneproteinThisiscalledtheHamburger,orChlorideShiftChlorideenteringthecelldrawswaterinalongitsosmoticgradient,increasingthehaematocritofvenousbloodrelativetoarterialblood
DissolvedGas
AsperHenry'sLaw,theamountofcarbondioxidedissolvedinbloodisproportionaltothePaCOAscarbondioxideis20xassolubleasoxygeninwater,dissolvedcarbondioxidecontributesmuchgreaterproportionofcarbondioxidecontentthandissolvedoxygendoestooxygencontent
CarbaminoCompounds
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CO canbinddirectlytoproteins(predominantlyhaemoglobin),whichdisplacesaH ion:
TheH ionisthenbufferedbyanotherplasmaprotein(alsopredominantlyhaemoglobin)
BoundCO doesnotcontributetothepartialpressuregradientCarbaminocompoundsareonlyasmallcontributortooverallCO carriage,butcontributeaboutonethirdofthearterio-venousCO differenceduetotheHaldaneeffectTheHaldaneeffectstatesthatdeoxyHbbindsCO moreeffectivelythanoxyHb.Thisisbecause:
DeoxyHbisabetterbufferofHpKaofdeoxyHbis8.2,comparedtothatofoxyHbwhichis6.6.
Enhancedbufferingcontributes~30%oftheHaldaneeffectDeoxyHbformscarbaminocompoundsmoreeasilyDeoxy-Hbhas3.5xtheaffinityforCO thanOxy-Hb.
Thisforms~70%oftheHaldaneeffect
CO DissociationCurve
ThiscurveplotsPCO againstbloodCO contentinml.100ml .
Keypoints:
MixedvenousCO contentis52ml.100ml ,ataPCO of46mmHgArterialCO contentis48ml.100ml ,ataPCO of40mmHgApproximately50%ofthearterial-mixedvenousdifferenceoccursduetotheupwardsshiftofthecurve,whichisduetotheHaldaneeffectThisisthemechanismforchangesinPO affectingtheCO dissociationcurve.
RemovalofCO
CO dissolvesfrompulmonaryarterialbloodintothealveolusdownaconcentrationgradient.AsinspiredCO isnegligible,PACO isafunctionofalveolarventilationandCO output,givenbytheequation:
Simplified,PaCO isinverselyproportionaltoalveolarventilation:
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DistributionofCarbonDioxide
CO inthebodycanbeconsideredasathree-compartmentmodel:
Well-perfused(blood,brain,kidneys)Moderately-perfused(restingmuscle)Poorly-perfused(bone,fat))
Eachofthesetissueshasadifferenttime-constant,suchthatamismatchofventilationwithmetabolicactivitymaytake20-30minutestoequilibrateacrosscompartments
ThereforehypoventilationandhyperventilationhavedifferenteffectsonPCO :HyperventilationcausesarapiddecreaseinPCO inblood,subsequent(slower)redistributionfromperipheralcompartmentsHypoventilationcausesariseinPaCO ,therateofwhichisdeterminedbothbyproductionanddistributionintoplasma
Withnoventilation,PCO risesat3-6mmHg.minDuetotheHaldaneeffectthePaCO willrapidlyincreaseduringpassagethroughthepulmonarycapillary(despitethefactthatcarbondioxidecontentisunchanged)astheproportionofOxyHbincreases
Therefore:PaO ismoresensitiveatdetectingearlyhypoventilationprovidedPAO isnormalSteady-statePCO givesthebestindicationofadequacyofventilation
Inacutehypoventilation,producedCO ispreferentiallystoredintissues,decreasingCO eliminationInacutehyperventilation,CO ismobilisedfromtissuesresultinginincreasedCO elimination
CO Cascade
Region Value(mmHg)
MixedVenous 46
Alveolar 40
(Arterial) 40
Mixed-expired 27
VenousCO diffusesintothealveolus,reachingequilibriumwitharterialPCOAlveolarCO isthendilutedbydeadspacegas,resultinginalowerME'CO
References
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1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. FRCA:AnaesthesiaTutorialoftheWeek-RespiratoryPhysiology
Lastupdated2018-04-24
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PositivePressureVentilationDescribethephysiologicalconsequencesofintermittentpositivepressureventilationandpositiveend-expiratorypressure.
Physiologicaleffectsofpositivepressureventilationaremostlyrelatedtotheincreasedmeanairwaypressure.Thisisafunctionof:
VentilationmodeTidalvolumeandpeak(andplateau)airwaypressureRespiratoryrateI:EratioPEEPPEEPhasamuchlargereffectthantheotherfactors.
PEEPisdefinedasapositiveairwaypressureattheendofexpirationPEEPisdistinctfrompositiveairwaypressure(whichisnotconfinedtoaphaseoftherespiratorycycle)andCPAP(whichisamodeofventilation)iPEEPreferstointrinsicPEEP,autoPEEPordynamichyperinflationiPEEPisPEEPgeneratedbythepatient,andoccurswhenexpirationstopsbeforethelungvolumereachesFRC.
ApplicationofexternalPEEPmaylimitthegenerationofiPEEPbymaintainingairwaypatencyinlateexpiration
RespiratoryEffectsDecreasedworkofbreathing
DecreasedVOMoreimportantwhenworkofbreathingishigh.
Alterationinanatomical/apparatusdeadspaceIntubationtypicallyreducesdeadspace,astheadditionalapparatusdeadspaceisofsmallervolumethantheanatomicaldeadspaceitreplacesNon-invasiveventilationmaskscausealargeincreaseindeadspace
Increaseslungvolume(andFRC,forPEEP)byanamountproportionaltothecomplianceofthesystemImprovesoxygenationviaalveolarrecruitmentImproveslungcomplianceviaalveolarrecruitment,reducingworkofbreathingElevatedairwaypressuresmayincreasetheproportionofWestZone1physiologyandalveolardeadspace
Inhealthylungsanincreaseinthe ratioisseenwhenPEEPexceeds10-15cmH O.ReducesairwayresistanceAirwayresistancedecreasesaslungvolumeincreases.
CardiovascularEffectsAlterationincardiacoutput
PEEPandIPPVgenerallydecreaseCOviadecreasingVRduetotheincreaseinintrathoracicpressure.LeadstoreductioninRVfillingpressure,LVfilling,andCO.
ThisisthepredominantreasonwhyCOfallswiththeapplicationofPEEPInawellpatient,COfallsby:
10%withIPPVandZEEP18%withIPPVand9cmH OofPEEP36%withIPPVand16cmH OofPEEP
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Thesechangesare:MoremarkedinhypovolaemiaChangesarereversedwithvolumeexpansion.LessseverewithpoorlungcomplianceReducedcompliancegreatlyreducestheeffectofPEEPandIPPVonthevasculature,asthechangeinintrapleuralpressureisreduced.
LVpreloadmayalsobereducedduetoincreasedRVafterloadIncreasedRVafterloadmayincreaseRVEDV,displacingtheinterventricularseptumintotheLVThebulgingseptumdecreasesLVEDV,causingLVdiastolicfunctionandreducedLVfillingThisisanexampleofventricularinterdependence.
ReducedLVafterloadduetoreducedLVtransmuralpressureInsomecases,IPPVaugmentscirculatoryfunctionbyreducingLVafterloadtoagreaterextentthanpreload.
Effectsinawellpatientareminimal,asPEEPisrelativelysmallinmagnitudecomparedtosystemicarterialpressuresInpatientsgeneratinghighlynegativeintrathoracicpressures,theLVtransmuralpressurecanincreasemarkedly,increasingLVafterloadandreducingcardiacoutput
ReductioninMAPMAPdecreasesasPEEPincreases.
ChangestooxygenfluxPEEPwilltendtoimprovePO whilstreducingCO.
ChangestopulmonaryvascularresistanceandRVafterloadIflungvolumeislowerthanFRC,thenPVRwillreduceasPEEPstretchesopenextra-alveolarvessels
Alveolarrecruitmentwillreducehypoxic-pulmonaryvasoconstriction,furtherreducingPVRIflungvolumeishigherthanFRC,thenPVRwillincreaseasPEEPcompressesalveolarvesselsTherefore,PEEPhasvariableeffectsonRVafterloaddependingonhowitchangeslungvolumewithrespecttoFRC
End-OrganEffects
Reducedurineoutputdueto:ReducedCOandrenalbloodflowADHreleaseasaconsequenceofreducedatrialstretchandANPreleaseMayworsenoedemainpatientswithprolongedperiodsofventilation.
Reducedhepaticbloodflowdueto:IncreasedCVPanddecreasedCOloweringthepressuregradientforhepaticflow
Mayresultincirculationonlyintermittentlythroughoutthecardiaccycle
References
1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. LueckeT,PelosiP.Clinicalreview:Positiveend-expiratorypressureandcardiacoutput.CriticalCare.2005;9(6):607-621.
doi:10.1186/cc3877.3. Yartsev,A.PositiveEnd-ExpiratoryPressureandit'sconsequences.DerangedPhysiology.4. Yartsev,A.PositivePressureandPEEP.DerangedPhysiology.5. Yartsev,A.IndicationsandContraindicationsforPEEP.DerangedPhysiology.6. Yartsev,A.EffectsofPositivePressureandPEEPonAlveolarVolume.DerangedPhysiology.7. Yartsev,A.[PEEPandIntrinsicPEEP}(http://www.derangedphysiology.com/main/core-topics-intensive-care/mechanical-
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ventilation-0/Chapter%202.1.6/peep-and-intrinsic-peep).DerangedPhysiology.
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HypoxiaExplainthephysiologicaleffectsofhyperoxia,hypoxaemia,hypercapnia,hypocapnia,andcarbonmonoxidepoisoning.
HypoxaemiaisalowpartialpressureofoxygeninbloodHypoxiaisanoxygendeficiencyatthetissues,dueto:
ImpairedoxygendeliveryImpairedoxygenextraction
Oxygendeliveryisgivenbytheequation:
,where:
1.34isHüfner'sconstantThisistheoxygencarryingcapacityofhaemoglobin,inml.g (ofHb).
Thetheoreticalmaximumis1.39Invivoitis1.34duetotheeffectofcarboxyhaemoglobinandmethaemoglobincompounds,whichlimitO binding
0.03isthesolubilitycoefficientofO inwaterat37ºC,inmls.mmHgCanalsobeexpressedas0.003mls.dL .mmHg (mlsperdeciliterpermmHg).Differenttextsusedifferentvalues,dependingonwhetherhaemoglobinisreporteding.L org.100ml .
ClassificationsandCausesofHypoxia
Hypoxiacanbecategorisedintofourtypes:
HypoxichypoxiaAnaemichypoxiaIschaemichypoxiaHistotoxichypoxia
HypoxicHypoxia
Hypoxichypoxia,orhypoxaemia,ishypoxiaduetolowPaO (andthereforelowSpO ),typicallydefinedasaPaO <60.
CausesofhypoxaemiacanbefurtherclassifiedbasedontheirA-agradient:
CausesofhypoxaemiawithanormalA-agradient:LowPiODecreasedalveolarventilation
CausesofhypoxaemiawitharaisedA-agradient:DiffusionlimitationShunt(Increasedoxygenextraction)
LowFiO
HypoxaemiaoccursathighaltitudeswhenthePO isdecreased.
Decreasedalveolarventilation
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Afallinalveolarventilation( )causesariseinPACO ,andthereforedecreasesPAO .DecreasedV canoccurwith:
Respiratorycentredepression:DrugsHeadinjury(RaisedICP,closedheadinjury)EncephalopathyFatigue
Nervedysfunction:SpinalcordinjuryGBSMND
NMJdysfunction:ParalysisMG
Musculardysfunction:MyopathyFatigueMalnutritionDystrophy
Chestwallabnormalities:KyphoscoliosisAnkylosingSpondylitisPleuralfibrosis
DiffusionLimitation
ImpaireddiffusionofO acrossthemembraneresultsinaloweredPaO .Diffusionlimitationoccursdueto:
DecreasedalveolarsurfaceareaIncreasedalveolarcapillarybarrierthickness
PulmonaryfibrosisARDS
Shunt
Shuntoccurswhenbloodreachesthesystemiccirculationwithoutbeingoxygenatedviapassagethroughthelung.Asthealveolusisperfusedbutnotventilated,thustheV/Qratiois0.
Administrationof100%O haslesseffectonPaO asshuntfractionincreasesOxygencontentofshuntedalveoliisidenticaltomixedvenouscontentOxygencontentofnon-shuntedalveolidoesnotincreaseappreciablyathighpartialpartialpressuresashaemoglobinisalreadyfullysaturated
Shuntphysiologyisexploredinmoredetailundershunt.
IncreasedOxygenExtraction
Increasedoxygenextraction(VO )willnottypicallycausehypoxiaThisisbecause:
NormalVO is250ml.minNormalDO is1L.min
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Maximaloxygenextractionratiois~70%(thoughitvariesbetweenorgans)ThereforeVO canincreaseuntilitreaches70%oftheDO ,apointcalledcriticalDO .
However,itmayworsenhypoxiainthepresenceofasupply-side(DO )pathology
AnaemicHypoxia
ImpairedoxygendeliveryduetolowHbTypicallyasymptomaticatrestbutlimitsexercisetolerance
Compensationoccursbyincreasinglevelsof2,3-DPG,causingaright-shiftintheHb-O dissociationcurvetofavouroxygenoff-loadingattissues
CarbonMonoxidePoisoning
COpoisoningisclassifiedasasubsetofanaemichypoxiaascarboxyhaemoglobinreducestheeffectiveamountofhaemoglobininsolutionCOhas210timestheaffinityforHbthanO
COrapidlydisplacesO fromHbandisliberatedslowlyCOpoisoningcausesheadacheandnausea,butnoincreasedrespiratorydrivesincethePaO isunchanged
IschaemicHypoxia
Ischaemichypoxiaisduetoimpairedcardiacoutputresultinginimpairedoxygendelivery
HistotoxicHypoxia
Histotoxichypoxiaisduetoimpairedtissueoxidativeprocesses,preventingutilisationofdeliveredoxygenMostcommoncauseofhistotoxichypoxiaiscyanidepoisoning,whichinhibitscytochromeoxidaseandpreventsoxidativephosphorylationManagedbyusingmethyleneblueornitrites,whichformmethaemoglobin,inturnreactingwithcyanidetoformthenon-toxiccyanmethaemoglobin
EffectsofHypoxia
WithanormalPaCO ,PaO mustfallto50mmHgbeforeanincreaseinventilationoccursWitharisingPaCO ,afallinPaO below100mmHgwillstimulateventilationviaactiononcarotidandaorticbodychemoreceptors
Theeffectsofeachstimuliaresynergistic,andgreaterthanwhatisseenwitheithereffectalone
Prolongedhypoxaemiawillalsoleadtocerebralacidosis(viaanaerobicmetabolism),whichwillstimulatecentralpHreceptorsandstimulateventilation
Acid-BaseChanges
Hypoxiaresultsinbothfixedandvolatileacid-basedisturbancesAnaerobicmetabolismresultsinlactateproductionProductionoffixedacidresultsinabasedeficit,andalowbicarbonateHypoxiaandmetabolicacidosisstimulateventilationandhypocarbia
CO retention
InchronichypercarbiatheCSFpHnormalises(asbicarbonateissecretedintoCSF),witharaisedCO
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FallinPaO becomesthepredominantstimulusforventilation
References1. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.2. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.3. CICMJuly/September20074. ICUBasicBook.
Lastupdated2019-07-18
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HypoandHypercapneaExplainthephysiologicaleffectsofhyperoxia,hypoxaemia,hypercapnia,hypocapnia,andcarbonmonoxidepoisoning
Carbondioxideislipidsolubleandcanrapidlycrossmembranes,allowingitaffectacid-basestatusinanycompartment.
Hypercapnea
RespiratoryEffects
IncreasedrespiratorydriveviachemoreceptorstimulationCVSeffects
PeripheralvasodilationMaycausetachycardiafromsympatheticstimulation
PulmonaryvasoconstrictionMyocardialdepressionIntracellularacidosis.Arrhythmogenic
CNSeffectsIncreasedCBFIncreasedICPsecondarytoincreasedCBFSNSactivationCNSdepressionWhenPaCO >100mmHg
HypocapneaRespiratoryEffects
Left-shiftofoxyhaemoglobindissociationcurveRespiratorydepression
CVSeffectsMyocardialdepressionIntracellularalkalosis.
CNSeffects
DecreasedcerebralbloodflowElectrolyteeffects
DecreasedserumKDecreasedserumCaLeadstoparesthesiasandtwitches.
Ca bindstoH bindingsiteonalbumin
References
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1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.
Lastupdated2019-07-18
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PositionandventilationExplaintheeffectofchangesinpostureonventilatoryfunction
AlteredpatientpositioncancausesignificantchangestoV/Qmatching.
LateralDecubitus
Inthelateralpositioninaspontaneouslyventilatingpatient:
Dependentlungventilationimprovesby~10%Duetoimpairedcomplianceofthenon-dependentlung(ithyperinflates)andimprovedcomplianceofthedependentlung(itislessexpanded).
DependentlungcorrespondsmoretoWestZone3Non-dependentlungcorrespondsmoretoWestZone2
Dependentlungperfusionimprovesby~10%Duetotheeffectofgravity.
Inthelateralpositioninapositive-pressureventilatedpatient:
Themajority(~55%)ofthetidalvolumeisdeliveredtothenon-dependentlungThemajorityofpulmonarybloodflowisdeliveredtothedependentlungThecomplianceofthedependentlungfallsduetocompressionfromthe:
MediastinumAbdominalorgansThesemovecephaladinaparalysedpatient.
ThedependentlungtypicallyreceivesgreaterbloodflowduetotheeffectofgravityThismayworsenV/QmatchingBloodflowisalsoaffectedby:
HPVAnatomicalfactorsBloodflowisgreaterincentralthanperipheralportions.LungvolumeAlterationsisextra-alveolarandintra-alveolarpressuresatFRCmayalterregionalbloodflow.
Whenbothlungsarebeingventilated,V/QmatchingcanbeimprovedwithselectiveapplicationofPEEPtothedependentlung,whichimprovescompliance
ThoracotomyOpeningofanon-dependenthemithoraxcauses:
IncreasedcomplianceandFRCofthenon-dependentlungReducedcomplianceandFRCofthedependentlung
References1. Dunn,PF.PhysiologyoftheLateralDecubitusPositionandOne-LungVentilation.ThoracicAnaesthesia.Volume38(1),
Winter2000,pp25-53.
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2. GraphfromBenumofJL,ed.Anesthesiaforthoracicsurgery.2nded.Philadelphia:WBSaundersCompany,1995.3. ANZCAAugust/September2015
Lastupdated2017-09-20
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HumidificationDefinehumidityandgiveanoutlineoftheimportanceofhumidification
Humidificationdescribestheamountofwatervapourpresentinair:
AbsoluteHumidityistheamountofwatervapourinagivenvolumeofair(g.m )RelativeHumidityistheratiobetweentheamountofwatervapourinasampleofair(absolutehumidity)andtheamountofwaterrequiredtofullysaturatethatsampleatitscurrentpressureandtemperature
Moistureisthewaterproducedbycondensationwhenrelativehumidityexceeds100%.
Humidificationofinspiredairisimportanttoavoiddryingoutmucosaandsputum,whichleadstotissuedamageandfailureofthemucociliaryelevatorOptimalfunctionrequiresarelativehumidityofgreaterthan75%
MechanismThenoseis:
OptimisedforhumidificationTheseptumandturbinatesincreasecontactofairwithmucosalsurfacesby:
IncreasingsurfaceareaGeneratingturbulentflow
ThepreferredorificeforbreathingunlessairwaysresistancebecomesasignificantlylimitingfactorThisisrelevantin:
Airwayobstruction(e.g.polyps)Athighminuteventilations(>35L. )
Humidifiesinspiredgasto90%,comparedto60%forthemouth
Methodofhumidification:
FluidliningtheairwayactsasaheatandmoistureexchangerIninspiration:
RelativelydryairisevaporateswaterfromtheairwayliningRelativehumidityisincreasedto90%inthenasopharynxand100%BTPSbythesecondgenerationofbronchiThisgivesawatervapourpressureof47mmHgatBTPS,withanabsolutehumidityof44g.m .
Inexpiration:AircoolsintheupperairwayAscoolerairhasalowersaturatedvapourpressure,moisturecondensesontheairway.MoistureisreabsorbedThisreducespotentialwaterlossesfromtheairwayfrom300ml.day to150ml.day .
References1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. WeatherFaqs.AbsoluteandRelativeHumidity.3. CICMSeptember/November2012
Lastupdated2018-09-21
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CoughReflexExplainthepathwaysandimportanceofthecoughreflex
Coughing:
IsanairwayprotectionreflexInvolvesdeepinspirationfollowedbyforcedexpirationagainstaclosedglottisThesuddenopeningofthecordscausesaviolentrushofairat>900km.h ,removingirritantsandsecretionsfromtheairways.
SensationVagusafferentshaveexquisitelysensitivelighttouchandcorrosivechemicalreceptorsinthelarynx,carina,terminalbronchioles,andalveoli.
IntegrationVagalafferentssynapseinthemedulla,whichcoordinatestheeffectorresponse.
EffectorAseriesofprocessesoccurinthreephases:
InspiratoryphaseAclosetovitalcapacitybreathistaken.CompressivephaseEffortclosureoftheepiglottistosealthelarynx,followedbyaviolentcontractionofabdominalmusculatureandinternalintercostals,causingarapidriseinintrapleuralpressureto>100mmHg.ExpulsivephaseWide-openingofthecordsandepiglottis,causingaviolentexpiration.
Compressionofthelungscausesnarrowingofthenoncartilaginousairwaysandincreasesturbulentflow,removingadherentmaterialfromthetracheobronchialtree
References
1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.
Lastupdated2019-07-18
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Non-RespiratoryFunctionsOutlinethenon-ventilatoryfunctionsofthelungs
Thelungsareauniqueorganas:
TheentirecardiacoutputpassesthoughthepulmonarycirculationTheyhaveahugecapillarybedwhichbloodisincontactwithTheyhavealargeinterfacewiththeexternalenvironment
Consequentlytheyareadaptedtoanumberofnon-respiratoryfunctions,whichinclude:
FiltrationImmunedefenceBloodresevoirMetabolismDrugDelivery
(Takingupdrugs)InhalationalAnaesthetics
SyntheticEndocrine
FiltrationTheentirecardiacoutputpassesthroughthe7μmpulmonarycapillaries,whichactasaneffectivesieveforparticulatematter.Thisfunctionmaybeimpairedbyintra-cardiacshunting(e.g.PFO)orpre-capillaryanastomoses.
Complementingthisrole,thelungsareabletoclearthrombimorerapidlythanotherorgansaspulmonaryendotheliumhasahighconcentrationofplasminactivatorandheparin.
Metabolism
Thepulmonaryendotheliumhasavarietyofeffectsondrugsandendogenoushormones:
Class Activated Inactivated
Amines 5-HT,Noradrenaline
Peptides AngiotensinI(viaACE) Bradykinin,ANP
Arachidonicacidderivatives Arachidonicacid Manyprostaglandins
OtherDrugs Lignocaine,fentanyl
BloodReservoir
Thehighlycompliantpulmonarycirculationcontainsaresevoirof~500mlofbloodwhichactsasavolumereservefortheLV.
Defence
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Thelargesurfacearearequiredforgasexchangeleavesthelungvulnerabletoinvasionbyairbornsubstances.Thisisattentuatedby:
MucousAmucouslayerprotectslargeairways,aslarge(>8μm)particlesimpactintothemucous.
MucousisexocytosedbygobletcellsinresponsetonoxiousstimuliincludingchemicalirritationaswellasinflammatoryandneuronalstimulationTheefficacyofthemucous-ciliasystemisenhancedbybronchoconstriction,whichreducesflowvelocityandcausesparticulatemattertosettle
CiliaCiliaareprojectionsfromepitheliumwhichbeatrhythmicallyat~12Hztopropelmucousoutoftheairwayatarateof~4mm.min .
Ciliaryfunctioncanbeimpededbypollutants,smoke,andinfectionCiliaryfunctionisstimulatedbyanaestheticagents
Inhaledparticleswhichreachtherespiratoryzonearenottrappedbymucous,butinsteadphagocytosedbyalveolarmacrophagesBronchoconstrictionreducesflowvelocityandcausesparticulateparticlestosettleinthemucous
DrugDelivery
Thesamepropertiesthatoptimisethelungforgasexchangeoptimiseitfordeliveryofinhaledagents.Drugsabsorbedinthepulmonarycirculationare:
LipophilicAlkaline(pKa>8)
EndocrineImportantendocrinefunctionsofthelunginclude:
Releaseofinflammatorymediatorssuchashistamine,endothelin,andeicosanoidsReleaseofnitricoxidetoregulatesmoothmuscleACEmetabolisesangiotensinItoangiotensinII
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
Lastupdated2019-07-18
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AltitudePhysiologyAltitudecausesanumberofphysiologicaleffects,relatedto:
ReduceatmosphericpressureReducedtemperatureReducedrelativehumidityIncreasedsolarradiation
PressureEffects
ReducedairpressureresultsinaproportionaldecreaseinPO :
At3,000m,alveolarPO is60mmHgAt5,400m,consciousnessislostinunacclimatisedindividualsAt10,400m,airpressureis187mmHgWith47mmHgofwatervapourandanalveolarPCO of40,breathing100%O givesanalveolarPO of100mmHg.At14,000m,consciousnessislostdespite100%OAt19,200m,theambientpressureissolowthattheboilingpointofwateris37°CThisistheArmstronglimit.
Respiratory
FallinPaO iscompensatedbyincreasingminuteventilation,whichdecreasesPACO andthereforeincreasesPAOLimitsofcompensationarereachedon100%oxygenat13,700m
Effectivecompensationislimitedbytherespiratoryalkalosis,thisisknownasthebrakingeffect:PeripheralchemoreceptorsdetecthypocapneaCentralchemoreceptorsdetectalkalosis
ThesubsequentrespiratoryalkalosisgeneratesacompensatorymetabolicacidosisThisacidosisrelaxesthebrakingeffectandallowsfurtherhyperventilation,andisthereforeamimportantpartofacclimatisation.
Thereisaninitialleft-shiftoftheoxygen-haemoglobindissociationcurveduetoalkalosisThisstimulatesacompensatoryincreasein2,3-DPGtoright-shiftthecurveandimproveoxygenoffloadingatthetissues
Cardiovascular
PVRincreasesduetoHPVHeartrateincreasesduetoincreasedSNSoutflow
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Strokevolumefalls(cardiacoutputremainsthesame)duetodecreasedpreload:Plasmavolumefallsdueto:
PressurediuresisInsensiblelossesfromhyperventilationandreducerelativehumidity
MyocardialworkincreasesIncreasedHRIncreasedviscosityofbloodduetohighhaematocritIncreasedRVafterloadfromhighPVRIncreasedpulmonarycapillaryhydrostaticpressuresleadtofluidtransudationandpulmonaryoedema
Haematological
IncreasedriskofthromboticeventstodueincreasedhaematocritIncreasedredcellmassduetoEPOsecretion
References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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RespiratoryChangeswithObesityDiscusstheeffectofmorbidobesityonventilation
Obesityisamultisystemdisorderdefinedbyanelevatedbodymassindex(BMI):
Normal:BMI<25Overweight:BMI25-30Obese:BMI>30MorbidlyObese:
ObesityrelateddiseaseandaBMI>35BMI>40
Characteristicsofobesityinclude:
ComplexgeneticandenvironmentalcausesIncreasedcaloricintakeIncreasedmetabolicrate(normalforBSA)
Morbidobesitycausesseveralchangestotherespiratorysystem:
AirwayIncreasedriskofOSAIncreasedriskofGORDandaspirationIncreasedriskofdifficultbag-maskventilationIncreasedriskofdifficultylaryngoscopy
ChangestorespiratorypatternIncreasedminuteventilation
SecondarytoincreasedVO andVCODuetotheincreaseinLBWandadiposity.IncreasedairwayreactivityCentraladiposityincreasescirculatingcytokines,includingTNF-α,IL-6,leptin.
ChangestovolumesandcapacitiesReducedrespiratorysystemcompliance
DecreasedchestwallcomplianceDuetoabdominalandchestwallfat.
FatdistributionmaybemoreimportantthanabsoluteBMIDecreasedlungcomplianceBasalatelectasisduetoabdominalcompressionandreducedrespiratorycompliance.
DecreasedERVandFRCNotethatRVisgenerallyrelativelyunchanged
IncreasedairwayresistanceDuetodecreasedairwayradiusatlowerlungvolumes.IncreasedworkofbreathingDuetoreducedrespiratorycomplianceandincreasedairwayresistance.ClosingcapacityencroachesonFRCAsFRCfalls,closingcapacitybecomesclosertoFRC.
Ifclosingvolumeexceedsexpiratoryreservevolume,thensmallairwayswillcollapseduringnormaltidalbreathing,causingshunt
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IncreasedA-agradientOccurswhenclosingcapacityexceedsFRC.
ChangestorespiratorycirculationPVRincreasesduetoreducedFRCcausingincreasedHPVMayleadtosecondaryPHTNandrightheartdysfunction.
References
1. AlvarezA,BrodskyJ,LemmensH,MortonJ.MorbidObesity:Peri-operativeManagement.Cambridge:CambridgeUniversityPress.2010.
2. LotiaS,BellamyMC.Anaesthesiaandmorbidobesity.ContinEducAnaesthCritCarePain2008;8(5):151-156.
Lastupdated2017-09-21
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RespiratoryChangesinNeonatesandChildren
TransitionatBirth
Transitionfromplacentalgasexchangetopulmonarygasexchangeoccurswithin20safterbirth:
CompressionofthethoraxthroughthevaginalcanalexpelsfoetallungwaterElasticrecoil,combinedwithcoolingoftheskinandmechanicalstimulation(whichstimulatetherespiratorycentre),facilitatefirstbreath
Therapiddropinpulmonaryvascularresistancewithspontaneousbreathingdrivesthechangesinthecardiaccirculation
ThefirstthreebreathsestablishfunctionalresidualcapacityLargechangesinintrathoracicpressureinthefirstthreebreathspressuredrivealveolaramnioticfluidintothecirculation,andestablishFRC.
NeonatesandChildrenComplianceNeonatalchestwallsarehighlycompliantrelativetotheirlungs(duetobothareducedlungcomplianceandincreasedchestwallcompliance),ascomparedtoadultswherelungandchestcomplianceisequal.Thereforeelasticworkofbreathingislargelydeterminedbythelungs.
OxygenationO consumptionis~10ml.kg .min inneonates,and6ml.kg .min inchildrenThereisa~10%shuntafterbirthwhichcontributestoagreaterA-agradient
VentilationObligatenosebreathersIncreasedCO productionduetohighermetabolicrateIncreasedminuteventilation,whichisduetoincreasedrespiratoryrate(25-40breathsperminute)
NeurologicalcontrolofbreathingRespiratorypatternschangefollowingbirth,andcompletechangetoadultrespiratorypatternsmaytakesomeweeks.Patternsinclude:
PeriodicbreathingisaslowlyoscillatingrespiratoryrateandVPeriodicapnoeaisintermittentapnoeainterspersedwithnormalbreathing.
Volumesandcapacities
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Closingcapacityisincreasedrelativetoadults,causingshuntFunctionalresidualcapacityisunchangedTidalvolumeanddeadspaceareunchanged
LaryngealanatomyLargeheadLargetongueLarge,stiff,U-shapedepiglottisElevatedlarynxGlottisisatC-3C4(C6inadults).Upperairwayisnarrowestatthecricoidring(ratherthantheglottis).Tracheaisshorterandnarrower4-5cmlong,6mmdiameterintheneonate.
SmallairwaysReducedbronchialsmoothmusclesobronchospasmisuncommonBronchiolescontribute50%ofairwaysresistanceBronchiolitismuchmoredistressinginneonatesandchildren.
References1. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.2. CICMMarch/May2013
Lastupdated2018-07-14
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Anti-AsthmaDrugsDescribethepharmacologyofanti-asthmadrugs.
OxygenIncreasesFiO andimprovessaturation.HelioxReducesspecificgravityofinhaledgasmixtures,improvinglaminarflow.β -agonistsActsonaG-proteincoupledreceptorto↑cellularlevelsofadenylylcyclase,↑cAMP,whichresultsinsmoothmusclerelaxationandbronchodilatation.CorticosteroidsGlucocorticoidsaresteroidhormonesthatbindtospecificintracellularreceptorsandtranslocateintothenucleus,wheretheyregulategeneexpressioninatissue-specificmanner.Theyareusedinasthmaastheycause:
BronchodilatationbyincreasingbronchialsmoothmuscleresponsetocirculatingcatecholaminesDecreasedairwayoedemabydecreasinginflammatoryresponsesandtransudateproduction
MuscarinicantagonistsAnti-muscarinicsaresyntheticquaternaryammoniumcompoundswhichcompetitivelyinhibitM3muscarinicreceptorsonbronchialsmoothmuscle,antagonisingthebronchoconstrictoractionofvagalimpulses.MethylxanthinesMethylxanthinesarephosphodiesteraseinhibitors,reducinglevelsofcAMPhydrolysisandincreasedintracellularlevelsofcAMP(viaadifferentmechanism,sotheyaresynergisticwithβ agonists)andcausingsmoothmusclerelaxation.KetamineIncreasessympatheticoutflowandrelaxesbronchialsmoothmuscle.VolatileAnaestheticAgentsVolatileanaestheticagentsreducesbronchialsmoothmuscleconstrictionwherethisispreexisting(suchasasthma).LeukotrieneAntagonistsSelectivelyinhibitsthecysteinylleukotrienereceptor,increasedactivityofwhichisinvolvedinairwayoedemaandbronchialsmoothmuscleconstriction.
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.
Lastupdated2019-07-18
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CardiacAnatomyDescribetheanatomyoftheheart,thepericardiumandcoronarycirculation
EchocardiographicAnatomy
Theleftventricleis:
DividedintofourpartsFrombasetoapex,inequalthirdsalongthelongaxisoftheventricle:
BasalMid-cavityIdentifiedbypresenceofthepapillarymuscles.ApicalApexTipoftheventricle,beyondwherethecavityends.
EachpartisdividedintosegmentsTotalofseventeensegmentsbetween:
6basalandmid-cavitysegmentsInferiorMid-cavitycontainsthepostero-medialpapillarymuscle.InferoseptalInferolateralAnteriorAntero-septalAntero-lateralMid-cavitycontainstheanterolateralpapillarymuscle.
4apicalsegmentsInferiorAnteriorLateralSeptal
Apicalcap
CoronarySupply
Thesegmentsofthebasalandmid-cavitypartsaresuppliedbyallthreevessels:
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Intheapicalpart,the:
LADSupplies:
AnteriorSeptal
LCxSupplies:
LateralRCASupplies:
Inferior
TheapicalcapissuppliedbytheLAD.
References
1. AlfredAnaestheticDepartmentPrimaryExamTutorialSeries2. AHA17SegmentModel.PMOD.
Lastupdated2018-08-01
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CoronaryCirculationDescribetheanatomyoftheheart,thepericardiumandcoronarycirculation
VascularAnatomy
CoronaryArteryAnatomy
Theleftmaincoronaryartery:
ArisesfromtheposterioraorticsinussuperiortotheleftcoronarycuspoftheaorticvalveEddycurrentsproducedinthesinusesofValsalva(outpouchingsoftheaorticwall)preventthevalvesoccludingtheosoftheLMandRCAduringsystole,sotheyremainpatentthroughoutthecardiaccycle.Theleftmainis5-10mmlong,andbifurcatestoformtheLADandLCx
TheLAD:
CoursesalongtheanteriorinterventriculargroovetotheapexoftheheartHere,itanastomoseswiththeposteriordescendingarteryfromtheRCA.Suppliestheanterolateralmyocardiumandanterior2/3oftheinterventricularseptumBranchesoftheLADinclude:
DiagonalvesselsBranchesarenamedsuccessivelyfromproximaltodistal,i.e.LADD ,LADD ,etc.1 2
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Septalperforators
TheLCx:
CoursesalongtheleftatrioventriculargroovebetweentheLAandLVintheepicardialfatpadSuppliestheinferolateralwalloftheLVGivesoffthreeobtusemarginalbranches(OM ,OM )whichfollowtheleftmarginoftheheartRunsincloseapproximationwiththecoronarysinusformuchofitscourse
TheRCA:
Arisesfromtheanterioraorticsinus,superiortotherightcoronarycuspoftheaorticvalveCoursesverticallydownwardsintherightatrioventriculargrooveSuppliestheRAandRV
Theposteriordescendingartery:
ArisesfromeithertheLCxorRCAThesevesselstravelinoppositedirectionsaroundtheatrioventriculargroove.DescendsintheposteriorinterventriculargroovebeforecoursingalongthebasetoanastomosewiththeLADattheapexoftheheartIsalsoknownastheposteriorinterventricularartery
CoronaryDominance
CoronarydominancereferstowhichvesselgivesrisetothePDA:
Inaright-dominantcirculationthePDAissuppliedbytheRCAInaleft-dominantcirculationthePDAissuppliedbytheLCx
Additionally:
TheSAnodeissuppliedbytheRCAin60%ofindividualsTheAVnodeissuppliedbytheRCAin90%ofindividuals
VenousAnatomy
85%ofvenousdrainageoccursviathecoronarysinus,whichisformedfromthecardiacveins:ThegreatcardiacveinrunswiththeLADThemiddlecardiacveinfollowsthePDAThesmallcardiacveinrunswiththeRCATheobliqueveinfollowstheposteriorpartoftheLA
MostoftheremainderisviaanteriorcardiacveinswhichdraindirectlyintotheRAAsmallproportionofbloodfromtheheartisdrainedviathethebesianveinsdirectlyintofourthecardiacchambersMostintotherightatrium,andleastintotheleftventricle.Theportionofblooddrainingintotheleftsideofthecirculationcontributestophysiologicalshunt.
CoronaryBloodFlowCoronaryBloodFlow:
Normalis~250ml.min (~5%ofrestingCO)Mayincrease4xduringstrenuousexerciseMyocardialworkmayincreaseupto9x,thoughasmyocardialoxygenextractionisunchangedefficiencyisactuallyimprovedduringexercise.
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CBFisdependenton:
CoronaryvascularresistanceCoronaryperfusionpressureThedifferencebetweenaorticrootpressureandthegreaterofRAPorintracavitypressure:i.e.
NotethatthepressuregradientisusuallyAorta-CavityratherthanAorta-RAThisisbecausethepressureintheventricleactsasaStarlingresistor-coronaryflowisindependentofRAPwhilst
HeartrateLVCBFisaffectedinsystoleduetothechangesinperfusionpressure,andcompressionofintramuscularvessels(causinganincreaseinCVR).
RVCBFislessaffected,astheforceofcontractionissignificantlysmallerandapressuregradientismaintainedTachycardiareducesdiastolictimeandsubsequentlyLVCBF
ControlofCoronaryBloodFlow
CBFisautoregulated:
MyogenicautoregulationThisiscommontomanyorgansystems,andoccurswithinthecoronaries.
Increasingtransmuralpressureincreasestheleakinessofsmoothmusclemembranes,depolarisingthemResistanceincreasesproportionallytopressure,suchthatflowremainsconstant
MetabolicautoregulationAnaerobicmetabolismresultsinproductionofvasoactivemediatessuchaslactateandadenosine,whichstimulatevasodilationandthereforeincreaseflow(andoxygendelivery).
ThisisthepredominantmeansforautoregulationintheheartTypicalmyocardialoxygenextractionis70%andraisingthisfurtherisdifficultTherefore,increasingoxygensupplyrequiresanincreaseinbloodflow.
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Autonomicmechanismsalsocontrolsomeaspectsofcoronarybloodflow:
Directeffectsinclude:Parasympatheticandsympatheticinnervationofcoronaryvessels,withreleaseofAChorNAandAdecreasingorincreasingcoronarybloodflow
IndirecteffectsAremoreimportantthandirecteffectsArerelatedtoautoregulationoccurringwithchanginglevelsofmyocardialworkinresponsetoparasympatheticorsympatheticstimuli
References
1. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:SaundersElsevier.2011.
2. CICMJuly/September20073. McMinn,RMH.Last'sAnatomy:RegionalandApplied.9thEd.Elsevier.2003.4. CoronaryArteryGraphbasedonCoronaryArterialCirculation-es.2/3/2013.(Image).ByAddicted04(Ownwork)CCBY
3.0,viaWikimediaCommons.
Lastupdated2019-07-18
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CardiacCycleDescribethenormalpressureandflowpatterns(includingvelocityprofiles)ofthecardiaccycle
Thecardiaccycle:
DescribessequenceofeventsthatoccurintheheartoveronebeatConsistsoftwophasesdividedintosixstagesTypicallyisdescriedasbeginninginlatediastolewhenthemyocardiumisrelaxedandtheventriclesarepassivelyfilling
Phasesofthecardiaccycle:
DiastoleIsovolumetricVentricularRelaxationRapidVentricularFillingSlowVentricularFilling(Thecyclebeginshere).AtrialContraction
SystoleIsovolumetricVentricularContractionEjection
PhasesoftheCardiacCycleEventsduringeachphaseofthecardiaccyclearerepresentedonWigger'sDiagram:
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SlowVentricularFilling(Diastasis)
Inslowventricularfilling:
TheAVvalvesareopenandthesemi-lunarvalvesareclosedTheventricleisrelaxedcompletelyandfillsslowlyTheventricleshavebeenmostlyfilledduringrapidventricularfillingandsothepressuregradientisreducing.
ThepressureineachventricleisalmostzeroArterialpressureisfalling,asitisend-diastoleCVPisslowlyrisingastheventricleandatriafillThisperiodoccursaftertheydescent.TheECGwillshowthebeginningsofaP-waveattheendofthisphase
AtrialContraction
Theatriacontract,andremainingbloodintheatriaisejectedintotheventricle.Thissupplies10%oftheventricularfillingatrest,butupto40%intachycardia.
Inatrialcontraction:
ArterialpressureisstillfallingTheCVPwaveformdemonstratestheawaveasatrialcontractionalsocausesbloodtorefluxintotheSVCTheECGwillshowthePRinterval
IsovolumetricVentricularContraction
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OncetheactionpotentialpassesthroughtheAVnodeandbundleofHis,ventricularcontractionbegins.
Inisovolumetriccontraction:
Ventricularpressurerises,andtheAVvalvescloseThisgivesrisetothefirstheartsound,S .
Asventricularpressureisstilllessthansystemicvascularpressure,thesemilunarvalvesremainclosedArterialpressureisstillfallingTheCVPwaveformshowstheC(closure)wave,asthetricuspidvalveherniatesbackintotheRAduringventricularcontractionThereisasimilarspikeinLApressureasthemitralvalvealsobulgesbackintotheLA.TheECGwillshowtheremainderoftheQRSorthestartoftheQTinterval
Atrialrepolarisationoccursatthisstage,butistypicallymaskedbyventriculardepolarisation
Ejection
Whenventricularpressureexceedsarterialpressure,thesemilunarvalvesopenandejectionoccurs.Initialejectionisrapid,butasventricularpressurefallsandsystemicpressurerisesthegradientfallsejectionbecomesslower.
Duringejection:
Arterialpressurerisesrapidly,andisslightlylessthanventricularpressureduringthisstageTheCVPwaveformshowsthexdescent,astheshorteningRVpullstheRAdown,rapidlyloweringCVPTheSTsegmentshowsontheECGastheventriclesarefullydepolarised,thoughtheTwavemayappearinlateejection
IsovolumetricRelaxation
Whencontractioniscomplete,theventriclesbegintorelax.Inertiameansthatejectioncontinuesforashorttime.
Duringisovolumetricrelaxation:
ThesemilunarvalvescloseThisgivesrisetothesecondheartsound,S ,andmarksthebeginningofisovolumetricrelaxation.
ThisoccurswhenventricularpressurefallsbelowvascularpressureArterialpressurebeginstofall,interruptedbythedicroticnotchwhichisabriefincreaseinarterialpressureasthesemilunarvalvescloseThevwaveisvisibleontheCVPwaveformDuetoatriafillingagainstclosedAVvalves.TheendoftheTwaveisvisibleontheECGasventricularrepolarisationoccurs
RapidVentricularFilling
Mostofventricularfillingoccursinthisphase.Thisisbecauseinearlyventriculardiastoletheventricleisstillrelaxingandsoapressuregradientismaintainedbetweentheatriaandventricle.
Duringrapidventricularfilling:
TheAVvalvesopenandventricularfillingoccursThisoccurswhenatrialpressureexceedsventricularpressure.ArterialpressureisfallingTheydescentoccurswhentheAVvalvesopen,causingarapiddropinCVPastheventriclesfillNoelectricalactivityisproduced-theECGshowstheTPinterval
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References
1. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:SaundersElsevier.2011.
2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. Wigger'sDiagram(withsomemodifictions)fromWigger'sDiagram.21/3/2012.(Image).ByDanielChangMD(revised
originalworkofDestinyQx);RedrawnasSVGbyxavax.CCBY3.0,viaWikimediaCommons.
Lastupdated2019-07-18
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CardiacActionPotentialExplaintheionicbasisofspontaneouselectricalactivityofcardiacmusclecells
Describethenormalandabnormalprocessesofcardiacexcitationandelectricalactivity
Anactionpotentialisapropagatingchangeinthemembranepotentialofanexcitablecell,usedincellularcommunicationandtoinitiateintracellularprocesses.Itiscausedbyalteringthepermeabilityofamembranetodifferentions.
PacemakerPotentialThispatternofelectricalactivityisseenintheSAandAVnodes.Ithasnorestingstate,andiscontinuallydepolarising.
PhasesofthePacemakerPotential
Phase0Beginsatthethresholdpotentialof-40mV,withapeakmembranepotentialof20mV.Drivenpredominantlybythevoltage-gatedL-type(long-lasting)Ca channelscausinganinfluxofcalciumions.Phase3Repolarisationphase,whichoccursasK channelsopenandCa channelsclose.Thenadiriscalledthemaximumdiastolicpotentialandis-65mV.Phase4Phase4consistsof:
ThefunnycurrentAsteadyinfluxofNa /K whichgraduallydepolarisesthecell.
Sympatheticstimulationincreasesthefunnycurrent,increasingtherateofdepolarisation.ParasympatheticstimulationincreasesK permeability,hyperpolarisingthecellandflattensthegradientofphase4.
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CalciumcurrentInphase4,thisisthetransientcalciumcurrent,drivenbyT-typecalciumchannels.Theyopenwhenthemembranepotentialreaches~-50mV,alsocausingdepolarisation.
VentricularActionPotential
Topreventtetaniccontraction(whichwouldbebad)ventricularmusclehasalongplateaupriortorepolarisation,whichlengthenstheabsoluterefractoryperiodto250ms.Therelativerefractoryperiodis50ms.
PhasesoftheVentricularActionPotential
Phase0:DepolarisationAtthethresholdpotential,voltage-gatedfast-Na channelsopenbriefly,causingdepolarisation.Themembranepotentialpeaksat30mV.Phase1:PartialRepolarisationTheclosureofNa channelsresultsinK fleeingthecelldownitselectrochemicalgradient,causingaslightdropinvoltagecalledpartialrepolarisation.Phase2:PlateauL-typeCa channelsopen,causingaslowinwardCa currentwhichmaintainsdepolarisationandfacilitatesmusclecontraction.Phase3:RepolarisationMembranepermeabilitynormalises,andoutwardpotassiumcurrentreturnsthemembranepotentialtonormal.Phase4:RestingPotentialMembranepotentialreturnstoitsresting-85mV.
PropagationoftheCardiacActionPotentialPacemakercells:
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AreresponsibleforautomaticityandrhythmicityoftheheartThefastestpacemakeristhefocusformyocardialconductionThisistypicallytheSAnode.
ShouldtheSAnodefail,thenextfastestpacemakerwilltakeoverThisprovidesanelementofredundancy
Conductionpathway:
AtrialConductionFromtheSAnode,theimpulsetravelsat~1m.s ,depolarisingtheatria.
CurrenttravelsdownBachmann'sBundle,whichconnectstherightatriumtotheleftatrium
AVnodeTheAVnodeistheonly(normal)siteofconnectionbetweentheatriaandventricles.AVnodalcells:
Transmitswithadelayof0.1sThisallowstimeforatrialcontractiontofinishbeforeventricularcontractionbegins.Haveaprolongedrefractoryperiodandcannotconductmorethan220impulsesperminute
Thisperiodisprolongedbyvagalstimulation,whichincreasespotassiumpermeabilityandhyperpolarisesthecellConversely,sympatheticstimulationincreasescalciumpermeabilityandallowsmorerapidtransmission
Conductsviathreepathways:BachmannPathwayAlsoconductstotheLA.WenckebachpathwayThorelpathway
VentricularConductionFromtheAVnode,thesignalpropagates:
InitiallyviatheBundleofHistotherightandleftbundlesSecondlyviathePurkinjefibreswhichconductat1-4m.sPurkinjefibreshavealongrefractoryperiod,andspontaneouslydepolarisewithanintrinsicrateof30-40bpm.Lastly,ventricularmuscleisdepolarisedEndocardium,papillarymuscleandseptumcontractfirst,followedbyapex,followedbythechambers.
AutonomicControlParasympatheticInnervation
SAnodebytherightvagusThereiscontinualPNSinput("Vagaltone")viainhibitoryAChGPCR,reducingtheSAnodefromitsintrinsicrateof90-120bpmtoamoresedate60-100bpm.AVnodebytheleftvagusTheatriaareinnervatedbyparasympatheticneurons,whilsttheventriclesareonlyminimallyinnervatedPNSstimulationthereforehaslittleeffectoninotropy,butdoesaffectchronotropy.
PNSstimulationmayhavenodirecteffectoninotropy,insteadactingindirectlyviachangesinchronotropy
SympatheticInnervationSNSactivitycausesreleaseofnoradrenaline(atpost-ganglionicsynapse)andadrenalinefromadrenalmedullawhichstimulatecardiacβ receptorscausing:
PositivechronotropyattheSAnodePositiveinotropyatventricularmusclePositivelusitropyShorteractionpotentialduration(duetoopeningofrectifyingK channelsIncreasedAVconduction
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CardiacTransplant
Thetransplantedhearthasnovagal/parasympatheticinnervationbutstillexpressesβ receptors,soit:
Defaultstoarestingheartrateof~100bpmBecomeshighlypreloaddependentasitcannotrespondquicklytochangesinSVRNotresponsivetoparasympatholytics(atropine,glycopyrrolate)orephedrine(asthisisindirectly-acting)toincreasechronotropy-isoprenalinemaybeusedGradualresponsetodemandsinexercise(lackslocalSNSinnervation,butwillstillrespondtocirculatingcatecholamines)Increasedsensitivitytocatecholaminesduetoincreasedexpressionofβ receptors
References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. MatsuuraW,SugimachiM,KawadaT,SatoT,ShishidoT,MiyanoH,NakaharaT,IkedaY,AlexanderJJr,SunagawaK.
Vagalstimulationdecreasesleftventricularcontractilitymainlythroughnegativechronotropiceffect.AmJPhysiol.1997Aug;273.
Lastupdated2019-07-18
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DeterminantsofCardiacOutputDefinethecomponentsanddeterminantsofcardiacoutput
CardiacoutputafunctionofHeartRate(HR)andStrokeVolume(SV):
.
Heartrateisfairlyintuitive
StrokevolumeisdefinedasthedifferencebetweenESVandEDV,i.e.Strokevolumeisafunctionofthreefactors:
PreloadAfterloadContractility
PreloadandafterloadhavealmostasmanydefinitionsastherearetextbooksForthepurposeoftheexam,it'sgoodtohavebothalaboratoryandaclinicaldefinitionThesedefinitionsarethosewhichhaveappearedinoldexaminerreports,orgiventomebycardiacanaesthetists
Preload
Preloadisdefinedasthemyocardialsarcomerelengthjustpriortocontraction.
Asthisisnotmeasurablewithoutremovingtheheartandcuttingitintotinypieces,clinicallyitisusuallyapproximatedbyEDVor,lessappropriately,byEDP
EDVistypicallycalculatedonechocardiographyEDPistypicallymeasuredusingaCVCorPAC
CVP≈RVEDPPCWP≈LVEDP
DeterminantsofPreload
Preloadisafunctionof:
VenousReturnIntrathoracicPressureMSFP
VenouscomplianceAdecreaseinvenouscompliancewillincreaseLVEDP.Volumestate
VentricularcomplianceReducedindiastolicdysfunction.PericardialcomplianceValvulardisease
AVvalvediseasewillimpairpreloadSemilunarvalvediseasewillincreasepreload
AtrialkickWallthicknessIncreasedventricularwallthicknessdecreasespreload.
HOCM/Hypertrophy
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PreloadandtheRespiratoryCycle
NegativeintrathoracicpressurecausesRAPandPCWPtofallThisincreasesRAfilling,soandRVEDPandRVEDVincreaserelativetothepleuralpressure(thoughabsolutepressureisstilllow)LVeffectsaremorevariableNegativeintrapleuralpressures:
IncreaseLVtransmuralpressureThisimpairsejection.CausebowingoftheinterventricularseptumintotheLVThisreducesLVEDV.
Frank-StarlingMechanism
TheFrank-StarlingLawoftheHeartstatesthatthestrengthofcardiaccontractionisdependentoninitialfibrelengthAtacellularlevel,additionalstretchincreases:
ThenumberofmyofilamentcrossbridgesthatcaninteractMyofilamentCa sensitivity
ThislawisrepresentedbytheventricularfunctioncurvePlotofpreloadagainststrokevolume(orcardiacoutput,assumingaconstantheartrate).
RightshiftofthecurvedemonstratesnegativeinotropyLeftshiftofthecurvedemonstratespositiveinotropy
Thefailingventricle:
Incardiacfailure,theventriclebecomesoverstretchedThisreducesthenumberofoverlappingcrossbridges,reducingcontractility.Thisislimitedintheacutesettingbyconstrictionofthepericardium,whichpreventsexcessiveventriculardilation
Afterload
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Afterloadisthesumofforces,bothelasticandkinetic,opposingventricularejection
Thisdefinitionisabitwordybutavoidsusingthewords"resistance"and"impedance",whicharestrictlydefinedinphysics(andcrudelyappliedinmedicine),andmaybeleaptonbythecruelexaminer
DeterminantsofAfterload
Afterloadisequaltoventricularwallstress,whichisgivenbytheequation:
,where:
isventricularwallstress
isventriculartransmuralpressureisventricularchamberradius
isventricularwallthickness
Eachofthesefactorsareinturninfluencedby:
VentriculartransmuralsystolicpressureTransmuralpressureisthedifferencebetweenintrathoracicpressureandtheventricularcavitypressureduringejection.
IntrathoracicPressureNegativeintrathoracicpressurewillincreaseafterload,astheventriclehastogenerateagreaterchangeinpressuretoachieveejection.
PEEPreducesLVafterloadNegative-pressureventilationwithahighworkofbreathingincreasesafterloadThisiswhyAPOdeteriorates-increasedworkofbreathingincreasesLVafterloadandworsensLVfailure,increasedpulmonaryoedema,causingincreasedworkofbreathing...
VentricularcavitypressureTofacilitateejection,theventriclemustovercome:
OutflowtractimpedanceValvulardisease
e.g.aorticstenosisHOCM
SystemicarterialimpedanceDeterminedbyresistance(SVR),inertia,andcompliance:
DeterminantsofresistancearestatedinthePoiseuilleEquation:
,where:η=ViscosityAffectedbyhaematocrit(e.g.increasedinpolycythaemia)l=VessellengthEssentiallyfixed.r=Vesselradius
GreatestdeterminantFunctionofdegreeofvasoconstrictionofresistancevessels
InertiaGivenbythemassofbloodinthecolumnAffectedbyheartrate
ArterialcomplianceDecreasedarterialcomplianceincreasesafterload.
Duringejection,theaortaandlargearteriesdistend,reducingpeaksystolicpressure(impedanceto
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furtherejection)Decreasedarterialcomplianceincreasesthechangeinpressureforanygivenvolume,increasingafterloadduringejectionDecreasedarterialcomplianceincreasesthespeedofpropagationofreflectedpressureswavesreturningtotheaorticroot
WavearrivalindiastoleaugmentscoronarybloodflowWavearrivalduringsystolefurtherincreasesafterload
Indiastolethearteriesrecoilandbloodpressureandflowaremaintained-theWindkesseleffect.
VentricularchamberradiusEnd-DiastolicVolumeIncreasedEDVincreasesventricularradiusandthereforewalltension.
MyocardialwallthicknessIncreasingwallthickness(seenclinicallyasventricularhypertrophy)decreasesafterloadbysharingwalltension(theproductofpressureandradius)betweenalargernumberofsarcomeres.
ContractilityContractilitydescribesthefactorsotherthanheartrate,preload,andafterloadthatareresponsibleforforchangesinmyocardialperformance.
DeterminantsofContractility
ContractilityisprimarilydependentonintracellularCa .Determinantsinclude:
DrugsDisease
IschaemiaReducedATPproductionsecondarytohypoxia,whichimpairssarcoplasmicreticulumCa function.Furtherexacerbatedbyintracellularacidosisfromanaerobicmetabolism.HeartFailureImpairedcontractilityreserve,i.e.minimalincreaseincontractilitywithsympatheticstimulation.
ReducedpeakCa andsarcoplasmicreticulumuptakeofCaAutonomicToneBowditchEffectContractilityimprovesatfasterheartrates.Thisisbecausethemyocardiumdoesnothavetimetoremovecalcium,soitaccumulatesintracellularly.AnrepEffectContractilityincreasesasafterloadincreases.
MeasuringContractility
Aswiththeotherdeterminantsofcardiacoutput,therehasbeensomedifficultyindevelopingmeasurableindicesforcontractilityAllmeasuresofcontractilityareaffectedbypreloadorafterloadtosomeextent
dP/dt ( )TherateofriseofLVP,assumingaconstantpreloadandafterload
ThisindexispreloaddependentbutafterloadindependentTypically,thedP/dt inisovolumetricventricularcontractionisused
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AgreaterrateofriseindicatesamoreforcefulcontractionMeasurementrequiresLVcatheterisation
End-SystolicPressure-VolumeRelationshipUsestheventricularPressure-VolumeRelationshipLineplottedatthetangenttothecurvefromtheend-systolicpoint(whenisovolumetricventricularrelaxationbegins)
Thesteeperthegradientthegreaterthecontractility
EjectionFractionMostcommonmethodusedclinicallyisejectionfraction:
FootnotesTheuseofwallstressforpreloadandafterloadcomesfromtheCardiovascularHaemodynamicstext,butisnotusedintheCICMtexts
Thissitehasaniceoverviewofwalltension,andtherelationshipofpressuretoradius
Thisarticlediscussesthewallstressdefinitionforpreloadandafterload
Changeswithventilationaredescribedwithprettygraphshere
References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. DerangedPhysiology-Haemodynamicchangesduringmechanicalventilation3. AnwaruddinS,MartinJM,StephensJC,AskariAT.Cardiovascularhemodynamics:anintroductoryguide,contemporary
cardiology.NewYork:Springer;2013.p.29–51.4. NortonJM.TowardConsistentDefinitionsforPreloadandAfterload.AdvancesinPhysiologyEducationMar2001,25(1)
53-61.5. ANZCAJuly/September2006
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VenousReturnDefinethecomponentsanddeterminantsofcardiacoutput
Thevenoussystemhastwokeycardiovascularfunctions:
BloodreservoirContains65%ofbloodvolume.Conduitforreturnofbloodtotheheart
Venousreturnistherateatwhichbloodisreturnedtotheheart(inL.min ).Atsteadystate,venousreturnisequaltocardiacoutput,andcanbeexpressedas:
,where:
isvenousreturn
isthemeansystemicfillingpressureThisisthemeanpressureofthecirculationwhenthereisnoflow.Itisanindicatorofcirculatoryfilling,andisafunctionofcirculatingvolumeandvascularcompliance.
Normalmeansystemicfillingpressureis~7mmHg
istherightatrialpressureAnelevatedRAPreducesvenousreturn.
istheresistancetovenousreturn
Thisrelationshipcanbeexpressedgraphically:
Whenvenousreturnis0,themeasuredrightatrialpressureisanindicationofmeansystemicfillingpressure
Alterationstocirculatingvolumeandcomplianceaffectbothvenousreturnandmeansystemicfillingpressure
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Alterationstotheresistancetovenousreturnaffectvenousreturnbutmeansystemicfillingpressureisunchanged
FactorsAffectingVenousReturn
Venousreturnwillbealteredbyanyofthevariablesintheaboveequation:
MSFPVolumee.g.Haemorrhage,resuscitation.Compliance
RAPRespiratorypumpNegativeintrathoracicpressurereducesRAP,improvingvenousreturn.PositivepressureventilationPericardialcompliance
ConstrictionTamponade
ResistancetoVenousReturnPostureVascularcompression
ObesityPregnancyLaparoscopy
OtherfactorsaffectingvenousreturnSkeletalmusclepumpContractionoflegmusclesincombinationwithanintactvenoussystempropelsbloodbacktowardstheheart.
InteractionbetweenVenousReturnandCardiacFunctionCurves
Guyton'scurvecanbesuperimposedonStarling'scurvetoexaminetheinteractionbetweenvenousandcardiacfunctionoverarangeofconditions:
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References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. BrandisK.ThePhysiologyViva:Questions&Answers.2003.3. HendersonWR,GriesdaleDE,WalleyKR,SheelAW.Clinicalreview:Guyton-theroleofmeancirculatoryfillingpressure
andrightatrialpressureincontrollingcardiacoutput.CriticalCare.2010;14(6):243.doi:10.1186/cc9247.
Lastupdated2019-07-18
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MyocardialOxygenSupplyandDemandDescribemyocardialoxygendemandandsupply,andtheconditionsthatmayaltereach
MyocardialoxygensupplyisafunctionofcoronarybloodflowMyocardialoxygendemandisdeterminedbymyocardialworkMyocardialischaemiaoccurswhendemandexceedssupply
MyocardialOxygenSupply
Myocardialoxygensupplyisdependenton:CoronaryarteryflowOxygencontentofbloodOxygenextraction
Functionally,coronaryarteryflowisthedeterminant.Thisisbecause:OxygencontentinindividualswithoutpulmonarydiseaseismaximalRestingmyocardialoxygenextractionisnear-maximal(~70%)ThishighERmakestheheartlesstolerantofanaemiathanorganswithalowER.
ThereforecoronarybloodflowisthelimitingfactorCoronarybloodflowisgivenbytheequation:
AorticrootpressureisthedrivingpressureforcoronaryflowCavity(ventricular)pressureactsasaStarlingresistorforcoronaryflow
NotethatifRAPexceedscavitypressure,RAPwillbethepressureopposingcoronaryflow(duetodownstreampressureatthecoronarysinus)
Notethatcavityandaorticrootpressurechangethroughoutthecardiaccycle,therefore:TheflowtoeachventricleisdifferentduringthecardiaccycleTheleftventricleisbestperfusedindiastoleThereforeheartrateisanimportantdeterminantofcoronarybloodflow,astachycardiawilldecreasecoronarybloodflow
Flowtoeachventricleisafunctionofhowrelationshipschangeoverthecardiaccycle
LeftVentricularCoronaryBloodFlow:
RightVentricularCoronaryBloodFlow:
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MyocardialOxygenDemand
Normalmyocardialoxygenconsumption(MVO )is21-27ml.min .Thethreemajordeterminantsare:
HeartrateAchangeinheartratewillchangethenumberoftension-generatingcycles,causingaproportionalchangeinMVO .
Contractility
Referstotherateoftensiondevelopmentaswellasitsmagnitude.Changing willchangeMVO .
VentricularwalltensionVentricularwalltensionispressurework,ortheworkdonebytheventricletogeneratepressurebutnottoejectvolume.
WalltensionisgivenbytheLawofLaPlace
,where:
=Pressureduringcontraction=Radius
Walltensionisthereforeafunctionof:AfterloadIncreasingafterloadwillincreasethepressureduringcontraction.PreloadIncreasingpreloadwillincreaseradius,buttoalesserextentthanincreasingafterload.
Thisisbecausevolumeandradiusarenotdirectlyproportional
Minordeterminantsofmyocardialworkare:
ExternalworkExternalworkcanalsobethoughtofasvolumework,ortheenergyexpendedtoejectbloodfromtheventricle.
Thisisencompassedbytheareaenclosedbythepressure-volumeloopConversely,internalworkisdefinedastheworkrequiredtochangetheshapeoftheventricleandprepareitforejectionOnthepressure-volumeloopinternalworkisrepresentedbyatrianglebetweenthepointof0pressureandvolume,theendsystolicpoint,andthebeginningofrapidventricularfilling.
Thisisaminordeterminantbecausethemajorityofventricularworkisgeneratingthepressurerequiredtoejectblood,notactuallymovevolumeExternalworkisofgreaterimportanceathighCOExternalworkisusedtocalculatecardiacefficiency,givenbytheequation:
Basaloxygenconsumption
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Basaloxygenconsumption(~8ml.min .100g )comprises~25%ofMVO .
References1. GrossmanW,BaimDS.Grossman'sCardiacCatheterization,Angiography,andIntervention.7thEd(revised).2006.
LippincottWilliamsandWilkins.2. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.3. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.4. MillerRD,ErikssonLI,FleisherLA,Weiner-KronishJP,CohenNH,YoungWL.Miller'sAnaesthesia.8thEd(Revised).
ElsevierHealthSciences.
Lastupdated2017-10-04
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Pressure-VolumeRelationshipsDescribethepressure-volumerelationshipsoftheventriclesandtheirclinicalapplications
LeftVentricularP-VLoop:
PlotofleftventricularvolumeversuspressureTimeisnotdirectlydemonstratedonthisgraph,butthestagesofthecardiaccyclecanbeinferred:
A-BisisovolumetricrelaxationVentricularpressureislessthanaorticpressurebutgreaterthanatrialpressure,sobothmitralandaorticvalvesareclosed.B-Cisrapidandslowventricularfilling,followedbyatrialsystoleAtrialsystoleissometimesdemonstratedbyasharp'bump'towardsC,asventricularpressurewillbrieflyriseoutofproportiontoventricularvolumeC-DisisovolumetriccontractionTheventriclecontracts.Asventricularpressureisgreaterthanatrialpressurebutlessthanaorticpressure,themitralvalvecloses(pointC)andtheaorticvalveremainsclosed.Pressureincreaseswithoutachangeinvolume.
ThisslopeofthislineisknownasthedP/dt ( ),andisanindexofcontractilityD-AisventricularejectionWhenventricularpressureexceedsaorticpressure,bloodisejectedintotheaortaandventricularvolumedecreases.
TheslopeofthelineB-CgivestheelastanceoftheventricleThisisalsoknownastheEnd-DiastolicPressureVolumeRelationship(EDPVR),andisoften(erroneously)referredtoasventricularcompliance.
ElastanceoftheventricleincreasesasitisfilledThisisdemonstratedbythedashedline.
TheventricleonlyoverfillsathighfillingpressuresIncreasedelastance(suchasindiastolicdysfunction)isdemonstratedbyanincreasedslopeofthisline,suchthatventricularpressurewillbehigheratanygivenvolumeBothventricularandarterialelastancearelowinnormalcircumstances(astateknownasventricular-arterialcoupling),asthisallowstheventricletoachieveawiderangeofvolumetransfersinejectionwithminimalchangeinfillingpressure.
ThehorizontaldistancebetweenpointB(ESV)andC(EDV)givethestrokevolumeEjectionfractioncanthenbecalculated.PreloadisgivenbytheEDVAfterloadis:
Technicallygivenbythepressure-volumerelationshipthroughouttheentiretyofejectioni.e.theslopeD-A.
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ThiscomesfromLaPlace'slaw:
UsuallyassumedtogivenbytheslopeofalinedrawnfromtheEDV(onthex-axis)totheend-systolicpoint(pointA)Thisisalsoknownasthearterialelastanceline.
ThegradientofthearterialelastancelinecanbeworkedoutfromtheloopsThisisdifferentfromtheaboveformulabecauseitonlyconsidersthepressure-volumerelationshipatend-systole,notthroughouttheentiretyofejection
isagoodsubstituteforafterloadbecauseitisrelativelyindependentofpreloadandcontractility,andwillvarywithchangesinafterload
i.e.Foragivenstrokevolume,anincreasein leadstoanincreaseinSBP.Similarly,iftheventricleisunable
tomaintainagivenstrokevolumeas increases,thenSBPwillfall.Contractilityisgivenbytheslopeoftheend-systolicpressurevolume-relationship
Alsoknownaselastanceatend-systole,or ,andisgivenbythetangenttothecurveatend-systole.Thismeasurementisnotentirelyindependentofotherfactors,asitisinfluencedbyafterload
BasicPressure-VolumeLoops
Theseloops:
ShowisolatedchangestoonefactoronlyArenotaccurateofreal-worldphysiologyInreality:
ChangingonefactorwillinfluenceotherfactorsThesevalueschangebeat-to-beat
LeftVentricularP-VLoop-IncreasedPreload:
EDVisincreased,bydefinitionTheslopeoftheESPVRremainsunchanged(ascontractilityisunchanged)
Theslopeoftheafterloadline( )isunchanged(asafterloadisunchanged),butitisright-shiftedduetotheincreasedend-diastolicvolumeESVisincreased,thoughlessthanEDV,suchthatstrokevolumeincreases
LeftVentricularP-VLoop-IncreasedAfterload:
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EDVisunchanged(aspreloadisunchanged)TheslopeoftheESPVRremainsunchanged(ascontractilityisunchanged)
Theslopeoftheafterloadline( )hasincreased,butitsx-interceptisunchangedNotethatthepressure-volumerelationshipthroughoutejectionisalsosteeper,anddiastolicpressurehasincreased.ESVisincreased,causingareductioninstrokevolume
LeftVentricularP-VLoop-IncreasedContractility:
EDVisunchanged(aspreloadisunchanged)
Theslopeandx-interceptoftheafterloadline( )isunchanged(asafterloadisunchanged)TheslopeoftheESPVRhasincreased,thoughitsx-interceptisthesameESVisdecreased,causinganincreaseinstrokevolume
AdvancedPressureVolumeLoopsTheeasiestwaytoapproachmorecomplicatedpressure-volumeloopsistoaddresseachofthebasicfactorsbeforetryingtodrawthecurve:
Howispreloadchanged?Howisafterloadchanged?Howiscontractilitychanged?Howareisovolumetriccontractionandisovolumetricrelaxationchanged?
Theseshowtheloopfortheprimaryphysiologicalchange,withoutcompensatoryresponses:
LeftVentricularP-VLoop-AorticStenosis:
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PreloadisincreasedduetothehigherESV,astheventriclestartsfillingfromahigherpointOutflowtractimpedanceincreasesventricularwallstressandthereforeafterloadThisleadstothedecreaseinstrokevolume.Contractilityisunchanged
LeftVentricularP-VLoop-AorticRegurgitation:
PreloadisdramaticallyincreasedastheventriclefillsfromboththeaortaandatriaduringdiastoleAfterloadisincreasedduetothegreaterwallstressduringejectionContractilityisunchangedThereisnotrueisovolumetricrelaxation,astheventriclewillbegintofillfromtheaortaatthecompletionofejectionDiastolicpressureisdecreasedandsotheperiodofisovolumetriccontractionisbrief
LeftVentricularP-VLoop-MitralStenosis:
PreloadisreducedduetotheincreasedgradientacrossthemitralvalveTheeffectofthisisheartratedependent,andwillworsenasheartrateincreases.AfterloadisunchangedAfterloadmayfallduetothereductioninventricularwallstress.
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ContractilityisunchangedESVdecreases(duetothereducedpreload),thoughlessthanEDV,suchthatstrokevolumeisreduced
LeftVentricularP-VLoop-MitralRegurgitation:
PreloadisincreasedastheregurgitantvolumeincreasesleftatrialpressureandthereforeventricularfillingpressureAfterloadisreducedasbloodisejectedintothelow-pressureatrialsystemContractilityisunchangedThereisnotrueisovolumetriccontractionphaseasbloodisejectedintotheatriawhileventricularpressureexceedsatrialpressureThereisnotrueisovolumetricrelaxationphase,asonceatrialpressureexceedsventricularpressuretheventriclewillbegintofillApparentstrokevolumeisincreasedduetothelargedifferencebetweenEDVandESV,howevereffectivestrokevolumeisreducedasonlyaportionofthisisforwardflow
RightVentricularP-VLoop:
TherightventricularcurveisverydifferenttotheleftventricularcurveRVpreloadisincreasedrelativetoLVpreloadNotethatstrokevolumeisthesame(asbothsidesshouldhavethesamecardiacoutput).RVafterloadisdramaticallyreducedduetothelow-resistancepulmonarycirculation
MuchoftheRVejectionoccursaftersystolicpressureisreachedTherightventricleisverysensitivetochangesinafterload
ContractilityisreducedRightheartcontractilityispartiallydependentoncoordinatedcontractionwiththeLV(particularlytheseptum),andthereforeisdecreasedwithLVsystolicfailureorconductingsystemdisease(suchasbundlebrachblock).
Footnotes
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TheKhanAcademyseriesChangingthePressure-VolumeLoopisafantasticintroductiontothetopic.
References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. Klabunde,RE.[VentricularPressure-VolumeRelationship(http://www.cvphysiology.com/Cardiac%20Function/CF024).
CardiovascularPhysiologyConcepts.2015.3. Desai,R.Arterialelastance(Ea)andafterload.KhanAcademy.4. Redington,AN.CardiopulmonaryandRight–LeftHeartInteractions.ThoracicKey.5. BorlaugBA,KassDA.Ventricular-VascularInteractioninHeartFailure.Heartfailureclinics.2008;4(1):23-36.
Lastupdated2019-07-18
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CardiacReflexesDescribethecardiacreflexes
Cardiacreflexesarefast-actingreflexloopsbetweentheCVSandCNSwhichcontributetothemaintenanceofcardiovascularhaemostasis.
Theyinclude:
BaroreceptorreflexAorticarchandcarotidsinusreflexes.
BainbridgereflexAtrialstretchreceptorreflexes.
ChemoreceptorreflexDecreasedPaO <50mmHgordecreasedpHsensedbyperipheralchemoreceptorscausessubsequenttachycardiaandhypertension.
CushingreflexBrainstemcompressioncausesischaemiaofthevasomotorcentreleadingtoCushings'Triad:
HypertensionMayhaveawidepulsepressure.BradycardiaDuetobaroreceptorresponsefromhypertension.Irregularrespirations
Bezold-JarischreflexStimulationofCfibresofthevagusnerveinthecardiopulmonaryregion.
Thiscauses:SignificantbradycardiaHypotensionApnoea,followedbyrapidshallowbreathing.Thesefibrescanbestimulatedbyanumberofsubstances,including:
CapsaicinSerotoninThoseproducedinmyocardialischaemia
OculocardiacreflexPressureontheglobeortractiononocularmusclescausesadecreaseinheartrate.Thisismediatedbythe:
Trigeminalnerve(afferentlimb)Vagusnerve(efferentlimb)IncreasedvagaltonereducesSAnodalactivity.
References
1. CICMSeptember/November20132. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.3. OpenAnaesthesia-Oculocardiacreflex:afferentpath
Lastupdated2019-07-18
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StarlingForcesDescribetheessentialfeaturesofthemicro-circulationincludingfluidexchange(Starlingforces)andcontrolmechanismspresentinthepre-andpost-capillarysphincters
Interstitialfluidisanultrafiltrateofplasma,withthenetfiltrationpressuredeterminedbytheneteffectofopposinghydrostaticandoncoticpressures:
ThesefourvariablesareknownasStarling'sforces.
Actualfluidmovementis(ofcourse)morecomplicated.Hydrostaticpressurefallsalongthecapillary,andmovementofsoluteandwaterareaffectedbyotherfactors.Someofthesearedescribedbythe:
Reflectioncoefficient(σ)Thisdescribesthefactthatasmallamountofproteinleaksfromthecapillary,slightlyincreasinginterstitialoncoticpressureandslightlydecreasingcapillaryoncoticpressure.Itisdependentontheinterstitialproteincontent,andhasavaluebetween0and1.
Filtrationcoefficient(Kf)Encompassesmembranepermeability(towater)andmembranesurfacearea.Variesbetweentissues:
TheStarlingEquationbecomes:
TypicalValuesforPressures(mmHg)
Arteriolarend Venousend
Capillaryhydrostaticpressure 25 10
Interstitialhydrostaticpressure -6 -6
Capillaryoncoticpressure 25 25
Interstitialoncoticpressure 5 5
Organ-SpecificValues
Intheglomerulus:
Reflectioncoefficientiscloseto1duetotheimpermeabilityoftheglomerulustoproteinKfishighduetobothhighpermeabilityandalargesurfacearea.HydrostaticpressureishighGlomerularoncoticpressureisessentially0
Intheliver:
Reflectioncoefficientiscloseto0inhepaticsinusoidsastheyareverypermeabletoprotein
Inthelungs:
Reflectioncoefficientof~0.5inthelungsduetosignificantleakofproteinProteinleakdecreasesasinterstitialoncoticpressurerises,limitingfurtheroedemaformation
Theoncoticpressuregradientissmall,andfavoursreabsorption
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Hydrostaticpressuregradientissmall,butfavoursextravasationoffluidInterstitialhydrostaticpressurebecomesmorenegativeclosertothehilum,drawingfluidintothepulmonarylymphatics
CausesofOedema
Oedemacanbelocalisedorgeneralised,andinbothcasescausedby:
IncreasedFiltrationPressureOccurswhencapillaryhydrostaticpressureexceedsinterstitialhydrostaticpressure.Causes:
IncreasedVenouspressureThisincludesanincreaseinCVP:
CCFTRIncreasedvenoconstrictionIncreasedMSFP
ImpairedvenousreturnObstructionRespiratorymusclepumpSkeletalmusclepump
Positioning
DecreasedOncoticPressureGradientDecreasedplasmaprotein
HepaticfailureCriticalIllness
IncreasedinterstitialoncoticpressureMannitol/starchextravasation
Increasedcapillarypermeability
InflammatoryproteinsSubstancePHistamineKinins
InadequateLymphFlow
References
1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. Brandis,K.Starling'sHypothesis.AnaesthesiaMCQ.3. ANZCAAugust/September2001
Lastupdated2017-09-22
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VariationsinBloodPressureDescribethephysiologicalfactorsthatmaycontributetopulsevariationsinbloodpressure
Bloodpressureisnotuniformthroughoutthecirculation.Ventricularejectiongeneratestwowaves:
AbloodflowwaveTravelsat~20cm.s .AnarterialpressurewaveDistendstheelasticwallsofthelargearteriesduringsystole,whichthenrecoilduringdiastoletofacilitatecontinualbloodflow.ThisistheWindkesseleffect.
Thiswavetravelsat4m.sThisiswhatisfeltwhenpulsesarepalpated,andwhatisseenonthearteriallinewaveform
Keypressuresmeasuredare:
SystolicbloodpressureMaximalpressuregeneratedduringejection.
Determinedby:StrokevolumeSystolictimeArterialcomplianceReflectedpressurewave
Relevantfor:Bleeding
ClotdisruptionAneurysmalwallpressure
DiastolicpressurePressureexertedbythecirculationupontheaorticvalve.
Determinedby:CirculatorycomplianceCirculatingvolumeAorticvalve(in)competence
Relevantfor:Coronaryperfusion
MeanarterialpressureAveragepressureinthecirculationthroughoutthecardiaccycle,asmeasuredbytheareaunderthecurveofthearteriallinewaveform.
Determinedby:SystolicbloodpressureDiastolicbloodpressureHeartrateIncreasingHRwilltendtoincreaseMAP,asoverallsystolictime(andthereforetimespentathigherpressure)isincreased.Shapeofthearterialwaveform/diastolicrunoffTheslowdecreaseinpressureafterpeaksystolicpressurerepresentelasticrecoiloflargearteries,increasingthepressuredrivingbloodintotheperipheralcirculation.Alongerdiastolicrunoffperiodleadstoalargerareaunderthecurve,andahigherMAP.
Relevantfor:Organperfusion
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ChangesbySiteofMeasurement
Measuredpressurechangespredictablyatmoredistalsites:
AllgradientsareincreasedArterialupstrokeandfalloffarebothsteeper.TheSBPincreasesDBPdecreasesMAPisconstantThedicroticnotchoccurslaterandbecomeslesssharpThisoccursduetoreflectionsinarterialpressurewaves.
RespiratoryVariationVentilationcausesvariationinpeaksystolicpressureduetodynamicchangesincardiacloadingconditions:
Negativepressurerespiration(i.e.regularbreathing)generatesanegativeintrathoracicpressureduringinspirationLeadstoincreasedVR,butalsopoolingofbloodinthepulmonarycirculationandrelativeunderfillingoftheLV,leadingtoadecreaseinSVandpeaksystolicbloodpressure.PositivepressureventilationcausesthereverseIncreasedintrathoracicpressureduringinspirationresultsinadecreasedvenousreturnbutincreasesLVfillingviacompressionofthepulmonarycirculation.Whenthischangeis>10mmHg,itisknownaspulsusparadoxusThemagnitudeofthiseffectvarieswith:
MagnitudeofintrathoracicpressurechangeLargechangesinintrathoracicpressurecausecorrespondinglylargerchangesinventricularfilling.Otherfactorsaffectingcardiovascularfunction
PreloadVolumestate
CompliancePericardialcompliance
ConstrictionTamponade
CardiaccomplianceDiastolicdysfunction
AfterloadPERaisedintrathoracicpressure
PEEPTensionPTHx
Thesedifferencescanbemeasured:QualitativelyBylookingatrespiratoryswingonanarteriallineorplethysmograph;orbypalpation.QuantitativelyUsingpulsepressureorstrokevolumevariation.
PulsePressureVariation
Describesthevariationinpulsepressureoverthecourseofarespiratorycycle.Pulsepressurevariationis:
Mathematicallydefinedas:
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Therefore,itiscalculatedasapercentUsedasanindicatoroffluidresponsiveness
PatientshigherontheFrank-Starlingcurvewillhavelesschangeinstrokevolumewithanincreaseinpreload,andtherefore:
ReducedPPVBelessfluidresponsive
APPVof>12%suggestsvolumeresponsiveness.Notethatthisdoesnotnecessarilymeanafluidresponsivepatientneedsfluid.
Reliantonseveralassumptions:RegularsinusrhythmIrregularheartrates(particularlyAF)leadtosignificantalterationsinventricularfillingandthereforepulsepressure,independentoftherespiratorycycle.ControlledmechanicalventilationNospontaneousefforts.AdequatetidalvolumesMustbe>8ml.kg .NormalchestwallcomplianceRequiresaclosedchest.
StrokeVolumeVariation
SVVis:
Alternatelydefinedas:Thepercentchangeinstrokevolumeduringinspirationandexpirationovertheprevious20secondsVariationofbeat-to-beatSVfromthemeanvalueovertheprevious20seconds
CalculatedbyspecialiseddevicesfromaninvasivearterialwaveformCalculationincorporates:PulsepressureVascularcomplianceEstimatedfromnomogramsbasedonpatientage,gender,height,andweight.VascularresistanceEstimatedfromarterialwaveformshape.
AnalternativetoPPVinmeasuringfluidresponsivenessReliesonsimilarprinciples.ProbablylessspecificbutmoresensitivethanPPVforidentifyingfluidresponders
CirculatoryFactors
Changesincirculatoryfunction:
Inotropy
Therateofsystolicupstrokeisrelatedto ,andthereforecontractility.SVRThegradientbetweenthepeaksystolicpressureandthedicroticnotchgivesanindicationofSVR.E.g.,asteepdownstrokesuggestsalowSVR,asthepressureinthecirculationrapidlyfallswhenejectionceases.Preload
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Abeat-to-beatvariationisseenwiththerespiratorycycle,duetothechangeinpreloadoccurringwithchangesinintrathoracicpressure.
PathologicalChanges
Somepathologicalcausesinclude:
AorticStenosisCausesareductionin:
PulsepressureDuetoreducedstrokevolume.GradientofupstrokeDuetoreducedstrokevolume.
AorticRegurgitationWidepulsepressureCombinationof:
IncreasedSBPduetotheincreasedforceofejectionduetoincreasedpreload(StarlingsLaw),whichoccursduetohighESVDecreasedDBPduetopartofthestrokevolumeflowingbackintotheventriclethroughtheincompetentvalve
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. Buteler,BenjaminS.Therelationofsystolicupstroketimeandpulsepressureinaorticstenosis.BritishHeartJournal.1962.3. Mark,JonathanB.Atlasofcardiovascularmonitoring.NewYork;Edinburgh:ChurchillLivingstone,1998.4. MarikPE.Techniquesforassessmentofintravascularvolumeincriticallyillpatients.JIntensiveCareMed.2009;24(5):329-
37.5. SolimanRA,SamirS,elNaggarA,ElDehelyK.Strokevolumevariationcomparedwithpulsepressurevariationand
cardiacindexchangesforpredictionoffluidresponsivenessinmechanicallyventilatedpatients.EgyptJCritCareMed.2015;3(1):9-16.doi:10.1016/J.EJCCM.2015.02.002
Lastupdated2019-07-18
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PulmonaryCirculationOutlinetheanatomyofthepulmonaryandbronchialcirculations
Describethephysiologicalfeaturesofthepulmonarycirculationanditsresistance
Understandthedifferencesbetweenthepulmonaryandsystemiccirculation
Thepulmonarycirculationis:
Alow-pressure,high-flow,high-pulsatilitycirculationSuppliedbythepulmonarytrunk(pressure25/8mmHg),drivenbytheRV(pressure25/0mmHg)
Arteriesandveinsrunwiththebronchiasfarastheterminalbronchioles,dividingatthesamepointsBeyondthis,theyformacapillarybedsothinitisessentiallysheetofflowingbloodpunctuatedbyalveoli
Thebronchialcirculation:
Arisesfromthesystemiccirculation,andsuppliesbloodtotheconductingzoneofthelungAthirddrainsbacktothesystemiccirculationTheremainderdrainsintothepulmonaryvessels-thisisaphysiologicshunt
Supplytotumoursispredominantlyfromthebronchialcirculation(ratherthanthepulmonarycirculation)asthesevesselsrespondtoangiogenicfactors.
DifferencesbetweenPulmonaryandSystemicCirculations
BloodPressure
Pulmonaryarterialpressureis25/8mmHg(MAP15mmHg)comparedto120/80mmHg(MAP100mmHg)inthesystemiccirculation.Thisisbecausethesystemiccirculationmust:
RegulateflowtodifferentorgansatdifferenttimesItthereforecontainsresistancevesselswhichallowittoallocatecardiacoutputaccordingly.Maintainflowtoorgansfarabovetheheart
Conversely,thepulmonarycirculationmust:
Accepttheentiretyofcardiacoutput,withlittlecapacitytoregulateflow(hypoxicvasoconstrictionbeingtheexception)Minimiseextravasationoffluid
AsperStarlingsLaw,fluidmovementoutofthecapillaryisgivenbythedifferenceinhydrostaticgradientsandoncoticgradientsThenetoncoticgradientissmall(butfavoursreabsorption),howeverthepulmonaryinterstitiumhasnohydrostaticpressureIncreasedpulmonarycapillarypressurethereforecausesextravasationoflargevolumesoffluid
Consequently,pulmonaryvesselsarethinwalledandcontainminimalsmoothmuscleThismakesthepulmonarycirculationhighlycompliant-thevolumeofbloodisabletochangesubstantiallywithminimalchangeinpressure
PulmonaryVascularResistance
VascularresistancefollowsOhmslaw,i.e.:
th
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Pulmonaryvascularresistanceis~1/10 thatofthesystemiccirculationThisisbecausethepressuredropacrossthepulmonarycirculationis10mmHg(MPAP-LAP),~1/10 thatofthesystemiccirculation,andflowisthesame
Determinantsofpulmonaryvascularresistanceare:
PulmonaryArteryPressureIncreasedPAPcausesadecreaseinPVR.Thisoccursbecause:
PreviouslyclosedpulmonarycapillariesarerecruitedwhentheircriticalopeningpressureisreachedThisismoreimportantwhenMPAPislow.VesselsdistendathigherpressuresThisismoreimportantwhenMPAPishigh.
LungvolumeLungvolumehasavariableeffectonPVR.
Atlargelungvolumes:Resistanceinlargeextra-alveolarvesselsdecreasesasthevesselsarepulledopeningbydistensionofelastictissuesResistanceinsmallintra-alveolarvesselsincreasesastheyarecompressedbythehighlungvolumes
Atsmalllungvolumes,thereverseoccurs
HypoxicPulmonaryVasoconstrictionLowPAO causesavasoconstrictioninthevesselssupplyingthatalveolus,increasingPVRanddirectingbloodtobetterventilatedalveoli.
LowalveolarPO istheprimarydeterminantLowmixedvenousPO alsocontributesConstrictionbeginswhenP O fallsbelow100mmHg,andbecomesdramaticbelow70mmHgThisisimportantin:
FoetalcirculationAlveolarconsolidation
PneumoniaCardiogenicpulmonaryoedema
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RaisedLVEDPincreasespulmonaryvenouspressures.Basalalveoliaremoreaffected.HPVcausesconstrictionofbasalvessels,increasingbloodflowtoapicalalveoliandresultinginupperlobediversionseenonchestx-ray.
HighaltitudeHPVisattenuatedby:
ElevatedLAPGreaterthan25mmHg.HighCO
MinorfactorswhichaffectPVR:IncreasePVR:
HypercarbiaHypothermiaAcidaemiaPain
DecreasePVR:BronchodilatorsVolatiles
ResponsetoSubstances
Oxygen:
ThepulmonarycirculationconstrictswhenPO falls,whilstthesystemiccirculationdilates
CarbonDioxide:
ThepulmonarycirculationconstrictionswhenPCO rises,whilstthesystemiccirculationdilates
DistributionofPulmonaryFlowGravityhasasignificanteffectonpulmonarybloodflow:
Intheuprightlung,flowdecreasesalmostlinearlywithheightInthesupinelung,flowtoposteriorregionsexceedsthatofanteriorregionsThisoccursduetothelowdrivingpressureofthepulmonarycirculation,whichmeansgravityhasamuchmoresignificantaffectonpulmonarybloodflowthansystemicbloodflow.
West'sZones
Thelungisdividedintofourzones,basedontherelationshipbetweenalveolarandvascularpressures:
West'sZone1InWest'sZone1,PA>Pa>Pv.
Thisshouldnotoccurinnormalconditions,becauseanormalpulmonaryarterypressureisnormally(just)sufficientThisisbecauseintheuprightlung,thehydrostaticpressuredifferencewillbeabout30cmH O.However,ifalveolarpressureisraised(e.g.IPPV),orarterialpressurefalls(shock),theremaybearegionwherealveolarpressureexceedsarterialpressure
West'sZone2InWest'sZone2,Pa>PA>Pv.
