OxygenationOxygenation

of the of the NeonateNeonate

AbbreviationsAbbreviations

OO22- oxygen- oxygen

FiOFiO22- inspired O- inspired O22 concentration concentration

POPO22- partial pressure of O- partial pressure of O22

PaOPaO22- arterial O- arterial O2 2 tension tension

SaOSaO22- arterial oxygen saturation - arterial oxygen saturation

What is oxygen?What is oxygen?

Most widely occurring element on EarthMost widely occurring element on Earth Considered by some to be a air pollutant Considered by some to be a air pollutant Catalyst for free radical formationCatalyst for free radical formation

– contains one or more unpaired electronscontains one or more unpaired electrons– superoxide theory of oxygen toxicitysuperoxide theory of oxygen toxicity

toxicity (oxidative stress) is due to excess toxicity (oxidative stress) is due to excess formation of superoxide radical (reduction formation of superoxide radical (reduction product of Oproduct of O22))

effects are countered by superoxide dismutase effects are countered by superoxide dismutase (antioxidant enzymes)(antioxidant enzymes)

Oxidative StressOxidative Stress– occurs when generation of reactive occurs when generation of reactive

oxygen species exceed the ability of oxygen species exceed the ability of the cell to remove themthe cell to remove them

produces physiologic, inflammatory and produces physiologic, inflammatory and histologic changeshistologic changes

produces injury in proteins (amino acids, produces injury in proteins (amino acids, DNA), membrane lipids, carbohydrates DNA), membrane lipids, carbohydrates

Protective ForcesProtective Forces– Compartmentalize processes which Compartmentalize processes which

create free radicalscreate free radicals– Superoxide dismutase and other Superoxide dismutase and other

enzymesenzymes– Vitamin E- most abundant antioxidantVitamin E- most abundant antioxidant– Vitamin CVitamin C– Bilirubin and other antioxidantsBilirubin and other antioxidants

Why is oxygen important?Why is oxygen important?

Mitochondria (power house of the Mitochondria (power house of the cell) is oxygen dependentcell) is oxygen dependent

Oxygen is necessary for aerobic Oxygen is necessary for aerobic metabolism (breakdown of metabolism (breakdown of glucose) glucose) – ATPATP– limited storage capacitylimited storage capacity

Fetal OxygenationFetal Oxygenation

Umbilical venous blood from Umbilical venous blood from placenta to fetus has a PaOplacenta to fetus has a PaO22 20-30 20-30 mm Hg.mm Hg.

Fetus able to survive secondary to Fetus able to survive secondary to low metabolic demands low metabolic demands (placenta/mother provide support)(placenta/mother provide support)

In fetus low PaOIn fetus low PaO22 causes pulmonary causes pulmonary vasoconstriction and ductus vasoconstriction and ductus arteriosus vasodilation arteriosus vasodilation

Introduction of oxygen Introduction of oxygen to bodyto body

Regulated by the oxygen pressure Regulated by the oxygen pressure gradientgradient

Convection of air into the lungs Convection of air into the lungs Diffusion of oxygen into the bloodDiffusion of oxygen into the blood Convection flow of blood to the tissueConvection flow of blood to the tissue Diffusion of oxygen into the cellsDiffusion of oxygen into the cells Diffusion of oxygen into the Diffusion of oxygen into the

mitochondriamitochondria

Oxygen transport is dependent onOxygen transport is dependent on– availability of oxygenavailability of oxygen– oxygen carrying capacity of bloodoxygen carrying capacity of blood– rate of blood flowrate of blood flow

Factors affecting oxygen carrying Factors affecting oxygen carrying capacity and delivery to tissuecapacity and delivery to tissue– respiratory status respiratory status – hemoglobin level and configurationhemoglobin level and configuration– cardiac outputcardiac output

blood pressureblood pressure heart rateheart rate

– tissue ischemia/edematissue ischemia/edema– disease statedisease state

Oxygen in the blood is foundOxygen in the blood is found– dissolved in plasmadissolved in plasma

small quantitysmall quantity linear relationship to POlinear relationship to PO22

~ 10% FiO~ 10% FiO22 equals 1% of blood’s O equals 1% of blood’s O22 content content

– bound to hemoglobinbound to hemoglobin larger quantitylarger quantity fully saturated- one gram hemoglobin will bind fully saturated- one gram hemoglobin will bind

1.34ml of oxygen1.34ml of oxygen nonlinear relationship to POnonlinear relationship to PO22

– oxygen dissociation curveoxygen dissociation curve

Oxygen Dissociation CurveOxygen Dissociation Curve

At low POAt low PO22 levels, O levels, O22 binds quickly to binds quickly to hemoglobin hemoglobin

