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Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
Injury Coughlin 7 7 08
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Injury Coughlin 7 7 08

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  • 1. Systemic Response to Injury & Metabolic Support a review of Schwartz’s Principles of Surgery- Chapter 1 L. Coughlin, M.D. July 7, 2008
  • 2. Introduction <ul><li>Inflammatory response to injury </li></ul><ul><ul><li>to restore tissue function </li></ul></ul><ul><ul><li>Eradicate invading microorganisms </li></ul></ul><ul><li>Local- limited duration, restores function </li></ul><ul><li>Major </li></ul><ul><ul><li>overwhelming inflammatory response </li></ul></ul><ul><ul><li>Potential multi-organ failure </li></ul></ul><ul><ul><li>Adversely impacts patient survival </li></ul></ul>
  • 3. Clinical Spectrum of SIRS <ul><li>Infection </li></ul><ul><ul><li>Identifiable source of microbial insult </li></ul></ul><ul><li>SIRS = 2 or more: </li></ul><ul><ul><li>Temp ≥38˚C or ≤36˚C </li></ul></ul><ul><ul><li>HR ≥ 90 bpm </li></ul></ul><ul><ul><li>RR ≥ 20 breaths/min or PaCO2 ≤ 32 mmHg or mechanical ventilation </li></ul></ul><ul><ul><li>WBC ≥ 12,000/µL or ≤ 4000/µL or ≥ 10% band forms </li></ul></ul><ul><li>Sepsis </li></ul><ul><ul><li>Infection + SIRS </li></ul></ul><ul><li>Severe Sepsis </li></ul><ul><ul><li>Sepsis + Organ Dysfunction </li></ul></ul><ul><li>Septic Shock </li></ul><ul><ul><li>Sepsis + Cardiovascular Collapse (requires vasopressors) </li></ul></ul>
  • 4. Signaling <ul><li>Humoral – inflammatory mediators in the circulation can induce fever and anorexia i.e. TNF- α </li></ul><ul><li>Neural – parasympathetic vagal stimulation attenuates the inflammatory response via Ach release </li></ul><ul><ul><li>Reduces HR, increases gut motility, dilates arterioles, constricts pupils, and decreases inflammation </li></ul></ul><ul><ul><li>Reduces macrophage activation </li></ul></ul><ul><ul><li>Reduces macrophage release of pro-inflammatory mediators (TNF- α , IL-1, IL-18) </li></ul></ul>
  • 5. Hormone Signaling <ul><li>Hormone classifications </li></ul><ul><ul><li>polypeptide (cytokine, insulin) </li></ul></ul><ul><ul><li>amino acid (epinephrine, serotonin, or histamine ) </li></ul></ul><ul><ul><li>fatty acid (cortisol, leukotrienes) </li></ul></ul><ul><li>Pathways </li></ul><ul><ul><li>Receptor Kinases – insulin </li></ul></ul><ul><ul><li>Guanine nucleotide binding (G-protein) - prostaglandins </li></ul></ul><ul><ul><li>Ligand Gated ion channels </li></ul></ul>
  • 6. Adrenocorticotropic Hormone <ul><li>Synthesized anterior pituitary </li></ul><ul><li>Regulated by circadian signals </li></ul><ul><li>Pattern is dramatically altered in injured patients </li></ul><ul><li>Elevation is proportional to injury severity </li></ul><ul><li>Released by: pain, anxiety, vasopressin, </li></ul><ul><li>angiotensin II, cholecystokinin, catecholamines, and pro-inflammatory cytokines </li></ul><ul><li>ACTH signals increase glucocorticoid production </li></ul>
  • 7. Glucocorticoids <ul><li>Cortisol – elevated following injury, </li></ul><ul><ul><li>duration of elevation depends on severity of injury </li></ul></ul><ul><li>Potentiates hyperglycemia </li></ul><ul><ul><li>Hepatic gluconeogenesis </li></ul></ul><ul><ul><li>Muscle and adipose tissue –> induces insulin resistance </li></ul></ul><ul><ul><li>Skeletal m.–> protein degradation, lactate release </li></ul></ul><ul><ul><li>Adipose -> reduces release of TG, FFA, glycerol </li></ul></ul>