Here,flowisdeterminedbythearterial-alveolarpressuregradientratherthanthearterial-venousgradientAlveolarpressureactsasaStarlingResistor,whereflowisindependentofdownstreampressure.
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West'sZone3Occurswhenalveolarpressurefallsbelowvenouspressure,i.e.Pa>Pv>PA.Flowisdependentonthearterial-venouspressuregradient.Capillarypressureincreasesalongtheirlength,increasingtransmuralpressureandmeanwidth.
West'sZone4Occursatlowlungvolumes,asextra-alveolarvesselscollapseandshuntoccurs.TheinterstitiumisactingasaStarlingresistor,whichcanbeexpressedas:Pa>Pint>Pv>PA.
HypoxicPulmonaryVasoconstriction
Asdiscussedabove,HPVallowsredirectionofbloodflowfrompoorlyventilatedregionsofthelung,andsoimproveV/Qmatching.HPVisrelevantindiseasestates,aswellasspecificphysiologiccircumstances:
Athighaltitude,thePAO isgloballyreduced,leadingtohighpulmonaryarterypressuresInutero,PAO isnegligible,andPVRisthereforeveryhighThisdivertsbloodfromthepulmonarycirculationintotheleftsideoftheheartviatheforamenovale.Whenthefirstbreathistaken,pulmonaryvesselsdilateandtheright-to-leftshuntisreversed.
References1. Dunn,PF.PhysiologyoftheLateralDecubitusPositionandOne-LungVentilation.ThoracicAnaesthesia.Volume38(1),
Winter2000,pp25-53.2. WestJ.RespiratoryPhysiology:TheEssentials.9thEdition.LippincottWilliamsandWilkins.2011.3. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.4. BrandisK.ThePhysiologyViva:Questions&Answers.2003.
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CerebralBloodFlowDescribethedistributionofbloodvolumeandflowinthevariousregionalcirculationsandexplainthefactorsthatinfluencethem,includingautoregulation.Theseinclude,butnotlimitedto,thecerebralandspinalcord,hepaticandsplanchnic,coronary,renalandutero-placentalcirculations
Withrespecttocerebralbloodflow:
Normalis~750ml.min or~15%ofrestingcardiacoutputNotethatthebrainmakesuponly~2%ofbodyweight.
Arelativelyhighbloodflowisrequiredduetothehighcerebralmetabolicrateforoxygen(CMRO )of50ml.minThebrainissensitivetointerruptionsinflowasithas:
AhighmetabolicrateNocapacitytostoreenergysubstrates
ThefactorsaffectingcerebralbloodflowcanbeclassifiedbythefactorsintheHagan-PoiseuilleEquation:
,where:
isthepressuredifferencedrivingflow,i.e.CPP
istheradiusofthebloodvessels
isthebloodviscosityThesearealsocalledrheologicfactors.
isthelengthofthetube,afixedquantity
FactorsAffectingPerfusionPressure{#cpp)
CerebralPerfusionPressureisthedifferencebetweenmeanarterialpressureandintracranialpressure:
AnormalCPPis~80mmHgInnormalindividuals,CBFisclassicallythoughttobeautoregulatedoveraCPPrangeof60-160mmHg
Thisoccursbymyogenicmeans,similartothekidneyInnormalcircumstances,thisisdependentonMAP(i.e.,withanormalICP<10mmHg,CBFisregulatedoveraMAPrangeof50-150mmHg).
NotethatmorerecentevidencewouldsuggestthatCBFisautoregulatedoveramuchnarrowerrangeofperfusionpressures,andhasagreatercapacitytobufferanincreasedratherthandecreasedperfusionpressure
Atthelowerlimit,thereducedperfusionpressuremeansflowcannotbemaintainedevenwithmaximalvasodilation
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Attheupperlimit,thehighperfusionpressureovercomesmaximalvasoconstrictionAdditionally,theincreasedCBFmayresultindamagetotheblood-brainbarrier
Thecurveisleft-shiftedinneonatesandchildren(duetolowernormalMAP)Thecurveisright-shiftedinchronichypertensionThecurveisprobablyinaccurateinthepathologicalconditionswhereitwouldotherwisebeuseful,suchasmalignancy,subarachnoidhaemorrhage,CVA,orTBI
Thismaybeduetodamagetoeitherthefeedbackmechanisms,ortheeffectors(vasculature)Flowmaybecomepressure-dependent,andsmallchangesinMAPcanhavelargechangesinCBF
FactorsAffectingVesselRadius
VasodilationandconstrictionaffectbothcerebralbloodflowandICP,asvasodilatationincreasescerebralbloodvolumeandthereforemayincreaseICPthroughtheMonroe-Kelliedoctrine.
Vesselcalibreisaffectedprimarilybyfourfactors:
CerebralmetabolismPaCOPaONeurohormonalfactorsTemperature
CerebralMetabolism
Cerebralmetabolism(typicallygivenbythecerebralmetabolicrequirementforoxygen,CMRO )hasalinearassociationwithcerebralbloodflow-thisisknownasflow-metabolismcoupling.Thisiscontrolledlocallythroughthereleaseofvasoactivemediators,suchasH ,adenosine,andNO.Determinantsofcerebralmetabolisminclude:
DrugsCerebralmetabolismmaybedecreasedbyuseofdrugssuchasbenzodiazepines,barbiturates,andpropofol.TemperatureCMRO decreaseslinearlyby~7%perdegreecentigrade,allowingprolongedperiodsofreducedCBFwithoutischaemiccomplications.
PaCO
Carbondioxideactsasacerebralvasodilator.
CBFisalmostlinearbetween20mmHgand80mmHgAbove80mmHg,thecirculationismaximallydilatedBelow20mmHg,thecirculationismaximallyconstrictedAdditionally,thealkalosiscausesaleft-shiftoftheoxyhaemoglobincurve.Thisreducesoffloadingofoxygen,causing
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hypoxiaandsubsequentvasodilation.Thereisaright-shiftinchronichypercapneaThemechanismofactioniscomplex,butinvolveslocalincreaseinH ions.ChangestoCBFwithCO aredependentoncurrentarteriolartone-vasodilatoryeffectsofCO aresignificantlyreducedwhentheperfusingpressureislow.
PaO
CBFincreasesrapidlywhenPaO fallsbelow60mmHgsothatcerebraloxygendeliveryismaintainedHypoxiacausesareleaseofadenosineandreducedcalciumuptake,withsubsequentvasodilation
Neurohormonal
Autonomiccontrolofcerebrovasculartoneislimited,thoughisresponsiblefortheright-shiftintheautoregulationcurvewithsustainedhypertension
FactorsAffectingBloodViscosityBloodviscosityisdependentonhaematocritReducedhaematocritisassociatedwithincreasedCBF,butreducedO -carryingcapacityTheoptimalhaematocritis~0.3-0.35,whichprovidesthebestbalancebetweenreductionofviscositytoimprovecerebralbloodflow,withoutreducingDO .
References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. HillL,GwinnuttC.CerebralBloodFlowandIntracranialPressure.FRCAWebsite.
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3. WillieCK,TzengYC,FisherJA,AinsliePN.Integrativeregulationofhumanbrainbloodflow.JPhysiol.2014Mar1;592(5):841-59.
4. MuizelaarJP.CBFandmanagementofthehead-injuredpatient.In:NarayanRK,WilbergerJE,PovlishockJT,eds.Neurotrauma.NewYork:McGraw-Hill,1996:553–561.
Lastupdated2019-07-18
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HepaticBloodFlowDescribethedistributionofbloodvolumeandflowinthevariousregionalcirculationsandexplainthefactorsthatinfluencethem,includingautoregulation.Theseinclude,butnotlimitedto,thecerebralandspinalcord,hepaticandsplanchnic,coronary,renalandutero-placentalcirculations
Theliverservesasabloodreservoir(30mlper100g,halfofwhichmaybemobilisedinhypovolaemia),andreceives25%ofcardiacoutputfromauniquedualbloodsupply:
Hepaticarterialsystem,whichsuppliesaboutone-thirdofblood,but40-50%ofOHepaticarterialbloodhasanSpO of~98%,aswouldbeexpected.Itisahigh-pressure,high-resistance,high-flowsystem(averagevelocity18cm.s ),withthecapacitytoautoregulate.
Portalvenoussystem,whichsuppliestheremainingtwo-thirdsofblood.Itisalow-resistance,low-pressure,low-velocitysystem(averageflow9cm.s ),withnocapacitytoautoregulate.TheSpO ofportalvenousbloodvariesdependingongutactivity:
Intherestinggut,SpO is~85%Intheactivegut,SpO is~75%
RegulationofFlow
Aswithotherorgans,bloodflowisautoregulatedviaintrinsicandextrinsicmechanisms,andmaybeaffectedbyexternalfactors.
IntrinsicAutoregulation
MyogenicautoregulationHepaticarterialbufferresponseThisisalsoknownasthe"hepaticartery-portalvenoussemi-reciprocalinterrelationship".
Hepaticarterialresistanceisproportionaltoportalvenousbloodflow,suchthatareductioninportalvenousflowcausesadecreaseinhepaticarterialresistanceandincreaseshepaticarterialflowThisisprobablymediatedbyadenosine.
ExtrinsicAutoregulation
AutonomicNervousSystemBoththehepaticandportalvasculaturehavesympatheticinnervation:
Thehepaticarteryhasdopaminereceptors,aswellasβ-andα-adrenoreceptorsTheportalveinhasonlyα-adrenoreceptorsActivationofthesereceptorscausesvenoconstriction,reducingthecomplianceofthehepaticvasculatureandmobilisingupto250mlofbloodintimesofsympatheticstress.
EndocrineandhormonaleffectsAnumberofsubstancesaffectportalflow:
Hormone PortalVeinEffect HepaticArteryEffect OverallEffectonFlow
Adrenaline Constriction Constriction(α),thendilation(β) Reduced
Glucagon Dilation - Increased
Secretin - Dilation Increased
AngiotensinII Constriction Constriction Reduced
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Vasopressin Constriction Constriction Reduced
PCO Constriction - Reduced
ExternalFactors
Flowinthehepaticveinisdependentonvenousreturn:
Increasedvenousreturn(e.g.negative-intrathoracicpressure)increaseshepaticflowDecreasedvenousreturn(e.g.positive-pressureventilation,tamponade,haemorrhage),reduceshepaticflow,andinextremecasesflowmayonlyoccurintermittentlythroughoutthecardiaccycle
Exercisereducesbothportalveinandhepaticarterialflow
Microvasculature
Hepaticarteriolesandportalvenulesformthehepatictriadwithabilecanaliculi.Hepaticarteriolesandvenulesanastomosetoformsinusoids,whichcreateaspecialisedlow-pressure(~2mmHg)capillarysystemwhichdrainsintothecentralveinsofthehepaticacinus.
Thisarrangement:
OptimiseshepaticO extractionIncreasedhepaticO demandismetbyincreasingO extraction,ratherthanbyincreasingflow(asoccursintheheart).Preventsshuntingandretrogradeflow
References1. CICMMarch/May20132. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.3. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.4. KogireM,InoueK,SumiS,DoiR,YunM,KajiH,TobeT.Effectsofgastricinhibitorypolypeptideandglucagononportal
venousandhepaticarterialflowinconsciousdogs.DigDisSci.1992Nov;37(11):1666-70.
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BaroreceptorsDescribethefunctionofbaroreceptorsandtorelatethisknowledgetocommonclinicalsituations.
Baroreceptorsarestretchreceptorswhichmonitorchangesinarterialpressure.Arterialpressureismonitoredbyreceptorsinthe:
AorticarchInnervatedbyCNX
CarotidsinusSmalldilationoftheICAatthelevelofthebifurcation.
InnervatedbyCNIXRememberthecarotidsinusisabaroreceptor,thecarotidbodyisachemoreceptor
Low-pressurestretchreceptors:
RespondtoincreasedvenousreturnAreinhibitedbypositivepressureventilationActbystretchandtypicallydescribedasvolumereceptorsArelocatedinthe:
AtrialwallsSVCandIVCPulmonarycirculation
BaroreceptorControlAfferentfibresfromCNIXandCNXtraveltotheNTSinthemedulla.EffectorneuronsfromtheRVLMareGABAergicandthereforeinhibitory,i.e.increasedbaroreceptordischargereducestonicsympathetictoneandincreasesvagaltone.
Increasedbaroreceptoractivitythereforeresultsin:
ArterialandvenousvasodilationHypotensionBradycardiaDecreasedcardiacoutputDecreasedrespiratoryrate
Conversely,increasedactivityoflow-pressurestretchreceptorsresultsinanincreaseratherthanadecreaseinheartrate.
BaroreceptorActivityBaroreceptorsare:
MoresensitivetopulsatilepressurethanconstantpressureAdecreaseinpulsepressurewithoutachangeinMAPwilldecreasebaroreceptorfiring.ActivethroughoutthecardiaccycleRapidcompensatoryresponsesarevitalintheshort-termcontrolofbloodpressure,e.g.withposture.Activeovertherangefrom50mmHgto200mmHg
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Thiscurveisleft-shiftedinchildrenandneonates,andright-shiftedinchronichypertension,thoughthisisreversible
Hormonalcontrol
Activationofatrial/ventricularstretchreceptorsstimulatesANP/BNPreleaserespectively,whichacttoreducebloodpressureinthefollowingways:
IncreasedGFRActtoconstricttheefferentarterioleanddilatesoftheafferentarteriole.ThissubsequentlyinhibitsreninsecretionthroughincreasedhydrostaticpressureattheJGAandincreasedNa andCl deliverytothemaculadensa.DecreasedaldosteroneViainhibitionofaldosteronesecretion.VasodilationCausesvasodilationofperipheralsmoothmuscle.
References1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. CICMSeptember/November20143. ANZCAJuly/August2000
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ValsalvaManoeuvreExplaintheresponseofthecirculationtosituationssuchaschangesinposturehaemorrhage,hypovolaemia,anaemia,intermittentpositivepressureventilation,positiveend-expiratorypressure,andtheValsalvamanoeuvre.
AValsalvaisforcedexpirationagainstaclosedglottis.ThiscanbeachievedbyincreasingP to40mmHgfor15seconds.Thisincreaseinintrathoracicpressurealtersmanyhaemodynamicparameters.
Phases
AValsalvamanoeuvreconsistsoffourphases:
PhaseI
P isincreasedto40cmH O,withacorrespondingincreaseinPSBPandDBPincreasedueto:
CompressionoftheaortaIncreasedLVpreloadduetoejectionofbloodinthepulmonaryvasculature
PhaseII
VRfallsduetoincreasedPCOfallsduetodecreasedVRSBPandDBPfallduetodecreasedCO
BaroreceptorsareactivatedbythefallinBP,andSNSoutflowincreases,causing:
IncreasedHRIncreasedSVR
BPthereforestartstorecoverlateinPhaseII
PhaseIII
TheValsalvaceases,andP returnsto0cmH OPVRrapidlydropsasalveolarvesselsre-expandSBPandDBPrapidlyfalldueto:
DecreasedPVRcausingdecreasedLVpreloadLossofhighintrathoracicpressurecompressingtheaorta
PhaseIV
VRnormalisesCOnormalisesduetonormalVRandPVRSBPandDBPtransientlyincreaseduetoanormalCOenteringabaroreceptor-drivenhigh-SVRvascularbed
BaroreceptorsrespondtohighSBPanDBPbyincreasingvagaltone:
HRfalls(reflexbradycardia)BPfalls
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AbnormalResponses
Abnormalresponsesoccurincardiacfailureandautonomicneuropathy.
CCF
InCCFasquare-wavepattenisproduced:
IncreasingP resultinginasustainedincreaseinSBPandDBPThereisaslightdecreaseinSBPandDBPforthefewsecondsinphaseIIIwhenairwaypressureisreleased
Appearstobeduetotheincreasedcirculatingvolume,asthisdifferenceresolvesinvenesectedcardiacpatients,andisdemonstratedinnormalindividualswhoaretransfusedtoahighcirculatingvolume.
AutonomicNeuropathy
BaroreceptorresponsetotheValsalvaisminimalinbothphaseIIandIV:
InphaseII,thereisnocompensatoryincreaseinsympatheticoutflow,soBPcontinuestofalluntilP returnsto0mmHgInphaseIV,thereisnocompensatoryincreaseinvagaltoneandsoBPreturnstonormalwithoutovershooting
References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. JudsonWE,HatcherJD,WilkinsRW.BloodPressureResponsestotheValsalvaManeuverinCardiacPatientswithand
withoutCongestiveFailure.Circulation.1955;11:889-899.
Lastupdated2019-07-20
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CVSChangeswithObesityDescribethecardiovascularchangesthatoccurwithmorbidobesity
Obesityisamultisystemdisorderdefinedbyanelevatedbodymassindex(BMI):
Normal:BMI<25Overweight:BMI25-30Obese:BMI>30MorbidlyObese:
ObesityrelateddiseaseandaBMI>35BMI>40
Characteristicsofobesityinclude:
ComplexgeneticandenvironmentalcausesIncreasedcaloricintakeIncreasedmetabolicrate(normalforBSA)
Theeffectofobesityonthecardiovascularsystemiscomplex,andcanbeclassifiedinto:
HormonalchangesAbdominalvisceralfatisresponsibleforsecretingalargenumberofhormoneswhichaffectcardiovascularparameters:
IncreasedleptinContributestocardiacremodellingandLVH.AngiotensinogenLeadstosystemichypertensionandLVremodelling.
Smallamountsareproducedinadipocytes,whichincreasesasfatvolumeincreasesPlasminogenactivatorinhibitor-1ReducesfibrinolysisandpredisposestoVTE.InflammatoryadipokinesImpairendothelialfunction,leadingtoincreasedSVR.CatecholaminesIncreasedcontractility,SVR,andworsenendothelialfunction.
Releasedwith:HypoxiaHypercapneaNegativeintrathoracicpressureFragmentedsleepDuetoOSA.
ChangesinkeycardiovascularparametersIncreasedVODuetoincreasedLBMandfatmass.IncreasedBloodVolumeDuetoincreasedangiotensinIIandaldosterone.IncreasedStrokeVolumeDueto:
Increasedpreload(majorfactor)Increasedcontractility(minorfactor)Duetoincreasedcirculatingadrenalhormones.
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TomaintainDO .Initiallywithpreservedejectionfraction
CardiacchangesDiastolicdysfunctionDuetomyocardialfibrosisimpairingrelaxation.Fattyinfiltrationofmyocardiumandconductingsystem
PredisposestoarrhythmiasRiskisworsenedbychangeinmyocardialarchitecture,hypoxia,andincreasedcirculatingcatecholamines.
BiventricularhypertrophyasaresponsetoincreasedafterloadLVafterloadincreasedduetosystemichypertensionLVHismuchmorecommonthanRVH.
EccentrichypertrophyduetovolumeoverloadConcentrichypertrophyduetopressureoverloadorhormonalchanges
RVhypertrophydueto:LVdiastolicfailureIncreasedPVR
HypoxiaDueto:
EffectsofOSAIncreasedshuntthroughcollapsedlungbases
Acidosis
References
1. AlvarezA,BrodskyJ,LemmensH,MortonJ.MorbidObesity:Peri-operativeManagement.Cambridge:CambridgeUniversityPress.2010.
2. LotiaS,BellamyMC.Anaesthesiaandmorbidobesity.ContinEducAnaesthCritCarePain2008;8(5):151-156.
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CardiovascularEffectsofAgeingDescribethecardiovascularchangesthatoccurwithageing.
CVSeffectsofageingcanbedividedintocardiac,vascular,andautonomicchanges:
CardiacchangesDecreasedreceptordensityandnumberDecreasedmaximumheartrateDuetofibrosisoftheSAnodecausingreducedpacemakercellnumberandfunction,andreductionincatecholaminereceptordensity.
DecreasedinotropyMinor.IncreasedrelianceonatrialkickReducedventricularcomplianceincreasestherelianceonatrialkicktoachieveadequatepreload.Decreaseddiastoliccompliance
Duetohypertrophyfromincreasedafterload
VascularchangesReducedcomplianceDuetolossofelastictissueinthelargearteries.IncreasedSVRReducedcomplianceresultsinincreasedvascularresistance.Reducedendothelialcellfunction(decreasedNO)Impairstheabilityofthevasculartreetoadapttochangesinpressure/volumeleadingto:
ElevatedSBPReducedDBPReducedelasticrecoilcausesdiastolicrunoffandafallindiastolicbloodpressure.
ReducedcatecholaminereceptordensityReducedresponsivenessto(andincreasednumberof)circulatingcatecholamines.
AutonomicImpairedautonomicfunctionDuetodecreasedcatecholamineresponsiveness.ImpairedbaroreceptorresponseDecreasedexercisetoleranceRelianceonpreloadtomaintaincardiacoutput.
References
1. ANZCAFebruary/April20162. CheitlinMD.Cardiovascularphysiology-changeswithageing.AmJGeriatrCardiol.2003Jan-Feb;12(1):9-13.
Lastupdated2019-07-20
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InotropesUnderstandthedetailedpharmacologyofinotropesandvasopressors
Inotropesareagentswhichaltermyocardialcontractility.
PositiveinotropesincreasecontractilityNegativeinotropesdecreasecontractility
ClassesofPositiveInotrope
Classes ClassI:IncreaseIntracellularCalcium
ClassII:CalciumSensitisers ClassIII:Metabolic/Endocrine
Examples Adrenaline,milrinone,glucagon,digoxin Levosimendan T3,Insulin
GeneralMechanismofAction
IncreaseintracellularCa byavarietyofdifferentpathways
IncreasesensitivityofactomyosintoCa
Variable.T3potentiatestheeffect(orincreasesexpressionof)cardiacβreceptors
References1. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.2. TielensET,ForderJR,ChathamJC,MarrelliSP,LadensonPW.AcuteL-triiodothyronineadministrationpotentiates
inotropicresponsestoP-adrenergicstimulationintheisolatedperfusedratheart.CardiovascularResearch32(1996)306-310.
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AdrenoreceptorsUnderstandthepharmacologyofadrenoreceptorblockingdrugs.
Thiscoversthepharmacologyofadrenoreceptors.Theproductionandmetabolismofendogenouscatecholaminesiscoveredunderadrenalhormones.Detailedinformationonspecificsympathomimeticagents,includingstructure-activityrelationships,isinthepharmacopeia.
Adrenoreceptorsareclassifiedbytheirvaryingsensitivitytodifferentcatecholamines.Additionally:
AlladrenoreceptorsareGprotein-coupledreceptorsEachreceptorcontainsseventransmembraneα-helicalsubunits,threeextracellularloops,andthreeintracellularloops
AlphareceptorshavedifferentsubunitsandmechanismsofactionAllbetareceptorsare:
G coupledActivateadenylatecyclaseincreasingcAMP,leadingtoincreasedNa/K<sup+ATPaseactivityandhyperpolarisation
AdrenoreceptorSubtypes
α -receptors:
ArepresentinsmoothmuscleAgonismcausesvasoconstriction,relaxationofGITmuscle(viapresynapticreceptors),andcontractionofGUmuscle.Theyare:
G coupledPhospholipaseCactivatedincreasesIP ,increasecalcium
α -receptors:
ArepresentintheCNS,arterioles,pancreasAgonismcausessedation,analgesia,vasodilatation,andinhibitionofinsulinrelease.Theyare:
G coupledInhibitsadenylatecyclase,decreasingcAMP
β -receptors:
ArepresentincardiacmuscleandtheJGACardiacagonismincreasesinotropy,chronotropy,anddromotropyJGAagonismincreasesreninrelease
IncreaseincAMPincreasesintracellularcalcium
β -receptors:
Arepresentinskeletalvascularandbronchialsmoothmuscle,theliver,andoncellmembranesAgonismcauses:
VasodilationandbronchodilationHepaticglycogenolysisIncreasesactivityoftheNa -K ATPasepump,increasingintracellularpotassium
IncreaseincAMPincreasesNa /K ATPaseactivityandhyperpolarisation
β -receptors:
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Agonismcauseslipolysisandthermogenesis.
References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.3. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.
Lastupdated2018-05-27
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AntiarrhythmicsUnderstandthepharmacologyofantiarrhythmicdrugs
AntiarrhythmicdrugsaretypicallyclassifiedusingtheVaughanWilliamsclassificationsystem,whichdividesdrugsintofourclassesbasedontheireffectonthecardiacactionpotential.Manydrugswillactviamultiplemechanisms.
ClassI:Blockvoltage-gatedNachannelsClassIa:IntermediatedissociationClassIb:FastdissociationClassIc:Slowdissociation
ClassII:β-BlockersClassIII:Prolongtheactionpotential(UsuallyviaK channelblockade)ClassIV:Ca antagonists
Thisclassificationisnotablyincomplete,assomedrugs(suchasamiodarone)fitintomultiplecategories,andothers(suchasdigoxin,adenosine,andmagnesium)fitintonone.
ClassINa -channelblockadeinhibitsactionpotentialprolongationbyblockingactiveandrefractorysodiumchannelsinause-dependentfashionThisinhibitstachyarrhythmiaswhilstallowingnormalconductionExtentofblockdependsontheheartrate,membranepotential,andthesubclassofdrugSodiumchannelblockadeincreasespacingthresholdanddefibrillationenergyrequirement
ClassIa
ClassIadrugshavemixedpropertiesofIbandIc,andalsohaveClassIIIeffectsAstheyprolongtheAVconductionandprolongtheactionpotentialtheyincreasebothQRSdurationandtheQTintervalExamplesincludeprocainamide
Pro-arrhythmiceffectsmayresultbecauseAVnodalconductionmaybeincreased,sodespitedecreasedatrialactivityincreasedventricularconductanceresultsinapotentiallyfatalshorteningofdiastolictime
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ClassIb
ClassIbdrugsbindtoopensodiumchannel,andwillassociateanddissociatefromasodiumchannelinthecourseofanormalbeatTachyarrhythmiasarepreventedbecausedissociationoccurstooslowlyforafurtheractionpotentialtobegeneratedClassIbdrugswillbindselectivelytorefractorychannels,suchasoccursinischaemiaAstheyhavelittleeffectonnormalcardiactissuetheyhavelittleeffectontheECGExamplesofclassIbagentsincludeincludephenytoinandlignocaine
ClassIc
ClassIcdrugsassociateanddissociateslowlycreatingasteady-statelevelofblockThiscausesindiscriminateblockadeandgeneralreductioninexcitabilityClassIcagentsareusedtosuppressunidirectionalorintermittentconductionpathwaysAstheymarkedlyslowconductionvelocitytheyincreaseQRSdurationExamplesofClassIcagentsincludeflecainide
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ClassII
Normalβ-adrenergicstimulationhasanumberofpro-arrhythmiceffects:
IncreasedpacemakerpotentialcurrentIncreasedslow-inwardCa currentIncreasedrepolarisingK andCl currentsIncreasedCa storedinthesarcoplasmicreticulum,whichmaybespontaneouslyreleasedcausingadelayed-after-depolarisationsReducedserum[K ]*
β-blockershaveanantiarrhythmiceffectbyantagonisingthesemechanisms.Theyareusefulfortreatmentofarrhythmiasoccurringwithsympatheticover-activation,suchaspostMI.
ClassIIIBlockingofoutwardK channelsslowscardiacrepolarisation,whichincreasesthecardiacrefractoryperiod.Thishasanumberofbeneficialeffects:
DecreasedautomaticityDecreasedectopyReduceddefibrillationenergyrequirementIncreasedinotropy
Duetotheprolongedrepolarisation,theywillalsocausealongQT(thoughinthecaseofamiodaronethisisnotassociatedwithanincreasedriskofTPD).
ClassIV
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ClassIVdrugsinhibitL-typeCa channels,inhibitingtheslowinwardcalciumcurrent,which:
SlowsSAandAVnodalconductionAVblockadeslowstransmissionofsupra-ventriculararrhythmias.ReducesinotropyPreventsafter-depolarisationsThissuppressesectopybyreducingcalciumleakfromsarcoplasmicreticulum.
AlternativestoVaughanWilliamsAstheVaughanWilliamsclassificationsystemdoesnotneatlydivideagents,andsomeagentsdonotfitintoanycategory,theymayalsobeclassifiedbytheiruses:
Indication Examples
SVT Digoxin,adenosine,verapamil,β-blockers
VT Lignocaine,mexiletine
SVT/VT Amiodarone,flecainideprocainamide,sotalol
Digoxintoxicity Phenytoin
References
1. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.2. BruntonL,ChabnerBA,KnollmanB.GoodmanandGilman'sThePharmacologicalBasisofTherapeutics.12thEd.
McGraw-HillEducation-Europe.2011.3. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-07-18
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FunctionalAnatomyandControlofRenalBloodFlowDescribethefunctionalanatomyofthekidneysandrenalbloodflow.
FunctionalAnatomy
Thefunctionalunitofthekidneyisthenephron.Nephrons:
Arecomposedoftheglomerulus,proximaltubule,loopofHenle,distaltubule,andcollectingductAredividedbytheirlocationinto:
SuperficialcorticalnephronsHaveshortloopsofHenle.JuxtamedullarynephronsHavelongloopsofHenle,andtheefferentarterioleformsthevasarectaforthekidney.Mid-corticalnephronsMayhaveeitherlongorshortloops.
ControlofRenalBloodflow
Thekidneys:
Receive22%ofcardiacoutputatrestExtractonly10%ofdeliveredOHaveahighrenalbloodflowexceedsthatrequiredformetabolismHighflowisinsteadneededtoproducethelargevolumeofglomerularfiltrate(125ml.min )requiredforexcretionofwaste.
Autoregulation
Renalbloodflowisautoregulatedoverawiderangeofmeanarterialpressures(60-160mmHg)via:
MyogenicautoregulationTubuloglomerularfeedback
Myogenicautoregulation:
DescribestheintrinsicconstrictionoftheafferentarterioleinresponsetoanincreasedtransmuralpressureThisincreasesvascularresistanceinproportiontotheincreaseinpressure,keepingflowconstant
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Tubuloglomerularfeedbackismorecomplicated,anddescribestheconstrictionordilationoftheafferentarterioleinresponsetoadenosineorNO(respectively)releasefromthemaculadensa:
ThemaculadensaliesinthewalloftheascendinglimboftheloopofHenleItdetectschangeintubularflowrate(probablyviachangingNa fluxacrossitsmembrane)
Increasedflowintheloopindicatesanincreasedperfusionpressure,promptingreleaseofadenosineandconstrictionoftheafferentarterioleDecreasedflowindicatesadecreasedperfusionpressure,reducingadenosinereleaseandpromptingthereleaseofNOandrenin,whichcausestheafferentarterioletodilate
Notably,flowtojuxtamedullarynephronsisnotautoregulated.Highbloodpressureincreasesjuxtamedullaryflow,increasingGFRandimpairingrenalconcentration,resultinginapressurediuresis.
NeuronalControl
Thekidneysareinnervatedbynoradrenergicsympatheticnerves,whichcauses:
AfferentandefferentarteriolarconstrictionThisincreasescapillaryhydrostaticpressure(increasingfiltration)andalsoincreasescapillaryoncoticpressure(decreasingfiltration).
ThisleadstoanoverallslightreductioninGFR
HormonalControl
Renin:
Isreleasedfromthejuxtaglomerularapparatusbyβ stimulationCatalysestheproductionofangiotensinIfromcirculatingangiotensinogenAngiotensinIisthenconvertedintoAngiotensinIIbycirculatingACE.
TheactionsoftheRAASaredescribedinmoredetailintheendocrinefunctionsofthekidney.
References
1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.3. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders
Elsevier.2011.
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GlomerularFiltrationandTubularFunctionDescribeglomerularfiltrationandtubularfunction.
Glomerulus
TheglomerulusisasetofcapillarieswhichinvaginateBowman'scapsuleFluidfiltersoutofthecapillarybedintoBowman'sspacebasedonStarlingforces:
MembranepermeabilityHydrostaticpressuregradientsOncoticpressuregradient
Reflectioncoefficient
GlomerularFiltrationRate
GlomerularFiltrationRateis:
ThevolumeofplasmafilteredbytheglomeruluseachminuteNormalrenalbloodflowis1.1L.min ,howeverrenalplasmaflowisless(600ml.min foranormalhaematocrit).Therefore,thenormalfiltrationfraction(proportionofrenalbloodflowwhichisfiltered)is~20%.Typically125ml.min
Decreaseswithage(partiallyduetolossofnephronnumber)
GFRcanbeexpressedastheproductofNetFiltrationPressureandthecombinationofmembranepermeabilityandmembranesurfacearea,designatedK (thefiltrationcoefficient):
NetFiltrationPressureisgivenbyopposingStarlingForcesacrosstheglomerularmembrane:
Asproteinisnotfilteredinnormalstates,theoncoticpressureinBowman'sSpaceisusuallyassumedtobe0mmHg.TheaveragecapillaryNFPis~17mmHgHydrostaticpressureDeterminedbyrenalbloodflowandtherelativeconstrictionoftheafferentandefferentarterioles.Hydrostaticpressuredecreasesalongthecapillary.Affectedby:
MAPCatecholaminesLocalautoregulation
MyogenicTubuloglomerularFeedbackHormones
AngiotensinIIconstrictstheefferentarteriolemorethantheafferentarteriole,causinganincreaseinrenalresistancewithonlyasmalldecreaseinGFR.ProstaglandinE2dilatestheafferentarteriole,increasingGFR
OsmoticpressureIncreasesalongthecapillary,asproteinfree-fluidisfilteredleavingahigherconcentrationofproteinwithinthecapillary.Thischangeincapillaryoncoticpressureisproportionaltothefiltrationfraction-agreaterfiltrationfractionwillcauseahigheroncoticpressureoffluidinthecapillary.
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MembranepermeabilityOverallpermeabilityis:
Afunctionof:Membranepermeability,inturnaffectedby:
CapillaryendotheliumBasementmembraneNegativelychargedmoleculeshavereducedfiltrationasthebasementmembraneisalsonegativelychargedwhichopposesmovementoutofthecapillary.FootprocessesofpodocytesMoleculeslessthan7000Daltonarefreelyfiltered,whilstlargermoleculesarefilteredless.
MembraneSurfaceAreaTypicallyveryhighforwaterandsolutes.Affectedby:
GlomerulonephritisChangeinbasementmembraneorpodocytefootprocesses
AngiotensinIIcausingcontractionofmesangialcells
TubularFunction
ProximalTubule
Theproximaltubulereabsorbs60%ofglomerularfiltrate.Itreabsorbsbasicallyeverything,includingprotein,andsecretesH ,organicions(suchasuricacidandsalicylates),ammonium,andupto60%offilteredureaload.
LoopofHenle
TheloopofHenleconsistsofathindescendinglimbandathickascendinglimb;
ThedescendinglimbreabsorbswateronlyThethickascendinglimb:
Reabsorbscommonions(Na ,K ,Cl )andHCOExcretesH
ThefunctionoftheloopistoconcentrateurineinstatesofwaterdeprivationThisisdoneviathecountercurrentmechanism.
CountercurrentMultiplier
Thecountercurrentconcentratingsystemis:
FormedfromtheloopofHenleandcollectingductsDrivenentirelybytheremovalofNaClfromtheascendinglimbMosteasilyunderstoodinstages:
NaClisactivelytransportedoutofthethickascendinglimb,increasinginterstitialosmolalityatthatlevelIncreasedinterstitialosmolalityresultsinwaterreabsorptionfromthedescendinglimb,increasingtubularosmolalityatthatlevelThismoreconcentratedtubularfluidthenflowstoadeeper,moreconcentratedlevel,andmorewaterisreabsorbedTheeffectisprogressiveconcentrationoftubularandinterstitialfluid,butwithalowandstableenergycostastherelativegradientsthateachtransportpumpworksagainstissmallTheendresultisadiluteurineleavingtheascendinglimb,butahighlyconcentratedmedullaryinterstitium
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Thevasarectaareperitubularcapillariesthat:
SurroundtheloopofHenleofjuxtamedullarynephronsFollowtheloopintothemedullaHavetypicallylowbloodflowThisprevents"washout"ofthecountercurrentmultiplier,astheslowbloodflowallowssoluteconcentrationstoequaliseateachleveloftheloop.
Inhypovolaemicsituations,renalbloodflowfallsandvasarectaflowdecreases,furtherreducingwashoutWhenrenalbloodflowishigh,vasarectaflowincreasesThiswashesoutpartofthemedullaryconcentrationgradientandreducestheconcentratingabilityofthekidney.
Distaltubules
Fluidenteringthedistaltubulehasaboutone-thirdtheosmolarityofplasma.Thedistaltubule:
Reabsorbs:Na ,Cl ,HCO ,CaSecretes:K ,H
CollectingDucts
Thecollectingductslieintheinterstitium(concentratedbytheloopofHenle)Intheabsenceofaquaporins,thecollectingductsareimpermeabletowater
Osmolalitycanfallaslowas50mmol.L duetocontinuedreabsorptionofsoluteInthepresenceofaquaporins,waterflowsdowntheosmoticgradientintotheconcentratedinterstitium,resultinginahighlyconcentratedurineADHalsoincreasescollectingductpermeabilityofurea
Ureamovesviasolventdragwithwater
References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. GregerR,WindhorstU.ComprehensiveHumanPhysiology:FromCellularMechanismstoIntegration.Springer-Verlag
BerlinHeidelberg.1996.3. CICMMarch/May2010
Lastupdated2019-07-18
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HandlingofOrganicSubstancesDescribetheroleofthekidneyinthehandlingofglucose,nitrogenousproductsanddrugs
Broadlyspeaking,thekidney:
ReabsorbsimportantsubstancesFiltersandsecreteswasteproducts
MethodsofReabsorptionReabsorptionfromtubuletobloodcanoccurviatwomechanisms:
TranscellularreabsorptionSubstanceisabsorbedintotubularepitheliumandthensecretedintoblood.Thisistypicallyachievedbysymporters,whichrelyonthelowintracellularsodiumconcentrationtomovesubstancesoutofthetubuleagainsttheirconcentrationgradient.ParacellularreabsorptionSubstancepassesthroughthematrixoftightjunctionsbetweenepithelialcells.
RateLimitation
Therearefunctionalupperlimitsontherateofreabsorptionofsubstancesfromthetubule.Therearetwolimits:
TubularMaximum(T )LimitedSaturationoftransportersoccur,soafurtherincreaseinsoluteconcentrationdoesnotincreasetherateofsubstancereabsorption.
ThemaximumsoluteconcentrationforaT systemisafunctionofthetransporter.
GradientLimitedLeaksinthetightjunctionswillresultinsolutemovingfromtheinterstitiumbackintothetubuleifthetubularconcentrationfallstoolow.
Themaximumsoluteconcentrationforagradientlimitedsystemisrelatedtothepermeabilityofthetightjunctions.
GlucoseGlucoseis:
FreelyfilteredattheglomerulusCompletelyreabsorbedviathetranscellularrouteintheproximalconvolutedtubuleundernormalcircumstancesActivelytransportedviatheSGLUT(Sodium-dependentGlucosesymporter)transmembraneprotein
Secondaryactivetransport(downtheestablishedSodiumgradient)TherearetwosubtypesoftheSGLUTprotein:
Low-affinity,high-capacityRapidlyreabsorbsglucose,butisineffectivewhenglucoseconcentrationislow.ItislocatedearlyinthePCT,andreabsorbs~90%offilteredglucose.High-affinity,low-capacitySlowlyreabsorbsglucose,butremainseffectiveevenwhenglucoseconcentrationislow.ItislocatedlateinthePCT,whereglucoseconcentrationislower(havingalreadybeenreabsorbedbythehigh-capacitytransporter),andreabsorbs~10%offilteredglucose.
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AsGFRincreases,glucosefiltrationandthereforeglucoseabsorptionincreaseAsglucoseisco-transportedwithNa ,absorptionofNa andH OalsoincreaseThisphenomenonisknownasglomerulo-tubularbalance
GlucosereabsorptionisaT system,andisoverwhelmedwhenfilteredglucoseexceeds300mg.min or16mmol.minThistypicallyoccurswhenplasma(andthereforefiltered)glucoseconcentrationsexceed12mmol.L
ConsequencesofGlycosuria
GlycosuriaoccurswhenfilteredglucoseexceedsthecapacityofthePCTtoreabsorbit,andcauses:
IncreasedurinevolumeGlucoseactsasanosmoticdiureticby:
ReducingNa reabsorptioninthePCTAssomeglucoseisnotabsorbed,thesodiumthatwouldnormallybereabsorbedwith(tubuloglomerularbalance)isremaininginthetubule.ReducingwaterandsaltreabsorptionintheLoopofHenleDuetohightubularflowrates.
Impairstheformationofthemedullaryconcentrationgradient,limitingconcentratingcapacityStimulatesADHrelease
ElectrolytederangementsHypokalaemiadueto:
ReducedK reabsorptionduetohightubularflowratesAldosteronereleaseduetohypovolaemia,increasingNa reabsorptionandK secretion
ADHreleaseinresponsetohypovolaemiaLossofsubstrateforATPgenerationIncreaseriskofurinaryinfections
NitrogenousProducts
Aminoacidsarereabsorbedbyamino-acidtransportersThesearenot(entirely)selective,andreabsorbseveralstructurallysimilaraminoacids.
ThesesharedpathwayscreatecompetitionforbindingsitesbetweenaminoacidsExcessofonesubstancewillleadtobothexcretionofthissubstanceinurine,aswellasinappropriateexcretionofrelatedsubstances
Largerproteins(suchasalbumin)areinfactfilteredattheglomerulus(thoughinverysmallamounts)Reuptakeoccursinseveralstages:
EndocytosisattheluminalmembraneThisisanenergy-dependentprocess,requiringproteintobindtomembranereceptors.Degradationofproteinintoindividualaminoacids
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Reuptakeacrossthebasolateralmembrane
Smallerproteinsandpeptides(e.g.insulin,angiotensinII)arecompletelyfilteredCatabolismoccursinthetubularlumenbymembrane-surfacepeptidasesAminoacidsarereabsorbedbystandardamino-acidtransporters
Urea
Ureaisasmall,watersolublemoleculeproducedintheliverfromammoniaasamethodforeliminatingnitrogenouswaste.
Ureaexcretioniscomplex,asithasanimportantroleinthecountercurrentmultiplier.Thismeansthatintheshortterm(hourstodays)eliminationmaynotmatchproduction,althoughoverweekstheywillbeequal.Ureais:
Freelyfiltered~50%offilteredloadisreabsorbedinthePCTbysolventdrag(withwaterreabsorption)Ureaconcentrationisslightlyincreasedasmorewaterisreabsorbedthanurea.TheureareabsorbedinthePCTisthensecretedintotheLoopofHenleviaUTuniporters
Luminalconcentrationofureaismuchhigherintheascendinglimbduetotheabsorptionofwater~50%isreabsorbed(again)inthemedullarycollectingductsHere,urinebecomessoconcentratedthatluminalconcentrationofureaexceedsmedullaryconcentration.
Overall,50%offilteredloadisexcreted
pHDependentDrugReabsorption
Manysubstances,suchasdrugs,areweakacidsorbasesReabsorptionofthesesubstancesispHdependent
WeakacidsareproportionallymoreionisedatapHabovetheirpKaWeakbasesareproportionallymoreionisedatapHbelowtheirpKaUnionisedsubstancesarelipidsoluble,andabletodiffuseintotubularcellsdownconcentrationgradientsIonisedsubstancesaretrappedwithinthelumen
References
1. EatonDC,PoolerJP.Vander'sRenalPhysiology.6thEd(Revised).McGraw-HillEducation-Europe.2004.
Lastupdated2019-07-18
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MeasurementofGFRDescribetheprinciplesofmeasurementofglomerularfiltrationrateandrenalbloodflow
Renalclearanceofasubstancequantifiestheeffectivenessofkidneysinexcretingsubstances.Thedefinitionofclearanceisthevolume(typicallyofplasma)clearedofadrugperunittime.Renalclearancecanthereforebeexpressedas:
,where:
=Clearance
=Urineconcentration
=Urineflowrate
=Plasmaconcentration
ClearanceandGFR
Astheeliminationofmostsubstancesisdependentonglomerularfiltration,clearanceofasubstancecanbeusedtoestimateGFR.Methodsinclude:
InulinInulinisanaturallyoccurringpolysaccharide.
InulinclearanceaccuratelymeasuresGFRasitis:FreelyfilteredbytheglomerulusNotsecretedatthetubulesNotreabsorbed
However,inulinisnotproducedbythebodyandsomustbegivenbyIVinfusionThislimitsitsclinicalutility.
CreatinineCreatinineisabyproductofmusclecatabolism.
Creatinineisusedclinicallytomeasurerenalfunctionbecauseitis:ProducedatarelativelyconstantrateFactorsaffectingcreatinineproductioninclude:
RaceMusclemass
AgeSex
DietNotmetabolisedFreelyfilteredbytheglomerulusMinimallysecretedAsGFRfallstheproportionofcreatininesecretedbyrenaltubulesincreases,soplasmacreatininewilloverestimateGFRwhenGFRislow.Notreabsorbed
GFRcanbeapproximatedbycreatinineclearance
Thisisgivenbytheequation:
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SerumCreatinine
ThisformulademonstratesthatGFRisinverselyproportionaltoserumcreatinineconcentration.
Thisisonlytruewhenbothcreatinineproductionandglomerularfiltrationareatsteady-stateAsuddendropinglomerularfiltration(e.g.aorticcross-clamp)willnotresultinanimmediateriseincreatinine.
DuringacutechangesinGFR,serumcreatininewillunderestimateGFRuntilanewsteadystateisreachedCreatininemustbeproducedandnoteliminatedforittorise.
EstimatingCreatinineClearance
Usingtheaboveformularequiresmeasurementofurinevolume.Thisis:
Typicallyperformedbytakinga24hoururinecollectionTedious,andsocreatinineclearanceisoftenestimatedAcommonmethodistheCockcroft-Gaultformula,whichhasacorrelationof~0.83withcreatinineclearance:
,where:
=Clearance
=Age
=Sexcoefficient(Male=1,Female=0.85)
=Creatinineinµmol.L
AlternativeformulasareMDRDandCKD-EPI.TheseequationshavetwoadvantagesofCockcroft-Gault:
TheyarebetterpredictorsofGFRTheydonotrequireweight,andsocanbecalculatedbythelaboratoryautomaticallyOtherrequireddata(e.g.age)canbetakenfromhospitalrecords.
Theseestimateshavesimilarweaknessestotheabove:
Dependentonserumcreatinine,whichcanbehighlyvariable.Formulasarederivedfromaveragevaluesofdependentvariables,andsowillbeunreliableatextremesof:
AgeMusclemassCriticallyillMalignancyDiet
References
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1. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:SaundersElsevier.2011.
2. CockcroftDW,GaultMH.PredictionofCreatinineClearancefromSerumCreatinine.Nephron1976;16:31-413. LeveyAS,StevensLA,SchmidCH,ZhangYL,CastroAF3rd,FeldmanHI,KusekJW,EggersP,VanLenteF,GreeneT,
CoreshJ;CKD-EPI(ChronicKidneyDiseaseEpidemiologyCollaboration).Anewequationtoestimateglomerularfiltrationrate.AnnInternMed.2009May5;150(9):604-12.
4. MDCalc-Cockcroft-GaultEquation.5. NIDDK.EstimatingGlomerularFiltrationRate(GFR)
Lastupdated2019-07-18
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EndocrineFunctionsoftheKidneyOutlinetheendocrinefunctionsofthekidney
Thekidneyisinvolvedinanumberofendocrineprocessesandproducesormetabolisesanumberofhormones:
RAASVitaminDEPOProstaglandins
Renin-Angiotensin-AldosteroneSystemTheRAASisasignalingpathwayinvolvedinbloodpressurecontrol.Itinvolvesanumberofhormones:
Angiotensinogenisproducedbytheliverinresponseto:GlucocorticoidsThyroidhormonesOestrogensAngiotensinIIVariousinflammatoryproteins
Reninisaproteaseproducedbythekidneysinresponsetoβ stimulationorhypotension,andexiststocleaveangiotensinogentoangiotensinI
ACEcleavesangiotensinItoangiotensinII,andalsocleavesbradykininintoinactivemetabolites
AngiotensinIIincreasesbloodpressureviaanumberofmechanisms:Simulatesaldosteronereleasefromtheadrenalcortex,increasingsodiumandwaterretentionVasoconstrictionofefferentgreaterthantheafferentarteriolesResultsinslightdecreaseinGFRatalowerperfusionpressure,butincreasesfiltrationfraction.
NB:Differentsourcesquotedifferentchanges(increaseordecrease)inGFRThefinaleffectmayvarydependingonthecontributionofotherautoregulatoryprocesses.
ReducesK throughconstrictionofglomerularmesangialcellsIncreasedSNSactivityandcentralandperipheralvasoconstrictionIncreasesthirstviahypothalamicstimulationStimulatesADHrelease,reducingrenalwaterexcretionStimulatesreleaseofangiotensinogen
Aldosteroneactsonthedistalconvolutedtubuleto:IncreasereabsorptionofNa andwaterIncreaseeliminationofK andH
VitaminDVitaminDhasacomplexmetabolicpathwaywhichmeandersthroughanumberoforgansystems:
VitaminD maybeabsorbedindietorproducedinskinbytheactionofUVlighton7-dehydrocholesterolVitaminD isthenhydrolysedintheliverbyCYP450enzymestoform25-hydroxycholecalciferol(25-OHD )25-OHD isthenconvertedintheproximaltubuletocalcitriol-theactiveform
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Erythropoietin
ErythropoiesisisstimulatedbyEPOrelease:
Inadults,EPOisreleasedfromthe:Peritubularcapillaryfibroblasts(85%)Liver(15%)
EPOisreleasedinresponseto:HypoxiaHypotensionLowHct
Erythropoiesisisinhibitedby:HighredcellvolumeRenalfailureProductionofEPOisdecreasedinrenalfailure,whichiswhypatientswithend-stagerenaldiseaserequireexogenousEPO.
References1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
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Acid-BaseBalanceDescribetheroleofthekidneysinthemaintenanceofacid/basebalance
Acidsproducedbythebodycanbe:
Volatile(CO )Bodyproducesandeliminates~13-20mol.dayRemovedbythelungs
Fixed(everythingelse)Includelactate,sulphate,phosphate,andketonesBodyproducesandeliminates10mmol.kg .dayEliminatedbythekidneyMechanismsforeliminationofacidinclude:
ReabsorptionofHCOThisisequivalenttotheremovalofthesameamountofH .
Asthereisusuallyanetproductionofacid,undernormalcircumstancesallfilteredHCO isreabsorbedNotethatremovalofanacidloadisassociatedwithgreaterHCO generationandreabsorption,notincreasedH secretion
BoundtofilteredbuffersAsammonium
TherateandextentofthesereactionsisdependentonECFpHandionconcentrations,whichgivesthekidneycontroloverionconcentrationsUrinarypHcanfallaslowas~4.4,beforetheactivetransportofH isinhibited
BicarbonateandtheKidneyBuffersystemsminimisechangesinpHuntilthekidneycaneliminateexcesshydrogen.
BicarbonateisthepredominantECFbuffersystem(seeAcid-Basephysiologyformoreonbuffers).ByadjustingthelevelofHCO thekidneyisabletoadjustpH,aspertheHenderson-Hasselbalchequation:
Where:
=6.1,thepKaofHCO
=24,thenormal[HCO ]inmmol.L
=1.2,thenormal[CO ]inmmol.L
Bicarbonateis:
Freelyfiltered4320mmol.day ofHCO isfiltered(24mmol.L x180L.day ,normalrangeis4-5mol.day )ReabsorbedinthePCT(90%),thickascendinglimb,DCT,andCT
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Adjustingrateofabsorptionallowscorrectionofanacidosisoralkalosis.AllHCO reabsorptionisequivalenttoalossofH .
ReabsorptionofBicarbonate
Reabsorptionofbicarbonateinvolvesseveralsteps:
H issecretedintothelumeninoneofthreeways:PrimaryH ATPaseinthePCTandDCTH -Na antiporterinthePCTandascendinglimbH -K ATPaseintheCT
SecretedH combineswithfilteredHCO toformCO andH OCO andH OdiffuseintothetubularcellCO andH OareconvertedbackintoHCO andH inthetubularcellHCO isreabsorbedintothecapillaryviatheHCO -Cl antiporter,andtheH ionisavailabletobesecretedintothetubule(inexchangeforK inthecollectingductsandNa intheproximaltubule)
ThiscomplicatedprocessallowsHCO tobemovedfromthetubuletothetubularcellandthentothecapillary.ThereisnoeliminationofH bythismethod-thepurposeofH secretionistofacilitatethereabsorptionofHCO intothetubularcell.
AmmoniaGlutamineprovidesamechanismforeliminationofalargenumberofH ions:
Thisisimportantin:EliminationofexcessmetabolicacidRenalcompensationforacidosis
Thisoccursvia:FilteredglutamineisabsorbedintoproximaltubularcellsandmetabolisedtoNH (ammonium)andHCOHCO diffusesintoblood,andtheNH issecretedintothetubuleviatheNH -Na antiporterandeliminatedinurine
The reactionhasapKaof9.2meaning:AmmoniacannotactasaneffectiveurinarybufferAmmoniaisnotatitratableacid,asitwillnotreleaseH ionsasurinarypHincreasesThismeansfilteredammoniadoesnotcontributetothelowerlimitofurinarypH(4.4),whichiswhyitissoimportantintherenalcorrectionofseveremetabolicacidosis.
BoundtoFilteredBuffers
SecretedH mayalsocombinewithafilteredbuffer(e.g.PO ).TheseH ionsarenotreabsorbed.About36mmolofH iseliminatedwithfilteredPO eachday,witheachPO bindingtwoH ions.
References
1. CICMSep/Nov20142. ANZCAFeb/April20123. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.4. Acid-BaseOnlineTutorial,UniversityofConneticut5. Brandis,K.RenalRegulationofAcid-BaseBalance,in'Acid-basepHysiology'.
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DialysisDialysisistheseparationofparticlesinaliquidbasedontheirabilitytopassthroughamembrane.
Indications
Failureofnormalrenalfunctions,i.e.:
AcidElectrolytederangementParticularlyhyperkalaemia.IntoxicationsOverloadUreamia
PhysicalMechanisms
Fluidandelectrolytescanberemovedbyfourdifferentmechanisms:
DiffusionDiffusionisthespontaneousmovementofsubstancesfromahigherconcentrationtoalowerconcentration,whererateofmovementisproportionaltotheconcentrationgradient(asperFick'sLaw).
UltrafiltrationMovementofwater,asdeterminedbyStarling'sForces.
Whenasolventpassesthroughamembrane,theprocessiscalledosmosis.Thefrictionalforcesbetweensolutesandwatermoleculeswillpulldissolvedsubstancesalong,aprocessknownasbulkfloworsolventdrag.
Implementation
HaemodialysisUsesdiffusion.
Bloodispumpedthroughanextracorporealcircuitthatcontainsadialyser.Dialysateflowiscountercurrent,whichmaximisesthegradientfordiffusion.Solutesmoveacrossamembranebetweenbloodanddialysate,asperFick'sLaw:
ConcentrationgradientbetweenbloodanddialysateFlowrateofbloodanddialysate
SolubilityofthesoluteMassChargeProteinbinding
DialysismembranepermeabilityThicknessPorositySurfacearea
HaemofiltrationUsesultrafiltration.
Bothapositivehydrostaticpressureinbloodandanegativehydrostaticpressureindialysateisgenerated,causing
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ultrafiltrationandremovalofsolutesviasolventdrag.
Eliminationviabulkflowisindependentofsoluteconcentrationgradientsacrossthemembrane.TransportisdependentonStarlingForces:
ThetransmembranepressuregeneratedThisisafunctionof:
BloodflowtothemembraneDetermineshydrostaticpressure.Oncoticpressuregradient
PorosityofthemembraneAdditionally,ahighfiltrationfractionwillcauseexcessivehaemoconcentration,andclottingofthefilterThefilteredfluid(ultrafiltrate)isdiscarded,andreplacedwithanotherfluiddependingonthedesiredfluidbalance.
Differences
RenalReplacementTherapy(RTT)canbevia:Peritonealdialysis(PD)Intermittenthaemodialysis(IHD)IHDcausesgreatercardiovascularinstabilitycomparedtoCRRTasthefluidandelectrolyteshiftsoccurmorerapidly.ContinuousRenalReplacementTherapy(CRRT)
ContinuousVeno-VenousHaemofiltration(CVVH)ContinuousVeno-VenousHaemodiafiltration(CVVHDF)
Methodchosendependsdesiredeffect:
Smallmolecules(<500Da)andelectrolytescanberemovedbyfiltrationordialysisMedium-sizedmolecules(500-5000Da)arebestremovedbyfiltrationLowmolecularweightproteins(5000-50000Da)areremovedbyfiltrationThisincludesremovalofinflammatoryproteins,whichmaybebeneficialinsepsis.Waterisbestremovedbyfiltration
PharmacokineticsofRRTPharmacokineticsareunpredictable,butarebroadlyaffectedby:
DrugfactorsFreedruginplasmaDrugswithasmallproportionoffreedruginplasmaare(unsurprisingly)poorlyremovedbyRRT(butmayberemovedviaplasmapheresis).Theseinclude:
Highly(>80%)proteinboundsubstancesExamplesincludedphenytoin,warfarin,andmanyantibiotics.
NotthatthismaynotapplyinoverdoseOnceproteinbindingsitesaresaturated,bothfreedrugfractionandefficacyofdialysisisincreased.
DrugswithaV greaterthan1L.kgSize/MolecularWeight
Smallmolecules(<500Da)aremoreeasilyclearedbydiffusivemethodsofRTTMolecules>15kDaarepoorlydialysedThisincludesproteins,heparins,andmonoclonalantibodies.
VolumeofdistributionDrugswithhighvolumesofdistributionarepoorlydialysed,asremovalofdrugfromplasmaonlyremovesasmallproportionoftotal-bodydrugcontent.
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Dose/FlowratesReducedflowrateswillreduceclearance.
Conventionalhigh-fluxhaemodialysishasmorerapidclearancecomparedtolower-fluxhaemoperfusionorCRRTMembranepermeabilityTimingDrugsgivenbetweenIHDorSLEDsessionswillnotbecleareduntilthenextsession.s
PatientfactorsResidualrenalfunctionPatientsresidualGFRwillalsoaffectpharmacokinetics.
AnIncompleteListofDrugs
DrugsRemovedonRRT DrugsnotremovedonRRT
Barbiturates Digoxin
Lithium TCAs
Aspirin Phenytoin
Sotalol/Atenolol Otherbeta-blockers
Theophylline Gliclazide
EthyleneGlycol Benzodiazepines
Methanol Warfarin
Aminoglycosides,metronidazole,carbapenems,cephalosporins,penicillins Macrolides,quinolones
References
1. JohnsonCA,SimmonsWD.DialysisofDrugs.NephrologyPharmacyAssociates.
Lastupdated2019-07-18
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SodiumandWaterDescribethefunction,distribution,regulationandphysiologicalimportanceofsodium,chloride,potassium,magnesium,calciumandphosphateions
NormaltotalbodyNa is60mmol.kg ,70%ofwhichisexchangeable.TotalbodyNa isdistributedas:
50%inECFSodiumisthedominantextracellularcation.
TypicalECF[Na ]of140mmol.L .45%inbone5%inICFAminorintracellularcation.
ICF[Na ]varieswithcelltype,butistypically12-20mmol.L .Concentrationiskeptlowbytheactionofthe2Na -3K ATPaseexchangepumpandthelowpermeabilityofthecellularmembranetoNa
FunctionofSodiumRegulationofECFvolumePrincipalECFcation.Changesinsodiumlevelscausecompensatoryfluidshifts.Lossofsodiumcontentwillresultinhypotension/hypovolaemia,withconsequentbaroreceptorstimulationandactivationoftheRAAS.Baroreceptorswillactivatewitha7-10%changeinvolume.
OsmolarityChangesinsodiumconcentrationaffectosmoreceptorsandwillaffectADHandthirstmechanisms.Osmoreceptorswillactivatewitha1-2%changeinosmolality.
Acid-BasebalanceNa -H exchangepumpsinthekidneyarestimulatedinacidosis.
RestingMembranePotentialAlterationsinsodiumconcentrationwillaffectintracellularpotassiumtoasimilardegree,whichwillaltertheRMP.
RegulationofSodiumandWater
Regulationofanysystemistypicallyabalancebetweeninputandoutput:
SodiumintakeisessentiallyunregulatedTherefore,sodiumconcentrationisafunctionof:
SodiumeliminationSodiumreabsorptionWaterhomeostasisControloftotalbodywaterisamajormechanismtoregulatesodiumconcentration.
SodiumElimination
Sodiumiseliminatedin:
SweatandGITObligatoryandnotamenabletoregulation.
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Acclimatisationtohotenvironmentsimprovestheefficiencyofsweatingbyreducingitstonicity,reducingsodiumlossGITUrine
AdjustrenaleliminationisthemainmechanismtoregulatesodiumconcentrationCanbeperformedintwoways:
ChangesinGFRChangesinGFRduetohyperorhypovolaemiawill(indirectly)adjustsodiumelimination.IncreasedplasmavolumeincreasesGFR,andviceversa.ChangesinsodiumreabsorptionThisisthemainmechanismforcontrollingsodiumineuvolaemia,andismediatedprimarilybyaldosterone.
SodiumReabsorption
Giventhat:
Normalglomerularfiltrateis~180L.dayThedominantosmoleinglomerularfiltrateissodiumNormalurineoutputis~1.5L
Themajorityoffilteredsodiummustbereabsorbed.ThisiscalledbulkreabsorptionandoccursinthePCTandLOH:
60%oftotalreabsorptionisbytheNa -K ATPasepumpinthePCT30%oftotalreabsorptionisbytheNa -K -2Cl co-transporterintheLOH
Theremaining10%ofsodiumreabsorptionoccursintheDCTandCT.Asitisundertheinfluenceofaldosterone,itisthecomponentwhichisimportantinregulation.AldosteroneincreasesNa reabsorptionbyincreasingthenumberoractivityofthesepumps:
Na -Cl pumpsintheDCTNa -K ATPasepumpsinprincipalcellsoftheDCTNa -H pumpsinintercalatedcellsoftheCT
WaterHomeostasis
Bodywaterhomeostasisinvolves:
SensorsOsmoreceptorspresentinthe:
MaculadensaCircumventricularorgansSubfornicalorganandthevascularorganofthelaminaterminalis.
Changeincellularvolumesecondarytochangesinosmolalityalterhormonesecretion.EffectorsPredominantlyhormonal:
ADHRAASNatriureticpeptides
References
1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. CICMSeptember/November2014
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3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.4. NationalResearchCouncil.RecommendedDietaryAllowances.10thEd.1989.NationalAcademiesPress.
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PotassiumDescribethefunction,distribution,regulationandphysiologicalimportanceofsodium,chloride,potassium,magnesium,calciumandphosphateions.
Potassiumisthemajorintracellularcation,with90%oftotalbodypotassiumpresentintheICF.Afurther8%issequesteredinbone,with2%presentintheECF.
NormalECFconcentrationis3.5-5mmol.LNormalICFconcentrationis~150mmol.L
FunctionandDysfunctionPotassiumisimportantfor:
RegulationofintracellularpHControlofintracellularvolumeDNAandproteinsynthesisEnzymaticfunctionRestingmembranepotential
Therestingmembranepotentialisdeterminedbytheratioofintracellular:extracellularpotassium,aspertheNernstequation:
SmallchangesinextracellularionconcentrationproducelargechangesinvoltageThishassignificanteffectonexcitabletissues.RapidchangesinpotassiumconcentrationcausesymptomsatlowerlevelsthanchronicchangesSymptomsarerelatedtothechangeinactionpotentialgeneration.
VentricularActionPotentialinHyperkalaemia:
Hyperkalaemia
Hyperkalaemiacauses:
TherestingmembranepotentialtobecomelessnegativeAspertheNernstequation.
Thisresultsintherestingmembranepotentialbeingclosertothethresholdpotential,increasingirritabilitySeveralsymptoms,including:WeaknessParalysisParasthesiasECGfindingsarethoseofprolongeddepolarisationandrapidrepolarisation:
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Serum[K ](mmol/L) ECGFindings
5.5-6.5 TalltentedTwaves
6.5-7.5 LossofPwave,lengtheningPRinterval
7.5-8.5 WideningQRS
>8.5 Sine-waveQRS
Hypokalaemia
Hypokalaemia:
Causestherestingmembranepotentialtobecomemore-negativeThismakesitmoredifficultforastimulustoreachthethresholdpotential,andthereforeitishardertogenerateandpropagateactionpotential.ECGfindingsarethoseofrapiddepolarisationandprolongedrepolarisation,andinclude:
ProlongedPRLongQTFlatTwavesorTWIUwavesSTdepressionSeverehypokalaemiamayresultin:FrequentsupraventricularandventricularectopicsSupraventriculararrhythmiasVentriculararrhythmias
Regulation
Serumpotassiumisdependentonintake,sequestration,andelimination.
Intake
Dietaryintakemaybehighlyvariable.PotassiumiscompletelyabsorbedfromtheupperGItract.
Sequestration
Severalfactorsaffectpotassiumsequestration:
Insulinandβ -agonismresultsinincreaseactivityoftheNa -K ATPasepump,shiftingpotassiumintocellsfollowingamealandduringexerciseAcidosiscausesanextracellularshiftofpotassium,ashydrogenionsareexchangedforpotassiumionsThereverseoccursinalkalosis.CelllysismayreleasealargeamountofpotassiumintocirculationandcausesignificanthyperkalaemiaifalargenumberofcellsaredestroyedAldosteroneincreasesuptakeofpotassiumintocells
Elimination
Eliminationofpotassiumoccursviathekidneys,andisdependentonproductionoflargevolumesofglomerularfiltrateandsecretionbythedistalconvolutedtubuleandcollectingduct.
Innormalconditions:
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ThePCTandascendinglimbreabsorbthemajorityofabsorbedpotassiumThisisessentiallyfixed.
PCTabsorbs~55%Ascendinglimbabsorbs~30%
TheprincipalcellsoftheDCTandcollectingductsecretepotassiumAlteringpotassiumsecretionisthemainmethodbywhichthekidneyregulatesserumpotassium.
ThecollectingducthasamuchgreaterrolethantheDCTWithnormaldietaryintake,morepotassiumissecretedthanreabsorbedThischangesinconditionsofpotassiumdepletion.
ControlofTubularSecretion
Tubularpotassiumsecretionismainlyafunctionof:
Plasma[K ]Increasedplasma[K ]stimulatestheNa -K ATPasepumpintheprincipalcells,andalsostimulatesaldosteronereleasefromtheadrenalcortex.TubularflowrateMovementofpotassiumoutofprincipalcellsoccursdownapassiveconcentrationgradient.IncreasingtubularflowrateincreasestheconcentrationgradientforpotassiumAldosteroneAldosteroneincreasesproductionoftheNa -K ATPasepump,whichincreasespotassiumsecretionanduptakeintocells.
Minorcontributorsinclude:
SodiumandwatercontentHighsodiumcontentinhibitsaldosteronerelease,reducingpotassiumeliminationHighwatercontentinhibitsADHexcretionandreducessecretionofpotassium,howeverhighwatercontentalsoincreasesflowthroughtherenaltubule,whichindirectlyincreasestubularsecretionofpotassium.
AlkalosisAlkalosisincreaseseliminationofpotassiumastheNa -K ATPasepumpisstimulatedbylowH ionconcentration.
References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders
Elsevier.2011.3. Nickson,C.Hyperkalaemia.LifeintheFastLane.4. ParhamWA,MehdiradAA,BiermannKM,FredmanCS.HyperkalemiaRevisited.TexasHeartInstituteJournal.
2006;33(1):40-47.
Lastupdated2017-10-04
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PrinciplesofAcid-BasePhysiologyExplaintheprinciplesunderlyingacid-basechemistry
Therehavebeenseveraldifferenttheoriesofacid-basechemistry.TheonemostrelevantfortheprimaryexamistheBrønsted–Lowrydefinition,whichdefines:
AnacidasaprotondonorAbaseasaprotonacceptor
pHStandsforthepowerofhydrogenIsameasureofhydrogenionactivityinasolution
Activitycanbeapproximatedbyconcentration
Therefore,pHcanbeexpressedasafunctionofhydrogenionconcentration:UsingpHratherthanconcentrationmakesiteasiertocomparedifferentsolutions.
pKaStrongacids(andbases)dissociatecompletelyinsolutionWeakacids(andbases)onlypartiallydissociateTheyhaveadissociatedstate(A-)andanundissociatedstate(HA)Theratioofconcentrationsoneachsidecanbeusedtocalculatetheaciddissociationconstant,Ka
Thisequationdescribesthestrengthofanacidbyindicatinghowreadilytheacidgivesupitshydrogen.SimilartopH,thisvalueisoftenlogtransformedtopKaproduceanindex,whichallowseasycomparisonofdifferentsubstances:
pKahasseveralusefulproperties:Anacidofbasewillbe50%ionisedwhenthepHofitssolutionequalsitspKaAcidsaremoreionisedabovetheirpKaBasesaremoreionisedbelowtheirpKaAnincreaseinpHof1abovethepKawillresultinthatsubstancebeingeither90%(foranacid)or10%(forabase)ionised
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SystemicEffectsofAcid-BaseDisorders
pHdisturbanceaffectsmanyorgansystems:
Respiratory
IncreasedPeripheralandcentralchemoreceptorsincreaseventilationinresponsetoafallinpH.Oxyhaemoglobin-DissociationCurve
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Right-shiftedbyafallinpH.BronchoconstrictionHypercapneacausesparasympathetically-mediatedbronchoconstriction.
CardiovascularInotropyInotropyfallsinacidosisduetoadirectmyocardialdepressanteffect.MaybeoffsetbyincreasedSNStoneinlow-gradeacidosis.Alkalosismayincreaseinotropybyincreasingresponsivenesstocirculatingcatecholamines.DecreasedresponsetocatecholaminesWhenpH<7.2.ArrhythmiasSecondarytoalteredSNStoneandelectrolytes.VasodilationDirectlyduetohypercapnea.
CNSH ionscannotcrosstheBBB,howeverCO can.FluidandElectrolyte
PlasmaK increasesby0.6mmol.L forevery0.1unitfallinpHThisisduetoimpairmentoftheNa /K -ATPaseH ionsbindtothesamesiteonalbuminascalcium,soionisedcalciumwillincrease
MSKBonesChronicmetabolicacidosisconsumesbonephosphatetobufferH ions,causingosteoporosis.
CellularEnzymefunctionDenaturationandfunctionalimpairment.MolecularionisationChangeinionisationmaychangeamoleculesabilitytocrosscellmembranes(e.g.reducingdoseofthiopentoneinacidosis),oraffecttheirfunctionRestingmembranepotentialChangeinionpermeabilitywillalterRMP,andthereforehoweasyitistogenerateanactionpotential.
ChangewithTemperature
pHistemperaturedependent:
pHincreasesby0.015forevery1°CfallintemperatureDuetodecreasedionicdissociationofwater.GassolubilityalmostalwaysincreaseswhentemperaturefallsDissolvingistypically(notalways)anexothermicreaction.Asthekineticenergycontentofamoleculefalls,itsabilitytodissociatefromsolutiondecreases.
AsCO dissolves,PaCO fallsAsbloodgasmachinesoperateat37°C,ameasurementerrorwilloccurifapatientisnotcloseto37°C
AhypothermicpatientwillhaveahigherpHandCO thanmeasured
TherearetwocommonmethodsformanagingpHofsignificantlyhypothermicpatients(e.g.,thoseonCPB):pH-statandalpha-stat.
pH-stat
CO isaddedtothecircuitsothatpHandPaCO arenormalwhencorrectedfortemperatureThistheoreticallyimprovesoxygendeliverybypreventingtheleft-shiftintheoxyhaemoglobindissociationcurveTheincreasedCO alsocausescerebralvasodilation,which:
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IncreasesspeedanduniformityofcerebralcoolingIncreasesriskofcerebralembolicevents
alpha-stat
pHandCO valuesaremaintainedat'normalfor37°C'Measuredvalueswillbedifferent,as:
pHwillbeincreasedCO willbedecreased
CellularautoregulationispreservedUnlikepH-stat,thisdoesnotcausecerebralvasodilation
References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. ANZCAJuly/August19993. Chemlab.Solubility.FloridaStateUniversity.
Lastupdated2019-07-18
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CompensationExplaintheprinciplesunderlyingacid-basechemistry
MetabolicAcidosis
Compensationtometabolicacidosisincludes:
BufferingOccursoverminutestohours.Includes:
ECFbuffersBicarbonatePlasmaproteins
AlbuminICFbuffers
Includephosphate,proteinsLeadstohyperkalaemiaduetoH /K exchangeK increasesby0.6mmol.L per0.1unitfallinpH.
BoneExchangeofNa andCa inbone.
LeadstodemineralisationandreleaseofalkalinecompoundsRespiratorycompensationOccursinminutes.
RapidresponseCannotcompensatecompletely
RenalcompensationOccursoverdaystoweeks.Includes:
EliminationofH boundtofilteredbuffersIncludeammonium,phosphate
ReabsorptionofbicarbonateActivesecretionofH intheDCT/CTUndercontrolofaldosterone.
References
1. Diaz,A.Describehowthebodyhandlesmetabolicacidosis.PrimarySAQs.
Lastupdated2017-09-20
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BuffersDescribethechemistryofbuffermechanismsandexplaintheirrelevantrolesinthebody
Abufferisasolutionwhichconsistsofaweakacidanditsconjugatebase,thatcanresistachangeinpHwhenastrongeracidorbaseisadded.
Buffering:
Isakeypartofacid-basehomeostasisAllowscompensationforlargechangesinacidoralkaliloadwithminimalchangeinhydrogenionconcentration
Inoneexperiment,dogswereinfusedwith14,000,000nmol.L ofH ,withacorrespondingriseinH ofonly36nmol.L
Efficacyofabuffersystemisdeterminedby:
pKaofthebuffer80%ofbufferingoccurswithin1pHunitofthepKaofthesystem.pHofthesolutionAmountofbufferWhetheritisanopenorclosedsystemAnopenbuffersystemcanhavetheamountofchemicalatone(orboth)endsadjustedbyphysiologicalmeans.
Thisalterstheconcentrationofreactantsateitherendoftheequation,thusalteringthespeedofthereactionviatheLawofMassAction
BufferSystems
Importantbuffersystemsinclude:
BicarbonatebuffersystemProteinbuffersystem
HaemoglobinbuffersystemPhosphatebuffersystem
AllbuffersystemsareinequilibriumwiththesameamountofH .Thisisknownastheisohydricprinciple.
BicarbonateBufferSystem
Thebicarbonatebuffersystemis:
ThemostimportantECFbuffersystemBicarbonateisformedintheerythrocyteandthensecretedintoplasmaBicarbonatediffusesintotheinterstitiumandisalsothedominantfluidbufferininterstitialspace
FormedintheerythrocyteAbufferpairconsistingofbicarbonateandcarbonicacidCarbonicacidisexceedinglyshortlivedinanyenvironmentevenremotelycompatiblewithlifeanditrapidlydissociatestoHCO andH .
Hydrogenionsareconsumedorreleasedbythefollowingreaction:
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Carbonicanhydrase(presentinerythrocytes)isanenzymewhichallowsrapidconversionofH OandCO toH CO (andbackagain)EachstageofthereactionhasanindividualpKa:
AsthepKaofthe systemis6.1,thesesubstancespredominateatphysiologicalpHThepKaforthesecondstageofthereactionis9.3andsoessentiallynoCO existsinbloodClincicallythisreactioncanbeignored.
Inclinicalconditions,thereactionbecomes:
Additionofastrongaciddrivestheabovereactiontotheleft,forming(briefly)H CO beforeitdissociatestoCO andH O
CO isthenabletobeexhaled,whichpreventsequilibrationandallowsthesystemtobuffermoreacid
Bicarbonateisaneffectivebufferbecauseitis:
PresentinlargeamountsOpenatbothends
CO canbeadjustedbychangingventilationBicarbonatecanbeadjustedbychangingrenaleliminationThispreventsthebicarbonatebuffersystemfromequilibratingandallowsittoresistlargechangesinpHdespiteitslowpKaHowever,becauseitreliesheavilyonchangesinpulmonaryventilationitisunabletoeffectivelybufferrespiratoryacid-basedisturbances.
ProteinBufferSystem
AllproteinscontainpotentialbuffergroupsHowever,theusefuloneatphysiologicalpHistheimidazolegroupsofthehistidineresidues.Extracellularly,proteinshaveasmallcontributionwhichisentirelyduetotheirlowpKaIntracellularlyproteinshaveamuchgreatercontributionbecause:
IntracellularproteinconcentrationismuchgreaterthanextracellularconcentrationIntracellularpHismuchlower(~6.8)andclosertotheirpKa
HaemoglobinBufferSystem
Haemoglobinis:
AproteinbuffersystemQuantitativelythemostimportantnon-bicarbonatebuffersystemofbloodThisisbecausehaemoglobin:
Existsingreateramountsthanplasmaproteins(150g.L comparedto70g.L )Eachmoleculecontains38histidineresiduesThisresultsin1gofHb~3xthebufferingcapacityof1gofplasmaprotein.
Inthecell:
Haemoglobinexistsasaweakacid( )aswellasitspotassiumsalt( )Inacidosis:
AdditionalH ionsareboundtoHbmoleculesHCO diffusesdownitsconcentrationgradientintoplasmaElectroneutralityismaintainedthroughtheinwardsmovementofCl .DissolvedCO willalsoformcarbaminocompoundsbybindingtotheterminalaminogroups
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ThepKaofHbisvariabledependingonwhetherithasboundoxygen:DeoxyhaemoglobinhasapKaof8.2BecauseofitshigherpKa,deoxyhaemoglobinwillmorereadilyacceptH ionswhichmakesitabetterbufferofacidicsolutions.OxyhaemoglobinhasapKaof6.6BothareessentiallyequidistantfromnormalpH,andareequallyeffectivebuffersQuantitatively,permmolofoxyhaemoglobinreduced,~0.7mmolofH canbebufferedTherefore0.7mmolofCO canenterbloodwithoutachangeinpH.
ThisisthemechanismbehindtheHaldaneeffect,andwhyvenousbloodisonlyslightlymoreacidicthanarterialblood
PhosphateBufferSystem
Phosphoricacidis:
TribasicandcanthereforepotentiallydonatethreehydrogenionsHowever,onlyoneofthesereactionsisrelevantatphysiologicalpH,withapKaof6.8:
ThequantitativeeffectislowdespitetheoptimalpKaduetothelowplasmaconcentrationofphosphateAthigherconcentrations,suchasintracellularlyandinurine,itisasignificantcontributorInprolongedacidosis,CaPO canbemobilisedfrombonesandcanbeconsideredasanalkalireserve
Footnotes
1. AlexYartsevoffersanexcellentdiscussiononbufferinginhisexcellenttrademarkproseatDerangedPhysiology2. Brandis'sanaesthesiaMCQisrequiredreading
References
1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
Lastupdated2019-07-18
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CerebrospinalFluidDescribethephysiologyofcerebrospinalfluid
CSFisatranscellularfluidintheventriclesandsubarachnoidspace.~150ml(2ml/kg)ofCSFexistinanormalindividual,dividedevenlybetweentheheadandspinalcolumn.
Functions
MechanicalProtectionDuetoitslowspecificgravity,CSFreducestheeffectiveweightofthebrain(byafactorof30)andthereforereducestraumacausedbytheaccelerationanddecelerationofthebrain.BufferingofICPCSFcanbedisplacedtothespinalsubarachnoidandhaveitsrateofreabsorptionincreasedinordertooffsetanincreaseinICPbyanotherspace-occupyinglesion.StableExtracellularEnvironmentNeuronsaresensitivetoionicchangesintheextracellularenvironment.IonicconcentrationsinCSFaretightlycontrolled,whichensuresstableneuronalactivity.Additionally,toxinsareactivelyremovedfromCSF.pHRegulationpHofextracellularfluidisimportantinthecontrolofrespiration,andisalsotightlyregulated.NutritionSupplyofO andsimplesugarsandaminoacids,andremovalofCO occursoccursinCSF.
Formation
CSFisproducedinthechoroidplexus(70%)andbraincapillaryendothelialcells(30%)atarateof0.4ml.min (500ml.day).Itisproducedbyacombinationofultrafiltrationandsecretionfromplasma:
Na isactivelytransportedDrivesflowofCl ionsandwater.Glucoseistransportedviafacilitateddiffusiondownitsconcentrationgradient
FactorsAffectingFormation
Formationisrelativelyconstantwithinnormalparameters(alteringtherateofabsorptionisthepredominantmeanstocontrolpressure),thoughitisreducedby:
DecreasedChoroidalBloodFlowCPP<70mmhgreduces=""CSFformation.
Contents
Content RelativeChange [CSF]
Na - 140mmol.L
Cl ↑ 124mmol.L
K ↓ 2.9mmol.L
Gluc ↓ 3.7mmol.L
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pH ↓ 7.33
PCO ↑ 50mmHg
Protein ↓ Variable*
Ca ↓ 1.12mmol.L
Mg ↑ 1.2mmol.L
*CSF[protein]isvariable:
HighestinthelumbarsacLowestintheventriclesAlwayslowerthanplasma[protein]ThismeansCSFisapoorbuffersolution,whichincreasesitssensitivitytoderangementsinrespiratoryacid-basestatus.
Insummary:
[Na ]isunchanged[Mg ]and[Cl ]areincreasedConcentrationsofeverythingelseisless
Circulation
CSFflowisdrivenbyrespiratoryoscillations,arterialpulsations,andongoingproductioninthechoroidalplexus.
ProductioninthechoroidalplexusinthelateralventriclesTothethirdventricleviatheForamenofMunroTothefourthventricleviatheAqueductofSylviusTothecisternamagnaviathetwolateralForaminaofLuschkaandthemidlineForamenofMagendieItmaynowpasseither:
Cranially,tothebasilarcisternsandviatheSylvianfissuretothecorticalregionsCaudally,tothespinalsubarachnoidspaceviathecentralcanal
Reabsorption
ReabsorptionofCSF:
Occursinthearachnoidvilli,whicharelocatedintheduralwallsofthesagittalandsigmoidsinuses85%ofreabsorptionoccursinintracranialarachnoidvilliRemainderbyspinalarachnoidvilli
IspredominantlyviapinocytosisandopeningofextracellularfluidspacesIspressure-dependent
ReabsorptionoccurswhentheCSFpressureis1.5mmHggreaterthanvenouspressureTypicallyanICP<7mmHgresultsinminimalCSFreabsorption.Abovethis,CSFabsorptionincreasesinalinearfashionupto22.5mmHg.
References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders
Elsevier.2011.
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Blood-BrainBarrierTheblood-brainbarrierisaphysiologicalbarrierwhichpreventssubstancesintheECFofthebodymovingfreelyintotheECFofthebrain.ThefunctionsoftheBBBare:
MaintainastableextracellularmilieuOptimisesneuronalfunctionbypreventingfluctuationsinplasmaK ,Na ,andH affectingcerebralcells.ProtectionofthebrainIsolatesthebrainfromtoxins.ProtectionofthebodyIsolatestherestofthebodyfromCNSneurotransmitters.
Anatomy
TheBBBoccursinthreelayers:
CapillaryendothelialcellsJoinedwithtightjunctions,preventingfreemovementofsolventandsolute.
SubstancesmustmovethroughcapillaryendotheliumtoreachthebrainCapillaryendothelialcellscontainhighnumbersofmitochondria,duetothehigherenergycostoftheactivetransportmechanisms.
BasementmembraneAstrocytesGlialcellwhichextendsfootprocessesaroundthebasementmembrane,andreducepermeabilityofendothelialcells.
Duetotheirfunction,severalimportantCNSstructuresmustexistoutsideoftheBBB.Theseareknownasthecircumventricularorgans,andinclude:
SensingstructuresChemoreceptortriggerzone(AreaPostrema)Identifiestoxinsinthesystemiccirculation,triggeringvomiting.HypothalamusOsmoreceptorsdetectsystemicosmolarity.SubfornicalorganRoleinCVSandfluidbalance.Organumvasculosum
SecretingstructuresPituitarySecreteshormones.PinealglandSecretesmelatonin.ChoroidplexusProducesCSFviasecretionandultrafiltrationofplasma.
MovementofSubstances
Substancescanmovevia:
DiffusionForlipidsolublemoleculesonly;e.g:
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FacilitateddiffusionFormovementoflarger/lesssolublemoleculesdowntheirconcentrationgradient,e.g:
GlucoseWater
ActivetransportResponsibleformovementofmostsmallions;e.g:
NaClKMgCa
Othersubstancesarespecificallyexcluded:
CatecholaminesMetabolisedbyMAOincapillaryendothelium,preventingtheiractionasCNSneurotransmitters.AminoacidsPreventactionasneurotransmitters.AmmoniaMetabolisedinastrocytestoglutamine,limitingitsneurotoxiceffects.
References1. LawtherBK,KumarS,KrovvidiH.Blood–brainbarrier.ContinuingEducationinAnaesthesiaCriticalCare&Pain,Volume
11,Issue4,1August2011,Pages128–132.2. BrandisK.ThePhysiologyViva:Questions&Answers.2003.
Lastupdated2019-07-18
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SpinalCordAnatomyDescribethemajorsensoryandmotorpathways(includinganatomy)
SpinalCordAnatomy
Thespinalcordintransversesectionconsistsofacentralsectionofgreymattercontainingneuronalcellbodiesandsynapses,andaperipheralsectionofwhitemattercontainingmyelinatedascendinganddescendingpathways.Importantpathwaysare:
CorticospinaltractMotorfunction.Crossesatthebrainstem.DorsalcolumnLighttouchandproprioception.Crossesatthebrainstem.SpinothalamictractPainandtemperature.Crosseswithintwovertebralsegments.
SpinocerebellartractUnconsciousproprioception.Doesnotcross.
SpinalCordSyndromesLesionstocertainanatomicalregionsofthespinalcordproduceaparticularconstellationsoffindings.
CompleteTransection
Acompletetransectionresultsinlossofmovementandsensationbelowthelevelofthelesion.Initially,paralysisisflaccid(andothersigns,suchaspriapism,maybeabsentinthis'spinalshock'phase)becomesspasticafterafewweeks.Bowelandbladderfunctionislost.
LesionsaboveT10willresultinimpairedcoughintheinitialstageastheabdominalwallisunabletocontract(intercostalmusclefunctionmaybeimpairedaswell,butthisisoflessimportanceclinically).
CentralCordSyndrome
Centralcordsyndromeresultsinaflacidparalysisandlossofsensationoftheupperlimbsgreaterthanthelowerlimbs.
AnteriorCordSyndrome
Anteriorcordsyndromesparesthedorsalcolumnsonly,thereforemotorfunctionandpainandtemperaturesensationareaffectedbelowthelevelofthelesion.
Brown-SequardSyndrome
Hemisectionofthecordresultsin:
IpsilaterallossofmotorfunctionbelowthelevelofthelesionIpsilaterallossoflighttouchandproprioceptionbelowthelevelofthelesionContralaterallossofpainandtemperaturesensationbelowthelevelofthelesionIpsilaterallossofpainandtemperaturesensationatthelevelofthelesion
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CaudaEquina
CaudaEquinasyndromeresultsfromcompressionoflumbosacralnerverootsbelowtheleveloftheconusmedullaris.ItmayproduceacombinationofUMNandLMNsigns:
RadiculopathySacralsensorylossAsymmetricLMNweaknessandatrophyErectiledysfunctionandinabilitytoejaculateUrinaryretentionandoverflowincontinenceConstipationandoverflowincontinence
References1. GoldberS.ClinicalNeuroanatomyMadeRidiculouslySimple.3rdEd.Medmaster.2005.2. McMinn,RMH.Last'sAnatomy:RegionalandApplied.9thEd.Elsevier.2003.
Lastupdated2017-09-22
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IntracranialPressureExplainthecontrolofintra-cranialpressure
NormalICPis
P1isthefirstpeak,andrepresentsarterialpulsationP2isthesecondpeak,andrepresentsintracranialcomplianceIfP2>P1,thisissuggestiveofpoorintracranialcomplianceP3isthethirdpeak,andisadicroticwaverepresentingvalveclosure
Inaddition,asecondsetofLundbergwavesaredescribed:
Awavesarepathological,andconsistofsquare-waveplateausupto50mmHglasting5-20minutes.Theyaresuggestiveofherniation,andarealwayspathological.BwavesarevariablespikesinICPat30-120secondintervals,suggestiveofcerebralvasospasmCwavesareoscillationsthatoccur4-8timesperminute,andareabenignphenomenaoccurringwithrespiratoryandbloodpressurevariations
RaisedintracranialpressuremaycausefocalischaemiawhenICP>20mmHg,andglobalischaemiawhentheICP>50mmHg:
MonroeKellieDoctrine
Thisstatesthat:
Theskullisarigidcontainerofafixedvolume,containingapproximately8partsbrain,1partblood,and1partCSFAsithasnegligibleelastance,anyincreaseinvolumeofonesubstancemustbemetwithadecreaseinvolumeofanotherorariseinICP
ElastanceistechnicallycorrectaswearediscussingachangeinpressureforagivenchangeinvolumeComplianceisachangeinvolumeforagivenchangeinpressure.
PhysiologicalResponsestoanIncreaseinICP
DisplacementofCSFintothespinalsubarachnoidspaceCompressionofvascularbedIncreasedCSFreabsorption
TheCushingreflexmayoccurinbrainstemherniationThisisatriadofhypertension,bradycardia,andirregularrespirationsecondarytoSNSactivation,andisareflexiveresponsetomedullaryischaemia.
Hypertension
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ToimproveCPP.BradycardiaDuetoabaroreceptorresponse.IrregularrespirationDuetorespiratorycentredysfunction.
PhysiologicalBasisofTreatment
TreatmentcanbeclassifiedaspertheMonroeKelliedoctrine:
Brain
OsmoticagentssuchasmannitolandhypertonicsalineIncreaseplasmaosmolalityandexpandbloodvolume,creatinganosmoticgradientbetweenbrainparenchymaandbloodwitharesultingreductioninbrainoedemaandICP.Timelyevacuationofmasslesionsandintracranialhaemorrhage
CSF
ExternalVentricularDrainFacilitatesremovalofCSF.
Blood
ReducingcerebralmetabolicrateResultsinreducedbloodflowduetoflow-metabolismcoupling.Maybeachievedwith:
CNSdepressantssuchaspropofol,benzodiazepines,orbarbituratesHaveseveralbeneficialeffects:DepresscerebralmetabolismwhichreducesoxygenrequirementsReduceseizurerisk,whichisdetrimentalbecauseitgreatlyincreasescerebralO demandandimpairsvenousreturnImprovesventilatordyssynchrony,limitingcoughingandbearingdown,andsubsequentrisesinICPHypothermiaCausesareductionincerebralmetabolismandriskofseizures.PreventionofhypoxiaorhypercapneaHypoxiaandhypercapneabothcausevasodilatation,withasubsequentincreaseincerebralbloodvolume,bloodflow,andICP.
