The body The body responseresponse to toinjury & injury & traumatrauma

Dr. Hiwa Omer Ahmed Dr. Hiwa Omer Ahmed

Assistant Professor in SurgeryAssistant Professor in Surgery

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The host response to injury—surgical, The host response to injury—surgical, traumatic, or infectious—istraumatic, or infectious—ischaracterized by various endocrine, characterized by various endocrine, metabolic, and immunologic metabolic, and immunologic alterations.alterations.

1. ENDOCRINE RESPONSE 1. ENDOCRINE RESPONSE TO INJURYTO INJURY

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The classic response to injury comprises The classic response to injury comprises multiple axes. These hormone response multiple axes. These hormone response pathways are activated by pathways are activated by

► (1) mediators released by the injured (1) mediators released by the injured tissue,tissue,

► (2) neural and nociceptive input (2) neural and nociceptive input originating from the site of injury, ororiginating from the site of injury, or

► (3) baroreceptor stimulation from (3) baroreceptor stimulation from intravascular volume depletion. intravascular volume depletion.

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. . Thehormones released in Thehormones released in response to these activating response to these activating stimuli may be dividedstimuli may be dividedinto those primarily under into those primarily under hypothalamopituitary control hypothalamopituitary control and those primarily under and those primarily under autonomic nervous system autonomic nervous system control control

Hormones Under Anterior Hormones Under Anterior Pituitary RegulationPituitary Regulation

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Pain, fear, anxiety, or emotional Pain, fear, anxiety, or emotional arousal generate neural signals to thearousal generate neural signals to theparaventricular nucleus of the paraventricular nucleus of the hypothalamus, stimulating the hypothalamus, stimulating the synthesis ofsynthesis ofcorticotropin-releasing hormone (CRH)corticotropin-releasing hormone (CRH),,

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ACTH is synthesized, stored, and ACTH is synthesized, stored, and released by the anterior pituitary uponreleased by the anterior pituitary uponCRH stimulation. ACTH is a 39–amino CRH stimulation. ACTH is a 39–amino acid peptideacid peptide

► being, ACTH release is regulated bybeing, ACTH release is regulated bycircadian signals; the greatest circadian signals; the greatest elevation of ACTH occurs late at night elevation of ACTH occurs late at night andandlasts until just before sunrise. lasts until just before sunrise.

In the nonstressed healthy In the nonstressed healthy humanhuman

In trauma In trauma

►Most injury is characterized by Most injury is characterized by elevationselevations in CRH and ACTH that are in CRH and ACTH that are proportional to the severity of injuryproportional to the severity of injury

Cortisol/GlucocorticoidsCortisol/Glucocorticoids

►Cortisol is the major glucocorticoid in Cortisol is the major glucocorticoid in human beings and is essential forhuman beings and is essential forsurvival after significant physiological survival after significant physiological stress.stress.

In traumaIn trauma

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. . Cortisol levels in response toinjury are not Cortisol levels in response toinjury are not under the influence of normal diurnal under the influence of normal diurnal variationsvariations and can remain persistently and can remain persistently elevated, depending on the type of systemic elevated, depending on the type of systemic stress.stress.Burn patients have demonstrated elevated Burn patients have demonstrated elevated circulating cortisol levels for up to 4 weeks, circulating cortisol levels for up to 4 weeks, and soft-tissue injury and hemorrhage may and soft-tissue injury and hemorrhage may sustain elevated cortisol levels for up to a sustain elevated cortisol levels for up to a weekweek

Thyrotropin-Releasing Thyrotropin-Releasing Hormone and Thyroid Hormone and Thyroid

StimulatingStimulatingHormoneHormone►

Thyrotropin-releasing hormone (TRH)Thyrotropin-releasing hormone (TRH) serves as the primary stimulant forserves as the primary stimulant forthe synthesis, storage, and release of the synthesis, storage, and release of thyroid-stimulating hormone (TSH)thyroid-stimulating hormone (TSH)in the anterior pituitary. TSH in turn in the anterior pituitary. TSH in turn stimulates thyroxine (T4) productionstimulates thyroxine (T4) production

In traumaIn trauma

► Although T3 levels are frequently Although T3 levels are frequently decreased decreased after injuryafter injury, there is no, there is nocompensatory rise in TSH release. After compensatory rise in TSH release. After major injury, reduced available T3major injury, reduced available T3and circulating TSH levels are observed and and circulating TSH levels are observed and peripheral peripheral conversion of T4 toconversion of T4 toT3 is impaired. T3 is impaired. concentrations remain concentrations remain relatively constant. relatively constant.