  • 8. Exogenous administration <ul><li>Adrenal suppression in the acutely ill </li></ul><ul><ul><li>Acute Adrenal Insufficiency </li></ul></ul><ul><ul><li>Atrophy of the adrenal glands </li></ul></ul><ul><ul><li>Weakness, n/v, fever, hypotension </li></ul></ul><ul><ul><li>Hypoglycemia, hyponatremia, hyperkalemia </li></ul></ul><ul><li>Immunosuppression </li></ul><ul><ul><li>Thymic involution, 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 </li></ul></ul><ul><ul><li>Down regulates pro-inflammatory cytokine production (TNF- α , IL-1, IL-6) </li></ul></ul><ul><ul><li>Increases anti-inflammatory mediator IL-10 </li></ul></ul><ul><ul><li>Useful in septic shock, surgical trauma, and CABG </li></ul></ul>
  • 9. Macrophage Inhibitory Factor <ul><li>Glucocorticoid antagonist </li></ul><ul><li>produced by anterior pituitary & T-lymphocytes </li></ul><ul><li>Reverses immunosuppressive effects of glucocorticoids </li></ul><ul><li>Potentiates G- and G+ septic shock </li></ul><ul><li>Experimentally improves survival </li></ul>
  • 10. Growth Hormone <ul><li>During stress -> protein synth, fat mobilization, and skeletal cartilage growth </li></ul><ul><li>2˚ to release of insulin-like growth factor (IGF1) </li></ul><ul><li>Injury reduces IGF1 levels </li></ul><ul><li>IGF1 inhibited by pro-inflammatory cytokines </li></ul><ul><ul><li>TNF- α , IL-1 α , IL-6 </li></ul></ul><ul><li>GH admin to pediatric burn patients shows improvement in their clinical course </li></ul>
  • 11. Catecholamines <ul><li>Severe injury activates the adrenergic system </li></ul><ul><li>Norepi and Epi immed. increase 3-4 fold and remain elevated 24-48hrs after injury </li></ul><ul><li>Epinephrine </li></ul><ul><ul><li>hepatic glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis </li></ul></ul><ul><ul><li>Decreases insulin and glucagon secretion </li></ul></ul><ul><ul><li>Peripheral- lipolysis, insulin resistance in skeletal m. </li></ul></ul><ul><ul><li>= stress induced hyperglycemia </li></ul></ul>
  • 12. Epinephrine – other effects <ul><li>Increase secretion of T3, T4, and renin </li></ul><ul><li>Reduces release of aldosterone </li></ul><ul><li>Enhances leukocyte demargination and lymphocytosis </li></ul>
  • 13. Aldosterone <ul><li>Synthesized, stored, released from the adrenal zona glomerulosa </li></ul><ul><li>Maintains intravascular volume </li></ul><ul><ul><li>Conserves sodium </li></ul></ul><ul><ul><li>Eliminates potassium and hydrogen ions </li></ul></ul><ul><ul><li>Acts on the early distal convoluted tubules </li></ul></ul><ul><li>Deficiency- hypotension, hyperkalemia </li></ul><ul><li>Excess- edema, HTN, hypokalemia, metab alkalosis </li></ul>
  • 14. Insulin <ul><li>Stress inhibited release + peripheral insulin resistance = hyperglycemia </li></ul><ul><li>Injury has 2 phases of insulin release </li></ul><ul><ul><li>Within hours- release is suppressed </li></ul></ul><ul><ul><li>Later- normal/xs insulin production with peripheral insulin resistance </li></ul></ul><ul><li>Activated lymphocytes have insulin receptors -> enhanced Tcell proliferation and cytotoxicity </li></ul><ul><li>Tight control of glucose levels esp. in diabetics significantly reduces mortality after injury </li></ul>
