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Systemic Response to Systemic Response to Injury & Metabolic Injury & Metabolic Support Support a review of Schwartz’s Principles of a review of Schwartz’s Principles of Surgery- Chapter 1 Surgery- Chapter 1 Anas MK hindawi PG1 Anas MK hindawi PG1 MGH straight intern MGH straight intern 21/6/2012 21/6/2012

Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

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Page 1: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Systemic Response to Systemic Response to Injury & Metabolic Injury & Metabolic

SupportSupporta review of Schwartz’s Principles of a review of Schwartz’s Principles of

Surgery- Chapter 1Surgery- Chapter 1

Anas MK hindawi PG1 Anas MK hindawi PG1 MGH straight internMGH straight intern

21/6/201221/6/2012

Page 2: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

IntroductionIntroduction

Inflammatory response to injuryInflammatory response to injury to restore tissue functionto restore tissue function Eradicate invading microorganismsEradicate invading microorganisms

Local- limited duration, restores Local- limited duration, restores functionfunction

MajorMajor overwhelming inflammatory responseoverwhelming inflammatory response Potential multi-organ failurePotential multi-organ failure Adversely impacts patient survivalAdversely impacts patient survival

Page 3: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Clinical Spectrum of Clinical Spectrum of SIRSSIRS

InfectionInfection Identifiable source of Identifiable source of

microbial insultmicrobial insult

SIRS = 2 or more:SIRS = 2 or more: Temp ≥38˚C or ≤36˚CTemp ≥38˚C or ≤36˚C HR ≥ 90 bpmHR ≥ 90 bpm RR ≥ 20 breaths/min or RR ≥ 20 breaths/min or

PaCO2 ≤ 32 mmHg or PaCO2 ≤ 32 mmHg or mechanical ventilationmechanical ventilation

WBC ≥ 12,000/µL or ≤ WBC ≥ 12,000/µL or ≤ 4000/µL or ≥ 10% band 4000/µL or ≥ 10% band formsforms

SepsisSepsis Infection + SIRSInfection + SIRS

Severe SepsisSevere Sepsis Sepsis + Organ Sepsis + Organ

DysfunctionDysfunction

Septic ShockSeptic Shock Sepsis + Cardiovascular Sepsis + Cardiovascular

Collapse (requires Collapse (requires vasopressors)vasopressors)

Page 4: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

SignalingSignaling

Humoral – inflammatory mediators in the Humoral – inflammatory mediators in the circulation can induce fever and anorexia i.e. circulation can induce fever and anorexia i.e. TNF-TNF-αα

Neural – parasympathetic vagal stimulation Neural – parasympathetic vagal stimulation attenuates the inflammatory response via Ach attenuates the inflammatory response via Ach releaserelease Reduces HR, increases gut motility, dilates Reduces HR, increases gut motility, dilates

arterioles, constricts pupils, and decreases arterioles, constricts pupils, and decreases inflammationinflammation

Reduces macrophage activationReduces macrophage activation Reduces macrophage release of pro-inflammatory Reduces macrophage release of pro-inflammatory

mediators (TNF-mediators (TNF-αα, IL-1, IL-18), IL-1, IL-18)

Page 5: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Hormone SignalingHormone Signaling

Hormone classifications Hormone classifications polypeptide polypeptide (cytokine, insulin)(cytokine, insulin)

amino acid amino acid (epinephrine, serotonin, or histamine(epinephrine, serotonin, or histamine)) fatty acid fatty acid (cortisol, leukotrienes)(cortisol, leukotrienes)

PathwaysPathways Receptor Kinases Receptor Kinases – insulin– insulin

Guanine nucleotide binding (G-protein) Guanine nucleotide binding (G-protein) - - prostaglandinsprostaglandins

Ligand Gated ion channels Ligand Gated ion channels

Page 6: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Adrenocorticotropic Adrenocorticotropic HormoneHormone

Synthesized anterior pituitarySynthesized anterior pituitary Regulated by circadian signalsRegulated by circadian signals Pattern is dramatically altered in injured Pattern is dramatically altered in injured

patientspatients Elevation is proportional to injury severityElevation is proportional to injury severity Released by: pain, anxiety, vasopressin, Released by: pain, anxiety, vasopressin,

angiotensin II, cholecystokinin, angiotensin II, cholecystokinin, catecholamines, and pro-inflammatory catecholamines, and pro-inflammatory cytokinescytokines

ACTH signals increase glucocorticoid ACTH signals increase glucocorticoid productionproduction

Page 7: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

GlucocorticoidsGlucocorticoids

Cortisol – elevated following injury, Cortisol – elevated following injury, duration of elevation depends on severity of duration of elevation depends on severity of

injuryinjury Potentiates hyperglycemiaPotentiates hyperglycemia

Hepatic gluconeogenesisHepatic gluconeogenesis Muscle and adipose tissue –> induces insulin Muscle and adipose tissue –> induces insulin

resistanceresistance Skeletal m.–> protein degradation, lactate Skeletal m.–> protein degradation, lactate

releaserelease Adipose -> reduces release of TG, FFA, glycerolAdipose -> reduces release of TG, FFA, glycerol

Page 8: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Exogenous Exogenous administrationadministration

Adrenal suppression in the acutely illAdrenal suppression in the acutely ill Acute Adrenal InsufficiencyAcute Adrenal Insufficiency Atrophy of the adrenal glandsAtrophy of the adrenal glands Weakness, n/v, fever, hypotensionWeakness, n/v, fever, hypotension Hypoglycemia, hyponatremia, hyperkalemiaHypoglycemia, hyponatremia, hyperkalemia

ImmunosuppressionImmunosuppression Thymic involution, decreased T-killer and NK fcn, Thymic involution, decreased T-killer and NK fcn,

graft vs host rxns, delayed hypersensitivity graft vs host rxns, delayed hypersensitivity responses, inability of monocyte intracellular responses, inability of monocyte intracellular killing, inhibition of superoxide reactivity and killing, inhibition of superoxide reactivity and chemotaxis in neutrophilschemotaxis in neutrophils

Down regulates pro-inflammatory cytokine Down regulates pro-inflammatory cytokine production (TNF-production (TNF-αα, IL-1, IL-6), IL-1, IL-6)

Increases anti-inflammatory mediator IL-10Increases anti-inflammatory mediator IL-10 Useful in septic shock, surgical trauma, and CABGUseful in septic shock, surgical trauma, and CABG

Page 9: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Macrophage Inhibitory Macrophage Inhibitory FactorFactor

Glucocorticoid antagonist Glucocorticoid antagonist produced by anterior pituitary & T-produced by anterior pituitary & T-

lymphocyteslymphocytes Reverses immunosuppressive effects Reverses immunosuppressive effects

of glucocorticoidsof glucocorticoids Potentiates G- and G+ septic shockPotentiates G- and G+ septic shock Experimentally improves survivalExperimentally improves survival

Page 10: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Growth HormoneGrowth Hormone

During stress -> protein synth, fat During stress -> protein synth, fat mobilization, and skeletal cartilage growthmobilization, and skeletal cartilage growth

2˚ to release of insulin-like growth factor 2˚ to release of insulin-like growth factor (IGF1)(IGF1)

Injury reduces IGF1 levelsInjury reduces IGF1 levels IGF1 inhibited by pro-inflammatory IGF1 inhibited by pro-inflammatory

cytokinescytokines TNF-TNF-αα, IL-1, IL-1αα, IL-6, IL-6

GH admin to pediatric burn patients shows GH admin to pediatric burn patients shows improvement in their clinical courseimprovement in their clinical course

