Endocrine dysfunction in the ICUPhysiology in trauma

Endocrine dysfunction in trauma/sepsisAdreno-corticalStress hyperglycaemiaThyroid dysfunctionGrowth hormoneCalcium metabolism

Metabolic response to traumaAny stressor will initiate the metabolic response to traumainjurysurgerysepsisburnsstarvationdehydrationvascular occlusion

Body respondsLocallywith inflammationcellularhumoral

Generally with a protective responseconservation of fluidprovision of energy for repair

Characterized byAcute catabolic reaction

preceded by

Metabolic process of recovery

Cuthbertson described anEbb and Flow phaseEbb phaseperiod of severe shockdepression of enzymatic activityincreased oxygen consumptiondepressed cardiac outputlactic acidosistemperature may be subnormal

Flow Phasedivided intoCatabolic phaseAnabolic phase

Catabolic phasefat and protein mobilisationassociated weight lossincreased secretion of urinary excretion

Anabolic phaseweight gainrestoration of fat and protein stores

In that time the body is HypermetabolicIncreased Cardiac outputIncreased Oxygen consumptionIncreased Glucose production

Influencing factorsThe magnitude of the response depends on the degree of traumaand concomitant contributing factorsdrugssepsissystemic illnessage, gender, nutritional statusless aggressive in kids and the elderlymore aggressive in burns

Initiating FactorsHypovolaemiahypoprefusion is the most potent precipitator of the metabolic response to trauma

Afferent impulseshormonal responsepain anxiety

Initiating factors

Wound factorstissue injury along 2 pathways

Inflammatory(humoral)Cellular

uncontrolled activation may play a role in the pathology of organ dysfunction

Immune response

Humoral via EicosanoidsCellularvia Phagocytic cells

Eicosanoidssynthesized from Arachidonic acid from phospholipids from damaged cells, WBCs and plateletsimplicated in induction of membrane dysfunctionProstanoidsProstaglandinProstacyclinThromboxanecause vasoconstriction, vasodilation, platelet aggregation, and platelet inhibitionLeucotrienscause vasoconstriction, increased capillary permeability, bronchoconstriction

Cellular pathwayActivation of phagocytic cells most NB Polymorphs, MO

Phagocytosis starts with the activation of Complement2 pathwaysClassical pathwayAlternative pathaygenerates Anaphylatoxins:C3a and C5aare Chemotactic factors

C3a and C5aResponsible for activation of Basophils, Mastcells, Platelets to secrete Histamine and Serotoninaggregation of neutrophils alter vascular permeabilityare vasoactive

stimulate MO to secrete IL-1 + Proteolyis inducing factor (PIF)these stimulate production of acute phase proteins

Hormonal response of trauma to the body

Release of various hormones, cytokines...catecholaminesadrenaline, noradrenalineendorphinscorticotropin and glucocorticoidsglucagonResulting in vascular instabilityhyperglycaemiahypermetabolic statehyperdynamic circulation

Hormones involved in endocrine dysfunction

CatecholaminesGlucocorticoids andMineralocorticoidsInsulinGlucagonThyroid hormoneGrowth hormoneParathyroid hormone

Release of Catecholamines

StimulateCH metabolism glycogenolysis in liver and muscle fibresstimulate gluconeogenesis in the liverinhibit glucose induced insulin secretionnett result is hyperglycaemia

Fat metabolismlipolysis of fatty acidssupply of energy

Catecholamines...CH and fat metabolism is increasedmetabolic rate is increasedresulting inincreased oxygen consumption/requirementsheat production

CVS(+)inotrope(+) chronotrope(+)dromotrope

InsulinCHCauses movement of glucose across insulin dependent cell membranescatabolism of glucose by insulin dependent cellsglycogenolysis by muscle fibreshepatocytesadipocytesFatpromotes lipogenesisstorage of fat

Insulin

Proteinpromotes protein synthesis

Glucagon

CHGlycogenolysis as well as gluconeogenesislipolysisProteolysis

thus increasing glucose concentrationincreasing energy

Summary of stress response

Cortisol Increased protein catabolismincreases the amino acids in blood forgluconeogenesis in the liverIncreased lipolysisdecreased glucose utilisation

nett resulthyperglycaemiaincreased energy

Hypothalamic response to traumaand resultant Adreno-cortical insufficiency

Hypothalamus is the highest level of integration of the Stress responseH-P-A axis Hypothalamus(CRH)Pituitary(ACTH)Adrenal cortex(Cortisol, Aldosterone)