Between 40-80mm Hg, binding slowsBetween 40-80mm Hg, binding slows Above 100mm Hg, binding is Above 100mm Hg, binding is

relatively static (hemoglobin is relatively static (hemoglobin is saturated)saturated)

Levels above 50-80mm Hg have the Levels above 50-80mm Hg have the potential to cause harmpotential to cause harm

Shifting of CurveShifting of Curve

To the left (increased affinity of To the left (increased affinity of hemoglobin to Ohemoglobin to O22))– hemoglobin saturation can be achieved at hemoglobin saturation can be achieved at

lower POlower PO2 2 levels levels greater percentage of fetal hemoglobingreater percentage of fetal hemoglobin decrease in 2,3-diphosphoglycerate contentdecrease in 2,3-diphosphoglycerate content

– occurs in premature infants with RDSoccurs in premature infants with RDS alkalemiaalkalemia hypocapniahypocapnia hypothermiahypothermia

To the right (decreased affinity of To the right (decreased affinity of hemoglobin to Ohemoglobin to O22))– hemoglobin saturation is achieved at hemoglobin saturation is achieved at

higher POhigher PO22 levels levels reduction in fetal hemoglobinreduction in fetal hemoglobin increased 2,3-DPGincreased 2,3-DPG acidemiaacidemia hypercapniahypercapnia hyperthermiahyperthermia

Hemoglobin is ~ 1/3 of hematocritHemoglobin is ~ 1/3 of hematocrit Hemoglobin levels are importantHemoglobin levels are important

– Hgb 15 X 1.34 ml = 20.1 ml OHgb 15 X 1.34 ml = 20.1 ml O22 (if (if 100% saturated)100% saturated)

– Hgb 10 x 1.34 ml = 13.4 ml OHgb 10 x 1.34 ml = 13.4 ml O22 (if (if 100% saturated)100% saturated)

– Hgb 7 x 1.34 ml = 9.38 ml OHgb 7 x 1.34 ml = 9.38 ml O22 (if 100% (if 100% saturated)saturated)

Adequate OxygenationAdequate Oxygenation

POPO22 necessary to deliver an necessary to deliver an amount of oxygen to the tissues amount of oxygen to the tissues for effective metabolism without for effective metabolism without creating a toxic effectcreating a toxic effect– Variable among individualsVariable among individuals– Continuous fluctuationsContinuous fluctuations

What is 21% FiOWhat is 21% FiO22??

Total pressure in the atmosphere at seaTotal pressure in the atmosphere at sealevel is 760mm Hg level is 760mm Hg Water vapor 47mm HgWater vapor 47mm Hg 21% of remaining pressure (760- 47) is 21% of remaining pressure (760- 47) is

exerted by oxygen- 150mm Hg (which exerted by oxygen- 150mm Hg (which means PaOmeans PaO22 of room air is 150mm Hg) of room air is 150mm Hg)

Nitrogen makes up the majority of the Nitrogen makes up the majority of the remaining air remaining air

Carbon dioxide is miniscule (0.001 %)Carbon dioxide is miniscule (0.001 %)

First breathsFirst breaths

Arterial-alveolar oxygen tension ratioArterial-alveolar oxygen tension ratio Normal term infantNormal term infant

– Initial PCOInitial PCO22 60-80mm Hg 60-80mm Hg

– Inhales room air (150mm Hg)Inhales room air (150mm Hg)– Mixing causes dilution of oxygen diffusing Mixing causes dilution of oxygen diffusing

into blood into blood

– At ~ 20 minutes of age PCOAt ~ 20 minutes of age PCO22 30-40mm Hg 30-40mm Hg

– Ultimately POUltimately PO22 diffusing into blood is ~80- diffusing into blood is ~80-100mm Hg100mm Hg

Lung DevelopmentLung Development

Individual variationsIndividual variations Stages overlapStages overlap

*Pictures are artistic renditions of lung development and are designed to emphasize terminal acinus development & not the entire conducting airway system

Behrman: Nelson Textbook of Pediatrics, 16th ed., 2000. Langston C, et al. Am Rev Respir Dis. 1984;129:607-13

Pseudoglandular Period

(7 to 16 weeks GA)

Canalicular Period

(16 to 26 weeks GA)

Saccular Period

(26 to 36 weeks GA)

Alveolar Period

(36 to 41 weeks GA)

Premature Term

• The lungs of premature infants are underdeveloped at birth

• Although alveoli are present in some infants as early as 32 weeks GA, they are not uniformly present until 36 weeks GA