InducedhypocarbiaCausesvasoconstrictionandasubsequentreductionincerebralbloodflowandbloodvolume.Thisleadsto:
ReductioninICPReductionincerebraloxygendeliveryConsequently,alow-normalETCO targetisusedtoavoidtissuehypoxia.
References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. CrossME,PlunkettEVE.Physics,Pharmacology,andPhysiologyforAnaesthetists:KeyConceptsfortheFRCA.2ndEd.
CambridgeUniversityPress.2014.3. StocchettiN,MaasAI.Traumaticintracranialhypertension.NEnglJMed.2014May29;370(22):2121-30.
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4. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.
Lastupdated2019-07-18
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IntraocularPressureNormalintraocularpressureis~15mmHg,witharangeof12-20mmHg.Regulationofintraocularpressureisimportantfor:
VisionSustainedhigh(>25mmHg)canleadtoblindnessduetocompressionofaxonsoftheopticnerveandtheopticarteryattheopticdisc.
DeterminantsofIntraocularPressure
Astheglobehastypicallypoorcompliance,asmallincreaseinvolumecancausealargeincreaseinintraocularpressure.Factorsaffectingvolumeinclude:
VolumeofaqueoushumorAqueoushumorisaclearfluidthatfillstheanteriorandposteriorchambersoftheeye,andprovidesavasculartissueswithnutrientsandoxygenwhilststillallowinglighttopassfreelybetweenthelensandretina.Volumeofaqueoushumorisafunctionof:
ProductionAqueoushumorisproducedbysecretionandfiltrationfromcapillariesintheciliarybodyintheposteriorchamber,andcirculatesthroughintotheanteriorchamber.
Productionisacceleratedbyβ2 agonismProductionisinhibitedbyα agonismCarbonicanhydraseinhibitorsdecreaseaqueoushumorproductionprobablybydecreasingsodiumsecretionintotheeye
ReabsorptionAqueoushumorisreabsorbedintovenousbloodinthecanalofSchlemm.
ThetrabeculaemeshworkisthemainsourceofresistancetoreabsorptionIfthisisblocked,asignificantreductioninreabsorptioncanoccurandIOPwillincrease.Reabsorptionisaffectedby:
HaemorrhageBlockstrabecularmeshwork.MuscarinicantagonismDilatespupil,whichbringstheirisclosertocanalanddecreasesabsorption.α agonismDilatesthepupil,decreasingabsorption.PGFRelaxesciliarymuscle,increasingabsorption.
VolumeofbloodwithintheglobeAffectedby:
MAPVenousobstruction
ExternalfactorsOtherfactorsaffectingvolumeorcomplianceoftheglobe:
ExtraocularmuscletensionExtraocularcompression
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References
1. ANZCAJuly/August20002. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders
Elsevier.2011.3. GoelM,PiccianiRG,LeeRK,BhattacharyaSK.AqueousHumorDynamics:AReview.TheOpenOphthalmologyJournal.
2010;4:52-59.
Lastupdated2019-07-18
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SleepDescribethephysiologyofsleep
Sleepisanaturallyoccurringstateofunconsciousnessfromwhichonecanbearousedbyanexternalstimuli.
Sleepisimportantin:
HomeostasisofmanyorgansystemsMemoryformationPreservationofcognitivefunction
StagesofSleep
StagesofsleepareclassifiedbasedonEEGchanges:
REMsleepCharacterisedbyEEGactivityresemblingthatofawakeindividuals.REMsleep:
Lastsfor5-30minutesEventfrequencydecreaseswithage.InREMsleep:
IrregulareyemovementsDreamingoccursIrregularHRandRRMusclecontractionoccurs(butmuscletoneisdecreased)
Non-REMsleepDeepsleep,characterisedbydepressionofHR,SVR,BP,RR,andmetabolicrate(~0.9METs)ItisdividedintofourstagesonEEG:
Stage1:4-6Hzθwavesreplaceα-wavesDosing,easilyroused.Stage2:Similartostage1withoccasionalhighfrequency50μVbursts(sleepspindles)Stage3:1-2Hzhigh-voltageδwavesappearStage4:LargeδwavesbecomesynchronisedDeepsleep.
PeriodsofREMsleepalternatewithnon-REMsleepduringthenight,withanaverageof4-5cyclesofREMsleeppernight.
RespiratoryEffects
GABAergicneuronsdepresstherespiratorycentre,leadingtorespiratorydepression:
DecreasedMVDecreasedVGreatestdecreaseoccursduringREMsleep,whereitfallsby~25%.UnchangedRR
IncreasedPaCODecreasedPOMorepronouncedinelderly.
Collapseofairwaysofttissue
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Duetoreducedtonicactivityofpharyngealmuscles.
References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.3. LumbA.Nunn'sAppliedRespiratoryPhysiology.7thEdition.Elsevier.2010.
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PainDescribethephysiologyofpain,includingthepathwaysandmediators
Keydefinitions:
PainPainisan"unpleasantsensoryoremotionalexperienceassociatedwithactualorpotentialtissuedamage,ordescribedinsuchterms."Paincanbebroadlyclassifiedby:
AetiologyNociceptivepainStimulationofnociceptorsbynoxiousstimuli.VisceralpainNeuropathicpainNervoussystemdysfunction.
DurationAcutepainPainduetosymptomsofcurrentpathology.ChronicpainPainoccurringafterthepathologicalprocesshasresolved.
HyperalgesiaIncreasedresponsetoanormallypainfulstimulus.
PrimaryhyperalgesiaLocalreductioninpainthreshold.SecondaryhyperalgesiaHyperalgesiaawayfromthesiteofinjuryduetoalterationinspinalcordsignaling.
AllodyniaPainfulresponsetoanormallypainlessstimuli.Occursduetopathologicalsynapsebetweensecond-orderneuronesinthespinalcord.
AnaesthesiadolorosaPaininanareawhichisanaesthetised.
PeripheralNociception
Nociceptorsarereceptorswhichrespondtoanoxiousstimulus.Nociceptors:
Canbestimulatedorsensitisedby:ChemicalsignalsSeetable.Mechanicalsignals
ShearstressThermalsignals
Hotnociceptorsactivateabove43°CColdnociceptorsactivatebelow26°C
StimulationinitiatesanervousimpulseSensitisationincreasesareceptorssensitivitytoastimulatingmediator
Keychemicalstimulatingandsensitisingmediatorsinclude:
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StimulatingMediators SensitisingMediators
H Prostaglandins
K Leukotrienes
ACh SubstanceP
Histamine NeurokininA
5-HT CalcitoninGRP
Bradykinin
Nociceptors
Impulsesareconductedbytwotypesofprimaryafferentfibres:
Aδfibres:Small(~2-5μmdiameter)MyelinatedConductsharppainatupto40m.sMediateinitialreflexresponsestoacutepainSynapseinlaminaeIinthedorsalhornSubstancePistheneurotransmitterattheNK1receptor.
Cfibres:<2μmdiameterUnmyelinatedConductdullpainat2m.sSynapseinlaminaeIIinthedorsalhornSubstancePistheneurotransmitterattheNK1receptor.
PainPathwayandSiteofActionofAnalgesicsTheresponsetoapainfulstimulusrequiresacascadeofprocesses:
ActivationofnociceptorsMembranedepolarisationinresponsetostimulus.Ifthestimulusisgreatenoughtoreachthethresholdpotential,anactionpotentialisgenerated.
NSAIDSreducenociceptormediatedinflammationOpiatesactonperipheralMOPreceptorsLocalanaestheticspreventsignalpropagation
SynapseinthedorsalhornInputfrombothAδandCfibres,anddescendinginterneurons.
DescendinginhibitoryinputreducesnociceptivetransmissionBasisof"gatecontrol"theory.Descendinginputincreasedwith:
TouchAβ'touch'fibresstimulateinhibitoryinterneuronsinthedorsalhorn,'closingthegate'byincreasingdescendinginhibitionandpreventsignalsfromperipheralCfibresfromrisingtothethalamus.ArousalOpioidreceptorsParticularlyMOP(pre-andpost-synaptically).
Opioidsactpre-synapticallytoreduceSubstancePandglutaminerelease.α receptors
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Clonidine,tricyclicantidepressants,noradrenaline-reuptakeinhibitors,andendogenouscatecholamines.Gabapentinandpregabalininhibitpresynapticneurotransmitterrelease
WidedynamicrangeneuronesReceiveafferentinputfromchemical,thermal,andmechanoreceptors.
TypicallymoredifficulttostimulateImportantinwind-upMediatedbyNMDAagonism.
KetaminereduceswindupandcentralsensitisationLeadtosecondaryhyperalgesiaLeadtoallodyniaViaadditionalsynapsestosensoryneuronesinlaminaIIIandIV.Interneuronsynapseswithasecond-orderneuronesfibreThesesecondaryafferents:
Crosswithin1-2vertebralsegmentsandascendsinthespinothalamictractReceivesinputfromdescendingfibresOpioidsactpost-synapticallytohyperpolarisesecond-orderneurones
Reflexarc
HighercentresPainperceptionoccursinthesomatosensorycortex.
NeuropathicPainPainduetoalesionofthesomatosensorysystem,ratherthanastimulusitself.Neuropathicpainisdividedinto:
CentralneuropathicpainFromCNSinjury,e.g.spinalcordinjury,CVA,multiplesclerosis.PeripheralneuropathicpainDamagefrom:
DiabetesIschaemiaofSchwanncellscausesdemyelination,causingtheexposedaxontogenerateactionpotentialsinappropriately.TraumaTransectedaxonsmayregrowwithendingsthatspontaneouslyfireorthathavealteredthresholdpotentials.
MechanismsofNeuropathicPain
NeuromaHealingofdamagednervesleadstoneuromaformation.Neuromas:
AremoresensitivetopainfulstimuliCausespontaneouspainMaysproutandinnervatelocaltissuesMovementofthesetissuesmayleadtopain.
WindupPhantomlimbpainNeuronsdamagedinremovalofalimbdevelopadditionalsynapses,leadingtophantomsensations.
FeaturesofNeuropathicPain
Neuropathicpainisassociatedwith:
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InjuryordiseasethatcausesnerveinjuryBurningorelectricalqualityReducedorabsentsensationPoorresponsetotypicalanalgesia
ChronicRegionalPainSyndrome
DamagetotheSNScanleadtoabnormalitiesinautonomicfunction:
ChangeintemperatureduetovasomotordysfunctionAlteredsweatingReducedhairgrowthOsteoporosisHyperalgesiaandallodynia
PainintheElderly
NervousSystemChanges:
PeripheralNervousSystemNervedeteriorationDecreasedmyelinationDecreasedconductionvelocityReducedrangeandspeedofANSresponsesIncreasedrestingsympathetictone
CentralNervousSystemDecreasedpainperceptionIncreasedsensitivitytoanaestheticandanalgesicsReachceilingeffectsmorerapidly.DegenerationofmyelinSubsequentcognitivedysfunctionduetoneuronalcircuitdysfunction.GeneralisedatrophyDecreasedneurotransmitterproduction
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SchugSA,PalmerGM,ScottDA,HalliwellR,TrincaJ.AcutePainManagement:ScientificEvidence.4thEd.2015.
AustralianandNewZealandCollegeofAnaesthetistsandFacultyofPainMedicine.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.4. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.5. MerskeyH,BogdukN.ClassificationofChronicPain.2ndEd.1994.IASPTaskForceonTaxonomy.IASPPress,Seattle.6. HalaszynskiT.InfluencesoftheAgingProcessonAcutePerioperativePainManagementinElderlyandCognitively
ImpairedPatients.TheOchsnerJournal.2013;13(2):228-247.7. MelzackR,WallPD.Painmechanisms:anewtheory.Science.1965.19;150(3699):971-9.8. GibsonS.PathophysiologyofPain.
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AutonomicNervousSystemDescribetheautonomicnervoussystem,includinganatomy,receptors,subtypesandtransmitters(includingtheirsynthesis,releaseandfate)
TheANSisthesectionofthenervoussystemwhichregulatesinvoluntaryandvisceralfunctions.Theseinclude:
HaemodynamicsDigestionUrinationanddefecationThermoregulationSexualfunction
Theautonomicnervoussystemcanbedividedinto
CentralANSControloccursinthehypothalamus,brainstem,andspinalcord.PeripheralANSDividedanatomicallyandfunctionallyintothe:
SympatheticnervoussystemParasympatheticnervoussystem
GRAPHFROMPAGE258ofGANONG
CentralControl
Thehypothalamuscontrolsautonomicfunctionsbyneuralandendocrinemechanisms.Itissubdividedanatomicallyintofourregions:
AnteriorhypothalamusControlsthePNSandthermoregulation.ItalsoreleasesADHinresponsetoincreasedplasmaosmolality,andoxytocin.MedialhypothalamusInhibitsappetiteinresponsetoincreaseinbloodglucose.LateralhypothalamusContainsthethirstcentreanddrivetoseekfood.PosteriorhypothalamusControlsvasomotorcentres,modulatingsympatheticvasoconstriction,aswellaspositiveandnegativeinotropyandchronotropy.Alsomodulateswakefulnessinresponsetosympatheticstimuli.
Signalsfromthehypothalamushaveatonicoutputto:
AllsmoothmuscleHeartExocrineorgansEndocrineorgansGITGU
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Inthegreymatterofthespinalcord,efferentnervessynapsewithtwoothernervesconnectedinseries.Thismaintainstonicautonomicoutflow.
FIGUREFROMPAGE67-POWERANDKAM
Efferentnervesexitthespinalrootanteriorly,andformtheventralroot.
Conversely,afferentnervesexitposteriorly,formingthedorsalrootandthendorsalrootganglion,beforesynapsinginthespinalcord.
SympatheticNervousSystem
Thesympatheticnervoussystemoptimisesthebodyforshort-termsurvival.
Sympatheticinnervationisfromthesympathetictrunks.These:
AreapairedbundleofsympatheticneuronswhichrunlateraltothevertebralbodiesfromT1toL2Thetrunkissubdividedintofourparts:
Thecervicalpartinnervatesthehead,neck,andpartofthethoraxThethoracicpartisfurthersubdividedinto:
UpperthoracicfromT1-T5,whichinnervatestheaorta,heart,andlungsLowerthoracicfromT6-T12,whichinnervatestheforegutandmidgut
ThelumbarpartformsthecoeliacplexusThepelvicpartinnervatethepelvicvisceralandlowerlimbvasculature
Containthesympatheticganglion,whichisasynapsebetweenthe:Shortpre-ganglionicfibreCellbodyislocatedinthelateralhornofthespinalcord,andconnectstothesympatheticganglion.
ReleasesAChtostimulatethepost-ganglionicfibre.Longpost-ganglionicfibreCellbodyislocatedinthesympatheticganglion,andstimulatestheeffectsite.
HasanicotinicAChreceptorReleasesNAattheeffectsiteSensitivity(forACh)andactivity(forNArelease)ismodulatedbyanumberofothersubstances:
EnkephalinNeuropeptideYDopamineAdrenalineProstaglandinGABANeurotensin
Therearethreeexceptionstotheabovestructure:
Theadrenalglandisamodifiedsympatheticganglion.Itis:DirectlyinnervatedbypreganglionicneuronsreleasingACh
Sweatglandshavemuscarinicreceptors,andarestimulatedbyAChratherthannoradrenalineSkeletalmusclearteriolesalsohavemuscarinicAChreceptors,andarestimulatedbyACh
Effect
Sympatheticstimulationhasanumberofeffectsbyeitherdirectneuralinnervationoradrenalinerelease.Theyareconsistentwitha'fightorflight'response,andoptimisethebodyforshort-termstressconditions.
Effector Sympathetic Response
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Organ Innervation Response
Eye Cervical Pupillarydilatation
Lungs Thoracic Bronchodilation
Heart Thoracic ↑↑↑Chronotropy,↑↑↑inotropy,↑↑↑lusitropy,↑↑dromotropy
Vasculature Sacral Constriction
MSK Sacral Sweating,contraction,lipolysis
Endocrine Lowerthoracic Adrenalineandnoradrenalinerelease
GIT Thoracic,lumbar DecreasedsalivationandGITmotility,increasedsphinctertone,gluconeogenesis
GU Pelvic Detrusorrelaxation,sphinctercontraction,↑uterinetone
ParasympatheticNervousSystem
Parasympatheticinnervationarisesfromthe:
CranialnervesFromCNIII,VII,IX,and(mostly)X.
Thevagusisthemajorcranialparasympathetic,innervatingthe:Heartviathecardiacplexus
TheSAnodeisinnervatedbytherightvagusTheAVnodeisinnervatedbytheleftvagusTheventriclesarealsosparselyinnervatedfromtheleftvagus.
LungsviathepulmonaryplexusStomach,liver,spleen,andpancreas,andgutproximaltothesplenicflexureviathegastricplexus.
HypogastricplexusArisesfromS2-S4,andinnervatesthebladder,uterus,andgutdistaltothesplenicflexure.
Theparasympatheticnervoussystemgangliasiteclosetothetargetorgan.Thismeansthatthe:
Pre-ganglionicfibreislongPreganglioniccellbodysitswithinthebrainstem(cranialnerves)orsacralgreymatter(hypogastricplexus)ReleasesAChtostimulatethepost-ganglionicneuroneatanicotinicAChreceptor
Post-ganglionicfibreisshortReleasesAChtostimulatethetargetorganatamuscarinicAChreceptor
Effect
EffectorOrgan ParasympatheticInnervation Response
CNS CNIIIviatheEdinger-Westphalnucleus,CNVII Pupillaryconstriction(CNIII),lacrimation(CNVII)
Lungs CNX Bronchoconstriction,increasedmucousproduction
Heart CNX
↓↓↓Chronotropy,↓↓↓dromotropy,↓inotropy,↓lusitropy(↓ininotropyandlusitropyisgreaterintheatriathantheventricles)
CNVII(submaxillaryandmandibularsalivaryglands),CNIX
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GIT (parotidgland),CNX(stomachtoproximaltwo-thirdsofthetransversecolon),hypogastricplexus(distalone-thirdofthetransversecolontorectum)
Salivation,decreasedsphinctertone,increasedmotility
GU Hypogastricplexus Detrusorcontraction,erection
GanglionBlockadeBlockadeoftheganglion(atthenicotinicAChreceptor)blockstransmissionandreducessympatheticandparasympatheticimpulsetransmission.ClinicaleffectofganglionblockadedependsonwhichpartoftheANSisdominantinthatorgansystem:
SNSdominantorgansystemsEffectivesympatholysis:
VasculatureVasodilation,hypotension.SweatglandsAnhydrosis.
PNSdominantorgansystemsEffectiveparasympatholysis:
HeartTachycardia.IrisMydriasis.GITDecreasedton.BladderUrinaryretention.SalivaryReducedsecretions.
EntericPlexus
TheentericplexusisasystemofautonomicnervesintheGITwhichisfreeofCNScontrol.Itconsistsofsensoryandintegrativeneuronsaswellasexcitatoryandinhibitorymotorneuronswhichgeneratecoordinatedmuscularactivity.
References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.3. Klabunde,RE.NeuralActivationoftheHeartandBloodVessels.Accessed2016.
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AnticonvulsantsAnunderstandingofthepharmacologyofanti-depressant,anti-psychotic,anti-convulsant,andanti-Parkinsonianmedication
Anticonvulsantsworkviaanumberofdifferentmechanisms:
SodiumChannelBlockers
Sodiumchannelblockers:
Stabilisetheinactivestateofthechannel,preventingreturntotheactivestateandpreventgenerationoffurtheractionpotentialsThishaltspost-tetanicpotentiationandlimitsthedevelopmentofseizureactivity.MayalsohaveClassIantiarrhythmicpropertiesDuetoNa blockingeffects.Include:
PhenytoinCarbamazepineLamotrigine
GABAMediatorsGABAisthekeyinhibitoryneurotransmitterintheCNS.GABAmediators:
EnhancetheeffectofGABAMultiplepotentialmechanisms:
DirectGABA-receptoragonistse.g.Benzodiazepinesandphenobarbital.Positiveallostericmodulatione.g.Propofolandthiopentone.GABAreuptakeinhibitione.g.Tiagabine.GABAtransaminaseinhibitione.g.Vigabatrin.IncreaseGABAsynthesise.g.SodiumValproate.
GlutamateBlockers
GlutamateisanimportantCNSexcitatoryneurotransmitter.Glutamateantagonists:
Aregenerallyavoidedduetotheirsideeffectprofile,whichincludespsychosisandhallucinationsIncludetopiramate
OtherAgentsGabapentinandpregabalin:
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DonotappeartomediateGABAInhibitofexcitatoryα δvoltage-gatedcalciumchannelsintheCNSThisgivesthemanticonvulsantproperties.
References1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. Medscape-AntiepilepticDrugs.AccessedDecember2015.
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NeurotransmittersDescribethemajorneurotransmittersandtheirphysiologicalrole,withparticularreferencetoGABA,excitatoryandinhibitoryaminoacids,acetylcholine,noradrenaline,dopamineandserotoninandNMDAreceptor
GABA
GammaaminobutyricacidisthemajorinhibitoryCNSneurotransmitter.GABAreceptorshavethreesubtypes:
GABAInotropicreceptorimportantfortheactionofmanydrugs.
Pentamericstructure2αBindGABA.2β1γ
Affectedbymanydifferentdrugs:BenzodiazepinesPositiveallostericmodulationatattheα/γinterface.GeneralanaestheticagentsIncludingpropofol,barbiturates,halogenatedvolatiles,andetomidate.
ActattheβsubunitCauseaconformationalchangewhichincreasesCl openingtime,hyperpolarisingthecell.
GABAMetabotropicreceptor.GABAInotropicreceptorlocatedonlyintheretina.
NMDA
N-methylD-aspartatereceptorisaninotropicreceptorthatis:
AgonisedbyglutamateGlycineisco-agonist
VoltagedependentCentralporeusuallyblockedbyanMg ionBecomesunblockedwhenpartiallydepolarised
ImportantintheactionofdrugswhichdonotactattheGABA receptorAntagonisedby:
KetamineXenonN O
References1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
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LocalAnaestheticsUnderstandingofthepharmacologyoflocalanaestheticdrugs,includingtheirtoxicity
Localanaestheticdrugscreateause-dependenttemporaryblockadeofneuronaltransmissionbyblockingthevoltage-gatedsodiumchannelinthecellmembrane,preventingdepolarisation.
MechanismofAction
Actionisdependentonblockadeofthesodiumchannel.Twotheoriesexist:
Unioniseddrugpassesthroughthecellmembrane,andthenbecomesionisedintracellularlyTheioniseddrugisthenabletobindtotheopensodiumchannel,andpreventconductionofsodiumandthereforegenerationofanactionpotential
LocalanaestheticsalsodisplayreducedaffinityforK andL-typeCa channelsThistheoryexplainsuse-dependentblockade,assodiumchannelscanonlybeblockedintheiropenstate
Analternativesuggestedmechanismofactionisthedrugentersthecellmembraneandmechanicallydistortsthechannel,renderingitineffective
OnsetisinverselyproportionaltothesizeofthefibreFromfastesttoslowest:
PainTemperatureTouchDeeppressureMotor
ChemicalStructureofLocalAnaestheticsAlllocalanaestheticsareweakbasesconsistingof:
AhydrophiliccomponentAlipophilicaromaticringAnamideoresterlinkconnectingthetwo
Chemicalstructureinfluencespharmacologicalbehaviour:
HydrophilicportionTypicallythetertiaryamine.
Determinesionisation3bonds:Lipidsoluble4bonds:Watersoluble
LipophilicportionTypicallyaromaticring.
Determineslipidsolubility,andthereforepotency,toxicity,anddurationofactionEstervs.amide
AmidesHepaticallymetabolised(hydroxylationandN-de-alkylation)Thisisslower,thereforethereisagreaterriskofsystemictoxicity.Stableinsolution
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EstersHeat-sensitiveCannotbeautoclaved.RapidlyhydrolysedinplasmaOrganindependentelimination.HaveagreaterincidenceofallergyDuetotheinactivemetabolitePABA.
AminegrouplengthPotencyandtoxicityincreaseascarbon-chainincreasesToxicity(butnotpotency)continuestoincreasebeyond10carbons
IsomerismAltersbehaviour:
LevobupivacaineislesstoxicR-ropivacaineislesspotentandmoretoxic
KeyCharacteristicsofLocalAnaesthetics
Characteristicsarerelatedtochemicalstructure.Theseinclude:
PotencyPotencyisexpressedwiththeminimumeffectiveconcentrationoflocalanaesthetic(C )ThisistheconcentrationofLAthatresultsincompleteblockofanervefibrein50%ofsubjectsinstandardconditions.MorepotentagentshavealowerC .Potencyisafunctionof:
LipidsolubilityPotency(andalsotoxicity)increaseswithgreaterlipidsolubility.VasodilatorpropertiesIngeneral,localanaestheticscausevasodilationinlowconcentrations,andvasoconstrictionathighconcentrations(exceptcocaine,whichcausesvasoconstrictionatallconcentrations).
DurationofactionDurationofactionisafunctionof:
DrugfactorsVasodilatorpropertiesVasoconstrictionincreasesthedurationofblock.UseofadditivesAdditionofadrenalinetolignocaineincreasesdurationofblock.LipidsolubilityIncreasedlipidsolubilityincreasesdurationofaction,asagentremainsinthenerveforlonger.
PotencythereforehasapositivecorrelationwithdurationofactionDurationofactionisincreasedwhenpHincreases,astheionisedportionfalls
ProteinbindingHighlyproteinboundagentshaveanincreaseddurationofactionduetoincreasedtissuebinding.
ProteinbindingdecreaseswithdecreasingpH,increasingthefractionofunbounddrugThisiswhyagentssuchasbupivacainearemorecardiotoxicinacidoticpatients.Localanaestheticsarepredominantlyboundtoα-1-acidglycoprotein(AAG)AAGisreducedinpregnancy,increasingthefreedrugfractionandthereforereducingthetoxicdoseofLAinpregnantpatients.
PatientfactorsTissuepHDecreaseddurationofblockwhentissuepHislow.
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MetabolicimpairmentHepaticfailureincreasesdurationofactionofaminosteroidsButylcholinesterasedeficiencyincreasesdurationofesterlocalanaesthetics
SiteofadministrationWellvascularisedtissue(e.g.intercostalarea)willhavegreatersystemicuptakeofdrugthanvesselpoortissue.
OnsetSpeedofonsetisrelatedto:
DrugfactorsDoseIncreasingthedoseincreasesthespeedofonset,asperFick'sLaw.
IncreasedconcentrationwillincreasespeedofonsetandblockdensityIncreasedvolume(withoutincreasingdose,resultingindecreasedconcentration)willdecreasespeedofonset
LipidsolubilityAnincreasedlipidsolubilityincreasesthespeedatwhichthelocalanaestheticentersthenerve.However:
LipidsolubilityalsocorrelateswithpotencyTherefore,inpractice,morelipidsolubleagentsareadministeredinlowerdoses,andsohaveareducedspeedofonsetThisisknownasBowman'sPrinciple.
IonisedportionOnlyunioniseddrugcancrosscellmembranes.Ionisationisafunctionof:
pKaTissuepH
Thisisalsowhyanaestheticsareineffectiveinanaesthetisinginfectedtissue,asthelowpHmakesthemajorityoftheLAionisedandunabletocrossthecellmembrane.
PatientfactorsNerveactivityLocalanaestheticsproduceafrequencydependentblockade,meaningnervesfiringfrequentlywillbeblockedmorerapidlythanquiescentnervesNervefibresizeLargernervesrequireanincreasedconcentrationoflocalanaesthetictoachieveblockadethansmallernerves.NervetypeDifferentnervefibresareaffectedatdifferentspeeds,whichismostly(thoughnotentirely)afunctionofcriticallength.
Aγ(proprioceptive)areaffectedfirstSmallmyelinatedAδ(sharppain,cold)fibresareaffectedsecondLargemyelinatednervesareaffectedthirdTheseincludeAα(motor)andAβ(touch)fibres.UnmyelinatednervesareaffectedlastTheseincludeC(dullpain,heat)fibres.
HyperkalaemiaReducesonsetofaction.
Toxicity
Localanaestheticsare:
ToxictoboththeCNSandCVSToxicityoccurswhenthereisanexcessplasmaconcentrationThisoccurswhentherateofdrugenteringthesystemiccirculationisgreaterthanthedrugleavingthesystemiccirculationduetoredistributionandmetabolism.
Toxicityisrelatedtothe:
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DrugfactorsDrugusedAgentsarecomparedusingtheCC/CNSratio,whichistheratioofthedoseofdrugrequiredtocausecardiovascularcollapse(CC)comparedtothedoserequiredtocauseseizure.Itisacrudealternativetothetherapeuticindex.DoseusedContinuousinfusionsaremorelikelytocauseadelayedonsetoflocalanaesthetictoxicity.
BlockfactorsSiteofadministrationThisaffectstherateofuptakeintothesystemiccirculation,andthelikelihoodofinadvertentintravascularinjection.Ranked(fromhighesttolowest):
Intravascular(obviously)ThisisthemostcommoncauseofLAtoxicity.
Siteisalsorelevanthere:aninjectionintothecarotidarterywillcausetoxicityatalowerdosethanifinjectedintoaperipheralvein.
IntercostalCaudalEpiduralBrachialplexusSubcutaneous
UseofadjunctsAdrenalineVasoconstrictorpropertiesreducesystemicabsorptionofLA.
TechniqueFrequentaspirationTestdoseUseofultrasound
PatientfactorsAnythingthatincreasespeak[plasma]canleadtoanincreasedriskofLAtoxicity.
Bloodflowtoaffectedareaα1-acidglycoproteinLowlevelsofthisproteinincreasefreedrugfraction.
NeonatesandinfantshavehalfthelevelofAAGthanadults.HepaticdiseaseReducesclearanceofamides,whichmaycausetoxicitywithrepeateddosesoruseofinfusions.AgeOrganbloodflow(andthereforeclearance),aswellaspharmacokineticinteractionsmayaffectclearanceofLA.BothchildrenandtheelderlyhavereducedclearanceofLA.AcidosisIncreasesunionisedportion.HypercarbiaIncreasescerebralbloodflow.
CardiacToxicity
Cardiactoxicityoccursdueto:
BlockingofthecardiacNa channel(K andCa channelsmayalsobeinvolved)Severityoftoxicitywillvarydependingonhowlongtheagentbindstothechannel,withlesstoxicitycausedbyagentsspendinglesstimebound:
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Spendstheshortesttimeboundtothechannel,socausestheleastamountoftoxicity.Thisisalsowhylignocainecanbeusedasanantiarrhythmic,butotheragentscannot.BupivacaineTakes10xaslongtodissociateaslignocaine.Thiscanleadtore-entrantarrhythmias,andthenVF.Theriskofthisisincreasedintachycardiaduetouse-dependentblockade.RopivacaineDissociatesmorerapidlyfromcardiacchannelsthanbupivacaine.
DirectmyocardialdepressanteffectsReducescAMPlevelsbydisruptingmetabotropicreceptors.
Cardiactoxicityistriphasic:
InitialphaseHypertensionTachycardia
Intermediatephase:HypotensionMyocardialdepression
Terminalphase:SeverehypotensionVasodilationVariousarrhythmias
SinusbradycardiaVariabledegreeheartblockVTVFAsystole
CNSToxicity
LocalanaestheticsintheirunionisedstatecancrosstheBBBandinterferewithCNSconduction.CNStoxicityisbiphasic:
Initially,inhibitoryinterneuronsareblockedThiscausesexcitatoryeffects:
PerioraltinglingSlurredspeechVisualdisturbancesTremulousnessDizzinessConfusionConvulsionsTypicallysignifiestheendoftheexcitatoryphase.
Secondly,thereisageneraldepressionofallCNSneuronsThiscausesinhibitoryeffects:
ComaApnoea
Treatment
ToxicityismanagedwithanABCapproach,thoughdefinitivemanagementusesIntralipidemulsion:
Intralipidisanemulsionofsoyaoil,glycerol,andeggphospholipids.Mechanismofactioninuncertain,buttheoriesinclude:
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LipidsinkILEbindsunionisedLA,causingittodistributeoffreceptorsites.FattyacidmetabolismCardiacfattyacidmetabolismisinterruptedbyLA.ILEprovidesasourceoffattyacidstoallowmetabolismtocontinue.CompetitiveantagonismILEmaydirectlyinhibitLAbinding.
DosingofIntralipid20%:Bolusof1.5ml.kg over1minuteInfusionat15ml.kg .hr
ComplicationsincludepancreatitisNotethatILEinterfereswithamylaseandlipaseassays,andsothesewillbeunreliable.
Notethatwhilstpropofolcanbeusedtotreatseizures,theamountoflipidcontainedinpropofolisinadequatetobindLA
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. ChristieLE,PicardJ,WeinbergGL.Localanaestheticsystemictoxicity.ContinuingEducationinAnaesthesiaCriticalCare
&Pain,Volume15,Issue3,1June2015,Pages136–142.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. BeckerDE,ReedKL.EssentialsofLocalAnestheticPharmacology.AnesthesiaProgress.2006;53(3):98-109.
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NeuraxialBlockadeDescribethephysiologicalconsequencesofacentralneuraxialblock
Centralneuraxialblockadereferstoblockadeoffibresinthespinalcordbyadministrationofintrathecalorepidurallocalanaesthetic.
RespiratoryResponses
Anincreasinglevelofblockwillleadtogreatereffects:
ThoracicImpedimenttoactiveexpirationandexpectorationduetoblockadeofintercostalsandabdominalwallmusculatureLossofvitalcapacityLossofsomeaccessorymuscleuse
CervicalImpedimentduetodiaphragmaticblockade.
CardiovascularResponsesOccurduetoblockadeofsympatheticchainfibresinthethoracolumbarregion.
Anincreasinglevelofblockwillleadtogreatereffects:
SacralParasympatheticblockadeonly.MinimalCVSeffects.Lowerthoracic/lumbarArteriolarandvenousvasodilationinlowerabdomenandlowerlimbs,causingafallinSVR,BP,andGFR.UpperthoracicLossofcardioacceleratorfibresaboveT5,causingareductioninheartrateandcontractility,compoundinghypotensionduetofallinSVR.CranialNervesVagalblockadewillreducePNStoneandattenuatesomeofthelossofSNStone.BrainstemInhibitionofvasomotorcentrewithprofoundfallinCVSparameters.
CNSResponsesAnincreasinglevelofblockwillleadtogreatereffects:
CervicalHorner'ssyndrome(miosis,anhydrosis,ptosis)duetolossofsympathetictrunks.CranialnervePupillarydilationduetoCNIIIblockade.BrainstemandCerebralCortexAnaesthesiaduetoblockadeofthereticularactivatingsystemandthalamus.
References
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1. Diaz,A.CardiovascularResponsetoCentralNeuraxialBlockade.PrimarySAQs.2. ANZCAJuly/August2007
Lastupdated2019-07-20
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AcetylcholineReceptorsUnderstandingofthepharmacologyofanticholinesterasedrugs.
Describetheadverseeffectsofanticholinesteraseagents.
ThiscoversthepharmacologyofacetylcholinereceptorsandtheproductionandmetabolismofACh.Detailedinformationonspecificagentsisinthepharmacopeia.
Acetylcholineisaneurotransmittervitalfornormalfunctionof:
CNSANSMusclecontraction
Synthesis,Release,andMetabolismAChisproducedisthenervecytoplasmbyacetyltransferasefrom:
CholineFromdietandrecycledACh.Acetyl-coenzymeAProducedintheinnermitochondrialmatrix.
Oncesynthesised,AChisthenpackagedintovesicles(eachcontaining~10,000AChmolecules),whicharereleasedinresponsetocalciuminfluxoccurringattheculminationofanactionpotential.
Acetylcholineismetabolisedbyacetylcholinesteraseonthepost-junctionalmembrane.AChE:
Hastwobindingsites:AnionicbindingsiteBindsthepositivelychargedquaternaryammoniummoiety.EsteraticbindingsiteBindstheestergroupofACh.
Oncebound,AChisacetylatedAcetylated-AChisthenhydrolysedtoproduceaceticacid
AChReceptorSubtypes
TherearetwotypesofAChreceptor:
NicotinicAChreceptorsInotropicLinkedtoanionchannel.
Non-specific-mayallowNa ,K ,orCa tocrossConsistsoffivesubunits:
TwoαBindACh.OneβOneδOneγ
Locatedin:
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Post-synapticNMJPreganglionicautonomicnervoussystemAntagonismcausesganglionblockade.Brain
KnownasnicotinicbecausenicotineagonisesthisreceptorActivation:
2AChmoleculesmustbindtoactivatethereceptorOncebound,receptorundergoesaconformationalchangewhichopensthecentralionporePermeabilitytoNa (andtoalesserextent,K andCa )increases,leadingtodepolarisation
MuscarinicAChreceptorsMetabotropicG-proteincoupled.KnownasmuscarinicbecausemuscarinealsoagonisesthisreceptorSubdividedinto:
M (Gq)SecretoryglandsandCNS.M (Gi)Heart.M GqBronchialandarteriolarsmoothmuscle.M (Gi)andM (Gq)CNS.
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-07-18
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OpioidsKeydefinitions:
Opiatesareallnaturally-occurringsubstanceswithmorphine-likepropertiesOpioidsisageneraltermforsubstanceswithanaffinityforopioidreceptorsOpiumisamixtureofalkaloidsfromthepoppyplant
ClassificationofOpioids
NaturallyoccurringEndogenousopioids
EndorphinsEnkephalinsDynorphins
OpiumderivativesPhenanthrenes
MorphineCodeine
SemisyntheticSimplemodificationstomorphine.
DiacetylmorphineBuprenorphineOxycodone
SyntheticPhenylpiperidines
FentanylAlfentanilRemifentanilPethidine
DiphenylpropylaminesMethadone
OpioidReceptorClassification
AllopioidreceptorsareGireceptors.Activation:
Inhibitsadenylylcyclase,reducingcAMPPre-synapticallyinhibitsvoltage-gatedCa channels
DecreasesCa influxReducesneurotransmitterrelease
Post-synapticallystimulatesactivatesK channelsCausesK effluxLeadstomembranehyperpolarisation
Receptor Actions NotableProperties
MOPAnalgesia(spinalandbrain),euphoria,meiosis(viastimulationoftheEdinger-Westphalnucleus),nauseaandvomiting(viaCTZ),sedation,bradycardia,inhibition
Onlyopioidreceptortocause
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ofgutmotility,urinaryretention,physicaldependence nausea/vomiting
KOP Analgesia(predominantlyspinal),sedation,meiosis,dysphoria Lessrespiratorydepression
DOP Analgesia,respiratorydepression,urinaryretention,physicaldependence Minimalconstipation
NOP Anxiety,depression,changeinappetite
Hyperalgesiaatlowdoses,analgesicathighdoses
Mechanismofeffects:
RespiratorydepressionDecreasescentralchemoreceptorsensitivitytoCO .ConstipationStimulationofopioidreceptorsinthegut.
Normallyactivatedbylocalendogenousopioids(usedasneurotransmitters)Agonismofthesereceptors(µ,k,andtoasmallerextent,δ)reducesGITsecretionsandperistalsis
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. KatzungBG,TrevorAJ.BasicandClinicalPharmacology.13thEd.McGraw-HillEducationEurope.2015.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
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InhalationalAnaestheticsStructure-activityrelationshipsofinhalationalagents
Describetheuptake,distributionandeliminationofinhalationalanaestheticagentsandthefactorswhichinfluenceinductionandrecoveryfrominhalationalanaesthesiaincludingthe:-Conceptsofpartitioncoefficients,concentrationeffectandsecondgaseffect-Relationshipsbetweeninhaledandalveolarconcentration-Significanceofthedistributionofcardiacoutputandtissuepartitioncoefficientsonuptakeanddistributionofvolatileagents
DescribetheconceptandclinicalapplicationofMACinrelationtoinhaledanaestheticagents
Describehowthepharmacokineticsofdrugscommonlyusedinanaesthesiainneonatesandchildrendifferfromadultsandtheimplicationsforanaesthesia
Propertiesofanidealinhalationalanaestheticagent
Inhaledanaestheticsarechemicalswithgeneralanaestheticpropertiesthatcanbedeliveredbyinhalation.Theycanbedividedinto:
VolatileanaestheticagentsVolatilityreferstothetendencyofaliquidtovapourise.Volatileagentsinclude:
SevofluraneIsofluraneDesfluraneMethoxyfluraneEnfluraneHalothaneEther
AnaestheticgasesNitrousoxideXenon
KeyPrinciplesofInhalationalAgents
Keyprinciples:
TheclinicaleffectofaninhalationalagentisdependentonitspartialpressurewithintheCNSAtequilibrium,thepartialpressureintheCNS(P )equalsthepartialpressureinblood(P ),andinthealveoli(P )Reachingequilibriumisrarelyachievedinpracticeasittakesmanyhours.Rateofonsetandoffsetofaninhalationalagentaredependentonbothphysiologicalandpharmacologicalfactorsaffectingthetransferofagent:
IntothealveoliFromthealveoliintobloodFrombloodintotheCNS
MinimumAlveolarConcentration(MAC)
MACisdefinedastheminimumalveolarconcentrationatsteadystatewhichpreventsamovementresponsetoastandardsurgicalstimulus(1cmforearmincision)in50%ofapopulation.
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Notethatthisdefinition:
DoesnotreflectlackofawarenessDoesreflecttheactionofanagentonspinalcordreflexesThisiswhy1MACisadequateforthemajorityofpatients,asawarenessandrecallaresuppressedatlowerMACvaluesthanarerequiredforimmobility.ConsciousnessisbetterestimatedbyMAC-awakeEnd-tidalconcentrationofagentthatpreventsappropriateresponsestoaverbalcommandin50%ofapopulation.
Notethatthistechnicallymeasuresawarenessratherthanmemory.MAC-awakeistypicallyone-thirdofMACforcommonly-usedagents
Isonlyvalidatsea-levelTheclinicaleffectofanagentisdependentonitspartialpressurenotconcentration.
At1atm,thesearealmostthesame1atm≃100kPa;therefore2%sevofluraneis≃2kPaAsaltitudeincreases,theactualpartialpressurewillfallforanygivenconcentrationi.e.2%sevofluraneat0.5atmis≃1kPaofsevoflurane.
MACis:
Ameasureofpotency(i.e.theEC oftheagent,wheretheoutcomeismovement)TheMACofanagentisinverselyproportionaltopotency;i.e.morepotentagentsrequiresmalleralveolarconcentrationstoproduceanaesthesia.
ThisgivesrisetotheMeyer-Overtonhypothesis,whichsuggeststhatanaesthesiarequiresasufficientnumberofmoleculestodissolveintotheneuronalcellmembrane.
Ifthiswastrue,theproductoftheoil:gaspartitioncoefficientandMACwouldbeconstant,whichisnotthecase.AdditiveTheMACsofdifferentagentsusedsimultaneouslyareadditive.Normally-distributedNotallpatientswillbeunresponsiveat1MAC.
Thestandarddeviationis0.1,so95%ofpatientswillnotmoveinresponsetoastimulusat1.2MACEstimatedclinicallyusingend-tidalgasmeasurementMACisnotbasedonarterialpartialpressure(F )ofagent.
Thisisanimportantdifference,becauseevenatsteady-state,F ≠FThisoccursdueto:
V/QmismatchShuntedalveoliwillnotabsorbanaestheticagent,andunperfusedalveoliwillcontainagentthatisnotbeingabsorbed.
ThisisworsenedbytheeffectsofanaesthesiaVolatileagentsareheavyandhavefinitediffusibility
However,thedifferencebetweenF andF foranyagentisthesameatsteadystate(andinabsenceofnitrousoxide)Thismeansthat,atsteady-state,MACwillbeproportionalto,andanaccuratemeasureof,P .
Oneofseveralrelatedterms:MACawakeConcentrationrequiredtopreventresponsetoaverbalstimuliinabsenceofnoxiousstimuli.
Typically~1/3 ofMACformostagents(sevoflurane,isoflurane,desflurane)Notablyhigherfornitrousoxide(MAC-awake~2/3 ofMAC)MAC-awakeistypicallylessthanMAC-asleepas:
HysteresisbetweenalveolarandeffectsiteconcentrationsDuringinduction,alveolarconcentrationishigherthaneffectsiteconcentration,andsooverestimateseffect.Duringwashout,alveolarconcentrationislessthaneffectsiteconcentration,andthereverseeffectoccurs."Neuralinertia"Intrinsicresistanceofnervecellstoachangeintheirstate.
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MAC-BARMinimumalveolarconcentrationrequiredtoblockadrenergicresponse,i.e.topreventariseinHRorBPfollowingskinincision.MACTheMACrequiredtopreventamovementresponsetoastandardsurgicalstimulusin95%ofthepopulation.MAC.hrTheamountoftimeapatientisexposedto1MACofanagent.Usedtocomparedifferentagents.
FactorsAffectingMAC
DecreasesMAC IncreasesMAC
Age(~6%/10years↑)andneonates Youth
Hypothermia Hyperthermia
Hypocapnea Hypercapnea
Hyponatraemia Hypernatraemia
Hypothyroidism Hyperthyroidism
AcutealcoholandotherCNSdepressantintoxication ChronicETOHandCNSdepressantabuse
Chronicamphetamineintake Acuteamphetamineintake
Hypovolaemia/Hypotension
Lithium
Hypoxia
Anaemia
Pregnancy
SNSactivationandanxiety
IncreasedP
Notethatadditionofotheragents(e.g.opioids)willaffectdifferentMACsubtypes(e.g.MAC vsMAC )differently.
PartitionCoefficients
Apartitioncoefficientdescribestherelativeaffinityofanagentfortwophases,andisdefinedastheratiooftheconcentrationofagentineachphase,whenbothphasesareofequalvolumeandthepartialpressuresareinequilibriumatSTP.
Theblood:gaspartitioncoefficientdescribesthesolubilityoftheagentinbloodrelativetoair,whenthetwophasesareofequalvolumeandinequilibriumatSTPAlowblood:gaspartitioncoefficientindicatesarapidonsetandoffset.Thisisbecause:
PoorlysolubleagentsgenerateahighP ,whichcreatesasteepgradientbetweenP andP ,givingarapidonsetofactionConversely,solubleagentsdissolveeasilyintopulmonarybloodwithoutsubstantiallyincreasingPThiscausesleadstoaslowonsetdueto:
AlargefallinP astheagentleavesthealveolus,decreasingthegradientforfurtherdiffusionAsmallgradientbetweenP andP
Theoil:gaspartitioncoefficientdescribesthesolubilityoftheagentinfatrelativetoair,whenbothphasesareofequalvolumeandinequilibriumatSTPAhighoil:gaspartitioncoefficientindicatesagreaterpotency,andthereforealowMAC.
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PharmacokineticsofInhalationalAgents
AchievingtherequiredP requiresmaintainingP atahighenoughlevel.ByincreasingP ,thepressuregradientfordiffusionintoblood,andthereforeCNS,isincreased.
Asdiscussedabove,rateofonsetofaninhalationalagentisdependentonrateofuptake:
IntothealveoliFromthealveoliintobloodFrombloodintotheCNS
Factorsaffectingalveolarconcentrationofagent:
InspiredconcentrationAhighinspiredconcentration(F )willincreasetherateofincreaseofalveolarconcentration(F ).Inspiredconcentrationisdependenton:
DeliveredconcentrationinfreshgasFreshgasflowIncreasingFGF(andtheconcentrationofagentintheaddedgas)increasesF .VolumeofthebreathingsystemAlowercircuitvolumewillincreasetherateatwhichthepatientreachesequilibriumwiththecircuit,andthereforeincreaseF .CircuitabsorptionAbsorptionofagentbythecircuitwilldecreaseF .
VIncreasedalveolarventilationincreasesF ,asitreplenishesagentthathasbeentakenupintothevasculature.
Similarly,increaseddeadspacewillprolonginduction,asanaestheticgaswillbedeliveredtonon-perfusedalveoliFRCAlargeFRCwilldilutetheamountofagentinspiredwitheachbreath,andsoreduceF .
ThisismeasuredwiththeV /FRCratioIncreasedratioincreasesspeedofonset.
Normalinadults:1.5:1Normalinneonates:5:1
SecondgaseffectUseofN OwithanotheragentwillincreasetheP ofthatagent.Thisisbecause:
N Ois20xassolubleinbloodaseitherbloodornitrogen,andisadministeredinhighconcentrations,soitisrapidlyabsorbedfromalveoliIfnitrousoxideisdeliveredathighconcentrations,it'srapidabsorptionmeansthatalveoliwillshrink,causing:
AnincreaseinthefractionalconcentrationofallothergasesThisisknownastheconcentrationeffect,andincreasesthepressuregradientdrivingdiffusionintoblood,increasingspeedofonset.
TheconcentrationeffectisthecauseofthesecondgaseffectTheconcentrationeffectismorepronouncedasFiN OincreasesTheconcentrationeffectismoreprofoundinlungunitswithmoderatelylowV/Qratios,causinginalargeincreaseinFThisresultsinalargervalueofF foranygivenF ,evenatsteadystate.
AugmentedventilationasmoreinhalationalagentisdrawninthealveolifromdeadspacegasThesecondgaseffectalsocausesdiffusionhypoxiaWheninspiredN Oisreduced,N Owillleavebloodandenterthealveolus,displacingothergasesinthealveolus.
ThiscancauseareductioninPAO ,andthereforehypoxaemiaDiffusionhypoxiaisavoidedbydelivering100%oxygen,whichmaintainsanadequatePAO asN Oisremoved
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NotethatN Oreachesahigherratiofasterthandesflurane,despiteitslowerblood:gaspartitioncoefficient,duetotheconcentrationeffect
Factorsaffectingdruguptakefromthelungs:
Blood:gaspartitioncoefficient
Agentswithalowblood:gaspartitioncoefficientreach equilibriummorerapidly.Theblood:gascoefficientisaffectedby:
TemperatureBlood:gaspartitioncoefficientsdecreaseastemperatureincreases.HaematocritVariableeffect,whichdependsontheparticularagentsaffinityforredcellsorplasma(andserumconstituents,e.g.albumin).
Anagentthatislesssolubleinredcells(e.g.isoflurane)willhaveadecreasedblood-gaspartitioncoefficientinanaemia.
FatBlood:gaspartitioncoefficientincreasesfollowingfatingestion.
AlveolarbloodflowIncreasedalveolarbloodflowincreasesuptakeanddeliverytotissues,includingtheCNS.
However,theincreaseduptakecausesareductioninPTherefore,rateofonsetisreducedwhenalveolarbloodflowishigh.
Thiseffectismorepronouncedwithagentswithahighblood:gaspartitioncoefficientAlveolarbloodflowisafunctionof:
CardiacoutputShunt
Alveolar-VenouspartialpressuregradientThedifferenceinpartialpressureofagentinthealveolusandvenousbloodisduetotheuptakeofdrugintissues.Tissueuptakeisdependenton:
TissuebloodflowAstheCNShasahighbloodflow,itwillequilibratemorequickly.Blood:tissuesolubilitycoefficients
Musclehassimilaraffinitytoblood,butequilibratesmoreslowlythantheCNSduetolowerbloodflowFathasamuchhigheraffinityforanaestheticthanmuscle,butequilibratesveryslowlyduetotheverylowbloodflowThisisofgreaterimportanceintheobese,especiallyduringprolongedanaesthesia,astheyhavealongerequilibrationtimeandthereforeprolongedemergence.
Wash-outofInhalationalAgents
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Recoveryisdependentonhowquicklyaninhalationalagentcanbeeliminatedfromtheeffectsite,andcanbegraphedbytheF /F ratioovertime:
Washoutcanbedividedinto:
RapidwashoutOfagentincircuitandFRC.
Thetimeconstantforremovalofagentfromthecircuitisafunctionofcircuitvolumeandfreshgasflow,i.e.
SlowwashoutOfagentinpatient.
ThetimeconstantforremovalofagentfromthepatientisafunctionofFRCandminuteventilation,i.e.
Factorsaffectingvolatilewashout:
Brain-BloodandTissue-BloodTissue:BloodcoefficientofagentDurationanddepthofanaesthesiaImportantforhighlysolubleagentsusedinlongcases.
Blood-AlveolusBlood:gascoefficientofagentHighlysolubleagentswillhaveanincreasedamountofdrugdissolvedintissue,soalargereservoirofdrugexiststhatwillhavetoberemoved.AlveolarCardiacoutputDecreasedcardiacoutputincreaseselimination.
ShuntDecreaseselimination.
Alveolus-AirMV /FRCIncreasedalveolarventilationincreaseselimination.
OtherfactorsMetabolismofagentAgentsundergoingmetabolismareeliminatedmorerapidly.AbsorptionofagentintocircuitPercutaneousloss
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Lossofagentbydiffusionfromtissuesintoexternalenvironment.
AlterationtoPharmacokinetics
Increasedrateofinductioninchildrendueto:
IncreasedV /FRCratioIncreasesP .LoweralbuminandcholesterolReducedblood-gassolubilitycoefficientsforsomeagents.
Increasedrateofinductioninelderlydueto:
LowerMACrequirementLoweralbuminReducesblood-gassolubilitycoefficientsforsomeagents.LowercardiacoutputP andthereforeP isestablishedmorerapidly.
Alteredrateofinductioninpregnancydueto:
IncreasedV /FRCratioIncreasedminuteventilationThisisofgreaterimportanceinspontaneousventilation,asthisiscontrolledbytheanaesthetistduringcontrolledventilation.DecreasedFRCIncreasesP ,increasingP andspeedofonset.
LoweralbuminReducesblood-gassolubilitycoefficientsforsomeagents.IncreasedCOReducesrateofriseofP ,reducingP andthereforespeedofonset.ReducedMACrequirementProgesteronehassomesedativeproperties.
AlterationtoPharmacokineticswithSpecialMethodsofAdministration
Intarget-controlledanaesthesia,FGFandagentF arecontrolledbythemachinetoreachthetargetF rapidlyatlowconcentrations.Thiscauses:
Aninitialover-pressureofF ,inordertofilltheFRCandreachthedesiredFAmorerapidinduction,asthetargetF isreachedmorerapidly
Inliquidinjection,anaestheticagentisinjectedintothebreathingsystem.Thiscauses:
AverylargedegreeofoverpressureInthiscircumstance,therateofriseofend-expiredagentconcentrationisidenticalfordifferentagents.
i.e.Onsetisindependentoftheblood:gascoefficient
MechanismofActionofInhaledAnaestheticAgents
Mechanismsofactioncanbedividedinto:
MacroscopicAtthelevelofthebrainandspinalcord.
Inthespineby:
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DecreasingtransmissionofnoxiousafferentsignalsatthethalamusInhibitionofspinalefferents,decreasingmotorresponses
Inthebrainby:GlobaldepressionofCBFandglucosemetabolism
MicroscopicSynapsesandaxonsby:
Inhibitingpre-synapticexcitatoryactivity:ACh5-HTGlutamine
Augmentingpost-synapticinhibitoryactivity:GABA
MolecularAnaestheticagentsmayalterthefunctionofmoleculeswithintheCNS.Theseinclude:
Alterationofα-subunitsoftheGABA receptorThisprolongsthetimeitspendsopenonceactivated,prolongingtheinhibitoryCl currentandincreasingthedegreeofhyperpolarisation.Enhancetheactivityoftwo-poreK channelsIncreasestherestingmembranepotentialofbothpre-synapticandpost-synapticCNSneurons.
IncompleteTheoriesoftheMechanismofActionofGeneralAnaestheticAgents
Meyer-OvertonHypothesis:
PotencyofanaestheticsrelatestotheirlipidsolubilityAnaestheticmoleculesdissolveintoCNSmembranes,disruptingtheireffectFlaws:
NotalllipidsolubledrugshavegeneralanaestheticaffectsOtherfactorsdisruptcellmembraneswithoutcausinganaesthesia
VolumeExpansion,PressureReversal(Mullin'sCriticalVolumeHypothesis):
CNScellmembranesexpandwithgeneralanaestheticagentsThisdistortschannelsresponsibleformaintainingmembranepotentialandgeneratingactionpotentials.IncreasedambientpressurereversesgeneralanaesthesiaFlaws:
Doesnotaccountforstero-selectivityofdrug-receptorinteractionsI.e.receptorsselectforonestereoisomeroverothers.
Structure-ActivityRelationshipsofInhaledAnaesthetics
Chemicalstructuresofdifferentvolatileanaestheticsarecoveredinthepharmacopeia.
Differentchemicalandphysicalpropertiesaltertheeffectofinhalationalagents:
PhysicalMolecularweightAdecreaseinmolecularweightdecreasesboilingpointandthereforeincreasesSVP.
ChemicalH contentGreaterhydrogencontent:
IncreasesflammabilityIncreasespotency
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F contentGreaterfluoridecontent:
DecreasesflammabilityDecreasesoxidativemetabolismThisdecreasestoxicity.Decreasespotency
Cl contentIncreasedchlorideincreasespotency.-CHF (Di-fluor-methylgroup)
ProducesCOinthepresenceofdrysodalime
TheIdealInhaledAnaestheticAgent
Fromthepropertiesdiscussedabove,wecanconstructthefollowingidealagent:
PhysicochemicalLiquidatroomtemperatureHighSVPLowspecificheatcapacityLongshelf-lifeLightstableHeatstableDoesnotreactwiththecomponentsinthebreathingcircuit
RubberMetalPlasticSodalime
Notflammable/explosiveSmellsnicePreservativefreeEnvironmentallyfriendlyCheap
PharmacokineticHighoil:gaspartitioncoefficientLowMAC.Lowblood:gaspartitioncoefficientRapidonsetandoffset.NotmetabolisedNon-toxic
PharmacodynamicDoesnotcauselaryngospasmorairwayhyperreactivityNoeffectonHDxparametersAnalgesicHypnoticAmnesticAnti-epilepticNoincreaseinICPSkeletalmusclerelaxationAnti-emeticNotocolyticeffects
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NotteratogenicorotherwisetoxicNodruginteractions
References1. KhanKS,HayesI,BuggyDJ.PharmacologyofanaestheticagentsII:inhalationanaestheticagents.ContinuingEducationin
AnaesthesiaCriticalCare&Pain,Volume14,Issue3,1June2014,Pages106–111.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.4. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.5. MillerRD,ErikssonLI,FleisherLA,Weiner-KronishJP,CohenNH,YoungWL.Miller'sAnaesthesia.8thEd(Revised).
ElsevierHealthSciences.6. ZhouJX,LiuJ.Theeffectoftemperatureonsolubilityofvolatileanestheticsinhumantissues.AnesthAnalg.2001
Jul;93(1):234-8.7. HendrickxJ,PeytonP,CaretteR,DeWolfA.Inhaledanaestheticsandnitrousoxide:Complexitiesoverlooked:thingsmay
notbewhattheyseem.EurJAnaesthesiol.2016Sep;33(9):611-9.8. AranakeA,MashourGA,AvidanMS.Minimumalveolarconcentration:ongoingrelevanceandclinicalutility.Anaesthesia.
2013May;68(5):512-22.doi:10.1111/anae.12168.9. LermanJ,GregoryGA,WillisMM,EgerEI2nd.Ageandsolubilityofvolatileanestheticsinblood.Anesthesiology.1984
Aug;61(2):139-43.
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HormonesAhormoneisachemicalmessengerproducedbyaductlessglandwhichhasitsactionatadistanttargetcellviaaspecificreceptor.
Lipidhormones,dividedinto:SteroidsSteroidsaresynthesisedfromcholesterol,andarereleasedastheyareproduced(theyarenotstored).Theyarehighlylipidsolubleandactoncytoplasmicandintra-nucleicreceptors.
AldosteroneTestosteroneOestrogenCortisol
EicosanoidsEicosanoidsareformedfromcellmembranephospholipid.
ProstaglandinsThromboxanesLeukotrienes
PeptidehormonesPeptidehormonesarestoreingranulesandreleasedbyexocytosis.Theyaredividedinto:
Short-chainInsulinADHOxytocinACTH
Long-chainGHProlactin
GlycopeptidesProteinswithcarbohydrategroups.
LHFSHTSH
MonoaminederivativesDerivedfromasingleaminoacid.
CatecholaminesStoredingranulesandactatmembranereceptors.
AdrenalineNoradrenaline
SerotoninThyroxine
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2017-09-17
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Insulin,Glucagon,andSomatostatinDescribethephysiologyofinsulin,glucagonandsomatostatin.
Insulin
Insulinisapolypeptidehormone,andis:
SynthesisedfromproinsulinintheroughendoplasmicreticulumofBcellsintheIsletsofLangerhansExcretedviaexocytosisinresponsetoanincreaseinintracellularCaMinimallyproteinboundwithatinyvolumeofdistributionV 0.075L.kg ,increasedto0.146L.kg indiabetics.Metabolisedinliver,muscle,andkidneybyglutathioneinsulintranshydrogenase,withrenaleliminationofinactivemetabolitesCirculatoryhalf-lifeof~5min.
ActionsofInsulin
Insulinbindstoaspecificinsulinreceptor(amembrane-spanningproteincomposedofαandβsubunits)onthecellmembrane.Thecomplexisinternalised,anditseffectsaremediatedbytyrosinekinase.
Seconds Minutes Hours
Muscle Increasedglucose,aminoacid,ketone,andK uptake Increasedanabolism,decreasedcatabolism
Fat Increasedglucose(viaGLUT4),aminoacid,andK uptake Increasedglycerolphosphatesynthesis Increasedfatty
acidsynthesis
Liver
Decreased:gluconeogenesis,ketogenesis.
Increased:glycogensynthesis,glycolysis,proteinsynthesis,lipidsynthesis
General Increasedcellgrowth
GlucoseTolerance
Hyperglycaemiaoccursindiabetesduetodecreasedperipheralutilisationasglucoseuptakeisreducedduetoabsenceoforresistancetoinsulin.Inaddition,thesuppressiveeffectofinsulinonhepaticgluconeogenesisisabsentorreduced.
GlucagonGlucagonisapolypeptidehormone,andis:
SynthesisedintheAcellsofthepancreasHasacirculatinghalf-lifeof~5minMetabolisedpredominantlyintheliverSecreteddirectlyintotheportalvein,andundergoesfirst-passmetabolismresultinginlowcirculatinglevels.
System Effect
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Liver Glycogenolysis,gluconeogenesis,glucoserelease,ketoneformation
CVS Inotropy
Fat Lipolysis
Metabolic Increasedmetabolicrate,GHrelease,somatostatinrelease,insulinrelease
Secretionofglucagonisinfluencedbyanumberoffactors:
StimulateRelease InhibitRelease
Hypoglycaemiaandstarvation Somatostatin
Aminoacids Secretin
Physiologicalstress:Exercise,infection FreeFattyAcids
β-agonists α-agonists
Cortisol Insulin
ACh Ketones
Theophylline GABA
SomatostatinSomatostatinisapolypeptidehormonethat:
Inhibitssecretionofotherhormonesincluding:GlucagonInsulinOtherpancreaticpeptides
MayfunctionasaneurotransmitterintheCNS
References
1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-07-18
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ControlofBloodGlucoseExplainthecontrolofbloodglucose
Normalbloodglucoseinthenon-diabeticis4-6mmol.L ,thoughwillriseafterconsumptionofcarbohydrate.Glucoseregulationcanbedividedinto:
Short-termRegulationviasecretionorinhibitionofinsulinandglucagonfromthepancreaticislets.Long-termRegulationviabothneuronal(SNSactivation)andhormonal(cortisol,GH)mechanisms.
HormonalMechanisms
ShortTerm
GlucoselevelsaresenseddirectlyinthepancreasandwillresultininsulinreleasewhentheBGLis>5.6mmol.L .PancreaticBcellsresponddirectlytoglucosebysecretinginsulininabiphasicfashion:
Aninitial,rapidincreaseinreleaseGlucoseentersviatheGLUT-2transporter,andisconvertedtopyruvatewhichentersthecitricacidcycleandproducesATPATPinhibitsATP-sensitiveK channels,reducingK effluxandcausingdepolarisationDepolarisationcausesCa release,resultinginexocytosisofinsulingranules
Aprolonged,slowincreaseinreleaseGlutamateisproducedasaby-productofthecitricacidcycleGlutamatestimulatesmaturationofotherinsulingranulesReleaseofthesegranulescausesthesecondphaseofinsulinrelease
Conversely,alowglucoselevelstimulatessecretionofglucagon.Thisistypicallylessimportantthantheeffectofinsulinunlessinsituationsofstarvationorseverephysiologicalstress.
LongTerm
Sustainedhypoglycaemiaincreasesfatutilisationanddecreasesglucoseutilisation(limitingfurtherdropsinbloodglucose),viastimulatingreleaseof:
GHCortisol
NeuronalMechanismsHypoglycaemiadirectlystimulatesthehypothalamus,causing:
IncreasedSNStoneAdrenalinereleaseinturnstimulateshepaticglucoserelease.
OrganEffects
Glucoselevelsareinfluencedbythe:
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LiverInsulinandglucagonactonthelivertocontinuallyadjusttherelativeratesofglycogenolysisandglycogenesis,allowingittofunctionasaneffectivebufferofbloodglucose.
Hepaticdiseasesignificantlylimitstheefficacyofthissystem,andresultsinawidely-fluctuatingbloodglucoselevelKidney
Atransientglycosuriamaybeseenashyperglycaemiadecreasesrenalabsorptionofglucose
PhysiologicalResponsestoHypoglycaemia
BSL(mmol.L ) Symptoms EndocrineResponse
4.6 Insulinsecretioninhibited
3.8 Autonomicdysfunction Glucagon,adrenaline,andGHsecretion
2.8 CNSdysfunction
2.2 Lethargy,Coma
1.7 Convulsions
0.6 Permanentbraindamage,Death
References1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.2. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders
Elsevier.2011.
Lastupdated2019-07-18
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HypothalamusandPituitaryDescribethecontrol,secretionsandfunctionsofthepituitaryandthehypothalamus
Hypothalamus
Thehypothalamusisacircumventricularorganthatregulatesalargenumberofautonomicprocesses:
ThermoregulatoryIntegratesthermoreceptorinputandcontrolsactivityofheatlossandheatgainmechanisms.SatietyFeelingsofhungeraremodulatedbyglucose,CCK,glucagon,andleptin.Waterbalance
ContainsosmoreceptorswhichcontrolADHreleasefromtheposteriorpituitaryAngiotensinIIstimulatesthirstandADHreleaseviathesubfornicalorganandorganumvasculosum
CircadianrhythmsBalancebetweenanteriorandposteriorhypothalamicstimulationcontrolssleep-wakecycle.Pituitarycontrol
Anteriorpituitarybyhormonesecretionintothelongportalvein.Secretedhormonesinclude:GnRH,stimulatesFSHandLHreleaseCRH,stimulatesACTHreleaseGHRH,stimulatesGHreleaseTRH,stimulatesTSHreleaseSomatostatin,inhibitsGHandTSHreleaseDopamine,inhibitsprolactinrelease
PosteriorpituitarybyneuronalinnervationBehaviourPunishmentandrewardcentres.Sexualfunction
Pituitary
Thehypothalamic-pituitaryaxisdescribesthecomplexfeedbackloopsbetweentheseendocrineorgans:
Short-loopfeedbackdescribesnegativefeedbackfromthepituitaryonthehypothalamus,e.g.GHinhibitingGHRHreleaseLong-loopfeedbackdescribesnegativefeedbackfromapituitarytargetgland(i.e.thyroid,adrenal,gonads)onthehypothalamus,e.g.cortisolinhibitingCRH(aswellasACTH)release.
Theseaxesarealsonamedwithtargetgland,e.g.hypothalamic-pituitary-adrenalaxis
PituitaryHormones
Thepituitaryglandsecreteseighthormonesfromtwolobes:
AnteriorPituitarySecretessixhormonesinresponsetohypothalamicendocrinestimulus.Theseareclassifiedas:
Stimulatinghormones,whichactatanothergland:ACTHShort-chainpeptidethatstimulatescortisolreleasefromthezonafasciculata.ReleaseisstimulatedbyCRH,andinhibitedbycortisol.
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TSHGlycoproteinthatstimulatessynthesisandreleaseofT andT .ReleaseisstimulatedbyTRH,andinhibitedbyT .FSHGlycoproteingonadotropin.ReleaseisstimulatedbyGnRH,andinhibitedbycirculatingsexsteroids.Hasdifferenteffectsdependingonsex:
Females:Stimulatesoestrogensynthesisandovarianfollicledevelopment.Males:Stimulatesspermmaturation.
LHGlycoproteingonadotropinwithdifferenteffectsdependingonsex:
Females:Rapidincreasestimulatesovulationandcorpusluteumdevelopment.Males:Stimulatestestosteronesynthesis.
Directactinghormones:GHLong-chainpeptidereleasedinapulsatilefashion.ReleaseisstimulatedbyGHRHandistypicallyhighwithexercise,hypoglycaemia,andstress.ReleaseisinhibitedbysomatostatinandIGF-1.GHhasgenerallyanaboliceffects:
Directlystimulateslipolysis,increasingcirculatingFFAIndirectlystimulatesIGF-1release,promotingcellgrowthanddevelopment
ProlactinLong-chainpeptidewhichpromotesbreastdevelopmentduringgestation,andlactationafterdelivery.
PosteriorpituitarySecretestwohormones:
ADHShort-chainpeptidewhichis:
ReleasedinresponsetoosmoreceptorsinthecircumventricularorgansdetectingachangeinosmolalityADHreleaseis:
Reducedwhenosmolalityis<275mosm.l-1</sup>Increasedwhenosmolalityis>290mOsm.L
Effectiveat:V receptorsinvascularsmoothmuscle,causingvasoconstrictionV receptorsinkidneycollectingductstoincreasewaterreabsorption,andonendotheliumtoincreasevWFandfactorVIIIreleaseV receptorsinthepituitarytostimulateACTHrelease
OxytocinShort-chainpeptide,structurallysimilartoADH,whichcauses:
UterinecontractionLet-downreflexStimulatesmilkreleaseonsuckling.PsychologicalPairbonding.
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. Nickson,C.Vasopressin.LITFL.
Lastupdated2019-07-18
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ThyroidDescribethecontrol,secretionsandfunctionsofthethyroid.
Thethyroidgland:
ProducesandsecretestwohormonesinresponsetoTSH:T (thyroxine,93%)T (tri-iodothyronine,7%)
Secretionsarecontrolledviaanegative-feedbacklooponthehypothalamic-pituitary-thyroidaxisIncreasedTSHresultsin:
IncreasediodineuptakeIncreasediodinationtoformT andTIncreasedproteolysisofthyroglobulin,whichreleasesT andT
SecretionsaredecreasedwithdecreasediodineuptakePerchlorateBlocksNa /I symporter.Wolff-ChaikoffeffectAreductioninthyroidhormoneproductionduetoahighcirculating[iodide].
SynthesisThyroidhormonesare:
SynthesisedinfolliclesAfollicleisformedofasinglelayerofcuboidalepitheliumaroundacentrallumen(follicularcavity)containingthyroglobulin.
IodideistransportedintofollicularcellsviaasecondaryactivetransportmechanismNa /I co-transporter.IodideisthenoxidisedtoiodineThyroglobulinissynthesisedintheendoplasmicreticulumofthefollicularcellandexcretedintothefollicularcavityIodineisexcretedintothefollicularcavityusingachlorideexchangepumpInthefollicularcavity:
Thyroidperoxidasecatalysestheiodinationofthyroglobulin,formingmono-iodotyrosineanddi-iodotyrosineThesearesubsequentlyoxidised,formingT andT respectively
Insummary:
Iodideistakenintothethyroidfolliclesbysecondaryactivetransport,andoxidisedtoiodineThyroglobulinissynthesisedinthefollicle,andexcretedintothefollicularcavityIodineissecretedintothefollicularcavity,whereitcombineswiththyroglobulintoproduceT andT
SecretionandMetabolism
Thyroidhormonesare:
SecretedinvesiclesviaendocytosisintothesurroundingcapillariesColloidentersthyroidcellviapinocytosisattheapicalmembraneVesiclesthenfusewithlysosomes
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ThyroidhormonecleavedfromthyroglobulinbyproteasesFreeT andT diffusethroughthebaseofthethyroidcellintosurroundingcapillaries
Highlyproteinboundtoalbuminandthyroxine-bindingglobulinT hasat of7daysT hasat of24hoursBotharedeiodinatedintheliver,kidney,andmuscle
55%ofT willbefirstdeiodinatedtoT
PhysiologicalEffects
Thyroidhormones:
ActonthyroidreceptorsinthecellnucleusIncreasinggenetranscription,proteinsynthesis,andmitochondriasizeandnumber.T is3-5xmoreactivethanT
Effectsofthyroidhormonearepredominantlymetabolic:
System Effect
Resp ↑MVdueto↑CO production
CVS ↑HR,↑inotropy,↑CO,↓SVR,↓DBP
CNS ↑Excitability:Seizures,tremor
MSK ↑Osteoblasticactivity
GU Impotence(men),oligomenorrhoea(women)
GIT ↑GITmotility
Metabolic↑BMRupto100%,↑carbohydratemetabolism(↑glucoseuptake,↑glycolysis,↑gluconeogenesis),↑fatmetabolism(↑lipolysis,↑non-shiveringthermogenesis,↓plasmacholesterol,↓plasmaphospholipids,↓triglycerides),↑proteinmetabolism(↑anabolismatphysiologicallevels,↑catabolismathighlevels)
References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. CICMSeptember/November2008
Lastupdated2019-07-18
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AdrenalHormonesDescribethecontrol,secretionsandfunctionsofrenalandadrenalhormones
Thiscoverstheproductionofadrenalhormones.Informationspecifictocatecholaminesreceptorfunctioncanbefoundunderadrenoreceptors,whilstdetailedinformationonspecificagents,includingstructure-activityrelationships,isinthepharmacopeia.
Theadrenalglandsarepairedtriangularglandsatthesuperiorpoleofthekidney.Theglandcanbedividedinto:
AdrenalcortexConsistsofthreelayerswhichproducesteroidhormones(AgoodmnemonicisGFRforthelayers,andACT(H)forhormones)
ZonaGlomerulosaPredominantlyproducesmineralocorticoids(aldosterone).ZonaFasciculataPredominantlyproducesglucocorticoids(cortisol).ZonaReticularisPredominantlyproducessexsteroids(testosterone).
AdrenalmedullaProducescatecholamines.
SteroidHormones
Mineralocorticoids
Aldosteroneisthekeymineralocorticoidhormone,accountingfor95%ofmineralocorticoidactivity:
Releaseisstimulatedby:IncreasedserumKIncreasedAngiotensinII
HypovolaemiaDecreasedosmolarity
IncreasedACTHDecreasedserumpH
Actstoincreasesodiumandwaterretention(andremovalofpotassium),via:IncreasedexpressionandactivationofNa /K pumpsonthebasolateralmembraneofDCTandCTcells,causingincreasedNa (andwater)reabsorptionandK eliminationStimulationoftheNa /H pumpinintercalatedcellsontheDCT
Glucocorticoids
Cortisol(hydrocortisone)istheprimaryglucocorticoidinthebody,accountingfor95%ofendogenousglucocorticoideffect.Cortisolis:
Producedat~15-30mg.dayReleasedinresponsetoACTHACTHisreleasedinresponsetoCRH,whichis:
ReleasedinresponsetostressModulatedbycircadianrhythms,anddemonstratesdiurnalvariation:
CRHpeaksjustbeforewakingCRHtroughsduringsleep
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Cortisolhaseffectsonmanyorgansystems,andinphysiologicalamountscause:
CVSIncreasedsensitivitytocatecholaminesIncreasesfluidretention
Metabolic(Essentiallyanti-insulineffects):
GluconeogenesisToprovidesubstrates,italsostimulates:
ProteolysisLipolysis
Decreasedglucoseuptake
Catecholamines
Naturallyoccurringcatecholaminesinclude:
AdrenalineNoradrenalineDopamine
Synthesisofcatecholaminesoccursintheadrenalmedulla,whichisamodifiedsympatheticganglioncomposedofchromaffincells.
SynthesisandreleaseisdependentonAChreleasebythepresynapticneuronUnlikemanyotherhormones,catecholaminesecretionisnotanegative-feedbackloop.
Processofcatecholaminesynthesis:
TyrosineisconcentratedintheadrenalmedullaTyrosineishydroxylatedtoDOPAbytyrosinehydroxylaseThisistherate-limitingstep,andisprobablythebestenzymetoremember.DOPAisdecarboxylatedtodopamineDopamineisconvertedtonoradrenalineNoradrenalineisconvertedtoadrenalinebyPNMT(PhenylethanolamineN-methyltransferase)Thismayonlyoccurintheadrenalmedulla.
Plasmahalf-livesofnoradrenalineandadrenalinearesmallasaconsequenceoftheirmetabolismandelimination.
Extraneuronaluptakeinthelungs,liver,kidney,andGITNeuronaluptakebysympatheticnerveendingsInactivationbyMAOinnervecytoplasmInactivationbyCOMTintheliverandkidney
References
1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2018-06-25
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CalciumHomeostasisDescribethefunction,distribution,regulationandphysiologicalimportanceofsodium,chloride,potassium,magnesium,calciumandphosphateions
Describethecontrolofplasmacalcium.
Calciumisabivalentcation.Almostall(99%)ofcalciumislocatedinbone,withtheremainderinplasmaandsofttissues.Normalplasmalevelsare2.2-2.55mmol.L ,which(inplasma)maybe:
Ionised(free)calcium(50%)Normalrange1.1to1.3mmol .Boundtoalbumin(40%)Ascalciumcompounds(10%)
FunctionsofCalcium
CellSignalingCalciumhasanumberofrolesincellsignaling:
AffectscellsodiumpermeabilityandthereforetheRMPofexcitablecellsCalciumtriggersexocytosisofneurotransmittervesiclesCalciumisanimportantsecondmessengerforsomeGproteins
BoneCalciumhastwofunctionsinbone:
PhysicalstructureAlkalireserveCalciumphosphatecanbemobilisedtobufferacidosis.
EnzymaticcofactorCalciumisanimportantcofactorinenzymaticpathways,includingthecoagulationcascade.Clinicalhypocalcaemiadoesnotcausecoagulopathyhowever,ascalciumlevelslowenoughtopreventcoagulationarenotcompatiblewithlife.
RegulationofCalcium
Calciumisregulatedtomaintainastableionisedcalciumlevel.Threehormonesareinvolvedintheregulationofcalcium:
ParathyroidHormoneProteinhormonesecretedbythefourparathyroidglands,locatedontheposteriorsurfaceofthethyroid,inresponsetoafalliniCa levels,andactstoincreaseplasmacalcium:
IncreasecalciumreabsorptioninthePCTandlateDCTIncreaseosteoclasticactivityinboneIncreasevitaminDactivationintheintestine,whichinturnincreasesintestinalabsorptionofdietarycalcium
VitaminD/CalcitriolOnceconvertedtocalcitriolinthekidney(viastimulationfromPTH),vitaminDactsto:
IncreasecalciumreabsorptionfromkidneyandgutIncreasebonecalcification
CalcitoninPeptidehormonesecretedbytheCcellsofthethyroidgland,inresponsetoariseiniCa greaterthan2.4mmol.L .
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Calcitoninactsto:DecreaseabsorptionofcalciumfromgutandkidneyDecreaseosteoclasticactivityofbone
References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2017-09-08
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HistamineDescribethephysiologyofhistamineandserotonin
Histamineisanendogenousamineproducedbydecarboxylationofhistidine.Histamineis:
PresentinalltissuesParticularlyabundantinthoseexposedtotheoutsideenvironment:
LungsGutSkin(lungs,gut,skin)
Producedinandreleasedby:MastcellsReleasedbyexocytosisduringinflammatoryandallergicreactions.BasophilsHistaminocytesinthestomachHistaminergicneuronsintheCNS
Metabolisedby:HistaminaseImidazoleN-methyltransferase
HistamineReceptorsandEffectsHistamineactson:
H receptorsGqreceptorinvolvedbroadlyininflammationandvasodilation.H receptorsGsreceptorinvolvedingastricacidsecretion.H receptorsGipresynapticreceptorintheCNS.H receptorsGireceptorlocatedinbonemarrowandothersolidhaematologicalorgans(spleen,liver,thymus).
System H H H H
Resp Bronchoconstriction Bronchodilation
CVS↑Vasodilation(endothelialeffect),coronaryvasoconstriction,↓AVnodalconduction
↑HR,↑inotropy,coronaryvasodilation,↑capillarypermeability
CNSPresynapticinhibitionofneurotransmission
MSK Wealduetolocalvasodilation,itch,↑nociception
GIT ↑Peristalsis ↑Gastricacidsecretion
HaemeAlterIL-16release
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References
1. ParsonsME,GanellinCR.Histamineanditsreceptors.BritishJournalofPharmacology.2006;147(Suppl1):S127-S135.doi:10.1038/sj.bjp.0706440.
2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.3. BowenR.Histamine.Vivo.ColoradoState.
Lastupdated2017-09-17
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ProstanoidsProstanoidsareadiversefamilyofeicosanoids(20-carbonmolecules),producedfromarachidonicacid,andinclude:
ThromboxaneProstacyclinProstaglandins
Synthesis
Arachidonicacidisconvertedinto:
LeukotrienesbyLOXCyclicendoperoxidasesbyCOXenzymesTheseundergofurthermetabolismtoproduce:
ThromboxanesThromboxaneA
ProstacyclinsPGI
ProstaglandinsPGE
EPEPEP
PGFPGD
Effects
Receptor Receptor Respiratory Vascular GIT GU Other
ThromboxaneA Gq Vasoconstriction Platelet
aggregation
PGI Gs BronchodilationVasodilation(renalandpulmonary)
PGE EP Gq Bronchoconstriction Increasedcontraction
Renalvasodilation
PGE EP Gs BronchodilationClosureofductusarteriosus
Decreasedcontraction
Renalvasodilation
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PGE EP Gi
Gastricmucousproduction,GITcontraction
Uterinecontraction
PGF Gq Bronchoconstriction Vasoconstriction Uterinecontraction
PGD Gs Renalvasodilation
Promotessleep
References
1. RicciottiE,FitzGeraldGA.ProstaglandinsandInflammation.Arteriosclerosis,thrombosis,andvascularbiology.2011;31(5):986-1000.doi:10.1161/ATVBAHA.110.207449.
Lastupdated2019-07-18
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SkeletalMuscleDescribetheanatomyandphysiologyofskeletal,smooth,andcardiacmuscle
Describethemechanismofexcitation-contractioncoupling
Skeletalmusclehasanumberoffunctions:
FacilitatemovementPostureViatoniccontractionofantagonisticmusclegroups.SofttissuesupportAbdominalwallandpelvicfloorsupportviscera.VoluntarysphinctercontrolHeatproduction
StructureandContents
Skeletalmuscleconsistsoflongtubularcells,knownasmusclefibres,whichrunthelengthofthemuscle.Skeletalmusclecells:
Areundervoluntarycontrolfromthesomaticnervoussystemviaα-motorfibresα-motorfibresmaycontrolmultiplemyofibres,formingamotorunit.Are10-100μmindiameterContainseveralhundredperipheralnucleiContainmultiplemitochondria
Slowoxidativefibres(redfibres)Containmultiplemitochondria,producesustainedcontraction,andareresistanttofatigue.Fastglycolyticfibres(whitefibres)Containlownumbersofmitochondriaandlargeamountsofglycogen,andproducestrongcontractionsbutaremoreeasilyfatigued.
ContainsarcoplasmicreticulumContainlargeamountsofglycogen~200gtotal.ContainmyoglobinAppearstriatedmicroscopicallyduetothearrangementofmyofibrils
MyofibrilsaremultiplemyofilamentsarrangedinparallelMyofilamentsareformedfrommultiplesarcomeresarrangedinseriesAsarcomereisthefunctionalunitofmuscle
Musclefibresaresurroundedbylayersofconnectivetissue:
EndomysiumThinlayerwhichsurroundseachmusclefibre.PerimysiumSurroundsbundlesofmusclefibres.EpimysiumThicklayerwhichsurroundsanentiremuscle.
Theselayersofconnectivetissuejoinattheendofamuscletoformatendonoraponeurosis.
Sarcomere
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Thesarcomereisthefunctionalcontractileunitofmuscle.Averagesarcomerelengthis2.5μm.
Thesarcomerecontainstwomainproteins:
Myosin(thick)filamentsMyosinisalargeproteinwithtwoheads,whichbindactinandATP.Themyosinheadflexesonitsneckduringcontraction.Actin(thin)filamentsActinisasmallerproteinthanmyosin,andpotentiatestheATPaseofmyosin.Actinfilamentshaveagroovewhichcontainsanotherproteincalledtropomyosin,towhichtroponinattachesto.
Troponinhasthreesubunits:TroponinT-bindstroponintotropomyosinTroponinI-preventsmyosinbindingtoactinbyphysicallyobstructingthebindingsiteTroponinC-BindsCa whichinitiatescontraction
Theseproteinsarearrangedtoformthreebandsandtwolines:
A-bandThemyosinfilaments.H-bandThesectionofmyosinfilamentsnotoverlappingwithactinfilaments.I-bandThesectionofactinfilamentsnotoverlappingwithmyosinfilaments.Z-lineEachendofthesarcomere.ActinfromadjacentsarcomeresareconnectedattheZline.M-lineBandofconnectionsbetweenmyosinfilaments.
Excitation-ContractionCoupling
Musclecontractionnormallyrequiresthecoordinationofelectrical(signaling)eventswithmechanicalevents.
InresponsetoAChstimulatingnicotinicreceptors,theNa andK conductanceoftheend-plateincreasesandanend-platepotentialisgeneratedMusclefibresundergosuccessivedepolarisationandanactionpotentialisgeneratedalongTtubulesThesedelivertheAPdeepintothecell,andclosetothesarcoplasmicreticulum.Ca isreleasedfromsarcoplasmicreticulumThisprocessinvolves:
DihydropyridineReceptorSpecialisedvoltage-gatedL-typeCa channel,activatedbyT-tubulardepolarisation.ResponsibleforasmallamountofCa transport.RyanodineReceptor
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AsecondCa channelwhichisattachedto,andactivatedby,thedihydropyridinereceptor,causingamuchlargerreleaseofCa .
Ca isreleasedfromtheSR(increasingintracellularCa 2000x)andbindstotroponinC,weakeningthetroponinI-actinlinkanduncoveringmyosin-bindingsitesonactinCross-linkagesformbetweenactinandmyosin,whichreleasesADPThereleaseofADPtriggersapowerstroke,whichisaprocessofattachment,pulling,anddetachmentEachcycleshortensthesarcomereby~10nm:
Themyosinheadrotatesonits'neck',movingtoanewactinbindingsiteATPbindstothe(nowfree)bindingsiteonthemyosinATPishydrolysedtoADP,intheprocess"re-cocking"themyosinheadThisprocesscausesthethickandthinkfilamentstoslideoneachother,withthemyosinheadspullingtheactinfilamentstothecentreofthesarcomere.Therefore,overthecourseofapowerstroke:
TheA-bandisunchangedTheH-bandshortensTheI-bandshortens
PowerstrokescontinueaslongasthereisATPandCa available
Inrelaxation:
Ca ispumpedbackintothesarcoplasmicreticulumThisisanATP-dependentprocess,andiswhymusclerelaxationisactive.TroponinreleasesCaBindingsitesareoccludedbytroponin,andnofurthercontractionoccurs
References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.3. Slomianka,L.Muscle.UniversityofWesternAustralia-SchoolofAnatomyandHumanBiology.
Lastupdated2019-07-18
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SkeletalMuscleInnervationExplaintheconceptofmotorunits
Describetherelationshipbetweenmusclelengthandtension
Describethemonosynapticstretchreflex,singletwitch,tetanusandtheTreppeeffect
MotorUnitsAmotorunitconsistsofanα-motorneuronandthegroupofmusclecellsthatitinnervates
AnactionpotentialinthisneuronwillcausecontractionofallthemyocytesintheunitLargemuscleshavemanymyocytesperunitSmall,precisemuscles(e.g.extraocular)havefewmyocytesperunit
ForceofContractionMuscletensionisdependentonthreefactors:
InitialmyocytefibrelengthOptimalstretchmaximisesthenumberofoverlappingactinandmyosinfilaments.NumberofcontractingmyocytesRecruitmentofadditionalmotorunitsincreasestheforceofcontraction.FrequencyofActionPotentialsHighfrequencyactionpotentialscauseaccumulationofcalciuminthecytoplasm(theBowditchorTreppeeffect),increasingforceofcontraction.
Astheabsoluterefractoryperiodofskeletalmuscleisshorterthancardiacmuscle,tetany,orsustainedmusclecontraction,canoccur
Proprioception
Proprioceptionistheabilityofthebodytodetermineit'spositioninspace.Therearetwokeyproprioceptivesensors:
MusclespindlesGolgitendonorgans
MuscleSpindles
Musclespindlessensechangesinmusclelength.They:
Areaspecialisedmusclefibre,knownasintrafusalfibresRunparalleltomyocytes(alsoknownasextrafusalfibres)Consistoftwoelements:
Central,non-contractileportionwhichsensestensionContractileendsThisallowsthemusclespindletoadjustitslengthwithitsmuscle,sothataconstanttensioninthenon-contractileportioncanbemaintainedoverarangeofmusclelengths.
Musclespindleshavebothafferentandefferentinnervation:
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AfferenttypeIafibresadjusttheirelectricaloutputtosignalbothcurrentfibrelengthandrateofchangeAfferenttypeIIfibresonlysignalfibrelengthEfferentγneuronsinnervatethecontractileelements
Voluntarymusclecontractionresultsincontractionofbothmotorunits(α1neurons)andintrafusalfibres(γ-motorneurons).
Tonicinnervationofγ-motorneuronsincreasesmuscletonebystretchingthenon-contractileportions,increasingIafiringandsubsequentα-motorunitfiring.
GolgiTendonOrgans
Golgitendonorgansarestretchreceptorslocatedbetweenmuscleandtendon.They:
RuninseriestomyocytesSensestretchCausereflexivemusclerelaxation,intendedtopreventmuscledamage
Reflexes
Areflexisaninvoluntary,predictablemovementinresponsetoastimulus.Therearetwotypes:
Monosynaptic:MotorneuronsynapsesdirectlywiththesensoryneuronMonosynapticreflexesarerapid,butonlygeneratesimpleresponses.Therearefivecomponentstoamonosynapticreflex:
SensoryreceptorTypicallymusclespindles.AfferentneuronTypeIaafferentsrelaysignalfrommusclespindletoventralhornviathedorsalroot.SynapsebetweenafferentandefferentneuronIntheventralhornEfferentneuronα-motorneurontravelsfromtheventralhornandinnervatesthemotorunit.EffectormuscleInnervatedmotorunitcontractsinresponse.