Page 11: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

CatecholaminesCatecholamines Severe injury activates the adrenergic Severe injury activates the adrenergic

systemsystem Norepi and Epi immed. increase 3-4 fold Norepi and Epi immed. increase 3-4 fold

and remain elevated 24-48hrs after injuryand remain elevated 24-48hrs after injury EpinephrineEpinephrine

hepatic glycogenolysis, gluconeogenesis, hepatic glycogenolysis, gluconeogenesis, lipolysis, and ketogenesislipolysis, and ketogenesis

Decreases insulin and glucagon secretionDecreases insulin and glucagon secretion Peripheral- lipolysis, insulin resistance in Peripheral- lipolysis, insulin resistance in

skeletal m.skeletal m. = stress induced hyperglycemia= stress induced hyperglycemia

Page 12: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Epinephrine – other Epinephrine – other effectseffects

Increase secretion of T3, T4, and Increase secretion of T3, T4, and reninrenin

Reduces release of aldosteroneReduces release of aldosterone Enhances leukocyte demargination Enhances leukocyte demargination

and lymphocytosisand lymphocytosis

Page 13: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

AldosteroneAldosterone

Synthesized, stored, released from the Synthesized, stored, released from the adrenal zona glomerulosaadrenal zona glomerulosa

Maintains intravascular volumeMaintains intravascular volume Conserves sodiumConserves sodium Eliminates potassium and hydrogen ionsEliminates potassium and hydrogen ions Acts on the early distal convoluted tubulesActs on the early distal convoluted tubules

Deficiency- hypotension, hyperkalemiaDeficiency- hypotension, hyperkalemia Excess- edema, HTN, hypokalemia, Excess- edema, HTN, hypokalemia,

metab alkalosismetab alkalosis

Page 14: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

InsulinInsulin Hyperglycemia and insulin resistance are Hyperglycemia and insulin resistance are

hallmarks due to the catabolic effects of hallmarks due to the catabolic effects of circulating mediatorscirculating mediators

Hyperglycemia during critical illness has Hyperglycemia during critical illness has immunosuppressive effectsimmunosuppressive effects

Injury has 2 phases of insulin releaseInjury has 2 phases of insulin release Within hours- release is suppressedWithin hours- release is suppressed Later- normal/xs insulin production with Later- normal/xs insulin production with

peripheral insulin resistanceperipheral insulin resistance Tight control of glucose levels esp. in Tight control of glucose levels esp. in

diabetics significantly reduces mortality diabetics significantly reduces mortality after injuryafter injury

Page 15: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Acute Phase ProteinsAcute Phase Proteins

Nonspecific markersNonspecific markers Produced by hepatocytesProduced by hepatocytes Response to injury, infection, Response to injury, infection,

inflammationinflammation C-reactive protein best reflects C-reactive protein best reflects

inflammationinflammation No diurnal variation, not affected by No diurnal variation, not affected by

feedingfeeding Affected only by hepatic insufficencyAffected only by hepatic insufficency

Page 16: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Inflammatory MediatorsInflammatory Mediators

Heat Shock ProteinsHeat Shock Proteins Reactive Oxygen MetabolitesReactive Oxygen Metabolites EicosanoidsEicosanoids Fatty Acid MetabolitesFatty Acid Metabolites Kallikrein-Kinin SystemKallikrein-Kinin System SerotoninSerotonin HistamineHistamine CytokinesCytokines

Page 17: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Heat Shock ProteinsHeat Shock Proteins

Induced by burn injury, inflammation, Induced by burn injury, inflammation, and infectionand infection

HSPs bind autologous and foreign HSPs bind autologous and foreign proteins and function as intracellular proteins and function as intracellular chaperones for ligands such as chaperones for ligands such as bacterial DNA and endotoxinbacterial DNA and endotoxin

Requires gene induction by a Requires gene induction by a transcription factortranscription factor

Production seems to decline with ageProduction seems to decline with age

Page 18: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Reactive Oxygen Reactive Oxygen MetabolitesMetabolites

Short-livedShort-lived Cause tissue injury by oxidation of Cause tissue injury by oxidation of

unsaturated fatty acids within cell unsaturated fatty acids within cell membranesmembranes

Produced by anaerobic glucose oxidation Produced by anaerobic glucose oxidation and reduction to superoxide anion in and reduction to superoxide anion in leukocytesleukocytes

Further metabolized to hydrogen peroxide Further metabolized to hydrogen peroxide and hydroxyl radicalsand hydroxyl radicals

Cells are protected by oxygen scavengers – Cells are protected by oxygen scavengers – glutathione and catalasesglutathione and catalases

In ischemia- production of oxygen In ischemia- production of oxygen metabolites are activated but nonfunctional metabolites are activated but nonfunctional due to no oxygen supply. After reperfusion, due to no oxygen supply. After reperfusion, large amounts are produced causing injurylarge amounts are produced causing injury

Page 19: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

EicosanoidsEicosanoids

Page 20: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

EicosanoidsEicosanoids derived primarily by oxidation of the membrane derived primarily by oxidation of the membrane

phospholipid arachidonic acid phospholipid arachidonic acid Induced by hypoxic injury, direct tissue injury, Induced by hypoxic injury, direct tissue injury,

endotoxin, norepinephrine, vasopressin, ang II, endotoxin, norepinephrine, vasopressin, ang II, bradykinin, serotonin, ACh, cytokines, histaminebradykinin, serotonin, ACh, cytokines, histamine

systemic effects : neurotransmission, vasomotor systemic effects : neurotransmission, vasomotor regulation, and immune cell regulation regulation, and immune cell regulation

Generate proinflammatory response Generate proinflammatory response Adverse effects include acute lung injury, Adverse effects include acute lung injury,

pancreatitis, renal failurepancreatitis, renal failure NSAIDs ,steroids and leukotriene inhibitors block NSAIDs ,steroids and leukotriene inhibitors block

the end products of eicosanoid pathwaysthe end products of eicosanoid pathways

Page 21: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Eicosanoid EffectsEicosanoid Effects Pancreas – glucagon Pancreas – glucagon

secretion- PGD2, PGE2 secretion- PGD2, PGE2 while Insulin secretion by while Insulin secretion by HPETEHPETE

Liver – glucagon stimulated Liver – glucagon stimulated glucose production- PGE2glucose production- PGE2

Adipose – lipolysis- PGE2Adipose – lipolysis- PGE2 Bone – resorption- PGE2, Bone – resorption- PGE2,

PGF2PGF2αα, PGI2, PGI2 Parathyroid – PTH Parathyroid – PTH

secretion- PGE2secretion- PGE2 Pulmonary – Pulmonary –

Bronchoconstriction- Bronchoconstriction- PGF2PGF2αα, TXA2, , TXA2, LTC4, LTD4, LTC4, LTD4, LTE4LTE4

Immune – suppress Immune – suppress lymphocytes- PGE2lymphocytes- PGE2

Hematologic Hematologic platelet aggregation- TXA2platelet aggregation- TXA2

Pituitary Pituitary Prolactin- PGE1Prolactin- PGE1 LH- PGE1, PGE2, 5-HETELH- PGE1, PGE2, 5-HETE TSH- PGA1, PGB1, PGE1, PGE1TSH- PGA1, PGB1, PGE1, PGE1αα GH- PGE1 GH- PGE1

Renal – renin secretion- PGE2, Renal – renin secretion- PGE2, PGI2PGI2

GI – cytoprotective- PGE2GI – cytoprotective- PGE2

Page 22: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Leukotrienes are potent mediators of Leukotrienes are potent mediators of capillary leakage as well as leukocyte capillary leakage as well as leukocyte adherence, neutrophil activation, adherence, neutrophil activation, bronchoconstriction, and bronchoconstriction, and vasoconstrictionvasoconstriction

Cyclooxygenase pathway products Cyclooxygenase pathway products inhibit pancreatic B-cell release of inhibit pancreatic B-cell release of insulin, whereas lipoxygenase pathway insulin, whereas lipoxygenase pathway products stimulate B-cell activity. products stimulate B-cell activity.