Prematurity: Interrupts Lung Prematurity: Interrupts Lung DevelopmentDevelopment

Normal Lung Development

Canalicular Period16 to 26 weeks

Saccular Period26 to 36 weeks

Alveolar Period36 to 41 weeks

Presented by K Stenmark, MD: ICRV, 2003

( Non-human primate lung sections)

Embryonic (0-7 weeks)Embryonic (0-7 weeks)– lung buds form, blood vessels connect lung buds form, blood vessels connect

to heartto heart Pseudoglandular (6-17 weeks)Pseudoglandular (6-17 weeks)

– pre-acinar airways and blood vessels pre-acinar airways and blood vessels developdevelop

Canalicular (16-27 weeks)Canalicular (16-27 weeks)– respiratory regions developrespiratory regions develop– peripheral epithelium and peripheral epithelium and

mesenchyme thinmesenchyme thin– type I and II pneumonocytes developtype I and II pneumonocytes develop

Alveolar (27 weeks to term)Alveolar (27 weeks to term)– saccules develop and produce alveolisaccules develop and produce alveoli

Post natal Post natal – alveoli and small blood vessels alveoli and small blood vessels

multiplemultiple

Complications of Complications of hyperoxiahyperoxia

Individual variations Individual variations Must keep in mind that all disease Must keep in mind that all disease

states are multifactorialstates are multifactorial Controlling oxygen exposure is Controlling oxygen exposure is

critical but other complicating critical but other complicating factors must also be addressedfactors must also be addressed

Retinopathy of PrematurityRetinopathy of Prematurity

Proliferative vascular diseaseProliferative vascular disease

Vitreous gelVitreous gel– clear gel that fills the inside of the eyeclear gel that fills the inside of the eye

Optic nerveOptic nerve– bundle of more than 1,000,000 nerve fibers that bundle of more than 1,000,000 nerve fibers that

carry visual messages from the retina to the carry visual messages from the retina to the brainbrain

MaculaMacula– small sensitive area of the retina that gives small sensitive area of the retina that gives

central vision central vision FoveaFovea

– center of macula, gives sharpest visioncenter of macula, gives sharpest vision

RetinaRetina– light sensitive tissue lining the back of the light sensitive tissue lining the back of the

eye, converts light into electrical impulses eye, converts light into electrical impulses that are sent to the brain via the optic nervethat are sent to the brain via the optic nerve

Iris Iris – colored part of eye, regulates amount of colored part of eye, regulates amount of

light entering the eye light entering the eye CorneaCornea

– clear outer part of eye’s focusing systemclear outer part of eye’s focusing system

PupilPupil– opening at center of the iris, adjusts the size opening at center of the iris, adjusts the size

of the pupil to control amount of light of the pupil to control amount of light entering the eyeentering the eye

LensLens– clear part of eye behind iris that helps focus clear part of eye behind iris that helps focus

light on retinalight on retina IrisIris

– colored part of eye, regulates the amount of colored part of eye, regulates the amount of light entering the eyelight entering the eye

Normal Eye DevelopmentNormal Eye Development

Eye starts development at ~ 16 weeksEye starts development at ~ 16 weeks– blood vessels of retina begin to form at the blood vessels of retina begin to form at the

optic nerveoptic nerve– grow towards the edge of the retina, grow towards the edge of the retina,

supplying oxygen and nutrientssupplying oxygen and nutrients Last trimesterLast trimester

– eye develops rapidlyeye develops rapidly Term Term

– eye growth is almost complete (vessels eye growth is almost complete (vessels have reached the edge of the retina)have reached the edge of the retina)

Risk factors for ROPRisk factors for ROP

PrematurityPrematurity Low birth weightLow birth weight Complicated hospital courseComplicated hospital course Co-morbiditiesCo-morbidities Oxygen exposure (toxicity)Oxygen exposure (toxicity)

Preterm Eye DevelopmentPreterm Eye Development Preterm eyePreterm eye

– blood vessels have not reached edges of the blood vessels have not reached edges of the retinaretina

– vessel growth may be arrestedvessel growth may be arrested– vessel growth is resumed and continues to vessel growth is resumed and continues to

periphery unless abnormalities occurperiphery unless abnormalities occur

ROPROP

PathogenesisPathogenesis– any factor causing vasoconstriction of any factor causing vasoconstriction of

immature retinal vesselsimmature retinal vessels– interruption of migration of blood vessels interruption of migration of blood vessels

from the optic nerve to the ora serratafrom the optic nerve to the ora serrata retina sends out signals to induce renewal of retina sends out signals to induce renewal of

growthgrowth abnormal vessels may develop (fragile, weak)abnormal vessels may develop (fragile, weak) leads to scarring which can lead to pulling on leads to scarring which can lead to pulling on

retinaretina

Stage IStage I– mild abnormal blood vessel growth mild abnormal blood vessel growth