Polysynaptic:MotorneuronisseparatedfromthesensoryneuronbyoneormoreinterneuronsinthedorsalhornThisallowsmodulationofsignal.Responsesareslowerbutmorecomplex,e.g.withdrawalofalimbfromahotobject.
TwitchandTetany
Atwitchistheresponseofamuscletoasinglestimulus(actionpotential)Atetaniccontractiondescribesthesustainedcontractionproducedbyrepetitivestimulationbeforerelaxationcanoccur
Thisstimulationmustbecausingaboveacriticalfrequency,whichisdependentontheactionpotentialdurationforacellRepetitivestimulationcausesrepeatedSRdepolarisation,leadingtosustainedhighintracellularCa levelsasCaentryexceedsCa exitForcefromtetaniccontractionisupto4xgreaterthanthatofatwitch
References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. ANZCAMarch/April2000
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NeuromuscularBlockersUnderstandingofthepharmacologyofneuromuscularblockingdrugs
Theneuromuscularjunctionisachemicalcommunicationbetweenthemotorneuronandthemusclecell.VesiclescontainingACharereleasedwhenactivatedbyCa ,andinfluxofwhichoccurswhentheactionpotentialreachesthenerveterminal.
NicotinicAChreceptorssitontheshouldersofjunctionalfoldsofmusclecells,whilstacetylcholinesteraseisburiedintheclefts.
FactorsAffectingNeuromuscularBlockade
PatientFactors
Factor Effect Mechanism
HepaticDisease Prolongeddurationofaminosteroidsandsuxamethonium
Decreasedmetabolism,decreasedproductionofpseudocholinesteraseinseveredisease
Pseudocholinesterasedeficiency Prolongeddurationofsuxamethonium Decreasedmetabolism
Age Increasedsensitivityinneonates,particularlyprematureinfants IncompletematurationofNMJ
Hypokalaemia Potentiatesnon-depolarisingblockade,reducesdepolarisingblockade
Increasesmagnitudeofstimulusrequiredtodepolarisecell
Hyperkalaemia Potentiatedepolarisingblockade,reducenon-depolarisingblockade
Decreasesmagnitudeofstimulusrequiredtodepolarisecell
Hypermagnesaemia Potentiatesblockade DecreasesAChrelease,decreasessensitivityofpost-synapticmembrane
Hypocalcaemia Potentiatesblockade DecreasespresynapticACHrelease,decreasessensitivityofpost-synapticmembrane
Respiratoryacidosis Potentiatesblockade EnhanceseffectofNMBagents
Hypothermia Potentiatesblockade Reduceshepaticmetabolism,renalelimination,Hoffmandegradation
Hypovolaemia Slowsrateofonsetandenhancesduration Prolongedcirculationtime
MyastheniaGravis Increasedsensitivitytonon-depolarisingagents
Autoimmuneblockadeofreceptorsgivespre-existinglevelofblock
Eaton-LambertSyndrome IncreasedsensitivitytoallNMBs Autoimmunedestructionofvoltage-gatedCa
channelspreventAChvesicleexocytosis
DrugFactors
Drugs Effect Mechanism
FrusemidePotentiatesblockadeatlowdose,reducesblockadeathighdose
Inhibitsproteinkinases(reducingAMP/ATPsynthesis)atlowdose,inhibitsPDEathighdoseswhichincreasesAChrelease
Inhalationalanaesthetics Potentiatesblockade
Stabilisepost-junctionalmembrane,blockadeofpresynapticAChreceptors
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Antibiotics Potentiateblockade Variable.Aminoglycosidesandtetracyclinesprolongblockade
Localanaesthetics Potentiateblockade ReduceAChreleaseandstabilisepost-junctionalmembrane
Anticholinesterases Reducesblockade IncreaseACHlevelsattheNMJbydecreasingbreakdown
OCP Potentiatesdepolarisingblockade Competesforbindingsitesonplasmacholinesterases
Ca -channelblockers Potentiateblockade InhibitCa dependentAChrelease
Lithium Potentiatesblockade AugmentsactionofNMBs
AdditionalFactorsAffectingOnsetofNeuromuscularBlockade
MostofthesecanberelatedtoFick'sLaw:
Factor Effect Mechanism
Potency
Lowpotencydecreasestimetoonset
Bowman'sprinciple:Lesspotentdrugsmustbeadministeredinhigherdoses,andsohaveagreaterconcentrationgradientdrivingdiffusiontotheeffectsite
Dose
Increaseddosedecreasestimetoonset
Greaterconcentrationgradient
CardiacOutput
Highoutputdecreasestimetoonset
Increaseddrugdelivery
Musclegroupflow
Highmuscularflowdecreasestimetoonset
Increaseddrugdelivery
PrimingPrinciple
(May)decreasetimetoonset
A'priming'doseofnon-depolarisingblockeristoanawakepatientgivenpriortoinduction.Thisoccupieslessthan70%ofreceptors,sodoesnotcausesignificantneuromuscularblockade.Afterinduction,aseconddoseisgiventooccupytheremainingreceptorsandcompleteblockade.
References1. SterlingE,WinsteadPS,FahyBG.GuidetoNeuromuscularBlockingAgents.2007.AnesthesiologyNews.2. ICUAdelaide.NeuromuscularBlockers.3. PinoRM.RevisitingthePrimingPrincipleforNeuromuscularBlockers:UsefulnessforRapidSequenceInductions.AustinJ
AnesthesiaandAnalgesia.2014;2(5):1030.4. ANZCAFebruary/April2011
Lastupdated2019-07-18
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BasalMetabolicRateDescribebasalmetabolicrateanditsmeasurement
Outlinethefactorsthatinfluencemetabolicrate
BasalMetabolicRateistheenergyoutputrequiredtosustainlifeatrest.
'Resting'isdefinedasanindividualwhois:Fastedfor12hoursInacomfortableexternalenvironmentAtmentalandphysicalrest
Normalvaluesare:100W.day70kcal.hr
Metabolicrateistheactualenergyconsumptionofanindividual,andisgreaterthanBMRduetoanumberoffactors.
FactorsAffectingMetabolicRateMetabolicRateisaffectedby:
AgeBMRdecreasesasageincreases.
NeonateshaveaBMRtwicethatofanadultChildrenhaveanincreasedBMRrelativetothatofanadultBMRdeclinesby2%foreachdecadeoflife
BodyCompositionLeanmusclehasagreaterenergyrequirementthanfat.
HigherbodyfatpercentageresultsinalowerBMRFemaleshavealowerBMRforthisreason-whenadjustedforleanmassthereisnodifference
DietDigestionincreasesBMRby~10%duetotheenergyrequiredtoassimilatenutrientsThisisknownasthespecificdynamicactionoffood.
Protein>carbohydrate>fatNotethattheSpecificDynamicActionforeachmacromoleculeisnotrelatedtotherespiratoryquotientforthatfoodtype.
StarvationdecreasestheBMRExercise
SkeletalmuscleisthelargestandmostvariablesourceofenergyconsumptionEnvironment
CoolerenvironmentsincreaseBMRTemperateenvironmentsdecreaseBMRupto10%
PhysiologicalstatesPregnancyincreasesBMRupto20%in2ndand3rdtrimesterLactationincreasesBMRCatecholaminesincreaseBMRCorticosteroidsincreaseBMR
DiseasestatesMalignancyincreasesBMR
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SepsisincreasesBMRHyperthyroidismincreasesBMR
MeasurementofBMRusingIndirectCalorimetry
BMRismeasuredusingindirectcalorimetry,whichcalculatesheatproductionviameasurementofVO andVCO .Anumberofmethodsexistsdependingonwhetherthepatientisintubatedornot,orwhethertheyarerequiringsupplementaryoxygen.
Ingeneral:
PatientsshouldberelaxedandfastedFiO needstobecalculated(ortakenfromtheventilatorsettings),andE CO andE O mustbemeasuredSteady-stateshouldbeachievedacrossafiveminuteperiod
TheaverageMVO andMVCO changesby<10%
Therespiratoryquotient( )changeby<5%Thisratiowillvarydependingonthesubstancesmetabolised:
Carbohydrates=1Protein≈0.8Fat≈0.7
RestingEnergyExpenditureisgivenbytheabbreviatedWeirequation:
inWattsperunittimeofmeasurement.
ErrorsinIndirectCalorimetry
AirleaksandmeasurementerrorsMeasuresconsumption(ratherthanrequirements)Pointestimateofadynamicprocess
Footnotes
Therespiratoryquotientisthevalueof atsteady-state,whilsttherespiratoryexchangeratioisaffectedbymetabolicrate.
References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ANZCAFeb/April20063. LITFL-IndirectCalorimetry
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FatMetabolismDescribethephysiologyandbiochemistryoffat,carbohydrateandproteinmetabolism
Digestion
Triglyceridesarethemainconstituentofbodyfatinanimalsandvegetables,andthereforeindietaryfat.Theyconsistofthreefattyacidmoleculesjoinedbyaglycerolmolecule.
Asfatsarenotwatersoluble,theytendtoclumptogetherinchymeandarehardtodigestduetothelowsurfacearea:volumeratio.Emulsificationspeedsupthedigestiveprocess,andoccursviatheactionof:
BilesaltsManybilesaltshaveahydrophobicandahydrophilicend,whichgiveadetergentaction.Bilesaltsboundtofattyacidsformamixedmicellewhichcanbefurtherdigestedbyenzymesordirectlyabsorbed.PartiallydigestedfatsMechanicalactionofthestomach
Onceemulsified,triglyceridescanbehydrolysedbylipaseintofattyacidsandmonoacylglycerol.
Absorption
Absorptionoccursinanumberofstages:
Mixedmicelles,freefattyacids,monoacylglycerol,andcholesterolsareabsorbedviafacilitateddiffusionintotheenterocyteFromtheenterocyte:
Short-chainfattyacids(thosewith<12carbonatoms)entertheportalveinandtraveldirectlytotheliverLong-chainfattyacidsarere-esterifiedandpackagedwithalayerofproteinandcholesteroltoformachylomicronRe-esterificationmaintainstheconcentrationgradientfordiffusionoffattyacids,allowingfurtheruptaketooccur.
ChylomicronsareejectedfromthecellintothelymphaticsandtraveltothesystemiccirculationChylomicronsareremovedfromcirculationbylipoproteinlipaseLipoproteinlipaseisfoundoncapillaryendotheliumandboundtoalbumin.LipoproteinlipasebreaksdowntriglycerideinchylomicronsandVLDLtofreefattyacidsandglycerolThisreactionusesheparinasacofactor.Freefattyacidsandglycerolarethenfreetoenteradiposetissue
StorageFatisstoredastriglycerides,andformsthebulkofenergystorageofthebody.
Triglyceridesaresynthesisedbytheliver:
OccurswheninsulinlevelsarehighandglycogenstoresarefullFromexcesscarbohydrateandaminoacidsTheseareconvertedtofattyacidsandglycerol,andthenesterifiedtoformtriglyceride.Thisisknownaslipogenesis.
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Freefattyacidscanbeabsorbedbyadipocytesforstorage,orbeβ-oxidisedtoacetylCoAintheliver,whichcanenterthecitricacidcycletoproduceATP.
References1. ChaneyS.OverviewofLipidMetabolism.UniversityofNorthCarolinaSchoolofMedicine.2005.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
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CarbohydrateMetabolismDescribethephysiologyandbiochemistryoffat,carbohydrateandproteinmetabolism
Storage
Carbohydratesarestoredinliverandmuscleasglucosepolymersknownasglycogen.
Thelivercontains~100gofglycogenThiscanmaintainplasmaglucosefor~24hours.Skeletalmusclecontains~200gofglycogenThiscannotbereleasedintocirculation,andisforuseonlybythemuscle.
Productionofglycogenisstimulatedbyinsulin,whichisreleasedasplasmaglucoselevelsrisefollowingcarbohydrateingestion.Whenplasmaglucoselevelsfall,thereleaseofglucagonandadrenalinestimulatesglycogenolysis.
GlycolysisGlycolysis:
DescribestheprocessofconvertingglucoseintopyruvateThisisknownastheEmbden-Meyerhofpathway.OccursinthecytoplasmDoesnotconsumeoxygenorproducecarbondioxideProduces2ATPGlycolysisallowsproductionofATPinanaerobicconditions.
Gluconeogenesis
Gluconeogenesisistheproductionofglucosefromothermolecules.Gluconeogenesis:
RequiresATPtoperformSomeorgans(heart,brain)relyonglucoseforATPHasmanypotentialsubstrates:
LactatePyruvateGlycerolAminoacidsCAC-intermediates
IsstimulatedbyglucagonIsinhibitedbybiguanides(metformin)
References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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ProteinMetabolismDescribethephysiologyandbiochemistryoffat,carbohydrateandproteinmetabolism
Essentialaminoacidscannotbeproducedbytransamination-theymustbesuppliedinthediet.
Metabolism
Proteincatabolisminvolvesthedeaminationofaminoacids.Deaminationcanoccurinoneoftwoways:
OxidativedeaminationHepaticdeamination,removingtheaminogrouptocreateaketoacidandammonia.Ammoniaproducedintheliverenterstheureacycleandbecomesurea,whichrequires3ATP.TransaminationAminogroupistransferredbyaminotransferasestoanotheraminoacidoraketoacidtoproduce:
Ketoacids,which:EnterthecitricacidcycleandproduceATPGetconvertedtoglucoseorfattyacids
AminogroupsEntertheureacycleandbecomeurea
FootnotesAmmoniacanalsobeproducedinthekidneybythedeaminationofglutamateinthekidney.Inthisinstance:
ItiseliminateddirectlyinurineasammoniumDoesnotentertheureacycle
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References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
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RequirementsandStarvationDescribethenormalnutritionalrequirements
Fasting
Fastingisthemetabolicstateachievedaftercompletedigestionandabsorptionofameal.
Fastingcanbedividedinto:
EarlyfastingLessthan24hours.
PlasmaglucosefallsduetoconsumptionLeadstohormonalchanges:
Insulinreleasedecreases,causing:Liver
DecreasedglycogenesisIncreasedgluconeogenesis
MuscleDecreasedglucoseutilisationDecreasedglycogenesisDecreasedproteinsynthesis
FatDecreasedlipogenesisDueto:
DecreasedglucoseuptakeDecreasedTGuptake
IncreasedlipolysisAdrenalinereleaseincreases,causing:
DecreasedinsulinreleaseIncreasedlipolysisIncreasedmuscleFFAuseIncreasedhepaticglycogenolysisandgluconeogenesis
GlucagonreleaseincreasesCellularmetabolismalters:
Decreasedglucoseuptakebynon-obligateglucoseconsumerse.g.Muscle.IncreasedFFAandketonebodyuseβ-oxidationofFFAstomeetATPrequirements,leadingtoformationofketonebody.
SustainedfastingGreaterthan24hours.Seestarvationbelow.
Starvation
Starvationisthefailuretoabsorbsufficientcaloriestosustainnormalbodyfunction,requiringthebodytosurviveonendogenousstores.
Days:
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EnergyisconservedthroughreductioninmovementHormonalchanges
Increasedgluconeogenesis,usingglycerol,lactate,andaminoacidsInsulinconcentrationsfallfurtherCortisollevelsincreaseGlucagonlevelspeakat4days
MetabolicchangesGlucoseusecontinuestofall,andFFAuseincreasesFurtherfallinmuscleproteinsynthesis
Weeks:Tissuesadapttometaboliseketones(withplasmalevelsrisingupto7mmol.L ,andgluconeogenesisfalls
Thebrainstillrequires100gofglucoseperdayBMRfallsAllbutlife-savingmovementceasesDeathtypicallyoccursafter30-60days,whenmusclecatabolismweakenstherespiratorymusclessuchthatsecretionscannolongerbecleared,andpneumoniaoccurs
RefeedingSyndrome
Refeedingsyndromeisaderangedmetabolicstatethatoccurswithfeedingafteraperiodofprolongedfasting,typically>5days.
Therearethreepathogenicmechanisms:
Alargespikeininsulincausesincreasedcellularuptake(andlowplasmalevels)of:GlucoseMagnesiumPhosphatePotassium
Sodiumandwaterretentionoccurs,whichmayprecipitatecardiacfailureIncreasedcarbondioxideproductionincreasesminuteventilationandworkofexhaustedrespiratorymuscles
Managementisbyslowinstitutionoffeedingandaggressiveelectrolytemanagement.
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. ANZCAAugust/September2001
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AnaerobicMetabolismDescribetheconsequencesofanaerobicmetabolismandketoneproduction
Lactate
TheEmbden-Meyerhofpathway:
Describestheconversionofglucosetopyruvate(andtwoATP)DoesnotconsumeO orproduceCOThereforeitoccursinbothanaerobicandaerobicconditions.ConsumestwoNAD andproducestwoNADH
Inanaerobicconditions(intheerythrocyte,andinthesettingofcellularhypoxia):
ThereisnooxygenavailabletoallowfurtherATPproductionviatheelectrontransportchainThereisalsonoregenerationofNAD intheETC.Inorderforglycolysistocontinue,NAD isregeneratedviaproductionoflactate
About1400mmoloflactateisproducedperday.Lactateiseither:
OxidisedinthecellThisrequiresrestorationofNAD ,e.g.resolutionofcellularhypoxia.CirculatedtotheliverLactateisthen:
OxidisedtopyruvateConvertedtoglucoseThisprocessisknownastheCoricycle.
Ketones
Ketones:
β-oxidationoffattyacidsintheliverproducesacetyl-CoAAcetyl-CoAusuallyentersthecitricacidcycletoproduceATPWhenlargeamountsofacetylCoAareproduced,theymayinsteadcondensetoformacetoacetate,whichcanthenbereducedtoβ-hydroxybutyrateThesesubstancesareknownasketones
Ketonescanonlybeproducedbytheliver,andonlyusedasasubstratebythekidney,aswellasskeletalandcardiacmuscle
Productionofketonesisacceleratedbyglucagonandadrenaline
References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ANZCAAugust/September2011
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RegulationofBodyTemperatureOutlinethemechanismsforheattransferbetweenthebodyanditsenvironment.
Definethethermoneutralzone,anddescribethemechanismsbywhichnormalbodytemperatureismaintained.
Regulationofbodytemperatureisdonebybalancingheatlossandheatproduction,predominantlythroughbehaviouralmechanismsandskinThebodyisabletomaintainarelativelyconstantcoretemperatureunderawiderangeofenvironmentalconditions
Thethermoneutralzoneistherangeacrosswhichthebasalrateheatproduction(andoxygenconsumption)isbalancedbytherateofheatloss
Foranadultitistypically27-31°CInneonatesitishigher,typically32-34°C.
PrinciplesNetfluxofheatisdeterminedbythebalanceofmetabolicheatproductionandthecontributionoffourmechanismsofheatloss:
RadiationConductionConvectionEvaporation
Radiative
Radiativeheatexchange:
DescribesthelossofheatthroughEMRbyallobjectsabove0°KRadiativeheatlossisproportionaltotemperatureRadiativeheatlossdoesnotrequireatransfermedium
Makesup~45%ofheatlossunderthermoneutralconditions.Dependsonthetemperaturedifferentialbetweenanindividualandtheirenvironment
Acoldenvironment(e.g.operatingtheatre)causesalargeradiantheatlossTheheatlossfromthepatientisgreaterthantheheatgainfromthesurroundingenvironment.
Conduction
Conductionisthetransferofheat(askineticenergy)bydirectcontactfromahighertemperatureobjecttothelowertemperatureone.Conduction:
RequiresphysicalcontactbetweenbodiestoconductheatSolidsconductheatbetterthangasesThereisnoconductioninavacuum
HeatlossviaconductionisminimalinairbutisamajorcauseofheatlossinimmersionAsarteriesandveinstypicallyrunnexttoeachother,arterialheattendstobetransferredtothe(cooler)veins,limitingfurtherheatlossThisissimilartocounter-currentexchangeinthekidney.
Asfatisapoorerconductorofheatthanmuscle,increasedbodyfatwillslowheatlossbyconduction
Convection
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Convectionislossofheatbyconductionbyamovingobject.Convectionis:
ThepredominantmechanismofheatlossinthenakedhumanEffectsaregreatereffectsathigherwindspeeds.
Evaporation
Evaporativelossesdescribethelossofheatenergyduetothelatentheatofvapourisationofwater.Evaporationof100mlofwaterwillreducebodytemperatureby~1°C.
TemperatureSensationandRegulation
Temperaturesensorsarecentralandperipheral,whilstregulationoccurscentrally.
CentralSensation
Centraltemperaturesensorsexistinthe:
AbdominalvisceraSpinalcordHypothalamusAnteriorhypothalamusisthemostimportantcentralthermoreceptor,andrespondstobothincreasedanddecreasedtemperaturesbyalteringtheirrateofdepolarisation,elicitinganarrayofneuronalandhormonalresponses.Brainstem
Theinter-thresholdrangeistherangeofcoretemperaturesnottriggeringaresponse.
Normalis0.2to0.4°C.Widensunderanaesthesiato~4°C
PeripheralSensation
Peripheraltemperaturesensorsare:
FreenerveendingsExtremelysensitiveAltertheirratesoffiringbyordersofmagnitudeinresponsetotemperaturechange.Dividedinto:
ColdreceptorsLiebeneaththeepidermis,andareexcitedbycooling(inhibitedbywarming),activefrom10-40°C,withastaticmaximaat25°C.WarmreceptorsLiedeeptothedermis,areexcitedbywarming(andinhibitedbycooling),activefrom30-50°C,withastaticmaximaat44°C.
Regulation
Temperaturesensationrunsfromcutaneousreceptorsviathespinothalamictractsandmedullatothehypothalamus.Corticalinputisreceivedviathethalamocorticalrelay,whilstprimitiveresponsesareeffectedviathemidbrain.
EffectorResponses
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Increaseheatloss Reduceheatloss/Increaseheatgain
CNS Removeclothing,sprawl,reduceactivity. Huddle,seekshelter,addclothing
Cardiovascular IncreaseperipheralvasodilationandAVshunting,andcardiacoutputtoimproveflowtocutaneoustissues
Vasoconstriction,peripheralcirculatoryshutdown
Musculocutaneous Sweating Piloerection,Shivering
Metabolic IncreasedBMR,non-shiveringthermogenesis
Vascularchangesaretheleastmetabolicallycostlyandcanresultindramaticincreases(upto60%ofcardiacoutput)inskinbloodflowWhenenvironmentaltemperatureexceedsbodytemperature,conductionandconvectionresultinheatgain-evaporativecoolingviasweatingistheonlywaytoreducebodytemperatureEfficacyofsweatingisrelatedtorelativehumidity
Piloerection(hairstandingonend)trapsalayerofwarmairclosetothebodytoactasaninsulatorThisisofmoreimportanceinotherprimatesthaninman,astheyhaveenoughbodyhairtomakeiteffective.
Increasingbasalmetabolicrateand'waste'heatproductionisessentialtomaintaintemperatureincoldenvironments.Thiscanbethrough:
ShiveringThesimultaneouscontractionofagonisticandantagonisticmuscles.Non-shiveringthermogenesis:
HormonalLevelsofthyroidhormoneandadrenalineincrease,raisingmetabolicrateinallcellsBrownfatBrownfatproducesheatthroughuncoupledoxidativephosphorylation,whichusestheelectrontransportchaintoproduceheatratherthanATP.Brownfatis:
Avitalmechanismforheatproductionintheneonate(theyhaveanimmatureshiveringresponse),andforms~5%ofneonatalmassLocatedin:
NeckSupraclavicularInterscapularSuprarenal
SympatheticallyinnervatedContainslargenumbersofβ receptors
EffectofAnaesthesia
Generalanaesthesiacausesa1-3°Cdropincorebodytemperature,whichoccursinthreephases:
RapidreductionCoretemperaturefallsby1-1.5°Cinthefirst30minutes.
Predominantlyduetovasodilation,whichisdueto:ReductioninSVR,withgeneralisedvasodilationandincreasedskinbloodflowHeatredistributionisthemajorinitialfactor(ratherthanheatloss),asvasodilationleadstoincreasedheatcontentofperipheries.ImpairsthermoregulatoryvasoconstrictiveresponsesInter-thresholdrangeiswidenedto4°C(upfrom0.4°C)
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GradualreductionFurtherdropincoretemperatureof1°Coverfollowing2-3hours.
DuetoheatlossexceedingheatproductionNon-shiveringthermogenesisistheonlyresponseavailabletoparalysed,anaesthetisedpatient.
PlateauOncecorebodytemperaturefallsfarenough,thermoregulatoryresponsesareactivatedandfurtherheatlossisattenuatedbyincreasedmetabolicheatproduction.
Neuraxialanaesthesia:
HypothermiaislessextremeasthermoregulationisonlyaffectedinareascoveredbytheblockadePlateaudoesnotoccurasvasoconstrictiveresponsesareinhibitedbytheblockade
References
1. Auerbach.WildernessMedicine.SixthEdition.Chapter4:Thermoregulation.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.3. DiazA.Define"thermoneutralzone".Brieflyexplainhowthebodyregulatestemperaturewhentheambienttemperature
exceedsthethermoneutralzone.PrimarySAQs.4. BuggyDJ,CrossleyAW.Thermoregulation,mildperioperativehypothermiaandpostanaestheticshivering.BrJAnaesth.
2000May;84(5):615-28.
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InflammationDescribethefactorsinvolvedintheprocessofinflammationandtheimmuneresponse,includinginnateandacquiredimmunity
Inflammationisanon-specificresponsetriggeredbyapathogenortissueinjury,whichaimstolimitfurthertissuedamage.
Inflammationisclassicallycharacterisedby:
PainHeatRednessSwellingLossoffunction
Thisisaconsequenceof:
VasodilationIncreasesbloodflowtoarea,whichincreasessupplyofimmunecellsandresourcesforcellularrepair.IncreasedvascularpermeabilityIncreasesextravasationofproteinandimmunecells.MigrationofphagocytesRemovepathogensandcellulardebris.
ProcessofInflammation
TissuedamageTraumacausesmechanicaldisruptionofvasculatureandmastcelldegranulation,causinglocalinflammationandactivationofhaemostaticmechanismsInfectionstimulatesdegranulationoflocalmacrophages,releasinginflammatorycytokinesandtriggeringmastcelldegranulation
LocalinflammatoryresponseHistaminecausesarteriolarandpost-capillaryvenuledilatationandsubsequentextravasationReleaseofchemotacticmoleculesattractscirculatinginflammatorycells
SystemicinflammatoryresponseSevereinflammationmayleadtocytokinesinthesystemiccirculation,causing:
FeverNeutrophilrecruitmentfrombonemarrowReleaseofacute-phaseproteinsfromliver
References1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2018-09-21
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InnateImmunityDescribethefactorsinvolvedintheprocessofinflammationandtheimmuneresponse,includinginnateandacquiredimmunity
Theinnateimmunesystemconsistsofprotectivemechanismswhicharepresentlife-long,andtypicallyformsthefirstlineofdefenceagainstpathogens.
Keyfeaturesofinnateimmunityinclude:
ImmediacyNon-specificresponseNotmodifiedbyrepeatexposures
Theinnateimmunesystemconsistsofthreecomponents:
PhysicochemicalbarriersHumoralmechanismsCellularMechanisms
PhysicochemicalBarriers
Theseinclude:
SkinMucousmembranes
MucousMucociliaryelevator
GastricacidUrinationOptimisedbyhighflowratesandlowresidualbladdervolumes.
InnateHumoralMechanisms
Humoralmechanismsdescribestheroleofinflammatoryproteinsininnateimmunity:
ComplementThecomplementsystemisacomplexgroupofabout25plasmaproteinsimportantinbothinnateandadaptiveimmunity.
Thecomplementsystemisactivatedby:Antigen-antibodycomplexesThe'classicalpathway.'SubstancesinthebacteriacellwallThe'alternativepathway.'
Complementhasanumberofinflammatoryfunctions:DestructionofbacteriaSeveralcomplementproteinscometogethertoformamembraneattackcomplex,whichcreateslargeporesincellmembranes,causingwatertodiffuseinandbacteriatoburst.OpsonisationofbacteriaBoundcomplementactsasabindingsiteforphagocytes.ActivationofmonocytesandphagocytesChemotaxis
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Attractsleucocytes.MastcelldegranulationAugmentsinflammation.
Acute-PhaseProteinsInflammatoryproteinswithanumberofeffects:
OpsonisationInflammatorymediatorsIncreasebloodflowanddeliveryofinflammatorycellsviathreemechanisms:
DilatationandincreasedcapillarypermeabilityEndothelialactivationincreasingleukocyteadhesionAttractionofneutrophilsandmonocytes
ProteolyticenzymesBactericidalenzymeslocatedinsaliva,tears,respiratorymucous,andneutrophils.
InnateCellularMechanismsCellularcomponentsoftheinnateimmunesysteminclude:
MastcellsExistinlooseconnectivetissueandmucosa,andcontainmanyintracellulargranulesofheparinandhistamine.
LeukocytesNeutrophils(60%ofallleukocytes)Phagocytosebacteriaandfungi(15-20perneutrophil).Thisprocessconsistsofanumberofsteps:
ExitcirculationbymarginatingalongcapillaryborderwhenactivatedMigrateviachemotaxistowardsthetissueinsultPhagocytoseopsonisedbacteriaandfungiKillorganismswitharespiratoryburst:Agranulecontaininghydrogenperoxide,hydroxylandoxygenradicalsfuseswiththetargetcellmembrane,destroyingboththetargetandtheneutrophil.
MonocytesBecomemacrophageswhentheyleavecirculationandentertissue.Macrophageshavealifespanof2-4months,andcanphagocytoseupto100bacteriabeforeitdies.Functionsinclude:
PhagocytosisanddestructionofpathogenEspeciallyintracellularpathogens(listeria,mycobacteria),parasites,andfungi.BreakdownofdamagedbodycellsPresentantigentoT-helpercellsSecretionofinflammatorymediators
EosinophilsKillmulticellularparasites.BasophilsContainheparinandhistamine.LymphocyteSubtypeofleukocyteimportantinadaptiveimmunity.Include:
NaturalKillercellsActiveagainstviralandtumourcells.BcellsTcells
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References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
Lastupdated2019-07-18
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AdaptiveImmunityDescribethefactorsinvolvedintheprocessofinflammationandtheimmuneresponse,includinginnateandacquiredimmunity
Theadaptiveimmunesystemrespondstoanexposure,demonstratingspecificityandmemory,withimprovedefficacyonrepeatexposure.
Adaptiveimmunitymaybe:
ActivePrimaryimmuneresponsegeneratedbyexposuretoantigen.
InfectionVaccinationAninactive(butstillforeignandthereforeantigenic)proteincomponentofapathogenisgiventothepatient,resultinginanimmuneresponse.Subsequentexposuretothewholepathogentriggersasecondaryimmuneresponse.
PassivePreformedantibodyisgiventothepatient.Thiswillprovidetreatment/coverageforthelifeoftheantibody,butimmunitywillbelostwhentheantibodybreaksdownorsuppliesareexhausted.
TransplacentalColostrumAdministrationofserum
Componentsoftheactiveimmunesysteminclude:
CellularPredominantlyTlymphocytesHumoralIncludingcomplementandantibody.
AdaptiveCellularImmunity
Lymphocytesaredividedintotwotypes:
BlymphocytesAreproducedinthebonemarrow,andmigratetolymphoid(nodes,spleen,MALT)wheretheyarerenamedplasmacellsandproduceantibody.Functionsinclude:
ProductionofantibodyagainstspecificantigensPresentationofantigentoT-cellstoactivethemProliferationtoformmemorycells
TlymphocytesAreproducedinthebonemarrowandmigratetothethymuswheretheymature.Tcellswhichexpressantibodytohostproteinapoptose,resultinginonly2%ofimmatureTcellssurviving.MatureTcellsthenspreadtolymphoidtissue.TherearefivetypesofTcells,ofwhichtwoaremostimportant:
HelperT-cells2/3 ofT-cellsarehelpercells,areareidentifiedbytheirCD4membraneprotein.Functionsinclude:
CytokineproductionBlymphocytestimulationMacrophageactivation
CytotoxicT-cells
rds
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AreidentifiedbytheirCD8membraneprotein.Functionsinclude:DestructionofvirallyinfectedandtumourcellsAllcellsexpressproteinsthattheyareproducingonmembraneMHCImolecules,forinspectionbyimmunecells.Infectedortumourcellswillexpressforeignproteins,andcauseactivationofcytotoxicTcells:
InduceapoptosisinthetargetcellRapiddivisionofcytotoxicTcell,whichtheninspectsothercellsforinfection
Transformationtomemorycells
AdaptiveHumoralImmunity
AntibodiesY-shapedimmunoglobulinswhich:
AreproducedinresponsetoapathogenArespecifictothatpathogen
Antibodyfunctionsinclude:
OpsonisationAgglutinationEachantibodycanbindmultiplepathogens,increasingtargetsizeforleukocytes.InactivationofpathogenAntibodybindingmaydisablethepathogen.ActivationofcomplementAntibody-antigencomplexescausecomplementactivation.
PrimaryImmuneResponse
Theprocessofinvasionofanewpathogentoantibodyproductiontakes~5days,andoccursinanumberofsteps:
APCphagocytoseapathogenAPCsincludemacrophagesanddendriticcells.APCexpressantigen(bitsofpathogen)oncellsurfaceAPCtraveltolymphoidtissueandpresentittoBandTcellsWhenanAPCfindsaBandTcellwithareciprocalantibody:
ThelpercellbecomesactivatedbyAPCThelpercellrapidlyproliferates('clonalexpansion')
ProportionbecomememorycellsBcellsareactivatedbyboththeAPCandaT-helpercell(requiresboth)Bcellsrapidlyproliferate
ProportionbecomememorycellsProportionbecomeplasmacells
Plasmacellsproduceantibodyatarateof2000moleculespersecond,whichoverridesnormalcellularhomeostasis,causingdeathwithinaweek.AntibodyproducedinaprimaryimmuneresponseisIgM,withsomeIgGproducedlateron.
SecondaryImmuneResponse
Repeatinvasionbythesamepathogenismetwithamuchmorerapidandaggressiveimmuneresponse:
APCsphagocytoseapathogenAPCsexpressandpresentantigenMemoryTandMemoryBcellsformedduringtheprimaryresponseareactivated,andbeginrapidlydividingandproducingantibody
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References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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HypersensitivityExplaintheimmunologicalbasisandpathophysiologicaleffectsofhypersensitivity,includinganaphylaxis.
Understandthepharmacologyofthedrugsusedinthetreatmentofanaphylaxis.
Hypersensitivityreactionsareexaggeratedimmuneresponsesthatcausehostinjury.
ClassificationofHypersensitivityReactionsTheGelandCoombssystemclassifieshypersensitivityreactionsbythemechanism.Itiscommonlyusedbutfailstoclassifymorecomplexdiseases.
Type Timing Mediator Pathophysiology Diseaseexample(s)
TypeI-Immediatehypersensitivity
Secondstominutes
IgE BasophilandmastcelldegranulationAnaphylaxis(systemic),Atopy(local)
TypeII-Cellularhypersensitivity
5-8hours IgM,IgG
Antibodybindingtocellsurfaceantigen,resultingincelldeathviacomplementmembraneattackcomplexes,orphagocytosisbymacrophages
Transfusionreactions,hyperacuteallograftrejection
TypeIII-Immune-complexdeposition
2-8hours
IgM,IgG,IgA
TissuedepositionofAb-Agcomplexes.AccumulationofPMNs,macrophages,andcomplement.
SLE,necrotisingvasculitis,post-StrepGN
TypeIV-Delayedhypersensitivity
24-72hours T-cell T-cellinducedmononuclearcellaccumulation.
Releaseofmonokinesandlymphokines.
TB,Wegener'sGranulomatosis,Granulomatousvasculitis
TypeIHypersensitivity
AntigensimulatesaBlymphocytetoproduceaspecificIgEagainstitThisIgEthenbindstoFcreceptorsonmastcells,sensitisingthemtothisexposureOnre-exposuretheantigenbinds(cross-links)IgEonmastcells,causingdegranulation:
Histamine,leukotrienes,andprostaglandinsarereleasedThismaycauselocalorsystemiceffects,dependingonmethodofexposure:
Asystemicreactioniscalledanaphylaxis,andmanifestsasacombinationof:HypotensionBronchospasmLaryngealoedemaRashes
Localreactionsdependontherouteofexposure,andincludeAsthmaInhaled.AllergicrhinitisNasopharyngealmucosa.
Non-immuneanaphylaxis(alsoknownasanaphylactoid)reactionsarecharacterisedbyaimmediategeneralisedreactionclinicallyindistinguishablefromtrueanaphylaxis,buttheimmunenatureisunknown,ornotduetoatypeIhypersensitivity
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reaction
ManagementofAnaphylaxis
Adrenalineisthedrugofchoice,asittreatscardiovascularcollapse,bronchospasm,anddecreasesoedemaformation.Inadults,0.3-0.5mgIMQ5-15minInchildren,0.01mg/kgIMQ5-15min
Glucagonmaybeusedinβ-blockedpatientsresistanttoadrenaline.Inadults,1-5mgIVover5minutes,followedbyinfusionat5-15microg/minInchildren,20-30mcg/kgupto1mgover5minutes
Non-pharmacologicalmanagementincludesearlyintubationtoprotectagainstairwayobstructionduetoangioedema.Adjunctsincludeantihistaminesandsteroids.Theyaresecondlineastheydonotattenuatecardiovascularcollapse,resolveairwayobstruction,orhavestrongevidencebehindtheiruse.Theyinclude:
Diphenhydramine25-50mgIV(Children:1mg/kgupto40mg)upto200mgin24/24Salbutamol,forbronchodilationMethylprednisolone1-2mg/kg,ostensiblytoprotectagainstreboundanaphylaxis(thoughthereisminimalevidence)
TypeIIHypersensitivity
AntibodiesbindtocellsurfaceantigenAntibody-AntigencomplexactivatescomplementComplementgeneratesaninflammatoryresponseCelldeathoccursvia:
ComplementmembraneattackcomplexPhagocytosis
Clinicalpicturedependsonaffectedorgans.Examplesinclude:
HyperacuteallograftrejectionTransfusionreactionsandhaemolyticdiseaseofthenewbornGoodpasture'ssyndromeAutoimmunecytopaeniasMyastheniaGravis
TypeIIIHypersensitivity
Immune-complexreactionwhereAb-AgcomplexesareformedanddepositedintissuesSubsequentcomplementactivationcausesinflammationandneutrophilsactivation,leadingtotissuedamageTherearetwosubtypesoftypeIIIreactions:
Formationofcomplexesincirculationandsubsequentdepositionintissuese.g.Serumsickness
FormationofcomplexesintissuesSmallamountsaretypicallyremovedbythereticuloendothelialsystem,butinthiscasetherearetoomany,ortheyaretoosmall,tobeclearedeffectively.
e.g.TheArthusreaction(alocalisedvasculitis,whichmaybenecrotising)
TypeIVHypersensitivity
AntigenispresentedtoTlymphocyteswhichproliferateandbecomesensitisedT-cellsthenreleasecytokines,attractingmacrophagesandleadingtolocalinflammationDuringprolongedexposure,macrophagesmayfusetoformgiantcellsandformagranuloma.Examplesinclude:TB
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Granulomatousvasculitis
References
1. CICMJuly/September20072. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
Lastupdated2019-07-18
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ClassificationofMicroorganismsDescribetheclassificationofmicro-organisms,includingviruses,bacteria,protozoaandfungi
Microorganismscanbeclassifiedasprokaryotes(bacteria),viruses,oreukaryotes(whichincludefungi,helminths,andprotozoa).
Bacteria
BacteriaareprokaryoticorganismsMostclinicallyrelevantbacteriacanbeclassifiedbyGramstainandshape
GramstainseparatesbacteriaaccordingtotheircellwallcompositionItcannotbeusedonorganismsthatlackacellwall,suchasmycoplasma.
Acrystalvioletfollowedbyaniodinesolutionisappliedtotheslide,whichisthenwashedwithasolventGram+veorganismswillretainthestainduetotheirthickpeptidoglycancellwall,whilstgramnegativeorganismsbecomecolourless
Asafraninpinkstainisthenapplied,whichstainsthegram-vebacteriapinkBacteriacanalsobeclassifiedbyshapeinto:
CocciAppearroundonmicroscopy.Rods
Combiningofthesetwosystemsclassifiesalargeproportionofmicrobes:
Examples: GramPositive GramNegative
Cocci StaphylococcusAureus,StreptococcusPneumoniae N.Meningitidis,N.Gonorrhoea
Rods Listeria,Clostridiumdifficile EscherichiaColi,Pseudomonasaeruginosa
BacterialSubclassification
Additionaltestingcanbedonetofurtherclassifybacteria:
CatalasetestingisperformedonGrampositivecocciHydrogenperoxideisaddedtoabacterialsample,andinthepresenceofcatalasewillproduceoxygen.
CatalasepositiveindicatesStaphylococciCatalasenegativeindicatesStreptococci(andenterococci)
CoagulasetestingisperformedonStaphylococcalspeciesCoagulaseisanenzymewhichcleavesfibrinogentofibrin.Thestaphylococcalcolonyisaddedtorabbitplasmaandincubated.Inthepresenceofcoagulase,fibrinisformed.
CoagulasepositivestronglysuggestsS.AureusCoagulasenegativeexamplesincludeS.epidermidisorS.saprophyticus
HaemolytictestingisperformedonStreptococcalspeciesBacterialcoloniesareaddedtobloodagar,andthecolourchange(duetohaemolysis)isnoted.
αhaemolyticorganismsproducedarkgreenagar,asmethaemoglobinisproducedbyhydrogenperoxideproducedbytheseorganisms.Examplesinclude:
Strep.pneumoniaeStrep.viridans
β-haemolyticorganismsproduceyellowagarfromcompletehaemolysis.Examplesinclude:
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Strep.pyogenesStrep.agalactiae
γ-haemolyticorganismsleavetheagarunchanged.Examplesinclude:E.faecalisE.faecium
Additionally,gramnegativerodsshouldbefurtherclassifiedintopseudomonalandnon-pseudomonalorganisms
Viruses
VirusesconsistofmoleculesofeitherDNAorRNAshieldedinaproteincoat.Theyrequiretheuseofhostcellstructuresforreproductionandarethereforeobligateintracellularparasites.Theycanbeclassifiedbyfiveproperties:
1. DNA/RNADNAvirusesreplicateinthecellnucleususingahostpolymerase.
2. Double-strandedorsingle-strandedi. MostDNAvirusesaredouble-stranded(dsDNA)ii. MostRNAvirusesaresingle-stranded(ssRNA)
3. Negative-senseorpositive-sense(RNAvirusesonly)i. Positive-sensegenomesmaybetranslateddirectlyintomRNAii. Negative-sensegenomesrequireanRNA-dependentRNApolymerasetotranslatethemtoapositive-sensestrandprior
totranslation.4. CapsidSymmetry
Theproteincoatmaybeeithericosahedralorhelical5. Envelopedornon-enveloped
Inadditiontoaproteincoat,virusesmayhavealipidmembrane(acquiredfromthehostcell)aroundtheirproteincoat.
EukaryoticOrganismsEukaryoticorganismsincludefungi,protozoa,andhelminths,aswellasplantsandanimals.Theydifferfromprokaryoticorganismsinanumberofways:
Property Prokaryotes Eukaryotes
Chromosomes Single,circular Multiple
NucleusandOrganelles None Membraneboundnucleusandorganelles
Cellwall Usually Inplants
Ribosome 70S 80Sincell,70Sinorganelles
Size 0.2-2mm 10-100mmm
Fungitypicallyfeedondead/decomposing/theimmunocompromisedandproducespores.Theyaresubclassifiedinto:YeastsYeastsareunicellular.Theyaredividedinto:
CandidaAlbicansNon-albicansMoredifficulttotreat.
CryptococcusMouldsMouldsarearefilamentous.
Aspergillus
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PenicilliumDimorphousHavecharacteristicsofbothyeastsandmoulds.
Histoplasma
Protozoaareparasiticsingle-celledeukaryotes.Theycanbeintracellularorextracellular.
Helminthsareparasiticmulti-celledeukaryotes.Theycanbeintracellularorextracellular.Theyaresubdividedintotapeworms(cestodes),flukes(trematodes),androundworms(nematodes).
Footnotes.Thisclassificationdoesnotcapturespirochetes,mycoplasmas,chlamydias,andotherlesscommonlyencounteredorganisms.Amorecompleteclassificationusessixproperties:↩
1. CellWallStructurei. Flexible(e.g.Spirochetes)ii. Rigidiii. Non-existent(e.g.Mycoplasmaspp.)
2. Morphologyi. Unicellularii. Filamentous
3. GrowthLocationi. Extracellularii. Obligateintracellularparasites(e.g.Chlamydiaspp.)
4. GramStaini. Grampositiveii. Gramnegative
5. Shapei. Cocciii. Rods
6. O tolerancei. Aerobesii. Anaerobes(e.g.Clostridiumspp.)
References1. HarveyRA,CornelissenCN,FisherBD.LippincottIllustratedReviews:Microbiology(LippincottIllustratedReviews
Series).3rdEd.LWW.2. CICMSeptember/November2008
Lastupdated2019-07-20
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AntimicrobialResistanceDescribetheprinciplesofanti-microbialresistance
Resistanceoccurswhenthemaximalleveloftheagenttoleratedisinsufficienttoinhibitgrowth.
Resistancecanoccurbroadlyviatwomechanisms:
GeneticAlterationSpontaneously,throughmutationandsubsequentnaturalselectionofresistantorganismsTransferalofresistancegenesfromorganismtoorganismviaplasmids
ProteinExpressionIncreasingordecreasingexpressionofproteinswithsubsequentchangeinefficacyofantimicrobials.
MechanismsSpecificmechanismsofresistance(whichmaybegeneticalterationsorchangesinproteinexpression)include:
PreventaccesstotargetDecreasepermeability
Narrowingofporinchannelse.g.StreptococcalresistancetopenicillinstypicallyoccursbyreducingaccesstoPBPs.Lossofnon-essentialtransporterchannelse.g.Anaerobeshavenooxygen-transportchannelwhichpreventspenetrationbyaminoglycosides.
ActiveeffluxofagentIncreasedefficiencyorexpressionofeffluxpumps.Canbe:
RemovedfromcellTrappedbetweencellwalllayerse.g.GlycopeptideresistanceinVRSA.
AlterantibiotictargetsiteChangesinbindingsiteproteinwillincreaseresistancetoagentswithlowaffinityOver-expressionoftargetproteinSynthesisoftarget-protectingproteins
ModificationorInactivationofDrugMetabolismofdruge.g.β-lactamaseshydrolyseβ-lactamrings
ModificationofMetabolicPathwaysDevelopmentofmetabolicpathwaystobypasssiteofactionofantibiotice.g.ResistancetoTrimethoprim-Sulfamethoxazolebyallowingbacteriatosynthesisorabsorbfolicacid.
References
1. HarveyRA,CornelissenCN,FisherBD.LippincottIllustratedReviews:Microbiology(LippincottIllustratedReviewsSeries).3rdEd.LWW.
2. CICMSeptember/November20083. BlairJM,WebberMA,BaylayAJ,OgboluDO,PiddockLJ.Molecularmechanismsofantibioticresistance.NatRev
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Microbiol.2015Jan;13(1):42-51.doi:10.1038/nrmicro3380.4. Microrao-MechanismsofAntimicrobialResistance
Lastupdated2019-07-18
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AntisepticsOutlinethepharmacologyofantisepticsanddisinfectants
KeyDefinitions
Relevantdefinitionsforantisepticsinclude:
CleaningPhysicalremovalofforeignmaterial.
Usedfornon-criticalitems,whichcomeintocontactwithhealthyskinbutnotmucousmembranes(e.g.bloodpressurecuff)
DecontaminationDestructionofcontaminantssuchthattheycannotreachasusceptiblesiteinsufficientnumbertocauseharm.DisinfectionEliminationofallpathologicalorganisms,excludingspores.
Usedforsemi-criticalitems,whicharethosethatcontactmucousmembranesbutdonotbreakthebloodbarrier(e.g.endoscopes,laryngoscopes)
SterilisationEliminationofallformsofmicrobiallife,includingspores.
Usedforcriticalitems,whicharethosethatentersterileorvasculartissueandposeahighriskofinfection(e.g.surgicalinstruments,vascularandurinarycatheters)
AntisepticAgents
Drug IsopropylAlcohol Chlorhexidine Povidoneiodine
PharmaceuticsTypically60-90%-requiressomewatertodenatureprotein.Flammable.
Maybeaqueousorcombinedwithisopropylalcohol.
Iodinecombinedwithapolymer(povidone)toenhancewatersolubility
AntiviralProperties Poorantiviral Poorantiviral Goodantiviral
AntibacterialProperties Broadspectrumantibacterial
Broadspectrumantibacterialandantifungal
Broadspectrumincludingfungi,spores(unlikeiodine),andtuberculosis
Toxic Irritantonmucousmembranesandopenwounds Hypersensitivity Hypersensitivity
Other Persistentantisepticeffect
Requirescontinualreleaseofiodinetoachieveeffect.Inactivatedbyorganicsubstances.Stains.
References
1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.2. SabirN,RamachandraV.Decontaminationofanaestheticequipment.ContinuingEducationinAnaesthesia,CriticalCareand
Pain.(2004).4(4),103–106.
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RespiratoryChangesofPregnancyExplainthephysiologicalchangesduringpregnancy,andparturition
Respiratorychangesinpregnancyareafunctionoftwothings:
AnatomicalcompressionofthechestIncreasedVO andVCO
AnatomicalChangesDiaphragmpushedupwardsby~4cmIncreasedAPandtransversediameterofthechestwall(~2-3cm)Largeairwaydilation,reducingairwayresistanceby~35%
VolumesandCapacitiesFromconceptionuntilterm:
V increasesby40%Inspiratorycapacityincreasesby10%Expiratorycapacitydecreasesby30%Totallungcapacitydecreasesby5%Vitalcapacityisunchanged
From~20weeksuntilterm:
ERVdecreasesRVdecreasesFRCdecreases
By20%erectBy30%supine
Ventilation
Progesteronestimulatesrespiratorycentres,shiftingtheO andCO responsecurvestotheleftwhichcauseshyperventilationandarespiratoryalkalosis.Fromconceptionuntilterm:
MVincreasesby50%10%increaseinRR40%increaseinV
PCO fallsto~26-32mmHg,withacompensatorydropinplasma[HCO ]to18-21mmol.L
LabourandPostpartumDuringlabour:
MVincreases70%duetopainandincreasedoxygendemandThiscauseshypocapnea,socessationofuterinecontractions(andtheassociatedpainandoxygendemand)arefollowedbya
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hypoventilatoryperiodproducingdesaturation
FRCandRVreturntonormalwithin48hoursofdelivery.
References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
Lastupdated2019-07-18
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CardiovascularChangesofPregnancyExplainthephysiologicalchangesduringpregnancy,andparturition
Physiologicalconsequencesofchangesinpostureduringpregnancy
Pregnancyisatimeofincreasedmetabolicdemand,whichcardiovascularchangesreflect.Thesechangesinclude:
IncreasedintravascularvolumeOccursviatwomechanisms:Increasedoestrogencausesanincreasedplasmavolume
Thisdecreasescapillaryoncoticpressure,predisposingtooedemaThismaybeexacerbatedbythegraviduteruscompressingtheIVC,especiallynear-term
IncreasedEPOcausesanincreasedredcellvolumeIncreasedvenousreturnDuetoincreasedintravascularvolumeandMSFP.
ThegraviduterusmaycompresstheIVCandimpairVR,hencepregnantwomenarepositionedwithaleftlateraltilttodisplacetheuterusofftheIVC
IncreasedVRcausesanincreaseinCO(withbothanincreaseinHRandSV,aswelladecreaseinSVR)DecreasedSVRresultsinSBP,DBPandMAPdropping(despitetheincreaseinCO)
MagnitudeofChangesbyTrimester
Parameter Direction FirstTrimester
SecondTrimester
ThirdTrimester Notes
Plasmavolume ↑ 35% 45% 50% Peaksbetween32-36 week,decreases
slightlythereafter
Bloodvolume ↑ 5% 15% 20% Increaseslessthanplasmavolume,
resultinginthefallinhaematocritto33%
HR ↑ 15% 18% 25% Increasesprogressivelythroughout
SV ↑ 20% 25% 30% Increasesprogressivelythroughout
CO ↑ 20% 40% 45% Increasesthroughoutanddramaticallyinlabour
ChangesDuringLabour
Uterinecontractionboluses~300mlofbloodintothematernalcirculationCausesanincreaseinCObyupto30%duringtheactivephaseand45%duringejection.
AssociatedwithcorrespondingincreaseinSBPandDBPby10-20mmHg
Post-partumCOisupto80%ofpre-labourvaluesduetoautotransfusion,andreturnstonormalwithin2weeksofdelivery
References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
Lastupdated2018-03-04
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FoetalCirculationExplainthephysiologicalchangesduringpregnancy,andparturition
InUtero
Thefoetalcirculationhasanumberofstructuraldifferences:
TwoumbilicalarteriesTheumbilicalarteryreturnsdeoxygenatedbloodtotheplacenta.
PO of18mmhg(SpO 45%)Over50%ofthecombinedoutputofbothfoetalventriclesenterstheplacenta
OneumbilicalveinTheumbilicalveinsuppliesoxygenatedbloodtothefoetus.
HasaPaO of28mmHg(SpO 70%)60%ofbloodfromtheumbilicalveinenterstheIVC40%ofbloodenterstheliver
Twoducts:DuctusvenosusShuntsbloodfromtheumbilicalveintotheIVC.DuctusarteriosusShuntsbloodfromthepulmonarytrunktothedescendingaorta.
AforamenovaleShuntsbloodfromtherightatriumtotheleftatrium.ImmaturemyocardiumFoetalmyocardiumdoesnotobeyStarlingsLaw,anddoesnotadjustcontractilityforanygivenpreload.Therefore:
SVisfixedCOisHRdependentNormalHRattermis110-160bpm.
Thesestructuraldifferencealterthepathwayofbloodcirculation:
Oxygenatedbloodreturnsviatheumbilicalvein40%flowstotheliver60%isreturnedtotheIVC
OxygenatedbloodintheIVCisdirectedviatheEustachianvalvethroughtheforamenovaleBloodreturningfromtheSVCisdirectedintotheRV,andthenintothedescendingaortabytheductusarteriosus
~10%ofRVoutputflowsthroughthepulmonarycirculation
Thisarrangementhasseveralfeatures:
BloodwiththemostoxygenisdeliveredtothearchvesselstosupplythebrainBloodwiththeleastoxygenisdeliveredtotheumbilicalarteriesforgasexchangeBoththeRVandtheLVejectintosystemiccirculations,andareofsimilarsizeandwallthickness
ChangesatBirth
Severalchangeshappenatbirth:
Placentalcirculationislost
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Thereisatransitionfromcirculationinparalleltocirculationinseries.AnFRCisestablishedReversalofhypoxicpulmonaryvasoconstrictionresultsinarapiddropinPVR.ThecordisclampedThesystemicvascularbedvolumefalls,andSVRincreasesduetothelossofthelow-resistanceplacentalcirculation.
ThefallinPVRlowersRVafterloadRAPfallsduetothelossofhypoxicpulmonaryvasoconstriction.
TheriseinSVRincreasesLVafterloadLAPrisesastheLVmovesuptheStarlingcurve.WhenLAPexceedsRAP,theforamenovaleclosesAdegree(~10%)ofresidualshuntremains.Shuntis:
BidirectionalLeft-to-rightshuntisunconcerningRight-to-leftshunthasusuallyonlyminoreffectsonsystemicSpOWillbeincreasedwith↑PaCO ,excessivePEEP,↓pH.
BewareembolicmaterialDon'tforgetthebubbles.
IncreasedleftsidedafterloadcausesflowreversalintheductusarteriosusThereisprogressiveclosureoftheductusoverhourstodays,undertheinfluenceofprostaglandinsandoxygenatedbloodflowingthroughtheduct.
Theductusvenosusprogressivelyfibrosesoveraperiodofdaystoweeks
References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. BrandisK.ThePhysiologyViva:Questions&Answers.2003.
Lastupdated2019-06-14
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ThePlacentaOutlinethefunctionsoftheplacenta,anddeterminantsofplacentalbloodflow.
Theplacentaisanorganofmaternalandfoetaloriginwhichsupportsthedevelopingfoetus.
PhysiologicalProperties
Theplacentahasthreebroadfunctions:
InterfacebetweenfoetusandmotherfornutrientexchangeImmunologicalbarrierEndocrine
NutrientandWasteExchangeFunctions
Theprimarypurposeoftheplacentaisdiffusionofnutrientsandoxygen,andremovalofwaste.
Aswiththelung,diffusionisdependentonFick'sPrinciple,i.e.:
,where:
=Flowofsubstanceacrossthemembrane
=Areaofthemembrane
=Diffusionconstantforthesubstance,whereMolecules<600Dainsizemorereadilydiffusedownconcentrationgradients
=ConcentrationdifferenceacrossthemembraneMaternalplacentalflowis~600mL.min atterm-doublethatoffoetalflow-whichimprovesdiffusionbyincreasingtheconcentrationgradientforsolutes
=Thicknessofthemembrane
O Diffusion
Attheendofpregnancy,PO forfoetalblood:
Enteringtheplacentaviatheumbilicalarteryis18mmHg(SpO245%)Leavingtheplacentaviaumbilicalveinis28mmHg(SpO270%)
ThefoetusisabletohaveadequatedeliveryofO despitethelowPO forfourreasons:
HighCardiacIndexIncreasedcardiacoutputincreasesDO .
FoetalHbContainstwogammasubunitsinsteadofbetasubunits.Thesepreventthebindingof2,3-DPG,whichresultinaleft-shiftedOxy-Haemoglobindissociationcurve,favouringoxygenloadingatalowPaO .
Foetal[Hb]is50%greaterthanmaternal[Hb]
TheDoubleBohreffect:
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TheBohreffectstatesthatanincreaseinPaCO right-shiftstheoxyhaemoglobindissociationcurve.Conversely,theaffinityofHbforO increasesinalkalaemia.ThedoubleBohreffectdescribesthishappeninginoppositedirectionsinthefoetalandmaternalcirculations,favouringtransferofO tothefoetus:
Intheplacenta,foetalCO diffusesintomaternalblooddownitsconcentrationgradientThismakesfoetalbloodrelativelyalkaline,andmaternalbloodrelativelyacidic.Therefore:
O unloadingofmaternalbloodisfavouredO loadingoffoetalbloodisfavoured
CO Diffusion
CO isextremelylipidsoluble,andsopasseseasilyacrossmembranes.FoetalPaCO is~50mmHg,andintervillousPCO is~37mmHg.CO offloadingisfavouredinthefoetusby:
AhighFoetal[Hb]increasestheamountofCO thatcanbecarriedascarbaminohaemoglobinTheDoubleHaldaneeffect:TheHaldaneeffectstatesthatdeoxygenatedHbbindsCO withmoreaffinitythanoxygenatedHb.ThedoubleHaldaneeffectdescribesthishappeninginoppositedirectionsinthematernalandfoetalcirculations,favouringCO transfertothemother:
AsmaternalbloodreleasesO ,thisfavoursmaternalloadingofCO withoutanincreaseinmaternalPCO (Haldaneeffect)ThereleaseofCO fromthefoetalHbfavoursO loading,whichinturnfavoursfurthermaternalO release.
NutrientDiffusion
Inlatepregnancy,foetalcaloricrequirementsarehigh(approximatelythesameasthemother).Facilitateddiffusionofglucoseviacarriermoleculesoccursintrophoblasts.
Activetransportoccursforaminoacids,Ca ,Fe,folate,andvitaminsAandC.Othertransportersactivelyremovesubstancesfromfoetalcirculation.
ImmunologicalFunction
TheplacentaisselectivelypermeabletoIgGviapinocytosis,whichallowsmaternalantibodiestoprovidepassiveimmunitytothefoetus.
EndocrineFunction
Synthesises:
βHCGhPLOestriol
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Progesterone
Development
Theplacentadevelopssimultaneouslyfromfoetusandmother:
Fromtheuterinewall,themotherproducesbloodsinusesaroundthetrophoblasticcordsTheseinturnsendoutplacentalvilli
Thiscreatesasinusofmaternalbloodinvaginatedbymultiplefoetalvilli
Foetalvilliaresuppliedbytwoumbilicalarteriesandasingleumbilicalvein
MaternalsinusesarefilledfromtheuterinearteriesThematernalsinusesaresuppliedbyspiralarteries
PropertiesoftheDevelopingPlacenta
Thick(er)membraneimpairspermeabilityPlacentalmembranepermeabilityissmallinearly-to-midpregnancy,reachingmaximumat~34weeksSmallersurfacearea
PropertiesoftheMaturePlacenta
Thickmembrane-improvedpermeabilitySurfaceareaof14mWeightof~500gBloodflowof600mL.min attermFlowisreducedduringcontractionsduetoincreaseduterinepressureandalsowithα-adrenergicstimulation.
References
1. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:SaundersElsevier.2011.
2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
Lastupdated2019-07-18
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GastricSecretionsDescribethecomposition,volumesandregulationofgastrointestinalsecretions
TheGITproducesaanumberofsubstanceswhichcanbeclassifiedbyregionandfunction:
SalivaH O(98%)Digestiveproteins
AmylaseLipaseMucinHaptocorrinBindsVitaminB12.
ImmunologicalproteinsLysozymeLactoferrinIgA
GastricDigestive
HClGastrinPepsinIntrinsicFactor
MucosalProtectionMucousHCO
SmallBowelDigestive
PancreaticLipaseAmylaseTrypsinogen
EndocrineSecretinSomatostatin
ControlofSecretionsSecretionoccursinthreephases:
CephalicThought/sight/taste/smelloffood,resultinginvagal-mediatedstimulustoreleasegastrin.Accountsfor~30%ofproduction.GastricStretchofthestomachstimulatesHClsecretionandgastrinrelease.Accountsfor~50%ofproduction.IntestinalAdropinpHoftheproximalduodenumreleasessecretintostimulatetheexocrinepancreas.
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SalivarySecretions
Approximately1Lofsalivaisproducedbytheparotid,submandibular,andsublingualglandseachday.
Salivahasfourmainfunctions:
LubricationMucin
DigestionAmylaseLipaseParticularlyimportantinneonateswhoproducelittlepancreaticlipase.
NeutralisationofacidForprotectionpriortovomiting.Antibacterial
GastricSecretions
Thestomachproduces~2Lofsecretionsperday:
AcidsecretionParietalcellscontainanH -K exchangepump.
H isproducedbycarbonicanhydraseonCO andwater,with'waste'HCO removedfromthecellinexchangeforCl .
HighlevelsofacidproductionresultinlargeamountsofbicarbonatebeingsecretedintobloodThiscreatesanalkalinetideasportalvenouspHincreasesdramaticallyRespiratoryquotientofthestomachmaybecomenegativeduetoconsumptionofCO
ThispumpisactivatedinresponsetoincreasedlevelsofintracellularCa fromstimulationby:AChHistamine(H )Gastrin
Inhibitedby:LowgastricpHSomatostatin
GastricGastinisapeptidefamilysecretedfromantralGcells.
Secretionisstimulatedby:Neural(vagal)stimulationinthecephalicphaseofdigestionMainmechanism.ProteinandaminoacidsinthestomachDrugs
AlcoholCaffeine
Secretionisinhibitedby:LowpHSecretinGlucagon
Gastrinhasanumberofpro-digestiveeffects:StimulatesgastricacidsecretionStimulatespancreaticsecretion
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StimulatesbiliarysecretionIncreasesgastricandintestinalmotility
PepsinogensChiefcellssecretepepsinogenIandisreleasedbyAChorβstimulation.Pepsinogeniscleavedtopepsininthegastriclumen,andbreaksdownprotein.
IntrinsicFactorParietalcellsproduceintrinsicfactor,whichformsacomplexwithB whichfacilitatesitslaterabsorptionintheterminalileum.
MucousNeckcellsproducemucopolysaccharide,glycoprotein,andHCO inresponsetostimulusbyprostaglandins,whichprotectsmucosaandlubricatesfood.
PancreaticSecretionsExocrinepancreaticsecretionsareproducedbytheacinarandductalcells,attherateof1.5Lperday.
Releaseisstimulatedby:CCKSecretinAChViavagalstimulation.
Consistof:HCOToalkalinisegastriccontents.
PancreaticbicarbonateproductionlowersvenouspH,andneutralise'sthealkalinetideofthestomach.WaterEnzymes
TrypsinogenProteolysis.AmylaseHydrolysisofglycogen,starch,andcomplexcarbohydrate.LipaseHydrolysisofdietarytriglycerides.
EndocrineFunctionCholecystokinin(CCK)isapeptidefamilysecretedbyintestinalenteroendocrinecells(Icells)inthemucosaoftheduodenumandjejunum.Cholecystokinin:
RegulatessatietyRegulatesleptinreleasefromfatStimulatessecretionsfromthegallbladderandduodenum
Secretinstimulatespancreaticrelease.Secretinis:ReleasedbytheproximalduodenuminresponsetolowpH
Motilinstimulatesthemigratingmotorcomplex.Motilinis:ReleasedcyclicallyfromMcellsinthesmallbowel
References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
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OesophagusDescribethecontrolofgastrointestinalmotility,includingsphincterfunction.
Theoesophagusisamusculartubeconnectingthepharynxtothestomach.Theoesophagushas:
SkeletalmuscleinitsupperthirdSmoothmuscleinitslowerthird
LowerOesophagealSphincterTheLoSis:
Themostdistal2-4cmoftheoesophagusMacroscopicallyindistinguishablefromtherestoftheoesophagus
HoweverithasahigherconcentrationofnervecellsandisabletoconstrictatahigherpressureTonicallyinnervatedbythevagusImportantinthepreventionofrefluxCompetencyoftheLoSisrequiredtopreventreflux
Barrierpressureisthepressuredifferencebetweenthepressureattheloweroesophagealsphincterandthepressureinthestomach,andistypically~15-25mmHgBarrierpressureisaffectedby:
ChangesinloweroesophagealsphincterpressureSwallowingBarrierpressuredecreasesduringswallowing,andtransientlyincreasesimmediatelyafterwards.Anatomical
AgeSphinctertoneisdecreasedinneonatesandtheelderly.DiaphragmAnexternalsphincterisformedbythediaphragmaticcrura,andexertsapinch-cockactionontheoesophagus.StomachAfoldinthestomachwalljustdistaltotheGOJcreatesaflapvalve,whichoccludestheGOJwhengastricpressurerises.OesophagusTheoesophagusentersthestomachatanobliqueangle,limitingretrogradeflow.
HormonalGastrin,motilin,α-agonismincreaseLoStoneProgesterone,glucagon,vasoactiveintestinalpeptide(VIP)decreaseLoStone
DrugsETOH,IVandvolatileanaestheticagents,andanticholinergicsdecreaseLoStoneSuxamethonium,metoclopramide,andanticholinesterasesincreaseLoStone
ChangesingastricpressureRaisedintraabdominalpressure
ObesityPregnancy
DiseaseHiatusherniaGOJmovesintothethorax,causing:
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Lossofpinch-cockactionNegativeintrathoracicpressurereducesLoSpressureandthereforebarrierpressure
--
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.2. ANZCAJuly/August19993. KahrilasPJ,PandolfinoJE.Hiatushernia.GIMotilityonline.2006.4. ANZCAAugust/September2015
Lastupdated2019-07-18
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ControlofGastricEmptyingDescribethecontrolofgastrointestinalmotility,includingsphincterfunction.
Gastricemptyingisaneurallyandhormonallymediatedprocesswhichaimstopresentfoodtothesmallbowelinacontrolledmanner.Differentdrugs,hormones,andphysiologicalstatescaneitherencourageorinhibitgastricemptying.
DeterminantsofGastricEmptying
Rateofgastricemptyingisafunctionof:
AntralpressureMaindeterminantaspyloricresistancetendstobelow,andisaffectedby:
StomachDuodenumSystemicfactorsDrugs
Pyloricresistance
Stomach
GastricdistensionVagalexcitationfromgastricstretchcausesreleaseofgastrin,increasingperistalticfrequency.Compositionofchyme:
LiquidsemptyfasterthansolidsLiquidshaveahalf-timeof~20minutes,andemptyinanexponentialfashionSolidshaveahalf-timeof~2hours,withadwelltimeof~30minutes,andemptyinalinearfashion
Proteinindependentlystimulatesgastrinrelease
Duodenum
Theduodenumhashormonalmechanismswhichhaveanegativefeedbackongastricemptying.Theseinclude:
DuodenaldistensionHypoosmolarandhyperosmolarchymeAcidicchymeInresponsetoacidtheduodenumreleasessecretinandsomatostatin:
SecretindirectlyinhibitsgastricsmoothmuscleSomatostatininhibitsgastrinrelease
FatandproteinFatandproteinbreakdownproductsstimulatereleaseofcholecystokinin,whichinhibitsgastrin.
Carbohydrate-richmealsemptyfasterthanprotein,whichemptyfasterthanfat.
Systemic
Motilinreleasedbythesmallbowelenhancesthestrengthofthemigratingmotorcomplex,aperistalticwaveofcontractionthroughthewholeGITwhichoccursevery60-90minutesSympatheticinputfromthecoeliacplexusinhibitsgastricemptyingPregnancyhasanumberofeffectsongastricemptying:
ProgesteronerelaxessmoothmuscleandinhibitsgastricsmoothmuscleresponsetoAChandgastrin,aswellascreating
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incompetenceoftheLoSleadingtoGORDGastrinproductionincreasesSomegastrinisproducedbytheplacenta.Gastricacidproductionisincreasedduringthethethirdtrimester
Parasympatheticinputenhancesgastricmotility
Effectofdrugs
Drugswhichincreasegastricemptyinginclude:
MetoclopramideErythromycin
Drugswhichinhibitgastricemptyinginclude:
OpioidsAlcoholAnticholinergicagents
References
1. CICMJuly/September20072. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
Lastupdated2019-07-18
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SwallowingDescribethecontrolofgastrointestinalmotility,includingsphincterfunction
Swallowingisdividedintothreephases:
OralPhaseVoluntaryFoodispushedagainsthardpalatebytongue
PharyngealPhaseInvoluntaryCoordinatedbymedulla.ClosureofnasopharynxAdductionofvocalcordsHyoidelevationanddeflectionofepiglottisPharyngealcontractionPropelsfoodbolustowardsoesophagus
OesophagealphaseInvoluntaryClosureofUoSRestingbarrierpressure100mmHg.RelaxationofLoSRestingbarrierpressure20mmHg,whichisabalancebetween:
LoSpressure(30mmHg)Antralpressure(10mmHg)
Oesophagealperistalsis
Impairmentofanyoftheseprocessesincreasesriskofaspiration:
ObtundationReducedcoughreflex.MuscularweaknessImpairedmedullarycoordination
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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PhysiologyofVomitingDescribethecontrolofgastrointestinalmotility,includingsphincterfunction
Vomitingistheactive,forcefulexpulsionofgastriccontentsfromthestomach.Itisdifferentfromregurgitationwhichisapassiveprocess.
ItisamechanismtoexpeltoxicsubstancesfromtheGIT.
StimulationStimulantstovomitingcanactcentrally,ordirectlyinthebowel:
CentralstimulationCentralstimulimayactdirectlyonthevomitingcentre.OthersactviatheCTZ,whichispartoftheareapostremalocatedoutsideoftheblood-brainbarrier,andsoitcanbestimulatedbycirculatingsubstances.Centralvomitingstimuliinclude:
Direct:EmotionPainOlfactoryVisual
ViatheCTZ:Vestibularactingon:
HACh
Drugs/Toxinsactingon:5-HTDμ-opioidreceptors
GITstimulationGITstimulitravelSNSandPNSafferentstothevomitingcentre.TheCTZisnotinvolvedandsoanti-emeticswhichactherearenotusefulinthistypeofvomiting.
GITvomitingstimuliincludedistensionandtoxins.Neurotransmittersinclude:
5-HT inmucosalstretchreceptorsAChinNTSafferentsH inNTSafferents
PostoperativeNauseaandVomiting
Centralstructuresinvolvedinclude:
ChemoreceptortriggerzoneNTSMultiplepathwaysexist(similartothosedescribedabove),andneurotransmittersinvolvedinclude:
5-HTDNKHmACh
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RiskfactorsPatientfactors
FemaleNon-SmokerYoungageHistoryofPONVormotionsickness
AnaestheticfactorsVolatileuseNitrousoxideuseRelativeriskof1.4.OpioiduseAnaesthesiaduration
SurgicalfactorsGynaecologicalsurgeryLikelynotanindependentriskfactor,andsimplyconfoundedbyfemalegender.Strabismussurgeryinchildren
Processofvomiting
Vomitingconsistsofasetofprocessescoordinatedbythevomitcentreinthemedullaoblongata,andisdividedintothreephases:
Pre-ejectionphaseProdromalnauseaSalivationRetrogradeintestinalcontractionwhichforcesintestinalcontentsintothestomach
RetchingPhaseDeepinspirationandbreath-holdingtosplintthechestEpiglotticclosureElevationofthesoftpalate(preventsnasalsoiling)
ExpulsivephaseRelaxationofoesophagealsphinctersPyloriccontractionViolentcontractionofthediaphragmandabdominalmuscles
References
1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. PierreS,WhelanR.Nauseaandvomitingaftersurgery.ContinuingEducationinAnaesthesiaCriticalCare&Pain,Volume
13,Issue1,1February2013,Pages28–32.
Lastupdated2019-07-18
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FunctionsoftheLiverDescribethestorage,synthetic,metabolicandexcretoryfunctionsoftheliver
Storage
Theliverisimportantinstorageandreleaseof:
CarbohydratesasglycogenTheadultliverstores~100gofglycogen.FatastriglyceridesAllfat-solublevitamins(A,D,E,K)ManywatersolublevitaminsincludingfolicacidandBIronCopper
Synthetic
Syntheticfunctionsinclude:
BileproductionPlasmaproteinsincluding:
ClottingfactorsAlbuminproduction120-300mg.kg ofalbuminisproducedperday,dependentonnutritionalstatus,plasmaoncoticpressure,andendocrinefunction.
MetabolicMetabolicfunctionsinclude:
CarbohydrateFatProteinBilirubinmetabolismDrugsandToxins
Carbohydrates
MonosaccharidesanddisaccharidespassivelydiffuseintohepatocytesGradientismaintainedbyconvertingglucosetoglucose-6-phosphatewhichisusedtoproduceglycogen.Thismaintainsthegradientfordiffusion.Glycogeniseithersynthesised(glycogenesis)orbrokendown(glycogenolysis)dependingonplasmaglucoseandinsulin:
Increasedbloodglucosestimulatesinsulinrelease,increasingtheformationofglycogenthroughactivationofglycogensynthetaseDecreasedbloodglucosestimulatesglycogenolysisandgluconeogenesisfromaminoacids.
Lipids
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Fatcanbe:StoredastriglyceridesHydrolysedtoglycerolandfattyacids,whichisusedforATPproduction
ProteinsandUrea
Aminoacidsareabsorbedfrombloodtobeusedforgluconeogenesisandforproteinsynthesis.InordertoproducesubstratesfortheCAC,Aminoacidsmaybe:
TransaminatedDeaminatedDecarboxylated
Thenitrogenousscrapofthesereactionsisurea,whichisproducedinseveralstages:
AvarietyofmetabolicprocessesconvertaminoacidstoglutamateGlutamateisconvertedtoammoniabyglutamatedehydrogenaseAmmoniathenenterstheureacycletoproduce(surprisingly)urea,atthecostof3ATP
Anormaldietof100gproteinperdayproduces~30gofurea,and1000mmolofhydrogenions
Endocrine
ProducesangiotensinogenProducesIGF-1ConvertsT4toT3
Immunoprotective
KupffercellsTissuemacrophagesofthehepaticreticuloendothelialsystem.Theyphagocytoseharmfulsubstancesincluding:
EndotoxinsBacteriaVirusesImmunecomplexesThrombinFibrincomplexesTumourcells
Acid-BaseBalance
Mayproduceorconsumelargenumbersofhydrogenions:
CarbondioxideproductionMetabolismoforganicacidanions
LactateKetonesAminoacids
AmmoniumProductionofplasmaproteinsNotablyalbumin
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References1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. BrandisK.ThePhysiologyViva:Questions&Answers.2003.
Lastupdated2019-07-18
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LaboratoryAssessmentofLiverFunctionDescribethelaboratoryassessmentofliverfunction
SyntheticFunction
Measuresofsyntheticfunctioninclude:
AlbuminMainplasmaprotein.
Normalrange28-58g.LHalf-life~20daysImportantin:
MaintenanceofplasmaoncoticpressureBinding
CalciumDrugs
Decreasedinliverdysfunctionandmalnutrition
CoagulationAssaysClottingfactorsareproducedbytheliver.Hepaticimpairmentmayresultinreducedproductionandabnormalityofclottingassays,althoughfunctionalclottingfunctionmaybenormal(aspro-coagulantproteinsareaffectedtoasimilarextent).
INRTestoftheextrinsicpathway.APTTTestofintrinsicpathway.
MetabolicFunctionTransaminasesarereleasedwhenliverparenchymaisdamaged,andareusedtoevaluatemetabolicfunction:
ALTNormalrange<54U.L .ASTNormalrange<35U.L .
ObstructiveTests
ALP(AlkalinePhosphatase)Enzymeinvolvedindephosphorylationofmanycompounds.ALPisfoundinallcells,butparticularlyintheliver,bileduct,bone,kidney,andplacenta.
Normalrangeis30-120U.LGGTEnzymefoundinbiliaryduct.
Normalrange:Males:11-50U.LFemales:7-30U.L
Bilirubin
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Byproductofhaemoglobinmetabolism.Maybemeasuredastotal,orasconjugatedandunconjugatedbilirubin.
References1. Diaz,A.Outlinetheclinicallaboratoryassessmentofliverfunction.PrimarySAQs.
Lastupdated2019-07-18
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BileDescribethephysiologyofbileanditsmetabolism
Bileisadarkgreensolutionproducedbythelivertofacilitateabsorptionoffatandfat-solublevitamins(ADEK)throughemulsification.Bileis:
Producedbytheliverattherateof1LperdayConcentratedinthegallbladderImportantintheabsorbanceoflipidandfat-solublevitaminsFormedfrom:
WaterProteinBilirubinBilesaltsThesodiumandpotassiumsaltsofbileacids.Bileacids:
AreareproducedfromcholesterolAreamphipathic,andactasemulsifiersoflipidBreakuplargefatglobulesintosmallermicelles,whichcanthenbeabsorbed.Majorbileacidsinclude:
CholicacidChenodeoxycholicacid
Areabsorbedintheterminalileum,andrecycledbytheportalcirculationLipidsElectrolytes
References1. Hall,JE,andGuytonAC.GuytonandHallTextbookofMedicalPhysiology.11thEdition.Philadelphia,PA:Saunders
Elsevier.2011.2. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.
Lastupdated2019-07-18
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ErythrocytesOutlinethephysiologicalproductionofbloodanditsconstituents
Erythrocytes:
Are7.5μmindiameterAre2umthickHavealifespanof120daysHave:
NonucleusMaximisescellvolumeavailableforHb.NomitochondriaCannotperformaerobicmetabolism-allATPisgeneratedviaglycolysis.NoribosomesIncapableofproducingprotein
HaveabiconcavediscshapeThismaximisessurfacearea(optimisinggastransfer)andmakesthecellsflexibleenoughtopassthroughcapillarybeds(whicharenarrowerthanthecell).Areimportantin:
DeliveringO tothetissuesanddeliveringCO tothelungsAcid-BasebalanceMetabolismofsomedrugs
Carry~29pgofhaemoglobinComprise40-50%ofbloodvolume
ProductionErythrocyteshaveamyeloidprogenitorwhichdifferentiatesintothemyeloidline.EPO(seeendocrinefunctionsofthekidneystimulatesmyeloidprogenitorcellsto:
DifferentiateProliferate
ProerythroblastsbeginsynthesisofHb,withongoingproductionoccurringuntilthecellismatureFurtherdifferentiationresultsinsuccessivelossoforganelles,increasingHbcontentThelossofribosomesandnucleusofthereticulocytearethefinalstageoferythropoiesisTheentireprocesstakes~7-10days
FunctionGasCarriageAcid-BaseBuffering
ProductionofHCOBindingofH toHb
MetabolismEsterases(andother-ases)inerythrocytesmetabolisemanydrugs,including:
RemifentanilSNP(reactswithHbtoformNO,CN,andMet-Hb)Esmolol
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Elimination
Oldredcellsareremovedfromcirculationvia:
Phagocytosisbymacrophagesin:SpleenMajormechanism.LiverBonemarrow
Haemolysis~10%ofredcellbreakdownoccursincirculation,wheretheHbdimersarethenboundtohaptoglobinbyhaemopexin.
Thisisimportanttopreventglomerularfiltrationofhaeme,andlossofiron
HaemoglobinMetabolism
Haemoglobinisbrokendowninto:
GlobinBrokendownintoconstituentaminoacids.IronRe-entershaemoglobinsyntheticpathway.HaemeComplexmetabolicpathway,notableasitistheonlymetabolicprocessthatproducescarbonmonoxide:
MetabolisedtobiliverdinbysplenicmacrophagesinthereticuloendothelialsystemofthespleenCirculatingerythrocytesarephagocytosedbysplenicmacrophagesHaptoglobinbindscirculatingHb,theHb-Haptoglobincomplexisthenphagocytosedbysplenicmacrophages
BiliverdinisreducedtounconjugatedbilirubinThisisfatsoluble,andbindstoalbumin.UnconjugatedbilirubinisconjugatedinthelivertoconjugatedbilirubinConjugatedbilirubinissecretedinbilebyactivetransportThisisimpairedduringhepaticdisease,leadingtoincreasedbilirubinlevelsinplasma.SecretedconjugatedbilirubinismetabolisedtourobilinogenbygutbacteriaUrobilinogenmayhaveanumberoffates:
Enterohepaticrecirculationandeliminationinbile(again)FurthermetabolismbygutbacteriatostercobilinogenandthentostercobilinEnterohepaticrecirculationandurinaryexcretion,whereitisoxidisedtourobilin
InDisease
Blood Urine Faeces
Prehepaticdisease ↑Unconjugatedbilirubin ↑Urobilinogen,
bilirubinnotpresent Normal
Intrahepaticdisease
↑Conjugatedbilirubin,↑Unconjugatedbilirubin Bilirubinpresent Maybepaleduetodecreased
urobilinogenexcretedinbile
Posthepaticdisease ↑Conjugatedbilirubin ↓Urobilinogen,
bilirubinpresent Pale
References
Haematology
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1. BarrettKE,BarmanSM,BoitanoS,BrooksHL.Ganong'sReviewofMedicalPhysiology.24thEd.McGrawHill.2012.
Lastupdated2019-07-18
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IronHomeostasisDescribethenormalnutritionalrequirements
Approximately3-5gofironisfoundinthebodyas:
Oxygen-carryingglobinmoleculesHaemoglobin(~70%)andmyoglobin(~5%).Catalystforbiologicalreactions(~25%)Catalase,peroxidase,andcytochromesallrequireiron.
AbsorptionDietaryironcomesintwoforms:
HaemegroupsDirectlyabsorbedviaspecialisedtransportproteins.Dietaryironsalts
Ferrous(Fe )ironissoluble,andisabsorbedviafacilitateddiffusionacrosstheenterocytemembraneReducedacidityofthestomachwillreducetheabsorptionofferrousiron
Ferric(Fe )ironprecipitateswhenpH>3,andsocannotbeabsorbedindependentlybythesmallbowel.Apathwaymayexistforabsorptionofferricironfromsolublechelates
Onceintheenterocyte,ironcanbe:Stored,boundtoferritinTransportedviaferroportinoutoftheenterocyte,whereitisthenoxidisedtoferrousironandboundtotransferrin
RegulationExcretionisuncontrolledRegulationofironlevelsisonlybyabsorptionHepcidinisaliverproteinwhichinhibitstheactionofferroportin
HighhepcidinpreventsirontransportfromtheenterocyteHepcidinisdeficientinhaemochromatosis
References
1. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
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PlateletsOutlinethephysiologicalproductionofbloodanditsconstituents
Describetheprocessandregulationofhaemostasis,coagulationandfibrinolysis
Plateletsaresmallcellfragmentswhicharevitalinhaemostasisviaformingaplateletplug.They:
Havealifespanof7-10daysAreremovedbythereticuloendothelialsysteminthespleenandliver
Production
Plateletsare:
Anuclearcirculatingcellbodies,whichbudfrommegakaryocytesAsthemegakaryocytecellvolumeincreases,thecellmembraneinvaginatesandsmallplateletsbudoff.
Thetimefromstemcelltoplateletis~10days,andisstimulatedbythrombopoietinNewplateletsareheldinthespleenfor36hoursuntiltheymature
Contentsα-granulesContainfibronectin,fibrinogen,vWF,PDGF,andThrombospondin,plateletfactor4.δ-granulesContain5-HT,ATP,ADP,andCa .ContractileproteinsFacilitateplateletdeformationwhenactivated.
ActivationPlateletsareactivatedby:
CollagenExposedbydamagedendothelium.AdrenalineADPThrombin
Activationresultsinseveralevents:ExocytosisofgranulesActivationofmembranephospholipaseA toformthromboxaneADeformationfromadisctoaspherewithlongprojectionsPromotionofthecoagulationcascadeChangeinglycoprotein(GP)expressionbytheactionofADP:ADPantagonists(e.g.clopidogrel)preventexpressionoftheGPIIb/IIIacomplex.
GPIb/IIb/IIIafacilitateplateletattachmenttovWFvWFalsobindstosub-endothelialconnectivetissue.GPIIb/IIIaarealsoreceptorsforfibrinogen,whichencouragesplateletaggregation
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References
1. KamP,PowerI.PrinciplesofPhysiologyfortheAnaesthetist.3rdEd.HodderEducation.2012.2. KraftsK.ClotorBleed:APainlessGuideforPeopleWhoHateCoag.PathologyStudent.
Lastupdated2019-07-18
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TransfusionUnderstandingtheadverseconsequencesofbloodtransfusion,includingthatofmassivebloodtransfusion
ProductionandStorageofBloodProducts
Redcells,platelets,andFFPhavedifferentstoragerequirements.
RedBloodCells
Storedblooddecaysovertime-thisisknownasastoragelesionPreservativesareusedtoextendthetimebloodcanbestored:
Keptat~4°C(balancebetweenfreezingandbeingtoowarm)ReducescellularmetabolicrequirementInhibitsbacterialgrowth
CollectedinanasepticfashionStoredinspecialsolutions:
SAGMiscurrentlyusedbytheAustralianRedCross:SalineAdenineSubstrateforATPsynthesisGlucoseSubstrateforRBCglycolysisMannitol
CPDA1(citrate-phosphate-dextrose-adenine)wastraditionallyusedCitratebindscalcium,preventingclottingPhosphateactsasabufferandphosphatesourceformetabolismDextroseAdenine
Astoragelesiondescribesthechangesthatoccurinstoredblood:Lossof2,3DPGLessofafactorinCPDA1blood.HaemolysisHyperkalaemiaTypicallynotclinicallyrelevantaspotassiumistakenupintoredcellswhenmetabolismresumes.AcidaemiaHyponatraemiaNotclinicallysignificant.
Bloodcanbestoredforupto35days,whichcorrespondsto70%survival
Platelets
Plateletsrequireparticularstorageconditionstoremainfunctional:
Temperature~22°CBelowthis,plateletsdeformandbecomenon-functionalGasexchangePlateletsarestoredinabagwhichallowsgasexchangetooccur,minimisinglacticacidandcarbondioxideproduction
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AgitationPlateletsarestoredonanagitatorwhichpreventsclottingandensurestheplateletsarewellmixed,whichmaximisesthediffusiongradientforgasexchangepHcontrolpHiskeptbetween6.2to7.8topreventdegranulation.
Asplateletsdonotcontainantigen,thereisnotastrictrequirementforplateletstobetypematched.However:
Rh(+)plateletsshouldbeavoidedinRh(-)patientsThesmallamountofcontaminatingredcellsmayprecipitaterhesusdisease.Plasmaincompatibilityshouldbeavoidedasthismayleadtohaemolysisofrecipientredcells
Childrenareatgreaterriskduetotheirproportionallysmallerbloodvolume
FreshFrozenPlasma
FreshFrozenPlasmais:
Preparedeithervia:SeparationfromwholebloodApheresisRemovalofalargevolume(typically800ml)ofplasmafromasinglepatient,withreturnofredcellstothedonor.
Oncecollected,itisfrozenandre-thawedinawaterbathpriortouse
Cryoprecipitate
CryoprecipitateispreparedbyremovingtheprecipitatefromFFPwhichformsat1–6°C.Cryoprecipitatecontainspredominantly:
FibrinogenFibronectinvWFFactorVIIIFactorXIII
WholeBlood
Wholebloodundergoesadditionalchanges:
Whitecellsbecomenonfunctionalwithin4-6hoursofcollection,thoughantigenicpropertiesremainPlateletsbecomenon-functionalwithin48hoursofstorageat4°CFactorlevelsdecreasesignificantlyafter21days
BloodGroups
Bloodgroupsrefertotheexpressionofsurfaceantigensbyredbloodcells,aswellasanyantibodyinplasma.Bloodgroupscanbedividedintothreetypes:
ABORhesusOtherantibodiesTheseareadditionalantibodiesthatapatientmayexpressinplasma,andincludeKell,Lewis,Duffy,etc.
ABO
TheABObloodgroupis:
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Acomplexcarbohydrate-basedantigensseriesThesemaybeeitherAorBantigen,andpatientsmayexpressone,both,orneither,givingfourbloodgroups(A,B,AB,O).ExpressedontheH-antigenstemofRBCs,andonthesurfaceoftissuecells.
TheBombayBloodGroup(orhhorOhgroup)describesindividualswhodonotexpresstheHantigenTheseindividuals:
Don'texpressA-orB-antigen(asthereisnoH-antigenstem)andare'universaldonors'ExpressH-antibodyCanonlyreceivebloodfromotherindividualswiththeBombayphenotype
IndividualsexpressIgMantibodytoforeignbloodgroupsThisdevelopswithin6monthsofbirth,likelyduetoenvironmentalexposuretosimilarantigens.AssociatedwithaseverehypersensitivityreactionifanABO-mismatchoccurs
Group RBC Plasma
A A-antigen B-antibody
B B-antigen A-antibody
O - A-antibodyB-antibody
AB A-antigenB-antigen -
Rhesus
TheRhesusbloodgroupisthenextmostimportantgroupafterABO.TheRhesussystem:
Consistsof~50differentantigens,themostimportantofwhichisDRhesusstatusisthereforeexpressedaspositive(D-85%ofthepopulation)ornegative(anything-but-D).RhesusantibodydoesnotnaturallyoccurinRh(-)individuals
ThisisrelevantinRhesusdiseaseARh(-)motherexposedtoRh(+)bloodwilldevelopAnti-Dantibody,whichcancrossplacentaandinduceabortioninafutureRh(+)foetus.Thiscanoccurwith:
IncompatibletransfusionFoetal-maternalhaemorrhage
CompatibilityTestingDonorbloodmustbetestedwithrecipientbloodtoavoidatransfusionreaction.Thisinvolvesthreeprocesses:
BloodTyping(ABO/Rh)Bloodistypedbymixingitinvitrowithplasma(andplasmawitherythrocytes)ofknowngroups(containingIgMantibody(Anti-A,Anti-B,Anti-AB)),andobservingforagglutination.AntibodyScreenForotherantibodies.