Human sepsis trials have failed to show Human sepsis trials have failed to show a mortality benefit of inhibiting a mortality benefit of inhibiting eicosanoid pathway by using NSAIDseicosanoid pathway by using NSAIDs

Page 23: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Fatty Acid MetabolitesFatty Acid Metabolites Omega 6 FA – precursors of inflammatory Omega 6 FA – precursors of inflammatory

mediators (LT, PG, platelet activating, factor)mediators (LT, PG, platelet activating, factor) Substituting Omega 3 FA attenuate the Substituting Omega 3 FA attenuate the

inflammatory responseinflammatory response Reduces TNFReduces TNFαα, IL6, PGE2 ,NF b , IL6, PGE2 ,NF b attenuates weight loss, increase small-bowel attenuates weight loss, increase small-bowel

perfusion, and may increase gut barrier perfusion, and may increase gut barrier protectionprotection

preoperative supplementation with omega-3 preoperative supplementation with omega-3 fatty acid was associated with reduced need for fatty acid was associated with reduced need for mechanical ventilation, decreased hospital mechanical ventilation, decreased hospital length of stay, and decreased mortality with a length of stay, and decreased mortality with a good safety profilegood safety profile

Page 24: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Kallikrein-Kinin SystemKallikrein-Kinin System

Bradykinins are potent vasodilatorsBradykinins are potent vasodilators Stimulated by hypoxic and ischemic injuryStimulated by hypoxic and ischemic injury

Hemorrhage, sepsis, endotoxemia, tissue injuryHemorrhage, sepsis, endotoxemia, tissue injury Magnitude proportional to severity of injuryMagnitude proportional to severity of injury

Produced by kininogen degradation by Produced by kininogen degradation by kallikreinkallikrein

Kinins increase capillary permeability Kinins increase capillary permeability (edema), pain, inhibit gluconeogenesis, renal (edema), pain, inhibit gluconeogenesis, renal vasodilation, incr bronchoconstrictionvasodilation, incr bronchoconstriction

In clinical trials, bradykinin antagonists help In clinical trials, bradykinin antagonists help reverse G- sepsis, but do not improve survivalreverse G- sepsis, but do not improve survival

Page 25: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

SerotoninSerotonin

Present in CNS neurons , intestinal Present in CNS neurons , intestinal chromaffin cells & plateletschromaffin cells & platelets

Vasoconstriction, Vasoconstriction, bronchoconstriction, platelet bronchoconstriction, platelet aggregationaggregation

Myocardial chronotrope and Myocardial chronotrope and ionotropeionotrope

Unclear role in inflammationUnclear role in inflammation

Page 26: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

HistamineHistamine

Stored in neurons, skin, gastric mucosa, mast cells, Stored in neurons, skin, gastric mucosa, mast cells, basophils, and plateletsbasophils, and platelets

H1 – bronchoconstriction, increases intestinal H1 – bronchoconstriction, increases intestinal motility and myocardial contractility , vasodilationmotility and myocardial contractility , vasodilation

H2 – stimulates gastric parietal cell acid secretionH2 – stimulates gastric parietal cell acid secretion H3 is an autoreceptor found on presynaptic H3 is an autoreceptor found on presynaptic

histamine-containing nerve endings and leads to histamine-containing nerve endings and leads to downregulation of histamine releasedownregulation of histamine release

H4 is expressed primarily in bone marrow, H4 is expressed primarily in bone marrow, eosinophils, and mast cellseosinophils, and mast cells

Page 27: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

CytokinesCytokines

Most potent mediators of inflammationMost potent mediators of inflammation Local- eradicate microorganisms, promote Local- eradicate microorganisms, promote

wound healingwound healing Overwhelming response- hemodynamic Overwhelming response- hemodynamic

instability (septic shock) or metabolic instability (septic shock) or metabolic derangements (muscle wasting)derangements (muscle wasting)

Uncontrolled- end-organ failure, deathUncontrolled- end-organ failure, death Self-regulatory production of anti-Self-regulatory production of anti-

inflammatory cytokines, but inappropriate inflammatory cytokines, but inappropriate release may render the patient release may render the patient immunocompromised and susceptible to immunocompromised and susceptible to infectioninfection

Page 28: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Tumor Necrosis Factor Tumor Necrosis Factor αα

Secreted from monocytes, Secreted from monocytes, macrophages, Tcellsmacrophages, Tcells

Potent evocation of cytokine cascadePotent evocation of cytokine cascade Induces muscle catabolism/cachexia, Induces muscle catabolism/cachexia,

coagulation, PGE2, PAF, coagulation, PGE2, PAF, glucocorticoids, eicosanoidsglucocorticoids, eicosanoids

Circulating TNF receptors compete Circulating TNF receptors compete with cellular receptors and may act as with cellular receptors and may act as a counter regulatory system to a counter regulatory system to prevent excessive TNF-prevent excessive TNF-αα activity activity

Page 29: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interleukin-1Interleukin-1

Released by activated macrophages, Released by activated macrophages, endothelial cellsendothelial cells

IL1IL1αα- cell membrane associated- cell membrane associated IL1IL1ββ- circulation- circulation 2types of receptors same as TNFR’s mech.2types of receptors same as TNFR’s mech. Synergistic with TNF- Synergistic with TNF- αα T ½ = 6 minT ½ = 6 min Induces febrile response by stimulating PG Induces febrile response by stimulating PG

activity in the anterior hypothalamusactivity in the anterior hypothalamus

Page 30: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interleukin-2Interleukin-2

Promotes T-lymphocyte proliferation and Promotes T-lymphocyte proliferation and differentiation, Ig production, gut barrier differentiation, Ig production, gut barrier integrityintegrity

T ½ < 10 minT ½ < 10 min Major injury or perioperative blood Major injury or perioperative blood

transfusions reduce IL-2 activity leading transfusions reduce IL-2 activity leading to a transient immunocompromised stateto a transient immunocompromised state

Its blockade used pharmacologically in Its blockade used pharmacologically in organ transplantationorgan transplantation

Page 31: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 32: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interleukin-4Interleukin-4 Produced by type 2 T Helper lymphocytesProduced by type 2 T Helper lymphocytes Important in antibody-mediated switching Important in antibody-mediated switching

and antigen presentationand antigen presentation Induces class switching to promote IgE & Induces class switching to promote IgE &

IgG4IgG4 Important in allergic and antihelmintic responsesImportant in allergic and antihelmintic responses

Anti-inflammatory- downregulates IL-1, TNF-Anti-inflammatory- downregulates IL-1, TNF-αα, IL-6, IL-8 and oxygen radical production, IL-6, IL-8 and oxygen radical production

Increases macrophage susceptibility to anti-Increases macrophage susceptibility to anti-inflammatory effects of glucocorticoidsinflammatory effects of glucocorticoids

Page 33: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interleukin-6Interleukin-6 Induced by IL-1 and TNF-Induced by IL-1 and TNF-αα Levels are detectable within 60 min of injury, Levels are detectable within 60 min of injury,

peak 4-6 hours, and persist up to 10 dayspeak 4-6 hours, and persist up to 10 days Levels are proportional to extent of tissue Levels are proportional to extent of tissue

injuryinjury High plasma IL-6 levels have been associated High plasma IL-6 levels have been associated

with mortality during intra-abdominal sepsiswith mortality during intra-abdominal sepsis Anti-inflammatoryAnti-inflammatory