Adrenocortical insufficiencyThe adrenal cortex synthesizes, and secretes 3 major types of hormonesGlucocorticoid Cortisol

MineralocorticoidAldosterone

Adrenal androgens

Cortisol and AldosteroneSecretion by the adrenal cortex is controlled by Adreno-cortico-trophic hormoneACTHwhich is regulated byCorticotrophin releasing hormoneCRH

Pain receptorsOsmo-receptorsBaro-receptorsChemoreceptorsstimulate ganglia in the Hypothalamus

Cortisolis stimulated by

circulating levels of cortisolstress ADH, oxytocin, Angiotensin IIsleep-wake cycle, diurnal secretory cyclecirculating levels of IL-1

CortisolStimulatesGluconeogenesisCatabolism proteincarbohydratelipid nnucleic acid metabolism

Anti-inflammatoryinhibits neutrophil and macrophage migrationmicrovascular stabilising effect

Aldosteronesecretion is stimulated byRenin-angiotensin system via Angiotensin IIHypovolaemiaHypotensionDecreased Na+Increased K+Increased osmolarity

AldosteroneIncreases Na+ conservationK+ lossby the kidneys, sweat glands, GIT

thereby increases water conservtion

major regulator of Extra-cellular fluid volume

Adrenal insufficiency in Sepsis

Difficulty defining Relative adrenal insufficiency

as opposed to Absolute adrenal insufficiency

Aim:to identify those patients at risk who might benefit from supportive cortisol replacement therapy

Who might benefit...Main concern in ICU setting

refractory septic shockshock that is unresponsive to catecholamine adminstration

Cortisol levels It is impossible to define an absolute serum cortisol threshold that would identify a patient with functional failure of the H-P-A axis

due todiurnal pattern of cortisol secretioninter-individual range of circulating cortisol levels during severe illness and stress

Defining Adrenal insufficiencyAbsolute adrenal insufficiency

when basal cortisol levels < 100 nmol/l stimulated values < 500-550 nmol/l(ACTH stimulation)cortisol increase does not occur during stress

causemalfunction in the H-P-A axis

Defining Adrenal insuff...Relative adrenal insufficiencyimpaired stress response of the H-P-A axis seen during severe illnessco-morbiditieshead injuryadrenal haemorrhagepharmacological agents (etomidate, opiates)inflammatory mediators (TNF, Interleukins)

The term relative or functional adrenal insuff. has been proposed for

hypotensiveseptic, critically ill patientswho are resistant to catecholamine administration

who show haemodynamic improvement to cortisolin the absence of factors known to impair the H-P-A axis

Relative adrenal insufficiencyThe cortisol levels may be > 550nmol/l or within the normal range

but are still considered to be inadequate for the given stress

and will be unable to respond to any further stressor

this syndrome is transient, and reverses with recovery from the illness

Relative adrenal insufficiency NB to recognise as

it is associated with a worsened outcome

Tests for adrenal dysfunctionNo strict biochemical criteria defining normal serum cortisol or ACTH levels or an adequate response to ACTH exists

Best consensus reference standard for diagnosis of integral failure of H-P-A axis is the Insulin induced hypoglycaemia testother testmeasurement of basal ACTH (elevated)ACTH determination is cumbersomeACTH has a short half life

Dilemma of diagnosis

only way is to rely on a clinical assessment of the severity of the stress and to estimate the adequacy of the measured cortisol level

Signs and symptomsClinician must be vigilant for subtle sings and symptomsvitiligodepression, fatigue nausea, abdominal pain haemodynamic instabilityunexplained feverhyponatraemiahypoglycaemiaunexplained eosinophilia

Glycaemic controlHypoglycaemia

Hyperglycaemia

Stress hyperglycaemia

Acute hyperglycaemia in response to stressdiabetes of in jury or Stress hyperglycaemia

demonstrates the obligatory metabolic responses required to cope with the stress

degree of hyperglycaemia seems to be a harbinger of severity of injury and outcome

Stress HyperglycaemiaDefinitionhyperglycaemia in the previously euglycaemic patient that resolves after the acute process

Prevalenceestimated range3-70%highly variable due toan inconsistently applied definitionpreviously un-recognized Diabetes mellitus