  • 15. Acute Phase Proteins <ul><li>Nonspecific markers </li></ul><ul><li>Produced by hepatocytes </li></ul><ul><li>Response to injury, infection, inflammation </li></ul><ul><li>Induced by IL-6 </li></ul><ul><li>C-reactive protein best reflects inflammation </li></ul><ul><ul><li>No diurnal variation, not affected by feeding </li></ul></ul><ul><ul><li>Affected only by preexisting hepatic failure </li></ul></ul><ul><ul><li>Accuracy surpasses that of ESR </li></ul></ul>
  • 16. Inflammatory Mediators <ul><li>Heat Shock Proteins </li></ul><ul><li>Reactive Oxygen Metabolites </li></ul><ul><li>Eicosanoids </li></ul><ul><li>Fatty Acid Metabolites </li></ul><ul><li>Kallikrein-Kinin System </li></ul><ul><li>Serotonin </li></ul><ul><li>Histamine </li></ul><ul><li>Cytokines </li></ul>
  • 17. Heat Shock Proteins <ul><li>Induced by hypoxia, trauma, heavy metals, and hemorrhage </li></ul><ul><li>Intracellularly modify and transport proteins </li></ul><ul><ul><li>Steroids </li></ul></ul><ul><li>Requires gene induction by a transcription factor </li></ul><ul><li>ACTH sensitive </li></ul><ul><li>Production seems to decline with age </li></ul>
  • 18. Reactive Oxygen Metabolites <ul><li>Short-lived </li></ul><ul><li>Cause tissue injury by oxidation of unsaturated fatty acids within cell membranes </li></ul><ul><li>Produced by anaerobic glucose oxidation and reduction to superoxide anion in leukocytes </li></ul><ul><li>Further metabolized to hydrogen peroxide and hydroxyl radicals </li></ul><ul><li>Cells are protected by oxygen scavengers – glutathione and catalases </li></ul><ul><li>In ischemia- production of oxygen metabolites are activated but nonfunctional due to no oxygen supply. After reperfusion, large amounts are produced causing injury </li></ul>
  • 19. Eicosanoids Phospholipids Arachadonic Acid Cyclic endoperoxidases (PGG2, PGH2) Hydroperoxyeicosatetraenoic acid (HPETE) Prostaglandins PGD2, PGE2, PGF2 α , PGI2 Thromboxane TXA2 Hydroxyeicosatetraenoic Acid HETE Leukotrienes Cyclooxygenase 1 & 2 Lipoxygenase Phospholipase A2 Corticosteroids Glucocorticoids (Cortisol)
  • 20. Eicosanoids <ul><li>Secreted by nucleated cells (not lymphocytes) </li></ul><ul><li>Induced by hypoxic injury, direct tissue injury, endotoxin, norepinephrine, vasopressin, ang II, bradykinin, serotonin, ACh, cytokines, histamine </li></ul><ul><li>Diverse systemic effects </li></ul><ul><li>Adverse effects include acute lung injury, pancreatitis, renal failure </li></ul><ul><li>NSAIDs acetylate COX which reduce prostaglandin levels </li></ul>
  • 21. Eicosanoid Effects <ul><li>Pancreas – glucagon secretion- PGD2, PGE2 </li></ul><ul><li>Liver – glucagon stimulated glucose production- PGE2 </li></ul><ul><li>Adipose – lipolysis- PGE2 </li></ul><ul><li>Bone – resorption- PGE2, PGF2 α , PGI2 </li></ul><ul><li>Parathyroid – PTH secretion- PGE2 </li></ul><ul><li>Pulmonary – Bronchoconstriction- PGF2 α , TXA2, LTC4, LTD4, LTE4 </li></ul><ul><li>Immune – suppress lymphocytes- PGE2 </li></ul><ul><li>Hematologic </li></ul><ul><ul><li>platelet aggregation- TXA2 </li></ul></ul><ul><ul><li>Capillary leakage- PGE2, LT </li></ul></ul><ul><ul><li>PMN adherence and activation- LT </li></ul></ul><ul><li>Pituitary </li></ul><ul><ul><li>Prolactin- PGE1 </li></ul></ul><ul><ul><li>LH- PGE1, PGE2, 5-HETE </li></ul></ul><ul><ul><li>TSH- PGA1, PGB1, PGE1, PGE1 α </li></ul></ul><ul><ul><li>GH- PGE1 </li></ul></ul><ul><li>Renal – renin secretion- PGE2, PGI2 </li></ul><ul><li>GI – cytoprotective- PGE2 </li></ul>
