Systemic Response to Injury & Metabolic Support

1. Systemic Response to Injury & Metabolic Support Amr Khayat, MBBS

2. Objective • Clinical Spectrum of SIRS. • Signaling • Humoral • Neural • Hormonal • Inflammatory Mediators. • Cell Mediated Inflammatory response. • Surgical Metabolism.

3. Introduction • Inflammatory response to injury • to restore tissue function • Eradicate invading microorganisms • Local- limited duration, restores function • Major • overwhelming inflammatory response • Potential multi-organ failure

4. Clinical Spectrum of SIRS • Infection • Identifiable source of microbial insult • SIRS = 2 or more: • Temp ≥38˚C or ≤36˚C • HR ≥ 90 bpm • RR ≥ 20 breaths/min or PaCO2 ≤ 32 mmHg or mechanical ventilation • WBC ≥ 12,000 or ≤ 4000 or ≥ 10% immature forms • Sepsis • Infection + SIRS • Severe Sepsis • Sepsis + Organ Dysfunction • Septic Shock • Sepsis + Cardiovascular Collapse (requires vasopressors)

5. Signaling • Humoral – inflammatory mediators in the circulation can induce fever and anorexia i.e. TNF-α • Neural – parasympathetic vagal stimulation attenuates the inflammatory response via Ach release • Reduces HR, increases gut motility, dilates arterioles, constricts pupils, and decreases inflammation • Reduces macrophage activation • Reduces macrophage release of pro-inflammatory mediators (TNF-α, IL-1, IL-18)

6. Hormone Signaling

8. Adrenocorticotropic Hormone • Synthesized anterior pituitary • Regulated by circadian signals • Pattern is dramatically altered in injured patients • Elevation is proportional to injury severity • Released by: pain, anxiety, vasopressin, angiotensin II, cholecystokinin, catecholamines, and pro-inflammatory cytokines • ACTH signals increase glucocorticoid production

10. Glucocorticoids • Cortisol – elevated following injury, • duration of elevation depends on severity of injury • Potentiates hyperglycemia • Hepatic gluconeogenesis • Muscle and adipose tissue –> induces insulin resistance • Skeletal m.–> protein degradation, lactate release • Adipose -> reduces release of TG, FFA, glycerol

11. Exogenous administration • Adrenal suppression in the acutely ill • Acute Adrenal Insufficiency • Atrophy of the adrenal glands • Weakness, n/v, fever, hypotension • Hypoglycemia, hyponatremia, hyperkalemia • Immunosuppression • Decreased T-killer and NK fcn, graft vs host rxns, delayed hypersensitivity responses, inability of monocyte intracellular killing, inhibition of superoxide reactivity and chemotaxis in neutrophils • Down regulates pro-inflammatory cytokine production (TNF-α, IL-1, IL-6)

12. Macrophage Inhibitory Factor Glucocorticoid antagonist produced by anterior pituitary & T-lymphocytes Reverses immunosuppressive effects of glucocorticoids

13. Growth Hormone • During stress -> protein synth, fat mobilization, and skeletal cartilage growth • Injury reduces IGF1 levels • IGF1 inhibited by pro-inflammatory cytokines • TNF-α, IL-1α, IL-6

17. Aldosterone • Synthesized, stored, released from the adrenal zona glomerulosa • Maintains intravascular volume • Conserves Na. • Eliminates potassium and hydrogen ions • Acts on the early distal convoluted tubules • Deficiency- hypotension, hyperkalemia • Excess- edema, HTN, hypokalemia, metab alkalosis

18. Insulin • Stress inhibited release + peripheral insulin resistance = hyperglycemia • Injury has 2 phases of insulin release • Within hours- release is suppressed • Later- normal/xs insulin production with peripheral insulin resistance • Activated lymphocytes have insulin receptors -> enhanced Tcell proliferation and cytotoxicity • Tight control of glucose levels esp. in diabetics significantly reduces mortality after injury

19. Acute Phase Proteins • Nonspecific markers • Produced by hepatocytes • Response to injury, infection, inflammation • Induced by IL-6 • C-reactive protein best reflects inflammation • No diurnal variation, not affected by feeding • Affected only by preexisting hepatic failure • Accuracy surpasses that of ESR