Severity and outcomeSH was previously considered a compensatory responsecauses a range of adverse effectsabnormal immune functionincreased infection ratehaemodynamic disturbanceselectro-myocardial disturbancesa number of studies have shown a direct relationship between the extent of SH and the severity and outcome

Insulin resistance also correlates to the severity of stressVarious studies showed that SH increases morbidity and mortality as confounding factors in MI, Strokes, head injuryincreased non-fatal re-infarctionincreased heart failure and major cardiovascular event admissions increased 1 year mortality post MI

Eg. Burned children with hyperglycaemia (>7,7mmol/l)had an increased incidence of (+) BClower percent graft takehigher mortality

Cause of SH

Multitude of factors

lack of muscular activityageinguse of dextrose solutionscertain drugscatecholaminesglucocorticoidsthiazides

underlying conditionsobesitypancreatitiscirrhosisDiabetes itself

Stress metabolismCytokinesOxidative stressStress signalling pathways

Stress metabolismInitiates a neuro-hormonal responseeg. Hypothalamusinvolving counter-regulatory hormoneseg Glucagon, cortisol...sympathetic activity raises glucose by increased glycogenolysisCatecholaminesthis is correlated to the degree of trauma and the circulating epinephrine

Stress metabolism

an influx of cortisol, glucagon, epinephrine, results inhypermetabolism (causing catabolism of proteins and fat), a negative nitrogen balance, hyperglycaemia, hyperinsulinaemiainsulin resistancehepatocytes respond with counter-regulatory stress hormones, by...

Stress metabolism

Increased synthesis of Acute phase proteins

CH-metabolism is altered such that the overall whole-body production of CH is increased and channeled towardimmune related activities of inflammationimmune cell functionwound healing

Stress metabolism

The liver becomes insensitive to auto-regulation by glucose itself and glucagon

glucose production and lactate extraction are typically increased x 2

glycerol contribution increases by 20%

glucose uptake is near maximal at non-insulin sensitve, immune-related sites

Summary of stress metabolism

The stressed pt characteristically

fasting and post-prandial hyperglycaemia

insulin resistance

increased hepatic glucose production

Insulin levels, although elevated are relatively lowstudies suggest insulin signalling is defective

Cause of SH...

Cytokinesmany of the metabolic changes arise from inter-related effects of pro-inflammatory cytokineseg. Tumour necrosis factorInterleukin-1 Interleukin-6counter-regulatory hormoneseffectsinduce insulin resistancehyperglycaemia by activation of the H-P-A axis

Insulin has anti-inflammatory propertiesinduction of euglycaemic hyperinsulinaemia byIL-6GHCortisolhyperglycaemia also causes expression of cytokinesraising S-glucose in healthy individuals, and suppressing insulin causes an increase inIL-6TNF-aIL-8

Cause of SH...Oxidative stressdefinitionimbalance between the production of highly reactive oxygen and/or nitrogen speciesand endogenous anti-oxidants

this causesan exacerbated oxidative stress on ICU pts with systemic inflammation

Oxidative stress

hyperglycaemic exposure to endothelial cells and smooth muscle cells stimulate oxygen radicals formation

hyperglycaemic exposure to pancreatic beta cells results in oxygen radical formation and decreased first phase of insulin secretion

Pancreatic beta cells seem to express low levels of anti-oxidants

acute hyperglycaemia also alters the ability of beta cells to couple insulin secretion to glucose changes

The deleterious effects of hyperglycaemia may be caused by the production of

free radicals and the associated oxidative stress

Oxidative stress leads todamage to DNA, proteins and lipidsdysfunctional glucose metabolism

Causes of SH

Stress signaling pathwayshyperglycaemia induced free oxygen radicalsfunction as an acute signaling factor for stress-sensitive pathwaysNuclear factor Kappa B(NF KB)c-Jun N-terminal kinase/stress activated kinasemitogen activated protein kinase(MAPK)

in stress situations these factors upregulate a host of pro-inflammatory cytokines

Cause defective insulin signallinginsulin resistance

In summaryCause of stress hyperglycaemiaCombination ofhigh levels of cytokinesbeta-cell dysfunction(pancreas)severity of oxidative stressglucose generating drugsstress signalling pathwaysinsulin resistanceunderlying genetic diabetic predisposition