  • 22. Fatty Acid Metabolites <ul><li>Omega 6 FA – precursors of inflammatory mediators (LT, PG, platelet activating, factor) </li></ul><ul><ul><li>found in enteral nutrition formulas </li></ul></ul><ul><li>Substituting Omega 3 FA attenuate the inflammatory response </li></ul><ul><ul><li>Reduces TNF α , IL6, PGE2 </li></ul></ul><ul><ul><li>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. </li></ul></ul>
  • 23. Kallikrein-Kinin System <ul><li>Bradykinins are potent vasodilators </li></ul><ul><li>Stimulated by hypoxic and ischemic injury </li></ul><ul><ul><li>Hemorrhage, sepsis, endotoxemia, tissue injury </li></ul></ul><ul><ul><li>Magnitude proportional to severity of injury </li></ul></ul><ul><li>Produced by kininogen degradation by kallikrein </li></ul><ul><li>Kinins increase capillary permeability (edema), pain, inhibit gluconeogenesis, renal vasodilation, incr bronchoconstriction </li></ul><ul><li>In clinical trials, bradykinin antagonists help reverse G- sepsis, but do not improve survival </li></ul>
  • 24. Serotonin <ul><li>Present in intestinal chromaffin cells & platelets </li></ul><ul><li>Vasoconstriction, bronchoconstriction, platelet aggregation </li></ul><ul><li>Myocardial chronotrope and ionotrope </li></ul><ul><li>Unclear role in inflammation </li></ul>
  • 25. Histamine <ul><li>Stored in neurons, skin, gastric mucosa, mast cells, basophils, and platelets </li></ul><ul><li>H1 – bronchoconstriction, increases intestinal motility and myocardial contractility </li></ul><ul><li>H2 – inhibits histamine release </li></ul><ul><li>H1/H2 – hypotension, decreased venous return/peripheral blood pooling, increased capillary permeability, myocardial failure. </li></ul>
  • 26. Cytokines <ul><li>Most potent mediators of inflammation </li></ul><ul><li>Local- eradicate microorganisms, promote wound healing </li></ul><ul><li>Overwhelming response- hemodynamic instability (septic shock) or metabolic derangements (muscle wasting) </li></ul><ul><li>Uncontrolled- end-organ failure, death </li></ul><ul><li>Self-regulatory production of anti-inflammatory cytokines, but inappropriate release may render the patient immunocompromised and susceptible to infection </li></ul>
  • 27. Tumor Necrosis Factor α <ul><li>Secreted from monocytes, macrophages, Tcells </li></ul><ul><li>Responds early, T ½ < 20min </li></ul><ul><li>Potent evocation of cytokine cascade </li></ul><ul><li>Induces muscle catabolism/cachexia, coagulation, PGE2, PAF, glucocorticoids, eicosanoids </li></ul><ul><li>Circulating TNF receptors compete with cellular receptors and may act as a counter regulatory system to prevent excessive TNF- α activity </li></ul>
  • 28. Interleukin-1 <ul><li>Released by activated macrophages, endothelial cells </li></ul><ul><li>IL1 α - cell membrane associated </li></ul><ul><li>IL1 β - circulation </li></ul><ul><li>Synergistic with TNF- α </li></ul><ul><li>T ½ = 6 min </li></ul><ul><li>Induces febrile response by stimulating PG activity in the anterior hypothalamus </li></ul><ul><li>Release of β -endorphins after surgery reduce perception of pain </li></ul>