► In severely injured orcritically ill patients, a In severely injured orcritically ill patients, a reduced free T4 concentration has been reduced free T4 concentration has been predictive ofhigh mortalitypredictive ofhigh mortality

Growth HormonesGrowth Hormones

►Hypothalamic Hypothalamic growth hormone growth hormone releasing hormone (GHRH)releasing hormone (GHRH) travels travels throughthroughthe hypothalamic-hypophyseal portal the hypothalamic-hypophyseal portal circulation to the anterior pituitary andcirculation to the anterior pituitary andstimulates the release of stimulates the release of growth growth hormone (GH)hormone (GH) in a pulsatile fashion in a pulsatile fashion mostlymostlyduring the sleeping hours.during the sleeping hours.

In traumaIn trauma

► There is a rise in circulating GH levels after There is a rise in circulating GH levels after injury,The role of GH during stress is to injury,The role of GH during stress is to promote protein synthesis whileenhancing promote protein synthesis whileenhancing the mobilization of fat stores. Fat mobilization the mobilization of fat stores. Fat mobilization occurs by directstimulation in conjunction occurs by directstimulation in conjunction with potentiation of adrenergic lipolytic with potentiation of adrenergic lipolytic effects oneffects onadipose stores. In the liver, hepatic adipose stores. In the liver, hepatic ketogenesis also is promoted by GH. GHketogenesis also is promoted by GH. GHinhibits insulin release and decreases glucose inhibits insulin release and decreases glucose oxidation, leading to elevatedoxidation, leading to elevatedglucose levelsglucose levels

SomatostatinSomatostatin

►Somatostatin is a 14–amino acid Somatostatin is a 14–amino acid polypeptide produced by various cellpolypeptide produced by various celltypes, including gastric antrum cells types, including gastric antrum cells and pancreatic islet D cellsand pancreatic islet D cells

somatostatinsomatostatin

►The roleof somatostatin in the The roleof somatostatin in the response to injury is unclear, but it response to injury is unclear, but it may regulatemay regulateexcessive nutrient absorption and the excessive nutrient absorption and the activities of GH and IGF duringactivities of GH and IGF duringconvalescence from injuryconvalescence from injury

Gonadotrophins and Sex Gonadotrophins and Sex HormonesHormones

►Luteinizing-hormone releasing Luteinizing-hormone releasing hormone (LHRH) or gonadotropin-hormone (LHRH) or gonadotropin-releasingreleasinghormone (GnRH) is released from the hormone (GnRH) is released from the hypothalamus and stimulates follicle-hypothalamus and stimulates follicle-stimulating hormone (FSH) and stimulating hormone (FSH) and luteinizing hormone (LH)luteinizing hormone (LH) release from release from thetheanterior pituitary.anterior pituitary.

In traumaIn trauma

► The most relevantThe most relevantclinical correlation is seen after injury, stress, clinical correlation is seen after injury, stress, or severe illness, when LH andor severe illness, when LH andFSH release is suppressed. The reduction in FSH release is suppressed. The reduction in LH and FSH consequentlyLH and FSH consequentlyreduces estrogen and androgen secretion.reduces estrogen and androgen secretion.

► Estrogens inhibit cell-mediated immunity, Estrogens inhibit cell-mediated immunity, natural killer cell activity, andneutrophil natural killer cell activity, andneutrophil function, but are stimulatory for antibody-function, but are stimulatory for antibody-mediated immunitymediated immunity

► . Androgens appear to be. Androgens appear to bepredominantly immunosuppressive.predominantly immunosuppressive.

ProlactinProlactin

►The hypothalamus suppresses The hypothalamus suppresses prolactin secretion from the anteriorprolactin secretion from the anteriorpituitary by the activities of pituitary by the activities of LHRH/GnRH and dopamineLHRH/GnRH and dopamine

In traumaIn trauma

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Elevated prolactin levels after injury Elevated prolactin levels after injury have been reported in adults, whereashave been reported in adults, whereasreduced levels are noted in children.reduced levels are noted in children.