Attenuate TNF-Attenuate TNF-αα and IL-1 activity and IL-1 activity Promote release of circulating TNF- Promote release of circulating TNF- αα receptors receptors

& IL-1 antagonists& IL-1 antagonists stimulates the release of cortisolstimulates the release of cortisol

Page 34: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 35: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interleukin-8Interleukin-8

Released from macrohages andd Released from macrohages andd endothelial cells mainly endothelial cells mainly

Chemoattractant for neutrophilsChemoattractant for neutrophils Stimulates release of IFN-Stimulates release of IFN- pLasma levels are associated with pLasma levels are associated with

disease severity disease severity

Page 36: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 37: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interleukin-10Interleukin-10

Anti-inflammatoryAnti-inflammatory Released from monocytesReleased from monocytes Down-regulates TNF-Down-regulates TNF-αα activity activity Increased plasma levels of IL-10 have Increased plasma levels of IL-10 have

been associated with mortality and been associated with mortality and disease severity after traumatic injurydisease severity after traumatic injury

significantly contribute to the significantly contribute to the underlying immunosuppressed state underlying immunosuppressed state during sepsis during sepsis

Page 38: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interleukin-12Interleukin-12 Promotes differentiation of type 1 T Helper cells Promotes differentiation of type 1 T Helper cells

so known as regulator cell mediatedso known as regulator cell mediated Released by activated phagocytes, including Released by activated phagocytes, including

monocytes, macrophages, neutrophils, and monocytes, macrophages, neutrophils, and dendritic cellsdendritic cells

IL-12 stimulates lymphocytes to increase IL-12 stimulates lymphocytes to increase secretion of IFN- with the costimulus of secretion of IFN- with the costimulus of interleukin-18 interleukin-18

stimulates natural killer cell cytotoxicity and stimulates natural killer cell cytotoxicity and helper T cell differentiationhelper T cell differentiation

IL-12 enhances coagulation as well as fibrinolysisIL-12 enhances coagulation as well as fibrinolysis

Page 39: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interleukin-13Interleukin-13

Similar to IL-4, overall anti-Similar to IL-4, overall anti-inflammatoryinflammatory

Modulates monocytes functionModulates monocytes function Unlike IL-4, has no effect on T Unlike IL-4, has no effect on T

lymphocyteslymphocytes Inhibits pro-inflammatory cytokinesInhibits pro-inflammatory cytokines Attenuates leukocyte interaction Attenuates leukocyte interaction

with activated endothelial surfaceswith activated endothelial surfaces

Page 40: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interleukin-15Interleukin-15

Derived from macrophages mainly Derived from macrophages mainly functions as a regulator of cellular functions as a regulator of cellular

immunityimmunity Shares receptor components with IL-Shares receptor components with IL-

2, and shares promoting lymphocyte 2, and shares promoting lymphocyte activation/prolif.activation/prolif.

acts as a potent inhibitor of acts as a potent inhibitor of lymphocyte apoptosis lymphocyte apoptosis

Page 41: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interleukin-18Interleukin-18

Formerly IFN-Formerly IFN-γγ-inducing factor-inducing factor Produced by macrophagesProduced by macrophages Pro-inflammatory, similar to IL-12Pro-inflammatory, similar to IL-12 Increased levels are pronounced Increased levels are pronounced

(especially in G- sepsis)(especially in G- sepsis) IL-18 regulation is in part mediated IL-18 regulation is in part mediated

through IL-18–binding protein (IL-18BP) through IL-18–binding protein (IL-18BP) which found to be secreted also by which found to be secreted also by molluscum contagiosum skin Pathogen molluscum contagiosum skin Pathogen

Page 42: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Interferon-Interferon-γγ

Helper T lymphocytes activated by bacterial Helper T lymphocytes activated by bacterial antigens, IL-2, IL-12, or IL-18 produce IFN-antigens, IL-2, IL-12, or IL-18 produce IFN-γγ

IFN-IFN-γγ can induce IL-2, IL-12, or IL-18 can induce IL-2, IL-12, or IL-18 Detectable in circulation by 6 hrs and remain Detectable in circulation by 6 hrs and remain

elevated for up to 8 dayselevated for up to 8 days Activate circulating and tissue macrophagesActivate circulating and tissue macrophages Induces acute lung inflammation by activating Induces acute lung inflammation by activating

alveolar macrophages after surgery or traumaalveolar macrophages after surgery or trauma Negative regulators of IFN- include IL4, IL-Negative regulators of IFN- include IL4, IL-

10, and glucocorticoids10, and glucocorticoids

Page 43: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Granulocyte-Macrophage Granulocyte-Macrophage Colony-Stimulating FactorColony-Stimulating Factor

upregulates both granulocyte and monocyte upregulates both granulocyte and monocyte cell lines from hematopoietic bone marrow cell lines from hematopoietic bone marrow stem cellsstem cells

Delays apoptosis of macrophages and PMNsDelays apoptosis of macrophages and PMNs Promotes the maturation and recruitment of Promotes the maturation and recruitment of

PMNs in inflammation PMNs in inflammation potentiate acute lung injury during critical potentiate acute lung injury during critical

illnessillness

Page 44: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

High Mobility Group Box High Mobility Group Box 11

DNA transcription factorDNA transcription factor Expressed 24-48 hrs after injuryExpressed 24-48 hrs after injury Associated with weight loss, food Associated with weight loss, food

aversion, shock, SIRS and Sepsisaversion, shock, SIRS and Sepsis Peak levels are associated with Peak levels are associated with

ARDS and deathARDS and death

Page 45: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Cell Signaling PathwaysCell Signaling Pathways Heat Shock ProteinsHeat Shock Proteins

produced in response to ischemia/injuryproduced in response to ischemia/injury HS Factors are activated upon injury, undergo HS Factors are activated upon injury, undergo

conformational changes, translocate into the conformational changes, translocate into the nucleus, and bind HSP promoter regionsnucleus, and bind HSP promoter regions

Attenuate inflammatory responseAttenuate inflammatory response Ligand Gated Ion ChannelsLigand Gated Ion Channels

When activated by a ligand, a rapid influx of ions When activated by a ligand, a rapid influx of ions cross the cell membrane. i.e. neurotransmitterscross the cell membrane. i.e. neurotransmitters

effectively convert a chemical signal into an effectively convert a chemical signal into an electrical signalelectrical signal

Page 46: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 47: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Cell Signaling PathwaysCell Signaling Pathways G-protein receptorsG-protein receptors

Largest family of signaling receptorsLargest family of signaling receptors Adjacent effector protein activated receptorAdjacent effector protein activated receptor Second messengers – cAMP or calciumSecond messengers – cAMP or calcium Can result in gene transcription or activation of Can result in gene transcription or activation of

phospholipase Cphospholipase C Tyrosine KinasesTyrosine Kinases

When activated, receptors dimerize, phosphorylate, When activated, receptors dimerize, phosphorylate, and recruit secondary signaling molecules and recruit secondary signaling molecules

Used in gene transcription and cell proliferation by Used in gene transcription and cell proliferation by mean of cell signaling for several growth factorsmean of cell signaling for several growth factors

i.e. insulin, PGDF, IGF-1i.e. insulin, PGDF, IGF-1

Page 48: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 49: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 50: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Cell Signaling PathwaysCell Signaling Pathways

Janus Kinase/Signal Transduction and Janus Kinase/Signal Transduction and Activator of Transcription (JAK-STAT)Activator of Transcription (JAK-STAT) IL-6, IL-10, IL-12, IL-13, IFN-IL-6, IL-10, IL-12, IL-13, IFN-γγ Ligand binds to the receptor, receptor dimerizes, Ligand binds to the receptor, receptor dimerizes,

enzymatic activation via phosphorylation enzymatic activation via phosphorylation propagates through the JAK domain and recruits propagates through the JAK domain and recruits STAT to the cytosolic receptor portion. STAT to the cytosolic receptor portion.