(demarcation line)(demarcation line) Stage IIStage II

– moderately abnormal blood vessels moderately abnormal blood vessels growth (ridge)growth (ridge)

Stage IIIStage III– severely abnormal blood vessel growth severely abnormal blood vessel growth

(extraretinal fibrovascular proliferation)(extraretinal fibrovascular proliferation)– blood vessel growth is towards the blood vessel growth is towards the

center of the eye instead of along center of the eye instead of along surface of retinasurface of retina

Plus DiseasePlus Disease– blood vessels of the retina are enlarging blood vessels of the retina are enlarging

and twisting “tortuosity”and twisting “tortuosity”

Stage IVStage IV– partially detached retinapartially detached retina– caused by traction from scarring and caused by traction from scarring and

abnormal vessel growthabnormal vessel growth Stage VStage V

– complete retina detachmentcomplete retina detachment– end stage of diseaseend stage of disease

Zone IZone I– most posterior, near optic nervemost posterior, near optic nerve

Zone IIZone II– extends to ora serrataextends to ora serrata

Zone IIIZone III– extends to peripheryextends to periphery

Oxygen’s implicationOxygen’s implication– retinal vessels form in an environment of low retinal vessels form in an environment of low

PaOPaO22 (20-30mm Hg) (20-30mm Hg)

– at birth, dramatic increase in PaOat birth, dramatic increase in PaO22 (even RA (even RA creates significant increase)creates significant increase)

– retinal vessels constrict in response to retinal vessels constrict in response to increased PaOincreased PaO22, diminishing flow and , diminishing flow and nutrientsnutrients

– down regulation of vascular endothelial down regulation of vascular endothelial growth factor (secondary to hyperoxia)growth factor (secondary to hyperoxia)

– as metabolic demands of growing eye as metabolic demands of growing eye increase, nonvascularized areas of increase, nonvascularized areas of the eye become hypoxicthe eye become hypoxic

– eye sends signals for helpeye sends signals for help– neovascularization and increased neovascularization and increased

levels of VEGF occurslevels of VEGF occurs– cycles of hyperoxia and hypoxiacycles of hyperoxia and hypoxia

TreatmentTreatment– preventionprevention– surgical interventionsurgical intervention

laser or cryotherapy- burns away periphery of laser or cryotherapy- burns away periphery of retina where abnormal vessels abound (loss retina where abnormal vessels abound (loss peripheral vision) (stage III with plus dz)peripheral vision) (stage III with plus dz)

scleral buckle- banding the eye to prevent scleral buckle- banding the eye to prevent vitreous gel from pulling on scar tissue, releases vitreous gel from pulling on scar tissue, releases pressure from retina (stage IV, V)pressure from retina (stage IV, V)

vitrectomy- replacing vitreous gel with saline in vitrectomy- replacing vitreous gel with saline in order to remove scar tissue (stage V)order to remove scar tissue (stage V)

Oxygen toxicity in the Oxygen toxicity in the LungLung

Incomplete development and Incomplete development and inadequate responsiveness of inadequate responsiveness of pulmonary antioxidant enzyme pulmonary antioxidant enzyme systemsystem

Cessation of transplacental substratesCessation of transplacental substrates Lungs are susceptible due to large Lungs are susceptible due to large

surface area of type I and II cells surface area of type I and II cells coming into direct contact with FiOcoming into direct contact with FiO22

Increased production of cytotoxic Increased production of cytotoxic oxygen free radicals oxygen free radicals

Overwhelms the antioxidant Overwhelms the antioxidant defenses in the capillary defenses in the capillary endothelial and alveolar cellsendothelial and alveolar cells

Radicals react with intracellular Radicals react with intracellular constituents producing chain constituents producing chain reactionreaction

Pulmonary ChangesPulmonary Changes

AtelectasisAtelectasis EdemaEdema Alveolar hemorrhageAlveolar hemorrhage InflammationInflammation Fibrin depositionFibrin deposition Thickening and hyalinization of Thickening and hyalinization of

alveolar membranesalveolar membranes

Plasma leakage through endotheliumPlasma leakage through endothelium Inactivation of surfactantInactivation of surfactant Damage to mucocilary functionDamage to mucocilary function Lung growth arrest and decreased Lung growth arrest and decreased

branching morphogenesisbranching morphogenesis

AKA- Bronchopulmonary DysplasiaAKA- Bronchopulmonary Dysplasia

Hypoxic effectHypoxic effect

Inadequate oxygenation forces a Inadequate oxygenation forces a change from aerobic to anaerobic change from aerobic to anaerobic metabolismmetabolism– decreases cellular energydecreases cellular energy

aerobic metabolism- net production of 36 ATPaerobic metabolism- net production of 36 ATP anaerobic metabolism- net production of 2 anaerobic metabolism- net production of 2