TestingissimilartoABOscreening,exceptplasmaismixedwithredcellscontainingknownantigen(e.g.Kell,Duffy),andmonitoredforagglutination.
Cross-matchInvolvestwoprocesses:
SalinetestErythrocytesaresuspendedinsalineandmixedwithantibodiesatroomtemperature,monitoringforagglutination.
ThisconfirmsABOtypeIndirectCoombs'test
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IdentifiesIgGantibodyinhostplasmawhichwouldcausehaemolysisoftransfusedredcells.Thisistypicallynolongerdone,asitoffersnegligibleextrasafetyovertheaboveprocesses.Doingitinvolves:
IncubatingBindsIgGAbtoantigenonRBCmembrane.WashingRemovesserumandunboundIgG.TestingwithanantibodytoIgG,knownasantiglobulinserum.
Apositivetestwillcauseclumpingofredcells,aseachantiglobulinserumwillbindtwoIgGmolecules,whichhaveinturnbeenboundtoredcellsAnegativetestwillcausenoagglutination,astheIgGhasnotbeenboundtoredcells
Ifnegative,theantiglobulinserumisre-usedonacontrolsampletoensurethatitisnotafalsenegative
TransfusionReactions
Transfusionreactionscanbeclassifiedaseitheracute(<24hours)ordelayed(>24hours),andasimmunologicalornon-immunological.
ImmunologicalAcuteReactions
Reaction Incidence Mechanism
ABOMismatch 1:40,000 ABOincompatibilitycausingrapidintravascularhaemolysis,whichmaycausechest
pain,jaundice,shock,andDIC.RhD-reactionstendtocauseextravascularhaemolysis.
Haemolytic(acute)
1:76,000(1:1.8millionfatal)
Immunologicaldestructionoftransfusedcells(TypeIIhypersensitivity).Presentswithfever,tachycardia,pain,progressingtodistributiveshock
Febrile,non-haemolytic
~1:100Cytokinereleasefromstoredcellscausingamildinflammatoryreaction,withtemperaturerisingto≥38ºCor≥1ºCabovebaseline(if>37ºC).Benign-butrequiresexclusionofahaemolyticreaction.
Urticaria 1:100 Hypersensitivitytoplasmaproteinsinthetransfusedunit
Anaphylaxis 1:20,000 TypeIhypersensitivityreactiontoplasmaproteinintransfusedunit
TRALI Variable DonorplasmaHLAactivatesrecipientpulmonaryneutrophils,causingfever,shock,andnon-cardiogenicpulmonaryoedema
Non-ImmunologicalAcuteReactions
Reaction Incidence Mechanism
MassiveTransfusionComplications Variable Seebelow
Non-immunemediatedhaemolysis Rare DuetophysicochemicaldamagetoRBCs(freezing,devicemalfunction).
Mayleadtohaemoglobinuria,haemoglobinaemia,tachycardiaandfevers.
Sepsis
1:75,000(platelets),1:500,000(RBC)
Contaminationduringcollectionorprocessing.Mostcommonorganismsarethosewhichuseironasanutrientandreproduceatlowtemperatures,e.g.YersiniaPestis.
TransfusionRelatedCirculatoryOverload(TACO)
<1:100Rapidincreaseinintracellularvolumeinpatientswithpoorcirculatorycomplianceorchronicanaemia.MayresultinpulmonaryoedemaandbeconfusedwithTRALI.
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DelayedImmunologicalReaction
Reaction Incidence Mechanism
Delayedhaemolytictransfusionreaction 1:2,500 Developmentofsensitisationwiththereactionoccurring2-14days
afterasingleexposure.TypicallyKidd,Duffy,Kellantibodies.
Post-transfusionPurpura Rare AlloimmunisationtoHumanPlateletAntigencausingsuddenself-
limitingthrombocytopenia
TA-GVHD Rare TransfusedlymphocytesrecognisehostHLAaspositivecausingmarrowaplasia,withmortality>90%
Alloimmunisation1:100(RBCantigens),1:10(HLAantigens)
Previoussensitisationleadingtoantibodyproductiononre-exposure.
Transfusion-relatedImmuneModulation
Notknown Transientimmunosuppressionfollowingtransfusionpotentiallyduetocytokinereleasefromleukocytes
DelayedNon-ImmunologicalReaction
Reaction Incidence Mechanism
IronOverload
Chelationafter10-20units,organdysfunction50-100units
EachunitofPRBCcontains~250mgofiron,whilstaverageexcretionis1mg.day .
ComplicationsofMassiveTransfusion
Amassivetransfusionisonewhere:
Greaterthanone-halfofcirculatingvolumein4hoursWholecirculatingvolumein24hours
Riskofcomplicationfromamassivetransfusionisinfluencedby:
NumberofunitsRateoftransfusionPatientfactors
Complication Mechanism
Airembolism Inadvertentinfusion
Hypothermia Cooledproducts
Hypocalcaemia Consumptionwithcoagulopathyandboundtocitrateaddedtotransfusedunits
Hypomagnesaemia Boundtocitrateintransfusedunits
Citratetoxicity Citrateisaddedtostoredunitsasananticoagulant
Lacticacidosis Hyperlactataemiaduetoanaerobicmetabolisminstoredunits
Hyperkalaemia Potassiummigratesfromstorederythrocytesintoplasmawhilstinstorage
References
-1
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1. BloodService.Classification&IncidenceofAdverseEvents.AustralianRedCross.2. NationalBloodAuthority.PatientBloodManagementGuidelines.AustralianRedCross.3. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.
Lastupdated2019-07-18
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HaemostasisDescribetheprocessandregulationofhaemostasis,coagulationandfibrinolysis
Haemostasisdescribesthephysiologicalprocessesthatoccurtostopbleeding.Itinvolvesthreeprocesses:
VesselconstrictionDecreasesflow,whichlimitsfurtherhaemorrhageandreducestheshearstresseswhichbreakupformingclotPlateletplugformationorPrimaryHaemostasisPlateletsadheretothedamagedvesselwallandaggregateFibrinformationorSecondaryHaemostasisFibrinisformedfromfibrinogen(viathecoagulationcascade),whichstabilisestheplateletplug
PrimaryHaemostasisFollowingavascularinjury,theexposureofsubendothelialproteinsstimulatesplateletstoformanocclusiveplugviaseveralprocesses:
AdhesionExposedcollagenbindstoGPIareceptoronplatelets.vWFalsobindstoplatelets.
ActivationMetabolicactivation,increasingPhospholipaseA andPhospholipaseC,increasingplateletintracellularCa andinitiatingatransformationfromadisctoaspherewithlongprojections.
Metabolicactivationisstimulatedby:CollagenAdrenalineADPThrombin
Additionally,plateletsreleaseADPandthromboxaneA fromtheiralphagranulesanddensebodies,amplifyingfurtherplateletaggregationandadhesion
AggregationWithotherplatelets-heldtogetherbyfibrin-formingaplug.
ContractionAftersometimeplateletscontract,retractingtheclotandsealingthewall.
SecondaryHaemostasis
Thecoagulationcascadeisanamplificationmechanismwhichactivatesclottingfactorsinordertoproducefibrin.
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Participatingfactorsinthecoagulationcascadecanbeeitherenzymesorcofactors:
Enzymescirculateintheirinactiveform,andbecomeactive(e.g.VII⇒VIIa)whenhydrolysedbytheirprecursorfactorCofactorsamplifythecascade
Pathways
Thecascadeisdividedintotheintrinsicpathwayandextrinsicpathway,whichjointoformthecommonpathway.Invitro,theintrinsicandextrinsicpathwaysoperateseparately.Thisisanartifactoflabmeasurement-invivothepathwaysareco-dependent.
ExtrinsicPathway
Theextrinsicpathwaycontainstwofactors,andtheprocessofactivationoccursinseconds:
TissueFactorMembraneproteinonsub-endothelialcells,whichisexposedwhenthevesselisdamaged(itisfoundinafewotherplacesaswell).ItbindstofactorVIItoformVIIa,andthusactivatestheextrinsicpathway.FactorVII
IntrinsicPathway
Theintrinsicpathwayisactivatedoverminutes,andcontains:
ContactfactorsOnlyimportantinvitrowhenconductinglabtesting-deficiencyofthesefactorsdoesnotcauseacoagulopathy.
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HMWKHMWKactivatesfactorXII.FactorXIIFactorXIIaactivatesfactorIX,asdoesthrombin.
FactorXIFactorIXFactorVIIIFactorVIIIcirculatesinacomplexwithvWF,preventingitfromdegradation.Whenactivatedbythrombin,itactsasacofactorforfactorIXatoactivatefactorX.
Theintrinsicpathwayisactivatedby:
ThrombinMainactivatoroftheintrinsicpathwayinvivo.CollagenGlassInvitro.
CommonPathway
Thecommonpathwaycontains:
FactorXFactorVCofactor(similartofactorVIII),whichwhenactivatedbythrombinallowsfactorXatoconvertprothrombinintothrombin.FactorII(prothrombin)Hasseveralkeyroles:
CleavesfibrinogentofibrinActivatesfactorXIIIFactorXIIIastabilisesclotbyformingcross-bridgesbetweenfibrininaplateletplug.AmplificationoftheclottingcascadebyactivatingfactorsVandVIIIActivatesproteinCThrombinbindswiththrombomodulintoformacomplexwhichinhibitscoagulation.
FactorI(fibrinogen)
TheCell-BasedModelofCoagulation
Thecascademodel(above)accuratelydescribestheprocessofclottinginvitro,butnotinvivoThecell-basedmodelhasseveralchanges,notingthecentralroleoftheplatelet:
InitiationphaseCoagulationbeginswithtissuefactorbeingexposed,whichalsoactivatesplatelets.AmplificationphaseApositivefeedbackloopoccurs:
ProductionofXacausesproductionofthrombin(IIa),primingthesystemThrombinthenactivatesfactorsV,VIII,andIX,acceleratingXaproductionandfurtherthrombingeneration
PropagationphasePlateletsbindactivatedclottingfactors,causinghighratesofthrombinformationaroundthem.
References
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1. KraftsK.ClotorBleed:APainlessGuideforPeopleWhoHateCoag.PathologyStudent.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. ClottingCascade22/4/2007.(Image).ByJoeD(Ownwork).CCBY3.0,viaWikimediaCommons.
Lastupdated2019-07-18
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HaemostaticRegulationDescribethemechanismsofpreventingthrombosisincludingendothelialfactorsandnaturalanticoagulants
Haemostasismustbecontrolledtopreventrampantclottingofthevasculartree.Thisinvolvesbothendothelialfactorsandproteins.
EndothelialRegulation
Intactendotheliumandtheglycocalyxpreventclottinginanumberofways:
MinimisestasisHighbloodflowEspeciallywhereflowisturbulent(largearteries).MaximiselaminarflowGlycocalyxsmoothsflow.
InhibitionofplateletadhesionandactivationNO,prostacyclin,andectonucleotidases(whichdegradeADP)inhibitplateletactivation.
Membrane-boundanticoagulantproteinsHeparan(notheparin)ActivatesantithrombinIII.ThrombomodulinBindsthrombin,preventingcleavageoffibrinogentofibrin.Thethrombin-thrombomodulincomplexactivatesproteinC(whichinturninactivatesfactorsVaandVIIIa).
PreventexposureofprocoagulantproteinCollagenvWFTissueFactor
tPAsecretion(see'ClotLysis')
ClotRegulation
EffectofbloodflowDilutesclottingfactorsActivatedclottingfactorsarewashedawayandmetabolisedbytheRES.LaminarflowCausesaxialstreamingofplatelets,minimisingendothelialcontactandchanceofactivation.fa
ActivationofanticoagulantfactorsTissueFactorPathwayInhibitorInhibitsVIIa,antagonisingtheactionoftissuefactorAntithrombinIIIInhibitstheserineproteases,i.e.thenon-cofactorfactorsinallthreepathways-IIa,VIIa,IXa,Xa,XIa,XIIa.ProteinCInactivatesproteinVaandVIIIa,andisactivatedbythrombin.ProteinSCofactorwhichhelpsproteinC.
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ClotLysis
Clotbreakdownisperformedby:
TissuePlasminogenActivator(tPA)Bindstofibrin,andthencleavesplasminogentoplasmin.Thiskeepstheplasminformationinthevicinityoftheclot,limitingitssystemicspreadof.
PlasmincleavesfibrinintofibrindegradationproductsFDPsconvenientlyinhibitfurtherthrombinandfibrinformation.
References
1. KraftsK.ClotorBleed:APainlessGuideforPeopleWhoHateCoag.PathologyStudent.2. VanHinsberghVWM.Endothelium—roleinregulationofcoagulationandinflammation.SeminarsinImmunopathology.
2012;34(1):93-106.
Lastupdated2019-07-18
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CoagulopathyTestingOutlinethemethodsforassessingcoagulation,plateletfunctionandfibrinolysis
CoagulationFactors
Allthesetestsmeasurehowlongittakestomakefibrin.Theyevaluatedifferentpartsofthecoagulationcascade,whichhelplocalisewhereacoagulopathymaybeoccurring.
Inthesetests:
CitrateisaddedtobloodBindscalciumandpreventsclotting.SampleiscentrifugedPlasmadecantedCalcium(toreplacethecalciumlostbybindingtocitrate)andareagentisaddedTimetakentoclotmeasured
ProthrombinTime/INR
Theprothrombintimemeasurestheextrinsicpathway.Tissuefactorhastobeaddedtothesampleinorderstartclotting-thisiswhyitisknownastheextrinsicpathwayasasubstanceextrinsictothesamplemustbeadded.AsthePTvariessignificantlybetweendifferentlabs,theINRisusedtoallowvaluestobecompared.
AnydisorderoftheextrinsicorcommonpathwayswillprolongthePT,i.e.deficiencyorinhibitionof:
FactorVIIFactorXFactorII(prothrombin)FactorVFactorI(fibrinogen)
Althoughwarfarinaffectsfactorsinallthreepathways,itsclinicaleffectsaremeasuredusingINR.Thisisbecause:
FactorVIIhastheshortesthalf-lifeoftheclottingfactorsaffectedbywarfarinThereforesoitslevelswillfallthequickest.ThereforeafallinFactorVIIlevelsistheearliestindicationofchangesincoagulationstatusduetowarfarinAsfactorVIIisonlyintheextrinsicpathway,thePT/INRaretheonlytestswhichcanevaluateitsfunction
(Activated)PartialThromboplastinTime
Thepartialthromboplastintimemeasurestheintrinsicpathway,whichbeginsproducefibrinwhenactivatedbytheadditionofphospholipidtothesample(phospholipidiscontainedinplatelets,andsoisnottechnically"extrinsic").Theactivatedpartialthromboplastintimeisthesametest,exceptanactivatingagentisaddedtospeedupthereaction.
AnydisorderoftheintrinsicorcommonpathwayswillprolongtheAPTT,i.e.deficiencyorinhibitionof:
FactorXIFactorIXFactorVIIIFactorXFactorV
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FactorII(prothrombin)FactorI(fibrinogen)
Heparinaffectsbothsidesofthepathway(IIa,IXa,Xa,XIa)howevertypicallyaffectsintrinsicfactorsmorethanextrinsic.
Inaddition,anti-phospholipidantibodieswillalsoprolongtheAPTTbybindingtheaddedphospholipid.
ActivatedClottingTime
ActivatedClottingTimeisusedtoforthedosingandreversalofheparinincardiopulmonarybypassandotherextracorporealcircuits.
Freshwholebloodisaddedtoatubewithanactivator(e.g.glassbeads)tostimulatetheintrinsicpathway.Thetimeuntilclotformationismeasuredinseconds.Differentactivatorswillhavedifferentnormalranges,andtargetrangesforthecircuitinuse.
PlateletFunction
EvaluatehowwellplateletsaggregateinresponsetofactorslikeADP,collagen,arachidonicacid,andadrenaline(i.e.,endogenousstimulatorsofplateletaggregation).
Inthistest,theaggregatingagentisaddedtoatubeofplatelets,andthechangeinturbiditymeasured.Differentpatternsofresponse(ornon-response)canbediagnosticofdifferentplateletfunctiondisorders.
PointofCareTestingPointofcarecoagulationtesting:
InvolvestestingofwholebloodTraditionaltestingusesplasmaonly.
Thereforeincludesthecell-basedmodelofcoagulationMaybetterrepresentactualclottingfunctioncomparedwithtraditionalcoagulationfactortesting.
Providesinformationonallphasesofclotting
ViscoelasticMethods
Include:
Thromboelastography(TEG)Continuousmeasurementanddisplayofviscoelasticpropertiesofabloodsamplefrominitialfibrinformationtoclotretraction,andultimatelyfibrinolysis.Involves:
Aknownvolume(typically0.36ml)ofwholebloodaddedtoactivatorsintwodisposablecuvettes(cups)heatedto37°CContactactivators(suchaskaolin)areaddedtothebloodtoaccelerateclottingAheparinasecuvetteisalsocommonlyusedsoclottingfunctioncanbemeasuredduringfullanticoagulation(e.g.CPB)
PinattachedtotorsionwireimmersedintobloodTorsiononthepinisconverted(byatransducer)intoaTEGtracing.Cuvetterotatesthrough4°45′inalternatedirectionsEachrotationtakes10s.Pininitiallyremainsstationaryasitrotatesthroughtheun-clottedbloodThisisrepresentedbyastraightlineonthetracing.Asbloodclots,cuprotationexertstorqueonthepinThestrongerthebloodclot,thegreaterthetorqueexertedonthepin
RotationalThromboelastometry(ROTEM)
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ModifiedversionofTEG:ApinfixedtoasteelaxisisrotatedinbloodviamovementofaspringThecuvetteremainsstationary.Twosamplesareused:
Tissuefactorisaddedtomeasuretheextrinsicpathway(knownastheENTEMcuvette)Contactactivatorisaddedtomeasuretheintrinsicpathway(INTEMcuvette)
Impedancetorotationisdetectedbyanopticalsystem:LEDMirroronthesteelaxisElectroniccamera
UsesdifferentreferencerangesandnomenclaturetoTEG
AdvantagesandDisadvantagesofTEG/ROTEM
Advantages Disadvantages
Rapidcomparedwithtraditionaltesting Stillmeasurescoagulationinartificialconditions
Useswholeblood,providingamorecompletepictureofplasma-RBC-plateletinteraction
Doesnotmeasurecontributionofendotheliumandthereforeconditionsaffectingplateletadhesion(e.g.vonWillebrand'sdisease)
Real-timedisplayofclotevolution HardertoinstituteQAoutsideoflaboratory
Reducesnon-evidence-basedtransfusion Measurementmethodologyisnotyetstandardisedbetweeninstitutions
Predictiveofpost-operativehypercoagulablestates Baselinemeasurementdoesnotpredictpost-operativebleeding
Verysensitivetoheparineffect Doesnotmeasureeffectofhypothermia
Requirestrainingandcompetencyofnon-labstaff
Moreexpensivethantraditionaltesting
InterpretingTEG/ROTEM
Notethatreferencerangesarenotincludedhere,andwillvarydependingonthe:
Technique(TEG/ROTEM)usedActivatorusedAdjuvantsaddede.g.Citratedvs.recalcifiedsamples.
Parameter(TEG)
Parameter(ROTEM) Definition Relevance
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R(reaction)time
CT(clottingtime)
Timeuntil2mmamplitude
Timeuntilinitialfibrinformation,dependentonplasmaconcentrationofclottingfactors
KtimeCFT(clotformationtime)
Timeforamplitudetoincreasefrom2-20mm
Measurementofclotkinetics(clotamplification),dependentonfibrinogen
αangle αangle
Anglebetweenthetangenttothetracingat2mmandthemidline
Rapidityoffibrinformationandcross-linking.Alternatemeasureofclotkinetics,dependentonfibrinogen
MA(maximumamplitude)
MCF(maximumclotthickness)
GreatestamplitudeIndicatespointofmaximalclotstrength,dependentpredominantlyonplatelets(80%)andfibrinogen(20%),bindingviaGPIIb/IIIa.TreatmentwithplateletsorDDAVP.
CL30(clotlysis30)
LY30Percentdecreaseinamplitude30minutesafterMA
Clotstability,dependentonfibrinolysis.ReducedCL30canbetreatedwithanantifibrinolytic,suchasTXA
References
1. KraftsK.ClotorBleed:APainlessGuideforPeopleWhoHateCoag.PathologyStudent.2. ActivatedClottingTime-PracticalHaemostasis.3. SrivastavaA,KelleherA.Point-of-carecoagulationtesting.ContinEducAnaesthCritCarePain.2013;13(1):12-16.
Lastupdated2019-07-18
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SIUnitsTheInternationalSystemofUnits(SI,orSystèmeInternationald'Unités),isasetofmeasurementstandardswhichdefines(almost)allstandardsintermsofuniformnaturalphenomena,andformthebaseofthemetricsystem.
BaseSIUnits
TherearesevenbaseSIunits,withmanyderivedunitsmadefromcombinationsofthese.BaseSIunitsaremutuallyindependent.Theyconsistof:
Quantity Unit Abbreviation Definition
Time Second sDurationof9,192,631,770periodsoftheradiationcorrespondingtothetransitionbetweentwohyperfinelevelsofthegroundstateofanatomofCs-133
Length Metre m Distancethatlighttravelsinavacuumin1/299,792,458 ofasecond
Current Ampere ATheconstantcurrentthatwouldproduceaforceof2x10 Newtonbetweentwoconductorsofinfinitelengthandnegligiblecrosssectioninavacuum
Temperature Kelvin °K1/273.16 ofthetriplepointofwater.Thetriplepointisthetemperatureatwhichasubstanceexistsinequilibriuminallthreephases(solid,liquid,gas).
Amount Mole mol Theamountofsubstancewhichcontainsasmanyelementaryentitiesasin0.012kgofCarbon12
LuminousIntensity Candella cd Luminousintensityofasourcewhichemitsmonochromaticradiation
at540x10 Hzatradiantintensityof1/683wattspersteradian
Mass Kilogram kg WeightoftheInternationalPrototypeKilogram(IPK)
DerivedUnits
Quantity Unit Abbreviation ConversiontoBaseSIUnits Definition
Area Squaremetre m
Velocity MetreperSecond m.s
Acceleration MetreperSecondperSecond m.s
Force Newton N Forcerequiredtoaccelerate1kgat1m.s
Pressure Pascal Pa Forceperarea
Energy/Work/QuantityofHeat Joule J Energyconvertedwhen1Nis
appliedto1kgover1m
DoseEquivalence Sievert Sv Radiationdosepermass
th
-7
th
12
2
-1
-2
-2
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Power Watt W second
ElectromotiveForce Volt V Measureofelectricalpotentialenergy
References
1. PhysicalMeasurementLaboratory.NationalInstituteofStandardsandTechnology.Andvarioussubpages
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ElectricalSafetyUnderstandtheconceptsofpatientsafetyasitappliestomonitoringinvolvingelectricaldevices
ElectricalPrinciples
ChargeisthepropertyofasubatomicparticlewhichcausesittoexperienceaforcewhenclosetootherchargedparticlesChargeismeasuredincoulombs(C).
CurrentistheflowofelectronsthroughaconductorCurrentismeasuredinamps(A).
VoltageisthestrengthoftheforcethatcausesmovementofelectronsBytradition,voltagesarequotedrelativetoground(orearth).Ifapotentialdifferenceexists,acurrentwillflowfromthatobjecttotheearthviathepathofleastresistance.Ifthispathcontainsaperson,anelectricalinjurymayresult.
ResistancedescribestowhatextentasubstancereducestheflowofelectronsthroughitResistanceismeasuredinohms(Ω).
SubstanceswithhighresistanceareinsulatorsSubstanceswithlowresistanceareconductors
Inductanceisthepropertyofaconductorbywhichachangeincurrentinducesanelectromotiveforceintheconductor,andanynearbyconductors
CapacitanceistheabilityofanobjecttostoreelectricalchargeMeasuredinFarads(F),whereonefaradiswhenonevoltacrossthecapacitorstoresonecoulombofcharge.
Acapacitorisanelectricalcomponentconsistingoftwoconductorsseparatedbyaninsulator(calledadielectric)Whenadirectcurrentflows,electrons(anegativecharge)buildupononeoftheseconductors(calledaplate),whilstanelectrondeficit(positivecharge)occursontheotherplate
CurrentwillflowuntilthebuildupofchargeisequaltothevoltageofthepowersourceCurrentcanberapidlydischargedwhenthecircuitischanged
Analternatingcurrentcanflowfreelyacrossacapacitor,andcausesnobuildupofcharge
ImpedancedescribestowhatextenttheflowofalternatingcurrentisreducedwhenpassingthroughasubstanceImpedancecanbethoughtofas'resistanceforACcircuits',andisacombinationofresistanceandreactance.
Reactanceisafunctionoftwothings:InductionofvoltageinconductorsbythealternatingmagneticfieldofACflowCapacitanceinducedbyvoltagesbetweentheseconductors
ElectricalInjury
Potentialelectricalinjuriescanbedividedinto:
VentricularFibrillationLikelihoodisafunctionof:
CurrentdensityFrequencyLowestcurrentdensityrequiredisat50Hz.
BurnsFunctionofcurrentdensity.Burnstypicallyoccurattheentryandexitpointasthisiswherecurrentdensityishighest.
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TetanicContractionFlexorsarestrongerthanextensors,whichmaymaintaingriponlivewire.DeathmayresultfromeitherVForasphyxiationfromsustainedrespiratorymusclecontraction.
ElectricalShock
Electricalshocksaredividedintotwotypes,basedontheirabilitytoinduceVF:
MicroshockCurrentrequiredtoinduceVFwhenapplieddirectlytomyocardium.
Typicalcurrentis0.05-0.1mAThisrequiresskinbreachPotentialcauses:
GuidewirePacingleadColumnofconductingfluidCVCPICC
MacroshockCurrentrequiredtoinduceVFfromsurfacecontact.
Typicalcurrentis100mAThisismuchhigherbecausemostofthiscurrentisnotgoingtotheventricle,andsothetotalcurrentmustbegreatertoachievesufficientcurrentdensityinthemyocardiumtoinduceVF
Otherdetrimentaleffectsseenatlowercurrentsinclude:
Current(mA) Effect
1 Tingling
5 Pain
8 Burns
15 Skeletalmuscletetany
50 Skeletalmuscleparalysis&respiratoryarrest
PrinciplesofElectricalSafety
Powerpointscontainthreewires:
Active240V.MeasuringvoltageforACcurrentisnotintuitive,asthevoltagewillbenegativehalfthetime.Therootmeansquare(RMS)isusedinstead-eachvalueforthevoltageissquared(givingapositivenumber),andthendividedbythenumberofsamplestogiveanaverage.Neutral0V,relativetoground.EarthDirectpathwayintoground.
Anelectricalcircuitiscompletedbetweenanapplianceandthepowerstationbyreturningcurrenttothestationviatheearth.Thisisanearthreferencedpowersupply.
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ActivewireshortstoequipmentcasingPrincipleofearthwire,whichprovidespathofleastresistanceforcurrenttotravelifanindividualtouchesthecase
HighcurrentdrainthroughawiregeneratesheatandstartsafirePrincipleoffuseswhichtriggerwhencurrentdrainis>15A
MethodsofElectricalSafety
InsulationConductorsarecoatedbyahigh-resistancesubstance,preventingcurrentflowingwhereitshouldn't.
FusesSafetydeviceswhichceaseallcurrentflowwhencurrentexceedsacertainthreshold(typically20A).Ifthereisafaultwhichgreatlylowersresistance(i.e.insulationbreaks,causingadevicetobecomeliveanddrainviatheearthwire),ahighcurrentwillflowandthefusewillbetriggered.
Afaultrequires:AfaultthatcausesahighcurrentflowThefusetoworkcorrectly
ResidualCurrentDevicesAnRCDmeasuresthecurrentdifferencebetweentheactiveandneutrallines.
Inannon-faultsituation,thesewillbeequalInafaultsituation,currentwillbebeingdeliveredbytheactivelinebutnotreturnedviatheneutralCurrentwillinsteadflowtogroundviafaultyequipment/throughthepatient.
TheRCDwilldetectifthereisa>10mAdifferencebetweentheactiveandneutrallines,anddisconnectpowerwithin10msifitdoesso
Afaultrequires:CurrenttoflowAsinglefaultwillturnoffthecircuit
Pros:SafeCons:Willshutoffpowertothedevice,whichisbadforECMO/CPB/ventilatorswithoutbatterybackup
LineIsolationSupply,withalineisolationmonitorAlineisolatedsupplyisa'transformer'withanequalnumberofwindings,suchthatthevoltageproducedisthesameoneachside.However,thepowerpointisnotphysicallyconnectedtothesupply,creatinganearth-referencedfloatingsupply.
Afaultrequires:TwofaultsThismakesafailurewithpotentialforshockmuchlesslikely.
ActivewiremustbeconnectedtogroundNeutralwiremustbeconnectedtogroundAcircuitthenexists:activewire-ground-neutralwire,andacurrentcouldflow
AlineisolatedsupplyispairedwithalineisolationmonitorThismonitorstateshowmuchcurrentcouldflow,ifasecondfaultcompletedthecircuit.
ThisiscalledaprospectivehazardcurrentThelineisolationmonitorcontinuouslychecksthehazardcurrentbyevaluatingtheimpedancebetweentheactivewireandground,andtheneutralwireandground
Inano-faultsituation,bothimpedancesshouldbethesameandclosetoinfinite(Impedancewon'tbeabsolutelyinfiniteastherewillalwaysbeasmallcurrentleakfromdevices).Inasingle-faultsituation,thecalculatedimpedancefortheaffectedlinewillbesignificantlylower,andthereforetheprospectivehazardcurrentwillincrease
Analarmwillsoundwhentheprospectivehazardcurrentexceeds20mAPros:Asinglefaultisnotdangerousandwillnotresultinapowerloss(importantforvitalequipment)
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Cons:Twoormorefaultsaredangerous,andwillstillnotresultinapowerloss
EquipotentialearthingThisistheonlymethodwhichpreventsmicroshock.
Ultra-lowresistanceearthcablesareattachedtoelectricaldevicesandthepatientsbedThesecablesarethenattachedtospecialwallearthconnectorsThisensuresallequipmentisreferencedtoacommonground,minimisingtheriskofleakagecurrentsbetweendevicesandthepatient
ClassificationofElectricallySafeEquipment
Theseclassificationsaredesignedtolimitmacroshock:
ClassI:EarthedAnypartthatcancontacttheuserisearthedtoground.
Ifafaultdevelopssuchthatpartsofthedevicethattheusercantoucharelive,thenthereisariskofshockIfthecaseisearthed,thepathofleastresistanceshouldbeviatheearthwireThiswillcausealargecurrenttoflow,andshouldblowafuse,ceasingcurrentflow.
ClassII:Double-insulatedAllpartsofthedevicethattheusercantouchhavetwolayersofinsulationaroundthem,reducingthechanceofthedevicebecominglive.
ClassIII:Low-voltageDeviceoperatesatlessthan40VDC/24VAC,limitingtheseverityofshockadevicecandeliver.
ClassificationofElectricallySafeAreas
Bareas:ProtectionagainstmacroshockResidualCurrentDevicesLineIsolationSupply
BFareas:Cardiac(microshock)protectionEquipotentialEarthingAlldevices,andthepatient,areearthedtoeachotherbythickcopper(i.e.low-resistance),suchthatanypotentialdifferencebetweendeviceswillbeequalisedviathepathofleastresistance(thewire,notthepatient).
Zareas:Noparticularprotections
ElectricalDeviceswhichAttachtoPatients
DevicessuchasECGandBISrequireanelectricalconnectiontothepatient.Riskofelectrocutionbythesedevicesisreducedby:
Highresistancewires
References1. ElectricityandElectricalHazards.2. AlfredAnaesthesiaPrimaryExamTutorialProgram3. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.Scion
PublishingLtd.2014.
Lastupdated2019-07-18
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WheatstoneBridgeTheWheatstonebridgeisanelectricaldeviceusedtoaccuratelymeasureverysmallchangesinelectricalresistance.TheWheatstonebridgeis:
Usedinmanyothermedicaldevices(e.g.invasivepressuremonitoring)AdevicewithinfinitegainAnulldeflectiongalvanometerNotanamplifierAsitdoesnotincreasecurrentamplitude.
Mechanism
TheWheatstonebridgeconsistsof:
BatteryFourresistors
and areknownandfixed
isknownandadjustable
isunknownGalvanometer
TheWheatstonebridgereliesontheratioofresistancesbetweentheknown( )andunknown( )legs:
When )equalcurrentflowsdowneitherlimbandthereisnocurrentflowacrossthegalvanometerAtthispointthebridgeissaidtobebalanced.
Theequationcanthenbere-arrangedtosolvefor :
Verysmallchangesin leadtoacurrentflowacrossthebridge
canthenbeadjusteduntilthebridgeisbalanced,andthevalueof calculated
References
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1. AlfredAnaestheticDepartmentPrimaryExamTutorialSeries
Lastupdated2017-10-02
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NeuromuscularMonitoringDescribetheconceptofdepthofneuromuscularblockadeandexplaintheuseofneuromuscularmonitoring
Describetheclinicalfeaturesandmanagementofinadequatereversalofneuromuscularblockade
Thedegreeofneuromuscularblockadecanbeassessed:
ClinicallyCrudecomparedtoelectricalassessment.Testsinclude:
Sustainedheadlift>5secondsSuggests<30%blockade.V >10ml.kgTongueprotrusion
ElectricallyUsinganervestimulator.Canbe:
Visual/tactileMonitoringoftwitchheightbyanaesthetist.ElectricalMonitoringoftwitchheightbyadevice:
Accelerometer
Accelerationisproportionaltoforceforanygivenmass( ),thereforeanaccelerometertapedtothethumbcanbeusedtoassessforceofcontraction.MechanicalforcetransducersMuscletensionismeasuredusingastraingauge.Requirescontrolpriortoadministration.ElectromyographyEMGresponseismeasuredusingelectrodesoverthemuscle.TheAUCoftheresponsecurvecanbeusedtocalculatedegreeofblockade.
NerveStimulator
Anervestimulator:
Consistsoftwoelectrodes,apowersupply,andsomebuttonsforcontrolProducesamonophasic,squarewaveatconstantcurrent,lastingnomorethan0.3msGeneratesasupra-maximalstimulusEnsureseverynervefibreisdepolarised,whichmeansaconsistentlyreproducibleresponsewillbegenerated.Asupra-maximalstimulusis25%greaterthanthemaximumrequiredtodepolariseallnervefibres.AllowsassessmentofdifferentmusclegroupsNotallmusclegroupsareaffectedequallybyneuromuscularblockade.
TypicallysmallermusclegroupsaremoresensitiveThepositive(red)leadisplacedproximalUlnarnerveElectrodesareplacedalongtheulnarborderofthewristattheflexorcrease,andthumbadductionisassessed.FacialnerveThepositiveelectrodeisplacedattheoutercanthus,andthenegativeelectrodeisplacedanteriortothetragus.Eyebrowtwitchingisassessed.PosteriortibialnerveElectrodesareplacedposteriortothemedialmalleolus,andplantarflexionisassessed.
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StimulationPatterns
Therearefivecommonstimulationpatterns:
TrainofFourFoursingletwitches(0.1ms)deliveredat2Hz(i.e.1.5sforall4).
NumberofobservedtwitchesgivesanindicationofreceptoroccupancyWithincreasingblockade,theamplitudeandnumberofobservedtwitchesdecreases.
FadeisthereductionoftwitchheightwithrepeatedstimuliduringapartialneuromuscularblockOccursduetotheeffectofnon-depolarisingagentsonthepresynapticmembrane,reducingAChproduction.Numberofobservedtwitchesdependsonthedegreeofblockade:
Notwitches≈100%blockadeOnetwitch≈90%blockadeTwotwitches≈80%blockadeThreetwitches≈75%blockadeReversalagentsshouldnotbegivenwithaToFcount<3.Fourtwitches≈<75%blockade
TheratiooftheamplitudeofT toT (ToFratio)canalsobeusedasameasureofblockade:ToFratio>90%isadequateforextubationToFratio>70%suggestsadequaterespiratoryfunction
Shouldnotberepeatedfasterthanevery10s
TetanicstimulationHighfrequency(50-200Hz)supramaximalstimulusfor5seconds.
NormalmusclewillexhibittetaniccontractionPartiallyparalysedmuscleexhibitsfadeDegreeoffadeisproportionaltodegreeofblockade,andisverysensitive.
Post-tetaniccount(PTC)UsedindeepblockadewhenthereisnoresponsetoToF.Atetanicstimulusisgiven,followed3slaterbysingletwitchesat1Hz.
NoresponsemaybeseeninverydeepblockadeHowever,twitchesmaybeseenpriortothereturnofaToFresponse.Thisiscalledpost-tetanicfacilitation,andoccursduetothetetanicstimulusmobilisingAChvesiclesintothepre-junctionalarea.
Typically,aToFof1willoccurwhenthePTC≈9Shouldnotberepeatedfasterthanevery6minutesDuetoresidualpost-tetanicpotentiation.
DoubleburstTwo0.2ms50Hz(tetanic)stimuliareapplied750msapart.
TwoidenticalcontractionsoccurinnormalmuscleAmplitudeofthesecondburstisreducedinpartiallyparalysedmuscleDBratioissimilartotheToFratio,butiseasiertoassessclinically.Aratio>0.9isrequiredforadequatereversal
SingletwitchAsinglestimuluslasting~0.2msisapplied.
>75%blockadecausesadepressedresponseAtwitchmustbeassessedpriortoblockadesoabaselinecanbeestablished
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References
1. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.2. Saenz,AD.PeripheralNerveStimulator-TrainofFourMonitoring.2015.Medscape.3. McGrathCD,HunterJM.Monitoringofneuromuscularblock.ContinuingEducationinAnaesthesiaCriticalCare&Pain,
Volume6,Issue1,1February2006,Pages7–12.
Lastupdated2019-07-18
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PressureTransductionDescribetheprinciplesofmeasurement,limitations,andpotentialsourcesoferrorforpressuretransducers,andtheircalibration
Describetheinvasiveandnon-invasivemeasurementofbloodpressureandcardiacoutputincludingcalibration,sourcesoferrorsandlimitations
Atransducerconvertsoneformofenergytoanother.Pressuretransducersconvertsapressuresignaltoanelectricalsignal,andrequireseveralcomponents:
CatheterTubingStopcockFlushTransducer
Thissystemmustbecalibratedintwoways:
StaticcalibrationCalibratestoaknownzero.DynamiccalibrationAccuraterepresentationofchangesinthesystem.
StaticCalibration
Staticcalibrationinvolves:
Levelingthetransducer(typicallytothelevelofthephlebostaticaxisattherightatrium,ortheexternalauditorymeatus)Achangeintransducerlevelwillchangethebloodpressureduetothechangeinhydrostaticpressure(incmH O).Zeroingthetransducer
OpeningthetransducertoairZeroingthetransduceronthemonitorAchangeinmeasuredpressurewhenthetransducerisopentoairisduetodrift,anartifactualmeasurementerrorduetodamagetothecable,transducer,ormonitor.
DynamicCalibration
Dynamiccalibrationensurestheoperatingcharacteristicsofthesystem(ordynamicresponse)areaccurate.Dynamicresponseisafunctionof:
DampingHowrapidlyanoscillatingsystemwillcometorest.
DampingisquantifiedbythedampingcoefficientordampingratioDescribestowhatextentthemagnitudeofanoscillationfallswitheachsuccessiveoscillationCalculatedfromtheratiooftheamplitudesofsuccessiveoscillationsinaconvolutedfashion:
,where:
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ResonantFrequencyHowrapidlyasystemwilloscillatewhendisturbedandleftalone.
Whendampingislow,itwillbeclosetothenaturalfrequency(orundampedresonantfrequency)
Dampingandnaturalfrequencyareused(ratherthanthephysicalcharacteristics)astheyarebotheasilymeasuredandaccurateindescribingthedynamicresponseThesepropertiesareactuallydeterminedbythesystemselasticity,mass,andfriction,butitisconceptuallyandmathematicallyeasiertousedampingandresonance
PressureWaveformsandDynamicResponse
ThedynamicresponserequiredisdependentonthenatureofthepressurewavetobemeasuredAccuratelyreproducinganarterialwaveformrequiresasystemwithagreaterdynamicresponsecomparedtoavenouswaveform
Anarterialpressurewaveformisaperiodic(repeating)complexwave,thatcanberepresentedmathematicallybyFourieranalysisFourieranalysisinvolvesexpressingacomplex(arterial)waveasthesumofmanysimplesinewavesofvaryingfrequenciesandamplitudes
Thefrequencyofthearterialwave(i.e.,thepulserate)isknownasthefundamentalfrequencyThesinewavesusedtoreproduceitmusthaveafrequencythatisamultiple(orharmonic)ofthefundamentalfrequency
Increasingthenumberofharmonicsallowsbetterreproductionofhigh-frequencycomponents,suchasasteepsystolicupstroke
Accuratereproductionofanarterialwaveformrequiresupto10harmonics-or10timesthepulserateAnarterialpressuretransducershouldthereforehaveadynamicresponseof30Hz
Thisallowsaccuratereproductionofbloodpressureinheartratesupto180bpm(180bpm=3Hz,3Hzx10=30Hz)
Resonance
Ifhighfrequencycomponentsofthepressurewaveformapproachthenaturalfrequencyofthesystem,thenthesystemwillresonateThisresultsinadistortedoutputsignalandasmallovershootinsystolicpressure.
Damping
Apressuretransductionsystemshouldbeadequatelydamped:
Anoptimallydampedwaveformhasadampingof0.64.Itdemonstrates:Arapidreturntobaselinefollowingastep-change,withoneovershootandoneundershoot
Acriticallydampedwaveformhasadampingcoefficientof1.Itdemonstrates:
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Themostrapidreturntobaselinepossiblefollowingastep-changewithoutovershootingAnover-dampedwaveformhasadampingcoefficientof>1.Itdemonstrates:
Aslowreturntobaselinefollowingastep-changewithnooscillationsSlurredupstrokeAbsentdicroticnotchLossoffinedetail
Anunder-dampedwaveformhasadampingcoefficientcloseto0(e.g.0.03).Itdemonstrates:Averyrapidreturntobaselinefollowingastep-changewithseveraloscillationsSystolicpressureovershootArtifactualbumps
Optimallydampedwaveformsareaccurateforthewidestrangeoffrequencyresponses:
TestingDynamicResponse
Dynamicresponsecanbetestedbyinducingastep-changeinthesystem,whichallowscalculationofboththenaturalfrequencyandthedampingcoefficient.Clinically,thisisperformedbydoingafast-flushtest.
Fastflushvalveisopenedduringdiastolicrunoffperiod(minimisessystemicinterference)Thepressurewaveproducedindicatesthenaturalfrequencyanddampingcoefficientofthesystem:
ThedistancebetweensuccessiveoscillationsshouldbeidenticalandequaltothenaturalfrequencyofthesystemTheratioofamplitudesofsuccessiveoscillationsgivesthedampingcoefficient
OptimisingDynamicResponse
Thelowerthenaturalfrequencyofamonitoringsystem,thesmallertherangeofdampingcoefficientswhichcanaccuratelyreproduceameasuredpressurewave.Therefore,theoptimaldynamicresponseisseenwhenthenaturalfrequencyisashighaspossible.Thisisachievedwhenthetubingis:
ShortWideStiffFreeofairIntroducinganairbubblewillincreasedamping(generallygood,sincemostsystemsareunder-damped),howeveritwilllowerthenaturalfrequencyandisdetrimentaloverall.
Footnotes
FundamentalsofPressureMeasurement
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Pressureexertedbyastaticfluidisduetotheweightofthefluid,andisafunctionof:
Fluiddensity(inkg.L )Acceleration(effectofgravity,inm.s )Heightofthefluidcolumn
Thiscanbederivedasfollows:
,thereforeCombiningtheaboveequations:
Thisisusuallyexpressedas:
NotethatthisexpressiondoesnotrequirethemassorvolumeoftheliquidtobeknownThisiswhypressureisoftenmeasuredinheight-substanceunits(e.g.mmHg,cmH O)
References
1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. AlfredAnaestheticDepartmentPrimaryExamProgram3. Miller,RD.ClinicalMeasurementofNaturalFrequencyandDampingCoefficient.In:Anesthesia.5thEd.Churchill
Livingstone.
Lastupdated2019-07-18
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PressureWaveformAnalysisDescribetheinvasiveandnon-invasivemeasurementofbloodpressureandcardiacoutputincludingcalibration,sourcesoferrorsandlimitations
Analysisofarterialpulsecontouris:
Real-timeandcontinuousUsedtoestimatecardiacoutputLessaccuratebutalsolessinvasive(e.g.thermodilution)ortechnicallydemanding(e.g.echocardiography)thanothermethods.
Thereforealsocalculate(andoftendisplay)strokevolumevariationandpulsepressurevariation
PrinciplesAllmodelsrecognisethattheamplitudeofthesystolicupstrokeis:
DirectlyproportionaltostrokevolumeInverselyproportionaltoarterialcompliance
Otherprinciplesusedbysome(butnotall)devicesinclude:
Three-elementWindkesselmodelCharacterisesthearterialtreeashavingthreemajorfeatures:
AorticImpedanceArterialCompliancePredictedusingpatientcharacteristics.SystemicVascularResistance
ConservationofMass
Devices
Devicescanbeclassifiedbasedonwhethertheyare:
Calibrated/UncalibratedCalibratedInitialestimationisrefinedusingadilutiontechnique.
Dilutionsmaybeby:Thermodilution
ColdsalineinjectedintoSVCUsinganIJVorSCVCVC.Temperaturechangedmeasuredatthefemoralartery
LithiumdilutionSmallamountsoflithiumchlorideinjectedintoacentralveinChangeinlithiumconcentrationmeasuredinradialarteryCObycalculatedStewart-Hamiltonequation
PeriodicallyrecalibratedtocorrectfordriftUncalibratedNotcorrectedforameasured'true'cardiacoutput.
Inaccurateforshorttermchangesinarterialproperties
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Notvalidatedin:ShockARDSHepaticsurgeryDuetochangesinarterialtone.Cardiacsurgery
Invasive/Non-invasiveInvasiveRelyona(usuallyfemoral)arterialcatheter.Non-invasiveRelyonthevolumeclampmethod:
InflatablecuffwrappedaroundfingerPlethysmographestimatesbloodvolumeinthedigitalarteriesCuffinflatesanddeflatesthroughoutthecardiaccycle,keepingthevolumeofthearteriesconstantArterialpressureisproportionaltocuffpressure.Inaccuratein:
PeripheraloedemaVasoconstrictedstates
CommonDevicesinUse
PiCCO/VolumeView/FloTracCalibratedInvasive3-elementWindkesselMechanism:
CalculatesareaundersystolicpartofthearterialcurveDividescalculatedareabyaorticcomplianceComplianceestimatedbyproprietaryalgorithmeachtimethedeviceiscalibrated.
SVRiscontinuouslyestimatedfromcalculatedCOandmeasuredBPLiDCO
CalibratedInvasiveConservationofmassComplianceinferredfrombiometricdata
Clearsight/CNAPUncalibratedNon-invasive
T-LineCalibratedProprietary,non-validatedauto-calibratingalgorithm.Non-invasiveUsesradialapplanationtonometry
References1. JozwiakM,MonnetX,TeboulJ-L.PressureWaveformAnalysis.AnesthAnalg.2017.2. Francis,SE.ContinuousEstimationofCardiacOutputandArterialResistancefromArterialBloodPressureusingaThird-
OrderWindkesselModel.MIT.2007.
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Non-InvasiveBloodPressureDescribetheinvasiveandnon-invasivemeasurementofbloodpressureandcardiacoutputincludingcalibration,sourcesoferrorsandlimitations
Non-invasivebloodpressuremeasurementsisperformedwitheithera:
DeviceforIndirectNon-invasiveAutomaticMeanArterialPressure(DINAMAP)Automaticbloodpressurecuff.VonRecklinghausen'soscillotonometer"Manual"bloodpressurecuff.
Usestwocuffs,andthereforetwotubes
DINAMAPComponents:
OnecuffPerformsbotharterialocclusionandmeasurement.TubingDeviceforinflatingtheocclusivecuffandgraduallydeflatingitPressuretransducerDisplay
Method:
CuffisinflatedaboveSBPCuffdeflatesatarateof2-3mmHg.sWhencuffpressureequals:
SBPTurbulentflowoccurspastthecuff,creatingpressureoscillations.ThepressureatwhichthesearefirstdetectedistheSBP.MAPThepressureatwhichamplitudeofoscillationsismaximal.
DBPiscalculatedfromMAPandSBP
Cons
RequiresanappropriatelysizedcuffCuffshouldbe~20%greaterthanarmdiameter.
Cuffsthataretoosmallwillover-readCuffsthataretoowidewillunder-read
RequiresaregularrhythmInaccurateatextremesofbloodpressureInaccuratewhenusedmorefrequentlythanonceperminuteInaccuratewhenthevesselisincompressible
HeavilycalcifiedvesselsWhenappliedtoforearm/foreleg
Maycauseneuropraxia
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VonRecklinghausen'sOscillotonometer
Components:
TwocuffsOcclusivecuffMeasurementcuff
TubingDeviceforinflatingtheocclusivecuffandgraduallydeflatingitAneroidbarometerfortransducingpressureDisplay
Process:
CuffisinflateduntiltheradialpressureisnolongerpalpableThisisapproximatesSBP.Cuffisdeflated,andre-inflatedto20mmHgabovetheestimatedSBPCuffisdeflatedatarateof2-3mmHg.s whilstauscultatingthebrachialarteryWhencuffpressureequals:
SBPTurbulentflowoccurspastthecuff,turbulentflowcausesthefirstoftheKorotkoffsounds(cleartappingpulsations)tobeheard.DBPThecuffnolongercompressesthevesselatall,sonoturbulentflowoccursandnothingisauscultated.
References
1. ANZCAJuly/August20002. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.Scion
PublishingLtd.2014.3. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.
Lastupdated2019-07-18
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CardiacOutputMeasurementDescribetheinvasiveandnon-invasivemeasurementofbloodpressureandcardiacoutputincludingcalibration,sourcesoferrorsandlimitations
Explainthederivedvaluesfromcommonmethodsofmeasurementofcardiacoutput(i.e.measuresofvascularresistance)
Cardiacoutputmeasurementcanbeperformed:
InvasivelyPulmonaryArteryCatheter
ThermodilutionFickPrinciple
TOEArterialwaveformanalysis
PiCCOVigileo
Non-invasivelyTTEMRIThoracicimpedance
Thermodilution
Thermodilutionremainsthegoldstandardofcardiacoutputmeasurement.
Thistechnique:
RequiresapulmonaryarterycatheterVariousdifferentdesignsexist.ForCOmeasurement,theyrequire:
AproximalportattheRA/SVCAtemperatureprobeatthetipTypicallyasiliconoxidethermistor.AballoonatthetipTofloatitintoposition.Adistal(PA)portisrequiredformeasuringPAPandthePCWP,butisnotrequiredforCOcalculation
MethodforIntermittentCardiacOutputMeasurementbyThermodilution
Aknownvolumeof(typicallydextrose)ataknowntemperature(classicallycooled,butthisisnotrequired)isinjectedintotheproximalportThetemperatureofbloodismeasuredatthetipThisproducesatemperature-timecurve.Theareaunderthecurvecanbeusedtocalculatecardiacoutput,asperthemodifiedStewart-HamiltonEquation:
,where:
=Cardiacoutput
=Volumeofinjectate
=Temperatureofblood
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=Temperatureofinjectate
=DensityconstantRelatestothespecificheatandspecificgravityofbothinjectateandblood.
=ComputationconstantAccountsforcatheterdeadspaceandheatexchangeduringinjection.
=Areaunderthechangeintemperature-timecurve
ErrorsinThermodilution
NaturalvariabilityCardiacoutputvariesupto10%withchangesinintrathoracicpressureduringrespiration.Therefore:
Ameanof3-5measurementsshouldbetakenMeasurementsshouldbetakenatend-expiration
IncorrectvolumeofinjectateToomuchunderestimatesCOToolittleoverestimatesCO
WarmfluidThecloserthetemperatureofinjectateistoblood,thegreaterdegreeoferrorintroducedtothemeasurement.
Colderinjectateismoreaccurate,butcarriestheriskofinducingbradyarrhythmiasPoorlypositionedPACThePACmustbepositionedinWest'sZone3forbloodflowtooccurpastthetip,andforthemeasuredtemperaturetobeaccurate.TricuspidregurgitationResultsinretrogradeejectionofinjectatebackpastthevalve.Arrhythmia
FickPrinciple
CardiacOutputcanalsobemeasuredusingtheFickPrinciple.Thistechnique:
UsestheFickPrincipleTheflowofbloodtoanorganisequaltotheuptakeofatracersubstancedividedbythearterio-venousconcentrationdifference.
Inthiscase,thetracersubstanceisoxygenThe'organ'isthewholebody
Thisproducestheequation: ,where:
isCardiacOutput
isthepatientsoxygenconsumptionTypicallyestimatedas3.5ml.kg .min
isarterialoxygencontent
ismixedvenousoxygencontentReliesonmixedvenousbloodsampledfromthepulmonaryartery,andarterialbloodsampledfromaperipheralarterialline
References
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1. Moise,S.F.,Sinclair,C.J.andScott,D.H.T.(2002),Pulmonaryarterybloodtemperatureandthemeasurementofcardiacoutputbythermodilution.Anaesthesia,57:562–566.
2. Nishikawa,T.&Dohi,S.Errorsinthemeasurementofcardiacoutputbythermodilution.CanJAnaesth(1993)40:142.
Lastupdated2019-07-18
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PulseOximetryDescribetheprinciplesofpulseandtissueoximetry,co-oximetryandcapnography,includingcalibration,sourcesoferrorsandlimitations
Pulseoximetryreliesonseveralprinciples:
OxygenatedanddeoxygenatedhaemoglobinabsorblightofdifferentwavelengthstodifferentextentsLightof660nmand940nmisused.
Deoxyhaemoglobinhasagreaterabsorbanceofred(660nm)lightthanoxyhaemoglobinOxyhaemoglobinhasagreaterabsorbanceofinfrared(940nm)lightthandeoxyhaemoglobinTherelativeabsorbanceofeachallowsdeterminationoftheproportionsofoxygenatedanddeoxygenatedhaemoglobin
TheBeer-LambertLaw(s):Absorptionoflightpassingthroughasubstanceisdirectlyproportionaltoboththedistanceittravelsthroughthesubstanceandtheconcentrationofattenuatingspecieswithinthesubstance.Itisacompositeof:
Beer'sLawAbsorptionoflightisproportionaltotheconcentrationof"attenuatingspecies"Lambert'sLawAbsorptionisproportionaltothethicknessofthesolution,ormoreprecisely,thateachlayerofequalthicknessabsorbsanequalproportionofradiationthatpassesthroughit
Bloodflowispulsatile
Method
Apulseoximeterconsistsof:
TwodiodesofthedesiredwavelengthsPhotocellMicroprocessor
Duringpulsatileflow,theexpansionandcontractionofthebloodvesselsaltersthedistanceandhaemoglobinconcentrations,changingtheabsorptionspectraofblood(aspertheBeer-LambertLaw).
Non-pulsatileelementsareduetotissuesandvenousblood
Thesearesubtractedfromthetotal,leavingthepulsatileelementwhichrepresentsthearterialcomponentTheratioofabsorbanceofthepulsatileelementsandthenon-pulsatileelementsiscalledR,andiscalculatedas:
RiscomparedwithasetofstandardisedvaluestodeliveracalculatedSpO
AnRof1givesanSpO of85%AnRof0.4givesanSpO of100%AnRof2givesanSpO of50%
TheIsobesticPoint
TheisobesticpointisthewavelengthatwhichlightisabsorbedequallybybothhaemoglobinspeciesLightabsorptionisthereforeindependentofsaturation,andisinsteadafunctionofhaemoglobinconcentrationThiscanbeusedtocorrectforhaemoglobinconcentrationTherearetwoisobesticpointsforoxygenatedanddeoxygenatedhaemoglobin,at590nmand805nm
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Limitations
RequiresdetectablepulsatileflowLimitedbypoorperipheralperfusion(shock,hypotension,hypothermia)andnon-pulsatileflow(ECMO,CPB)Bodymovementsconfoundreadings(shivering,seizing)
LowsaturationsInaccuratebelow70%,andcompletelyunreliablebelow50%.
VenouspulsationDetectedaspulsatileflow,anderroneouslyinterpretedbythemicroprocessorasarterialflow.
ConfoundedbyambientlightThediodesarecycledatseveralhundredtimespersecondwhichallowsthedetectortocompensatefortheeffectofambientlight(thevalueswhenthediodesareoffgivetheeffectofambientlight).
Absorptionspectraconfoundedby:Haemoglobinopathies
Carboxyhaemoglobincausesthepulseoximetertoreadartificiallyhighduetoasitalsoabsorbs660nmlightMethaemoglobinaemiacausestheSpO totrendtowards85%,asthoughitabsorbs660nmlightisalsoabsorbs940nmlighttoagreaterdegree
DyesMethylenebluewillcausetheSpO toread<65%forseveralminutesIndocyaninegreenwillalsocauseadecreasedSpO
References1. DavisPD,KennyD.BasicPhysicsandMeasurementinAnaesthesia.5thEd.Elsevier.2003.2. MardirossianG,SchneiderRE.LimitationsofPulseOximetry.AnesthProg39:194-1961992.3. CICMMarch/May20144. TremperKK,BarkerSJ.Pulseoximetry.Anesthesiology.1989Jan;70(1):98-108.5. WilliamsGW,WilliamsES.BasicAnaesthesiologyExaminationReview.OxfordUniversityPress.2016.
Lastupdated2019-07-18
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OxygenAnalysisDescribetheprinciplesofmeasuringoxygenconcentration
Asoxygenisamoleculecontainingtwosimilaratoms,itspartialpressurecannotbedeterminedusinginfraredtechniques(unlikeCO ).Oxygencontentofagasisinsteaddeterminedusing:
ParamagneticanalysesFuelCells
ParamagneticAnalysisPrinciplesofparamagneticanalysis:
OxygenisparamagneticThismeansitisattractedbymagneticfields,butdoesnotpropagatethefield.
Thisisbecauseitstwounpairedvalentelectronshavethesamespin.Manyothergasesweaklyrepelledbymagneticfields(diamagnetic)
Theattractionofagasmixturetoamagneticfieldisthereforeproportionaltoitsoxygencontent
Manydifferentmethodsexistwhichusethispropertytodetermineoxygencontent
PressureMethod
GastestedflowsintoatubeAreferencegasflowsintoaparalleltubeBothgasesthenpassthrough:
FlowrestrictorsMagneticfieldThisisbeingturnedonandoffat~100Hz.
ThegasescombineinthemagneticfieldThegreatertheoxygencontentofthegas,themoreitwillmoveintothemagneticfieldThismovementcreatesanegativepressurebehindthegas.Thepressuredifferencebetweenthetestedgasandthereferencegasisproportionaltotheoxygencontentofthetestgas.
TemperatureMethod
Usedinmanymoderndevices.
Gasflowsthroughamagneticfield,causingtheparticlestoalignThischangesthethermalconductivityoftheoxygenmolecules.ThechangeinthermalconductivityofthegasmixtureisproportionaltotheoxygencontentThisisdetectedbymeasuringcurrentpassingthroughaheatedwire
Pros
AccurateRapidresponsetimeModernanalyserscanidentifybreath-to-breathvariationinFiO .Don'trequireregularcalibration
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Cons
WatervapourreducesaccuracyInterferencefromotherparamagneticgases
NitricoxideEffectisminimalasnitricisdeliveredinfarsmallervolumesthanoxygen,andisonlyweaklyparamagnetic.
FuelCells
Fuelcellsrelyonreductionofoxygentomeasureoxygenpartialpressure.Theyconsistof:
OxygenpermeablemembraneKOHsolutionThiscontains:
LeadanodeLeadisconsumedasthefuelcelloperates.Goldcathode
Method
OxygendiffusesacrossthemembraneintothepotassiumhydroxidesolutionAtthecathode:
Attheanode:
Theoxygenconsumptionisproportionaltothecurrentgenerated,whichismeasuredwithanammeter
Pros
NopowerrequiredSmallAccurate
Cons
WillaccumulatenitrogeninthepresenceofN OResultsinanunder-readingofPO .Mustbereplacedafter6-12monthsRequiresregulartwo-pointcalibration21%and100%oxygenareused.Relativelyslowresponsetimecomparedtoparamagneticanalysers~20s.
References1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.Scion
PublishingLtd.2014.
Lastupdated2019-07-18
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OxygenAnalysis
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End-TidalGasAnalysisDescribetheprinciplesofpulseandtissueoximetry,co-oximetryandcapnography,includingcalibration,sourcesoferrorsandlimitations
Principles
SeveralmechanismsforE CO measurementexist:
InfraredSpectroscopyColourimetricMethodsRaymanScatteringGasChromatography
InfraredSpectroscopy
Infraredspectroscopyreliesonthefactthat:
GaseswithtwoormoredifferentatomswillabsorbinfraredradiationDifferentgasesabsorbingdifferentwavelengthstodifferentdegreesMeasuringtheabsorbedwavelengthsandcomparingwiththelikelycompositionofamixture,asystemcanbedesignedusingaspecificwavelengthtomeasuregasconcentrationsandavoidinterference
End-tidalgasanalysisusinginfraredlightisusedinthemeasurementof:
COCapnographyisthecontinuousmeasurementandgraphicaldisplayofthepartialpressureofCO inexpiredgas.ThisisthemostcommonmethodtomeasureE CO .Anaestheticagents
MeasurementofCOComponents:
SapphiresamplingchambercontaininggassampleCO absorbsinfraredradiationatapeakwavelengthof4.28μmThesapphirelensonlyallows4.28μmlightthrough
EmitterDetectorMicroprocessorDisplay
Method:
LightisemittedandpassesthroughthesamplingchamberAlensisusedtofocusemittedlight.LevelsofradiationaremeasuredontheothersideofthechamberLevelscorrespondtotheamountofgaspresentinthesampleThelessradiationthatreachesthedetector,themoregasthereisinthesampleabsorbingit
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EquipmentErrors
Errorscanbeclassifiedinto:
SpecifictotechniqueThecollisionbroadeningeffectIntermolecularforcesvarydependingontheirproximitytoothermoleculesinthegasmixture.Achangeinintermolecularforcesmayaltertheirbond-energyandthefrequenciesatwhichtheyabsorbradiation.Itcanbeovercomeby:
CorrectingforthepresenceofothergasesManuallyadjustingtheobtainedvalues
CrossoverwithothergasmixturesCO andN Ohavesimilarabsorbancespectra,andmayleadtoerrorwhenadeviceisnotdesignedtomeasurebothwavelengths.
FailureofequipmentThesecanbeovercomebyuseofdouble-beamcapnometer.ThisusesareferencechamberwhichcontainsCO -freeair,andthesameemitter-detectorsystem.Allabsorptionfromthissystemmustoccurduetoartifact(asnoCO ispresent).Theartifactualcomponentisthensubtractedfromthevaluedetectedinthemainchamber.Thiscorrectsfor:
VariableamountofinfraredradiationreleasedVariablesensitivityofthedetectorVariableefficacyofthecrystalwindowandlenssystem
RelatingtotypeofcapnometerusedE CO maybeeitherside-streamorin-line.
Side-streamCO involvesalengthofnarrowtubingdrawinggasfromtheexpiratorylimbofthebreathingcircuit(typicallyfromtheHMEfilter)tothecapnograph
Side-streamrequiresaflowof150ml.minHasa(prettyinsignificant)delay(<1s)inmeasurementMaybeblockedbywatervapour,andrequireuseofawatertraptoremovecondensation
In-linesystemshaveasamplingchamberattachedin-linewiththeETTThesamplingchamberslightlyincreasesthedead-spaceofthecircuitMayberelevantinchildrenorverydifficulttoventilatepatients.AddsweighttopatientendofthebreathingcircuitRequireheatingto41°Ctoavoidcondensation
NormalE CO Waveform
Thenormaltraceconsistsoffourcomponents:
1. ThebaselineThisconsistsof:
Inspiratorytime
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Earlydead-spaceexhalationThisistheperiodimmediatelybeforephase2,wheresomegaswithaPCO of0isexhaled.
2. Alveolarexhalation,wherePCO risesrapidly3. Alveolarplateau,wherePCO flattens
Thehighest-pointofthiscurveislabeledE CO .4. Inspiration,wherePCO returnsto0
E CO WaveformVariations
Airwayobstruction:
Occursduetounevenemptyingofalveoliwithdifferenttime-constants
Hyperventilation:
LowerE CO withshorterbaselinePlateauphasemaynotoccuratveryhighrespiratoryrates
Rebreathing:
BaselineincreasesasinspiredCO ismeasuredfromgasanalyser
ChangesinE CO
NormalE CO is32-42mmHg,whilstnormalPaCO is35-45mmHg.
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HighE CO
Thismaybefrom:
DecreasedventilationDecreasedRRDecreasedVIncreasedV andthereforeagreaterV :V ratio
IncreasedproductionofCOIncreasedmetabolicrate
SepsisTourniquetreleaseROSCfollowingarrest
IncreasedinspiredRebreathing(i.e.equipment/ventilatormalfunction)ExternalsourceofaddedCO
LowE CO
RapidLossofE CO
FailureofventilationCircuitdisconnectAirwayobstructionBronchospasm
FailureofcirculationCardiacarrestShock
GradualLossofE CO
IncreasedV (i.e.increasedMV)DecreasedCO production
HypometabolicstateHypothermia
IncreasedV ,i.e.V/QmismatchIncreasedWestZoneIphysiology:
HypotensionIncreasedRVAfterload:
PEHighPEEP
SamplingerrorAirentrainmentintothesamplechamberInadequateV
DiscrepancybetweenE CO ,PACO ,andPaCO
ThenormalgradientbetweenPaCO andE CO is0-5mmHg.Healthyandawakeindividualsshouldhaveessentiallyno(<1ml)alveolardeadspace,andsoessentiallynogradient.Thisgradientisincreasedinpatientswith:
V/QmismatchE CO willunderestimatearterialCO asgasfromun-perfusedalveoli(withnegligibleCO )willdiluteCO expiredgas
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ColourimetricMethods
Litmuspaperwhichchangescolourwhenexposedtohydrogenions(producedbyCO )canbeusedtoconfirmendo-trachealintubation,thoughtheymaygeneratefalse-positiveresultsduetogastricpH.
References
1. CrossME,PlunkettEVE.Physics,Pharmacology,andPhysiologyforAnaesthetists:KeyConceptsfortheFRCA.2ndEd.CambridgeUniversityPress.2014.
2. DavisPD,KennyD.BasicPhysicsandMeasurementinAnaesthesia.5thEd.Elsevier.2003.3. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.
Lastupdated2019-07-18
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BloodGasAnalysisDescribethemethodsofmeasurementofoxygenandcarbondioxidetensioninbloodandbloodpH
Bloodgasmachinesdirectlymeasurethreevariablesandcalculatetheremainder.Measuredvariablesare:
POCOpH
Calculatedvariablesinclude:
BicarbonateUsingthepH,CO andtheHenderson-Hasselbalchequation.BaseExcessCalculatedusingtheHenderson-HasselbalchandSiggaard-Andersonequation.Canbeexpressedintwoways:
BaseExcessTheamountofalkalithatmustbeaddedtothesampletoreturnittoanormalpH,atatemperatureof37°CandaPaCO of40mmHg.StandardisedBaseExcessAsbaseexcess,butcalculatedforbloodwithaHbconcentrationof50g.L .ThisisthoughttobetterrepresenttheECFasawhole.
OxygenTensionOxygentensionismeasuredwithaClarkeelectrode.Thisconsistsof:
AchamberforthebloodsampleAchambercontainingapotassiumchloridesolution,which:
Isseparatedfromthebloodchamberbyanoxygen-permeablemembraneThispreventsbloodbeingindirectcontactwiththecathode,whichwouldleadtoproteindepositiononthecathodeandincorrectmeasurement.ContainsaplatinumcathodeContainsasilver/silverChlorideanode
Abatteryapplying0.6Vacrosstheelectrodes
Method
Avoltageof0.6Visappliedacrosstheelectrodes,causingthesilvertoreactivewithchlorideinthesolutiontoproduceelectrons:
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Thispotentialdifferenceisrequiredtostartthereaction0.6Vischosenbecauseitisenoughtostartthereactionbutwillhaveminimaleffectonmeasuredcurrentflow
Atthecathode,oxygencombineswithelectronsandwatertoproducehydroxylions:
Foreachoxygenmoleculepresentatthecathode,fourelectronscanbeconsumedIncreasingtheoxygenavailableatthecathodeincreasesthenumberofelectronsconsumed,andthereforeincreasescurrentflow
OxygenwillmovefromthesamplechambertothemeasuringchamberaccordingtoitspartialpressureMeasuredcurrentflowisthereforeproportionaltooxygentensioninblood
Calibration,Limitations,andAccuracy
CalibrationisperformedwithstandardgasmixturesRequiresregulartwo-pointcalibration.CathodemustbekeptcleanfromproteinandnotdamagedCathodemustbekeptat37°CMayreadfalselyhighwithhalothane
pHMeasurement
pHisameasureofthehydrogenionconcentration insolution,andisdefinedasthenegativelogarithmtothebase10ofthe[H ]:
ApHof7.4isa[H ]of40nmol.L at37°CAchangeinapHunitof1isequivalenttoa10-foldchangeinthe[H ]AchangeinpHof0.3isequaltodoublingorhalvingthe[H ]
ThepHelectrodeconsistsof:
AchamberforthebloodsampleAmeasuringchamber,separatedfromthesamplebyH -permeableglass,whichcontains:
AbuffersolutionAsilver/silverchloridemeasuringelectrode
Areferencechamber,alsoseparatedfromthechamberbyH -permeableglass,whichcontains:AKClsolutionHasnobufferingproperties.
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Amercury/mercurychloridereferenceelectrode
Method
ReliesontheprinciplethattwosolutionswithdifferentH activitieswilldevelopapotentialdifferencebetweenthem(proportionaltotheconcentrationgradient)H passesthroughtheglassalongaconcentrationgradient:
Avariablepotentialdifferenceisgeneratedinthemeasuringchamber,asH ionsarebufferedandtheconcentrationgradientismaintainedAconstantpotentialdifferenceisgeneratedinthereferencechamber,asthereisnobufferofH ionsintheKClsolution
OnceH hasequilibratedbetweenbloodandtheKClsolution,thepotentialdifferencebetweenthemeasuringandreferenceelectrodesisproportionaltotheH concentrationinblood
Calibration,Limitations,andAccuracy
Calibrationisperformedwithtwophosphatebuffersolutionscontainingtwodifferent(known)[H ]Mustbekeptat37°CHypothermiaincreasessolubilityofCO andthereforelowersPaCOAreducedpartialpressureofCO isrequiredtokeepthesamenumberofmoleculesdissolved(asperHenry'sLaw)
Therefore,asbloodcoolsitspHwillincreaseElectrodesmustbekeptcleanfromproteinandnotdamaged
CarbonDioxideTension
CarbondioxidetensionismeasuredwithaSeveringhauselectrode,whichisbasedonthepHelectrode,asPaCO2isrelatedto[H ].TheSeveringhauselectrodeconsistsof:
Achamberforthebloodsample,separatedfromthebicarbonatechamberbyaCO permeablemembraneAchambercontainingbicarbonatesolutioninanylonmesh,andseparatedfromboththemeasuringandreferencechambersbyH -permeableglassAmeasuringchambercontaining:
AbuffersolutionAsilver/silverchloridemeasuringelectrode
Areferencechambercontaining:AKClsolutionAmercury/mercurychloridereferenceelectrode
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Method
CO diffusesfrombloodintothebicarbonatechamberCO reactswithwaterinthebicarbonatechambertoproduceH ionsFromhere,theprocessisidenticaltothepHelectrode,exceptbicarbonatetakestheplaceofblood:
H ionsdiffuseintothereferencechamberuntiltheH ionconcentrationhasequilibratedH ionscontinuallydiffuseintothemeasuringchamber(astheyarebuffered)
ThisestablishesaconstantpHgradientThisgradientisproportionaltheH ionconcentrationinthebicarbonatechamber,whichisproportionaltotheCO contentofblood.
Calibration,Limitations,andAccuracy
CalibrationisperformedwithsolutionsofknownCO concentrationMustbekeptat37°CHypothermiadecreasessolubilityofCO andthereforedecreasespHElectrodesmustbekeptcleanfromproteinandnotdamagedSlowresponsetimerelativetopHelectrodeduetotimetakenforCO todiffuseandreactThiscanbeacceleratedwithcarbonicanhydrase
Footnotes
.TechnicallypHisdefinedastheactivityofH inasolution.Clinically,activityisidenticaltoconcentration,soinmedicinethesedefinitionsarefunctionallythesame.↩
References1. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.
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2. (FRCA-MeasurementofpO2,pCO2,pH,pulseoximetryandcapnography)[http://www.frca.co.uk/article.aspx?articleid=100389]
3. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.
Lastupdated2018-09-21
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GasFlowDescribethemeasurementofflow,pressureandvolumeofgases
TypesofFlow:
LaminarflowFluidmovinginasteadymannerwithoutturbulence.TurbulentflowIrregularfluidmovementinradial,axial,andcircumferentialaxes.
Laminarflowismoreefficientthanturbulentflow,asitrequiresasmallerpressuregradienttogeneratethesameflowFortwofluidsmovingatthesamespeed,thevelocityofindividualparticlesinlaminarflowwillbebothhigherandlower
TransitionalflowMixtureoflaminarandturbulentflow.Flowistypicallyturbulentinthecentre,andlaminarattheedges.
Devicesusedtomeasuregasflowinclude:
Variable-OrificeFlowmetersFixed-OrificeFlowmetersPneumotachograph.Hotwireflowmeter
NoteorificebasedflowmetersrelyontheHagan-PoiseuilleEquation:
Viscosity( )andlength( )arefixedbybothdevicesFixedorificeflowmetersalsofixradius( ),suchthatthechangeinpressuremustthereforebeproportionaltoflow:
,where isaconstant
Variableorificeflowmetersalsofixpressure( ),suchthatflowcanbecalculatedfromtheradius:
Flowmeters
Constantpressure,variableorificeflowmetersarefoundonwallandcylindergases.Theyconsistof:
Aninverseconicaltube(i.e.narroweratthebottom,andwideratthetop)AneedlevalveAbobbinMayhaveagroovewhichcausesthebobbintospin,confirmingitisnotstuck.
Method:
GasflowsfromthebottomtothetopofthetubeThebobbinobstructsflowThereforethereisapressuredifferenceacrossit.
Remember:
Atequilibrium,thepressureexertedbythebobbinontheflowofgas( )
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isequaltothepressureexertedbythegasonthebobbin
Asflowisincreased,thebobbinispushedfurtheruptheflowmeterduetotheincreasedpressureThebobbinwillreachanewequilibriumpositionwhentheorificeoftheflowmeterhasbecomewideenoughforthepressureonthebobbintoequalthepressureofgravity
Flowmetersarecalibratedforindividualgasesas:
Laminar(typicallylowflows)flowisproportionaltoviscosityTurbulent(typicallyhighflows)flowisproportionaltodensity
Pros
CheapNoadditionalpowersupplyrequiredAccurateReadingsmaybealteredby:
ChangeintemperatureaffectsviscosityanddensityofgasChangeinpressureaffectsdensityofgas
Cons
MustbeverticalBobbinscanbecomestuck
PneumotachographsConstantorifice,variablepressureflowmeter.Severaldifferentdesignsexist,andinclude:
FleischpneumotachographConsistsofseveralfineboreparalleltubesplacedinthegascircuitDecreasedradiusandincreasedresistancereducesgasflowvelocity,improvinglaminarflow.AdifferentialpressuretransducerisplacedateitherendofthetubesThepressuredropacrossthetubingisdirectlyproportionaltoflow
PitottubesConsistsoftwotubesplacedintothegascircuit:
OnefacesintothegasflowTheotherfacesawayfromthegasflow
Thepressuredifferencebetweentubesisproportionaltoflow
Pros
AccurateContinualmeasurementAllowcalculationofvolumes
Cons
IncreasedresistanceIncreaseddeadspaceRequirelaminarflow
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Inaccuratewhen:FlowsarehigherthanwhatthesystemisdesignedforAlterationingasdensity
ChangeingasmixtureAlterationingastemperature
HotWireFlowmeter
Components:
TwofineplatinumwiresinthegascircuitOneheatedto180°CatOL.minOneat0°C
Ammeter
Method:
Asgasflows,thewirecoolsRateofheatdissipationisproportionaltogasflowTheamountofcurrentrequiredtoreturnthewireto180ismeasured,andisproportionaltoflow
Pros
AccurateFast
Cons
Fragile
References
1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.
Lastupdated2019-07-18
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PrinciplesofUltrasoundDescribethephysicalprinciplesofultrasoundandtheDopplerEffect.
Ultrasoundisanimagingtechniquewherehigh-frequencysoundwaves(2-15MHz)areusedtogenerateanimage.Anultrasoundwaveisproducedbyaprobeusingthepiezoelectriceffect:
CertaincrystallinestructureswillvibrateataparticularfrequencywhenacertainvoltageisappliedacrossthemTheconversionofelectricalenergytokineticenergyishowtheultrasoundprobecreatesanultrasoundwave.Similarly,theycangenerateavoltagewhenavibrationisinducedinthemThisishowtheprobeinterpretsreflectedwaves.
BasicPrinciplesSpatialresolutionHowclosetwoseparateobjectscanbetoeachotherandstillbedistinguishable.Itisdividedinto:
Axialresolution,howfaraparttwoobjectscanbewhenoneisabovetheother(inthedirectionofthebeam)Lateralresolution,howfaraparttwoobjectscanbewhensideside-by-side
Contrastresolutionishowsimilartwoobjectscanappear(inechogenicappearance)andstillbedistinguishable
Higherfrequencysettingsoffergreaterspatialresolutionbutdecreasedpenetration
LowerfrequencysettingsofferreducedspatialresolutionbutincreasedpenetrationTheyareusedforvisualisingdeepstructures.
AffectofTissuesonUltrasoundAttissueinterfaces,thewavemaybe:
AbsorbedSoundislostasheat,andincreaseswithdecreasedwatercontentoftissues.ReflectedSoundbouncesbackfromthetissueinterface,andreturnstotheprobe.
Reflectionisdependentonthe:DifferenceinsoundconductionbetweenthetwotissuesAngleofincidence(closeto90°improvesreflection)Smoothnessofthetissueplane
Theamplitudeofsoundreturningtotheprobedeterminesechogenicity,orhowwhitetheobjectwillbedisplayedThetimetakenforthesoundtoreturndeterminesdepth
Thetimetakenforawavetoreturnisproportionaltotwicethedistanceoftheobjectfromtheprobe
Depthcanbecalculatedusing ,where:
isDepthisthespeedofsoundintissue,andisassumedtobe1540ms
tisTimeTransmittedSoundpassesthroughthetissue,andmaybereflectedorabsorbedatdeepertissues.ScatteredSoundisreflectedfromtissuebutisnotreceivedbytheprobe.
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Attenuationdescribesthelossofsoundwavewithincreasingdepth,andisafunctionoftheabovefactors.AttenuationismanagedbyincreasingthegainGainreferstoamplificationofreturnedsignal.Time-gaincompensationreferstoamplificationofsignalswhichhavetakenlongertoreturn,whichamplifiessignalsreturnedfromdeeptissues
Modes
Ultrasoundmodesinclude:
B-Mode(brightnessmode)Thestandard2Dultrasoundmode,andplotsthemeasuredamplitudeofreflectedultrasoundwavesbythecalculateddepthfromwhichtheywerereflected.M-Mode(movementmode)Selectsasingleverticalsectionoftheimageanddisplayschangesovertime(i.e.depthonthey-axis,andtimeonthex-axis).
DopplerEffect
Thedopplereffectisthechangeinobservedfrequencywhenawaveisreflectedoff(oremittedfrom)amovingobject,relativetothepositionofthereceiver.Inmedicalultrasound,thisisthechangeinfrequencyofsoundreflectedfromamovingtissue(e.g.anerythrocyte).Itisgivenbytheequation:
where:
=Velocityofobject
=Frequencyshift=Speedofsound(inblood)
=Frequencyoftheemittedsound
=Anglebetweenthesoundwaveandtheobject
Reflectedfrequenciesarehighertowardstheprobeandloweraway.
CalculationofCardiacOutput
Remember, .
HeartrateismeasuredStrokevolumeiscalculatedby:
Measuringthecross-sectionalareaoftheleftventricularoutflowtractObtainedbymeasuringthediameterusingultrasound.MeasuringthestrokedistanceObtainedviaintegratingthevelocity-timewaveformfortimeacrosstheleftventricularoutflowtract(LVOTVTI).
Theintegralofflow(m.s andtime(s))fortime(s),producesadistance(m)MultiplyingtheLVOTcross-sectionalarea(m )bythestrokedistance(m),producesavolume(m )Thisisthestrokevolume.
References
-12 3
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1. CrossME,PlunkettEVE.Physics,Pharmacology,andPhysiologyforAnaesthetists:KeyConceptsfortheFRCA.2ndEd.CambridgeUniversityPress.2014.
2. CICMJuly/September2007.
Lastupdated2019-07-18
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TemperatureandHumidityDescribethemeasurementoftemperatureandhumidity
Temperatureisthetendencyofabodytotransferheatenergytoanotherbody,andismeasuredindegrees.Itisdistinctfromheat,whichisthekineticenergycontentofabody,andismeasuredinJoules.Thetwoarerelatedbythespecificheatcapacity,whichdescribeshowmuchenergy(J)mustbeappliedtoabodytoraiseitstemperaturefrom14°Cto15°C,withoutachangeinstate.
Humiditymaybeeitherabsoluteorrelative:
AbsoluteHumidityisthemassofwatervapourinavolumeofairRelativeHumiditymeasuresthepercentagesaturationofairatcurrenttemperature,ormoreformally:
MeasurementofTemperature
Temperatureismeasuredbyanumberofmethods:
LiquidExpansionThermometry
Thisisusedinmercurythermometers.Theseconsistof:
Agraduatedevacuatedcapillaryofnegligiblevolume,attachedtoAmercuryreservoir,ofmuchgreatervolume,separatedbyAconstrictionringPreventstravelofmercuryupthecapillarybygravity.
Mechanism:
Whenheated,thekineticenergyofthemercuryincreasesanditexpands,forcingitupthecapillaryAsthethermalexpansioncoefficientforallliquidsisverysmall,thecapillarymustbeofaverysmallvolumetocreateausabledevice.Thespeedthatthisoccursisrelatedtothetime-constantofthesystemThisistypically30seconds.Measurementthereforetakes~4time-constants,or2minutes.
Pros
EasytouseAccurateReusableSterilisableCheap
Cons
SlowresponseOnlyaccurateonceithasreachedthermalequilibrium.GlasscanbreakMaycausereleaseofmercuryoralcohol.Inaccurateat:
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LowtemperatureswithmercuryFreezesat-38.8°C.HightemperatureswithalcoholBoilsat78.5°C.
Electrical
Electricalmethodsinclude:
ResistancethermometerPlatinumwireincreaseselectricalresistancewithincreasingtemperature.
ThereforethevoltagedropacrossthewirewillcorrespondtothetemperatureofthewireChangeinresistanceislinearacrossthetemperaturerangeHowever,theseareexpensive.
ThermistorMetal(e.g.SiO )semiconductorwhichchangesitsresistanceinapredictablynon-linearfashion(run-awayexponent)withtemperature.
CanbemanufacturedsothatchangeislinearovertheclinicalrangeMuchcheaperthanwireresistancemethodsThedegreeofvoltagedropisusuallyverysmall,howeverthiscanbeamplifiedusingaWheatstonebridge
ThermocoupleAtthejunctionoftwodissimilarmetals,apotentialdifferencewillbeproducedproportionaltotheirtemperature.ThisisknownastheSeebeckeffect.
Non-linear(washinexponent)Degradeovertime
MeasurementofHumidity
Humiditycanbemeasuredbyanumberofmethods:
HairHygrometerHair(actualhair)changeselasticitydependingonthehumidityofair.Changesinelasticitycanberelatedtochangesinhumidity.
WetandDryBulbThissystemmeasuresbothtemperatureandrelativehumidity.
TwothermometersareusedOneiswrappedinawick,whichisattachedtoawaterreservoirThisisthewetthermometer.Thedrythermometergivesameasurementofsurroundingairtemperature
ThewetthermometeriscooledduetoevaporativecoolingfromthewickHighenergywatermoleculesbecomevapour,leavingonlylowenergymoleculesbehind.Thetemperaturedifferencebetweenthethermometersisafunctionof:
LatentheatofvapourisationofwaterHowmuchevaporativecoolingisoccurringThisisfunctionofhumidity.
At100%relativehumidity,noevaporativecoolingwilltakeplaceandthetemperatureswillbeequalAshumiditydecreases,evaporativecoolingwillcoolthewetthermometer,andthetemperaturedifferenceallowshumiditytobedetermined
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References
1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.
2. AlfredAnaestheticDepartmentPrimaryExamTutorialSeries
Lastupdated2019-07-18
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ElectrocardiographyDescribetheprinciplesbehindtheECG
TheECGisagraphicalrepresentationoftheelectricalactivityoftheheart,asmeasuredbythesumofelectricalvectorsatthepatientsskin.
Components
AnECGconsistsof:
ElectrodesDisposable,stickycomponentswhichactasconductorsduetoasilver/silverchloridecoating.Toreduceelectrodeimpedance,skinshouldbe:
HairlessDryClean
CablesShieldedtopreventcurrentsbeinginducedandelectrocutingthepatient.ProcessorMonitor
ECGLeads
ECGleadsarecreatedbytakingthepotentialdifferencebetweentwoelectrodes,whichvariesby0.5-2mVthroughthecardiaccycleasmyocardiumdepolarises.ECGleadsaredividedinto:
LimbleadsPotentialdifferencebetweenlimbelectrodes:
I:RAtoLAII:RAtoLLIII:LAtoLL
AugmentedleadsPotentialdifferencebetweentheaverageofthelimbleads(calledtheindifferentelectrode)andeachindividuallimblead.
AugmentedleadsareofmuchlowervoltageandmustbeamplifiedThreeaugmentedleadsexist(oneforeachlimbelectrode)
PrecordialleadsPotentialdifferencebetweentheindifferentelectrodeandoneofthesixadditionalelectrodesplacedonthechestwall.
TherelationshipbetweenelectrodesandleadsisdescribedwithEinthoven'sTriangle:
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Method
Asthemyocardialmembranepotentialchangesacrossthecardiaccycle,apotentialdifferencecanbemeasuredattheskin.Adepolarisationwavetravelingtowardsthepositiveelectrode(orarepolarisationwavetravelingaway)willcauseanupwarddeflectionintheECG
Thesepotentialdifferencesareverysmall,andthereforeneedtobe:DistinguishedfrombackgroundinterferenceSeveraltechniquesexist:
CommonmoderejectionIdenticalelectricalactivityoccurringinmultipleelectrodesislikelyduetointerferenceratherthancardiacactivity,andisremovedfromthemeasuredsignal.
AgroundelectrodeistypicallyusedforthispurposeECGmodesECGscanbesettovaryinglevelsofsensitivity.
DiagnosticmodeRespondstohigherrangeoffrequencies,butisatgreaterriskofinterference.MonitormodeECGrespondstoalowerrangeoffrequencies,reducinginterferencebutalsoresolution.Thisiscommonon3-leadECG.
HighinputimpedanceMinimisessignalloss.
AmplifiedFrequenciesinthedesiredsignalrangeareamplified.
SourcesofError
ImprovesignaldetectionGoodadherenceOptimalskincontactEnsuredryandhairless.
MinimiseexternalelectrostaticforcesEarthedDiathermyShivering
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Risks
ECGelectrodescanactasanexitelectrodeforsurgicaldiathermy
References
1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.
2. CICMFebruary/April2016
Lastupdated2019-07-18
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HumidifiersHumidifiersaddwatervapourtoinspiredgas,takingtheplaceofnormalbodymechanismswhicharebypassedorimpededbyinvasiveandnon-invasiveventilation.Maintainingadequatehumidityofinspiredgasisimportantin:
ReducingmetabolicloadHumidificationofinspiredgasaccountsfor~15%ofbasalheatexpenditure.MaintainingfunctionofthemucociliaryelevatorInspirationofdrygasincreasesviscosityofmucous.ReducingwaterlossWaterwillbeabsorbedfrommucosatohumidifygas.
Humidifierscanbeclassifiedintoactiveorpassive.
PassiveHumidifiersPassivehumidifiers:
DonotrequirepowerDonotrequirewater
TheHeatandMoistureExchange(HME)filteristheclassicpassivehumidifier:
PlacedbetweenthepatientandthepatientY-pieceConsistsof:
AmoistureexchangelayerPleated,hygroscopicallycoatedfoamorpaper.
Expiredgascoolsasitpasses,condensingontothefoam,withcondensationpromotedbyhygroscopiccoating(usuallythisisNaCl)Thelatentheatofvapourisationresultsinadecreasedtemperatureofexpiredgas
AfilterlayerTypicallyaelectrostaticorhydrophobicmaterial.
ExpiredgasiscooledanddriedInspiredgasisthenheatedandhumidifiedAnHMEtakesupto20minutestobefullyeffective,andcanachievearelativehumidityupto70%Efficacydependsuponthepatient'scoretemperatureandtheconditionoftheairway
Pros
CheapLightweightStraightforwardMaycontainanti-bacterialfilter
Cons
MaybeblockedwithvomitandsecretionsIncreaseairwayresistanceIncreasedeadspaceNotaseffectiveaspoweredactivesystemsOnlylast24hours
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Takes15-20minutestobecomefullyeffective
ActiveHumidifiers
ActiveHumidifiers:
Requireeither:PowerUnpoweredhumidifiersaretypicallylesseffective,andonlyoperatewellatlowerflowrates.Water(Orboth)
Consistof:AwaterbathTypicallysterilewater.AheatingelementToheatthewaterbath.AgaspipeInspiredgasesarebubbledthroughthewaterbathtohumidifythem.AwatertrapTotrapcondensedwater.Shouldbechangedregularlytominimiseinfectionrisk.