STAT dimerizes and translocates into the nucleus STAT dimerizes and translocates into the nucleus as a transcription factor within minutes of JAK’s as a transcription factor within minutes of JAK’s binding to cytokinesbinding to cytokines

Suppressors of cytokine signaling (SOCS) block Suppressors of cytokine signaling (SOCS) block JAK-STATJAK-STAT

Page 51: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 52: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Mitogen-Activated Protein Mitogen-Activated Protein KinasesKinases

(MAPK) pathway is a major cellular (MAPK) pathway is a major cellular inflammatory signaling pathway inflammatory signaling pathway with regulatory roles over cell with regulatory roles over cell proliferation and cell deathproliferation and cell death

MAPK isoforms exhibit appreciable MAPK isoforms exhibit appreciable “cross-talk,” which can modulate the “cross-talk,” which can modulate the inflammatory responseinflammatory response

Page 53: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 54: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Nuclear Factor-Nuclear Factor-κκBB

NF-κB activates genes important for the NF-κB activates genes important for the activation of proinflammatory cytokines activation of proinflammatory cytokines and acute phase proteinsand acute phase proteins

Cytosolic NF-κB is maintained by Cytosolic NF-κB is maintained by binding to the inhibitor protein I-κBbinding to the inhibitor protein I-κB

Low intracellular I-κB appears to prolong Low intracellular I-κB appears to prolong the inflammatory response and enhanced the inflammatory response and enhanced activity of NF-κB appears to delay the activity of NF-κB appears to delay the apoptosis of activated immune cellsapoptosis of activated immune cells

Page 55: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 56: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Toll-Like Receptors and Toll-Like Receptors and CD14CD14

Lipopolysaccharide (LPS), an endotoxin, Lipopolysaccharide (LPS), an endotoxin, is an important mediator of is an important mediator of gramnegative sepsis syndromegramnegative sepsis syndrome

TLR4 is primarily the receptor for gram-TLR4 is primarily the receptor for gram-negative endotoxins and TLR2 is the negative endotoxins and TLR2 is the counterpart for gram-positive sepsiscounterpart for gram-positive sepsis

Specific point mutations in the TLR gene Specific point mutations in the TLR gene change susceptebility for infections change susceptebility for infections among patients among patients

Page 57: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 58: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Tumor Necrosis FactorTumor Necrosis Factor

ApoptosisApoptosis - normal fcn of cellular - normal fcn of cellular disposal w/o activating the disposal w/o activating the immune/inflammatory systemimmune/inflammatory system

2 receptors2 receptors TNFR-1 : inflammation, apoptosis, circulatory TNFR-1 : inflammation, apoptosis, circulatory

shockshock TNFR-2 : no inflammation or shockTNFR-2 : no inflammation or shock

CD95 (Fas) receptor similar structure to CD95 (Fas) receptor similar structure to TNFR-1TNFR-1 Initiates apoptosisInitiates apoptosis

Page 59: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Cell Mediated Cell Mediated InflammationInflammation

PlateletsPlatelets Source of eicosanoids and vasoactive Source of eicosanoids and vasoactive

mediatorsmediators Clot is a chemoattractant for PMNs/monocytesClot is a chemoattractant for PMNs/monocytes Modulate PMN endothelium adherenceModulate PMN endothelium adherence Migration occurs within 3 hrs of injury Migration occurs within 3 hrs of injury

Mediated by serotonin, PAF, PGE2Mediated by serotonin, PAF, PGE2 EosinophilsEosinophils

Migrate to parasitic infection and allergen Migrate to parasitic infection and allergen challenge to release cytotoxic granuleschallenge to release cytotoxic granules

Reside in the GI, lung, and GU tissuesReside in the GI, lung, and GU tissues Activated by IL-3, GM-CSF, IL-5, PAF, and Activated by IL-3, GM-CSF, IL-5, PAF, and

anaphylatoxins C3a and C5aanaphylatoxins C3a and C5a

Page 60: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Cell Mediated Cell Mediated InflammationInflammation

LymphocytesLymphocytes T-helpers produce IL-3, TNF-T-helpers produce IL-3, TNF-αα, GM-CSF , GM-CSF

TH1: IFN-TH1: IFN-γγ, IL-2, IL-12, IL-2, IL-12 TH2: IL-4, IL-5, IL-6, IL-9, IL-10, IL-13TH2: IL-4, IL-5, IL-6, IL-9, IL-10, IL-13 Severe infection – shift toward more TH2Severe infection – shift toward more TH2

Mast CellsMast Cells First responders to injuryFirst responders to injury Produce histamine, cytokines, eicosanoids, Produce histamine, cytokines, eicosanoids,

proteases, chemokines, TNF-proteases, chemokines, TNF-αα (stored in granules) (stored in granules) Cause vasodilation, capillary leakage, and recruit Cause vasodilation, capillary leakage, and recruit

immunocytesimmunocytes

Page 61: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 62: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Cell Mediated Cell Mediated InflammationInflammation

MonocytesMonocytes Downregulation of receptor TNFR is clinically Downregulation of receptor TNFR is clinically

and experimentally correlated with CHF, and experimentally correlated with CHF, nonsurvival in sepsisnonsurvival in sepsis

NeutrophilsNeutrophils Modulate acute inflammationModulate acute inflammation Maturation is stimulated by G-CSFMaturation is stimulated by G-CSF Rolling (L-selectin (fast), P-selectin (slow)Rolling (L-selectin (fast), P-selectin (slow) Adhesion/transmigration – ICAM 1, 2, PECAM Adhesion/transmigration – ICAM 1, 2, PECAM

1, VCAM 1, CD181, VCAM 1, CD18

Page 63: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Endothelium-Mediated Endothelium-Mediated InjuryInjury

Neutrophil-Endothelium InteractionNeutrophil-Endothelium Interaction Increased vascular permeability – Increased vascular permeability –

facilitate oxygen delivery and facilitate oxygen delivery and immunocyte migrationimmunocyte migration

Accumulation of neutrophils at injury Accumulation of neutrophils at injury sites can cause cytotoxicity to vital sites can cause cytotoxicity to vital organsorgans

Ischemia-reperfusion injury potentiates Ischemia-reperfusion injury potentiates this response by releasing oxygen this response by releasing oxygen metabolites and lysosomal enz.metabolites and lysosomal enz.

Page 64: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Nitric OxideNitric Oxide

Derived from endothelial surfaces Derived from endothelial surfaces responding to Ach, hypoxia, responding to Ach, hypoxia, endotoxin, cellular injury, or shear endotoxin, cellular injury, or shear stresses of circulating bloodstresses of circulating blood

T ½ = secondsT ½ = seconds Reduces microthrombosis, mediates Reduces microthrombosis, mediates

protein synthesis in hepatocytesprotein synthesis in hepatocytes Formed from oxidation of L-arginine Formed from oxidation of L-arginine

via NOSvia NOS

Page 65: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Prostacyclin (PGI2)Prostacyclin (PGI2)

Endothelium derived in response to Endothelium derived in response to shear stress and hypoxiashear stress and hypoxia

VasodilatorVasodilator Platelet deactivation (increases Platelet deactivation (increases

cAMP)cAMP) Clinically used to reduce pulmonary Clinically used to reduce pulmonary

hypertension (especially pediatric)hypertension (especially pediatric)

Page 66: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

EndothelinsEndothelins

Produced as a response to a variety Produced as a response to a variety of factors – injury, anoxia, thrombin, of factors – injury, anoxia, thrombin, IL-1, vasopressin IL-1, vasopressin