  • 29. Interleukin-2 <ul><li>Promotes T-lymphocyte proliferation, Ig production, gut barrier integrity </li></ul><ul><li>T ½ < 10 min </li></ul><ul><li>Major injury or perioperative blood transfusions reduce IL-2 activity leading to a transient immunocompromised state </li></ul><ul><li>Regulates lymphocyte apoptosis </li></ul>
  • 30. Interleukin-4 <ul><li>Produced by type 2 T Helper lymphocytes </li></ul><ul><li>Important in antibody-mediated switching and antigen presentation </li></ul><ul><li>Induces class switching to promote IgE & IgG4 </li></ul><ul><ul><li>Important in allergic and antihelmintic responses </li></ul></ul><ul><li>Anti-inflammatory- downregulates IL-1, TNF- α , IL-6, IL-8 and oxygen radical production </li></ul><ul><li>Increases macrophage susceptibility to anti-inflammatory effects of glucocorticoids </li></ul>
  • 31. Interleukin-5 <ul><li>Released from T lymphocytes, eosinophils, mast cells and basophils </li></ul><ul><li>Promotes eosinophil proliferation and airway inflammation </li></ul>
  • 32. Interleukin-6 <ul><li>Induced by IL-1 and TNF- α </li></ul><ul><li>Levels are detectable within 60 min of injury, peak 4-6 hours, and persist up to 10 days </li></ul><ul><li>Levels are proportional to extent of tissue injury </li></ul><ul><li>Pro-inflammatory </li></ul><ul><ul><li>Mediates hepatic acute phase response during injury and convalescence </li></ul></ul><ul><ul><li>Induces and prolongs neutrophil activity </li></ul></ul><ul><li>Anti-inflammatory </li></ul><ul><ul><li>Attenuate TNF- α and IL-1 activity </li></ul></ul><ul><ul><li>Promote release of circulating TNF- α receptors & IL-1 antagonists </li></ul></ul>
  • 33. Interleukin-8 <ul><li>Released from monocytes, macrophages, T lymphocytes </li></ul><ul><li>Activity similar to IL-6 </li></ul><ul><li>Chemoattractant for PMNs, basophils, eosinophils, and lymphocytes, activates PMNs </li></ul><ul><li>Proposed biomarker for risk of multiple organ failure </li></ul>
  • 34. Interleukin-10 <ul><li>Anti-inflammatory </li></ul><ul><li>Released from T lymphocytes </li></ul><ul><li>Down-regulates TNF- α activity </li></ul><ul><li>Also attenuates IL-18 mRNA in monocytes </li></ul><ul><li>Studies in animal sepsis and ARDS models suggest induced IL-10 decreases the systemic inflammatory response and reduces mortality </li></ul>
  • 35. Interleukin-12 <ul><li>Promotes differentiation of type 1 T Helper cells </li></ul><ul><li>Promotes PMN and coagulation activation </li></ul><ul><li>In primate studies, IL-12 induces inflammatory responses independent of TNF- α and IL-1 </li></ul><ul><li>In animal studies of fecal peritonitis and burns, IL-12 administration increases survival, whereas IL-12 neutralization increases mortality </li></ul>
  • 36. Interleukin-13 <ul><li>Similar to IL-4, overall anti-inflammatory </li></ul><ul><li>Modulates macrophage function </li></ul><ul><li>Unlike IL-4, has no effect on T lymphocytes </li></ul><ul><li>Inhibits NO production </li></ul><ul><li>Inhibits pro-inflammatory cytokines </li></ul><ul><li>Attenuates leukocyte interaction with activated endothelial surfaces </li></ul>