Pros
GreaterhumidificationAppropriateforlong-termventilation
Cons
BulkyExpensiveRequirepowerInfectionriskfromwaterbath
References
1. McNultyG,EyreL.Humidificationinanaesthesiaandcriticalcare.ContinuingEducationinAnaesthesiaCriticalCare&Pain,Volume15,Issue3,1June2015
Lastupdated2019-07-18
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SupplementalOxygenDescribedifferentsystemstodeliversupplementaloxygenandtheadvantagesanddisadvantagesofthesesystems
Devicesfordeliveryofoxygencanbeclassifiedinto:
VariableperformancedevicesFixedperformancedevices
VariablePerformanceDevicesVariableperformancedevices:
DonotdeliverafixedFiOThisisbecauserespiratoryflowisnon-uniformAlthoughminuteventilationmaybe5-6L.min ,peakinspiratoryflowsaresubstantiallyhigher.DeliveredFiO isdependentonoxygenflowandinspiratoryflow
IncreasingoxygenflowratewillincreaseFiO ,buttheeffectwillvarydependingonthedevice(volume,seal)andthepatient
Include:NasalCannulaeProngsdeliveringgasat1-4L.min .
Higherflowsmaydrymucosa,andleadtoepistaxisNasopharynxactsasanoxygenreservoir,somewhatincreasingFiOWelltolerated
Alloweating,drinking,andtalkingHudsonMaskSimpleunsealedmask,allowinggasflowupto15L.min .
CheapLesswelltoleratedRebreathingmayoccur
Non-RebreatherMaskModifiedversionoftheHudsonmask,containingareservoirbag.
ReservoirbagisfilledduringexpirationGasisdrawnfromthereservoirbagduringinspiration,increasingFiOSomeairisentrainedfromaroundthemaskandsoFiO is<1.
FixedPerformanceDevices
Fixedperformancedevices:
TheoreticallydeliverafixedFiOTheseareusuallyflowlimitedaswell,andsoFiO maydecreaseathigherinspiratoryflows.Include:
VenturiConsistsofaconethroughwhichoxygenflows.Aperturesonthesideoftheconeentrainroomair.
Airisentrainedvia:FrictionaldragofmoleculesTheventurieffect(thoughthisiscontroversial)
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Thewideningoftheconeleadstoanincreaseinfluidvelocityandthereforeadecreaseinpressure,asperthe
Bernoulliprinciple.Entrainedairisproportionaltoflowrate,sotheratioofoxygentoairisconstantforanygivenaperturesizeThisisknownastheentrainmentratio.WilldeliverthespecifiedFiO providedoxygenflowisabovetheminimumrateThereforebecomevariableperformancedeviceswheninspiratoryflowgreatlyexceedsoxygenflow.
References1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.Scion
PublishingLtd.2014.
Lastupdated2019-07-18
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BispectralIndexDescribetheprinciplesbehindtheBIS
BispectralIndex(BIS)isaproprietarysignal-processedEMGandEEGmonitorusedtoestimatedepthofanaesthesia.
TheBISoutputsfourvalues:
BISDimensionlessindexbetween0and100where:
0representscorticalelectricalsilence85-100representsnormalawakecorticalactivity40-60isconsistentwithgeneralanaesthesia
SignalQualityIndex(SQI)Dimensionlessindexbetween0and100whichgivesanindicationoftheaccuracyoftheBISvalue.ElectromyographyGivesanindicationoftheinfluenceofmuscleactivityonBISvalues.SuppressionRatio(SR)Percentageofprevious63secondswhereEEGisisoelectric.
Method
Proprietary,butinvolves:
MultivariatelogisticregressionofEEGfeaturesthatcorrelatewithclinicallevelsofsedationInitialvalidationonacohortofhealthyvolunteers,notundergoingsurgeryUseoffourfrontotemporalEEGmonitors
Analytictechniques:
CompressedSpectralArrayThesignaloverashortperiod(e.g.5-10seconds)ofEEGrecordingsareanalysedtogetherEachperiodisknownasanepoch.AFouriertransformationisperformedThisbreakstheEEGsignaldownintothesinewavesusedtoproduceit.AhistogramofeachfrequencyisplottedAsanaesthesiadeepens,lowerfrequenciesbegintodominateThespectraledgefrequencyisthefrequencygreaterthan95%ofthefrequenciesinthecompressedspectralarrayItisanindicatorofanaestheticdepth,butnotofdrugconcentration.
CoherenceUnderanaesthesia,theelectricalactivityindifferentsectionsofthebrainfallsoutofphase.
Pros
ReducedanaestheticawarenessinhighriskpatientgroupsTrauma,GAcaesariansection,cardiacsurgery.Non-invasiveUseappearstoresultinreducedanaestheticuseandmorerapidemergence
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Cons
ProprietaryalgorithmExpensiveMaybeinaccuratewith:
HypothermiaHypercarbiaHypoxiaMusclerelaxantsBISmayfallinappropriately.Non-GABAergicagents(e.g.ketamine,nitrousoxide)Maynotfallappropriately.
References
1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.
Lastupdated2019-07-18
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MedicalGasSupplyDescribethesupplyofmedicalgases(bulksupplyandcylinder)andfeaturestoensuresupplysafetyincludingpressurevalvesandregulatorsandconnectionsystems
Production
FractionalDistillation
Oxygenisproducedontheindustrialscalebyfractionaldistillationofatmosphericair.Thisprocess:
ReliesonthefactthatdifferentgaseshavedifferentboilingpointsByliquefyingairandthenheatingitgradually,eachgascanberemovedseparatelyasitboils.Occursinstages:
AtmosphericairisfilteredRemovesdustandothercontaminants.Airiscompressedto6atmandthencooledtobelowambienttemperatureWatervapourcondensesandisremoved.CompressedairpassedthroughazeolitesievewhichremovesCOCompressedairisallowedtore-expandAsitdoessoitlosesheatenergyasperGay-Lussac'sLaw,andliquefies.
AirmustbecooledbelowtheboilingpointofthedesiredgasesThisrequiresgettinggasesverycold,andsotheprocessmaybemechanicallyassistedusingaturbine,and/oraheatexchanger.Keyboilingpoints(at1atm):
Nitrogen:77°KOxygen:90°KHelium:4°KHeliumcanbeproducedbyfractionaldistillation,butliquefyingitisunderstandablydifficultgiventhevery,verylowboilingpoint.Heliumcanalsobemined,asheliumproducedbyalphadecayofradioactivematerialsmaybetrappedingaspocketsundertheearth.
LiquidairisthenfractionallydistilledTemperatureofliquidairisraisedslowly.
Astheboilingpointofeachgasisreached(e.g.77°Kfornitrogen),thatgaswillbegintovapourisefromtheliquid,andcanbecollectedTheremainingliquidcanthenbefurtherheated,untiltheboilingpointforthenextgasisreachedThisprocesscanberepeateduntilallthedesiredgaseshavebeenseparated
OxygenConcentrator
Oxygenconcentrators:
Produceupto95%oxygenfromairbyremovingnitrogenBuiltusingtwozeolitelattices
PressurisedairisfilteredthroughonelatticeNitrogenandwatervapourareretainedinthelatticeOxygenandargonareconcentratedProducesa95%oxygen/5%argonmixture.
Theunusedcolumnisheatedtoreleasetheboundnitrogenandwater
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Pros
CheapReliableAvoidneedforoxygendelivery
Cons
ResultinanaccumulationofargonwhenusedatlowflowsonacirclesystemRequirecontinuouspowerFireandexplosionrisk
Storage
MedicalGasCylinders
Gascylindersare:
MadefromchromiummolybdenumoraluminiumUsedas:
BackupforapipedsupplyWhenapipedsupplyisnotavailable(transports)Whenthegasisuncommonlyused(e.g.nitricoxide)
ThecommoncylinderusedinhospitalisCDThiscontains460Lofoxygenat15°Cand137bar.
Cylindersarenotcompletelyfilled,toreduceriskofoverpressureandexplosionsifthetemperaturerisesThefillingratioistheweightofliquidinafullcylindercomparedtotheweightofwaterthatwouldcompletelyfillthecylinder
Incoolclimates,thefillingratiois~0.75Inwarmerclimates,thefillingratioisreducedto~0.67
Cylindersaretestedforsafetyevery5-10yearsTestsinclude:
EndoscopicexaminationTensiletests1%ofcylindersaredestroyedtoperformtestingonthemetal.
Pros
PortableReusable
Cons
HeavyLimitedsupply
CylinderManifolds
Cylindermanifoldsareformedofsetsoflargegascylindersusedinparallel.
Allcylindersinagroupareusedtogether
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Whenthepressurefallsbelowasetlevel,apressurevalvewillswitchandgaswillbedrawnfromanothercylindergroupThefirst(nowempty)cylindergroupisexchangedforfullcylinders
Pros
CheapUsefulasabackupsupply
Cons
LesscapacitythanaVIEFireandexplosionrisk
VacuumInsulatedEvaporator
TheVIE:
StoresliquidoxygenItisvacuuminsulatedasitmustkeepoxygenbelowitscriticaltemperature(-119°C).TheVIEtypicallystoresoxygenbetween-160°Cand-180°C,andat700kPa.
ThegasisstoredbelowitscriticaltemperatureandaboveitsboilingpointTheamountofoxygenremainingiscalculatedfromitsmass
DoesnotrequireactivecoolingInsteaditiscooledby:
InsulationEvaporationHeatenteringtheVIEcausesliquidoxygentoevaporate.OxygenvapourisdrawnofftheVIEtothepipelinesupply,sotheVIEremainscoolandatasteadypressureprovidedoxygenisbeingdrawnfromit.
HasapressurereliefvalvetopreventexplosionsifoxygenisnotbeingusedHasanevaporatortoevaporatelargevolumesofoxygenrapidlyifdemandishigh
Thisissimplyanuninsulatedpipeexposedtotheoutsidetemperature
Pros
CheapestoptionforoxygendeliveryandstorageStoringoxygenasaliquidismuchmoreefficientthanasagasDoesnotrequirepower
Cons
Set-upcostsareexpensiveRequiresaback-upsetupWillwastelargevolumesofoxygenifnotbeingusedcontinuouslyFireandexplosionrisk
SafetyinMedicalGasSupply
Manysystemsexisttoensuresafety:
ColourcodingofcylindersandhosesOxygeniswhiteNitrogenisblack
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AirisblackwithwhiteshouldersNitrousoxideisblueHeliumisbrown
HelioxisbrownwithwhiteshouldersCarbondioxideisgrey-green
LabelingofconnectionsThepinindexsystemUsedtopreventthewronggasyokebeingconnectedtoacylinder.
PinsprotrudefromthebackoftheyokeHolesexistonthevalveblockPinsandholesmustlineupforthecylindertobeconnectedTherearesixpositions,dividedintotwogroupsofthreeCommoncombinationsinclude:
Oxygen:2-5Air:1-5Nitrousoxide:3-5
SleeveIndexSystemUsedinAustraliawhenconnectingpipelinegases.
WallblockcontainsasleevewhenpreventsfittingtheincorrectgashosetothewallScrewthreadisidenticalinallcases
Non-InterchangeableScrewThread(NIST)Used(butnotinAustralia)whenconnectingpipelinegases.
NISTconnectorshaveaprobeandanutProbediameterisgas-specific,preventingthewronggasfrombeingconnected
TestingMustdemonstrate
CorrectoxygenconcentrationsAbsenceofcontaminationDeliveryofadequatepressurewhenseveralothersystemsonthesamepipelineareinuse
Testingmustbeperformedtwiceonanewinstallation:FirstbyengineersSecondbyamedicalofficerIntheatres,thisshouldbethedirectoroftheanaestheticdepartmentortheirdelegate,whoshouldholdfellowshipofANZCA.
References
1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.
2. ANZCAAugust/September20163. TheEssentialChemicalIndustryOnline-Oxygen,Nitrogen,andtheraregases.4. Thompson,C.TheAnaestheticMachine-GasSupplies.UniversityofSydney.
Lastupdated2019-07-18
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VapourisersDescribetheprinciplesandsafeoperationofvapourisers
Deliveryofgasthatisfullysaturatedwithanaestheticagentwouldresultinlethaldosesbeingadministered.Theuseofavapouriserallowsasafedoseofanaestheticagenttobegiven.Vapouriserscanbedividedinto:
VariablebypassvapourisersAirthatisfullysaturatedwithgasismixedwitha'bypass'streamofgas,dilutingthedeliveredconcentration.Furthersubdividedinto:
PlenumRequiressupra-atmosphericpressuretooperate.
MoreaccurateDraw-overDrivenbythepatientsinspiratoryeffort.
Portable
VariableBypassVapouriserVariablebypassvapourisersaimtodeliverthesameconcentrationofanaestheticagentoverarangeofflows.Theyachievethisby:
FlowmanagementBafflesandwicksincreasethesurfaceareaoftheliquid/gasinterface,increasingtherateofvapourisation.
ExcessivelyhighflowratesmayresultingasnotbeingfullysaturatedwithagentwhenitexitsthevapouriserstreamThesearelesseffectiveindraw-overvapourisers,asresistancemustbeminimised
TemperaturemanagementTheSVPofvolatileagentsincreasesnon-linearlyastemperatureincreases.Temperaturechanges:
Occurthrough:ChangesinambienttemperatureLossthroughlatentheatofvapourisationLiquidagentfromthevapouriserwillcooloverthecourseofananaesthetic.
Aremanagedwith:TemperaturestabilisationUseofmaterialswithbothahighthermalconductivityandspecificheatcapacity,allowingthevapourisingchambertobufferchangesinsurroundingtemperature.TemperaturecompensationAdjustsflowintoeitherthevapourisingchamberorbypasschambertoaccountforchangesinenvironmentaltemperature.Methodsinclude:
BimetallicstripMetalstripwhichbendsinresponsetoenvironmentaltemperature,adjustingtheamountofgasenteringthevapourisingchamber.AneroidbellowsConnecttoaconeintheopeningofthebypasschamber.Astemperaturedecreases,thebellowscontractandtheconepartiallyobstructsthebypasschannel.
DifferenceBetweenPlenumandDraw-OverVapourisers
Plenumvapourisersare:
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MoreaccurateDesignedtodeliveraccurateagentconcentrationsoverawiderange(0.25-15L.min )offlowrates
Below250ml.min theresistanceoftheflowsplittingvalvebecomesmoresignificant,causingtheamountofgasinthebypassstreamtobehigherthanintendedAbove15L.min gasmaynotbefullysaturated
HeavierTypicallybuiltofmetalssuchascoppertomaximisethermalstability.Highinternalresistance
Mustbeusedout-of-circleMustbeusedwithpositive-pressure
Draw-OverVapourisersare:
LessaccurateLessuseofbafflesandwickstominimiseinspiratoryresistance
LessthermallystableOxfordMinatureVapouriserdoesnothaveabimetallicstripOxfordMinatureVapouriserusesglycolasathermalbuffer
MeasuredFlowVapourisersMeasuredflowvapourisershaveaseparatestreamofagent-saturatedgasthatisaddedtothegasflow.Thisrequiresthedeviceto:
MeasurefreshgasflowrateAdjustvapour-gasflowratesothedesiredconcentrationisdelivered
Thissystemisusedforthedeliveryofdesflurane,asdesflurane:
HasaveryhighSVPRequireshighbypassflowratetodilutetoaclinicallyusefulconcentration.HasalowboilingpointIntermittentlyboilsatroomtemperature,whichwillcauselargefluctuationsindelivery:
ExcessiveagentdeliveryduringboilingThiswillleadtocoolingduetothelatentheatofvapourisation.CooleddesfluranewillhaveamuchlowersaturatedvapourpressureSignificantunder-deliverywillthenoccur.
TheTec6vapouriser:
Heatsdesfluraneto39°CSVPofdesfluraneatthistemperatureis1500mmHg.GaseousdesfluraneisthenaddedtothefreshgasflowTheamountaddeddependson:
DesiredconcentrationFreshgasflowrateAsflowincreasestheresistancetoflowofdesfluranevapourdecreases.
GeneralSafetyFeaturesofVapourisersAgentspecificity:
KeyindexedfillingPinindexedsafetysystemconnectors
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Colourcodingofunitandagentcontainers
Singleagentadministration:
InterlockmechanismPreventsmultiplevapourisersbeingturnedon.Singlecartridgeslot(Aladdinsystem)
Tippingandoverfilling:
LongvapourisationchamberinflowHeavyconstructionTransportmodesSidefillingandoverflowports
Anti-pumping:
Checkvalvesandlongvapourisationchamberinflowprevententrainmentofvapourisergasintheinflowofthebypasschannel
Agentdepletion:
FillinggaugesLowpressurealarms(Tec6)
OtherFactorsAffectingVapourisers
CarrierGasComposition:
NitrousoxideandairaremoreviscousthanoxygenThisleadstodecreasedflowthroughthevapourisingchamberwhenFiO islowThiseffectisnotclinicallysignificant.
Altitude:
ClinicaleffectofvolatileagentisafunctionoftheirpartialpressureintissuesAsSVPisindependentofatmosphericpressure,thisisunchangedataltitudeAvapourisersetat2%willdeliver4%gasat0.5atmpressure,howeverastheatmosphericpressureisreducedthesamepartialpressureofvapourisdelivered
Thedeliveredconcentrationofanagentataltitudeisgivenbytheequation:
,where:
istheconcentrationofagentinthegasdeliveredtothepatientThismustbemultipliedbytheatmosphericpressuretofindthepartialpressureofagentdeliveredtothepatient.
istheconcentrationdialeduponthevapouriser
istheatmosphericpressurewherethevapouriserwascalibrated
istheatmosphericpressurewherethevapouriserisbeingused
References
1. MillerRD,ErikssonLI,FleisherLA,Weiner-KronishJP,CohenNH,YoungWL.Miller'sAnaesthesia.8thEd(Revised).
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ElsevierHealthSciences.2. BoumphreyS,MarshallN.Understandingvapourizers.ContinuingEducationinAnaesthesiaCriticalCare&Pain.Volume
11,Issue6,1December2011,Pages199–203,
Lastupdated2019-07-18
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BreathingSystemsThisprovidesageneraloverviewofanaestheticbreathingsystems.Thecirclesysteminparticulariscoveredelsewhere.
Classifications:
OpenAnaestheticgasesnotconfinedtothecircuit.
LimitedcurrentpracticalapplicationExpensive,environmentalcontamination.e.g.Ethermasks
Non-rebreathingNoexpiredgasisre-inspired;requiresaone-wayvalve.
LimitedpracticalapplicationRequiresalow-resistancedraw-overvapourisere.g.Tri-serviceapparatus
RobustInexpensive
RebreathingsystemsExpiredgasisre-inspired.
AbsorptionsystemsRequiresmethodforCO absorption.
CircleCommonanaestheticcircuit,coveredindetailunder.Canbe:
VapouriserOut-of-CircuitCommonsystem,coveredindetailundercirclesystem.
Vapouriserin-circuitUncommonsystem.
Inaspontaneousventilationmode,thepatientwillincreaseagentconcentrationasminuteventilation↑Thismeansthatassurgicalstimulus↑,depthofanaesthesiaalso↑.
WatersMaplesonBorCwithaCO absorptioncanisterbetweenbagandFGF.
Non-absorptionRebreathingexpiredgasispartofcircuitdesign.MaplesonSystems
MaplesonSystemProperties:
RebreathingofexpiredgasdoesnotnecessarilyequatetoCO retention,providedtheFGFisaboveacertainmultiple(circuitdependent)ofthepatientsMV
PaCO isafunctionofFGFandCO productiononlyIncreasingMVwithoutincreasingFGFwillresultinre-breathingofCO andunchangedPaCO .
Inanyspontaneousventilationmode,patientswillhyperventilateifFGFisinadequate
Types:
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MaplesonASetup
APLvalveclosetomaskTubingbetweenbagandmaskFGFclosetobag
Flowrequirements
Spontaneousventilation:APLvalveissetlow.Initialexhalation(whichismostlydeadspace,andnotcontainingCO )willfillbaguntilbagpressureexceedsAPLvalveopeningpressure.ProvidedtheAPLvalveissetlow,themajorityofCOcontainingexhalationwillexitthroughtheAPLvalve,andFGFrequiredtoclearCO fromthecircuitislow.
Controlledventilation:APLvalveissethigh.Moreoftheexhalationwillfillthebag,andsoagreaterFGFisrequiredtopreventre-breathing.
MaplesonB&CSetupAPLvalveandFGFaresituatedclosetothemask.
MaplesonBhaslongtubingbetweenthemaskandbagMaplesonChasshorttubingbetweenthemaskandbag
Flowrequirements
Spontaneousandcontrolledventilationaresimilar,at .MaplesonD
SetupFGFisisclosetomaskValveisclosetobagTubingbetweenFGFandAPLvalveCo-axialversionsexist,butarefunctionallysimilar.
FlowrequirementsOverall,generallythebestcircuittomaximiseefficiencyacrossbothspontaneousandcontrolledventilation.
Spontaneousventilation:
Controlledventilation:Bestcircuitforcontrolledventilation.
MaplesonE/Ayre'sT-pieceSetup
T-shapedcircuitwithnovalveorbagMaplesonF/Jackson-ReesmodificationtotheAyre'sT-piece
SetupBag(withhole)addedtothestemoftheTofaMaplesonEAllowsmonitoringofventilation,andoccludingtheholeofthebagallowscontrolledventilation.FunctionallyidenticaltoaMaplesonD,withanoperator-controlledAPLvalve
FlowrequirementsAsperMaplesonD.
Spontaneousventilation:
Controlledventilation:
References1. Westhorpe,R.PaediatricBreathingSystems.RCHAnaestheticTutorialProgram.2019.
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CircleSystemThiscoversthecirclebreathingsystem.Ageneraloverviewofanaestheticbreathingsystemsiscoveredunderanaestheticcircuits.
Thecirclebreathingsystemisahighlyefficientsystemwhich:
HasseveralkeyadvantagesPreservesanaestheticgasesmakingvolatileanaesthesiacost-effectivePreservesmedicalgases(oxygen)whichisusefulinresource-limitedsettings(e.g.prehospital)PreservesheatandmoistureReducesfireriskParticularlywitholderagents.
Requiresre-breathingofexpiredgasesCO isactivelyremoved.Isaclosed-circuitsystem
Theonlygaseswhichmustbereplacedarethose:Consumedbythepatient
OxygenAbsorbedandmetabolisedvolatileagents
Lostvialeak
PrinciplesAcirclecircuitconsistsof:
AY-piece,connectingthecircuittothepatientExpiratoryandinspiratoryvalves,ensuringunidirectionalflowAmeansofgeneratingpressureInmostsystemsthisconsistsofbothaventilatorandareservoirbagwithAPLvalveattached,withabag/ventswitchtoswapbetweencircuits.
ThesearetypicallyplacedontheexpiratorylimbsothatgascanberemovedviascavengingpriortopassagethroughsodalimeThisreducessodalimeconsumption,assomeCO willbescavenged.
SodalimeToabsorbCO .Freshgasflow
Includesoxygen,airandnitrousoxideOxygenenterstheback-barlastWhenthevapouriserisout-of-circuit,allfreshgasflowwillpassthroughthevapouriserpriortoenteringthecircle
Aseparatehigh-pressurehigh-flowoxygenflush,whichbypassesthevapouriser
SodaLime
Sodalime:
Consistsofgranulesof:81%Ca(OH)4%NaOH15%H OSilicates
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Hardensgranules.
pHindicatorVisualrepresentationofuptakeofCO bysoda-lime.
PhenolphthaleinRedtowhite.EthylvioletWhitetopurple.
Granulesare4-8meshinsizeWillpassthroughameshwith4holespersquareinch,butnot8Balancebetweensurfacearea(speed/efficacyofreaction)andresistancetoflow
AbsorbsCO byfollowingreaction:
ThisincreasesthepHofthesodalime,causingthepHindicatortochangecolour100gofsodalimecanabsorb~26LofCO
Pros
CheapertooperateConservesgases,heat,andmoistureLowdeadspaceReducedgreenhouseeffects
Cons
GasmixturesettingsarenotdeliveredtothepatientSettingsaffectthefreshgasflowmixture,whilstthepatientrespiresgasfromthecircuit.Thesearenotidentical,especiallyatlowflows.Nitrogenmaybuildupinthecircuitduringlow-flowanaesthesia,andpotentiallyleadtodeliveryofahypoxicgasmixtureLessportablethanopen-circuitsystemsIncreasedcircuitresistanceRequiressodalime,whichcanbetoxic
ProducesCompoundA-EfromsevofluraneProducescarbonmonoxidefromdesflurane,isoflurane,andenfluraneDangerousifaspirated
References
1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.
Lastupdated2019-07-18
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ScavengingDescribethehazardsofanaestheticgaspollutionandthemethodsofscavenginganaestheticgases
Scavengingistheremovalandsafedisposalofwasteanaesthesiagasesfromthebreathingcircuittoavoidcontaminationofthetheatreenvironment.Thisisimportantascontinuousexposureofstafftoanaestheticgaseshasbeenimplicatedin:
CognitiveimpairmentSpontaneousabortionInfertilityHaematologicalmalignancy
MethodsofScavengingAscavengingsystemconsistsof:
GascollectionassemblyConnectstotheAPLvalveandventilatorreliefvalveCollectsgasventedfromthecircuit.Usesa30mmconnectorPreventsaccidentalconnectiontothebreathingsystem.
TransfertubingScavenginginterfaceThestructureofthescavenginginterfacedependsonthetypeofscavengingsystem.
OpeninterfaceActivescavengingsystemsuseapumptogenerateapressuregradientdrawinggastothedisposalassembly.Thescavenginginterfaceisopentoairtopreventthenegativepressurebeingtransmittedtothepatient.ClosedinterfacePassivescavengingsystemsuseaseriesofpositiveandnegativepressurereliefvalves.
Whengaspressureinthecollectionassemblyexceeds5cmH O,thepositivereliefvalveopensandgasentersareservoirbagWhengaspressureinthedisposalassemblyfallsbelow0.5cmH O,thenegativereliefvalveopensandgasentersthedisposalassembly
MoretransfertubingDisposalassembly
References
1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.
Lastupdated2019-07-18
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Scavenging
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DiathermyDiscusstheprinciplesofsurgicaldiathermy,itssafeuseandthepotentialhazards
Diathermyistheuseofanelectricalcurrenttocuttissueandcoagulatebloodvialocalisedheating.Diathermy:
Useshighfrequency,alternatingcurrentpassingbetweentwoelectrodesFrequenciesbetween300kHzand2MHzareused,whichhaveanegligibleriskofinducingarrhythmia.
Heatenergyproducedisproportionaltoelectricalpowerdissipated( )Reliesontheprincipleofcurrentdensity
AhighcurrentdensityattheelectrodecausestissuedamageAlowcurrentdensity(e.g.attheplateofaunipolarelectrode)causesheatingwithoutdamage
DiathermyTypesDiathermycanbeeither:
UnipolarConsistsofaprobecontainingoneelectrode,andalargeplate(placedelsewhereonthepatient)containingtheotherprobe.BipolarConsistsofapairofforcepswitheachpointcontainingaseparateelectrode.Minimisesthecurrentpassingbetweenprobes,andisusedwhenusingdiathermyonelectricallysensitivetissues(e.g.brain).
DiathermyModes
Diathermymodesinclude:
CuttingLow-voltagemodeproducingahighcurrentintheshapeofacontinuoussinewave.CoagulateHigh-voltagemodeproducingadampedsinewaveresponse.BlendedMixtureofcuttingandcoagulateondifferenttissues.
RisksBurnsFromincorrectlyappliedunipolarplate.ElectrocutionMayinjurepatient,staff,ordamageequipmentandimplants.ElectricalInterferenceMayinhibitpacingincertainpacemakers,ortriggerICDs.SmokeproductionRespiratoryirritant,disseminationofviralparticles,andmaybecarcinogenic.TissuedisseminationPotentialsourceofmetastaticseeding.
Diathermy
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References1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.Scion
PublishingLtd.2014.
Lastupdated2017-09-16
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LasersDescribetheprinciplesofsurgicallasers,theirsafeuseandthepotentialhazards
Alaserisadeviceforlightamplificationbystimulatedemissionofradiation.Laserlightis:
Non-divegentAllphotonsmoveinparallel.CoherentAllphotonsareinphase.MonochromaticAllphotonshavethesamewavelength.
Lasersareusedclinicallyfor:
PreciseincisionsDestructionofcellsbylocalisedvapourisationofwater.DestructionofchemicalsTattoos,oncologicaldrugs.TissuedestructionwithoutheatingOpthalmology.
PrinciplesMethod:
Anenergysourceispassedthroughalasingmedium,housedinaresonatormadeofmirrorsAsthelasingmediumisexcited,electronsenterahigherenergylevelWhenmorethan50%ofelectronsareatahigherenergylevel,populationinversionhasoccurred.Aselectronsfallbacktotheirrestingstate,theyreleaseaphoton
AspontaneousemissionoccurswhenanelectronentersitsrestingstatespontaneouslyAstimulatedemissionoccurswhenanelectronentersitsrestingstateafterbeingstruckbyaphotonreleasedfromaspontaneousemission
StimulatedemissionsresultinamplificationoflightreleaseThemirrorsintheresonatingchamberensuremostlightisreflectedbackintothechamber,causingmorestimulatedemissionsTheexitfromthechambercanbebeadjustedsoonlycertainpolaritiesoflightareemittedAlensmaybeusedtofocusthelaserbeam
Lasersmaybe:PulsewaveUsesshortburstsoflaserlighttominimisecollateraldamage.ContinuouswaveMayleadtoexcessiveheating.
Pros
Precisesurgeryandhaemostasis
Lasers
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Cons
RequiremultiplesafetyprecautionsLasersafetyofficerEyeprotectionWarningsignsondoorsCovertheatrewindowsNon-combustibledrapesMattefinishonequipmenttominimisechanceofreflection
AdditionalrisksinairwaysurgeryUselowestFiO possibleAvoidN OConsideruseofhelioxUsespecialisedlasertubesNormalPVCETTsarecombustible.
References
1. AstonD,RiversA,DharmadasaA.EquipmentinAnaesthesiaandIntensiveCare:AcompleteguidefortheFRCA.ScionPublishingLtd.2014.
Lastupdated2019-07-18
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Lasers
552
SubclavianVeinDescribetheanatomyrelevanttocentralvenousaccess(includingfemoral,internaljugular,externaljugular,subclavianandperipheralveins)
Thesubclavianvein:
IsacontinuationoftheaxillaryveinasitcrossestheuppersurfaceofthefirstribTravelsposteriortotheclavicle,separatedfromthesubclavianarterybytheanteriorscaleneJoinswiththeinternaljugularveintoformthebrachiocephalicvein
BordersAnteriorlybytheclavicle,subclaviusmuscle,andpectoralismajorPosteriorlybyanteriorscalenemuscleandsubclavianarteryInferiorlybyfirstribandlungapexSuperiorlybyskin,subcutaneoustissue,andplatysmaMediallybythebrachiocephalicveinLaterallybytheaxillaryvein
SurfaceAnatomyTheneedleisplacedinthedeltopectoralgroove,inferiorandlateraltothemiddlethirdoftheclavicle.Theneedleisinsertedatashallowangle,passingunderthemiddlethirdoftheclavicleaimingatthesternalnotch.
References1. McMinn,RMH.Last'sAnatomy:RegionalandApplied.9thEd.Elsevier.2003.
Lastupdated2019-07-18
ProceduralAnatomy
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InternalJugularVeinDescribetheanatomyrelevanttocentralvenousaccess(includingfemoral,internaljugular,externaljugular,subclavianandperipheralveins)
Theinternaljugularvein:
OriginatesatthejugularbulbThisisadilatationformedbytheconfluenceoftheinferiorpetrosalsinusandthesigmoidsinus.ExitstheskullviathejugularforamenDescendslaterallytotheinternalcarotid(andlaterthecommoncarotid)inthecarotidsheathTerminatesbehindthesternalendoftheclavicle,whereitjoinswiththesubclavianveintoformthebrachiocephalicvein
BordersAnteriorlybySCMPosteriorlybythelateralmassofC1,scalenemuscles,andlungpleuraMediallybytheinternalcarotid
RelationshipsVagusnerveliesbehind/betweenthecarotidandIJVCervicalsympatheticplexusliesposteriortothecarotidsheathDeepcervicallymphnodeslieclosetotheveinExternaljugularcrossesthesternomastoidbellyofSCM,runningposteriorlyandmoresuperficialtotheIJV,laterperforatingdeepfasciatodrainintothesubclavianveinPleurarisesabovetheclavicle,andisclosetotheveinatitsterminationThoracicductpasseslateraltotheconfluenceoftheleftIJVandSCV,andmaybeinjuredduringleftIJVcannulation
TherightlymphaticductmaybeinjuredduringrightIJVcannulation,butduetoitssmallersizethisislesscommon
SurfaceAnatomyIdentifythetriangleformedbythetwoheadsofSCMandtheclavicle.Palpatetheartery,andensurethesiteofentryislateraltothecarotid.Aim:
Caudally,ata30angletothefrontalplaneParalleltothesagittalplaneTowardstheipsilateralnipple
UltrasoundAnatomy
IdentifytheveindeeptoSCM,notingthatitis(unliketheadjacentICA):
Non-pulsatileThinwalledCompressible
InternalJugularVein
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Approaches
AnteriorAtthemedialborderofSCM,3-4cmabovetheclavicle.Requiresretractionofthecarotidmedially.CentralapproachAttheapexofthetriangleformedbyeachmusclebellyofSCMandtheclavicle.PosteriorapproachAttheposterioredgeofSCM,justsuperiortowheretheEJVcrossesthesternomastoid.
References
1. Lasts2. http://radiopaedia.org/articles/internal-jugular-vein3. http://www.frca.co.uk/article.aspx?articleid=1000304. Internaljugularveincatheterisation:PosteriorandCentralApproach
Lastupdated2019-07-18
InternalJugularVein
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IntercostalCatheterDescribetheanatomyrelevanttotheinsertionofanintercostalcatheter
Anintercostalcatheterdrainstheintrapleuralspace.
SurfaceAnatomy
AnICCshouldbeplacedinthesafetriangle:
Thisisbordered:
AnteriorlybypectoralismajorPosteriorlybylatissimusdorsiToofarposteriorwillinjurethelongthoracicnerve.SuperiorlybythebaseoftheaxillaInferiorlybythe5 intercostalspaceToofarinferiorlyrisksplacementintheliverorspleen.
LayersofDissectionSkinSubcutaneoustissueExternalintercostalInternalandinnermostintercostalmusclesNotetheneurovascularbundlewhichsitsontheinferioraspectoftheribs,thereforeaimtoplacetheICCatthebottomoftheintercostalspace-"abovetheribbelow".Parietalpleura
References
1. LITFL-ChestDrain
Lastupdated2017-09-18
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IntercostalCatheter
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IntercostalCatheter
557
AntecubitalFossaDescribetheanatomyrelevanttocentralvenousaccess(includingfemoral,internaljugular,externaljugular,subclavianandperipheralveins)
Theantecubitalfossaisatriangularspaceontheanterioraspectoftheforearm.
Borders
Thetriangularbordersareformed:
MediallybypronatorteresLaterallybybrachioradialisSuperiorlybyanimaginarylinebetweenthemedialandlateralepicondyles
Theroofofthefossaisformedbysubcutaneoustissue
Thefloorisformedbybrachialisandsupinator
ContentsFrommedialtolateral:
MediannerveBrachialarteryBicepstendonandaponeurosisRadialandposteriorinterosseousnervesVeins
BasilicveinCephalicveinVenousvariations:
AmediancubitalveinconnectingthebasilicandcephalicveinsAmedianveinoftheforearm,whichdividesintoamedianbasilicandmediancephalicveinwhichdrainintothebasilicandcubitalveins
References1. FRCA-TheCubitalFossa
Lastupdated2019-07-18
AntecubitalFossa
558
TracheostomyDescribetheanatomyrelevanttotheperformanceofanaso,orendo,trachealintubation,acricothyroidotomyortracheostomy
Trachea
Thetracheaisfibrocartilagenoustubewhich:
ExtendsfromthelarynxsuperiorlytothePlaneofLouisinferiorlyTerminatesbydivisionintotherightandleftmainstembronchiRunsat15degreesparalleltothesurfaceoftheneck,suchthatthedistaltracheaisdeeperthantheproximaltracheaHasaD-shapedcrosssection
Anteriorwallisformedby18-22incompletecartilaginousringswhichmaintaintrachealpatencyPosteriorwallofthetracheaisspannedbylongitudinalsmoothmuscleknownastrachealis
Istypically:10cmlong2.3cmwide1.8cminAPdiameter
Relationships
Lateraltothetracheaarethe:CarotidsheathsContainsthecarotidartery,internaljugularvein,andvagalnerves.Thyroidlobes(andinferiorthyroidarteries)Recurrentlaryngealnerves.
InferiortothethyroidisthmusliesthethyroidveinsPosteriortothetracheaarethe:
OesophagusVertebralcolumn
SurfaceAnatomy
Midlineneckstructuresarerelevantsurfaceanatomy:
LaryngealstructuresIncluding:Hyoid,thyroidcartilage,cricothyroidmembrane,cricoidcartilage.SternalnotchThyroidlobesLielateraltotrachea.
LayersofDissectionSkinSubcutaneousfatSuperficialandDeepPretrachealfasciaTrachealwall
Tracheostomy
559
Ideallybetween1stand2ndrings
References1. McMinn,RMH.Last'sAnatomy:RegionalandApplied.9thEd.Elsevier.2003.
Lastupdated2019-07-18
Tracheostomy
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ToxicAlcoholsAlcoholsinclude:
EthanolMethanolEthyleneGlycol
Intoxicity:
AllpresentwithsymptomsofalcoholintoxicationAllcontributetotheosmolargapDifferenttoxicitiesoccurduetothedifferentmetabolites
Ethanol
Ethanolisaweakalcoholwithacomplicatedmechanismofactionsimilartovolatileanaestheticagents:
EnhancedGABA-mediatedinhibitionThisisreversiblewithflumazenil.InhibitionofCa entryInhibitionofNMDAfunctionInhibitionofadenosinetransport
Property Drug
Dosing Oneunitis~8g/10mlofpureethanol
Absorption RapidPOabsorption
Metabolism
Saturatablekineticsat>4mmol.L duetohighdosesrequiringextensiveNAD foroxidation,limitingmetabolismto~1unitperhour.Low(0.2)extractionratio,sohighportalveinconcentrationsfromrapidabsorption(e.g.shots)causesagreaterpharmacologicaleffect.Ethanolismetabolisedbyalcoholdehydrogenasetoacetylaldehyde,whichismetabolisedbyaldehydedehydrogenasetoacetylCoA.
Elimination 10%eliminatedunchangedinairandurine
Resp Respiratorydepression
CVS Vasodilatationincreasingheatloss,reducedcardiovasculardiseasemortalityduetoincreasedHDLandinhibitionofplatelets.Alcoholiccardiomyopathyinabuse.
CNS Slurredspeech,intellectualimpediment,motorimpediment,euphoria,dysphoria,increasedconfidence.Dementia,encephalopathy,peripheralneuropathy,andcerebellaratrophywithchronicuse.
Endocrine StimulatesACTHreleaseand'pseudo-Cushing'ssyndrome'.Inhibitstestosteronerelease.Maycauselacticacidosisandhypoglycaemiaintoxicity.
Renal InhibitionofADHrelease,causingdiuresis.Ethanolisosmoticallyactiveandcontributestotheosmolargap.
GIT Gastritis.Fattyliver,progressingtohepatitis,necrosis,fibrosisandcirrhosis
GU Tocolyticeffect
Haeme Inhibitionofplateletaggregation
Metabolic Highenergycontentcomparablewithfat(29kJ.g )
Other SynergisticwithotherCNSdepressants.Metabolicinteractionswithwarfarin,phenobarbitone,andsteroids
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Methanol
MetabolisedbyalcoholdehydrogenasetoformaldehydeandthenformicacidFormicacidisneurotoxicDamagesretinaandtheopticnerve.
EthyleneGlycol
Metabolisedbyalcoholdehydrogenasetoglycoaldehyde,and(viaseveralintermediatesteps)tooxalicacidOxalicacidbindscalcium,whichcauses:
HypocalcaemiaLongQT
Acuterenalfailure
References
1. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.2. HolfordNH.Clinicalpharmacokineticsofethanol.ClinPharmacokinet.1987Nov;13(5):273-92.3. LITFL-ToxicAlcoholIngestion
Lastupdated2019-07-18
Toxicology
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NaloxonePureMOPantagonistusedfor:
TreatmentofopioidoverdoseReducingconstipationIncombinationwithPOoxycodone.
Property Drug
Class μ-selectiveopioidreceptorcompetitiveantagonist
Uses Opioidoverdose,neuraxialopioidsideeffects(e.g.pruritus),preventionofconstipationincombinationwithoralopioids
Presentation Clear,colourlesssolutionat400mcg.ml
RouteofAdministration IV,IM,PO
Dosing 0.1-0.4mgQ5min,0.5mg.kg .hr byinfusion
Absorption Veryhighfirstpassmetabolismleadingto~2%PObioavailability
Distribution 50%proteinbound.V 2L.kg ,highlylipidsoluble.
Metabolism Rapidhepaticglucuronidation
Elimination Renalelimination
Resp Reversalofopioid-inducedrespiratorydepression(↑RR,↑V )
CVS ↑SVR&↑BP,arrhythmiadue↑inSNStone
CNS ↓Analgesia,↓sedation,↓miosis.Antanalgesicinopioidnaivepatients.Precipitationofopioidwithdrawal.
Otherconsiderations
Durationofactionis~30-40minutesisshorterthansomeopioids,whichmayleadtore-narcosisifnotgivensubsequentdosesorbyinfusion
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.
Lastupdated2019-07-18
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FlumazenilCompetitiveantagonistandinverseagonistofthebenzodiazepinereceptor.
Property Action
Class Imidazo-benzodiazepine
Uses ReversalofBZD
RouteofAdministration IV
Dosing 0.1mgbolusesupto2mg
Onset Within2minutes
Distribution Moderatelipidsolubility,50%proteinbound.t β<1hour-mayrequireinfusion.
Metabolism Hepatictoinactivemetabolites
Elimination Renalofmetabolites
CNS MayprecipitateseizuresorBDZwithdrawalduetoinverseagonisteffect
GIT N/V
References
1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2017-09-17
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Oxygen
Property Action
Class Naturallyoccurringgas
Uses ImproveFiO ,COpoisoning,hyperbaricO therapy
Pharmaceutics Clear,colourless,odourlessgasatSTP.Criticaltemperature-119°C,manufacturedbyfractionaldistillation.Highlyflammable.
RouteofAdministration Inhaled
Dosing 0.21-1.0FiO
Absorption Diffusionacrossthealveolarcapillarymembraneinproportiontomembraneareaandpartialpressuregradient,andinverselyproportionaltomembranethickness
Distribution BoundtoplasmaHb,anddissolvedinplasma
Metabolism MetabolisedinmitochondriaofcellsduringthecitricacidcycletoproduceATP,creatingCO
Elimination ExhalationasCO ,orcombinedwithH OtoproduceHCO andeliminatedinurine
Resp↓Respiratorydriveinallindividuals.Mayresultinafatal↓inthosedependentonhypoxicdrive.PulmonarytoxicityduetofreeradialformationwhenPiO >0.6bar-pneumonitis/ARDSduetolipidperoxidationofthealveolar-capillarymembrane.Absorptionatelectasis.
CVS ImprovementinallCVSparametersinthesettingofhypoxia.However,hyperoxia↓CO,↓PVR,↓PAP,andcausescoronaryvasoconstrictionwithprolongedadministration
CNSCNSO toxicity,typicallyatpressures>1.6barthoughthisisvariable.Presentswithavarietyofneurologicalsymptoms,progressingtodisorientationandseizure.RetrolentalfibroplasiainneonatesexposedtohighFiO .
Other Firerisk
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. RAHAdvancedDivingMedicineCourseNotes:Chapter6OxygenandCarbonDioxideToxicity
Lastupdated2019-07-18
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HeliumHeliumisaninertgaswhichisusedtoreducethespecificgravityofinhaledgasmixtures.Itistypicallyprovidedasa0.79/0.21Helium-Oxygen(Heliox)mixture(thoughotherdilutionsexist).
Helium Heliox(0.79/0.21) Oxygen
SpecificGravity(ascomparedtoair) 0.18 0.34 1.09
ReducedspecificgravityresultsinaproportionalreductioninReynoldsNumber,improvinglaminarflowwithintheairways.
Property Action
Class InertGas
Uses Obstructivelungdisease,deepwaterdiving
Presentation Clear,colourlesssolution
RouteofAdministration Inhaled
Dosing TypicallyasHeliox:79%He/21%O
Absorption Diffusionacrossthealveolarcapillarymembraneinproportiontomembraneareaandpartialpressuregradient,andinverselyproportionaltomembranethickness
Distribution Distributesproportionallytosolubilityandtissuepartialpressures
Metabolism Notmetabolised
Elimination Respiratoryexhalationalongapressuregradient
Resp Significantlydecreasesthespecificgravityofinhaledgasmixtures
ToxicEffects HighPressureNeurologicSyndromeat>16atm
References
1. RAHAdvancedDivingMedicineCourseNotes:Chapter6OxygenandCarbonDioxideToxicity
Lastupdated2017-12-22
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Helium
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BetaAgonistsThiscoverstheinhaledβ-agonistsusedforbronchodilation.Informationoncatecholaminesandsympathomimeticswithactivityonβ-receptorsiscoveredunderadrenergicvasoactives.
CommonFeatures
PharmacodynamicEffects β-agonists
Resp Bronchodilatation,↓HPVcausing↑shuntandpotential↓PaO ifO isnotco-administered.
CVS ↑HR(β withhigherdoses),↓BP(β withlowerdoses)
GU Tocolytic.
Metabolic Hypokalaemiafromβ stimulationofNa /K ATPase,hyperglycaemia.
Other Potentiatesnon-depolarisingmusclerelaxants
Differences
Property Salbutamol Salmeterol
Class Syntheticsympathomimeticamine Syntheticsympathomimeticamine
Uses Acuteasthma/bronchospasm,hyperkalaemia Nocturnalandexercise-inducedasthma
Presentation MDI(100µg),solutionat2.5-5mg.ml fornebulisation MDI
RouteofAdministration Inhaled,IV Inhaled
Dosing 1-2puffsviaMDI,5mgnebulised.0.5mcg.kg .min asIVinfusion.
Onset Rapid Slow
Distribution Lowproteinbinding
Metabolism Highfirstpasshepatictoinactivemetabolites,t β6hours. ExtensivehepaticviaCYP3A4
Elimination Urinaryeliminationofactive(30%)drugandinactivemetabolites Renalofmetabolites
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.
Lastupdated2017-09-07
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Bronchodilators
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Bronchodilators
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Antimuscarinics(Respiratory)AntimuscarinicswithpredominantlycardiaceffectsarecoveredatAntimuscarinics(Cardiac),whilstatropineiscoveredseparately.
TheseagentscompetitivelyantagoniseAChatM receptorsinbronchialsmoothmuscle,preventingparasympatheticmediatedbronchoconstriction.
Property Ipratropium Tiotropium
Class Muscarinicantagonist Muscarinicantagonist
Uses Bronchodilatation Bronchodilatation
Presentation MDIorsolutionfornebulisation MDI
RouteofAdministration Inhaled Inhaled
Dosing 18mcgMDI,500µgnebuliser
Absorption 5%bioavailabilityviainhaledroute
Metabolism Hepatictoinactivemetabolites
Elimination Equalrenalandfaecalelimination
Resp Bronchodilation Bronchodilation
GIT DecreasedGIsecretionsinlargedoses DecreasedGIsecretionsinlargedoses
CNS Mydriasisifdepositedineye Mydriasisifdepositedineye
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.
Lastupdated2017-08-02
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PhosphodiesteraseInhibitors/MethylxanthinesMethylxanthinesnon-selectivelyinhibitphosphodiesterase,whichresultsinreducedlevelsofcAMPhydrolysisandthereforeincreasedintracellularcAMP,andsubsequentsmoothmusclerelaxation.Thiseffectissynergisticwithβ agonists,whichalsoincreasecAMPbyincreasingproduction.
Property Theophylline
Class Methylxanthine/Non-selectivephosphodiesteraseinhibitor
Uses AsthmaandCOAD
RouteofAdministration IVorPO
Dosing 4-6mg.kg IVload,thenat0.4mg.kg .hr targetingserumconcentrationof10mcg.ml
Absorption Highoralbioavailability
Distribution V 0.5L.kg ,40%proteinbinding.
Metabolism HepaticviaCYP450toactivemetabolites(caffeineand3-methylxanthine),lowhepaticextractionratio
Elimination Highlyvariableeliminationaffectedbyage,renaldisease,hepaticdisease
Resp Bronchodilation,↑Diaphragmaticcontractility
CVS ↑Inotropy,↑chronotropy.Narrowtherapeuticrangeduetoarrhythmogenic(VF)properties
CNS ↓Seizurethreshold
Renal Natriuresisandhypokalaemia
ToxicEffects Lowtherapeuticindex,withtoxicitymanifestedastachyarrhythmiasincludingVF,tremor,insomniaandseizures
References
1. Lexicomp.Theophylline:DrugInformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2019-07-18
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LeukotrieneAntagonistsSelectivelyinhibitthecysteinylleukotrienereceptor,increasedactivityofwhichisinvolvedinairwayoedemaandbronchialsmoothmuscleconstriction.
Property Montelukast
Class LeukotrieneAntagonist
Uses Asthma,allergicrhinitis
RouteofAdministration PO
Dosing 10mgdaily
Absorption 64%PObioavailability
Distribution t 5hours,>99%proteinbound
Metabolism HepaticbyCYP3A4
Elimination Predominantlyfaecal
Resp Bronchodilatation
References
1. .Lexicomp.Montelukast:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.
Lastupdated2017-09-20
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LeukotrieneAntagonists
571
CorticosteroidsGlucocorticoidsareendogenous(hydrocortisone)andsynthetic(prednisolone,methylprednisolone,dexamethasone)steroidhormoneswithmetabolic,anti-inflammatory,andimmunosuppressiveeffects.Theybindtospecificintracellularreceptorsandtranslocateintothenucleus,wheretheyregulategeneexpressioninatissue-specificmanner.
Corticosteroidshavemultipleindicationsincluding:
Replacementinadrenalsuppressionorothercortisol-deficientstatesAutoimmunedisordersAnaphylaxisandatopicdisorders,includingasthmaHypercalcaemiaChemotherapyImmunosuppressionfollowingtransplantation
CommonFeatures
System Effect
Resp ↑Bronchialsmoothmuscleresponsetocirculatingcatecholamines,↓airwayoedema
CVS ↑Inotropy,↑vascularsmoothmuscleresponsetocirculatingcatecholamines(↑receptorexpression),↑BPsecondarytomineralocorticoideffects
CNS Moodchanges,sleepdisturbance,psychosis
MSK Atrophy,thinningofskin
Renal Glycosuria,Na andfluidretention(mineralocorticoideffect),hypokalaemia
GIT Gastriculceration
Metabolic ↑Gluconeogenesis,diabetes,↑proteincatabolism,fatredistribution,adrenalsuppression(negativefeedbackonACTH),↑lipolyticresponsetocirculatingcatecholamines
Immune ↓Transudateproduction,↓productionofinflammatorymediators,↓macrophagefunction,↓transportoflymphocytes,↓T-cellfunction,↓antibodyproduction,↑susceptibilitytoinfection,
ToxicEffects Relativesteroiddeficiencyinadrenalsuppressedindividualswithinfectionorsurgery
ComparisonofCorticosteroids
Property Hydrocortisone Prednisolone Methylprednisolone Dexamethasone
RouteofAdministration IV/PO PO PO/IV/IM IV
RelativeDoseEquivalents 100mg 25mg 20mg 4mg
Absorption 50%PObioavailability
100%PObioavailability
60%PObioavailability
Distribution
Variableproteinbindingdependingonconcentration,V 0.5L.kg
Variableproteinbindingdependingonconcentration,V0.5L.kg
V 1L.kg
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Metabolism Hepatic Hepatic Hepatic Hepatic
Elimination Eliminationt is2hours
Eliminationt is3hours
Eliminationt is3hours
Eliminationtis4hours
Relativemineralocorticoideffect
+++ ++ + +
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. NiemanLK,LacroixA,MartinKA.Pharmacologicuseofglucocorticoids.In:UpToDate,Post,TW(Ed),UpToDate,
Waltham,MA,2017.4. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2019-07-18
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PulmonaryVasodilators
Property NitricOxide Iloprost Sildenafil
Class Inorganicgas Syntheticeicosanoidwithprostacyclinactivity
Uses ARDS,RVF,PHTN PHTNPHTN,erectiledysfunction
Presentation Aluminiumcylinderswith100/800ppmNO/N Syntheticanalogofepoprostenol
RouteofAdministration Inhaled Inhaled PO
Dosing 1-40ppm,viainspiratorylimbofventilator 20mgTDS
Absorption 40%PObioavailability
Distribution AvidlyboundtoHb95%proteinbound,V of100L
MetabolismMetabolisedtomethaemoglobinandnitritepriortoreachingsystemiccirculation-tof<5s
HepaticbyCYP450
Elimination Faecal
MechanismofAction
StimulatescGMPwhichreducesintracellularCa
StimulatescAMPwhichreducesintracellularCa andsmoothmusclegrowth
InhibitscGMP
Resp InhibitsHPV,improvesV/Qmatching
CVS↓vascularresistance,↓PVRinventilatedalveoliandimprovingV/Qmatching.↑Capillarypermeability.
↓BPwithcompensatory↑HR ↓PVR
CNS ↑CBF
Haeme Inhibitsplateletaggregation.MetHb Inhibitsplateletaggregation
Other ReboundpulmonaryHTNonabruptcessation
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.
Lastupdated2019-07-18
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PulmonaryVasodilators
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AdrenergicVasoactivesThiscoversthepharmacologyofspecificcatecholaminesandsympathomimetics.Thesynthesisofendogenouscatecholaminesiscoveredunderadrenalhormones,whilstspecificsofcatecholaminereceptorfunctioniscoveredunderadrenoreceptors.
Adrenergicdrugs:
Actvia:Dopamine(D)Adrenoreceptors(αandβ)
Canbe:Direct-actingStimulatethereceptor.Indirect-actingStimulatethereleaseofnoradrenalinetocauseeffects.
Classifiedaseither:Naturally-occurringcatecholaminesSyntheticcatecholaminesSyntheticsympathomimeticsDrugswhichactonadrenoreceptorsbutarenotclassifiedascatecholaminesduetotheirchemicalstructure.
ComparisonofCommonlyUsedAdrenergicAgents
Properties Noradrenaline Adrenaline Phenylephrine Metaraminol Ephedrine
Class NaturalCatecholamine
NaturalCatecholamine
Sympathomimeticphenylethylaminederivative
Syntheticsympathomimetic
Syntheticsympathomimetic
Uses ↑SVR
Cardiacarrest,anaphylaxis,inotropy,chronotropy,adjunctinlocalanaesthetics
↑SVR ↑SVR ↑SVRwithout↓inHR
Dosing Startat0.05µg/kg/min
Infusionstartsat:0.01µg/kg/min
Bolusstartat50-100mcg Bolus0.5-2mg 3-6mgbolus
Route IV IV/IM/ETT/SC IV/IM/SC IV IV
Presentation
Clear,colourless,light-sensitivesolution.Sodiummetabisulfiteasexcipient.
Aclear,colourlesssolutiontypicallyat0.1-1mg/ml
Clear,colourlesssolutionat100mcg/ml
Clear,colourlesssolutioninampouleat10mg/ml,typicallyreconstitutedto0.5mg/ml
Clear,colourlesssolutionin30mg/mlampoule
Absorption IVonlyVariableETTandSCabsorption
IMonset15minutes,durationupto1hour
IVonly IVorIM
t 2min.MetabolisedbymitochondrialMAOand
t 2min.MetabolisedbymitochondrialMAOand Someuptakeinto
Hepatic(notmetabolisedbyMAOandCOMT),givinga
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Metabolism COMTinliver,kidney,andbloodtoVMAandmetadrenaline.
COMTwithinliver,kidney,andbloodtoVMAandmetadrenaline.
HepaticbyMAO adrenergicnerveendings
longer(10-60minute)durationofactionandat βof3-6hours
Elimination
Pulmonaryuptakeofupto25%.Urinaryexcretionofmetabolites
Urinaryexcretionofmetabolites
Renalofmetabolites,t β2-3hours
50%unchangedinurine
Mechanismofaction α>>β
β>αatlowerdoses.Athighdosesα effectsdominate.
Directα
Directandindirect(via↑NArelease)αagonism
↑NArelease(indirectα )anddirectαandβagonism
Respiratory ↑MV,bronchodilation
↑MV,bronchodilation Bronchodilation
CVS
↑SVR,↑MyocardialOconsumption,↑Coronaryflow.
↑Inotropy,↑HR,↑SVRandPVR,↑BP,↑CO,↑myocardialOconsumption.Coronaryvasodilation.Arrhythmogenic.
↑SVRandBP,potentialreflexbradycardia.Notarrhythmogenic.
↑SVR/PVR,reflexbradycardia.Indirect↑incoronaryflow.
Directandindirect(viaNArelease)↑inHR,BP,andCO.Arrhythmogenic.
CNS ↑Painthreshold,↑MAC
↑MAC,mydriasis.
MSK Necrosiswithextravasation
Necrosiswithextravasation
Renal ↓RBF ↓RBFand↑insphinctertone ↓RBF ↓RBF ↓RBF
Metabolic
↑BMR,↑lipolysis,↑gluconeogenesisandBSL,↑Lactate.Initially↑insulinsecretion(β),then↓(α)
GU↓Uterinebloodflowandfoetalbradycardia
↓Uterinebloodflow
↓Uterinebloodflow
ComparisonofLessCommonAdrenergicAgents
Properties Dopamine Isoprenaline Dobutamine
Class NaturalCatecholamine SyntheticCatecholamine SyntheticCatecholamine
Uses Haemodynamicsupport Severebradycardia Stresstesting,increasingCO
Dosing Start1µg/kg/min Infusionfrom0.5-10µg/min 0.5-20µg/kg/min
Route IV IV IV
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CardiovascularPharmacology
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Presentation Clear,colourlesssolutionwith200mgor800mginwater
Clearsolutionat1mg/ml
250mgdobutaminein20mlwater
Metabolismt 3min.25%ofdoseconvertedtonoradrenaline.RemainderismetabolisedbyMAOandCOMTsimilartonor/adrenaline.
HepaticbyCOMT t 2min.COMTtoinactivemetabolites.
Elimination Renal,t β3minutesUrinaryexcretionofunchangeddrugandmetabolites
Mechanismofaction D ,D ;β>αatlowerdose β >β β >>β ,D
Respiratory Potentbronchodilation Bronchodilation
CVS ↑Inotropy,↑HR,↑CO,coronaryvasodilation.Athighdoses,↑SVRandPVR,↑VR.
↑SVR,potentialreflexbradycardia.Notarrhythmogenic.
↑HR,CO,contractility,andautomaticity.Βeffectsmay↓SVRandBP.
CNS Inhibitsprolactin.Nausea. Stimulant Tremor
MSK Necrosiswithextravasation
Renal
↑RBFand↑urinaryoutputwithnoimprovementinrenalfunction
GIT Mesentericvasodilation
Structure-ActivityRelationshipsofSympathomimetics
Catecholaminesconsistof:
AcatecholringAbenzeneringwithtwohydroxylgroupsinthe3and4position.
LosingonehydroxylgroupIncreaseslipidsolubilityanddecreasesthepotency10-fold
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578
PreventsmetabolismbyCOMT,prolongingdurationofactionLosingbothhydroxylgroupsdecreasesthepotency100-fold
Changingthehydroxylgroupstothe3and5positionincreasesbeta-2selectivitywhenthereisalsoalargesubstitutionpresentontheaminegroup
AnethylaminetailConsistsof:
BetacarbonThefirstcarbon.
AddingahydroxylgroupdecreaseslipidsolubilityandCNSpenetrationAddinganygroupincreasesalphaandbetaselectivity
AlphacarbonThesecondcarbon.
AddingagrouppreventsmetabolismbyMAO,prolongingdurationofactionMethylationincreasesindirectactivity
AminegroupTheterminalnitrogen.
AdditionofamethylgroupgenerallyincreasesbetaselectivityAsthechainlengthincreases,sodoesthebetaselectivity.
Dopamine
Dopamineistheprototypicalcatecholamine,towhichothersarecompared
Noradrenaline
CardiovascularPharmacology
579
Noradrenalinehasahydroxylgroupaddedtothebetacarbon,increasingitsalphaselectivity
Adrenaline
AdrenalineissimilartonoradrenalinewithanadditionalhydroxylgrouponthebetacarbonAdrenalinealsohasamethylgroupaddedtotheterminalamine,increasingbetaselectivity
Metaraminol
CardiovascularPharmacology
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MetaraminolhasanadditionalhydroxylgrouponthebetacarbonMetaraminolhasonlyonehydroxylgrouponthephenolring,so:
ItisnolongerclassifiedasacatecholamineItisnotmetabolisedbyCOMT,prolongingitsdurationofactionIthasreducedpotency,requiringadministrationinhigherdoses
Metaraminolhasanadditionalmethylgrouponthealphacarbon,preventingmetabolismbyMAOandfurtherprolongingitsdurationofaction
Ephedrine
Likemetaraminol,ephedrinehasahydroxylgrouponthebetacarbonandamethylgrouponthealphacarbonEphedrinehasnohydroxylgroupsonthephenolring,furtherreducingitspotencyandincreasingitseliminationhalf-lifeEphedrinehasamethylgroupontheamine,increasingitsbetaselectivity
References1. BrandisK.ThePhysiologyViva:Questions&Answers.2003.2. ChambersD,HuangC,MatthewsG.BasicPhysiologyforAnaesthetists.CambridgeUniversityPress.2015.3. YartsevA.DerangedPhysiology-StructureofSyntheticCatecholamines4. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-07-18
CardiovascularPharmacology
581
CardiovascularPharmacology
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Non-AdrenergicVasoactivesKeynon-adrenergiccardiovasculardrugsincludevasopressin(anditsanalogues,terlipressinandornipressin),phosphodiesteraseIIIinhibitorssuchasmilrinone,andcalciumsensitiserssuchaslevosimendan.
Property Vasopressin(ADH) Milrinone Levosimendan
Class Naturalnonapeptide PhosphodiesteraseIIIinhibitor
Calciumsensitiserandphosphodiesteraseinhibitor
UsesHaemorrhage,DI,catecholamine-sparingvasopressor
RefractoryCCFandlowCOstates Severeacuteheartfailure
Dosing 5-10unitsIVbolus,upto4U/hrinfusion
Load12-24mcg/kgover10min,theninfusionat0.05-2mcg/kg/min
Route IV/SC/IM IV IV
Presentation Clearsolution Yellowsolutionat1mg/ml 2.5mg/mLin5ml&10mlvials
Distribution 70%proteinbound Veryhighproteinbinding>90%
Metabolismt 10minutes.Metabolisedbytissuepeptidasesandrenalelimination.
t 1-2.5hourst 1hour.Hepatictoactivemetabolitewithat~70hours
Elimination 80%ofdrugisexcretedunchanged
Mechanismofaction
V receptors(kidney,platelets)areadenylatecyclasemediated.V (vascularsmoothmuscle)andV receptors(pituitary)arephospholipaseC/inositoltriphosphatemediated
InhibitsphosphodiesterasebreakdownofcAMP,increasingintracellularCalevels.AlsoincreasesspeedofCa uptakeintocardiacmuscle,increasinglusitropy.
BindstotroponinCincreasingmyofilamentCa sensitivity.AlsoopensK channelscausingvasodilation.ItmayalsohavesomePDIIIinhibitioneffect.
CVS ↑SVRthroughvasoconstriction
Increasedinotropy,increasedlusitropy,decreasedSVRandPVR(PVRdecreasesmorethanSVR).Increaseddysrhythmias.
IncreasedCOwithoutincreasedO demand,vasodilation,prolongedQTcwithriskofarrhythmia
GIT GITsmoothmusclecontraction
Renal
↑Aquaporininsertionintotheapicalmembraneofcollectingductswhich↑waterreabsorption
Haematological↑Coagulationfactormobilisationand↑plateletaggregation
Metabolic Hyponatraemia
References
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1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. BruntonL,ChabnerBA,KnollmanB.GoodmanandGilman'sThePharmacologicalBasisofTherapeutics.12thEd.
McGraw-HillEducation-Europe.2011.
Lastupdated2019-07-18
Non-adrenergicVasoactives
584
CentrallyActingAnti-Hypertensives
Property Clonidine Methyldopa
Class Centralα -agonist(200:1α :α ) Phenylalaninederivative
Uses Analgesia,sedation,anti-hypertensive Antihypertensive(especiallyinpregnancy)
Presentation Clearcolourlesssolutionat150μg.mlTablets-notappropriateforurgentbloodpressurereduction
RouteofAdministration
PO/IVat10-200mcguptoQID.Canbeaddedtoneuraxialblockadeat1-2mcg.kg todecreaseopioidrequirement. PO/IV.
Dosing 50-200μgQID. 250-500mgPOBD/TDS.
Absorption 100%PObioavailabilitywithrapidabsorption HighlyvariablePObioavailability
Distribution 20%bound,V 2L.kg 50%proteinbound,V0.3L.kg
Metabolism 50%hepatictoinactivemetabolites,t β9-18hours Intestinalandhepatic
Elimination 50%renaleliminationunchanged 40%renaleliminationunchanged
MechanismofAction
Agonistofcentralα2receptor,↓SNStoneviadecreasedNAreleasefromperipheralnerveterminals.
Metabolisedtoα-methyl-noradrenalineintheCNS,whichagonisescentralα2receptors.
CVS
Initial↑inBPduetoα stimulation,evidentwithbolusdosing.Followedbyprolonged↓inBP,↑PR,↓AVconduction,↑baroreceptorsensitisation(lowerHRforagivenincreaseinBP).CessationmaycausereboundHTN.
↓SVRwithunchangedHRorCO
CNSSedation,analgesiadueto↓NAreleasewhich↓opioidrequirement.Adjunctinchronicpainandinopioidwithdrawal.Anxiolysisatlowdoses.Centralantiemeticeffect.
May↓MAC
Metabolic Stressresponsetosurgicalstimulusisinhibited
Renal DiuresissecondarytoinhibitionofADH
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.
Lastupdated2017-09-12
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Antihypertensives
585
CalciumChannelBlockersCa -channelblockers:
HaveaffinityforL-typecalciumchannelsL-typechannelsexistinmyocardium,nodal,andvascularsmoothmuscle.
Variableaffinityforeachcausesapreferenceforeithernodalandinotropic,orvasculareffectsPreventCa entryintocellsinause-dependentfashion
Class ChemicalStructure Drugs
ClassI Phenylalkylamines Verapamil
ClassII Dihydropyridines Nifedipine,amlodipine,nimodipine
ClassIII Benzothiazepines Diltiazem
ComparisonofCalciumChannelBlockers
Property Verapamil Amlodipine Diltiazem
Class Phenylalkylamine Dihydropyridine Benzothiazepine
Uses SVT,excludingAFwithWPW HTN,AnginaAngina,HTN,SVT,Raynaud's,migraine,oesophagealdysmotility
Presentation 20-240mgtablet,POsolution,IVat2.5mg.ml Tablet Tablet
IsomerismRacemicpreparation.TheD-isomeralsohassomelocalanaestheticactivity
RouteofAdministration PO/IV PO PO
Dosing 80-160mgBD/TDS 2.5-10mgdaily 30-120mgTDS
Absorption 20%bioavailability 60%bioavailability 40%bioavailability
Distribution 90%proteinbound 90%proteinbound,lipidinsoluble. 80%proteinbound
Metabolism Hepatictoactivenorverapamil Hepatictoinactivemetabolites Hepatictoactivemetabolites
Elimination Renaleliminationofactivemetabolites
Renalofinactivemetabolites
Renalofactivemetabolites.t2-7hours
CVS↓HRvia↓SAand↓AVnodalconduction,↓inotropy,↓SVR,↓BP,arrhythmiaincludingHB
↓SVR,↓BP,withreflexive↑HR,↑inotropy,↑CO
↓AVnodalconductionbuttypicallystableHR,↓SVR,↓CVR,↓MVO ,↑CO
CNS ↓Cerebralvascularresistance↓Cerebralvascularresistancewithnimodipine
GIT ↓LOStone
InteractionsContraindicatedwithconcurrentβ-blockeruseduetoprofound↓HR,↓
Contraindicatedwithconcurrentβ-blockeruseduetoprofound↓
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inotropy HR,↓inotropy
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.
Lastupdated2019-07-18
CalciumChannelBlockers
587
DirectVasodilatorsDirectvasodilatorsinclude:
Ca channelblockers(seeCalciumChannelBlockers)NitratesIncreaseproductionofNO:
NOactivatesguanylatecyclase,increasingcGMPcGMPinhibitsCa uptakeintosmoothmuscleandenhancesitssequestrationintosmoothendoplasmicreticulumThedecreaseincytoplasmic[Ca ]causessmoothmusclerelaxationandvasodilation
HydralazineMultimodalmechanismofaction,including:
OpensK channels,hyperpolarisingvascularsmoothmuscleDecreasesintracellularCa invascularsmoothmuscleActivationofguanylatecyclase
Property SodiumNitroprusside GTN Hydralazine
Class InorganicNitrate OrganicNitrate Directvasodilator
Uses Afterload(withsomepreload)reduction Afterload&preloadreduction,angina HTN
Presentation Solutionat10mg.ml ,mustbeprotectedfromlight
Spray,tablets,patch,IVsolutionwhichisabsorbedintoPVC-requiresapolyethyleneadministrationset
20mgampouleorpowder.Shouldnotbereconstitutedwithdextrose.
RouteofAdministration IVonly IV,topical,sublingual PO,IV
Dosing 0.5-6µg.kg .min 10-200µg.min 5-20mgIV
Absorption <5%PObioavailability
30%bioavailabilityduetohighfirstpassmetabolism
Metabolism
Prodrug.ReactswithOxy-HbinRBCtoform1xNO,5xCN ,andMetHb.MetHbreactswithCNtoformcyanomethaemoglobin.CNismetabolisedintheliverandkidneytoformSCN,themajorityofwhichisexcretedinurine(thoughmaybere-convertedtoCN).
CNmayalsocombinewithhydroxocobalamin(vitaminB )toformcyanocobalamin,whichiseliminatedinurine.
Prodrug.MetabolisedtoNOandglyceroldinitrate(whichisthenalsoconvertedtoNO)intheliver.
N-acetylatedingutandliver
EliminationRenaleliminationofSCNandcyanocobalamin.ImpairedinrenalfailurewhichmayworsenCNtoxicity.t forSCNis2-7days
t 1-4mins.Urinaryexcretion
Dependentonacetylationrates
Resp Inhibithypoxicpulmonaryvasoconstrictionleadingto↑shunt Bronchodilation
Vasodilationpredominantlyof
Arteriolarvasodilation
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CVS ↓SVR>venodilation.↓SBPand↓preload,↑HRmaintainsCO,↓MVO
capacitancevessels,↓preload,↓VR,↓EDP,↓walltensionimprovingsubendocardialbloodflow,↓MVO
withcompensatorytachycardiaandincreasedCO
CNS ↑CBFfollowingcerebralvasodilatation↑CBFfollowingcerebralvasodilatation,whichmaycauseheadache
IncreasedCBF
Haematological Methaemoglobinemia Methanoglobinaemia
ToxicEffects Threemechanisms:hypotension,thiocyanatetoxicity,CNtoxicity.
MethaemoglobinaemiacanoccurwithGTN
GTNpatchesmayexplodeifleftonduringDCcardioversion.
NitrateToxicityNitratetoxicitycanberelatedto:
CyanideThiocyanateMethaemoglobinaemia
CyanideToxicity
CyanidetoxicityoccursonlywithSNP,asCN isproducedasabyproductofmetabolism.
KineticsRapidcellularuptakeSmallVHepaticallymetabolisedtothiocyanate,usingthiosulfateasasubstrate
MechanismCN bindstocytochromeoxidase,preventingoxidativephosphorylation.Thiscauseshistotoxichypoxia,andischaracterisedby:
RapidlossofconsciousnessandseizuresMetabolicacidosisLactataemiaArrhythmiaIncreasedMVOHypertensionDuetotachyphylaxistoSNP.
RiskofcyanidetoxicityfromSNPisrelatedto:InfusionrateInfusionduration
ManagementSupportivecare,includinginotropesCyanidechelatorsBindCN,removingitfromthecirculation.Include:
DicobaltedetateHydroxycobalamin(VitaminB )Sulfurdonors
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Provideadditionalsulfhydrylgroups,allowingfurtherhepaticmetabolismofCN toSCN.Include:
ThiosulfateNitritesConvertsOxy-HbtoMet-Hb,whichhasahigheraffinityforCN thancytochromeoxidase.Include:
SodiumnitriteAmylnitrite
ThiocyanateToxicity
ThiocyanteisproducedwithhepaticmetabolismofCN .Toxicityoccurswhenthiocyanateaccumulates,whichoccursin:
LongdurationSNPinfusions7-14days.PatientswithrenalfailureReducedclearance,mayoccurin3-6days.PatientsgiventhiosulfateformanagementofCN toxicity.
EffectsMultisystemic,including:
RashAbdominalpainWeaknessCNSdisturbance
TreatmentDialysis
Methaemoglobinaemia
MethaemoglobinaemiaoccurswhentheFe (ferrous)ioninhaemoglobinisoxidisedtotheFe (ferric)form,whichisunabletobindoxygen.
Duetothehighconcentrationofoxygeninerythrocytes,methaemoglobiniscontinuallybeingformedSeveralendogenousreductionsystemsexisttokeepMetHblevelsstableat~1%
Predominantlycytochrome-b reductaseNADPH-MHbreductaseThisreducesmethaemoglobinaemiainthepresenceofareducingagent,classicallymethyleneblue.ReducedglutathioneMoreimportantinpreventingoxidativestressinothercellsthantheRBC.
Diseaseoccursduetothelossinoxygen-carryingcapacityfromthelossofeffectivehaemoglobine.g.a20%MetHblevelgivesatheoreticaloxygencarryingcapacityof80%oftheactualhaemoglobinThereisinfactaslightleftshiftoftheoxyhaemoglobindissociationcurve,asoxygenbindsmoretightlytothepartially-oxidisedhaemoglobin.
References
1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. CICMSeptember/November20085. LITFL-CyanidePoisoning
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6. ThomasC,LumbA.Physiologyofhaemoglobin.ContinuingEducationinAnaesthesiaCriticalCare&Pain,Volume12,Issue5,1October2012,Pages251–256.
7. WrightRO,LewanderWJ,WoolfAD.Methemoglobinemia:Etiology,Pharmacology,andClinicalManagement.AnnalsofEmergencyMedicine,Volume34,Issue5,1999,Pages646-656.
8. RusswurmM,KoeslingD.NOactivationofguanylylcyclase.TheEMBOJournal.2004;23(22):4443-4450.
Lastupdated2019-07-18
DirectVasodilators
591
AngiotensinConvertingEnzymeInhibitorsACEinhibitorspreventtheconversionofangiotensinItoangiotensinIIbyangiotensinconvertingenzyme(ACE)inthelungs,inturnreducingeffectsofangiotensinII.Theseeffectsinclude:
VasoconstrictionNoradrenalinereuptakeinhibitionThirstADHreleaseACTHreleaseAldosteronereleaseReducesKf,reducingGFR
Indications
HypertensionParticularlyininsulindependentdiabeteswithdiabeticnephropathyLesseffectiveforthisindicationintheblackpopulationContributetopost-operativehypertensionandmaybewithheldperioperatively
CardiacfailureAllgrades.
MIwithLVdysfunctionImprovedprognosis.
Classification
Canbedividedintothreegroupsbasedonpharmacokinetics:
ActivedrugwithactivemetabolitesCaptopril.ProdrugRamipril.NotmetabolisedandexcretedunchangedinurineLisinopril.
CommonFeaturesofACEInhibitors
Property Drug
Resp Bradykinincough
CVS ↓SVRandBP.UnaffectedHRandbaroreceptorresponse.
Endocrine Hypoglycaemiaindiabetics
Renal Withanormalrenalperfusionpressure,natriuresisresults.However,afallinrenalperfusionpressuremaycausepre-renalfailure(e.g.renalarterystenosis).
Haeme Agranulocytosis,thrombocytopenia
ACEInhibitors
592
Immune Angioedema
Metabolic ↑Reninrelease.
Interactions ↓Aldosteronerelease,which↑theefficacyofspironolactoneandmayprecipitatehyperkalaemia.PharmacodynamicinteractionwithNSAIDstodroprenalperfusionpressure.
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-11-02
ACEInhibitors
593
AngiotensinReceptorBlockersAngiotensinreceptorantagonistsareverysimilartoACEinhibitors,except:
BradykinindoesnotaccumulateasitisstillbrokendownbyACEThereforethereisnocoughandpatientcomplianceisimproved.TheAT receptorincardiactissueismorecomprehensivelyblockedwhichmayimprovecardiacoutcomesTheAT receptorisnotblocked,whichmayalsoimprovecardiacoutcomes
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2017-07-27
12
AngiotensinReceptorBlockers
594
PotassiumChannelActivatorsPotassiumchannelactivatorsstimulateATPsensitiveK channels,causinganincreaseinintracellularcGMPandsubsequentrelaxationofsmoothmuscleinthe:
HeartVenouscapacitancevesselsArterioles
Property Nicorandil
Uses HTN,angina,CHF
RouteofAdministration PO
Dosing 10-30mgBD
Absorption 80%PObioavailability
Distribution Negligibleproteinbinding
Metabolism Hepaticdenitration
Elimination Renaleliminationofactivedrugandmetabolites
CVS ↓Preload,↓afterload,↓BP,↑coronaryflow
CNS Headache,improveswithongoinguse
Haeme Inhibitionofplateletaggregation
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2017-09-22
+
PotassiumChannelActivators
595
SodiumChannelBlockersSodiumchannelblockersinclude:
ClassIa:ProcainamideQuinidineDisopyramide
ClassIb:LignocaineMexiletine(lignocaineanalogue)
ClassIc:Flecainide
Ingeneral:
IVpreparationsaregivenforVTGoodPObioavailabilityandlowproteinbindingMetabolitesarerenallycleared
Property Procainamide Lignocaine Flecainide
Class ClassIaamide ClassIbamidelocalanaesthetic ClassIcamidelocalanaesthetic
Uses SVT/VT VT SVT/VT
Presentation Clearsolutionat10-20mg.ml (1-2%)
RouteofAdministration PO/IV IV PO/IV
Dosing 100mgIVload,followedbyinfusionat2-6mg.ml
Loadat1mg.kgfollowedbyinfusionat1-3mg.min
2mg.kg (upto150mg)loadover10-30minutes,followedbyinfusionat1.5mg.kg .hr ,aimingforlevelsof<0.9mg/ml
Absorption 75%bioavailability IVonlyforarrhythmia 90%orallybioavailable
Distribution 33%unionised,70%proteinbound 50%proteinbound
MetabolismHepatictoactivemetabolitesviaacetylation-slowacetylatorsatincreasedriskofsideeffects
Hepaticamidasestoinactivemetabolites Hepatictoactivemetabolites
MechanismofAction
Reducestherateofriseofphase0,raisesthethresholdpotential,andprolongstherefractoryperiodwithoutprolongingtheactionpotential
Reducestherateofriseofphase0oftheactionpotential.Repolarisationphaseisshortened.
Reducestherateofriseofphase0oftheactionpotential.Repolarisationisunchanged.
CVS↓HR,↓SVR,↓BP,↓CO,heartblock,may↑HRwhenusedforSVT,↑QTwithriskofTDP
AVblock,myocardialdepressioncausingunresponsive↓BP
Precipitatepre-existingconductiondisorders,↓inotropy,↑pacinganddefibrillationthreshold
CNS
Circumoraltingling,dizziness,parasthesia,confusion,seizures,coma
Dizziness,parasthesia,headache
-1
-1
-1
-1
-1
-1 -1
Antiarrhythmics
596
ImmuneLupoidsyndromein20-30%,reducesantimicrobialeffectofsulfonamides
InteractionsPharmacokineticinteractionswithdigoxin,propranolol,amiodarone
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.
Lastupdated2019-07-18
Antiarrhythmics
597
Beta-Blockersβ-blockersarecompetitive(oftenhighlyselective)antagonistsofβ-adrenoreceptors.Theyaresub-classifiedintointoselectiveandnon-selectiveagents:
Selective(β antagonism)(BEAM)BisoprololEsmololAtenololMetoprolol
Non-selective(β andβ antagonism)PropranololSotalolTimolol
Non-selective(β&αantagonism)CarvedilolLabetalol
Indications
CardioAnginaArhythmia
Rate-controlinAFParoxysmalSVTSinustachycardiafrom↑catecholamines
CardiacFailureSecondarypreventionforMI
VascularHypertension(2 line)AlsousefulforaggressivecontrolofBP.HypotensiveanaesthesiaAttenuatehypertensiveresponsetolaryngoscopy
Non-CVSThyrotoxicosisGlaucoma(topically)AnxietyMigraineprophylaxis
CommonFeatures
Property Action
KineticsVariabilityprimarilyduetolipidsolubility.Poorlipidsolubilityconferspoorgutabsorptionandminimisesneedforhepaticmetabolism.LipidsolubleagentswillhaveCNSeffectsandbeexcretedinbreastmilk.
Respiratory Bronchospasm.
1
1 2
nd
Beta-Blockers
598
CVS ↓Inotropy,↓HR,↓MVO ,↓BP,↑SVR(β effect),worsenarrhythmia.
CNS Tiredness,nightmares,andsleepdisturbancewithlipidsolubleagents.↓IOP.
Metabolic ↓Insulinreleaseandbluntedhypoglycaemicresponse(β effect).
Interactions ContraindicatedwithcardioselectiveCa channelblockers.duetoextreme↓HR&↓inotropy.
ComparisonofBetaBlockers
Property Esmolol Metoprolol Atenolol Propranolol Labetalol
Class Cardioselective Cardioselective Cardioselective βnon-selective
Non-selectiveβ&selectiveα Ratioofβ:αantagonismis3:1afterPOand7:1afterIVadministration
Uses
Short-termtreatmentoftachyarrhythmiaandHTN
MI,HTN,migraine,thyrotoxicosis
HTN,angina,tachyarrhythmias,acuteMI
HTN,Angina,dysrhythmia,essentialtremor,anxietyHOCM,phaeochromocytoma,migraine,oesophagealvarices
HTN,MI
Presentation Clear,colourlesssolution
Clear,colourlesssolution,50mgTablet.
25/50/100mgtablets,syrup,colourlesssolution.
Tabletsandsolutionat1mg.ml
Tabletsandsolutionat5mg.ml
RouteofAdministration IV PO/IV PO/IV PO/IV PO/IV
Dosing 50-200μg.kg.min
IV:1mgbolusesPO:12.5-100mgBD
PO:50-100mgdailyIV:2.5mgIVupto10mg
PO:10-100mgBD/TDSIV:1mgbolusestitratedtoresponse
PO:100-800mgBDIV:10-20mgIVbolus,followedby20-80mgQ30minupto300mg.Alternativelybyinfusionat1-2mg.min
Absorption IVonly
50%bioavailability,improveswithregularuse
45%PObioavailability 30%bioavailability
Highlyvariablebioavailability:10-80%
Distribution 60%proteinbound
20%proteinbound.Lipidsoluble
5%proteinbound 95%proteinbound 50%proteinbound
Metabolism
RBCesterasestoaninactivemetaboliteandmethylalcohol.t of10minutes
Hepaticwithgeneticvariabilityint ofactivemetabolites
Minimalmetabolism-dosereduceinrenalfailure
Hepatictoactiveandinactivemetabolites
Considerablehepaticfirstpassmetabolismwithinactivemetabolites
Renal
2 2
22+
1
-1 -1
-1 -1
1/21/2
Beta-Blockers
599
Elimination Renaleliminationofactivedrug
Renaleliminationofmetabolites
eliminationofinactivemetabolites
CVS Venousirritant
↓SVR,↓BP.Doesnottendto↓HRor↓COwhengivenacutely.
CNS Orthostaticdizziness
References
1. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.4. MacCarthyEP,BloomfieldSS.Labetalol:areviewofitspharmacology,pharmacokinetics,clinicalusesandadverseeffects.
Pharmacotherapy.1983.Jul-Aug;3(4):193-219.
Lastupdated2019-07-18
Beta-Blockers
600
AmiodaroneAmiodaroneisanantiarrhythmicagentwithacomplexmechanismofactionandmanyeffects.
K channelblockadeincardiacmyocytes,inhibitingtheslowoutwardcurrentandslowingrepolarisation(ClassIII)β-blocker-likeactivityonSAandAVnodes,decreasingautomaticityandslowingnodalconduction(ClassII)Ca channelblocker-likeactivityonL-typeCa channels,decreasingtheslowinwardCa current,increasingdepolarisationtimeanddecreasingnodalconduction(ClassIV)α-blocker-likeactivity,decreasingSVR
Property Amiodarone
Class ClassIIIantiarrhythmic,thoughexhibitsactionfromall4classes.
Uses VT/VF,resistantarrhythmia,ALS.
Presentation 100/200mgtablets,IV:150mgampouletobereconstitutedinD5W.
RouteofAdministration IV/PO.
Dosing IV:Loadwith5mg.kg over1/24,withafurther15mg.kg overthefollowing24/24PO:200mgTDSfor1/52,200mgBDfor1/52,200mgODthereafter.
Absorption PoorPOabsorptionwithbioavailability~50%.
Distribution HighlyproteinboundwithveryhighV of~70L.kg sduetoaccumulationinfatandmuscle.
Metabolism HepaticmetabolismwithinhibitionofCYP3A4,totheactivedesmethylamiodarone.
Elimination Verylongt ofupto~55days.Biliary,skin,andlacrimalelimination,with<5%ofdrugeliminatedrenally.Notremovedbydialysis.
Resp 10%3-yearriskofpneumonitis,fibrosis,pleuritis.
CVS ↓HR,↓BP,↓SVR,↑QTwithoutriskofTDP.Irritanttoperipheralveins.
CNS Mildblurringofvisionfromcornealdeposition,sleepdisturbance,vividdreams,peripheralneuropathy.
MSK Photosensitivity,greyskin.
Endocrine Hyperthyroidism(1%)andhypothyroidism(6%).
GIT Nausea,vomiting,cirrhosis,hepatitis,andjaundice.
Other
AmiodaronehaspotentialtocauseanumberofdruginteractionsduetoitsinhibitionofCYP3A4anditshighproteinbinding.Aselectioninclude:Digoxin,statins,warfarin,phenytoin,andotherantiarrhythmics.Contraindicatedinporphyria.
AmnemonicforsomeoftherarereffectsisBITCH:
BlueskinInterstitiallungdiseaseThyroidCornealHepatic
+
2+ 2+ 2+
-1 -1
D-1
1/2
Amiodarone
601
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.Peckandhill
2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.
Lastupdated2019-07-18
Amiodarone
602
SotalolTheD-isomerofsotalolisaclassIIIantiarrhythmic,whilsttheL-isomeralsohasclassIIactivity.
Property Action
Class ClassIIIantiarrhythmic
Uses Tachyarrhythmiaprophylaxis
Presentation Solutionat10mg.ml andtablets
Isomerism Racemicmixture
RouteofAdministration PO/IV
Dosing PO:40-160mgBDIV:50-100mgover20minutes
Absorption >90%bioavailability
Distribution Noproteinbinding
Metabolism Notmetabolised
Elimination Excretedunchangedinurine
Resp Bronchospasm
CVS Torsades(<2%)-morecommonwithhighdoses,longQT,andelectrolyteimbalances
CNS Maskingsymptomsofhypoglycaemia
GU Sexualdysfunction
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-07-18
-1
Sotalol
603
DigoxinDigoxinisacardiacglycosideusedinthetreatofatrialarrhythmiasandincardiacfailureasapositiveinotrope.
Digoxinhasbothadirectandindirectmechanismofaction:
DirectInhibitscardiacNa /K ATPase,causing:
Increasingintracellular[Na ],increasingactivityoftheNa /Ca pumpIncreasedintracellularCa increasesinotropyDecreasedK resultsprolongsrefractoryperiodoftheAVnodeandbundleofHis
IndirectParasympathomimeticeffectsbyincreasingAChreleaseatcardiacmuscarinicreceptors.
SlowsAVnodalconductionandventricularresponseThisimprovescoronarybloodflow,increasingtimeforventricularfilling,andimprovingcardiacoutput.
Property Action
Class CardiacGlycoside
Uses Arrhythmia-particularlyAF/Flutter,andCCF
Presentation Tablets,elixir,clearcolourlesssolution
RouteofAdministration PO/IV
Dosing PO:62.5μg-250μg,IV:250-500μgload
Absorption >70%bioavailabilitythoughvarieswithformulation
Distribution 25%proteinbound.V 5-11L.kg ,dependentonleanmass
Metabolism Minimalhepaticmetabolism
Elimination Renaleliminationofactivemetabolitest 35hours-increasedinrenalfailure
CVS ↓HR,↑inotropy,arrhythmiasincluding;bigeminy,PVCs,1 /2 /3 degreeAVblock,SVT,VT
CNS Derangedred-greencolourperception,visualdisturbances,headache
Immune Eosinophiliaandrash
Metabolic Gynaecomastia
ToxicEffects NarrowTI.SeverearrhythmiawithDCcardioversion
Interactions
Interaction Drug
Increasedlevel Amiodarone,captopril,erythromycin,verapamil
Decreasedlevel Antacids,cholestyramine,phenytoin,metoclopramide
References
+ ++ + 2+
2++
D-1
1/2st nd rd
Digoxin
604
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2018-09-21
Digoxin
605
AdenosineAdenosineactsviaA adenosinereceptorsintheSAandAVnode,whichwhenstimulatedopenK channelscausinghyperpolarisationandareductioninCa current,withsubsequentblockadeofAVnodalconduction.