ET-1 is a potent vasoconstrictor, 10x ET-1 is a potent vasoconstrictor, 10x more potent than angiotensin IImore potent than angiotensin II

Works in synergism with NO acc. To Works in synergism with NO acc. To vascular smooth muscle tone vascular smooth muscle tone

Page 67: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Platelet Activating Platelet Activating FactorFactor

Phospholipid component of cell Phospholipid component of cell membranes, constitutively expressed at membranes, constitutively expressed at low levelslow levels

Released by PMNs, platelets, mast cells, Released by PMNs, platelets, mast cells, monocytes during acute inflammationmonocytes during acute inflammation

Further activates PMNs and plateletsFurther activates PMNs and platelets Increases vascular permeabilityIncreases vascular permeability PAF antagonists reduce PAF antagonists reduce

ischemia/reperfusion injuryischemia/reperfusion injury

Page 68: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Metabolism During Metabolism During FastingFasting

Comparable to changes Comparable to changes seen in acute injuryseen in acute injury

Requires 25-40 Requires 25-40 kcal/kg/day of carbs, kcal/kg/day of carbs, protein, fatprotein, fat

Normal adult body Normal adult body contains 300-400g contains 300-400g carbs (glycogen) – 75-carbs (glycogen) – 75-100g hepatic, 200-250g 100g hepatic, 200-250g muscle (not available muscle (not available systemically due to systemically due to deficiency of G6P)deficiency of G6P)

Mass Mass (kg)(kg)

Energy Energy (Kcal)(Kcal)

Days Days AvailabAvailablele

WaterWater 4949 00 00

ProteinProtein 66 24,00024,000 1313

GlycogGlycogenen

0.20.2 800800 0.40.4

FatFat 1515 140,00140,0000

7878

TotalTotal 70.270.2 164,80164,8000

91.491.4

Page 69: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Metabolism During Metabolism During FastingFasting

A healthy 70kg adult will use 180 g /d A healthy 70kg adult will use 180 g /d of glucose to support obligate of glucose to support obligate glycolytic cells (neurons, RBCs, PMNs, glycolytic cells (neurons, RBCs, PMNs, renal medulla, skeletal m.)renal medulla, skeletal m.)

Glucagon, Norepi, vasopressin, AngII Glucagon, Norepi, vasopressin, AngII promote utilization of glycogen stores promote utilization of glycogen stores

Glucagon, Epi, and cortisol promote Glucagon, Epi, and cortisol promote gluconeogenesisgluconeogenesis

Precursors include lactate (sk.m., rbc, Precursors include lactate (sk.m., rbc, pmn), glycerol, and aa (ala, glutamine)pmn), glycerol, and aa (ala, glutamine)

Page 70: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi
Page 71: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Metabolism of Simple Metabolism of Simple StarvationStarvation

Lactate is not sufficient for glucose Lactate is not sufficient for glucose demandsdemands

Protein must be degraded (75 g/d) Protein must be degraded (75 g/d) for hepatic gluconeogenesisfor hepatic gluconeogenesis

Proteolysis from decreased insulin Proteolysis from decreased insulin and increased cortisoland increased cortisol

Elevated urinary nitrogen (7 -> 30 Elevated urinary nitrogen (7 -> 30 g/d)g/d)

Page 72: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Metabolism of Prolonged Metabolism of Prolonged StarvationStarvation

Proteolysis is reduced to 20g/d and Proteolysis is reduced to 20g/d and urinary nitrogen excretion stabilizes to 2-urinary nitrogen excretion stabilizes to 2-5g/d5g/d

Organs (myocardium, brain, renal cortex, Organs (myocardium, brain, renal cortex, sk.m) adapt to ketone bodies in 2-24 dayssk.m) adapt to ketone bodies in 2-24 days

Kidneys utilize glutamine and glutamate Kidneys utilize glutamine and glutamate in gluconeogenesisin gluconeogenesis

Adipose stores provide up to 40% calories Adipose stores provide up to 40% calories (approx 160 g FFA and glycerol)(approx 160 g FFA and glycerol) Stimulated by reduced insulin and increased Stimulated by reduced insulin and increased

glucagon and catecholaminesglucagon and catecholamines

Page 73: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Metabolism Following Metabolism Following InjuryInjury

Magnitude of expenditure is Magnitude of expenditure is proportional to the severity of injuryproportional to the severity of injury

Changes in Changes in Lipid AbsorptionLipid Absorption Lipid OxidationLipid Oxidation Carbohydrate metabolismCarbohydrate metabolism

Page 74: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Lipid AbsorptionLipid Absorption Oxidation of 1g fat = 9 kcal energyOxidation of 1g fat = 9 kcal energy Dietary lipids require pancreatic lipase and Dietary lipids require pancreatic lipase and

phospholipase to hydrolyze TG into FFA and phospholipase to hydrolyze TG into FFA and monoglycerides within the duodenummonoglycerides within the duodenum

After gut absorption, enterocytes resynthesize TG After gut absorption, enterocytes resynthesize TG from monoglycerides + fatty acyl-CoAfrom monoglycerides + fatty acyl-CoA

Long chain TG (>12 carbons) enter the circulation Long chain TG (>12 carbons) enter the circulation as chylomicrons. Shorter FA chains directly enter as chylomicrons. Shorter FA chains directly enter portal circulation and are transported via albuminportal circulation and are transported via albumin

Under stress, hepatocytes utilize FFA as fuelUnder stress, hepatocytes utilize FFA as fuel Systemically TG and chylomicrons are used from Systemically TG and chylomicrons are used from

hydrolysis with lipoprotein lipase (suppressed by hydrolysis with lipoprotein lipase (suppressed by trauma and sepsis)trauma and sepsis)

Page 75: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Fatty Acid OxidationFatty Acid Oxidation FFA + acyl-CoA = LCT are transported FFA + acyl-CoA = LCT are transported

across the mitochondrial inner membrane across the mitochondrial inner membrane via the carnitine shuttlevia the carnitine shuttle

Medium-chain TG (MCT) 6-12 carbons Medium-chain TG (MCT) 6-12 carbons long, freely cross the mitochondrial long, freely cross the mitochondrial membranemembrane

Fatty acyl-CoA undergoes Fatty acyl-CoA undergoes ββ-oxidation to -oxidation to acetyl-CoA to enter TCA cycle for acetyl-CoA to enter TCA cycle for oxidation to ATP, CO2, and wateroxidation to ATP, CO2, and water

Excess acetyl-CoA is used for ketogenesisExcess acetyl-CoA is used for ketogenesis

Page 76: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Carbohydrate Carbohydrate MetabolismMetabolism

Carbohydrates + pancreatic intestinal Carbohydrates + pancreatic intestinal enzymes yield dimeric units (sucrase, enzymes yield dimeric units (sucrase, lactase, maltase)lactase, maltase)

Intestinal brush border disaccharidases Intestinal brush border disaccharidases break them into simple hexose units which break them into simple hexose units which are transported into the intestinal mucosaare transported into the intestinal mucosa

Glucose and galactose are absorbed via a Glucose and galactose are absorbed via a sodium dependent active transport pumpsodium dependent active transport pump

Fructose absorption via facilitated diffusionFructose absorption via facilitated diffusion

Page 77: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Carbohydrate Carbohydrate MetabolismMetabolism

1g carbohydrate = 4 kcal energy1g carbohydrate = 4 kcal energy IV/parenteral nutrition 3.4 kcal/g IV/parenteral nutrition 3.4 kcal/g

dextrosedextrose In surgical patients dextrose In surgical patients dextrose

administration is to minimize muscle administration is to minimize muscle wastingwasting