Non-thyroidal illnessDefinitionclinically euthyroid pts, with non-thyroidal illnesswho have low T3,and N or low T4N or low TSH (inappropriately)

In severe systemic non-thyroidal illness (NTI)profound changes occur in the H-P-A axiscalled the Euthyroid sick syndrome

typicallynormal TSH and T4low T3suggests a change in the H-P-A axis setpoint

NTIthought to be a homeostatic correction by which the body diminishes the effects of biologically active T3decreased de-iodination of T4 to T3 (active)

NTI occurs in most patients with systemic illness

important to recognise becausemorbidity and morality rate of NTI is high

Thyroid changes in NTI

Fall in circulating total T3 and free T3increase in the inactive rT3

the greater the severity of the disease, the lower the S-T3 level becomes

T4 may be decreasedin chronic illness the T4 is low and is associated with an increased mortality

Cause of NTI

Decrease in peripheral production of T3due to decreased extra-thyroidal conversion of T4 to T3 (by enzyme type 1 iodo-thyronine -5-deiodinase)

circulating TSH levels are low-N despite decreased T3

there is a blunted response of TSH to TRH and low TSH levels are associated with a poor prognosis

H-P-A axis

critically ill pts show diminished TSH pulsatility

a major change in thyroid hormone setpoint regulation seems to occur in NTIin the hypothalamus

Is the pt with NTI euthyroid

First exclude pre-existing thyroid disease

clinically displays the classic symptoms hypothyroidism

unrelated hypotensiondry skin bradycardiahypothermia

Diagnosis

In primary hypothyroidism the TSH levels sharply increaseIn NTITSH typically stays low or in the normal range the TSH level probably relatively accurately reflects the amount of T3 available at the pituitary and indirectly tissue thyroid hormone concentrations

Diagnosis

a normal TSH most likely excludes primary thyrotoxicosis and hypothyroidism

and suggests that the patient is euthyroid and does not require L-thyroxine therapy

Primary hypothyroidism

Pts with overt 1 hypothyroidism almost always have raised levels of TSHwith decreased T4and in severe cases also T3

TSH measurement is good for early detection of 1HTbut poor measure of clinical and metabolic severity

Difficult diagnosis of NTI...

Diagnosis is very difficult if not impossiblelook for signs of hypothyroidismlook for other signs of pituitary failureCTB may be of value

Thyroid crisis

Is the life-threatening clinical extreme of hyperthyroidismmore common in womanmortality rate 10-20% in treatedonset is usually abruptprecipitating factor identified in 50%

most pts have have unrecognised or poorly controlled Graves disease

Provoking factorsinfectiontraumasurgeryuncontrolled DMlabour eclampsia

Sx + Txhyper-pyrexiatachycardiaAFdelirium or comaagitation vomiting, diarrhoeamuscle weakness

May have sx of profound exhaustionhyporeflexiasevere myopathymarked weight losshypotension

DDXSepsis

hyper-thermic syndromesdelirium tremensopioid withdrawaladrenergic or cholinergic overdose

Myxoedema coma

Hypothyroid crisisat any age, occurs typically during winter in the elderly females

represents the terminal stage of decompensated hypothyroidismhas a high mortality

Sx and TxCardinal symptomdeterioration of the pts mental statusthose presenting in coma, have long standing unrecognised thyroid hypofunction(usually auto-immune, thyroidectomy, radioiodine therapy)

diagnosis should be made with care

Hypotensionaccompanied by sinus bradycardiabaroreceptor dysfunctiontissue hypoxia compounded by shock and anaemiamyocardial myxoedematous infiltratespericardial effusionscardiac tamponade

Hypoglycaemiacommon and needs early recognition

Other symptoms

Cold intolerancedecreased energymuscular weaknessbradykinesiadementiadelayed reflexesdry skinconstipation weight gainIHDanaemia

Comadue to combination ofhypothermiahypercarbiahypoxiacerebral oedemaother metabolic derangements

Growth HormoneSecreted from anterior pituitaryunder hypothalamic controlsecreted in characteristic diurnal and pulsatile pattern

GH...Metabolic activitieslipolysisenhanced amino acid transport into muscle cellsanti-insulin properties

most prominentlymitogenic and anabolic activityvia increased Insulin growth factor production (IGF-1)