►Like growth hormone, prolactin has Like growth hormone, prolactin has immunostimulatory propertiesimmunostimulatory properties

Endogenous Opioids & in Endogenous Opioids & in trauma trauma

►Elevated endogenous opioids are Elevated endogenous opioids are measurable after major operations ormeasurable after major operations orinsults to the patient insults to the patient

►Endorphins also influence the immune Endorphins also influence the immune system by increasing naturalsystem by increasing naturalkiller cell cytotoxicity and T cell killer cell cytotoxicity and T cell blastogenesis. Interleukin-1 activates blastogenesis. Interleukin-1 activates

Hormones Under Posterior Hormones Under Posterior Pituitary RegulationPituitary Regulation

►Arginine VasopressinArginine Vasopressin►Vasopressin or arginine vasopressin Vasopressin or arginine vasopressin

(AVP) (or antidiuretic hormone, ADH) is (AVP) (or antidiuretic hormone, ADH) is synthesized in the anterior hypothalamus synthesized in the anterior hypothalamus and transported by axoplasmic flow to and transported by axoplasmic flow to the posterior pituitary for storage.the posterior pituitary for storage.

In trumaIn truma

► Elevated AVP secretion is another Elevated AVP secretion is another characteristic of trauma,characteristic of trauma,hemorrhage, open-heart surgery, and other hemorrhage, open-heart surgery, and other major operations. Thismajor operations. Thiselevated level typically persists for 1 week elevated level typically persists for 1 week after the insult.after the insult.

► This effectThis effectin the splanchnic circulation may cause the in the splanchnic circulation may cause the trauma-inducedtrauma-inducedischemia/reperfusion phenomenon that ischemia/reperfusion phenomenon that precedes gut barrier impairment.precedes gut barrier impairment.

OxytocinOxytocin

►Oxytocin and AVP are the only known Oxytocin and AVP are the only known hormones secreted by the posteriorhormones secreted by the posteriorpituitarypituitary

►but the role of oxytocin in thebut the role of oxytocin in theinjury response is unknowninjury response is unknown

3. Hormones of the Autonomic 3. Hormones of the Autonomic SystemSystem

►CatecholaminesCatecholaminesCatecholamines exert significant Catecholamines exert significant influence in the physiologic response influence in the physiologic response totostress and injury.stress and injury.

►Both of the major catecholamines, Both of the major catecholamines, norepinephrine and epinephrine, are norepinephrine and epinephrine, are increased inincreased inplasma after injury, with average plasma after injury, with average elevations of three to four times aboveelevations of three to four times abovebaseline immediately after injury, baseline immediately after injury, reaching their peak in 24 to 48 h reaching their peak in 24 to 48 h beforebeforereturning to baseline levelsreturning to baseline levels

AldosteroneAldosterone

►The mineralocorticoid aldosterone is The mineralocorticoid aldosterone is synthesized, stored, and released insynthesized, stored, and released inthe adrenal zona glomerulosa. Its the adrenal zona glomerulosa. Its release may be induced by release may be induced by angiotensin II,angiotensin II,hyperkalemia, and the pituitary hyperkalemia, and the pituitary hormone known as aldosterone hormone known as aldosterone stimulatingstimulatingfactor (ASF),.factor (ASF),.

In traumaIn trauma

► but ACTH is the most potent stimulus for but ACTH is the most potent stimulus for aldosterone release in the injured patientaldosterone release in the injured patient

► The major function of aldosterone is to The major function of aldosterone is to maintain intravascular volume bymaintain intravascular volume byconserving sodium and eliminating conserving sodium and eliminating potassium and hydrogen ions. potassium and hydrogen ions. . After injury, ACTH stimulates a brief. After injury, ACTH stimulates a briefburst of aldosterone release. Angiotensin II burst of aldosterone release. Angiotensin II induces a protracted aldosterone release that induces a protracted aldosterone release that persists well after ACTH returns to baseline.persists well after ACTH returns to baseline.

Renin-AngiotensinRenin-Angiotensin

► Renin is synthesized and stored primarily Renin is synthesized and stored primarily within the renal juxtaglomerularwithin the renal juxtaglomerularapparatus near the afferent arteriole. The apparatus near the afferent arteriole. The juxtaglomerular apparatuscomprises the juxtaglomerular apparatuscomprises the juxtaglomerular neurogenic receptor, the juxtaglomerular neurogenic receptor, the juxtaglomerularcell, and the macula densa. juxtaglomerularcell, and the macula densa. Renin initially exists in an inactive form asRenin initially exists in an inactive form asprorenin. The activation of renin and its prorenin. The activation of renin and its release is mediated by ACTH, AVP,glucagon, release is mediated by ACTH, AVP,glucagon, prostaglandins, potassium, magnesium, and prostaglandins, potassium, magnesium, and calcium.calcium.