Glucose can be utilized in a variety of Glucose can be utilized in a variety of pathways – phosphorylation to G6P then pathways – phosphorylation to G6P then glycogenesis or glycogenolysis, pyruvic glycogenesis or glycogenolysis, pyruvic acid pathway, or pentose shuntacid pathway, or pentose shunt

Page 78: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Protein and Amino Acid Protein and Amino Acid MetabolismMetabolism

Average adult protein intake 80-120 Average adult protein intake 80-120 g/dayg/day every 6 g protein yields 1 g nitrogenevery 6 g protein yields 1 g nitrogen 1g protein = 4 kcal energy1g protein = 4 kcal energy

Following injury, glucocorticoids Following injury, glucocorticoids increase urinary nitrogen excretion increase urinary nitrogen excretion (>30g/d), peak at 7d, persist 3-7 (>30g/d), peak at 7d, persist 3-7 wkswks

Page 79: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Nutrition in the Surgical Nutrition in the Surgical PatientPatient

Nutritional assessment to determine the Nutritional assessment to determine the severity of deficiencies/excessseverity of deficiencies/excess

Wt loss, chronic illnesses, dietary habits, Wt loss, chronic illnesses, dietary habits, quality/quantity of food, social habits, quality/quantity of food, social habits, medsmeds

Physical exam – loss of muscle/adipose Physical exam – loss of muscle/adipose tissue, organ dysfunctiontissue, organ dysfunction

Biochemical – Cr excretion, albumin, Biochemical – Cr excretion, albumin, prealbumin, total lymphocyte count, prealbumin, total lymphocyte count, transferrintransferrin

Page 80: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Surgical NutritionSurgical Nutrition Support the requirements for protein synthesisSupport the requirements for protein synthesis Nonprotein calorie : nitrogen objective ratio = Nonprotein calorie : nitrogen objective ratio =

150:1150:1 A lower rate of 80-100:1 may be beneficial in A lower rate of 80-100:1 may be beneficial in

some critically ill or hypermetabolic patients some critically ill or hypermetabolic patients

Basal Energy Expenditure (BEE):Basal Energy Expenditure (BEE):men = 66.47 + 13.75(W) + 5(H) – 6.76(A) kcal/dmen = 66.47 + 13.75(W) + 5(H) – 6.76(A) kcal/d

women = 655.1 + 9.56(W) + 1.85(H) – 4.68 (A) kcal/dwomen = 655.1 + 9.56(W) + 1.85(H) – 4.68 (A) kcal/d

W= wt in kg, H= Ht in cm, A= age in W= wt in kg, H= Ht in cm, A= age in yearsyears

Page 81: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Enteral FeedingEnteral Feeding

Less expensive and risks than parenteralLess expensive and risks than parenteral Reduced intestinal atrophyReduced intestinal atrophy 44% reduction in infections over 44% reduction in infections over

parenteral in the critically illparenteral in the critically ill Healthy patients without malnutrition Healthy patients without malnutrition

undergoing uncomplicated surgery can undergoing uncomplicated surgery can tolerate 10 d of maintenance IV fluids tolerate 10 d of maintenance IV fluids only before significant protein catabolism only before significant protein catabolism beginsbegins

Page 82: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Initiation of Enteral Initiation of Enteral FeedingFeeding

Immediately after adequate fluid Immediately after adequate fluid resuscitation (UOP)resuscitation (UOP)

Not absolute prerequisites: presence Not absolute prerequisites: presence of bowel sounds, passage of flatus or of bowel sounds, passage of flatus or stoolstool

Gastric residuals of >200ml in 4-6 Gastric residuals of >200ml in 4-6 hrs or abdominal distention requires hrs or abdominal distention requires cessation/lowering the ratecessation/lowering the rate

Page 83: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Enteral FormulasEnteral Formulas

Low-residue isotonic Low-residue isotonic caloric density 1.0kcal/ml, 1500-1800 ml/daycaloric density 1.0kcal/ml, 1500-1800 ml/day Provide carbs, protein, lytes, water, fat, water Provide carbs, protein, lytes, water, fat, water

sol vitamins, calorie:Nitrogen of 150:1.sol vitamins, calorie:Nitrogen of 150:1. No fiber bulk = minimum residueNo fiber bulk = minimum residue Standard for stable patients with an intact GI Standard for stable patients with an intact GI

tracttract Isotonic with fiberIsotonic with fiber

Soluble and insoluble fiber (soy)Soluble and insoluble fiber (soy) Delay GI transit time and reduce diarrheaDelay GI transit time and reduce diarrhea Not contraindicated in the critically illNot contraindicated in the critically ill

Page 84: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Enteral FormulasEnteral Formulas Immune-EnhancingImmune-Enhancing

Glutamine, argenine, omega-3 FA, nucleotides, beta-Glutamine, argenine, omega-3 FA, nucleotides, beta-carotene.carotene.

Benefits not consistent in trialsBenefits not consistent in trials ExpensiveExpensive

Calorie-DenseCalorie-Dense 1.5-2 kcal/ml, higher osmolality (ok for intragastric 1.5-2 kcal/ml, higher osmolality (ok for intragastric

feeding)feeding) for fluid restriction/inability to tolerate larger for fluid restriction/inability to tolerate larger

volumesvolumes High-ProteinHigh-Protein

Isotonic and nonisotonic availableIsotonic and nonisotonic available calorie:Nitrogen ratio of 80-120:1calorie:Nitrogen ratio of 80-120:1

Page 85: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Enteral FormulasEnteral Formulas ElementalElemental

Contain predigested nutrients, small peptidesContain predigested nutrients, small peptides Limited complex carbs and fat (long/med Limited complex carbs and fat (long/med

chains)chains) Easily absorbed, but limited long term useEasily absorbed, but limited long term use High osmolality = slow infusion or dilutedHigh osmolality = slow infusion or diluted Expensive Expensive

Renal-FailureRenal-Failure Lower fluid volume, K, phos, and MgLower fluid volume, K, phos, and Mg Essential aa, high calorie : nitrogen ratio, no Essential aa, high calorie : nitrogen ratio, no

vitaminsvitamins

Page 86: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Enteral FormulasEnteral Formulas

Pulmonary-FailurePulmonary-Failure Fat content is increased to 50% of total Fat content is increased to 50% of total

caloriescalories Reduces CO2 production and ventilation Reduces CO2 production and ventilation

burdenburden Hepatic-FailureHepatic-Failure

50% of aa are branched chains (Leu, Ile, 50% of aa are branched chains (Leu, Ile, Val)Val)

Potentially reverses encephalopathyPotentially reverses encephalopathy Controversial, no clear benefits in trialsControversial, no clear benefits in trials

Page 87: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Enteral AccessEnteral Access Nasogastric Tube - requires intact mental status Nasogastric Tube - requires intact mental status

and laryngeal reflexes to reduce aspirationand laryngeal reflexes to reduce aspiration Difficult to place, requires radiographic confirmationDifficult to place, requires radiographic confirmation If required >30 d, convert to PEGIf required >30 d, convert to PEG Problems: clogging, kinking, inadvertent removalProblems: clogging, kinking, inadvertent removal

Percutaneous Endoscopic Gastrostomy – Percutaneous Endoscopic Gastrostomy – Impaired swallowing/obstruction, major facial trauma Impaired swallowing/obstruction, major facial trauma Contraindications: ascites, coagulophathy, gastric Contraindications: ascites, coagulophathy, gastric

varices, gastric neoplasm, lack of suitable locationvarices, gastric neoplasm, lack of suitable location Tubes can be use for 12-24 mosTubes can be use for 12-24 mos Requires endoscopic transillumination of abdominal wall Requires endoscopic transillumination of abdominal wall

and passage of catheter into an insufflated stomachand passage of catheter into an insufflated stomach Complications in 3% of cases: infection, peritonitis, Complications in 3% of cases: infection, peritonitis,

aspiration/pneumonia, leaks, dislodgement, bowel aspiration/pneumonia, leaks, dislodgement, bowel perforation, enteric fistulas, bleedingperforation, enteric fistulas, bleeding