GH in critical illness

Mean concentration is acutely increasedsustained increase in interpulse GH levelsstudies show that pro-inflammatory cytokines induce a GH resistance statepulsatile secretion of anterior pituitary hormone is reduced during the chronic phase of illnessnon-survivors generally have higher levels of GH than survivors

Para-thyroids

Regulation of Calcium homeostasisFunction of calciumcardiac, skeletal and smooth muscle excitationcardiac action potentials and pacemakingrelease of neurotransmitterscoagulation of bloodbone formation and metabolismhormone releaseciliary motility

Hormonal regulation

Parathyroid hormonein response to hypocalcaemiaPTH secretion is stimulated stimulates increases osteo-clastic activity in bone (resorption)renal re-absorption of calciumrenal synthesis of calcitriol (active Vit. D)promotes urinary excretion of phosphates

Vit. D increases gut, and to a lesser extent renal reabsorpion of calcium

Metabolic factors influencing Ca homeostasis

Changes in S-protein(protein binding)S-phosphatepHmagnesium

Ca and phosphateHPO4 (2-)+ Ca(2+)-->CaHPO4(-)

Magnesiumis required for PTH secretionand end organ responsiveness

Hyper-Ca in critically ill pts

Frequency is not well establishedbut less common than hypo-Cacommon causesmalignancy related to hyper-Carenal failurepost-hypo-Ca hypercalcaemia

Hyper-Ca

may be due to an increase in PTHhomeostatic feedback is preservedcalled equilibrium hyper-Ca

may be non-parathyroid mediatedbreakdown of homeostatic feedbackcalled dysequlibrium hyper-Ca

Mechanisms of hyper-Ca

Malignancy related from bony metastasishumoral hyper-Ca of malignancyPTH like substances, calcitriol,osteoclast activating factor and prostaglandins are releasedcausing tumour osteolysis of boneseen with bronchogenic CA and hypernephroma

post hypo-Ca hyper-Catransient phenomenenafter hypo-Cadue to parathyroid hyperplasia

Mechanisms of hyper-Ca

Immobilisation hyper-Caimbalance between bone deposition and resorptionleads to loss of bone mineralsand hyper-Caseen in states of rapid bone turnover

Intra-vascular volume depletionreduces renal calcium excretionreduced GFRincreased tubular reabsorption

Manifestations of hyper-Ca

CVShypertensionarrhythmiasdigitalis sensitivitycatecholamine resistance

Urinary systemnephrocalcinosisnephrolithiasistubular dysfunctionrenal failure

Manifestations of hyper-Ca

Gastro-intestinalAnorexia , nausea, vomitingconstipation peptic ulcerpancreatitis

Neuro-muscularweaknessNeuro-psychiatricdepression, psychosiscoma, seizuresdisorientation

InvestigationsS-Ca + S-phosphateALPPTHrenal functionsskeletal survey

Hypo-Ca

Estimated incidence70-90%commonhigher mortality increased ICU stay

Aetiology

Various causes

Ca chelationAlkalosis-increased binding of Ca by albuminCitrate toxicityHyperphosphataemiaPancreatitisTumour lysis syndromeRhabdomyolysis

Aetiology

HypoparathyroidismHypo- and hyper-magnesaemiaSepsisdecreased PTH secretioncalcitriol resistanceintracellular shift of CaBurnsdecreased PTH secretionNeck surgeryremoval of parathyroid glandscalcitonin release during surgeryhungry bone syndrome post parathyroidectomy

AetiologyHypovitaminosis Dinadequate intakemalabsorptionliver diseaserenal failureReduced bone turnoverosteoporosiselderly cachexia

AetiologyDrug inducedPhenytoinDiphosphonatesCis-platinumprotaminegentamycin

Diagnosis

Patterns of recognitioneg.Renal failureelevated blood urea nitrogenelevated phosphatehypomagnesaemiareduced ionized Cahypokalaemia

Sx and Tx of Hypocalcaemia

Mild degrees usually asymptomatic

CNScircumoral and peripheral paraesthesiamuscle crampstetanyseizuresextrapyrmidaltremor, ataxia, dystoniaproximal myopathydepression, anxiety, psychosis

Sx and Tx of Hypocalcaemia

CVSarrhythmiashypotensioninotrpoe unresponsivenessprolonged QT intervals, T wave inversionloss of digitalis effectRespiratoryapnoealaryngospasmbronchospasm

Confused?