ATPATP

– toxic by-products (lactic acid)toxic by-products (lactic acid)– leading to cellular damage and deathleading to cellular damage and death

Middle GroundMiddle Ground

GoalsGoals

Minimize hypoxic/hyperoxic swingsMinimize hypoxic/hyperoxic swings Reduce titration of FiOReduce titration of FiO22

Avoid high saturationsAvoid high saturations

Obtaining Blood GasesObtaining Blood Gases

May alter results by aspirating room May alter results by aspirating room air into blood gas syringe/tubeair into blood gas syringe/tube– Remember room air PORemember room air PO22 is ~ 150 mm is ~ 150 mm

Hg, PCOHg, PCO2 2 is <2 mm Hgis <2 mm Hg

– If aspirated into sample may give false If aspirated into sample may give false valuesvalues

increase the PaOincrease the PaO22 reading reading decrease the PaCOdecrease the PaCO22 reading reading

Pulse OximetryPulse Oximetry

Pulse oximetry- determines the amount Pulse oximetry- determines the amount of saturated hemoglobin by the of saturated hemoglobin by the absorption of light absorption of light – setting the limitssetting the limits– interferenceinterference

movement, poor perfusion, loose probemovement, poor perfusion, loose probe

Pulse ox becomes unreliable predictor Pulse ox becomes unreliable predictor of PaOof PaO22 as Hgb becomes > 90% as Hgb becomes > 90% saturatedsaturated

Oxygen ManagementOxygen Management Know your target audienceKnow your target audience

– older infants have different biological older infants have different biological needsneeds

– some disease states require increased some disease states require increased PaOPaO22 for appropriate management for appropriate management

Don’t start at 100%Don’t start at 100%– select situations may call for select situations may call for

increasing to 100%increasing to 100%– don’t use 100% Odon’t use 100% O22 breaths breaths

Watchful waitingWatchful waiting– especially if normal heart rateespecially if normal heart rate

Don’t increase FiODon’t increase FiO22 by more than 5% at by more than 5% at a timea time

Wean FiOWean FiO22 as soon as recovery process as soon as recovery process stabilized (don’t wait for high stabilized (don’t wait for high saturations)saturations)

Keep ambu bag FiOKeep ambu bag FiO22 at appropriate level at appropriate level

MonitoringMonitoring Attend to cause of desaturationsAttend to cause of desaturations

– Is it real?Is it real?– know where the ETT is (especially on x-ray)know where the ETT is (especially on x-ray)– bronchospasmbronchospasm– activityactivity– gastroesphogeal refluxgastroesphogeal reflux– hypotensionhypotension– apneaapnea– blocked airwayblocked airway– vagal stimulationvagal stimulation

Take responsibility for the role we Take responsibility for the role we play in the long term outcome of play in the long term outcome of these infantsthese infants

ReferencesReferences

Chow, L., Wright, K., & Sola, A. (2003) Can Chow, L., Wright, K., & Sola, A. (2003) Can Changes in Clinical Practice Decrease the Changes in Clinical Practice Decrease the Incidence of Severe Retinopathy of Incidence of Severe Retinopathy of Prematurity in Very Low Birth Weight Prematurity in Very Low Birth Weight Infants? Infants?

Fanaroff, A. & Martin, R. (2002) Neonatal-Fanaroff, A. & Martin, R. (2002) Neonatal-Perinatal Medicine, Diseases of the Fetus Perinatal Medicine, Diseases of the Fetus and Infant, 7and Infant, 7thth ed. ed.

Goldsmith, J. & Karotkin, E. (2003) Assisted Goldsmith, J. & Karotkin, E. (2003) Assisted Ventilation of the Neonate, 4th ed.Ventilation of the Neonate, 4th ed.

Greenough, A. & Milner, A. (2003) Greenough, A. & Milner, A. (2003) Neonatal Respiratory Disorders, Neonatal Respiratory Disorders, 2nd ed.2nd ed.

Halliwell, B. & Cross, C. (1994) Halliwell, B. & Cross, C. (1994) Oxygen-derived Species: Their Oxygen-derived Species: Their Relation to Human Disease and Relation to Human Disease and Environmental Stress.Environmental Stress.

http://www.nei.nih.gov/health/rophttp://www.nei.nih.gov/health/rop