Page 88: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Percutaneous Endoscopic Percutaneous Endoscopic Gastrostomy-JejunostomyGastrostomy-Jejunostomy

Feeding administered past the pylorusFeeding administered past the pylorus Cannot tolerate gastric feedings/signif Cannot tolerate gastric feedings/signif

aspirationaspiration Passes a catheter through an existing Passes a catheter through an existing

PEG past the pylorus into the PEG past the pylorus into the duodenumduodenum

Long term malfunction >50% due to Long term malfunction >50% due to retrograde tube migration into the retrograde tube migration into the stomach, kinking, cloggingstomach, kinking, clogging

Page 89: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Direct Percutaneous Direct Percutaneous Endoscopic JejunostomyEndoscopic Jejunostomy

Same technique as PEG placement Same technique as PEG placement but requires an but requires an enteroscope/colonscope to reach the enteroscope/colonscope to reach the jejunumjejunum

Less malfunction than PEG-J Less malfunction than PEG-J Kinking/clogging reduced by placing Kinking/clogging reduced by placing

larger caliber catheterslarger caliber catheters

Page 90: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Surgical Gastrostomy and Surgical Gastrostomy and JejunostomyJejunostomy

With complex abdominal With complex abdominal trauma/laparatomy there may be an trauma/laparatomy there may be an opportunity for placementopportunity for placement

Contraindication: distal obstruction, Contraindication: distal obstruction, severe intestinal wall edema, radiation severe intestinal wall edema, radiation enteritis, inflammatory bowel disease, enteritis, inflammatory bowel disease, ascites, severe immunodeficiency, bowel ascites, severe immunodeficiency, bowel ischemiaischemia

Adverse effects: abdominal/bowel Adverse effects: abdominal/bowel distention, cramps, pneumotosis distention, cramps, pneumotosis intestinalis, small bowel necrosisintestinalis, small bowel necrosis

Page 91: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Parenteral NutritionParenteral Nutrition

Continuous infusion of hyperosmolar Continuous infusion of hyperosmolar carbs, proteins, fats and other nutrients carbs, proteins, fats and other nutrients through a catheter into the SVCthrough a catheter into the SVC

Optimal > 100-150 kcal/g nitrogens Optimal > 100-150 kcal/g nitrogens Higher rates of infection compared to Higher rates of infection compared to

enteralenteral Studies with parenteral nutrition and Studies with parenteral nutrition and

complete bowel rest results in increased complete bowel rest results in increased stress hormone and inflammatory stress hormone and inflammatory responsesresponses

Page 92: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Parenteral Nutrition Parenteral Nutrition RationaleRationale

Seriously ill patients with malnutrition, Seriously ill patients with malnutrition, sepsis or surgery/trauma when use of sepsis or surgery/trauma when use of the GI tract for feeding is not possiblethe GI tract for feeding is not possible Short bowel syndrome after massive Short bowel syndrome after massive

resectionresection Prolonged paralytic ileus (>7 days)Prolonged paralytic ileus (>7 days) Severe intestinal malabsorptionSevere intestinal malabsorption Functional GI disorders – esophageal Functional GI disorders – esophageal

dyskinesiadyskinesia Etc.Etc.

Page 93: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Total Parenteral Total Parenteral NutritionNutrition

Central parenteral nutrition, aka Central parenteral nutrition, aka TPNTPN

Requires access to a large diameter Requires access to a large diameter veinvein

Dextrose content is high (15-25%)Dextrose content is high (15-25%)

Page 94: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Peripheral Parenteral Peripheral Parenteral NutritionNutrition

Lower osmolalityLower osmolality Reduced dextrose (5-10%)Reduced dextrose (5-10%) Protein (3%)Protein (3%) Not appropriate for severe Not appropriate for severe

malnutrition due to need for larger malnutrition due to need for larger volumes of some nutrientsvolumes of some nutrients

Shorter periods, < 2 wksShorter periods, < 2 wks

Page 95: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Parenteral NutritionParenteral Nutrition

Dextose 15-25%Dextose 15-25% Amino acids 3-5%Amino acids 3-5% Vitamins (Vit K is not included)Vitamins (Vit K is not included) Lipid emulsions to prevent essential FA Lipid emulsions to prevent essential FA

deficiency (10-15% of calories)deficiency (10-15% of calories) Prepared by the pharmacy from Prepared by the pharmacy from

commercially available kitscommercially available kits If prolonged – supplement trace If prolonged – supplement trace

mineralsminerals Zinc (eczematous rash), copper (microcytic Zinc (eczematous rash), copper (microcytic

anemia), chromium (glucose intolerance)anemia), chromium (glucose intolerance)

Page 96: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Parenteral NutritionParenteral Nutrition

Insulin supplement to insure glucose Insulin supplement to insure glucose tolerancetolerance

IV fluids/electrolytes if high fluid IV fluids/electrolytes if high fluid losseslosses

Freq. monitor fluid status, vital Freq. monitor fluid status, vital signs, UOP, electrolytes, BUN, and signs, UOP, electrolytes, BUN, and LFTs. Glucose q6hLFTs. Glucose q6h

Page 97: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

ComplicationsComplications Hyperglycemia – pt with impaired glc tolerance or Hyperglycemia – pt with impaired glc tolerance or

high infusion ratehigh infusion rate Tx- volume replacement, correct electrolytes, insulinTx- volume replacement, correct electrolytes, insulin Avoid by monitoring daily fluid balance, glc, & lytesAvoid by monitoring daily fluid balance, glc, & lytes

Overfeeding – results in CO2 retention and Overfeeding – results in CO2 retention and respiratory insufficiencyrespiratory insufficiency

Hepatic steatosisHepatic steatosis Cholestasis and gallstonesCholestasis and gallstones Hepatic abnormalities – serum transaminase, alk Hepatic abnormalities – serum transaminase, alk

phos and bilirubinphos and bilirubin Intestinal - atrophy from disuse, bacterial Intestinal - atrophy from disuse, bacterial

overgrowth, reduced lymphoid tissue and IgA overgrowth, reduced lymphoid tissue and IgA production, impaired gut immunityproduction, impaired gut immunity

Page 98: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

Special FormulationsSpecial Formulations Glutamine and ArginineGlutamine and Arginine

Glutamine – nonessential aa, comprises 66% of free Glutamine – nonessential aa, comprises 66% of free amino acidsamino acids

During stress glu is depleted and shunted as a fuel During stress glu is depleted and shunted as a fuel source to visceral organs and tumorssource to visceral organs and tumors

Inconclusive data for benefits of increased Inconclusive data for benefits of increased supplementationsupplementation

Arginine – nonessential aa, promotes net nitrogen Arginine – nonessential aa, promotes net nitrogen retention and protein synthesis in the critically retention and protein synthesis in the critically ill/injured. Benefits still under investigation.ill/injured. Benefits still under investigation.

Omega-3 Fatty AcidsOmega-3 Fatty Acids Canola or fish oil. Displaces omega-6 FAs, Canola or fish oil. Displaces omega-6 FAs,

theoretically reducing pro-inflammatory responsestheoretically reducing pro-inflammatory responses NucleotidesNucleotides

? Increase cell proliferation, DNA synthesis, T Helper ? Increase cell proliferation, DNA synthesis, T Helper cell functioncell function

Page 99: Systemic response to injury and metabolic support ,Chapter 2 of schwartz by Anas Mk Hindawi

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