Property Action
Class Naturallyoccurringpurinenucleoside
Uses SVT
Presentation Colourlesssolutionat3mg.ml
RouteofAdministration IV
Dosing 3mg/6mg/12mginincreasingdoses
Metabolism Rapidlydeaminatedinplasma.t <10s
Resp Bronchospasm,↑RRandV
CVS ↓↓AVnodalconduction,maycauseAF/lutter
ToxicEffects Contraindicatedinsick-sinussyndrome,2 /3 degreeAVblock
Interactions
Interaction Drug
Increasedeffect Dipyridamole
Decreasedeffect Methylxanthines,suchasaminophyllineandcaffeine
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2017-07-27
1+
2+
-1
1/2
T
nd rd
Adenosine
606
MagnesiumMg isacationthatisimportantforneurotransmissionandneuromuscularexcitability.Magnesium:
InhibitsAChreleaseattheNMJActsacofactorinmultipleenzymesystemsIsimportantintheproductionof:
ATPDNARNA
Property Action
Uses HypoMg,arrhythmia,eclampsia,tocolysis,bariumpoisoning,asthma,tetanus,autonomichyperreflexia
Presentation 2mmol.ml ,madeupinto10mmolin100mlforperipheraladministration
RouteofAdministration PO/IV
Dosing IV:10-20mmol
Distribution 30%proteinbound
Elimination Significanturinaryexcretion,evenwhendeficient
Resp Bronchodilation
CVS ↓SVR,hypotension,↓HR
CNS CNSdepression,anticonvulsant
GU ↓Uterinetoneandcontractility
ClinicalEffectsofMagnesium
[Plasma] Effect
<0.7mmol.L Arrhythmia
4-6mmol.L Nausea,hyporeflexia,speechimpairment
6-10mmol.L Weakness,respiratorydepression,bradycardia
>10mmol.L Cardiacarrest
References1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.
Lastupdated2017-09-20
2+
-1
-1
-1
-1
-1
Magnesium
607
Magnesium
608
AtropineNaturallyoccurringtertiaryaminewhichcompetitivelyantagonisesAChatthemuscarinicreceptor,causingparasympatholyticeffects.
Property Atropine
Class Naturallyoccurringtertiaryamine.Muscarinicantagonist.
Uses Bradycardia,organophosphatepoisoning,antisialagogue,treatmentofPDPH
Presentation Clear,colourlesssolutionat600μg.ml .Racemicmixture,withonlytheL-isomeractive
RouteofAdministration IV
Dosing 600μg-3mg
Distribution 50%proteinbound,V 3L.kg .CrossesBBB.
Metabolism Extensivehepatichydrolysis
Elimination Renaleliminationofmetabolitesandunchangeddrug
Resp Bronchodilation,↓secretions
CVS ↑HRdueto↑AVnodalconduction,peakswithin2-4minutesandlasts2-3hours
CNS Centralanticholinergicsyndrome,confusion,↑IOP,↑CSFsecretioninchoroid,cerebralvasoconstriction
MSK Inhibitssweating
GIT ↓LoStone
References
1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. Mahmoud,AhmedAbdelaalAhmed,AmrZakiMansour,HanyMahmoudYassin,HazemAbdelwahabHussein,Ahmed
MoustafaKamal,MohamedElayashy,MohamedFaridElemady,etal.‘AdditionofNeostigmineandAtropinetoConventionalManagementofPostduralPunctureHeadache:ARandomizedControlledTrial’127,no.6(2018):6.
Lastupdated2019-07-18
-1
D-1
Atropine
609
DiureticsAnunderstandingofthepharmacologyofdiuretics.
Diureticsaredrugsthatactonthekidneytoincreaseurineproduction.Theycanbeclassifiedbytheirmechanismofactioninto:
ThiazidesLoopdiureticsPotassiumsparingAldosteroneantagonistsOsmoticCarbonicAnhydraseinhibitors
CommonFeaturesofDiuretics
Property Diuretics
Absorption Typicallypoorbioavailability(exception:acetazolamide)
Distribution Variableproteinbinding
Metabolism Generallynotmetabolised.Keyexceptions:Spironolactoneisextensivelymetabolisedwithactivemetabolites,andasmallamountoffrusemideismetabolisedtoglucuronide.
Elimination Renaleliminationofunchangeddrug
CVS Reducedintraandextravascularvolume
Renal
Anydiureticwhichinhibitssodiumreabsorptioncanprecipitatehypokalaemia(asagreaterintra-luminalconcentrationofsodiumresultsinexchangeofsodiumforpotassiumions),hyponatraemia(asthereisstillanetlossofsodium),andalkalosis(fromlossofhydrogenionsexchangedforsodium,ortheoverallraisedstrongiondifference).
ComparisonofDiuretics
Thiazides LoopDiuretics PotassiumSparing
Aldosteroneantagonists Osmotic
Example Hydrochlorothiazide Frusemide Amiloride Spironolactone Mannitol
Site Distaltubule LoopofHenle Distaltubule Distaltubule Glomerulus
Mechanismofaction
InhibitNa andClreabsorption,andincreaseCareabsorptionintheDCT
InhibitNKCC2,theNa /K /2.Cltransportproteininthethickascendinglimb,impedingthecounter-currentmultiplier.Thisreducesthehypertonicityofthemedulla,andsubsequentwaterreabsorptioninthecollectingsystem.
InhibitsNa /Kexchangepump.Weakeffect.
Competitivealdosteroneantagonist.AldosteronestimulatesNareabsorption,whichinturnstimulatesKsecretion.
Filteredattheglomerulusandnotreabsorbed,increasingfiltrateosmolarityandincreaseswaterexcretion.
+ -
2+
+ + -
+ ++
+
Renal
610
Resp
Cardiac
AntihypertensiveduetoreducedplasmavolumeandSVR
Arteriolarvasodilation,reducingSVRandpreload
Increasesintravascularvolume,increasingpreload.MayincreaseCOorresultincardiacfailure.
CNS ↓ICP
Renal ReducedrenalbloodflowandGFR
IncreasedrenalbloodflowandGFR
Increasedrenalbloodflow
Metabolic
Hypokalaemic,hypochloraemicalkalosis.Hyperglycaemia.
Hypochloraemia,hyponatraemia,hypokalaemia,hypomagnesaemia.Occasionalhyperuricaemiaprecipitatinggout.
Hyperkalaemia. Hyperkalaemia,hyponatraemia.
Miscellaneous Blooddyscrasias
Deafness,typicallyfollowinglargedoses.Morecommoninkidneyimpairmentandwithaminoglycosideuse.
Gynaecomastiaandmenstrualirregularityduetoanti-androgynismfromaldosteroneantagonism
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.
Renal
611
3. Auerbach.WildernessMedicine.SixthEdition.
Lastupdated2019-07-18
Renal
612
IntravenousFluidsIntravenousfluidscanbeclassifiedinto:
CrystalloidsCanpassfreelythroughasemipermeablemembrane.Canbefurtherclassifiedinto:
ECFreplacementsolutionsHavea[Na ]similartoECF,suchthattheyareconfinedmostlytotheECF.MaintenancesolutionsDesignedtodistributethroughoutTBW.SpecialsolutionsThesesolutionsdon'tfitintotheabovetwocategories,andinclude:
HypertonicsalineMannitol8.4%SodiumBicarbonate
ColloidsSubstanceevenlydispersedthroughoutanothersolutioninwhichitisinsoluble.Canbeclassifiedinto:
NaturallyoccurringAlbuminHeat-treatedhumanalbumin.
ProducedatlowpHbutnottechnicallysterileUsewithin3hoursofopening.ContributestoplasmaoncoticpressureContributestodrugandendogenoussubstancebinding
SyntheticDextransHighmolecularweightsugarssynthesisedfromsucrosebybacteria.
InterferewithhaemostasisduetovWFinhibitionInterferewithbloodcrossmatchRiskofanaphylaxis
GelatinsHighmolecularweightproteinsproducedbycollagenhydrolysis.
GreatestanaphylaxisriskDonotinterferewithclotting
Hydroxyl-ethylstarchesRiskofanaphylaxisRiskofrenalimpairmentAccumulateinthereticuloendothelialsystem
ComparisonofCrystalloids
Contents(mmol.L ) 0.9%NaCl Hartmann's Plasmalyte
Na 154 130 140
Cl 154 109 98
K 4
Ca 3
+
-1
+
-
+
2+
2+
IntravenousFluids
613
Mg 1.5
Lactate 28
Acetate 27
Gluconate 23
pH 5.0 6.5 5.5
References
http://www.anaesthesiamcq.com/FluidBook/fl7_2.php
Lastupdated2019-07-18
2+
IntravenousFluids
614
PropofolPropofol(2-6di-isopropylphenol)isaphenolicderivativewitheffectsonmanyreceptorsincluding:
GABAPotentiatestheeffectofGABA,prolongingCl channelopeningandhyperpolarisingthecell.GlycineNicotinicAChD receptors
Property Action
Class Phenolicderivative
Uses Inductionofanaesthesia,sedation,TIVA
Presentation
Whiteoil-in-wateremulsionatapHof7-8.5containing:-10-20mg.ml propofol-10%Soybeanoil(solubilisingagent)-1.2%Purifiedeggphosphatide(emulsifier)-2.25%Glycerol(fortonicity)Bacteriostaticadditivesincluding:-Generics:Sodiummetabisulfite-Diprivan:Disodiumedetate(lessallergenic)Riskofbacterialcontaminationlimitsshelflife.Energycontentis1.1kcal.ml
pKa 11-almostallisunionised(andactive)atphysiologicpH
RouteofAdministration IVonly
Dosing Induction:1-2.5mg.kg Maintenance:4-12mg/kg/hr.Targetplasmaconcentrationof4-8μg.ml tomaintaingeneralanaesthesia
Distribution 98%proteinbound.VeryhighV at4L.kg .Rapidinitialdistribution:t α(fast)1-3minutes,intermediatedistributiont α(slow)30-70minutes.t
MetabolismHepaticandextra-hepaticmetabolismtoinactiveglucuronidesandsulphates;t β2-12hours.Clearanceof30-60ml.kg.min ,unaffectedbyrenalandhepaticdisease.Contextsensitivehalf-timepeaksat50minutesfollowinga9hourinfusion.
Elimination Tri-exponential.Renaleliminationofinactivemetabolites.
Resp Respiratorydepression,apnoea.Strongsuppressionoflaryngealreflexes.↓Responsetohypoxiaandhypercapnea.Bronchodilation.
CVS↓Arterialandvenousvasodilation(viastimulatingNOrelease)causing↓SVRand↓VR,with↓BP.↓Inotropyvia↓inSNStone,↓MVO .Depressesbaroreceptorreflex.Painoninjectionduetolipidemulsion.
CNSHypnosis.RapidLoC(within1arm-braincirculationtime).↓CMRO2,CBF,andICP.Anticonvulsant.↓IOP.Paradoxicalexcitatoryeffectsseenin~10%-dystonicmovementsofsubcorticalorigin.EEGdemonstratesnon-specificseizure-likeactivity.
MSK Painoninjectionintosmallveins
Renal Greenurine
GIT Anti-emetic.↓HepaticBloodFlow
Metabolic Fatoverloadsyndrome,lipaemiafollowingprolongedinfusion.Inhibitsmitochondrialfunction.
Propofolinfusionsyndrome:Acidosis,bradycardia,andMODSfollowingprolongedinfusion(>24
A-
2
-1
-1
-1 -1
D-1
1/21/2 1/2 </sub>of2.7min.ke0
1/2-1
2
-1 -1
Neuropharmacology
615
mitochondrialdefects.Believedduetoinhibitionofmitochondrialfunction.
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. CICMJuly/September2007http://ceaccp.oxfordjournals.org/content/4/3/76.full.pdf
http://www2.pedsanesthesia.org/meetings/2007winter/pdfs/Morgan-Friday1130-1150am.pdf
Lastupdated2019-07-18
Neuropharmacology
616
BarbituratesThiopentoneisapositiveallostericmodulatoratGABA receptors(ataseparatesitetobenzodiazepines)intheCNS.Barbituratescause:
DecreasedrateofdissociationofGABAIncreasesthedurationofchannelopening,causingeffectivehyperpolarisationduetoincreasedCl conductance.
Clinicaleffectsdifferfrombenzodiazepinesasbenzodiazepinesincreasefrequencyofopening,whilstbarbituratesincreaseduration
Directactivationofthechannelathigherdoses
Property Thiopentone
Class Barbiturate
Uses Inductionofanaesthesia,statusepilepticus,controlofICPrefractorytoothermeasures
Presentation500mgofyellowpowderwithNaCO forreconstitutionasa2.5%solution.Containerusesnitrogenasafillergas(topreventHCO formationwhenCO combineswithwaterduringreconstitution,which↓pHandthereforewatersolubility).pHof11whenreconstituted-bacteriostaticsolution.
Isomerism Tautomer.pKaof7.6,suchthat60%isunionisedatpH7.4(i.e.watersolubilitydecreasesonceinjected).
RouteofAdministration IV
Dosing 3-7mg.kg .Consider75mgboluses,assessinghaemodynamicandneuronaleffects.
Distribution65-85%proteinbound.HighlipidsolubilityandCBFgivesarapid,reliableonset.Rapidoffsetduetoredistribution,withafastt αof8minutes.Prolongedeliminationhalflife(11hours)contributestolongCSHT.Increasedunionisedportioninacidosis.t
Metabolism CapacitydependentCYP450metabolism-saturatesathighdoses(longCSHTwithinfusion).Metabolisedto(active)pentobarbital,whichalsoincreasesthedurationofitsclinicaleffects.
Elimination Renalofmetabolites,<1%excretedunchanged
Resp Respiratorydepression,bronchospasm,laryngospasm
CVS Vasodilationandvenodilation(↓MSFP),↓inotropy,withcompensatorytachycardia(baroreceptorresponsepreserved)
CNS
Hypnosisandanaesthesiawithin40secondsofinjection,withreliablelossoflashreflex.Anticonvulsant.Dose-dependentflatteningoftheEEG(βαθδburstsuppressionisoelectric),causingprogressive↓CMRO (55%ofmaximalduringburstsuppression),↓CBF,and↓ICP.
Resolutionofinductiondosein5-10minutesduetoredistribution.
Endocrine ↓RBFcausing↓UO
GIT Hepaticenzymeinduction
Immune Anaphylaxis~1;20,000
Metabolic Mayprecipitateacuteporphyriccrisesandiscontraindicatedinthesepatients
Other
IntraarterialinjectioncausesprecipitationaswatersolubilitydecreasesatbloodpH.Microembolisationandischaemiaresult,whichshouldbetreatedwithintraarteriallocalanaesthesia,analgesia,anticoagulation,andsympatheticblockadeofthelimb.
Tissuenecrosisonextravasation.
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References
1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.2. LITFL-Thiopentone3. Hill,SA.Pharmacokineticsofdruginfusions.ContinuingEducationinAnaesthesia.2004.
Lastupdated2019-07-18
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KetamineKetamineisaphencyclidinederivativeusedforinduction,sedation,analgesia,andasabronchodilatorinsevereasthma.
Ketamineactsvia:
Non-competitiveantagonistofNMDAandglutamatereceptorsintheCNSReducespresynapticglutamatereleaseSodiumchannelinhibitionLocalanaesthetic-likeeffect.Potentialmonoaminergic,muscarinic,andnicotinicantagonism
Property Action
Class Phencyclidinederivative
Uses Inductionofanaesthesia,sedation,analgesia,asthma
Presentation Clear,colourlesssolutionforminganacidicsolution(pH3.5-5.5)
Isomerism RacemicmixtureorthesingleS(+)enantiomer,whichis2-3xaspotentastheR(-)enantiomerbuthaslessbronchodilatoryproperties
RouteofAdministration IV,IM,PO,PR,PN,viaepidural(withpreservative-freesolution)
Dosing Induction:1-2mg.kg IV,5-10mg.kg IM,Sedation:0.2-0.5mg.kg IV
Distribution 25%proteinbound.t α10-15minutes
Metabolism HepaticmetabolismtoactivenorketaminebyCYP450andthentoinactivemetabolites,t β2-4hours
Elimination Renaleliminationofinactivemetabolites.Actionofnorketamineprolongedinrenalfailure.
Resp Bronchodilation,tachypnea,relativepreservationoflaryngealreflexes.Apnoeawithrapidinjection.PreservedcentralresponsetoCO .
CVS ↑Sympatheticoutflow:↑HR,↑BP,↑SVR,↑MVO .Actsdirectlyasamyocardialdepressant-bewaremaximallystimulatedpatient.Depressesbaroreceptorreflex.
CNS
Dissociation,analgesia,emergencephenomena(hallucinations,delirium)reducedbyconcurrentBDZadministration(increasingriskwithhigherdosesandrapidadministration).
Producesdissociativeanaesthesiawithin90secondsbydissociatingthalamocorticalandlimbicsystemsonEEG.Purposefulmovementsunrelatedtostimulusmayoccurevenduringsurgicalanaesthesia.
↑IOP.
Renal Cystitiswithlong-term,high-doseuse
GIT N/V
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. CICMJuly/Sept2007
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4. LuptonT,PrattO.Intravenousdrugsusedfortheinductionofanaesthesia.
Lastupdated2019-07-18
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DexmedetomidineDexmedetomidineisacentralα -agonist(α :α activity1600:1)usedforitssedationandanalgesicproperties.
Property Action
Class Imidazolederivative
Pharmaceutics D-stereoisomerofmedetomidine(theL-stereoisomerisinactive)
Uses Sedationwithoutrespiratorydepression
Presentation Clearcolourlesssolutionat10µg.ml
RouteofAdministration IVonly
Dosing 0.2-0.7µg.kg .hr
Distribution 95%proteinbound
Metabolism Hepatictoinactivemetabolites
Elimination Renalofmetabolites,t βof2hours
CVSInitialtransient↑SVRandBPduetoα effects,followedby↓MAP,↓HR.
Rebound↑BPwhenabruptlyceased.
CNSSedation,anxiolysisatlowdose(anxiogenicathighdose),amnesia.↓MAC.
↓SNSoutflow.
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2017-09-16
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LocalAnaestheticAgentsLocalanaestheticdrugsdeliverause-dependent,temporaryblockadeofneuronaltransmissionUnioniseddrugpassesthroughthecellmembrane,andthenbecomesionisedintracellularlyTheioniseddrugisthenabletobindtotheionchannel,andpreventconductionofsodiumandthereforegenerationofanactionpotential
Alllocalanaestheticsconsistof:AhydrophiliccomponentAlipophilicaromaticringAnamideoresterlinkconnectingthetwo
CommonFeaturesofLocalAnaesthetics
Property Action
Class Amide(-NHCO-)orEster(-COOH-)
Pharmaceutics Amidesarestableinsolution,estersareunstableinsolution.Allareformulatedasahydrochloridesalttoensurewatersolubility.
pKa Allareweakbases,andhaveapKa>7.4
Onset
Onsetisrelatedtodose(Fick'sLaw)andpKa,withalowpKagivingafasteronsetasthereismoreunioniseddrugpresentandthereforemoredrugabletocrossthecellmembrane.Thisiswhylocalanaestheticsarepooratanaesthetisinginfectedtissues,asthetissuepHislowresultinginagreaterproportionofioniseddrug,andlessdrugreachingtheeffectsite.
DurationofAction
Durationofactionisrelatedtoproteinbinding,withgreaterproteinbindinggivingalongerdurationofaction
Potency Potencyisrelatedtolipidsolubility(higherlipidsolubilityincreasespotency)andvasodilatorproperties(weakervasodilatorshavinggreaterpotency)
AbsorptionSystemicabsorptionvarieswithsiteofentry(fromhighestabsorptiontolowest:IV,intercostal,caudalepidural,lumbarepidural,brachialplexus,subcutaneous),dose,andpresenceofvasoconstrictors
Distribution Amidesareextensivelyproteinbound,estersareminimallybound
Metabolism Amidesarehepaticallymetabolised,estersarehydrolysedbyplasmacholinesterases(givingamuchshortert )
CVSVasodilatationatlowconcentrations,vasoconstrictionathighconcentrations.InhibitionofcardiacNachannels,inhibitingmaximumrateofriseofphase0ofthecardiacactionpotential.Negativeinotropyproportionaltopotency.
CNSDoes-dependentCNSeffects:circumoraltingling,visualdisturbances,tinnitus,tremors,dizziness,slurredspeech,convulsions,coma,apnoea.PotentiatedbyotherCNSdepressantsandhypercarbia(dueto↑CBFand↓seizurethreshold).
ToxicEffects Estershaveahigherincidenceofallergyduetotheirmetabolitepara-aminobenzoicacid(PABA).LocalanaesthetictoxicityispredominantlyCNSandCVS.
ComparisonofLocalAnaesthetics
Property Lignocaine Bupivacaine Ropivacaine Cocaine
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Class Amide Amide Amide Ester
Uses Local/regional/epidural,ventriculardysrhythmia Local/regional/epidural Local/regional/epidural
Topicalanaesthesiaandvasoconstriction
Presentation
Clear,colourlesssolutionat0.5/1/2%withorwithoutadrenaline.Spray.Ointment.4%solution.
Clear,colourlesssolutionat0.25/0.5%
Clear,colourlesssolution
1-4%solution,Moffat'ssolution(8%cocaine,1%NaCO ,1:2000adrenaline)
pKa 7.9 8.1 8.1 8.6
RouteofAdministration SC,epidural,IV SC,epidural SC,epidural Topical
Onset/Duration Rapidonset,shortduration
Intermediateonset,longduration
Intermediateonset,longduration 20-30minutes
MaximumDose
Analgesia:4mg.kgwithoutadrenaline,7mg.kg withadrenaline
2mg.kg 3mg.kg 3mg.kg
Distribution 70%proteinbound Highlyproteinbound
Lowerlipidsolubilityreducesmotorblockcomparedtobupivacaine
Highlyproteinbound
Metabolism Hepaticwithsomeactivemetabolites
Hepatictoinactivemetabolites
Hepatictoactivemetabolites
Plasmaesterases,somehepaticmetabolism(unlikeotheresters)
Elimination Reducedinhepaticorcardiacfailure
Eliminationofactivedrugandinactivemetabolites
CC/CNSratio 7 3 5
Other
MosttoxicofLAagentsasittakeslongertodissociatefromthemyocardialNa channel.Levobupivacaineislesscardiotoxictheracemicmixture,possiblyasithasmoreintrinsicvasoconstrictiveproperties.
Maycause↑BP,↑HR,coronaryvasoconstriction,myocardialdepression,VF,↑temperaturedueto↑serotonin,dopamine,andnoradrenalinereuptake
LignocaineToxicity
Serumconcentration(µg.ml ) Phase Effect
2 Safe Antiarrhythmic.Maybegintohavelightheadedness,circumoraltingling,numbness
5 Excitatory Dysarthria
8 Excitatory Visualchanges
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10 Excitatory Seizures
12 Depressive Lossofconsciousness
20 Depressive Respiratorydepression
25 Depressive CVSdepression
PharmaceuticsofTopicalLocalAnaesthetics
EffectoftopicallocalanaestheticsisgovernedbyFick'sLaw.
Characteristic Effect
PharmaceuticFactors
Presentation Aerosolimprovesspeedofonsetbymoisturisingskin
Concentrationofactivecomponent Increasespeedofonset
Stability
pH ↑pHensuresmorelocalanaestheticisintheunionisedform,↑absorption.
Additives AffectpHandvasoconstrictoractivity
DrugFactors
Molecularweight Smallmoleculeswilldiffusemoreeasily
pKa Affectsionisationandthereforelipidsolubility
Lipidsolubility ↑lipidsolubilityimprovesspeedofonset.
Potency Determinesamountofdrugneededtoproduceaneffect
Vasoconstrictoractivity Willaffectbothspeedofonsetanddegreeofsystemicabsorption
PatientFactors
Site Degreeofvascularityofsite
Skin Skinthicknessandareawillaffectonset
References1. CICMMarch/May20092. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.4. OpenAnaesthesia.LocalAnaestheticsSystemicToxicity5. GadsdenJ.LocalAnaesthetics:ClinicalPharmacologyandRationalSelection.NYSORA.6. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.7. ChristieLE,PicardJ,WeinbergGL.Localanaestheticsystemictoxicity.ContinuingEducationinAnaesthesiaCriticalCare
&Pain,Volume15,Issue3,1June2015,Pages136–142.
Lastupdated2017-09-20
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BenzodiazepinesBenzodiazepinesaredouble-ringedpositiveallostericmodulatorsoftheGABAreceptorsintheCNS.They:
Bindtotheα/γinterfaceofthereceptor,increasingaffinityofthereceptorforGABAThisleadstohyperpolarisationofthecellmembranesanddecreasedneuronaltransmissionThemechanismvariesbetweenreceptors:
GABA isaligandgatedpost-synapticCl ionchannelActivationincreasesCl conductanceviaincreasingfrequencyofchannelopening.GABA isapre-andpost-synapticG-proteincoupledreceptorActivationincreasesK conductance.
CommonFeaturesofBenzodiazepines
Property Action
Uses Sedation,anxiolysis,hypnotic,anticonvulsants,amnestic,musclerelaxation
Absorption
Distribution Highlylipidsolubleandproteinbound,verylowV
Metabolism Generallyactivemetabolites.
Elimination Renaleliminationofactiveandinactivemetabolites.
Resp ↓V ,↑RR,apnoea.
CVS ↓SVR,↓SBP,↓DBP,↑HR.TypicallystableCO.
CNS Hypnosis,sedation,anterogradeamnesia,anticonvulsant,↓CBF.↓MAC.
MSK Skeletalmusclerelaxation.
Metabolic ↓Adrenergicstressresponse.
ComparisonofBenzodiazepines
Property Midazolam Diazepam Clonazepam
Physicochemical
pKa6.5.StructureisdependentonsurroundingpH-atapH<4itsringstructureopensanditbecomeswatersoluble.
40%propyleneglycol.
RouteofAdministration PO/IV/IM. PO/IV/IM. PO.
Absorption 50%PObioavailability. GoodPObioavailability.
Distribution V 1.5L.kg ,95%proteinbound. 95%proteinbound.
MetabolismPartiallymetabolisedtooxazepamand1-α-hydroxy-midazolam.Clearance~7ml.kg .min .
Hepatictoallactivemetabolitesincludingoxazepam,temazepam,anddes-methyl-diazepam(hast βupto100hours).
Hepatictoinactivemetabolites.
Eliminationt β2-4hours,prolongedwithcirrhosis,CHF,obesityandinthe t β20-45hours.
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elderly.
References
1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.
Lastupdated2019-07-18
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AntidepressantsSymptomsandmanagementofTCAoverdoseiscoveredunderTricyclicAntidepressantOverdose.
Antidepressantdrugsinclude:
TricyclicAntidepressants(TCAs)Mechanismofactionbymultipleeffects,including:
CompetitivelyinhibitreuptakeofNAand5-HTMuscarinicantagonismLeadstoanticholinergicsideeffects(drymouth,blurredvision,constipation,urinaryretention).H andH antagonismα antagonismNMDAantagonism
SelectiveSerotoninReuptakeInhibitors(SSRIs)Inhibitneuralreuptakeof5-HTPreferredoverTCAsas:
SimilareffectivenessBettersideeffectprofile
MonoamineOxidaseInhibitors(MAO-Is)Inhibitmonoamineoxidaseonexternalmitochondrialmembrane,increasingthelevelofamineneurotransmittersintheCNSandPNSTwoenzymesexist:
MAO-ADominantenzymeinCNSActsonserotonin,noradrenaline,adrenaline
MAO-BDominantinGITandplateletsResponsiblefor75%ofMAOactivityPreferentialmetabolismofnon-polaramines
MAO-IsclassifiedbytheirmechanismandselectivityNon-selective,irreversibleBindcovalentlytotheenzyme,permanentlyinactivatingit.
MayleadtohypertensivecrisiswhencatecholaminelevelsincreasedTyramineinfoodMetabolisedbyMAO-B.IndirectlyactingsympathomimeticsAbsolutelycontraindicated.
RiskofserotoninsyndromewithserotoninreuptakeinhibitorsInclude:
PhenelzineIsocarboxazidTranylcypromine
Enzymelevelswilltake2-3weekstorecoverfollowingcessationMAO-Aselective,reversible
HypertensivecrisisislesscommonMAO-Bunaffected-tyramineismetabolisedShortactingEnzymelevelsnormaliseafter24hoursofcessation.
Include:
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MoclobemideMAO-Bselective
MuchlowerriskofhypertensivecrisisInclude:
SelegilineDiscontinuationsyndromemayoccurifabruptlyceased
Property TricyclicAntidepressants SelectiveSerotoninReuptakeInhibitors
MonoamineOxidaseInhibitors
Example Amitriptyline Fluoxetine
Uses Depression,treatmentofchronicpainandtrigeminalneuralgia Depression,anxiety
Treatmentresistantdepression.Nowlargelysupersededduetoside-effectprofile
Absorption HighPObioavailability HighPObioavailability
DistributionHighlylipidsolublewithHighV .Veryhighlyproteinbound-leadstointeractionswithwarfarin,digoxin,andaspirin
Highlyproteinbound,highV
Metabolism Hepaticwithactivemetabolites.Largeinterpatientvariability
Hepaticwithnon-linearkinetics
VenlafaxinedoesnotaffectCYP450enzymes.
Elimination Unaffectedbyrenalimpairment
Resp Drymouth
CVS
Posturalhypotension,↑HR.QTprolongationandwideningQRSinoverdose,witharrhythmiamorelikelywhenQRSexceeds0.16s.
LesscardiotoxicthanTCAs,mayprecipitateserotoninsyndrome
CNSSedation,blurredvision,loweredseizurethreshold.Excitation,followedbyseizuresanddepressioninoverdose.
IdenticalantidepressanteffecttoTCAs.Lesssedation
Renal Urinaryretention
GU SexualdysfunctionGreaterincidenceofsexualdysfunctioncomparedwithTCAs
GIT ConstipationGreaterincidenceofN/VcomparedwithTCAs
Other
Multiplecomplexdruginteractions,includingarrhythmiasandvariableBPwithsympathomimetics,centralanticholinergicsyndrome,serotoninsyndrome,andseizures.
↑Sensitivitytocatecholamines-suggestavoiding:-Indirectlyactingsympathomimetics-Ketamine-Surgicalstress
Continueduringperioperativeperiodtoavoidriskofdiscontinuationsyndrome.
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SerotoninSyndrome
SerotoninsyndromeisexcessiveserotoninintheCNS,typicallyasaconsequenceofdruginteractions.Thesyndromemaybemild,moderate,orsevere,andpresentswithsomeorallof:
AlteredmentalstateConfusion
MotorchangesMyoclonusHyperreflexiaTremor
AutonomicinstabilityDiaphoresisShiveringFever
Serotoninsyndromeistypicallyself-limitingandresolveswithcessationofthedrug.
References
1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.2. AltamuraAC,MoroAR,PercudaniM.Clinicalpharmacokineticsoffluoxetine.1994Mar;26(3):201-14.3. BromheadH,FeeneyA.Anaesthesia&PsychiatricDrugs-Antidepressants.AnaesthesiaTutorialoftheWeek(164).2009.
Lastupdated2019-07-18
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AntipsychoticsAntipsychoticsaredrugsusedforthemanagementofpsychosesandthoughtdisorders.Theyhaveacomplicatedmechanismofactionwitheffectsonmultiplereceptors:
Centraldopamine(typicallyD ,butvarieswithagent)antagonismResponsiblefortheantipsychoticproperties5-HT antagonism
Otherreceptorswhicharequantitativelylessimportant:H antagonismα antagonismMuscarinicAChantagonism
Basedontheiraffinitytovariousreceptors,theyare(loosely)classifiedaseither:
Typicalor1 generationantipsychoticsHigheraffinityforD receptors(subsequentlylessblockadeof5-HT ),causingagreatereffecton'positive'symptoms'andagreaterincidenceofextrapyramidalsideeffectsAtypicalor2 generation,whichtypicallyhavefewermotoreffectsHavegreatereffectonnegativesymptoms.
CommonFeaturesofAntipsychotics
Property Drug
Uses Behaviouralemergencies,schizophrenia/psychosis
CVS QTprolongation
CNS Apathy,↓initiative,↓responsetoexternalstimuli,↓aggression.Nolossofintellectualfunction.
Endocrine ↑Prolactin(typicalantipsychotics)
Haeme Leukopeniaandagranulocytosis(predominantlyclozapine,butcanbeall)
Metabolic Weightgain,diabetes,hypercholesterolaemia(allatypical>typical)
OtherToxicities Neurolepticmalignantsyndrome,EPSE
NeurolepticMalignantSyndrome
AntipsychoticMalignantSyndromeisrareandpresentssimilarlytoMH,witharapidriseinbodytemperatureandconfusion.Ithasahighmortality(upto20%).
Extra-PyramidalSideEffects
MotordisturbancesfromantipsychoticusearetermedEPSEs,andaredividedintotwomaintypes:
AcuteDystonicReactionsareinvoluntarymovementsandparkinsoniansymptoms.Theyare:
MorecommonwithtypicalagentsDeclinewithongoinguseReversiblewithcessationoftheagent
TardivedyskinesiaissimilartoADR,except:
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InvoluntarymovementsaremorepronouncedanddisablingItoccurswithlongtermuse(10-20years)Theyareirreversible,andworsenwhentherapyisstopped
ComparisonofAntipsychotics
Property Haloperidol Olanzapine Clozapine
Class Typical Atypical Atypical("3 gen")
Uses BehaviouralEmergencies BehaviouralEmergencies,Psychosis/Schizophrenia Treatmentresistantschizophrenia
Presentation Tablets,syrup,clearsolutionforinjectionat5mg.ml
Tablets,solutionforinjection Yellowtablet
RouteofAdministration PO/IM/IV PO/IM PO
Dosing 1-5mgIV,2-30mgIM,1-15mgPO IM5-10mg,PO5-20mg Mustbeprescribedbya
psychiatrist
Absorption 50%PObioavailability 60%PObioavailability Rapidabsorption
Distribution 92%proteinbound 93%proteinbound,V~14L.kg V 2L.kg
Metabolism Hepatictolargelyinactivemetabolites
Hepatictoinactivemetabolites
Mayobeyzero-orderkineticsattheupperlimitofthedoserange
Elimination Renalofmetabolites Renalofinactivemetabolites
Renalofactivedrug(~25%)andinactivemetabolites
CVS Hypotension Myocarditis(potentiallyfatal)
CNS Seizures
GIT Antiemetic Hepatitis
Haeme Agranulocytosis,thromboembolicdisease
ReferencesRangandDaleSmith,Scarth,SasadaCriticalCareDrugsManualhttp://lifeinthefastlane.com/book/critical-care-drugs/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=8248https://www.ncbi.nlm.nih.gov/pubmed/8453823
Lastupdated2019-07-18
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AnticonvulsantsIngeneral,anticonvulsantsare:
WellabsorbedorallyHighlyproteinboundHepaticallymetabolisedbyCYP450enzymes,andinducetheirownmetabolism(aswellasthatofotherdrugs)RenallyeliminatedInteractwitheachother
Property Phenytoin SodiumValproate Carbamazepine Levetiracetam
UsesGTCS,partialseizures,trigeminalneuralgia,ventriculararrhythmias
PartialseizuresAntiepileptic,trigeminalneuralgia
GTCS,partialseizures,myoclonicseizures,seizureprophylaxis
Presentation
Capsules,syrup,solution.IVformulationincompatiblewithdextrose.
Tablets,syrup,solution
Tablets,suppositories,syrup
Tablets,oralliquid,IVliquid
RouteofAdministration PO,IV,IM PO,IV PO PO,IV(over15
minutes)
Dosing15-20mg.kg load,aimingplasmalevels10-20mcg.ml
300-1250mgBD 50-800mgBD
Typically1gloading,then500mgBDincreasingupto1.5gBD.Doseadjustedinrenalimpairment.
MechanismofAction
StabilisesNa channelsintheirinactivestate,inhibitinggenerationoffurtheractionpotentials.
StabilisesNachannelsintheirinactivestateandGABAergicinhibition
StabilisesNachannelsintheirinactivestateandpotentiatesGABA
Unknown,butdifferenttootherantiepilepticsandmayberelatedtoinhibitionofN-typeCa currents
Absorption SlowPOabsorption.PObioavailability90%
PObioavailability100%
95%PObioavailability
Near100%PObioavailability
Distribution Highlyproteinbound Highlyproteinbound
Highlyproteinbound
Nilsignificantproteinbinding,V ~0.5L.kg
Metabolism
Hepatichydroxylationwithhighlyindividualvariationindosing.Obeysfirst-orderkineticsinthetherapeuticrange,andzero-orderkineticsjustabovethetherapeuticrange.MetabolisedbyCYP450.Induceswarfarin,benzodiazepines,OCPmetabolism.Inhibitedbymetronidazole,chloramphenicol,isoniazid.Geneticpolymorphismresultsin
Hepatictoinactiveandactivemetabolites
HepaticHepatichydrolysistoinactivemetabolites
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reducedmetabolismin5-15%ofpatients.
EliminationRenaleliminationofinactivemetabolitesandactivedrug
Renaleliminationofmetabolitesandactivedrug
Renalelimination
Renalofactivedrug(majorroute)andmetabolite(minorroute)
CVS
↓BP,heartblock,andasystolewithrapidadministration,antiarrhythmicproperties
Antiarrhythmic
CNS
↑Seizurethreshold,paraesthesia,ataxia,nystagmus,slurredspeech,tremor,vertigo.
↑Seizurethreshold ↑Seizurethreshold
↑Seizurethreshold,anxiolytic.Minimal↓inseizurethresholdoncessation.
RenalWaterretentionfromADH-likeeffects
RarelyprecipitatesAKI
GITHepatotoxicity(idiosyncratic).Nauseaandvomiting.
Hepatotoxicity.
Haeme Aplasticanaemiaandotherblooddyscrasias
Thrombocytopenia,leukopenia(requiresregulartesting)
Thrombocytopenia
Immune Rash SJS
Metabolic Hyperammonaemia
Other
Requiresmonitoringduetonarrowtherapeuticwindowandsignificantpharmacokineticvariation.Gumhyperplasia.Teratogenic.Mayprecipitateporphyria.
Reducesefficacyofaminosteroids.Teratogenic.
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. CICMMarch/May20104. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.5. Levetiracetam-DrugInformation.FDA.2009.
Lastupdated2019-07-20
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GABAAnaloguesGabapentinandpregabalin:
ArebothstructuralanaloguesofGABAHavenodirectactionontheGABA receptorActontheα δsubunitofvoltagegatedCa channelsintheCNS,inhibitingneurotransmitterreleaseMayhavesomeNMDAreceptoractivity
ComparisonofGABAAnalogues
Property Gabapentin Pregabalin
Uses Focalseizures,neuropathicpain Focalseizures,neuropathicpain,anxiety
RouteofAdministration PO
Dosing 100mgTDS,increasingupto1200mgTDS 50mgBD/TDS,upto600mgindivideddoses(BDorTDS)
Absorption PObioavailabilityof60%,decreaseswithincreasingdoseduetosaturationoftransporter
90%PObioavailability,delayedbyfoodbutunaffectedbydose
Distribution Minimallyproteinbound Minimallyproteinbound
Metabolism Notmetabolised Notmetabolised
Elimination Renaleliminationofactivedrug,t β6hours Renaleliminationofactivedrug,t β6hours
CNS Drowsiness,ataxia,psychiatricsymptoms Confusion,psychiatricsymptoms,drowsiness
GIT N/V
References
1. TaylorCP,AngelottiT,FaumanE.Pharmacologyandmechanismofactionofpregabalin:thecalciumchannelalpha2-delta(alpha2-delta)subunitasatargetforantiepilepticdrugdiscovery.EpilepsyRes.2007Feb;73(2):137-50.Epub2006Nov28.
2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-07-18
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InhalationalAnaestheticAgentsDescribetheeffectsofinhalationalagentsonthecardiovascular,respiratoryandcentralnervoussystems
Describethetoxicityofinhalationalagents
Describethecomparativepharmacologyofnitrousoxide,halothane,enflurane,isoflurane,desflurane,sevoflurane,xenonandether
Thissectioncoversfeaturesandstructuresofinhalationalanaesthetics.Structure-activityrelationshipsarecoveredunderinhalationalanaesthetics.
CommonFeaturesofInhalationalAgents
Property Action
MetabolismHepaticCYP450(CYP2E1)metabolisesC-halogenbondstoreleasehalogenions(F ,Cl ,Br ),whichcanbenephrotoxicandhepatotoxic.TheC-FbondisminimallymetabolisedcomparedtotheC-Cl,C-Br,andC-Ibonds.Allagentsundergohepaticoxidation,exceptforhalothanewhichisreduced.
RespAllhalogenatedagents↓V and↑RR,withanoverall↓inMVandthereforecausePaCO to↑;and↓sensitivityofcentralrespiratorycentrestoCO .ImpairmentofHPVmayworsenV/Qmatchingand↑shunt.
CVS ↓MAP(predominantlyby↓inSVRduetoNOreleaseandCa channelblockade),↓inotropyduetoCa channelblockade.
CNS
Hypnosis.↓CMRO .Above1MACthereisuncouplingoftheCBF-CMRO relationship,andCBF↑despite↓CMRO duetocerebralvasodilation.ICPmaymirrorCBFchanges.
Allexcepthalothanehavesomeanalgesiceffect.↓EEGfrequencysuchthatθ-andδ-wavedominatetheEEGasdepth↑.Maycauseburstsuppression.
MSK MusclerelaxationviablockadeofCa channels.AdditionalaugmentationoftheeffectsofNMBDduetoskeletalmusclevasodilation.MayprecipitateMH.
Renal
Dosedependent↓inRBF,GFR,andUOsecondaryto↓inMAPandCO.
FluorinatedethersproduceF ionswhenhepaticallymetabolised,whichmayproducehigh-outputrenalfailureatserumconcentrations>50μmol/L.Thisisprobablyonlyaconcernwithmethoxyflurane(asithassignificant(>70%)hepaticmetabolism)whenusedatanaestheticdoses.
GIT ↓Hepaticbloodflow.
GU Tocolysis.
ToxicEffects Decreasedfertilityandincreasedriskofspontaneousabortioninoperatingtheatrepersonnel.
ComparisonofCommonInhalationalAgents
Property Sevoflurane Isoflurane Desflurane
Pharmaceutics
Minimallysoluble,lightstable,notflammable.Formulatedwith300ppmofH OtopreventformationofHFacidbyLewisacidsinglass.
Solubleinrubber,lightstable,notflammable.
Lightsensitive,flammableat17%.
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Structure
MolecularWeight 200.1 184.5 168.0
Boilingpoint 58.5°C 48.5°C 23.5°C
SVP(mmHg)at20°C 158 239 669
Blood:gascoefficient 0.7 1.4 0.42
Oil:gascoefficient 50 98 29
MAC 2 1.15 6.6
Metabolism
3-5%CYP2E1metabolismtohexafluoroisopropanolandinorganicF (whichmaybenephrotoxic)
0.2%hepatictonontoxicmetabolites
RespBronchodilation,↓MV.Smallest↓inV andthereforesmallest↑inPaCO
Bronchodilation,airwayirritability.↓MV(greaterthanhalothane)with↑inRR
Airwayirritabilitymanifestascoughingandbreath-holding,↑secretions
CVS
↑QT,↓SVRcausing↓MAPwithoutareflex↑HR.Inotropyunchanged.Smallest↓inBPofanyinhalationalagent.
Reflex↑HRdueto↓MAPfrom↓SVR.Small↓inotropyandCO,equivalenttosevofluranebutgreaterthandesflurane.Maycausecoronarysteal.
Minimal↓inotropy(leastofallinhalationalagents),butgreater↓inSVRandBPthansevoflurane.↑inHR,withabiggerincreaseat>1.5MAC.
Large↑inSNStonewithrapid↑indesfluraneconcentration.
CNS
↑Post-operativeagitationinchildrencomparedtohalothane.Smallest↑inCBFat>1.1MAC,withnoincreaseinICPupto1.5MAC.Cerebralautoregulationintactupto1.5MAC.
Bestbalanceof↓CMROfor↑inCBF.
ToxicEffects
SevofluraneinteractswithsodalimetoproduceCompoundA(aswellasBthroughE,whichareunimportant),whichisnephrotoxicinrats(butnot,itseems,inhumans).
-CHF groupmayreactwithdrysodalimetoproduceCO.
Desfluranehasmuchgreatergreenhousegaseffectsthansevofluraneorisoflurane.
ComparisonofUncommonInhalationalAgents
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Property Enflurane Halothane Xenon
Pharmaceutics
Structuralisomerofisofluranewithdifferentphysicalproperties
Lightunstable.Corrodessomemetalsanddissolvesintorubber.
Notflammable.Veryexpensivetoproduce.
Structure
MolecularWeight 184.5 197 131
Boilingpoint 56.5°C 50.2°C -108°C
SVP(mmHg)at20°C 175 243 -
Blood:gascoefficient 1.8 2.4 0.14
Oil:gascoefficient 98 224 1.9
MAC 1.7 0.75 71
Metabolism
~25%undergoesoxidativephosphorylationbyCYP450systems,producingtrifluoroaceticacid,whichbindstoproteinandcancauseaT-cellmediatedhepatitis,whichcanbefatalin~1/10,000anaesthetics.
Notmetabolised.
RespLargest↓inV ,thereforelargest↑inPaCO
↑InRR,↓inV withoverallunchangedPaCO
↓RR,↑inV suchthatMVisconstant.3xasdenseand1.5xasviscousasN O,whichincreaseseffectiveairwayresistance.Doesnotappeartocausediffusionhypoxia.
CVSGreatest↓ininotropy,HR,SVR,andMAP.Significant↑incatecholaminesensitivity.
MorestableMAP,↓HR
CNS
Produces3Hz"spikeandwave"EEGpatternathighconcentrations,resemblinggrandmalseizures
Greatest↑inCNSbloodflowat>1.1MAC Analgesic,↑PONV
MSK Musclerelaxationwhen>60%.DoesnottriggerMH.
Renal
Directnephrotoxicity,potentiallyrelatedtofluoride(thoughthisassociationisnotpresentwithotheranaestheticagents)
GU Leasttocolyticeffect
Toxiceffects ProducesF ions
Hepaticdamagemaybe:-Reversibletransaminitis-Fulminanthepaticnecrosis,witha
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mortalityof50-75%.
References
1. KhanKS,HayesI,BuggyDJ.PharmacologyofanaestheticagentsII:inhalationanaestheticagents.ContinuingEducationinAnaesthesiaCriticalCare&Pain,Volume14,Issue3,1June2014,Pages106–111.
2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. MillerRD,ErikssonLI,FleisherLA,Weiner-KronishJP,CohenNH,YoungWL.Miller'sAnaesthesia.8thEd(Revised).
ElsevierHealthSciences.PeckandHill5. LeslieRA,JohnsonEK,GoodwinAPL.DrPodcastScriptsforthePrimaryFRCA.CambridgeUniversityPress.2011.6. LawLS,LoEA,GanTJ.XenonAnesthesia:ASystematicReviewandMeta-AnalysisofRandomizedControlledTrials.
AnesthAnalg.2016Mar;122(3):678-97.
Lastupdated2017-10-07
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NitrousOxideDescribethepharmacologyofnitrousoxide
Describethecomparativepharmacologyofnitrousoxide,halothane,enflurane,isoflurane,desflurane,sevoflurane,xenonandether
Property NitrousOxide
Pharmaceutics
Non-flammablebutsupportscombustion.Producedbyheatingammoniumnitrateto250°C.PotentialcontaminantsincludeNH ,N ,NO ,andHNO .
Storedasaliquid,suchthatthegaugepressureisonlyaccuratewhenallremainingN Oisinthegaseousphase.
ThefillingratioisthemassofN Ointhecylindercomparedtothemassofwateritcouldhold,andis0.75intemperateregions,and0.67inwarmerregions.
MolecularWeight 44
Boilingpoint -88°C
CriticalTemperature/Pressure 36.5°C/72bar
SVP(at20°C) 39,000mmHg
Blood:gascoefficient 0.47
Oil:gascoefficient 1.4
MAC 105(MACawake68)
MechanismofAction
Severaldifferentmechanisms,including:-Stimulatesdynorphinrelease(actsatKOPreceptor)-PositiveallostericmodulatoratGABA receptor-NMDAantagonist
Metabolism <0.01%hepaticreduction.
Resp Diffusionhypoxiaduetosecondgaseffect.Small↓inV ,↑inRRsuchthatMVisunchanged.
CVS ↑SNStone,mildmyocardialdepression.↑PVR-bewareinpulmonaryhypertension.
CNS Powerfulanalgesicwhen>20%,viaendorphinandenkephalinmodulation,andonopioidreceptors.↑CBF.Lossofconsciousnesscommonat80%.1.4xrelativeriskofPONV
GU Nottocolytic-usefuladjuvantinGAcaesariansectiontoreducevolatileanaestheticuse
GIT Expansion
Metabolic ↑Homocysteine.
ToxicEffects
MoresolublethanN meansitwillrapidlydiffuseintoair-filledcavities,increasingthevolumeofcompliantcavities(PTHx,bowel),andincreasingthepressureofnon-compliantcavities(middleear).
Prolongeduse(>6hours)oxidatescobaltioninvitaminB ,preventingitsactionasacofactorformethioninesynthetase,preventingDNAsynthesis.Thisleadsto:-Megaloblasticchangesinbonemarrow-Agranulocytosis-Peripheralneuropathy-Possibleteratogenicity-avoidinearlypregnancy
Greenhousegas.
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EntonoxEntonoxisa50/50mixtureofnitrousoxideandoxygen,usedasanalgesiainlaborandminorprocedures.
Property Entonox(50%O ,50%N O)
Pharmaceutics Thegasesdissolveeachotherandbehavedifferentlythanwouldbeexpectedfromtheirindividualproperties.ThisisthePoyntingeffect.
CriticalTemperature/Pressure
Pseudocriticaltemperatureof-6°C,belowwhichitwillseparateintoliquid50%N O(withsomedissolvedO ),andgaseousO .Thisismostlikelytooccurat117bar,andcanleadtodeliveryofahypoxicmixture.
Deliveryofahypoxicmixispreventedby:-Storingcylindershorizontally(↑areafordiffusion)-Storingcylindersattemperatures>5°C-Usingadiptubesothatliquid50%N Oisusedbeforethegaseousmixture
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. ANZCAFebruary/April20064. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.5. EmmanouilDE,QuockRM.AdvancesinUnderstandingtheActionsofNitrousOxide.AnesthesiaProgress.2007;54(1):9-
18.doi:10.2344/0003-3006(2007)54[9:AIUTAO]2.0.CO;2.6. Hendrickx,J.,Peyton,P.,Carette,R.,&DeWolf,A.(2016).Inhaledanaestheticsandnitrousoxide.EuropeanJournalof
Anaesthesiology,33(9),611–619.7. BrownS,SneydJ.Nitrousoxideinmodernanaestheticpractice.2016.BJAEducation,16(3),87–91.
Lastupdated2019-07-18
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Opioids
CommonFeatures
Property Effect
Uses Analgesia,sedation,eliminationofsympatheticresponsetolaryngoscopy/surgicalstressresponse
Resp ↓CNSsensitivitytoCO causingrespiratorydepression(↓RR>↓V )-↑relianceonhypoxicdrive(thereforerespiratorydepressionmaybepotentiatedbyhighFiO )
CVS ↓HR.May↓BPduetohistaminerelease(lesswithsyntheticagents).↑PVR
CNS Sedation,euphoria.NauseaandvomitingduetoCTZstimulation.MeiosisduetostimulationoftheEdinger-Westphalnucleus.↓MACupto90%
Renal ↓RPF,↑ADH,↑uretericandsphinctertone
MSK Musclerigidity,pruritus(especiallywithintrathecaladministration)
Metabolic ↓ACTH,prolactin,gonadotrophichormonesecretion.↑ADHsecretion
GIT ↓PeristalsisandGITsecretionswithsubsequentconstipation
Immunological Impaired:chemotaxis,lymphocyteproliferation,andantibodyproduction
ComparisonofNaturallyOccurringOpioids
Property Morphine
Receptor MOP,KOP
RouteofAdministration SC/IM/IV/Intrathecal
pKa 8.0,23%unionisedatphysiologicpH.
Absorption Low(relative)lipidsolubility-sloweronsetandSCabsorption.POpreparationsabsorbedinsmallbowel,bioavailability30%-highfirstpassmetabolism.
Distribution ~35%proteinbinding.V 3.5L.kg
Clearance(ml.kg.min ) 15
Metabolism Hepaticglucuronidationto70%inactivemorphine-3-glucuronideand10%activemorphine-6-glucuronide,whichis13xaspotentasmorphine.t βof160minutes.
Elimination Renaleliminationofactivemetabolites-accumulationinrenalfailure
TimetoPeakEffect(IV) 10-30minutes
Duration(IV) 3-4hours
EquianalgesicDose(IV,to10mgIVmorphine) 10mg
ComparisonofSemisyntheticOpioids
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Property Oxycodone Buprenorphine
Receptor MOP,KOP,DOPPartialMOPagonist,KOPantagonist(antanalgesiceffect)
RouteofAdministration PO/IV Topical
pKa 8.5,<10%isunionisedatphysiologicpH.
Absorption PObioavailability60-80% Significant1stpassmetabolism
DistributionAslipidsolubleasmorphine,45%proteinbound,V 3L.kg .MorerapidonsetthanmorphinedespitehigherpKapotentiallyduetoactiveCNSuptake
Clearance(ml.kg.min ) 13
MetabolismHepaticdemethylationtonoroxycodone(80%,viaCYP3A)andthemorepotentandactiveoxymorphone(20%,viaCYP2D6).t β200minutes.
Hepatictoactivenorbuprenorphine
Elimination Renaleliminationofactivedrugandmetabolites70%biliary,30%renalelimination,t β40hours
TimetoPeakEffect(IV) 5minutes
Duration(IV) 4hours
EquianalgesicDose(IV,to10mgIVmorphine)
10mg.Note10mgPOoxycodoneis≈15mgPOmorphineduetohigherfirstpassmetabolismofmorphine
ComparisonofSyntheticOpioids
Property Fentanyl Alfentanil Remifentanil
Receptor MOP MOP MOP
RouteofAdministration SC/IM/IV/Epidural/Intrathecal/Transdermal IV
IV(containsglycine,socannotbeadministeredintrathecally)
pKa 8.4,<10%unionisedatpH7.4 6.5,90%unionisedatpH7.4conferringrapidonset
7.3means58%unionisedatphysiologicpH.
AbsorptionRapidonsetofaction(<30s,peakat5min)duetolipidsolubility(600xthatofmorphine).
90xmorelipidsolublethanmorphine,butmorerapidonsetthanfentanyl.Thisisdueto:1.LowpKameansagreaterproportionisunionisedatphysiologicalpH.2.Lowerpotencyofalfentanilcomparedtofentanylmeansagreaterdoseisrequired(Bowman'sPrinciple)
20xmorelipidsolublethanmorphine.
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Distribution600xaslipidsolubleasmorphineconferringalargerV (4L.kg ).85%proteinbound.
90xaslipidsolubleasmorphine,smallV of0.6L.kg .90%proteinbound
20xaslipidsolubleasmorphine,verysmallV of0.4L.kg .70%proteinbound.CSHTisconstantduetorapidmetabolism.
Clearance(ml.kg .min ) 13 6 40
Metabolism
Significantfirstpasspulmonaryendothelialuptake.Hepaticdemethylationtoinactivenorfentanyl.t βof190minutes,longerthanmorphineduetohigherlipidsolubilityandV .
Shortereliminationt βthanfentanyl(100minutes)despitelowerclearanceduetolowerV .ProlongedwithadministrationofmidazolamduetoCYP3A3/4competition.
Rapidmetabolismbyplasmaandtissueesterases-t β10minutes
Elimination Renaleliminationofinactivemetabolites Renaleliminationofmetabolites
Renalofinactivemetabolites
TimetoPeakEffect(IV) 5minutes 90seconds 1-3minutes
Duration(IV)
Variabledependingondoseanddistribution.Withdoses>3μg.kg tissuesbecomesaturatedandthedurationofactionissignificantlyprolonged
5-10minutesOffset5-10minutesfromceasinginfusion
EquianalgesicDose(IV,to10mgIVmorphine)
150mcg 1mg 50mcg
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. ANZCAJuly/September20105. SchugSA,PalmerGM,ScottDA,HalliwellR,TrincaJ.AcutePainManagement:ScientificEvidence.4thEd.2015.
AustralianandNewZealandCollegeofAnaesthetistsandFacultyofPainMedicine.
Lastupdated2019-07-18
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COXInhibitorsCyclo-oxygenaseinhibitorsaretypicallyusedtotreatmildtomoderatepain.OralCOXinhibitorstypicallyhave:
RapidabsorptionHighproteinbindingLowV
MechanismofAction
Therearetwo(ish)isoenzymesofCOX:
COX-1Importantforhomeostaticfunction.COX-2Inducedwithtissuedamageandcontributestoinflammation.COX-2:
Existsinthevascularendotheliumwhereitsynthesisesprostacyclin(whichopposestheactionofthromboxanes)Inhibitionmayresultinarelativeabundanceofthromboxane,causingplateletaggregationandvasoconstriction
COX-3VariantofCOX-1whichexistscentrallyandmediatestheanalgesicandantipyreticeffectsofparacetamol.
Effectsoccurdueto:
DecreaseinendoperoxidasesInhibitedbyCOX.Increaseinotherarachidonic-acidderivedfactorsDuetothediversionofarachidonicaciddownotherpathways.
COXinhibitionhasdifferenteffectsindifferenttissues:
PreventssubsequentconversionofprostaglandinstothromboxaneA andPGIPeripherally,inhibitionofprostaglandinsynthesisisanti-inflammatoryCentrally,itisanti-pyreticInthestomach,itdecreasesmucousproductionandleadstomucosalulceration
Aspirin(anon-specificCOXinhibitor),preventsproductionofboththromboxaneA andPGIAsplateletshavenonucleus,theCOXinhibitionremainsfortheentiretyoftheplateletlifespanEndothelialcellswillproducenewCOXwithinhours,andsoitsanti-inflammatoryeffectsaretemporary
AdverseEffects
Asthma/BronchospasmSecondarytoincreasedleukotrienesynthesisduetoincreasedarachidonicacidlevels.Occursin20%ofasthmaticswithNSAIDuse.
PlateletdysfunctionAconsequenceofCOX-1inhibitiononly,andmayresultinincreasedperioperativebleedingrisk(thoughdecreasedAMIandCVArisk).
Thromboticevents,includingMIandCVARiskisgreaterwithCOX-2inhibitors,duetoselectiveinhibitionofprostacyclin.withNNHfornon-fatalMIbeing500patient-years,andNNHforfatalMIbeing1000patient-years.
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ImpairedGFROccursasaconsequenceofuninhibitedafferentarteriolarconstriction.Worsewithconcurrenthypovolaemia,renalarterystenosis,orconcurrentACE-Iuse.
GastricerosionAconsequenceofimpairedmucosalsecretionthroughCOX-1inhibition.Thiscanresultinpain,anaemia,orfatalbleed.Ingeneral,riskofgastricerosionis(fromhighesttolowestrisk):
KetorolacDiclofenac/naproxenIbuprofen(<1.2g/day)COX-2Inhibitors
TransaminitismayoccurfollowingNSAIDuse
ComparisonofCOXInhibitors
Characteristic Aspirin Diclofenac Ketorolac Ibuprofen Celecoxib Parecoxib
MechanismofAction
Irreversibleinhibitionofplateletthromboxaneproduction.Asplateletsareanucleate,theyareunabletoregeneratethromboxane.
Non-selectiveCOXinhibitor
Non-selectiveCOXinhibition
Non-selectiveCOX-inhibition
COX-2inhibitor(30:1infavourofCOX-2)
COXinhibitor(61:1infavourofCOX
Uses
Preventionofarterialthromboembolism,MI,CVA,migraine,analgesia,others(e.g.Still'sdisease)
Mild-to-moderatepain
Potentanti-analgesic,minimalanti-inflammatoryproperties
Mild-to-moderatepain
Analgesia,particularchronicarthriticpain
Acuteinflammatorypain
Distribution
85%proteinbound.WeakacidwithapKaof3,unionisedinthestomachandionisedatphysiologicalpH
97%proteinbound
AbsorptionGastricabsorption(pKa3)leadstorapidonset.
Metabolism
Hepaticmetabolismtosalicyluricacidandglucuronides.Mayhavezero-ordereliminationinoverdose.
CYPtoinactivemetabolites
CYP2C9toinactivemetabolites
CYP2C9toinactivemetabolites
Elimination
Renal.Eliminationmaybeincreasedwithurinaryalkalinisation.
Low-dose(100mg
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Dose
daily)selectivelyinhibitsplateletCOX,whilstpreservingendothelialCOX,resultingindecreasedplateletaggregationwhilstmaintainingvasodilation.300-900mgforanalgesia/migraine.
50mgBD/TDS
15-30mgIM/IVQ6H
400-800mgTDS,or10mg/kg
100-200mgBD 20-40mgBD
Route PO PO/PR/IM/IVIM/IV(off-labelinAustralia)
PO/PR PO IV
Respiratory
Aspirinuncouplesoxidativephosphorylation,increasingOconsumptionandCO production.Italsomaystimulate,and(athigherdoses)depresstherespiratorycentre.Inoverdose,thesearesignificant,andmayresultinamixedrespiratoryandmetabolicacidosis.
CVSMIandCVAriskreduction.Increasedbleeding.
RiskofMIsimilartoCOX-2inhibitors.LocalthrombuswithIVinjection.
Lowerdosenotassociatedwithprothromboticevents.
UncleareffectonCVAandMI,butrecommendedtoavoiduseinIHD/CVD
UncleareffectonCVAandMI,butrecommendedtoavoiduseinIHD/CVD
Metabolic
Reye'ssyndromeismitochondrialdamage,hepaticfailure,andcerebraloedema(andencephalopathy)inchildren<12.Mortality40%.
References
PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-07-18
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TramadolTramadolisananalgesicagentwithacomplicatedmechanismofaction:
Actionatallopioidreceptors,butparticularlyMOP,causinganalgesiaaswellasnauseaandvomitingInhibits5-HTreuptakewhichprovidesdescendinginhibitoryanalgesiaInhibitsNAreuptakedescendinginhibitoryanalgesiaNMDAreceptorantagonist
Properties Tramadol
Class Cyclohexanolderivative.Racemicmixtureof(+)TramadolwhichhasgreaterMOPand5HTreuptakeeffects,and(-)Tramadol,whichmediatesNAreuptakeinhibition
Uses Analgesia
Presentation Racemicmixture-eachisomerhascomplementaryeffects.IVsolutionisclearat50mg.ml
RouteofAdministration PO/IV/Topical
Dosing 50-100mgQID.Potency1/5 thatofmorphine.
Absorption Bioavailability70%
Distribution V 4L.kg
Metabolism Hepatictoactiveandinactivemetabolites
Excretion Urinaryofpredominantlyinactivemetabolites,t β300minutes
Respiratory Minimalrespiratorydepression
CVS AvoidconcomitantMAO-IusegivenNAreuptakeinhibition
CNS IncreasedseizureriskinthosewithepilepsyorconcurrentSSRI/SNRI/TCAuse.Minimaladdictionpotential
GIT N/V
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-07-18
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ParacetamolParacetamolananalgesicandantipyreticwhichistypicallyclassedasanNSAID,thoughitisuniqueandimportantenoughtogetitsownpage.Ithasanumberofmechanismsofaction:
Non-selectiveCOXinhibition,includingCOX-3ThisconferssomeoftheanalgesicpropertiesInhibitionofcentralprostaglandinsynthesisThisconferstheantipyreticeffectbyinhibitingprostaglandinEsynthesisintheanteriorhypothalamusinresponsetopyrogensSerotonergicinhibitionProvidessomeadditionalanalgesicactionCannabinoidinhibitionProvidessomeadditionalanalgesicactionviaendocannabinoidreuptakeinhibition.
Property Effect
Class NSAID,acetanilidederivative
Uses Analgesia,antipyretic
Presentation Tablets,capsules,syrup,clearcolourlesssolutionforIVadministration
RouteofAdministration PO/PR/IV
Dosing 10-15mg.kg Q4Hupto90mg.kg .day
Onset IV:5mins,peakat40minsPO/PR:40mins,peakat1hour
Absorption Rapidabsorption(viasmallbowel,thereforeproportionaltogastricemptying),variablebioavailability(upto90%)-greaterbyPRroute
Distribution 10%proteinbound,smallV :0.5-1L.kg (thoughlargerthanotherNSAIDs)
Metabolism Predominantlyhepaticglucuronidation.However,10%ismetabolisedtoNAPQIbyCYP2E1whichishepatotoxic.
Elimination Activesecretionintorenaltubules-considerdosereductioninrenalimpairment
Resp Mayexacerbateanalgesicasthmaduetoglutathionedepletion
CNS Excellentanalgesia.Synergisticwithotheranalgesics,resultinginagent-sparingeffectandreducedsideeffects
Metabolic Antipyretic
Haeme Cytopaenias(rare)
ToxicityParacetamolispartiallymetabolisedtothetoxicN-acetyl-p-amino-benzoquinoneimine(NAPQI)
InnormalcircumstancesthisrapidlyconjugatedwithglutathioneIntoxicity,glutathioneisexhaustedNAPQIthencovalentlybindstocriticalproteinsinhepatocytes,causingcentrilobularhepaticnecrosisandcelldeath
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Toxicdoses:>200mg.kg inasingleingestionRepeatedingestionof>150mg.kg .day fortwodays>100mg.kg .day forthreedays
Riskfactorsfortoxicity:Glutathionedeficiency
ExtremesofageMalnutritionHepaticdysfunction
Enzymeinducers:Anti-epileptics
CarbamazepinePhenytoinPhenobarbitone
RifampicinETOHOCP
FeaturesofOverdose
ConsciousNausea,vomiting,andepigastricpainHaemolyticanaemiaDistributiveshockHyperglycaemiaLate(>48hours)hepaticfailureLater(3-5days)coagulopathyFulminanthepaticfailure(3-7days)
TreatmentofOverdose
Activatedcharcoalwithtabletingestionifseenwithin1hourofingestion.
SerumparacetamolleveltodeterminerequirementforNAC(N-acetylcysteine)basedonthenomogramIVNACisusedasitisaglutathioneprecursor,replenishingdepletedglutathioneandfacilitatingfurtherconjugationofNAPQI
References1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.3. ParacetamolPoisoning.RoyalChildren'sHospital.4. HinsonJA,RobertsDW,JamesLP.MechanismsofAcetaminophen-InducedLiverNecrosis.Handbookofexperimental
pharmacology.2010;(196):369-405.
Lastupdated2019-07-18
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650
Paracetamol
651
Antimuscarinics(Cardiac)AntimuscarinicsusedforbronchodilationarecoveredunderAntimuscarinics(Respiratory),whilstatropineiscoveredseparately.
Antimuscarinicsareascompetitive,reversibleantagonistsofAChatthemuscarinicreceptor.Theyaredividedinto:
NaturallyoccurringtertiaryaminesThesecancrosstheblood-brainbarrier,andhavecentraleffects.
AtropineHyoscine
SyntheticquaternaryaminesDonotcrosstheblood-brainbarrier.
Glycopyrrolate
Property Glycopyrrolate Hyoscine
Class Quaternaryamine.Muscarinicantagonist Tertiaryamine
Uses Bradycardia,antisialagogue Antisialagogue,motionsickness
Presentation Clear,colourlesssolutionat200μg.ml .Incompatiblewithdiazepamandthiopentone.
Racemic,onlyL-isomeractive
RouteofAdministration IV/IM PO,SC,IV/IM
Dosing 200-400μg 20-40mgIVslowpushorIM
Absorption MinimalPOabsorption-notusedviathisroute. <50%PObioavailability
Distribution CrossesplacentabutnotBBB,V 0.5L.kg V 2L.kg
Metabolism Minimalhepatichydrolysis Extensivemetabolismbyhepaticesterases
Elimination Renalof85%unchangeddrug Renalofmetabolites
Resp Bronchodilation,antisialagogue Bronchodilation,greatestantisialagogueeffect
CVSInitialbradycardiaduetopartialagonisteffect.Reversesvagalcausesofbradycardia,maycausetachycardiaindoses>200μg.HRpeaksat3-9minutesfollowingadministration.
Leastlikelyanticholinergictocausetachycardia
CNSMostlikelyanticholinergictocausecentralanticholinergicsyndrome
MSK Anhydrosis
GIT Reducedoralandgastricsecretions,andgastricmotility
Reducedoralandgastricsecretions,andgastricmotility.Increasesbiliaryperistalsis
GU Difficultmicturition
References
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Autonomic
652
1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2018-07-29
Autonomic
653
AnticholinesterasesAnticholinesterasesantagoniseAChE,decreasingthebreakdownofAChandthereforeincreasingitsavailabilityatthe:
NicotinicreceptorIncreasesmusclestrength.
Reversalofnon-depolarisingneuromuscularblockadeMuscarinicreceptorIncreasesparasympathetictone.
Anticholinesterasescanbe:
ReversibleFormacarbamylatedenzymecomplexIrreversible
Property Neostigmine Organophosphates
Class Quaternaryamine,formscarbamylatedenzymecomplex Irreversibleanticholinesterase
Uses Reversalofnon-depolarisingNMB,myastheniagravis,analgesia Insecticides,pesticides,chemicalweapons
Presentation Clear,colourless,lightstablesolutionat2.5mg.ml
RouteofAdministration PO,IV,intrathecal Topical
Dosing 0.05mg.kg forreversal,15-30mgPOforMG
Absorption LowPObioavailability Rapidtopicalabsorptionduetohighlipidsolubility
Distribution DoesnotcrossBBB,V 0.7L.kg CrossesBBB
Metabolism Majoritybyplasmaesterasestoquaternaryalcohol,withsomehepaticmetabolism Notmetabolised
Elimination 55%unchangedinurine t αofweeks
Duration 50minutes UntilnewAChEissynthesised
Resp Bronchospasm,↑secretion Bronchospasm,↑secretion
CVS ↓HR(maybeprofound),↓CO ↓HR,↓CO
CNS N/Vandanalgesicwhenadministeredintrathecally,cerebralvasoconstriction Centralcholinergicsyndrome
MSK ReversalofNMB,↑fasciculations,↑sweating,maycauseparalysis Paralysis
GIT ↑Peristalsis,↑LoStone,N/V ↑Peristalsis,↑LoStone,N/V
Other Muscarinicreceptorsaffectedatlowdose,nicotinicreceptorsathighdose
Maybereversedininitialstages(beforeorganophosphate-AChEcomplexhas'aged')withpralidoxime
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654
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. ANZCA2007Feb/April3. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.4. Mahmoud,AhmedAbdelaalAhmed,AmrZakiMansour,HanyMahmoudYassin,HazemAbdelwahabHussein,Ahmed
MoustafaKamal,MohamedElayashy,MohamedFaridElemady,etal.‘AdditionofNeostigmineandAtropinetoConventionalManagementofPostduralPunctureHeadache:ARandomizedControlledTrial’127,no.6(2018):6.
Lastupdated2019-07-18
Anticholinesterases
655
DepolarisingNMBsSuccinylcholinebindstothenicotinicAChreceptorcausingdepolarisation.ItcannotbehydrolysedbyacetylcholinesteraseintheNMJ,andsoremainsboundtothereceptor.This:
Producesasustaineddepolarisationwhichkeepsvoltage-gatedsodiumchannelsintheirinactivestatePreventsthepost-junctionalmembranefromrespondingtofurtherAChrelease
Property Succinylcholine
Class Depolarisingmusclerelaxant.
Uses Facilitatetrachealintubation.
Presentation ColourlesssolutionofpH3,at50mg.ml .Structurally,itistwoAChgroupsjoinedattheacetylgroups.
RouteofAdministration IV,IM.
Dosing 1-2mg.kg IV,3-4mg.kg IMupto150mg.
OnsetandDuration
IVonsetin30sto1minute,lasting2-3minutes,withoffsettypicallywithin10minutes.OffsetoccursduetodissociationofdrugoutofNMJintoplasma,asaconcentrationgradientisestablishedbydrugbreakdowninplasma.Prolongeddurationinpatientswithpseudocholinesterasedeficiency.IMonsetin2-3minutes.
Distribution 30%proteinbound.Nildistributionduetorapidmetabolism-V 0.25L.kg .Crossesplacentainverysmallamounts.
Metabolism Rapidhydrolysisbyplasmacholinesterasessuchthatonly20%ofadministereddosereachestheNMJ.
Elimination Minimalrenaleliminationduetorapidmetabolism.
Resp Apnoea,andsuxamethoniumapnoea.Maycausemasseterspasm.↑Salivationduetomuscariniceffects.
CVS ArrhythmiaduetoSAnodestimulation,aswellassecondarytohyperkalaemia.Bradycardia(duetomuscariniceffectswithsecond/largedoses,orinchildren).
CNS ↑ICP(duetocontraction),↑IOP(by10mmHg-thisissignificant)suchthatitiscontraindicatedinglobeperforation.
Metabolic MalignantHyperthermia.
MSK Myalgiaspostdepolarisation,particularlyinyoungfemales.Prolongedblockadewithpseudocholinesterasedeficiency.
RenalandElectrolyte
Hyperkalaemia(K ↑by~0.5mmol.L )duetodepolarisationcausingK efflux,↑inburns(>10%),paraplegia(first6months)andneuromusculardisordersincludingmusculardystrophyandmyopathies(includingcriticalillnessmyopathy).
GIT Intragastricpressure↑by10cmH O,matchedby↑inLoSpressure.
Immunological Anaphylaxis-highestriskofallNMBsat~11/100,000
AdverseEffectsTheadverseeffectsofsuxamethoniumcanberememberedasthreemajor,threeminor,andthreepressures:
Major
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AnaphylaxisSuxamethoniumApnoeaMalignanthyperthermia
MinorHyperkalaemiaMyalgiasBradycardia
PressureIOPICPIntragastricpressure
PhaseIandPhaseIIBlockade
InitialblockadeistermedPhaseI,whichisapartialdepolarisingblock.SustaineduseofsuxamethoniummaycausesaPhaseIIblockwhich:
Appearssimilartoanon-depolarisingblockMaybedueto:
PresynapticinhibitionofAChsynthesisandreleaseDesensitisationofthepost-junctionalreceptor
Keydifferencesinclude:
Property PhaseIBlock PhaseIIBlock
BlockAmplitude Reduced Reduced
Train-of-fourratio >0.7 <0.7
Post-tetanicpotentiation No Yes
Effectofanticholinesterases Blockaugmented Blockinhibited
MalignantHyperthermia
RareautosomaldominantgeneticconditionTriggeredbysuxamethoniumandvolatileanaestheticagentsMutationoftheryanodinereceptorcausesexcessiveamountsofcalciumtoleavethesarcoplasmicreticulum,causingcontinualmusclecontraction
Resultsingreatlyincreasedcarbondioxide,lactate,andheatproductionCelllysiswithmyoglobulinaemiaandhyperkalaemiaresults
SuxamethoniumApnoea
AdeficiencyofbutylcholinesterasecausessuxamethoniumtonotbemetabolisedMaybecongenital(genetic)oracquired(hepaticfailure)Canbetreatedwithfreshfrozenplasma
References
Neuromuscular
657
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SuxamethoniumChlorideInjectionBPPRODUCTINFORMATION3. Appiah-AnkamJ,HunterJM.Pharmacologyofneuromuscularblockingdrugs.ContinuingEducationinAnaesthesiaCritical
Care&Pain,Volume4,Issue1,1February2004,Pages2–7.4. CookT,HarperN.Anaesthesia,Surgery,andLife-ThreateningAllergicReactions:ReportandfindingsoftheRoyalCollege
ofAnaesthetists'6thNationalAuditProject:PerioperativeAnaphylaxis.RoyalCollegeofAnaesthetists'.2018.
Lastupdated2019-07-18
Neuromuscular
658
Non-DepolarisingNeuromuscularBlockersNon-depolarisingNMBsaremusclerelaxantsusedto:
FacilitatelaryngoscopyandtrachealintubationControlICPImproverespiratorysystemcomplianceImprovepatientsafetyontransportation
MechanismofactionisbycompetitiveantagonismofAChattheNMJ,preventinggenerationofend-platepotentials.Effectivepharmacodynamicresponserequires>70%receptoroccupation.
CommonFeaturesofNeuromuscularBlockers
Property Action
RouteofAdministration IV/IM
Distribution SmallV astheyarepolarandunabletocrosslipidmembranes
Elimination Reducedurinaryclearancewhichprolongsthemechanismofactionofaminosteroidsinrenalfailure
Resp Apnoea
MSK ↑Durationinhypothermia
Renal ↑Durationinacidosis,↑durationinhypokalaemia,↓durationinhyperkalaemia,↑durationinhypermagnesaemia
Metabolic CriticalIllnessMyopathyinpatientswithlong-termrelaxantuse
TheED is:
Thedoseofaneuromuscularblockingdrugrequiredtoproducea95%reductionintwitchheightin50%ofthepopulationAcommonly-usedtherapeuticend-pointforneuromuscularblockingdrugsTypically,inductiondosesusedare2-5xtheED .
ComparisonofNeuromuscularBlockers
Property Rocuronium Vecuronium Pancuronium Atracurium Cisatracurium
Class Aminosteroid AminosteroidBis-quaternaryaminosteroid
Benzylisoquinoliniumderivative
Benzylisoquinoliniumderivative
Presentation
Clear,colourlesssolutionat10mg.ml
10mgpowderforreconstitutioninwater.ContainsmannitolandNaOH.
Colourlesssolutionat2mg.ml ,whichmustbestoredat4°C
Colourlesssolutionat10mg.ml ,whichshouldbestoredat4°C.Mixtureofalltenextantdiastereoisomers.
R-Cis,R'-Cisisomerofatracurium,whichis15%ofatracuriumbyweightbutprovides50%ofitsNMBDaction.
Colourlesssolutionat2-5mg.ml ,whichshouldbestoredat4°C
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IntubatingDose
0.6-1.2mg.kg 0.1mg.kg 0.05-0.1
mg.kg 0.5mg.kg 0.15-0.2mg.kg
ED 0.3mg.kg 0.05mg.kg 0.07mg.kg 0.25mg.kg 0.05mg.kg
Onset 45-90s 90-120s 90-150s 90-120s 60-180s
Duration
~30minuteswithnormalrenalfunction,repeatdosesmaybemoreunpredictable
45-65minutes
60-100minutes 15-35minutes 25-30minutes
Metabolism
<5%hepaticdeacetylationtoinactivemetabolites
20%hepaticdeacetylationwithweaklyactivemetabolites
20%hepaticdeacetylationwithweaklyactivemetabolites
60%byesterhydrolysis,withremainderbyHofmannelimination.
Metabolisedtolaudanosine,whichcausesseizuresinhighconcentrations(relevantwhenadministeredbylonginfusion)
Hofmannelimination
Elimination
60%biliary,40%urinary.Prolongeddurationinhepaticandrenalfailure
70%biliary,30%urinary
80%biliary,20%urinary
RespSlightriskofbronchospasmwithrapidinjection
Slightriskofbronchospasmwithrapidinjection
CVS ↑HRathighdoses No↑HR
↑HRandMAPduetomuscarinicantagonism
Riskof↓BPwithrapidinjection
Riskof↓BPwithrapidinjection
Immune
Higherriskofanaphylaxis,~6/100,000.Anaphylaxisriskassociatedwithuseofpholcodineintheprevious3years.
NotablynoanaphylaxisrecordedinNAP6
Anaphylaxis~4/100,000.
OtherReversiblewithsugammadex
Reversiblewithsugammadex
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. CrillyH,RoseM.Anaphylaxisandanaesthesia–cantreatingacoughkill?.AustPrescr.2014;37:74-6.
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4. Lexicomp.Rocuronium:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.5. Lexicomp.Vecuronium:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.6. Lexicomp.Pancuronium:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.7. Lexicomp.Atracurium:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.8. Lexicomp.Cisatracurium:Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.9. CookT,HarperN.Anaesthesia,Surgery,andLife-ThreateningAllergicReactions:ReportandfindingsoftheRoyalCollege
ofAnaesthetists'6thNationalAuditProject:PerioperativeAnaphylaxis.RoyalCollegeofAnaesthetists'.2018.
Lastupdated2019-07-20
Non-DepolarisingNMBs
661
DantroleneDantroleneisaryanodine(RYR1)receptorantagonist,whichpreventsreleaseofCa fromthesarcoplasmicreticulum,uncouplingtheprocessofexcitation-contraction.
Property Dantrolene
Uses MH,NMS,ecstasyintoxication,chronicmusclespasticity
Presentation Vialsoforangepowdercontaining20mgdantroleneand3gmannitol,reconstitutedwith60mlofH Otoformanalkalinesolution.
Dosing 2.5mg.kg IVevery10-15minutes,upto10mg.kg .Onceresolved,continuegiving1mg.kg every4-6hoursfor24hours.
Absorption IVonly,maycauseskinnecrosisifextravasates.
Distribution 85%proteinbound
Metabolism Hepaticmetabolismtoactive5-hydroxy-dantrolene
Elimination Renalofmetabolites,t βof12hours
Resp Respiratoryfailureduetoskeletalmuscleweakness
CVS Volumeoverloadduetolargevolumegivenwithadministration
MSK Skeletalmusclerelaxation
Renal Diuresis
GIT Hepaticfailure
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. ANZCAAugust/September2011
Lastupdated2017-09-16
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662
Sugammadex
Property Sugammadex
Class Gammacyclodextrin.
Uses Reversalofneuromuscularblockinducedbyrocuroniumandvecuronium.
Presentation Clearcolourlesssolutionat100mg.ml .
Pharmaceutics Storebelow30°C.
RouteofAdministration IVonly.
Dosing2mg.kg ifToF>2.4mg.kg ifPTC>2.16mg.kg forreversalfollowingRSIdose.
Distribution V of11-14L.kg .
Metabolism Notmetabolised.
Elimination Renaleliminationofactivedrugandcomplex.
MechanismofAction Formsacomplexwithrocuroniumandvecuronium,causingreversalofneuromuscularblockade.
CVS Rarelymayprecipitatebradycardia-canresultincardiacarrest.
Immune Anaphylaxis.
Other
InteractswithOCP-treatasmissedpillShorteneddurationofrocuroniumandvecuroniumwhenusedwithin24hoursofsugammadexadministration.Onsetisdelayedupto5minutes,anddurationshortenedby10-15minutes.Thisperiodmaybeextendedinrenalfailure.
References1. SugammadexFullPrescribingInformation.FDA.
Lastupdated2019-07-20
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663
Anticoagulants
Property Warfarin Heparin Enoxaparin
Uses AF,DVT/PE,ProstheticValves AF,DVT/PE,Extra-corporealCircuitAnticoagulation DVTProphylaxis
Pharmaceutics
Marevanandcoumadinmaypotentiallyhavedifferentbioavailabilities(ithasnotbeenassessed)andsoshouldnotbesubstituted
Mucopolysaccharideorganicacidwhichoccursnaturallyintheliverandinmastcells,withahighlyvariablemolecularweight(between5,000and25,000Da)
Smallerfragmentsofheparin(preparedfromUFH),withameanmolecularweightof5,000Da
MechanismofAction
PreventsthereturnofvitaminKtoitsreducedform,andthereforethegamma-carboxylationofvitamin-Kdependentclottingfactors(II,VII,IX,X),aswellasProteinCandProteinS).
PotentiatestheeffectofATIII,rapidlyincreasingitsanti-IIaandanti-Xaeffect(1:1effect).
InhigherconcentrationsalsoinhibitsIXa,XIa,XIIa,andplateletaggregation.
PotentiatestheactionofATIII,increasinginhibitionofXaandIIa,but(unlikeUFH)ina4:1ratio.
MorepredictableeffectonXastandardisesdosingandjustifieslackofmonitoringrequirement.
Onset
8-12hours.Peakat72hoursduetothehalf-lifeofexistingclottingfactors,andthetotalbodystoresofvitaminK
ImmediateIVonset
Absorption 100%bioavailability IV,SC SConly
Distribution 99%proteinbound Lowlipidsolubility,highlyproteinbound
Doesnotbindtoheparin-bindingproteins
Metabolism
Completehepaticmetabolism.Significantpharmacokineticinteractionwithenzymeinducersandinhibitors.
Hepaticinteractionsduetoenzymaticinduction(ETOH,amiodarone,salicylates,NSAIDs)andinhibition(OCP,barbiturates,carbamazepine)
Renaleliminationofmetabolites
Elimination Faecalandrenaleliminationofmetabolites,t βof40hours Renalofinactivemetabolites
Renalofactivedrugandinactivemetabolites
CVS Microthrombi HypotensionwithrapidIVadministration
Metabolic Lessosteoporosisduetolessprotein(andthereforetissue)binding Osteoporosis
Renal Inhibitsaldosteronesecretion
GIT N/V
Haeme Haemorrhage Haemorrhage,HITTs
Haemorrhage,lowerriskofHITTsthanUFH.Lessthrombocytopaenia.
Immune Hypersensitivityreactions
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Haematological
664
Reversal-Waiting-VitaminK-FFP-Prothrombinex
Reversedwithprotamine(1mgper100U).
Incompletereversalwithprotamineasonlytheanti-IIaeffectisinhibited.
OtherTeratogenic.ComplicatedpharmacokineticsrequiringmonitoringusingINR.
RequiresmonitoringwithAPTTorATIIIlevels.LargeinterpatientvariabilityduetovariableamountsofATIII.
1unitistheamountofheparinrequiredtoprvent1mlofbloodclottingfor24hoursat0°C
Nomonitoringrequired.
HITTs
Heparin-InducedThromboticThrombocytopeniacomesintwoflavours:
TypeI:Isnon-immunemediatedOccurswithin4daysofanticoagulantdosesIsanisolatedthrombocytopeniawithoutclinicalsignificance
TypeII:IsimmunemediatedOccurswithin4-14daysIsassociatedwithseriousthrombosisandhighmortality(typicallyfromPE)andmorbidity(fromCVAandlimbischaemia)
Protamine
Protamineis:
Abasiccationicproteinderivedfromsalmonspermwhichcombineswiththeacidicanionicheparintoformastable,inactivesaltinsolutionClearedmorerapidlythanheparinReboundanticoagulationmayoccur.
Adverseeffectsfromprotamineinclude:
HistaminereleaseBronchospasmHypotension
PulmonaryhypertensionThiscanbeprofoundandresultinadramaticincreaseinRVafterloadandEDV,withacorrespondingfallinLVpreload(interventricularinterdependence),leadingtodramatichypotensionandarrest.
MediatedbythromboxanesDuetoprotamine-heparincomplexes,ratherthanprotaminealoneAdministrationofprotamineinabsenceofheparindoesnotleadtopulmonaryhypertension.
AnticoagulationWhengiveninexcess.
References
Haematological
665
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.3. ANZCAAugust/September20114. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.
Lastupdated2019-07-18
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DirectThrombinInhibitorsDirectthrombininhibitorspreventcleavageoffibrinogentofibrin,andarethereforeveryeffectiveanticoagulants.
Property Dabigatran
Class NOAC
Uses VTEprophylaxis,AF
Presentation 75/110mgCapsules
RouteofAdministration PO
Dosing VTE:220mgdaily,AF:150mgBD
Absorption 6.5%bioavailability
Distribution 35%proteinbound
Metabolism Prodrug-activatedbyplasmaandhepaticesterases
Elimination Renaleliminationofactivedrug
Haeme Haemorrhage
Immune Allergy
Other Significantinteractionswithamiodarone,quinidine,St.John'sWort,aswellasotheranticoagulantandantiplateletagents.Dialysable.Potentiallyreversiblewithidarucizumab.
References
1. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.2. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.
Lastupdated2019-07-18
DirectThrombinInhibitors
667
AntifibrinolyticsAntifibrinolyticsincludeaprotinin,aminocaproicacid,andtranexamicacid.Allpreventthebreakdownoffibrin(!)byvariousmechanisms.TXAcompetitivelyinhibitsplasminogenactivator,reducingrateoffibrinolysis.
Property TranexamicAcid(TXA)
Class Antifibrinolytic
Uses Trauma(within3hours),cardiacsurgery,obstetricsurgery,andmenorrhagia
Presentation Tablets,syrup,clearcolourlesssolutionforinjection
RouteofAdministration IV,PO
Dosing 1gslowIV,whichmaybefollowedbyinfusionof1gover8hours
Absorption 50%bioavailability
Distribution Lowplasmaproteinbinding,V 9-12litres
Metabolism Minimalhepaticmetabolism
Elimination Renalofactivedrug-dosereduceinrenalimpairment
GIT Nausea,vomiting
Haematological Reducesfibrinolysis,possibleincreaseinDVT/PE
Immunological Allergicdermatitis
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. LITFL-TranexamicAcid
Lastupdated2019-07-18
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AntiplateletsNoteaspirinisincludedunderCOXinhibitors.
ClassificationofAntiplateletAgents
Antiplateletagentscanbeclassifiedbywhichstageofplateletfunctiontheyaffect:
AdhesionvWFinhibitorse.g.Dextran70.
ActivationProstacyclinse.g.Epoprostenol.Phosphodiesteraseinhibitione.g.Dipyridamole.COXinhibitorsPreventthromboxaneA2production,e.g.aspirin.
AggregationADPreceptorantagonistsPreventactivationofGPIIb/IIIareceptors,e.g.clopidogrel.GPIIb/IIIareceptorantagonistsPreventplateletaggregationviafibrinlinkagesbetweenGPIIb/IIIareceptors,e.g.tirofiban.
ComparisonofCommonAntiplateletAgents
Property Clopidogrel Dipyridamole Tirofiban
Class ADPantagonist Phosphodiesteraseinhibitor GPIIb/IIaantagonists
Uses PVD,STEMI,NSTEMI,stentprophylaxis CVA UA,NSTEMI
RouteofAdministration POonly PO/IV IVonly
MechanismofAction
IrreversiblypreventsADPfrombindingtoitsreceptorontheplatelet,preventingactivationoftheIIb/IIIareceptor
Inhibitsplateletadhesiontowalls,potentiatesprostacyclinactivityandincreasesplateletcAMP,↓Ca andinhibitingplateletaggregationanddeformation.Alsoactsasacoronaryvasodilator.
ReversibleantagonismofIIb/IIIareceptor,preventingplateletaggregation
Dosing 300mgload,75mgdailythereafter 200mgBDforCVA
Load25mcg.kg ,maintenance15mcg.kg
Absorption Rapidabsorptionandonsetwithin2hours VariabledependingonoralintakeIVonly.Onsetwithin10minutes
Distribution Highlyprotein-bounddrugandmetabolites Highlyproteinbound 65%protein
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Metabolism
Prodrug.Majorityhydrolysedbyesterasestoinactivedrug,withasmallproportionhepaticallymetabolisedbyCYP450toactiveform.ProlongeddurationofactionduetoirreversibleADPblockaderatherthanlongeliminationhalf-life.
Partialhepatictoinactivemetabolites
Notmetabolised.
Elimination Urinaryandfaecal Renalandfaecal
Urinaryasunchangeddrug.Plateletaggregationreturnstobaselinewithin4-8hours
CVS VasodilatationmaydropCPPinASandrecentMI
Coronaryarterydissection
GIT Mucosalirritation
Haeme Haemorrhage Thrombocytopaeniaandhaemorrhage Haemorrhage
Other
Manypharmacokineticinteractions,includinggeneticvariability.Previouslythoughttokineticallyinteractwithomeprazole-morerecentlydisproved.