In traumaIn trauma

►their secreation increased in injurytheir secreation increased in injury►The renin-angiotensin systemThe renin-angiotensin system

participates in the response to injury participates in the response to injury by maintaining volume homeostasisby maintaining volume homeostasis

InsulinInsulin► The netresult of impaired insulin production and The netresult of impaired insulin production and

function after injury is stress-induced function after injury is stress-induced hyperglycemia, which is in keeping with the hyperglycemia, which is in keeping with the general catabolic state.general catabolic state.

► . In the injured patient, a biphasic pattern of insulin. In the injured patient, a biphasic pattern of insulinrelease is observed. The first phase occurs within a release is observed. The first phase occurs within a few hours after injuryand is manifested as a few hours after injuryand is manifested as a relative suppression of insulin release, reflecting relative suppression of insulin release, reflecting thetheinfluence of catecholamines and sympathetic influence of catecholamines and sympathetic stimulation. The later phase ischaracterized by a stimulation. The later phase ischaracterized by a return to normal or excessive insulin production return to normal or excessive insulin production but with persistent hyperglycemia, demonstrating but with persistent hyperglycemia, demonstrating a peripheral resistance to insulina peripheral resistance to insulin

GlucagonGlucagon►The release of glucagon afterThe release of glucagon after

injury is initially decreased, but returns injury is initially decreased, but returns to normal 12 h later. By 24 h,to normal 12 h later. By 24 h,glucagon levels are supranormal and glucagon levels are supranormal and can persist for up to 3 days.can persist for up to 3 days.

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IMMUNE IMMUNE RESPONSE TO RESPONSE TO INJURYINJURY

► Even after the normalization ofEven after the normalization ofmacroendocrine hormone function after macroendocrine hormone function after the primary injury, the persistencethe primary injury, the persistenceof systemic inflammation, the of systemic inflammation, the progression of organ dysfunction, and progression of organ dysfunction, and evenevenlate mortality indicate the presence of late mortality indicate the presence of other potent mediators influencingother potent mediators influencingthe injury response. the injury response.

► These mediators usually are small proteins These mediators usually are small proteins or lipidsor lipidsthat are synthesized and secreted by that are synthesized and secreted by immunocytes. These micromolecules, immunocytes. These micromolecules, collectively referred to as cytokines, are collectively referred to as cytokines, are indispensable in tissue healing andindispensable in tissue healing andin the immune response generated against in the immune response generated against microbial invasions. Asmounting evidence microbial invasions. Asmounting evidence suggests, the activities of these cytokine suggests, the activities of these cytokine mediators aremediators areintegrally related to classic hormone integrally related to classic hormone function and metabolic responses to injuryfunction and metabolic responses to injury

Cytokine-Mediated ResponseCytokine-Mediated Response►

Cytokines exert their influence by Cytokines exert their influence by binding to specific cell receptors andbinding to specific cell receptors andactivating intracellular signaling activating intracellular signaling pathways leading to modulation of genepathways leading to modulation of genetranscription. By this mechanism, transcription. By this mechanism, cytokines influence immune cellcytokines influence immune cellproduction, differentiation, proliferation, production, differentiation, proliferation, and survivaland survival

Tumor Necrosis Factor-Tumor Necrosis Factor-alphaalpha► The release of TNF-a in response to acute The release of TNF-a in response to acute

injury is rapid and short-lived.Experiments injury is rapid and short-lived.Experiments simulating an acute inflammatory response simulating an acute inflammatory response by means ofby means ofendotoxin challenge in human subjects have endotoxin challenge in human subjects have demonstrated a monophasidemonstrated a monophasitumor necrosis tumor necrosis factor (TNF)factor (TNF) appearance curve, peaking at appearance curve, peaking at approximately 90 min and followed by a approximately 90 min and followed by a return to undetectable levels within 4 h . return to undetectable levels within 4 h . Even with a half-life of 15 to 18 min, the Even with a half-life of 15 to 18 min, the brief appearance of TNF caninduce marked brief appearance of TNF caninduce marked metabolic and hemodynamic changes and metabolic and hemodynamic changes and activate cytokines distally in the cascade. activate cytokines distally in the cascade.

Interleukin-1Interleukin-1

►TNF-a also induces the biosynthesis TNF-a also induces the biosynthesis and release of interleukin-1 (IL-1)and release of interleukin-1 (IL-1)from macrophages and endothelial from macrophages and endothelial cells.cells.