20. Inflammatory Mediators Heat Shock Proteins Reactive Oxygen Metabolites Eicosanoids Fatty Acid Metabolites Kallikrein-Kinin System Serotonin Histamine Cytokines

21. Heat Shock Proteins Induced by hypoxia, trauma, heavy metals, and hemorrhage Requires gene induction by a transcription factor ACTH sensitive Production seems to decline with age

22. Reactive Oxygen Metabolites Cause tissue injury by oxidation of unsaturated fatty acids within cell membranes Produced by anaerobic glucose oxidation and reduction to superoxide anion in leukocytes Further metabolized to hydrogen peroxide and hydroxyl radicals Cells are protected by oxygen scavengers – glutathione and catalases In ischemia- production of oxygen metabolites are activated but nonfunctional due to no oxygen supply. After reperfusion, large amounts are produced causing injury

23. Eicosanoids

24. Eicosanoids • Secreted by nucleated cells (not lymphocytes) • Induced by hypoxic injury, direct tissue injury, endotoxin, norepinephrine, vasopressin, ang II, bradykinin, serotonin, ACh, cytokines, histamine • Diverse systemic effects • Adverse effects include acute lung injury, pancreatitis, renal failure

26. Fatty Acid Metabolites • Omega 6 FA – precursors of inflammatory mediators (PG, platelet activating factor) • found in enteral nutrition formulas • Substituting Omega 3 FA attenuate the inflammatory response • Reduces TNFα, IL6, PGE2 • Reduces the metabolic rater, normalizes glucose metabolism, attenuates weight loss, improves nitrogen balance, reduces endotoxin induced acute lung injury, minimizes reperfusion injury to the myocardium, small intestine, and skeletal muscles.

27. Kallikrein-Kinin System • Bradykinins are potent vasodilators • Stimulated by hypoxic and ischemic injury • Hemorrhage, sepsis, endotoxemia, tissue injury • Magnitude proportional to severity of injury • Produced by kininogen degradation by kallikrein • Kinins increase capillary permeability (edema), pain, inhibit gluconeogenesis, renal vasodilation, incr bronchoconstriction

28. Serotonin Present in intestinal chromaffin cells & platelets Vasoconstriction, bronchoconstriction, platelet aggregation Myocardial chronotrope and ionotrope Unclear role in inflammation

29. Histamine Stored in neurons, skin, gastric mucosa, mast cells, basophils, and platelets H1 – bronchoconstriction, VD, increases intestinal motility and myocardial contractility H2 – stimulates gastric parietal cell acid secretion. H3 – downregulation of histamine release.

30. Cytokines Most potent mediators of inflammation Local- eradicate microorganisms, promote wound healing Overwhelming response- hemodynamic instability (septic shock) or (muscle wasting) Uncontrolled- end-organ failure, death Self-regulatory production of anti-inflammatory cytokines, but inappropriate release may render the patient immunocompromised and susceptible to infection

31. Tumor Necrosis Factor α Secreted from monocytes, macrophages, Tcells Responds early, T ½ < 20min Potent evocation of cytokine cascade Induces muscle catabolism/cachexia, coagulation, PGE2, PAF, glucocorticoids, eicosanoids

32. Interleukin-1 Released by activated macrophages, endothelial cells IL1α- cell membrane associated IL1β- circulation Synergistic with TNF- α T ½ = 6 min Induces febrile response by stimulating PG activity in the anterior hypothalamus Release of β-endorphins after surgery reduce perception of pain

33. Interleukin-2 Promotes T-lymphocyte proliferation, Ig production, gut barrier integrity T ½ < 10 min Major injury or perioperative blood transfusions reduce IL-2 activity leading to a transient immunocompromised state Regulates lymphocyte apoptosis

34. Interleukin-4 • Produced by type 2 T Helper lymphocytes • Important in antibody-mediated switching and antigen presentation • Induces class switching to promote IgE & IgG4 • Important in allergic and antihelmintic responses • Anti-inflammatory- downregulates IL-1, TNF-α, IL-6, IL-8 and oxygen radical production

35. Interleukin-5 Released from T lymphocytes, eosinophils, mast cells and basophils Promotes eosinophil proliferation and airway inflammation