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. RangHP,DaleMM,RitterJM,FlowerRJ.RangandDale'sPharmacology.6thEd.ChurchillLivingstone.
Lastupdated2019-07-18
Antiplatelets
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PenicillinsPenicillinsarebactericidalantibioticsthatpreventcell-wallsynthesisbypreventingcross-linkingofpeptidoglycansbyreplacingthenaturalsubstratewiththeirβ-lactamringPenicillinsbindtopenicillinbindingproteins(PBPs)inthebacterialwallPenicillinsonlyrarelyachievecompleteeradicationofsensitiveorganismswithoutadditionofasynergisticantibiotic(suchasgentamicin)
CommonFeatures
Property Effect
Absorption Typicallywellabsorbedorally.IMdosingtendtocauselocalisedpainandirritation.
Distribution Typicallyhavegoodtissuepenetration.Onlycrosstheblood-brainbarrierandenterboneifitisinflamed.Typicallylowproteinbinding(exceptionisflucloxacillin,whichis95%proteinbound).
Metabolism Typicallysmallproportionishepaticallymetabolised.
Elimination Majority(60-90%)iseliminatedunchangedinurinepredominantlybyactivetubularsecretion,withrenalclearanceproportionaltototalrenalplasmaflow.Asmallquantityissecretedinbile.
MechanismsofResistance
AlterationorprotectionofPBPsGramnegativebacteriamayhavealteredpermeabilityofporinsintheiroutermembrane,whichprotectsthePDP
Hydrolysisbyβ-lactamase-producingbacteriaClavulanicacidandtazobactaminhibitβ-lactamase,whichcanrenderotherwiseresistantbacteriasensitiveNotably,flucloxacillinhasamodifiedbeta-lactamringthatisnotsensitivetoβ-lactamases
ComparisonofPenicillins
Narrowspectrum,naturallyoccurring
Narrowspectrum,synthetic
Extended-spectrum Antipseudomonal
Examples Benzylpenicillin,phenoxymethylpenicillin Flucloxacillin Ampicillin,
amoxacillinPiperacillin,ticarcillin
Indications
Grampositivesandanaerobes,particularlystreptococciandmeningococci.Alsolisteria,Clostridia,andTreponema.
Grampositivecocci,particularlystaphylococcibutalsostreptococci.
Grampositive,particularlyenterococci.Somegramnegative.
Grampositive,gramnegativeincludingpseudomonas.
Otherbits Highlybactericidal
Lessactivethanbenzylpenicillinonorganismssensitivetoboth.
Canpenetratesomegram-negatives.
Gramnegativecover.
References
Antimicrobials
671
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. BarzaM,WeinsteinL.Pharmacokineticsofthepenicillinsinman.ClinPharmacokinet.1976;1(4):297-308.3. BruntonL,ChabnerBA,KnollmanB.GoodmanandGilman'sThePharmacologicalBasisofTherapeutics.12thEd.
McGraw-HillEducation-Europe.2011.4. CICMJuly/September2007
Lastupdated2019-07-18
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GlycopeptidesNon-β-lactamagentsthatinhibitcellwallsynthesis.Theyare:
Activeagainstgram-positiveanaerobesandaerobesBacteriostaticagainstenterococciandstreptococciBacteriocidalagainststaphylococci
Property Vancomycin
Uses MRSA,C.difficile
Presentation Powderforreconstitution
RouteofAdministration PO,IV,Intrathecal
Dosing Peaklevelsdeterminedbydose,troughlevelsbydoseandinterval
Absorption Nooralbioavailability.PoorCSFpenetration
Distribution V 0.4-1L.kg .PoorCSFpenetrationevenwithinflamedmeninges-higherlevelsarerequiredforCNSpenetration.~50%proteinbound.
Metabolism Minimalhepaticmetabolism
Elimination 90%secretedunchangedinurine-significantlyprolongedinrenalimpairment
CVS Phlebitis,redmansyndrome(profoundnon-anaphylactichistaminereleasewithrapidinjection)
CNS Ototoxicity
Renal Nephrotoxicity,typicallytemporaryandresolvesoncessation
Haematological Thrombocytopenia
Immunological 'Redmansyndrome'duetohistaminereleasewithrapidinjection,withaccompanying↑HR↓BP.Neutropenia.
Other Synergisticactionwithcephalosporins,aminoglycosides,andrifampicin
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. WellingtonICUDrugManual3. RybakMJ.Thepharmacokineticandpharmacodynamicpropertiesofvancomycin.ClinInfectDis.2006Jan1;42Suppl
1:S35-9.
Lastupdated2019-07-18
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AminoglycosidesBactericidalantimicrobialsthatpreventproteinsynthesisbyirreversiblebindingtothe30Sribosomalsubunit,preventingmRNAtranscription.
Astheyarelarge,polarmolecules,theymustbeactivelytransportedintothecellThisoccurswithanoxygendependenttransporterThereforetheyarenoteffectiveagainstanaerobes.
TransportisinhibitedbyincreasedCa ,Mg ,lowpH,andlowOAminoglycosidekillingisdependentonthepeakconcentrationoverMICTypicallypeakconcentrationmustbe8-10xMIC.
Exposuretoaminoglycosidescausesbacteriatodown-regulateaminoglycosideuptake,andthereforeincreasesMICThiseffectdisappearsafter~24hours,andisonejustificationfordailydosingofaminoglycosides.Additionaljustificationsinclude:
Allowslargersingledosestobeused,increasingbactericidaleffectAminoglycosidesexhibitapost-antibioticeffectOngoingbactericidalactivityevenafterconcentrationfalls.
Property Gentamicin
Uses/Spectrum Gramnegativeincludingpseudomonas,limitedgrampositive(staph,limitedstrep),synergisticeffectswithβ-lactamsandvancomycin.
RouteofAdministration IVonly.
Dosing 4-7mg.kg .
Distribution 70%proteinbound.VerysmallV of0.2L.kg ,whichmayresultinsignificantpharmacokineticchangeswithoedema.
Metabolism Notmetabolised.
Elimination Eliminatedunchanged,eliminationt prolongedupto70hoursinrenalimpairment.
CNS Ototoxicityduetoaccumulationinperilymph,andisusuallypermanent.Increasedriskwithconcomitantfrusemideuse.
MSK Muscleweakness.
Renal Nephrotoxicityduetoaccumulationintherenalcortex,typicallyreversible.
ToxicEffects Narrowtherapeuticindex,requiresmonitoringanddosereductioninrenalimpairment.
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. StubbingsW,BostockJ,InghamE,ChopraIMechanismsofthepost-antibioticeffectsinducedbyrifampicinandgentamicin
inEscherichiacoli.JAntimicrobChemother.2006Aug;58(2):444-8.3. DerangedPhysiology-KillCharacteristicsofAntibioticAgents
Lastupdated2017-08-12
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Aminoglycosides
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LincosamidesInhibitproteinsynthesisbydisruptingthe50Sribosomalsubunit.Maybebacteriostaticorbacteriocidal,dependingontheconcentrationandtheparticularorganism.
Property Clindamycin
SpectrumofActivity
Grampositivecocci,anaerobes.Littleactionagainstgramnegativeaerobes.Alsoactiveagainstsomeprotozoa,suchasP.falciparum.
RouteofAdministration PO/IV
Dosing 150-300mgQ6H
Absorption 90%PObioavailability
Distribution Excellentbonypenetration
Metabolism Hepatictoactiveandinactivemetabolites
Elimination Renaleliminationofallmetabolites
MSK Maycauseneuromuscularblockadeinoverdose
GIT ReasonableincidenceofGITupset,withfatalpseudomembranouscolitisreported.DerangedLFTs
Immune Atopy,eosinophilia,DRESS
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. Lexicomp.Clindamycin(systemic):DrugInformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.
Lastupdated2019-07-18
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MetronidazoleMetronidazoleinterruptscellularmetabolismbypreferentialreduction,capturingelectronsthatwouldbeusuallytransferredtoothermolecules.Thisleadstoabuildupofcytotoxicintermediatemetaboliccompoundsandfreeradicals,thatresultinDNAbreakageandsubsequentcelldeath.
Property Drug
Class Nitroimidazole
Uses Anaerobesandprotozoa
RouteofAdministration PO/IV
Dosing 500mgBD
Absorption 100%bioavailability
Distribution CrossesBBB
Metabolism Hepatictoactivemetabolites
Elimination Renalofactivemetabolites
Metabolic Significantrash,nausea,vomiting,headache,flushing
GIT Nausea,vomiting,metallictaste
Immunological Hypersensitivityreactions
Interactions Disulfiram-likereactionwithETOH
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. Lexicomp.Metronidazole(systemic):Druginformation.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2017.
Lastupdated2019-07-18
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AntifungalsAntimicrobialagentstargetingeukaryoticandheterotrophicmicrobes.Canbedividedbyclassinto:
AzolesInhibitergosterolsynthesis.Subdividedinto:
TriazolesFluconazoleItraconazoleVoriconazolePosaconazole
ImidazolesKetoconazole
EchinocandinsInhibitglucansynthesis.
CaspofunginMicafunginAnidulafungin
PolyenesDisruptcellmembrane.
AmphotericinBNystatin
CommonFeatures
MechanismsofAntifungalResistance
Threebroadmechanisms:
IncreasedeffluxIncreasedexpressionoftransportproteinsremovingdrugfromcell.AlterationoftargetenzymeChangestoproteintargetpreventdrugbindingorinactivation.
TypicallyonlyrequireschangesinafewaminoacidsAlterationofdrugmetabolismReducedenzymeactivitypreventsaccumulationoftoxicproduct.
Amphotericinresistanceisrareinvivo,andistypicallyviadifferentmechanisms:
DecreasedergosterolcontentAlteredsterol:phospholipidratio
ComparisonofAntifungals
Drug Fluconazole Voriconazole Caspofungin AmphotericinB
Class Azole AzoleEchinocandins Polyenes
Candida(includingazoleresistant
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SpectrumofActivity
Candidaalbicans(mostotherspecies,especiallyC.glabrataandtoalesserextentC.kruseiareresistant),asresistancerapidlydevelops),cryptococcus,coccidioides,histoplasma,blastomyces,andsomeaspergillus(resistancemayalsodeveloprapidly).Atleastasgoodasamphotericininsusceptibleorganisms.
Asfluconazole,butbroaderspectrumofactivity
C.glabrataandC.kruseiandCandidabiofilms),aspergillus.Notablynoactivityagainstcryptococcus,fusarium,andtrichosporon.
Additionally,echinocandinstypicallyhavenocross-resistancewithotherantifungals
Effectiveagainstmanyfungi,withnotableexceptionsbeingChromoblastomycosis,Aspergillusterreus,Candidalusitaniae,Scedosporium,andsomeFusarium.
Pharmaceutics Poorwatersolubility Poorwatersolubility
Poorwatersolubility
Fourdifferentformulations,mostcommonisamphotericinBcolloidaldispersion(ABCD)
Dosing 100-800mgOD,adjustinrenalfailure
Typically70mgloadingdose,followedby50mgdaily;dosereducedinhepaticimpairment
Loadwith0.25-0.5kg.kg ,followedby0.25-1.5mg.day ,reducedinsevererenalimpairment
RouteofAdministration IVorPO IVonly(high
MW)IVforsystemicindications
Absorption
HighPObioavailability,POabsorptionatlowpH(interactionwithantacids,vitaminsupplements)
<5%PObioavailability
DistributionCrossesBBB-goodCSFpenetration.Verylowproteinbinding(~10%)
Notdialysableduetoveryhighproteinbinding,V .Goodtissuepenetration.
EssentiallynoCSFpenetration,97%proteinboundinserum
Rapiduptakebyreticuloendothelialsystem.Bindstoorganicaniontransportingpeptides(importantinhepatocytedrugbinding),importantinkeydruginteractions(suchastacrolimus)
Metabolism
MetabolisedbyandcausereversibleinhibitionofmultiplehepaticCYP450enzymes(including3A4,2C19,2C9),leadingtoincreasedconcentrationsofmanydrugs/metabolites
Asfluconazole
ExtensivehydrolysisandN-acetylationtoinactivemetabolites
Minimalmetabolism
Elimination 80%offluconazolerenallyeliminatedunchanged
Mostlyclearedvialiver.
Renalofmetabolites
Renalandfaecaleliminationofunchangeddrug
MechanismofInhibitergosterolsynthesis
Preventcellwallsynthesis Bindssterols,
disruptingosmotic
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Action byinhibitingCYP450enzyme
Asfluconazole byblockingproductionofbeta-glucan
integrityofthecellmembrane
CVS HTN LongQT Histaminerelease
CNS Headache,visualdisturbances
Hallucinations,psychosis
Renal
AKIviaafferentarteriolarconstrictionanddirecttubulartoxicity,hypokalaemia,renaltubularacidosis
GIT HepatotoxicityMildhepatotoxicityinupto~15%
Haeme Thrombophlebitis,normocyticanaemia
References
1. AndersonJB.Evolutionofantifungal-drugresistance:mechanismsandpathogenfitness.NatRevMicrobiol.2005Jul;3(7):547-56.
2. DrewRH.PharmacologyofAmphotericinB.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2018.3. AshleyED,PerfectJR.Pharmacologyofazoles.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2018.4. LewisRE.Pharmacologyofechinocandins.In:UpToDate,Post,TW(Ed),UpToDate,Waltham,MA,2018.5. BekerskyI,FieldingRM,DresslerDE,LeeJW,BuellDN,WalshTJ.Pharmacokinetics,excretion,andmassbalanceof
liposomalamphotericinB(AmBisome)andamphotericinBdeoxycholateinhumans.AntimicrobAgentsChemother.2002Mar;46(3):828-33.
Lastupdated2019-07-18
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InsulinsInsulinsaresyntheticpolypeptidehormones.They:
HaveasimilarmechanismofactionandpharmacodynamicsofendogenousinsulinOneunitofinsulinisdefinedastheamountrequiredtomakeapreviouslyhealthy2kgrabbithypoglycaemic
TypesofInsulin
Differentinsulinsarecategorisedbytheirtimeofonset,peak,andduration,andareclassifiedaseither:
FastactingIntermediateactingLongacting
FastActing
FastactinginsulinsareusedforcontrollingBSLspikespostmeals,andforcontrolofhyperglycaemia.Administeredsubcutaneouslytheyhavehavean:
Onsetof5-15minutesPeakat1-2hoursLast4-6hours.
Fastactinginsulinsinclude:
InsulinAspart(Novorapid)InsulinLispro(Humalog)
IntermediateActing
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IntermediateactinginsulinsareusedforcontrolofBSLbetweenmealsasapseudo-basalbolus.Administeredsubcutaneouslytheyhavean:
Onsetof1-2hoursPeakat4-6hoursLast>12hours
Intermediateactinginsulinsinclude:
NPHProtophane
LongActing
Longactinginsulinsareusedforcreatingabaselineinsulinlevel.Administeredsubcutaneouslytheyhavean:
Onsetof1-1.5hoursPeakat5hoursLast24hours
Long-actinginsulinsinclude:
Insulinglargine(Lantus)Insulindetemir(Levemir)
PharmacokineticsofExogenousInsulinPreparations
Property Drug
Class Syntheticpolypeptidehormones
Uses Diabetes,hyperglycaemia,hyperkalaemia,β-blockertoxicity,Ca -blockertoxicity
Presentation Clearcolourlesssolutiontypicallyat100IU.ml
RouteofAdministration SC,IM,IV
Absorption Variable,asdescribedabove.Insuliniscomplexedwithdifferentsubstances(e.g.protamine,zinc),whichalteritsrateofabsorption
Distribution MinimalproteinbindingandminimalredistributionoutofECF-V 0.075L.kg
Metabolism Glutathioneinsulintranshydrogenase.Metabolismisconstant-durationofactionisentirelyduetodifferentratesofsubcutaneousabsorption.
Elimination Renalofinactivemetabolites
References
1. DiabetesEducationOnline.TypesofInsulin.UCSF.AccessedJanuary2016.2. Graphofinsulinactivityprofilesfrom:DiabetesEducationOnline.TypesofInsulin.UCSF.AccessedJanuary2016.3. MudaliarS,MohideenP,DeutschR,CiaraldiTP,ArmstrongD,KimB,ShaX,HenryRR.Intravenousglargineandregular
insulinhavesimilareffectsonendogenousglucoseoutputandperipheralactivation/deactivationkineticprofiles.DiabetesCare.2002Sep;25(9):1597-602.
4. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.
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OralHypoglycaemics
Class Biguanides Sulfonylureas Glitazones Gliflozins
Example Metformin Gliclazide Pioglitazone Dapagliflozin
Uses T2DM T2DM T2DM T2DM
MechanismofAction
Delayglucoseabsorption,increaseperipheralinsulinsensitivity,inhibithepaticgluconeogenesis
Increaseinsulinsecretionfrompancreaticβ-cells.Mayincreaseinsulinsensitivity
ActivatestheintranuclearPPARγreceptor,affectinggenetranslationandincreasinginsulinsensitivity
InhibitsglucosereabsorptionbytheS-GLUT co-transporterinthekidney,increasingglucoseeliminationinurine
Dosing 500mg-2gBD 40-160mgBD 15-30mgdaily 5-10mgdaily
Absorption Bioavailability60%
Bioavailability80%
Highbioavailability.DelayedonsetandlatepeakeffectgivenMoA
Bioavailability>75%
Distribution Minimallyproteinbound
Extensivelyboundtoalbuminbynon-ionicforces,suchthattheydonottendtodisplaceotherhighlyproteinbounddrugs
LowV(0.6L.kg )
Metabolism NotmetabolisedPartialhepatictoinactivemetabolites
ExtensivehepaticphaseItoinactiveandactivemetabolites
Extensivehepatictoinactivemetabolites
EliminationRenaleliminationofactivedrug
Renaleliminationofactivedrugandinactivemetabolites
RenalandGIeliminationofactiveandinactivemetabolites
Renalofinactivedrug
CVSMayprecipitatefluidretention
Renal
Contraindicatedinrenalimpairmentduetoincreasedriskoflacticacidosis
Contraindicatedinrenalimpairment(<60ml.min )asithasnobenefit
MSK Photosensitivity
Metabolic
↑Appetite,weightgain.Hypoglycaemia
Weightloss,reducedinsulinrequirements
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infasting.
Renal IncreasedUTIandthrushrisk
GIT Nausea,Diarrhoea Cholestasis
Toxic
Severelacticacidosissecondarytoinhibitionofoxidativeglucosemetabolism,especiallyinrenalfailureandalcoholics
Crossplacenta,causingfoetalhypoglycaemia.
Mayleadtoeuglycaemicdiabeticketoacidosisduetobluntedinsulinproductioninthefaceofstresshormones.ConsiderinpatientswithDKAsymptoms(drowsiness,abdominalpain,nausea/vomiting),elevatedketones,andmetabolicacidosisinthesettingofanormalBSL.
References1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. DapaglifozinforType2Diabetes.2013.AustPrescr2013;36:174-9.4. KilovG,LeowS,ThomasM.SGLT2inhibitionwithdapagliflozin:Anovelapproachforthemanagementoftype2diabetes.
AmericanFamilyPhysician.Volume42,No.10,October2013Pages706-710.5. ANZCA.SevereEuglycaemicKetoacidosiswithSGLT2InhibitorUseinthePerioperativePeriod.2018.
Lastupdated2019-07-18
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OxytocicsOxytocicsareagentswhichincreasetheforceofuterinecontraction.
Property Oxytocin Ergometrine PGF(Dinoprost) Carboprost
Class
Endogenous(typicallysyntheticversionused)posteriorpituitaryhormone
Ergotalkaloid Prostaglandin
UsesAugmentationoflabour,increaseuterinetone(PPH)
PPH SeverePPH SeverePPH
Presentation Clearliquidat5-10U.mlClearliquidat250μg.ml ,upto8doses(2mg)
RouteofAdministration IV IV,IM Intramyometrial
injection,IM Intramyometrial,IM
Dosing 1.5-12mU.min250μgIM(IVinemergencyviaslowpush)
500μgIM
Metabolism Oxytocinasesinliverandkidney
MechanismofAction
OxytocinGPCRintheuterus,increaseCainflux.StructurallysimilartoADH.
Actsonαand5HT receptorsonuterineandvascularsmoothmuscle
Resp Bronchospasm(maybesevere)
Bronchospasm(severeifIVsothisrouteiscontraindicated)
Bronchospasm,APOdueto↑PVRwithsubsequenthypoxia
CVS ↑HR,↓BPfollowingboluses
↑SVR,↑BP(maycause,↓HR)coronaryvasoconstriction
↑SVR,↑BP ↑SVR,↑BP(usuallytransient)
CNS Headache,nausea,vomiting Headache,nausea Nausea,
vomiting Headache
Renal↓UOduetoADH-likeeffectswithprolongedinfusions
GU
↑Uterinetone(↑frequencyatlowdose,tetaniccontractionathighdose),foetaldistress,lactation
↑Uterinecontractionfrequencyandtone
↑Uterinecontractionfrequencyandtone
↑Uterinecontractionfrequencyandtone,contraindicatedinpelvicinflammatorydisease
Other
Maybemetabolisedbyoxytocinasesinbloodproductsifco-administeredonthesameline
Contraindicatedinpre-eclampsiaduetoHTN
Deprecatedbycarboprost,increasedbodytemperature
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References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.3. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.4. RoyalWomen'sHospita.PostpartumHaemorrhage-Carboprost.2017.
Lastupdated2019-07-18
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TocolyticsTocolyticsareagentswhichdecreaseuterinetone.Tocolyticsinclude:
β -agonistsCa -channelantagonistsCOXInhibitorsMgSONitratesVolatileanaestheticagents
Alltocolyticsarediscussedinmoredetailelsewhere-thiscoversjustthemechanismofactionoftheiruterineeffects.
Drug β -agonists Ca -channelantagonists COXInhibitors
Example Salbutamol,Terbutaline Nifedipine Indomethacin
MechanismofAction
ActivateGPCR,↑cAMP,whichactivatesproteinkinaseAandleadstoinhibitionofmyosinlightchainkinaseandrelaxation
BlockL-typeCa channels,causingrelaxation
Inhibitprostaglandinsynthesis,whicharevitalforuterinecontraction
References
1. Diaz,A.Describethemechanismofactionandsideeffectsofthreeclassesofdrugsthatareusedtoincreaseuterinetone,andthreeclassesofdrugsusedtodecreaseuterinetone.PrimarySAQs.
Lastupdated2019-07-18
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AcidSuppression
PropertyNon-
ParticulateAntacids
ParticulateAntacids ProtonPumpInhibitors H receptorantagonists
Example Sodiumcitrate
AluminiumHydroxide/Calciumcarbonate
Omeprazole Ranitidine
Uses Aspirationprophylaxis
Aspirationprophylaxis
Aspirationprophylaxis,GORD,pepticulceration
Aspirationprophylaxis,GORD,pepticulceration
Absorption
Rapidabsorptionduetohighwatersolubility
Lowerwatersolubilityresultsinslowerabsorptionandonsetbutnoriskofalkalosis
Absorbedinsmallbowel,highPObioavailability 50%PObioavailability
Distribution LowV of0.3L.kg 15%proteinbound
Metabolism
Prodrug,activatedwithinparietalcell.CYP450metabolised,inhibitsCYP2C19(reducing,amongotherthings,theantiplateleteffectofclopidogrel)
PartialhepaticbyCYP450
Elimination Renalofmetabolitesandactivedrug
Renalofmetabolitesandactivedrug
MechanismofAction
Basereactswithgastricacidtoproducesaltandwater
Basereactswithgastricacidtoproducesaltandwater
IrreversibleantagonismoftheparietalH /K ATPase
Competitiveantagonismofthe(Gs)H receptor,which↓cAMPproduction,↓intracellularCa ,and↓activityoftheH /K ATPase
Resp
Lowerriskofpneumonitisifaspirated
Greaterriskofpneumonitisifaspirated
Potentiallyincreasedseverityofpneumoniaifaspirationoccurs(riskwithmicro-aspirationinlong-termintubatedpatients)
Pneumonitis/pneumoniaasperPPI
CVS↓HR,↓BP,andarrhythmogenicwithrapidIVadministration
RenalPotentialmetabolicalkalosis
Noriskofalkalosis Interstitialnephritis
GIT ↑GastricpH ↑GastricpH ↑GastricpH(pH↑by~1),↓
volumeofsecretions
Other Tastebad
References1. PetkovV.EssentialPharmacologyForTheANZCAPrimaryExamination.VesselinPetkov.2012.2. ANZCAFeb/April2012
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3. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.OxfordUniversityPress.4thEd.2011.
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AntiemeticsAntiemeticdrugscanbeclassifiedbytheirmechanismofaction:
SerotoninantagonistsOndansetron
CorticosteroidsDexamethasoneHasadditionaleffectsonpostsurgicalpainandfatigue.
DopamineantagonistsPhenothiazines
ChlorpromazineProchlorperazine
ButyrophenonesDroperidol
BenzamidesMetoclopramide
AnticholinergicsHyoscineAtropine
AntihistaminesCyclizine
NK antagonistsAprepitant
OthersBenzodiazepinesCannabinoidsPropofol
ComparisonofAntiemeticDrugs
Property Ondansetron Droperidol Metoclopramide Cyclizine
Class SerotoninantagonistBenzamidedopamineantagonist
DopamineantagonistPiperazinederivative/Hantagonist
Uses
Nausea.Ineffectiveforvomitingduetomotionsicknessordopamineagonism
Antiemetic,sedation,behaviouralcontrol
Prokinetic,antiemetic
Antiemetic(includingmotionsicknessandradiationsickness)
PresentationTablet,wafer,clearsolutionforinjectionat4mg.ml
Clearsolutioninbrownglass,incompatiblewiththiopentoneandmethohexital
Clearsolutioninplastic
50mgtabletsor50mg.mllight-sensitivesolution
RouteofAdministration PO/SL/IV IV IV/PO PO/IV/IM
Dosing4-8mgTDSGiveoninductionfor
IVGiveatendofsurgeryfor
25-50mgIV(note10mghasnoantiemeticproperties
1mg.kg upto150mgperday
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PONV PONV
Absorption PObioavailability60% PObioavailability30-90%
PObioavailability80%
Distribution 75%proteinbound90%proteinbound,V2L.kg
Minimalproteinbinding,V ~3L.kg
Metabolism
Hepatictoinactivemetabolites.Dosereductioninhepaticimpairment.t3/24.
Extensivehepaticmetabolism Hepaticmetabolism
Hepatictoinactivemetabolites
Elimination Renaleliminationofinactivemetabolites
Renalandhepaticofdrugandmetabolites
Renalof20%unchangeddrugandremainderasmetabolites
Renalofmetabolites
MechanismofAction
Centralandperipheralantagonismof5-HTreceptors,reducinginputtothevomitingcentre
CentralDblockadeandpost-synapticGABAantagonism
AntiemeticactivityviacentralD antagonism,prokineticactivityviamuscarinicagonism,peripheralD antagonism
CompetitiveHantagonistandanticholinergicatM ,M ,Mreceptors
CVS
BradycardiawithrapidIVadministration,QTprolongation
QTprolongation,hypotensionsecondarytoαantagonism
↑/↓HR,↑/↓BP↑HRand↓BPduetoαantagonism
CNS Headache
Sedation(neurolepsis),extrapyramidalsymptomsin~1%
Extrapyramidalsymptoms,neurolepticmalignantsyndrome
Sedation
GIT Constipation Antiemetic Antiemetic,prokinetic IncreasedLoStone
Endocrine Hyperprolactinaemia
References
1. PeckTE,HillSA.PharmacologyforAnaesthesiaandIntensiveCare.4thEd.CambridgeUniversityPress.2014.2. SébastienPierre,MD,RachelWhelan.NauseaandVomitingAfterSurgery.ContinEducAnaesthCritCarePain2013;13
(1):28-32.doi:10.1093/bjaceaccp/mks0463. SmithS,ScarthE,SasadaM.DrugsinAnaesthesiaandIntensiveCare.4thEd.OxfordUniversityPress.2011.
Lastupdated2017-08-01
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IntravenousContrast
Intravenouscontrastmaybedividedinto:
X-rayContrastTheseagentsareallbasedonatri-iodinatedbenzenering,whichabsorbsx-rayradiation.Alterationstothisringaltertoxicity,lipophilicity,andelimination.
Agentsareclassifiedbythesestructuraldifferencesinto:IonicIonicsubstancesarestrongacidsandarewatersolubleduetoionisation.Theyarefurtherdividedinto:
MonomersTypicallyhighmolecularweight.Dimers
Non-IonicWatersolubleduetohydrophilicsidechains.Lowermolecularweightthanioniccontrastagents.
MonomerAgentofchoiceforangiography.
EasytoinjectWatersolubleatphysiologicpH
DimerHardertoinjectthanmonomersduetohigherviscosity.Typicallyusedforurography.
Allarerenallyeliminated,andmayberetainedinrenaldysfunctionGadoliniumContrastGd ,duetoitssevenunpairedelectrons,isparamagneticandwillaltersthemagneticfieldofanMRImachine.
FreegadoliniumisnephrotoxicandmustbechelatedThisincreasesitssolubilityandallowsittoberenallyeliminatedGadoliniumalsoattenuatesx-rays,butisnotusedasx-raycontrastasdosesrequiredwouldbetoxic
AdverseReactions
Adversereactionstolow-osmolarityagentsareuncommon(3%),withseverereactionsbeingveryrare(0.04%)andfatalreactionsbeingextremelyrare(1:170,000).
GeneralAdverseReactions
Adversereactionsinclude:
ChemotoxicityPlateletinhibitionIncreasedvagaltone
NegativeinotropyNegativechronotropy
IonictoxicityCellularmembranedysfunctionMayworsenmyastheniagravis.
OsmotoxicityPainEmesisIncreasedPAP
3+
OtherDrugs
693
DecreasedPVRHypersensitivityreactionTypicallyoccurwithin20minutesofinjection.
Riskfactorsinclude:
AsthmaoratopyCriticallyillCardiacdiseaseRenaldisease
ContrastNephropathy
Definedasanincreaseincreatinineby25%abovebaselinewithinthreedaysofIVcontrastadministration.
Itistheorisedthatosmoticstressanddirecttubulartoxiceffectsleadtorenaltubularinjury,andmaycauseacutetubularnecrosisTypicallyisbenign,withcreatininereturningtobaselinewithin10-14daysSignificantuncertaintyastowhethercontrastmediadocauseacutekidneyinjuryIFthisriskispresent,itisprobablyonlyrelevantinpatientswhohave:
ImpairedrenalfunctionArterialcontrast
Rehydrationandvolumecorrectionareeffectiveinpreventingariseincreatinine
References
1. DickinsonMC,KamPC.Intravasculariodinatedcontrastmediaandtheanaesthetist.Anaesthesia.2008Jun;63(6):626-34.2. TheRoyalAustralianandNewZealandCollegeofRadiologists.IodinatedContrastMediaGuideline.Sydney:RANZCR;
2016.
Lastupdated2019-07-18
OtherDrugs
694
DefinitionsThisappendixisalistofkeydefinitionsthatarecommontomanytopics.
A
AbsoluteHumidityMassofwatervapourinagivenvolumeofair.Measuredinmg.L .
AbsorptionTherateatwhichadrugleavesitssiteofadministrationandtheextenttowhichthisoccurs.
AccuracyTheabilityofameasuringdevicetomatchtheactualvalueofthequantitybeingmeasured.
AcidAprotondonor.
AcidaemiaArterialbloodpH<7.35.
AcidosisAprocesswhichleadstoanexcessofhydrogenions,andmayleadtoacidaemiaifthereisinadequatecompensation.Canbesubdividedinto:
Respiratoryacidosis:PaCO >45Metabolicacidosis:HCO <22
ActivityTheeffectiveconcentrationofasubstanceinareactingsystem.
AcutePainDefinedaspainof:
RecentonsetLimitedprobabledurationIdentifiablecausalandtemporalrelationshiptoinjuryordisease
AdiabaticAprocessthatoccurswithouttransferofheatormatter.Forexample,gasesheatupwhencompressed(greaterthantheenergyusedtocompressthem),andcoolwhenallowedtoexpand(adiabaticcooling).
AffinityAbilityofadrugtobindtoareceptor.
AfterloadSumofforces,bothelasticandkinetic,opposingventricularejection.
AgingNaturallyoccurring,physiologicaldeclineinthestructureandfunctionalreserveofallorgansystems.
AgonistDrugwhichproducesamaximalresponseatreceptorsite.
AlkalaemiaArterialbloodpH>7.45.
-1
23-
Definitions
695
AlkalosisAprocesswhichleadstoadeficitofhydrogenions,andmayleadtoalkalaemiaifthereisinadequatecompensation.Canbesubdividedinto:
Respiratoryalkalosis:PaCO <35Metabolicalkalosis:HCO >26
AllodyniaPaincausedbyapreviouslynon-painfulstimulus.
AllostericModulatorSubstancewhichbindsareceptordistanttotheligand-bindingsite,andmodifies(positivelyornegatively)theeffectoftheligand.Hasnoactivityinabsenceofaligand.
AnaesthesiaWithoutsensation.
AnalogueSignalWheretheoutputofthetransducervarieswiththeinputsignal.
AnionNegativelychargedion.
AnodeTheelectrodewhichconventionalcurrentflowsinto.
AnrepeffectMethodofmyocardialautoregulationinwhichanincreaseinafterloadcausesanincreaseincontractility.
AntagonistDrugwhichproducesnoresponseatthereceptor,butpreventsotherligandsbinding.
AutoregulationAbilityofanorgantomaintainhomeostasisinthepresenceofdynamicphysiologicalconditions.
AzeotropeAmixtureoftwosubstancesthatcannotbeseparatedbyfractionaldistillation,aseachcomponentsharessameboilingpoint.Thisistypicallytemperaturedependent.
B
BaseProtonacceptor.
BaseExcessAmountofacidthatmustbeaddedtoasolutiontoloweritspHto7.4,at37°CandwithaPaCO of40mmHg.
BathmotropyDegreeofmyocardialexcitability.Usedwitheitherpositiveornegativebathmotropy.
Bell-MagendieLawTheprinciplethatinthespinalcordthedorsalrootsaresensoryandtheventralrootsaremotor.
BiasThesystematicdistortionoftheestimatedinterventioneffectawayfromthe“truth”,causedbyinadequaciesinthedesign,conduct,oranalysisofatrial.
23-
2
Definitions
696
Black-bodyradiationElectromagneticradiationgivenoffbyallbodiesatgreaterthan0°K.Wavelengthofradiationemitteddependsonthetemperatureofthebody.
BohrEffectAnincreasein[H ]orPaCO decreasesHbaffinityforO2.
BoilingPointThetemperatureatwhichthevapourpressureofaliquidequalstheenvironmentalpressuresurroundingtheliquid.
Thereforeboilingpointdecreasesasenvironmentalpressurefalls,asthereislessexternalpressurekeepingmoleculesintheirliquidstateBoilingdiffersfromevaporationasmoleculesanywhereintheliquidmayenterthegaseousphase,whilstevaporationoccursonlyatthesurface
BowditchEffectIncreaseincontractilityseenwithanincreaseinHR.AlsoknownastheTreppeeffect.
Boyle'sLawPressureofagasisinverselyproportionaltovolume.
BufferSolutioncontainingaweakacidanditsconjugatebaseandwillresistachangeinpHwhenastrongeracidofbaseisadded.
C
CalibrationAprocessofcheckingamonitoringdeviceforlinearityofcorrelationbetweenactualandmeasuredvaluesoveragivenmeasurementrange.
CapacitanceAbilityofasystemtostoreelectricalcharge.MeasuredinFarads.
CentralBloodVolumeVolumeofbloodinheartandlungs.
CentralSensitisationIncreasedresponsivenessofnociceptiveneuronsinthecentralnervoussystem(i.e.,post-synaptic)totheirnormalorsubthresholdafferentinput.
ChemotaxisMovementofcellsalongagradientofincreasingconcentrationofanattractingmolecule.
ChronicPainPainthat:
PersistsbeyondthetimeoftissuehealingFrequentlyhasnoclearlyidentifiablecause
ClearanceVolumeofplasmacompletelyclearedofasubstanceperunittime.
CoronaryBloodFlowAtrestis~5%ofCO,or225ml.min ,andmayincrease3-4xduringexercise.
ColloidSubstanceevenlydispersedthroughoutanothersolutioninwhichitisinsoluble.
ColligativeProperties
+2
-1
Definitions
697
Thepropertiesofasolutionthatdependontheratioofsolutetosolvent,andnotonthetypeofmoleculespresent.These
include:VapourpressureBoilingpointFreezingpointOsmoticpressure
ComplianceDistensibilityofasystem.Expressedasthechangeinvolumeforagivenchangeinpressure.
ConcentrationEffectDescribesthedisproportionatelyrapidriseinFi/FAratioofnitrousoxide,asitsrapiddiffusionacrossthealveolarmembraneincreasestheconcentrationofalveolargas,andalsoaugmentsrespirationbydrawingindeadspacegas.
Context-SensitiveHalf-TimeTimetakenforplasmadrugconcentrationtofallto50%ofitsstartingvalueaftercessationofadruginfusionaimedtomaintainaconstantplasmaconcentration.Varieswiththecontext,orduration,ofdruginfusion.
ContractilityFactorsaffectingmyocardialperformance,independentofpreloadandafterload.
CriticalLengthThelengthofaxonwhichmustbeblockedinordertopreventactionpotentialtransmission.Itisdependentonmyelinationandfibrediameter.
CriticalPointThepointonaphasediagramwheretheliquidandgasphasesofasubstancehavethesamedensity,andarethereforeindistinguishable.
Thispointiswhereasubstanceisatbothitscriticaltemperatureandcriticalpressure
CriticalPressurePressurerequiredtoliquefyavapouratitscriticaltemperature.
CriticalTemperatureTemperatureabovewhichasubstancecannotbeliquified,irrespectiveofhowmuchpressureisapplied.
CriticalVolumeThevolumeoccupiedbyagivenamountofsubstanceatitscriticalpoint.
DDaltonUnitofmassequalto1/12 ofthemassofCarbon-12.
Dalton'sLawThepartialpressureofagasinamixtureisequaltothepressurethatgaswouldexertifitoccupiedthevolumealone.
DeadSpaceInspiredgasnotparticipatingingasexchange.Includes:
ApparatusdeadspaceGasintheventilatororbreathingcircuit.AnatomicaldeadspaceGasintheconductingzoneofthelung.AlveolardeadspaceAlveolargasnotparticipatingingasexchange.AlsoknownasWestZone1.
th
Definitions
698
PhysiologicaldeadspaceSumofalveolarandanatomicaldeadspace.
DensityMassperunitofvolume.
DependenceWhenacharacteristicwithdrawalsyndromeoccurswhenadrugiswithdrawn,oranantagonistadministered.
DiffusionPassivemovementofasubstancedownanactivitygradientbyBrownianmotion.
DiffusionHypoxiaFallinalveolarPAO duetodilutionofalveolargasbyN Odiffusingfrombloodtoalveoli.
DigestionProcessofbreakingdownmacromoleculesintoreadilyabsorbedcompounds.
DopplerEffectAlterationinfrequencyofasignalduetoarelativedifferenceinvelocitybetweentheemitterandobserver.Detectedfrequencieswillbe:
HigheriftheemitterismovingtowardtheobserverLoweriftheemitterismovingawayfromtheobserver
DownregulationDecreaseinreceptornumberduetochronicagonistexposure.
DriftAfixeddeviationfromthetruevalueatallpointsinthemeasuredrange.
DrugSubstanceadministeredtocauseachangeinaphysiologicalsystem.
DuplicatePublicationWherethesamesetofresultsarepublishedinmultiplejournals.Academicallyunethical,andwillcauseasystematicbiasinameta-analysesasthesamesetofpatientsareincludedtwice.
DyneForcerequiredtoaccelerate1gby1cm.sec .
E
EfficacyMaximaleffectproducedbyadrug.Analogoustointrinsicactivity.
ElectrocardiogramGraphicalrecordingofthevectorsumofcardiacelectricalactivity,asmeasuredbyelectrodesontheskin.
EmulsionAfinedispersionofminutedropletsofoneliquidinanotherinwhichitisnotsolubleormiscible.
EnzymeBiologicalcatalyst.
EutecticAmixtureofsubstanceswiththelowestpossiblemeltingpointthananyothermixtureofthesamesubstances(andlowerthanthatofeithersubstance).
2 2
-2
Definitions
699
ExcitabilityHowrapidlyanexcitablecelldepolarises.Givenbythegradientofphase0oftheactionpotential,andisdependentonthefunctionofvoltage-gatedsodiumchannels.
ExponentialFunctionMathematicalfunctionwheretherateofchangeisproportionaltothecurrentvalue.
ExternalValidityHowwellfindingsfromonesettingcanbeappliedtoanother.
FFahraeus-LindqvisteffectDecreaseinapparentviscositythatoccurswhenasuspension(e.g.blood)flowsthroughatubeofsmallerdiameter.
FastingMetabolicstateachievedaftercompletedigestionandabsorptionofamealpriortotheonsetofstarvation.
FickPrincipleBloodflowtoanorganequalstheuptakeofatracersubstancebythatorgan,dividedbythearterio-venousconcentrationdifference.
FlowQuantityoffluidpassingapointperunittime.
FourierAnalysisDeconstructionofacomplexwaveformbyseparatingitintoitsconstituentsinewaves.Theslowestcomponentisknownasthefundamentalfrequency.
FreeradicalExtremelyreactivemolecularconstituentcarryinganunpairedelectron.
FreezingpointTemperatureatwhichmolecularmovementbegins.
FunctionalResidualCapacityVolumeofgasinthelungsattheendofanormaltidalexpiration,whentherecoilpressureofthelungsequalstheexpansilepressureofthechestwall.
GGalvanometerDevicetomeasureelectricalcurrent,usuallyviadeflectionofawireinamagneticfield.
GasSubstanceaboveitscriticaltemperature.
GeneralanaesthesiaDruginduced,controlled,andreversibleproductionofunconsciousness.
Gibbs-DonnanEffectDescribesthetendencyofdiffusableionstodistributethemselvessuchthattheratiosoftheconcentrationsareequalwhentheyareinthepresenceofnon-diffusableions.
GrahamsLawThespeedofdiffusionofagasthroughamembraneisinverselyproportionaltothesquarerootofthemolecularweight.
Definitions
700
H
HaldaneeffectDeoxygenatedbloodformscarbaminocompoundsandbuffersH betterthanoxygenatedblood.
Half-LifeTimetakenfordrugconcentration(typicallyinplasma)tofallbyhalf.
HeatKineticenergycontentofabody,asmeasuredinjoules.
Henry'sLawAmountofgasdissolvedinasubstanceisdirectlyproportionaltothepartialpressureofgasatthegas-liquidinterface.
HeterometricautoregulationChangeinventricularfunctionbasedonmyocardialfibrelength.AlsoknownasStarling'sLaw.
HomeometricautoregulationMechanismswhichaltermyocardialperformanceindependentoffibrelength.
HormoneChemicalmessengersecretedbyaductlessglandandhasactiononadistanttargetcell.
HyperalgesiaGreaterthannormalamountofpainfromanoxiousstimulus.Maybe:
PrimaryOccurringintheregionoftissuedamage,e.g.inaninflamedareaaroundawound.SecondaryExtendingbeyondtheregionoftissuedamage.
HypoxaemiaWhenPaO islessthan60mmHg.
HypoxiaThepointatwhichinadequateoxygenationoftissuesresultsinanaerobicmetabolism.
HysteresisWhenthefuturestateofasystemdependsnotonlyonitscurrentstate,butonthestatesprecedingit.
I
IdealGasAgaswhichwillobeytheidealgaslaw.Anidealgasmusthave:
NegligibleintermolecularattractionAsmallmolecularvolumecomparedtothespacebetweenthemolecules
IdiosyncrasyAneffectofadrugaffectingonlyasmallnumberofpatients,typicallyduetotheactionofaparticularmetabolite.
InductancePropertyofaconductorbywhichachangeincurrentinducesanelectromotiveforceintheconductorandanynearbyconductors.
InotropeDrugwhichaltersmyocardialcontractility.
+
2
Definitions
701
IntrinsicActivityMaximaleffectproducedbyadrug.Analogoustoefficacy.
ImpedanceResistancetoalternatingcurrent.
InternalValidityWhereacausalrelationshipbetweenvariableshasbeenproperlydemonstrated,i.e.alackofbias.
IrritabilityHoweasilyanexcitablecellcanbestimulated.Givenbyhowclosetherestingmembranepotentialistothresholdpotential.
IsomerCompoundwiththesamechemicalformula,butdifferentchemicalstructureorarrangementofatoms.
IsothermLineofconstanttemperaturedrawnonapressure-volumegraphforagas,whichdescribestherelationshipbetweenpressure,temperature,andvolumeforaparticulargas.
J
JouleEnergytransferedtoanobjectwhenitisactedonby1Nfor1m.
L
LaminarFlowFlowoccurringsmoothlyandwithoutturbulence.
LocalAnaestheticDrugwhichreversiblypreventstheconductionofthenerveimpulseintheregiontowhichitisapplied,withoutaffectingconsciousness.
M
MACTheminimalalveolarconcentration(measuredin%of1atm)atsteadystatewhichpreventsamovementresponsetoastandardsurgicalstimulus(midlineincision)in50%ofapopulation.
ManometerDevicewhichmeasuresgaspressure.
MeanSystemicFillingPressureThepressuremeasuredanywhereinthesystemiccirculationwhenallflowofbloodisstopped.
MixedVenousBloodBloodfromtheIVC,SVCandcoronarysinus,whichhasbeenmixedbythepumpingactionoftheRVandistypicallysampledfromthepulmonaryartery.
MoleAmountofasubstancewhichcontainsasmanyrepresentativeparticlesasthereareatomsin12gofcarbon-12.
MolalityNumberofmolesofsoluteperkgofsolvent.
Definitions
702
MolarityNumberofmolesofsoluteperLofsolvent.Varieswith:
TemperatureSolventdensitySolutevolume
N
NaturalFrequencyFrequencyatwhichasystemwilloscillateatifdisturbedandleftalone.
NauseaUnpleasantsubjectivesensationassociatedwithurgetovomit.
NeuropathicPainPaincausedbyalesionordiseaseofthesomatosensorynervoussystem.
NociceptionNeuralprocessofencodinganoxiousstimulus.
O
OddsRatioEstimateofrisk,wheretheORistheratioofoddsofanoutcomeinthosetreatedvs.thosenottreated.OR=1suggestsnoeffect,≤1suggestsreducedrisk>1suggestsincreasedrisk.
OhmResistancewhichwillallowoneampereofcurrenttoflowpervoltofpotentialdifference.
OpiateNaturallyoccurringsubstancewithmorphine-likeproperties.
OncoticPressureProportionofosmoticpressureduetocolloid.
OpioidDescribesanysubstancewithactivityatopioidreceptors,andwhichcanbereversedbynaloxone.
OsmosisMovementofasolventacrossasemipermeablemembranetoanareaofgreatersoluteconcentration.
OsmoticPressurePressurethatmustbeappliedtoasolutiontopreventthemovementofasolventfromenteringasolutionwithhigherosmolality.
OxygenFluxVolumeofoxygendeliveredtothetissuesperminute.
P
p50Thepartialpressureatwhichanoxygen-carryingproteinis50%saturated.
Definitions
703
PainUnpleasantsensoryandemotionalexperienceassociatedwithactualorpotentialtissuedamage,orexpressedintermsofsuchdamage.
PartitionCoefficientDescribetherelativeaffinityofanagentfortwophases.Itisdefinedastheratiooftheconcentrationofagentineachphase,whenbothphasesareofequalvolumeandthepartialpressuresareinequilibriumatSTP.
PasteurPointPO atwhichoxidativephosphorylationceases.
PEEPSupra-atmosphericairwaypressureattheendofexpiration.
pHThepowerofhydrogen.Describestheactivityofhydrogenionsinasolution,andisexpressedas
.
PreloadLoadimposedonamusclebeforecontraction,andmeasuredastheaveragemyocardialfibrelengthattheonsetofsystole.MaybeapproximatedclinicallyusingEDV.
PrecisionTheabilityofameasurementdevicetoprovidereproducibleresultsuponrepeatedmeasurement.
Pseudo-criticaltemperatureTemperatureatwhichagasmixturewillseparateintoitsconstituentcomponents.
RRadiationTransferofenergyviaelectromagneticradiation.
ReceptorComponentofacellwhichbindstoaligandandresultsinachangeinfunction.
ReductionReactionwhichresultsinagainofanelectron.
ReflexUnconscious,predictableresponsetoastimulus.
RegurgitationPassivepassageofgastriccontentsintothemouth.
RelativeHumidityRatioofmassofwatervapourinagivenvolumeofair,tothemassrequiredtosaturatethatvolumeatthattemperature.Expressedasapercentage.
RespiratoryExchangeRatioRatioofCO producedtoO consumedatanygivenpoint.
RespiratoryQuotientRatioofCO producedtoO consumedatsteady-state.
ReynoldsNumberDimensionlessindexwhichpredictsthelikelihoodofturbulentflow.
2
2 2
2 2
Definitions
704
S
SaturatedVapourVapourwhichisinequilibriumwithitsownliquidstate,i.e.thereareasmanymoleculesenteringthevapourphaseastheretherearethosecondensingintotheliquidphase.
Asaturatedvapourcontainstheleastamountofenergypossiblewithoutcondensing
SaturatedVapourPressurePressureexertedbyavapourwhichisinequilibriumwithitsliquidstate.Increaseswithtemperature,sinceasthekineticenergy(heat)contentofmoleculesincrease,moreofthementerthevapourphase.
SecondGasEffectDisproportionatelyrapidriseinFA/Firatioseenwhenananaestheticagentisco-administeredwithnitrousoxide.
SeebeckeffectThegenerationofapotentialdifferenceatthejunctionoftwodissimilarmetals,withitsvaluedependentonthetemperatureofthejunction.
ShiveringInvoluntary,oscillatory,muscularactivitythataugmentsmetabolicheatproduction.
ShuntBloodenteringtheleftsideofthecirculationwithoutbeingoxygenatedviapassagethroughthelungs.
SpecificGravityDensityofaliquid,inmassperunitvolume.
SpecificHeatCapacityAmountofheatenergyrequiredtoraisethetemperatureof1kgofasubstanceby1°Kwithoutachangeinstate.
StandardBaseExcessThebaseexcesscalculatedforanHbof5g.L ,andwhichgivesabetterrepresentationofECFpH.
SurfaceTensionDescribesthetendencyofafluidtominimiseitssurfacearea.
SuspensionParticlesofanyphasedispersedinaliquid.
SynergismWhentwodrugsinteracttoproduceagreatereffectthanwouldbeexpected.
TTemperatureAbilityofabodytotransferheatenergytoanotherbody,asmeasuredindegrees.
ThirstConscioussensationofthephysiologicalurgetodrink.
TimeconstantTimeitwouldtakeforanexponentialfunctiontocompleteiftheinitialrateofchangecontinued.Aprocessis:
63%completeat1T86.5%completeat2T95%completeat3%
-1
Definitions
705
TonicityEffectiveosmolalityofasolution.Givenbytheosmolality,minustheconcentrationoffreelydiffusableosmoles(inplasma,theseareureaandglucose).
TonometerDevicewhichmeasurespressureofliquid.
TransducerDevicewhichchangesasignalfromoneenergyformtoanother.
TreppeEffectIncreaseincontractilitywithanincreaseinHR.AlsoknownastheBowditcheffect.
TurbulentFlowIrregularmovementinradial,axial,andcircumferentialaxes.
VValsalvaManoeuvreForcedexpirationagainstaclosedglottis.
VapourSubstanceinagaseousphasebelowitscriticaltemperature.
VapourpressurePressureexpertedbyavapour.
VenousadmixtureAmountofmixedvenousbloodthatmustbeaddedtopulmonaryend-capillarybloodtogivetheobservedarterialoxygencontent.
ViscosityDescribesthetendencyofafluidtoresistflow.
VoltPotentialdifferencewhichdissipates1Wofenergyper1Aofcurrent.
VolumeofDistributionApparentvolumeintowhichadrugisdistributedtoproducetheidentifiedplasmaconcentration.
Lastupdated2019-07-20
Definitions
706
KeyGraphsGraphs:
HelpyoutoconveyknowledgeandunderstandingefficientlyinthewrittenAreoftenafeatureofthevivaastheyallowexaminerstoassessdepthofunderstanding
Youwillbeaskedtodemonstratehowtheychangeunderdifferentphysiologicalstates
Itiseasytogetdistractedbythecurve,andforgetthebasics(especiallyinthewritten).Toavoidthis,approachtheminthesamewayeachtime:
AxisFirstdrawtheaxis.
Iftheaxisiscontinuous(e.g.PaO ),ensureyouplaceanarrowatthefarendIftheaxisendsatafixedpoint(e.g.SpO ),ensureyouplaceabarattheendtosignifyitdoesnotcontinueindefinitely
LabelsLabeleachaxiswithwhatitisrepresenting.UnitsGiveeachlabelappropriateunits.
Intheviva,youcanjustsaythisoutloudasyou'redrawingtheaxesCurveDrawthecurve.SpecialPointsIdentifythekeypointsofthecurveandlabelthesepoints.Theseinclude:
InterceptsInflectionpointsImportantvaluese.g.Themixedvenouspoint.
Pharmacology
Dose-Response:
Doseresponsecurveisawash-inexponentialDifficulttocomparedifferentdrugsusingthiscurve
Log -Response:
22
Dose
KeyGraphs
707
Log-transformofdoseallowsdifferentdrugstobecomparedBothredandbluedrugsarefullagonists(astheybothreach100%response),howeverthebluedrugismorepotentasithasalowerE 50
Agonists:
Partialagonistsdonotreach100%responseInverseagonistshaveanegativeresponse
Antagonists:
Non-competitiveantagonistspreventmaximalresponsebeingreachedCompetitiveagonistsrightshiftthecurve,astheycanbeovercomewithincreasingdoseofagonist
TherapeuticIndex:
D
KeyGraphs
708
CanbecalculatedfromtheratiooftheLD andED
Models
TheOne-CompartmentModel:
DrugisaddedtoandremovedfromthesinglecentralcompartmentThereisnodistributionpossible.V isequaltothevolumeofdistributionk istherateconstantforelimination
Three-CompartmentModel:
DrugisaddedtoandremovedfromthecentralcompartmentDrugwillalsodistributeto(andredistributefrom)theperipheralcompartmentsPlasmaconcentrationwilldependon:
RateofdrugdeliveryRateofdrugdistributionandredistribution
50 50
110
KeyGraphs
709
Rateofdrugelimination
Effect-Site:
DrugdistributestotheeffectsitefromthecentralcompartmentEffectsitehasnovolume,butdoeshaverateconstantst ke0isgenerallydrawnwithdrugbeingeliminatedfromtheeffectsite,howeverinrealitythisdoesnotoccurasdrugshouldonlybeeliminatedfromthecentralcompartment
Pharmacokinetics
Zero-orderkinetics:
AconstantamountofdrugiseliminatedperunittimeHalf-lifeisnotaconstantvalueHalf-lifeprogressivelyshortens,asthetimetakentogofrom50%to25%ishalfthetimeittooktogofrom100%to50%.
First-OrderKinetics:
AconstantproportionofdrugiseliminatedperunittimeHalf-lifeisaconstantvalue
1/2
KeyGraphs
710
Biexponentialelimination:
Notethatconcentrationhasbeenlog-transformedThisdescribestheeliminationofdrugfromatwocompartmentmodel
Pharmacodynamics
Isobologram:
Plotslinesofequalactivityversusconcentrationoftwodrugs
Plasma-SiteTargeting:
TCIgraphsareeasytodrawifyourememberthat:
Thepumpaimstoachievethetargetedconcentration:AsrapidlyaspossibleWithoutovershoot
KeyGraphs
711
EffectsiteconcentrationsfallslowerthanplasmasiteconcentrationsDrugcanonlyredistributebacktoplasmawheneffectsiteconcentrationisgreaterthanplasmaconcentration.
Thereforeinplasmasitetargeting:
PlasmaconcentrationrisesrapidlywithinitialbolusdoseDoesnotovershootEffectsiteconcentrationrisesmoreslowly
Exponentialwashincurveastheconcentrationgradientbetweenplasmaandeffectsitefallsovertime
Effect-SiteTargeting:
Plasmaconcentrationovershootseffect-sitetargetandthendeclinesrapidlyEffectsiteconcentrationrisesrapidly,andisachievedmorequicklycomparedwithplasma-sitetargetedmodel
Statistics
Boxplot:
Boxisdefinedbythe25 and75 centilesLineinthemiddleoftheboxisthemedian("50 centile")"Whiskers"eithersideoftheboxdefinethe10 and90 centiles
Thesemayalsorefertothe5 and95 centilesResultsoutsideofwhiskersaredefinedasoutliers,andarerepresentedbysingledots
Respiratory
Oxygen
OxygenCascade:
th ththth th
th th
KeyGraphs
712
GraphoflocationversusoxygenpartialpressureAtmospheric(dry)airhasaPO of160mmHgTracheal(humidified)gashasaPO of149mmHgReducedduetosaturatedvapourpressureofwater.AlveolargashasaPO of105mmHgReducedtothepresenceofCO ,asperthealveolargasequation.ArterialbloodhasaPO of~100mmHgReducedtotheAlveolar-arterialoxygengradient.TissueshaveaPO of~5mmHgMixedvenousbloodhasaPO of~40mmHgGreaterthantissuePO asnotalloxygeninblooddiffusesintoorisconsumedbytissues.
OxyhaemoglobinDissociationCurve:
GraphofPaO versusoxygensaturationNotethatPaO2 iscontinuous,andsoanarrowshouldbedrawnatthetipofthex-axis,whilstsaturationisfiniteandsothey-axisshouldbecappedat100%ThecurveisasigmoidshapeKeypoints:
At10mmHg,saturationis10%
22
22
2
22
2
22
KeyGraphs
713
Thep50isat27mmHgThemixedvenouspointisat40mmHg,wherehaemoglobinis75%saturatedNotethatduetotheHaldaneeffect,themixedvenouspointdoesnottechnicallyexistonthearterialcurve.Thisisasmallpointandisignoredinmostgraphs(includingthisone),butmaybeworthstatingifyou'refeelingconfidentintheviva.The"ICUpoint"(theupperinflection)isat60mmHgwherehaemoglobinis93%saturatedThearterialpointis97%saturatedat100mmHg
Thecurvemayberight-shiftedby:IncreasedHIncreasedPaCOIncreasedtemperatureIncreased2-3DPG
Theseshiftsaredefinedbyamovementofthep50
Double-BohrEffect:
ThedoubleBohreffectcaneasilybecomeconfusing,especiallywhenyouareunderpressureandonlyallowedonecolour(asinthewrittenexam)Hereisastraightforwardmethodwhichminimisestheconfusion:1. Drawanadultcurvewithap50of27mmHg2. Drawafoetalcurvewithap50of17mmHg3. Drawaright-shiftedadultcurve4. Drawaleft-shiftedfoetalcurve
PaO andMinuteVentilation:
+
2
2
KeyGraphs
714
ExponentialcurveMinuteventilationdoublesasPaO decreasesfrom100mmHgto60mmHgInflectionpointis~50-60mmHgBelowthisthereisalargeincreaseinventilation.HypercapnealeadstoagreaterminuteventilationforanygivenPaO
IsoshuntDiagram:
PlotstherelationshipbetweenPAO versusPaO fordifferent(fixed)shuntfractionsTheseareknownasisoshuntlinesKeyisoshuntlinesare:
At50%shunt,PaO2isessentiallyindependentofPAO2At30%shunt,PaO2willnotincreaseabove100mmHgon100%oxygenatatmosphericpressure
CarbonDioxide
CarbonDioxideDissociationCurve:
GraphofcarbondioxidecontentversuspartialpressureKeypointsonthiscurve:
2
2
2 2
-1
KeyGraphs
715
ArterialCO contentis48mls.100ml ofbloodat40mmHgMixedvenousCO contentis52.mls.100ml ofbloodat46mmHg
Notethatthemixedvenouscurveisup-shiftedduetotheHaldaneeffectRememberthat50%ofthedifferenceinCO contentisduetotheHaldaneeffect.Therefore:
ThemixedvenouscurveshouldbedrawnsuchthatCO contentis50mls.100ml at40mmHgThearterialcurveshouldbedrawnsuchthatCO contentis50mls.100ml at46mmHg
PaCO andMinuteVentilation:
GraphsthechangeinminuteventilationforprimarychangeinPaCORememberthatminuteventilationincreasesby~3L.min forevery1mmHgincreaseinPaCOFromthis,therelationshiptootherstatescanbederived:
Minuteventilationisreducedduringsleep,butthecentralresponsetoCO isonlyminimallyaffectedThecentralresponsetoCO isheavilyaffectedduringanaesthesiaMinuteventilationisincreasedforanygivenPaCO inthesettingofacidosis
AlveolarVentilationandPaCO :
GraphsthechangeinPaCO foraprimarychangeinminuteventilationExponentialcurveasPaCO isinverselyproportionaltominuteventilationMinuteventilationisincreasedforanygivenPaCO duringexercise
AnatomicalandPhysiologicalInteractions
ClosingCapacityandAge:
2-1
2-1
22
-1
2-1
2
2-1
2
22
2
2
22
2
KeyGraphs
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NotethatalthoughFRCincreasesslightlywithage,thisisnotgenerallyshownonthisgraphClosingcapacityincreaseswithincreasingageKeyintersectionsare:
GreaterthanFRCwhensupineat44yearsofageGreaterthanFRCwhenerectat66yearsofage
DiffusionandPerfusionLimitation:
ClassicallydrawnaspartialpressureversusdistancealongthecapillaryTimealongcapillarymayalsobeused,howevernotethattotaltransittimewillchangewithcardiacoutput.Notethatatthebeginningofthecapillary,oxygenpartialpressurewillbeequaltothatofmixedvenousblood
Inperfusionlimitation,PaO willequalPAO beforetheendofthecapillaryIndiffusionlimitation,partialpressureswillnotbeequalattheendofthecapillaryInnormalcircumstances,PaO equalsPAO at~1/3 ofthedistancealongthecapillaryIftimeisbeinggraphedonthex-axis,thenthiswilloccurat~0.25s,astotalcapillarytransittimeis~0.75s.
Nitrousoxiderapidlydiffusesintobloodandisandnottypicallypresentinmixedvenousblood,sothiscurvebeginsattheoriginandPaN OwillrapidlyreachPAN O(inthisinstance100mmHg)CarbonmonoxidebindsavidlytohaemoglobinandsoPaCOincreasesslowly,resultingindiffusionlimitation
RegionalVentilationandPerfusion:
2 2
2 22
2 2
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GraphofalveolarventilationandalveolarbloodflowversusribnumberintheerectpersonBasalalveolarhavegreaterperfusionandventilationthanapicalalveoliNotetheperfusiongradientissteeperthantheventilationgradientNotethattheV/Qratiois:
~1atthe3 rib~3.3attheapex~0.63atthebase
AirwayResistanceandAirwayGeneration:
GraphofairwayresistanceversusairwaygenerationAirwaygenerationsarefrom1to23,andsothisgraphshouldnotextendoutsidethesevaluesAirwayresistanceismaximalatthe5 generationThishasthelowesttotalcross-sectionalarea.Airwayresistanceisnegligibleintherespiratoryzone,whichexistsafterthe15 generation
AirwayResistanceandLungVolume:
Airwayresistancedecreasesaslungvolumeincreasesasradialtensiondistendsairways,increasingtheircross-sectionalareaandloweringairwayresistance
rd
th
th
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PulmonaryVascularResistanceandPulmonaryArteryPressure:
PulmonaryvascularresistancedecreasesaspulmonaryarterypressureincreasesArterialpressurehasagreatereffectonPVRthanvenouspressure
LungandChestWallVolumeandPressureRelationships:
GraphoflungvolumeversusrecoilpressureExpressinglungvolumeasapercentageoftotallungcapacitymaymakeiteasiertorememberthekeypointsonthisgraphNotethatrecoilpressureisthepressuregeneratedbetweenthelungandthechestwallwhentheyaredistended,itisnotintrapleuralpressure
ThisgraphiscomplexanditiseasytodrawincorrectlyThisisanapproachtomakeitaseasyaspossible:1. Drawasigmoidgraphforthepressure-volumerelationshipoftherespiratorysystemasawhole
Asrecoilpressureis0atFRCthiswillbethey-interceptThegraphwillasymptoteatresidualvolume,asvolume(bydefinition)cannotbecomelowerthanthisvolume
2. Drawasteeprun-awayexponentialforthepressure-volumerelationshipofthechestwallRecoilpressureshouldbe~-5cmH OatFRCRecoilpressureshouldbe0cmH Oat~75%ofTLCRecoilpressureshouldnotexceed~5cmH OatTLC
3. Drawasteepwash-inexponentialforthepressure-volumerelationshipofthelungRememberlungvolumecannotfallbelowresidualvolumeRecoilpressureshouldbe~5cmH OatFRCThisshouldbeequalandoppositetotherecoilpressureforthechestwall,asthesumofthesemustbe0atFRC.Notethatthiscurveshouldslightlyexceedthecurvefortherespiratorysystemasrecoilpressureincreases
WorkofBreathing:
22
2
2
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Graphoflungvolume(aboveFRC)versusintrapleuralpressureNotethatintrapleuralpressurebecomesmorenegativealongthex-axis.Theareaunderdifferentsectionsofthiscurvegivetheworkofbreathing
ElasticinspiratoryworkofbreathingisgiventhebluetriangleResistiveworkofexpirationisgivenbytheredareaNotethatasthisisentirelycontainedwithintheareaofelasticinspiratorywork,expirationispassiveanddoesnotrequireadditionalenergyexpenditure.Resistiveworkofinspirationisgivenbythegreenarea
WorkofBreathing-ActiveExpiration:
Whenresistiveexpiratoryworkexceedselasticinspiratorywork,activeexpirationmustoccurInthisgraph,activeexpirationisgivenbytheredareanotcontainedwiththebluetriangle
NeonatalFirstBreath:
Thisgraphdescribesthepressure-volumechangesoftheneonateasittakesitsfirstbreathsandestablishesFRCThisgraphiseasytodrawprovidedyourememberthat:
Priortothefirstbreath,lungvolumeis0Asthelunginitiallyhasverypoorcompliance,theintrapleuralpressuremustbecomeverynegativemorelungvolume
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increasessubstantiallyAttheendofeachbreath,intrathoracicpressureiscloseto0Witheachsubsequentbreath:
LungcomplianceimprovesThereforethemagnitudeofpressureswingsisreduced.FRCincreasesLungvolumeatend-inspirationisincreased.
Spirometry
ForcedVitalCapacity:
Graphofexpiredvolume(vitalcapacity)overtime~80%oftotalvolumeisexpiredwithinthefirstsecond(FEV )TotalFVCis4.5Linthe70kgGuytonManThegradientofinitialexpirationisthepeakexpiratoryflowrate
Spirometry:
GraphoflungvolumeovertimeIncludesanormaltidalbreathandavitalcapacitybreath
Flow-VolumeLoops
Normalloop:
1
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Peakexpiratoryflowis~8L.sPeakinspiratoryflowis~6L.sEffortindependentexpirationoccursduringexpiration
ObstructiveDisease:
ResidualvolumeandtotallungcapacityareincreasedduetogastrappingPeakexpiratoryflowisreducedThereisscallopingoftheeffort-independentportionofthecurveAlsoknownasaconcavecurve.
RestrictiveDisease:
TotallungcapacityisreducedResidualvolumeisnormalPeakexpiratoryflowmaybereduced(asseenhere)HowevertheFEV :FVCratiowillbenormalinpurelyrestrictivelungdisease.Effort-independentexpirationislinearandwilljoinwiththenormalcurve
FixedUpperAirwayObstruction:
-1-1
1
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ObstructionthatdoesnotchangecalibrethroughouttherespiratorycyclePeakexpiratoryandinspiratoryflowratesarelimited
ExtrathoracicObstruction
Obstructionworsensduringinspirationasitis'pulledin'bynegativeintrathoracicpressure
IntrathoracicObstruction
Obstructionworsensduringexpirationasitiscompressedbydynamicairwayscompression
AnaestheticAgents
F /F :A I
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GraphofthealveolaroverinspiredagentfractionversustimeforvariousvolatileagentsIndicatestherelativespeedofonsetofdifferentagentsUptakeofagentisproportionaltosolubilityinblood,andthereforeisinorderoftheirblood:gascoefficients
Theexceptionisnitrousoxide,whichhasafasterrateofrisethandesfluranedespiteitsgreaterblood:gascoefficientduetotheconcentrationeffect
F /F :
GraphofalveolaragentfractionversustimeforavolatileagentNotethelogarithmicscaleonthey-axisExponentialwashoutcurveFunctionoftwoseparatewashoutcurves
RapidwashoutwithremovalofagentfromcircuitandFRCSlowwashoutduetodiffusionofagentfromtissuesintoblood,andthenalveolus
Cardiovascular
LeftVentricularCoronaryBloodFlow:
GraphofbloodflowtotheleftventricleovertimeSystoleshouldbeclearlyidentified.LeftventricularflowoccurspredominantlyindiastolePeakflowis~115ml.min .Thereisabriefperiodofflowreversalduringisovolumetriccontraction
RightVentricularCoronaryBloodFlow:
A A0
-1
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GraphofbloodflowtotherightventricleovertimeRightventricularflowoccursthroughoutthecardiaccycleThisisbecauseaorticrootpressureexceedscavitypressurethroughoutthecardiaccycle.Peakflowis~15ml.min
BaroreceptorResponse:
GraphofheartrateversussystolicbloodpressureNotethattheRRintervalisinverselyproportionaltoheartrate.Heartrateresponsesasymptoteatextremesofbloodpressure
StarlingCurve:
Typicallydrawnasagraphofstrokevolume(orcardiacoutput,assumingaconstantheartrate)versuspreload(typicallyestimatedasend-diastolicvolume,butmayalsobeend-diastolicpressure)GraphdoesnotcrosstheoriginasEDVisnever0ml
StarlingCurve-Failing:
-1
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Myocardiumthathasbeenoverloadedbyhighend-diastolicvolumesmayleadtoadecreaseintensiongeneratedbythemyocardium
VenousReturn:
GraphofvenousreturnversusrightatrialpressureThex-interceptisthepointofnoflowwithinthecirculation(asVR=CO),andthereforeisthemeansystemicfillingpressureThecurveflattenswhenRAPbecomesnegative,asexternaltissuesactasaStarlingresistorandpreventfurtherincreasesinflow
VenousReturn-ComplianceandVolume:
Decreasingvenouscomplianceorincreasingcirculatingvolumeresultsinanincreaseinmeansystemicfillingpressure(asforanygivencompliance,pressuremustincreaseifvolumeincreases)andanincreaseinvenousreturnforanygivenrightatrialpressureTheoppositeoccurswithadecreaseincirculatingvolumeoranincreaseinvenouscompliance
VenousReturn-ResistancetoVenousReturn:
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Alteringresistancetovenousreturn(e.g.duringpregnancy,orlaparoscopicsurgery)willaltervenousreturnwithoutchangingmeansystemicfillingpressure
CirculatoryFunctionCurve:
PlottingthevenousreturncurveandtheStarlingcurveonthesameaxesgeneratesthisgraphThisisonlyvalidatsteadystate,i.e.whenCO=VR
Notethatassteady-stateexistswhenCO=VR,theinterceptofthesetwocurvesistheoperatingpointofthecirculation
WiggersDiagram:
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WiggersdiagramisagraphicalrepresentationoftheeventsduringeachphaseofthecardiaccycleKeypointstonote:
AorticdiastolicpressureoccursjustpriortoaorticvalveopeningAcommonmistakeistolabeldiastolicpressureatthedicroticnotch.VentricularpressureexceedsaorticpressureduringejectionAorticpressurewillslightlyexceedventricularpressureduringthelastpartofejectionThisisduetotheinertiaofejectedbloodcausingongoingforwardflowdespitethepressuregradient.ThedicroticnotchoccursontheaorticpressurecurveAcommonmistakeistodrawthisontheventricularcurve.CVPslightlyexceedsventricularpressureduringventricularfillingTheCwaveoccursduringisovolumetriccontractionTheVwavebeginspriortotheTwave,butpeaksaftertheTwavehasfinishedElectricaleventsslightlyproceedventricularmechanicalevents
ActionPotentials
PacemakerPotential:
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Thepacemakerpotentialhasonlythreephases,andnotablyno'restingphase'Thisisduetothefunnycurrent.Maximaldiastolicpotentialis-65mVPeakmembranepotentialis~20mV
PacemakerPotential-IonFlux:
DemonstratesthetimingofelectrolytepassageacrossthecellmembraneFunnycurrentoccursthroughoutphase4andtheearlypartofphase0T-typecalciumcurrentbeginsinlatephase4andterminatespriortotheonsetofphase0L-typecalciumcurrentoverlapswiththeT-typecurrentandcontinuesthroughoutphase3Outwardrectifyingpotassiumcurrentbeginsduringphase3andcontinuesduringphase4,restoringmembranepotential
PacemakerPotential-AutonomicTone:
Alterationtoautonomictonealterstheslopeofthefunny-current(Somesourcesalsonoteachangetomaximaldiastolicpotential,althoughthisisnotshownhere).
VentricularActionPotential:
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Theventricularactionpotentialconsistsof5phases0:Rapiddepolarisation1:PartialrepolarisationDuetoinitialeffluxofpotassiumwithoutproportionalcalciuminflux.2:PlateauOutwardpotassiumcurrentismatchedbyinwardcalciumcurrent.3:RepolarisationNotethattheabsoluterefractoryperiodendswhenrestingmembranepotentialfallsbelow-50mV,whichtypicallyoccursat~250ms.4:RestingmembranepotentialNotethat:
RestingMembranePotentialistypically~-85mVTherelativerefractoryperiodendswhenthemembranepotentialisatitsrestingstate
VentricularActionPotential-Hyperkalaemia:
Inhyperkalaemia:Theventricleismoreirritableasrestingmembranepotentialislessnegative,bringingitclosertothresholdpotentialThedurationoftheactionpotentialisshorter,increasingthechanceforare-entrantarrhythmia
BasicPressure-VolumeLoops
Pressure-volumeloopsarecoveredindetailunderpressure-volumerelationships.
LeftVentricularP-VLoop:
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LeftVentricularP-VLoop-IncreasedPreload:
LeftVentricularP-VLoop-IncreasedAfterload:
LeftVentricularP-VLoop-IncreasedContractility:
Advanced-PressureVolumeLoops
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Whendrawingchangestomoreleft-fieldpressure-volumeloopswhichyoumaynothaveseenbeforeapproachtheminthefollowingway:
Howispreloadchanged?Howisafterloadchanged?Howiscontractilitychanged?Howareisovolumetriccontractionandisovolumetricrelaxationchanged?
Advancedpressure-volumeloopsarecoveredindetailunderpressure-volumerelationships.
RightVentricularP-VLoop:
LeftVentricularP-VLoop-AorticStenosis:
LeftVentricularP-VLoop-AorticRegurgitation:
LeftVentricularP-VLoop-MitralStenosis:
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LeftVentricularP-VLoop-MitralRegurgitation:
Antiarrhythmics
VentricularActionPotential-ClassIa:
Prolongtherateofriseofphase0Lengthenthemyocardialactionpotential
VentricularActionPotential-ClassIb:
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Prolongtherateofriseofphase0Shortenthemyocardialactionpotential
VentricularActionPotential-ClassIc:
Prolongtherateofriseofphase0Donotalterthelengthofthemyocardialactionpotential
PacemakerPotential-ClassII(Beta-Blockade):
Sympatholyticeffectreducesthemagnitudeofthefunnycurrent
VentricularActionPotential-ClassIII:
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Prolongdurationofphase3ofthemyocardialactionpotentialThisprolongstherefractoryperiodandreducesthechanceofare-entrycircuitoccurring,andthereforereducestachyarrhythmiasbutmayincreasetheriskoftorsadedepointesduetoanincreasedriskofafterdepolarisations.
PacemakerPotential-ClassIV(CalciumChannelBlockade):
Inthepacemakercell,reducethemagnitudeofT-typeandL-typecalciumcurrents,reducingtherateofriseofphase0ofthepacemakeractionpotential
CNSMonroe-KellieDoctrine:
Graphstheintracranialpressureversusthevolumeofacomponent(blood,brain,orCSF)inthecranialvaultNotethatoverallvolumeisnotcorrect,asthisisunchanged-ifoverallvolumeincreasedthepressurewouldreduce(e.g.suchasadecompressivecraniectomy).Notetheinitialperiodofcompensation,whichoccursduetodisplacementofCSFtothespinalsubarachnoid,decreasedcerebralbloodvolume,andadecreaseinCSFvolume.OncecompensatoryresponsesareexhaustedICPwillincreaserapidlyduetothepoorelastanceofthecranialvault
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FocalischaemiaoccurswhenICPexceeds20mmHgGlobalcerebralischaemiaoccurswhenICPexceeds50mmhg
CerebralBloodFlowandCerebralPerfusionPressure:
CerebralbloodflowisautoregulatedforaCPPof50-150mmHg(Notethatthisclassicrelationshipisprobablyincorrect,andthatCBFisprobablyonlyautoregulatedacrossanarrowrangeofbloodpressures).
CerebralBloodFlowandPaCO :
CBFincreasesby~3%forevery1mmHgincreaseinCOBelowaPaCO of20mmHg,CBFcannotdecreasefurtherasthereducedflowresultsintissuehypoxia,andmetabolicautoregulatoryresponsesAboveaPaCO of80mmHg,CBFcannotincreasefurtherasvesselsaremaximallydilated
CerebralBloodFlowandPaO :
AboveaPaO of60mmHg,CBFisessentiallyindependentofPaOBelowaPaO of60mmHg,CBFincreasesrapidly
CerebralBloodFlowandTemperature:
2
22
2
2
2 22
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Cerebralmetabolicratefallsby~6%per°CdecreaseintemperatureThisresultsinaconcomitantreductioninCBFThisisanalmostlinearresponse.
Renal&Acid-Base
IonisedpotentialvspH-Acids:
AcidsareionisedabovetheirpKa
IonisedpotentialvspH-Bases:
BasesareionisedbelowtheirpKa
GlomerularFiltrationandMeanArterialPressure:
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GFRisautoregulatedforaMAPbetween60and160mmHg
GlomerularFiltrationRateandSerumCreatinine:
Atsteady-state,GFRandserumcreatinineareinverselyproportionalFollowingastep-changeinGFR,itwilltake~48hoursbeforesteady-stateisachievedagainDuringthisperiod,estimatesofGFRusingserumcreatininewillbelessaccurate.
GlucoseFlux:
Asglucoseisfreelyfilteredattheglomerulus,filteredplasmaglucosewillbedirectlyproportionaltoserumglucoseThisrelationshipisgivenbythedottedblackline.Undernormalcircumstances,allfilteredglucosewillbereabsorbedThisrelationshipisgivenbytheoverlapoftheredanddottedblacklines.Whenglucosefiltrationexceedsglucosereabsorption,glucosewillbegintobeexcretedinurine.Thisisgivenbythedottedblueline.
Theserumconcentrationofasubstanceatwhichthisoccursisknownasthetransportmaximum,orTInreality,someglucosewillbefilteredbeforeT isreached.ThisisduetothedifferentaffinityofS-GLUTchannels,andisthecauseofthegentlecurvesseenontheplotsofreabsorptionandexcretion.
Theserumconcentrationatwhichglucosestartstoappearinurineisknownasthethresholdconcentration
maxmax
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ThedifferencebetweenthresholdconcentrationandT isknownassplay
Haematology
CoagulationCascade:
Thecoagulationcascadeiscoveredindetailunderclotting
Thromboelastography:
TEG/ROTEMcanbeusedtoguidecoagulopathytreatmentas:ProlongedRtimeIndicatesdecreasedclottingfactorconcentration;giveFFP.
max
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Decreasedα-angle/prolongedKtimeDecreasedrapidityoffibrinogencross-linking;givefibrinogen.DecreasedMA(maybeassociatedwithprolongedKtime)Decreasedmaximalclotstrength;giveplateletsorDDAVP.DecreasedCL30/CL60Fibrinolysis;giveantifibrinolytic.
Other
HeatLossUnderAnaesthesia:
Heatlossunderanaesthesiaoccursinthreephases:1. Rapidreduction:1-1.5°Cin30minutes2. Gradualreduction:1°Cover2-3hours3. Plateau:Furtherheatlossattenuatedbymetabolicheatreduction
Doesnotoccurinneuraxialanaesthesiaasvasoconstrictiveresponsesarepreventedbysympathectomy
Equipment&MeasurementEinthoven'sTriangle:
Einthoven'striangledemonstratestherelationshipbetweendifferentlimbleadsandaugmentedleadsontheECGUnderstandingthetrianglemeansonecanidentifymisplacedECGelectrodesbythechangesinECGmorphology
e.g.iftheRAandLAelectrodesareswitched:LeadIwillinvertitspolarity
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LeadIIandIIIwillbeswitchedLeadsaVLandaVRwillbeswitchedLeadaVFwillbeunchanged
DampingCoefficients:
Followingastep-change:Anoptimally-dampedwaveformwillreturntobaselinewithoneovershootandoneundershootAnunder-dampedwaveformreturnstobaselinerapidlybutovershootsandundershootsseveraltimesAcriticallydampedwaveformreturnstobaselineasfastaspossiblewithoutovershootingAnover-dampedwaveformreturnstobaselineslowerthanacriticallydampedwaveform,anddoesnotovershoot
WheatstoneBridge:
CoveredindetailunderWheatstonebridge
GasAnalysis
ClarkElectrode:
CoveredindetailunderOxygenTension
pHElectrode:
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CoveredindetailunderpHMeasurement
SeveringhausElectrode:
CoveredindetailunderCarbonDioxideTension
Capnography
Capnograph:
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Thecapnographwaveformconsistsoffourcomponents:1. Baseline
Inspirationandearlydead-spaceexpiration(containingnoCO ).2. Alveolarexhalation3. Alveolarplateau
HighestpointisdefinedasE CO .4. Inspiration
VariationsonthewaveformarecoveredunderE CO WaveformVariations
References
1. Wigger'sDiagram(withsomemodifications)fromWigger'sDiagram.21/3/2012.(Image).ByDanielChangMD(revisedoriginalworkofDestinyQx);RedrawnasSVGbyxavax.CCBY3.0,viaWikimediaCommons.
2. ClottingCascade22/4/2007.(Image).ByJoeD(Ownwork).CCBY3.0,viaWikimediaCommons.
Lastupdated2019-07-18
2
T 2
T 2
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LawsandEquationsThisappendixisalistofthekeylawsandequationscommontomanytopics:
GeneralLaws
Fick'sLawofDiffusionDiffusionofasubstanceacrossamembraneisgivenby:
,where:
=Areaofthesheet
=Diffusionconstant,whichisproportionaltothesolubilityofthegasandinverselyproportionaltothesquareroot
ofthemolecularweight,i.e.
=Thicknessofthesheet
Hagan-PoiseuilleEquationCalculatestheflowforagivenpressuredifferentofaparticularfluid.Mayalsoberearrangedtocalculatepressureorresistance.
Givenbytheequation:
,where:QistheflowPisthedrivingpressureηisthedynamicviscosityListhelengthoftubingristheradius
Hasseverallimitations:OnlymodelslaminarflowFluidmustbeincompressibleNottechnicallyvalidforair,butprovidesagoodapproximationwhenusedclinically.FluidmustbeNewtonianFluidmustbeinacylindricalpipeofuniformcross-section
ReynoldsNumberReynoldsNumberisadimensionlessindexusedtopredictthelikelihoodofturbulentflow.R<2000islikelytobelaminar,R>2000islikelytobeturbulent.Givenbytheequation:
,where:
visthelinearvelocityoffluidin
disthefluiddensityinristheradiusin
nistheviscosityin
CellPhysiology
LawsandEquations
744
NernstEquationCalculatestheelectrochemicalequilibriumforagivenion:
,where:
istheequilibriumpotentialfortheion
isthegasconstant(8.314J.deg .mol )
isthetemperatureinKelvin
isFaraday'sConstantistheionicvalency(e.g.+2forMg ,-1forCl )
Goldman-Hodgkin-KatzEquationCalculatesthemembranepotentialforgivenvaluesofintracellularandextracellularionicconcentrations:
,where:
isthepermeabilityconstantfortheion,
Ifthemembraneisimpermeableto ,then .
Henderson-HasselbalchCalculatesthepHofabuffersolution:
,where:
isthepHofthesolution
isthepKaofthebuffer
istheconcentrationofbase
istheconcentrationofacid
RespiratoryLawsModifiedBohrEquationTheratioofdeadspacetotidalvolumeventilationequationsthearterial-mixed-expiredCO2difference,overthearterial
CO2.
LaPlace'sLawThelargerthevesselradius,thelargerthewalltensionrequiredtowithstandagiveninternalfluidpressure.Forathin-walled
sphere,WallTension(T)ishalftheproductofpressureandradius,i.e.
AlveolarGasEquationThealveolarPO2isequaltothePiO2minusthealveolarCO2/therespiratoryquotient,i.e.:
GasLawsBoyle'sLaw
,i.e.pressureandvolumeareinverselyrelatedatconstanttemperatureandpressure.
-1 -1
+2 -
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BoylesLawcanbeusedtoworkouthowmanylitresofgasareremainingingascylinder,e.g.:AstandardCcylinderis1.2LinsizeNormalcylinderpressureis~137bar,andatmosphericpressureis~1bar
Therefore,thecylindercontains~164LofoxygenThiscanbeusedtocalculatethevolumeofgasremaininginthecylinderduringuse,usingthevolumeofthecylinder(fixed)andthecurrentpressureasmeasuredattheregulator
Charle'sLaw
,i.e.volumeandtemperaturearelinearlyrelatedwhenpressureisconstant.
Gay-Lussac'sLaw/TheThirdGasLaw ,i.e.pressureandtemperaturearelinearlyrelatedwhenvolumeisconstant.
TheUniversalGasEquation
,i.e.combinationofBoyle's,Charle'slawcombiningeachvariableandtheuniversalgasconstant,R(8.13).
Henry'sLawThenumberofmoleculesofdissolvedgasisproportionaltothepartialpressureofthegasatthesurfaceoftheliquid
Graham'sLawofDiffusionDiffusionratesthroughorificesareinverselyproportionaltothesquarerootofthemolecularweight
Dalton'sLawofPartialPressuresInamixtureofgases,eachgasexertsthepressurethatitwouldexertifitoccupiedthevolumealone.
CardiovascularEquations
Fick'sPrincipleFlowofbloodthroughanorganequalstheuptakeofatracersubstancebytheorgandividedbytheconcentrationdifferenceofthesubstanceacrossit,i.e.:
Starling'sLawofFluidExchangeFlowoffluidacrossthecapillariesisproportionaltothehydrostaticpressuredifferenceandtheoncoticpressuredifference(timesthereflectioncoefficient),alltimesbythefiltraitoncoefficient,i.e.:
VenousAdmixtureCalculatestheshuntfractionbyidentifyinghowmuchmixedvenousbloodmustbeaddedtoidealpulmonarycapillaryblood
toproducetheidentifiedarterialoxygencontent.
Equipment
DopplerequationCalculatesthevelocityofanobjectbasedonthechangeinobservedfrequencywhenawaveisreflectedoff(oremittedfrom)
LawsandEquations
746
theobject:
where:
=Velocityofobject
=Frequencyshift=Speedofsound(inblood)
=Frequencyoftheemittedsound
=Anglebetweenthesoundwaveandtheobject
References1. Davis&Kenny.BasicPhysicsandMeasurementinAnaesthesia,5thEdition.2. Gorman.RAHDivingandHyperbaricMedicine.Chapter3:Thephysicsofdiving.
Lastupdated2019-07-18
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StructuresforSAQsStructuredanswersarevital:
StructureaidsbothlearningandrecallofinformationAstructuredformatiseasytofollowlesslikelytoirritatethedrunk/tired/hungovermindoftheexaminerYoumaygetmarksforincompleteanswersifyourstructuredemonstratesyouhaveanunderstandingofthetopic,evenifthedetailsarenotfilledin
Somequestionslendthemselvesmoreeasilytoaparticularstructurethanothers,butallquestionscanbemadetofitevenabasicstructure.
RegulationofPhysiologicalResponsesSensorIntegrationEffector
ChangeinLevelofaSubstanceIntakeDistributionElimination
CompareandContrast(Drugs)ClassPharmaceutics
UsesChemicalPresentationHeat/lightstabilityRoutesofadministrationDoses
PharmacokineticsAbsorptionDistributionMetabolismElimination
PharmacodynamicsMainActionModeofActionEffects(Seethephysiologicalapproach)SideEffectsToxiceffects
AllergicDose-dependentIdiopathic
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Druginteractions
DescribeWhyTwoDrugsareUsedinCombination
DefinitionBrief,ofeachdrug.
ConsiderthecomponentsofanaesthesiathateachprovidesPharmacokinetics
InteractionsRelativeonsetMetabolism
Noeffect/Induces/InhibitsElimination
PharmacodynamicsIsobologramSynergistic/additive/antagonistic.Thenlisttheeffectsofeachdrug,andhowtheyaremodifiedbytheother
e.g.ifdrugsaresynergistic,thendecreaseddoseswillberequiredIncreasesbeneficialeffectsDecreasesadverseeffects
DescribethePhysiologyof...
RespiratoryBronchodilation/constrictionVasodilation/constrictionVRRSecretionLaryngealreflexes
CVSPreloadContractility/Pumpeffects
InotropyChronotropy/rhythmDromotropyLusitropyBathmotropyNodaleffectsCoronaryBloodFlow
Afterload/PipeeffectsSBPDBPMAPSVRPVR
IntraarterialinjectionCNS
Sedation
T
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AnalgesiaPro/anticonvulsantAmnesticCerebralMetabolicRateCerebralBloodFlowICPIOP
MusculocutaneousBloodFlowNMJ
EndocrineGynaecomastiaHairBone
RenalandGURenalBloodFlowNephrotoxicityBladdertoneUterinetone
GITandHepaticHepatotoxicity/LFTsSecretionsGastricemptyingN/V/D/C
HaematologicalG6PDPorphyriasBonemarroweffects
ImmunologicalAnaphylaxisHistaminergicNeutrophilfunction
Metabolic
AnatomicalStructure
AnatomyofthestructureRelationshipsRelevantsurfaceanatomyLayersofdissection
PhysicsandMeasurement
DefinitionUsesPhysicalprinciplesComponentsCalibrationAdvantages/Disadvantages
StructuresforSAQs
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References
Dr.PodcastWisdomfromdrunk,tired,and/orhungoverexaminers.
Lastupdated2019-07-18
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