In trumaIn truma

►Among its effects, IL-1 induces the Among its effects, IL-1 induces the classic inflammatory febrile response toclassic inflammatory febrile response toinjury by stimulating local prostaglandin injury by stimulating local prostaglandin activity in the anterioractivity in the anteriorhypothalamus. Associated with the hypothalamus. Associated with the hypothalamic activity is the induction ofhypothalamic activity is the induction ofanorexia by an IL-1 effect on the satiety anorexia by an IL-1 effect on the satiety centercenter

Interleukin-2Interleukin-2

►Although necessary as an inflammatory Although necessary as an inflammatory mediator in promoting Tmediator in promoting Tlymphocyte proliferation, immunoglobulin lymphocyte proliferation, immunoglobulin production, and gut barrierproduction, and gut barrierintegrity, IL-2 has not been readily integrity, IL-2 has not been readily detectable in the circulation duringdetectable in the circulation duringacute injury. Similar to IL-1, its short half-acute injury. Similar to IL-1, its short half-life of less than 10 min adds tolife of less than 10 min adds tothe difficulty in detecting it after injurythe difficulty in detecting it after injury

►METABOLIC METABOLIC RESPONSE TO RESPONSE TO INJURYINJURY

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The description of human biochemical The description of human biochemical responses to injury and theresponses to injury and theclassification of such responses into an classification of such responses into an ebb and flow phase by Cuthbertsonebb and flow phase by Cuthbertsonand others provides a useful model by and others provides a useful model by which the metabolic response towhich the metabolic response toinjury may be characterizedinjury may be characterized

Ebb & flow phaseEbb & flow phase

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Ebb & flowEbb & flow

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Except with the most minor injury, the flow Except with the most minor injury, the flow phase is ushered in byphase is ushered in bycompensatory mechanisms resulting from compensatory mechanisms resulting from volume repletion and cessationvolume repletion and cessationof initial injury conditions. The metabolic of initial injury conditions. The metabolic response associated with the flowresponse associated with the flowphase serves to direct energy and protein phase serves to direct energy and protein substrates so as to preservesubstrates so as to preservecritical organ function and repair damaged critical organ function and repair damaged tissues.tissues.

Energy balanceEnergy balance

►These changes can reflect theThese changes can reflect thedegree of underlying injury degree of underlying injury

► Injury of any magnitude beyond the Injury of any magnitude beyond the most trivial is associated with anmost trivial is associated with anincrease in energy expenditure and increase in energy expenditure and increases in oxygen consumption thatincreases in oxygen consumption thatvary directly with the severity of injuryvary directly with the severity of injury

Fat metabolismFat metabolism

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Free fatty acids are a principal source Free fatty acids are a principal source of energy after injury. Lipolysis isof energy after injury. Lipolysis isenhanced by the immediate elevations enhanced by the immediate elevations in ACTH, cortisol, catecholamines,in ACTH, cortisol, catecholamines,glucagon, and growth hormone levels, glucagon, and growth hormone levels, reduction in insulin level, andreduction in insulin level, andincreased sympathetic nervous system increased sympathetic nervous system activityactivity

Carbohydrate MetabolismCarbohydrate Metabolism

► Systemic glucose intolerance is well Systemic glucose intolerance is well documented in injured patients. Bydocumented in injured patients. Bycontrast, basal insulin levels are elevated by contrast, basal insulin levels are elevated by several times during the earlyseveral times during the earlyflow phase, indicating a state of relative flow phase, indicating a state of relative insulin resistance.insulin resistance.

► Increases in plasma glucose levels are Increases in plasma glucose levels are proportional to the severity of injuryproportional to the severity of injuryand to some extent are correlated with and to some extent are correlated with survivasurviva

Protein and Amino Acid MetabolismProtein and Amino Acid Metabolism

►The intake of protein for a healthy The intake of protein for a healthy young adult is approximately 80 to 120young adult is approximately 80 to 120g, or 13 to 20 g of nitrogen per day. g, or 13 to 20 g of nitrogen per day. Daily fecal and urinary excretion ofDaily fecal and urinary excretion ofnitrogen is 2 to 3 g and 13 to 20 g, nitrogen is 2 to 3 g and 13 to 20 g, respectively. After injury, dailyrespectively. After injury, dailynitrogen excretion in the urine nitrogen excretion in the urine increases to 30 to 50 g as urea nitrogenincreases to 30 to 50 g as urea nitrogenand represents net proteolysis.and represents net proteolysis.

►The magnitude of nitrogen loss also is The magnitude of nitrogen loss also is related to the age, sex, and physicalrelated to the age, sex, and physicalcondition of the patient. Young healthy condition of the patient. Young healthy males lose more protein in responsemales lose more protein in responseto an injury than do women or the to an injury than do women or the elderly, presumably because they elderly, presumably because they have ahave ahigher lean body mass than the latter higher lean body mass than the latter two patient subsets.two patient subsets.