36. Interleukin-6 • Induced by IL-1 and TNF-α • Levels are detectable within 60 min of injury, peak 4-6 hours, and persist up to 10 days • Levels are proportional to extent of tissue injury • Pro-inflammatory • Induces and prolongs neutrophil activity • Anti-inflammatory • Attenuate TNF-α and IL-1 activity • Promote release of circulating TNF- α receptors & IL-1 antagonists

37. Interleukin-8 Released from monocytes, macrophages, T lymphocytes Activity similar to IL-6 Chemoattractant for PMNs, basophils, eosinophils, and lymphocytes, activates PMNs

38. Interleukin-10 Anti-inflammatory Released from T lymphocytes Down-regulates TNF-α activity Also attenuates IL-18 mRNA in monocytes Reduces mortality in animal sepsis and ARDS models

39. Interleukin-12 Promotes differentiation of type 1 T Helper cells Promotes PMN and coagulation activation

40. Interleukin-13 Similar to IL-4, overall anti-inflammatory Promotes B-lymphocyte function Unlike IL-4, has no effect on T lymphocytes Inhibits NO production and endothelial activation

41. Interleukin-15 Derived from macrophages promotes lymphocyte activation. promotes neutrophil phagocytosis in fungal infections

42. Interleukin-18 Produced by macrophages Pro-inflammatory, similar to IL-12 Increased levels are pronounced (especially in sepsis) and can last up to 21 days high levels found in cardiac deaths

43. Interferon-γ Helper T lymphocytes activated by bacterial antigens, IL-2, IL-12, or IL-18 produce IFN-γ IFN-γ can induce IL-2, IL-12, or IL-18 Detectable in circulation by 6 hrs and remain elevated for up to 8 days Activate circulating and tissue macrophages Induces acute lung inflammation by activating alveolar macrophages after surgery or trauma

44. Granulocyte-Macrophage Colony-Stimulating Factor • Delays apoptosis of macrophages and PMNs • Promotes the maturation and recruitment of PMNs in inflammation and perhaps wound healing • May contribute to organ injury such as ARDS

45. High Mobility Group Box 1 DNA transcription factor Facilitates the binding of regulatory protein complexes to DNA Secreted by macrophages, natural killer cells, and enterocytes. Expressed 24-48 hrs after injury Associated with weight loss, shock, SIRS and Sepsis. Peak levels are associated with ARDS and death

46. Cell Mediated Inflammation • Platelets • Source of eicosanoids and vasoactive mediators • Clot is a chemoattractant for PMNs/monocytes • Modulate PMN endothelium adherence • Migration occurs within 3 hrs of injury • Mediated by serotonin, PAF, PGE2 • Eosinophils • Migrate to parasitic infection and allergen challenge to release cytotoxic granules • Reside in the GI, lung, and GU tissues • Activated by IL-3, GM-CSF, IL-5, PAF, and anaphylatoxins C3a and C5a

47. Cell Mediated Inflammation • Lymphocytes • T-helpers produce IL-3, TNF-α, GM-CSF • TH1: IFN-γ, IL-2, IL-12 • TH2: IL-4, IL-5, IL-6, IL-9, IL-10, IL-13 • Severe infection – shift toward more TH2 • Mast Cells • First responders to injury • Produce histamine, cytokines, eicosanoids, proteases, chemokines, TNF-α (stored in granules) • Cause vasodilation, capillary leakage, and recruit immunocytes

48. Cell Mediated Inflammation • Monocytes • Downregulation of receptor TNFR is clinically and experimentally correlated with CHF, nonsurvival in sepsis • Neutrophils • Modulate acute inflammation • Maturation is stimulated by G-CSF • Rolling (L-selectin (fast), P-selectin (slow) • Adhesion/transmigration – ICAM 1, 2, PECAM 1, VCAM 1, CD18

49. Endothelium-Mediated Injury • Neutrophil-Endothelium Interaction • Increased vascular permeability – facilitate oxygen delivery and immunocyte migration • Accumulation of neutrophils at injury sites can cause cytotoxicity to vital organs • Ischemia-reperfusion injury potentiates this response by releasing oxygen metabolites and lysosomal enz. • Neutrophils – rolling 10-20min (p-selectin), >20min

50. Nitric Oxide Derived from endothelial surfaces responding to Ach, hypoxia, endotoxin, cellular injury, or shear stresses of circulating blood T ½ = seconds Reduces microthrombosis, mediates protein synthesis in hepatocytes Formed from oxidation of L-arginine.