  • 37. Interleukin-15 <ul><li>Derived from macrophages </li></ul><ul><li>Shares receptor components with IL-2, and shares promoting lymphocyte activation/prolif. </li></ul><ul><li>In neutrophils, it induces IL-8 and nuclear factor к B -> enhanced phagocytosis against fungal infections </li></ul>
  • 38. Interleukin-18 <ul><li>Formerly IFN- γ -inducing factor </li></ul><ul><li>Produced by macrophages </li></ul><ul><li>Pro-inflammatory, similar to IL-12 </li></ul><ul><li>Increased levels are pronounced (especially in G- sepsis) and can last up to 21 days </li></ul>
  • 39. Interferon- γ <ul><li>Helper T lymphocytes activated by bacterial antigens, IL-2, IL-12, or IL-18 produce IFN- γ </li></ul><ul><li>IFN- γ can induce IL-2, IL-12, or IL-18 </li></ul><ul><li>Detectable in circulation by 6 hrs and remain elevated for up to 8 days </li></ul><ul><li>Activate circulating and tissue macrophages </li></ul><ul><li>Induces acute lung inflammation by activating alveolar macrophages after surgery or trauma </li></ul>
  • 40. Granulocyte-Macrophage Colony-Stimulating Factor <ul><li>Delays apoptosis of macrophages and PMNs </li></ul><ul><li>Promotes the maturation and recruitment of PMNs in inflammation and perhaps wound healing </li></ul><ul><li>May contribute to organ injury such as ARDS </li></ul><ul><li>Peri-operative GM-CSF undergoing major oncologic procedures and burn patients demonstrate enhances neutrophil counts and fcn </li></ul>
  • 41. High Mobility Group Box 1 <ul><li>DNA transcription factor </li></ul><ul><li>Expressed 24-48 hrs after injury </li></ul><ul><li>Associated with weight loss, food aversion, shock, SIRS and Sepsis </li></ul><ul><li>Peak levels are associated with ARDS and death </li></ul>
  • 42. Cell Signaling Pathways <ul><li>Heat Shock Proteins </li></ul><ul><ul><li>produced in response to ischemia/injury </li></ul></ul><ul><ul><li>HS Factors are activated upon injury, undergo conformational changes, translocate into the nucleus, and bind HSP promoter regions </li></ul></ul><ul><ul><li>Attenuate inflammatory response </li></ul></ul><ul><li>Ligand Gated Ion Channels </li></ul><ul><ul><li>When activated by a ligand, a rapid influx of ions cross the cell membrane. i.e. neurotransmitters </li></ul></ul>
  • 43. Cell Signaling Pathways <ul><li>G-protein receptors </li></ul><ul><ul><li>Largest family of signaling receptors </li></ul></ul><ul><ul><li>Adjacent effector protein activated receptor </li></ul></ul><ul><ul><li>Second messengers – cAMP or calcium </li></ul></ul><ul><ul><li>Can result in gene transcription or activation of phospholipase C </li></ul></ul><ul><li>Tyrosine Kinases </li></ul><ul><ul><li>When activated, receptors dimerize, phosphorylate, and recruit secondary signaling molecules </li></ul></ul><ul><ul><li>Used in gene transcription and cell proliferation </li></ul></ul><ul><ul><li>i.e. insulin, PGDF, IGF-1 </li></ul></ul>
  • 44. Cell Signaling Pathways <ul><li>Janus Kinase/Signal Transduction and Activator of Transcription (JAK-STAT) </li></ul><ul><ul><li>IL-6, IL-10, IL-12, IL-13, IFN- γ </li></ul></ul><ul><ul><li>Ligand binds to the receptor, receptor dimerizes, enzymatic activation via phosphorylation propagates through the JAK domain and recruits STAT to the cytosolic receptor portion. </li></ul></ul><ul><ul><li>STAT dimerizes and translocates into the nucleus as a transcription factor </li></ul></ul><ul><ul><li>Suppressors of cytokine signaling (SOCS) block JAK-STAT </li></ul></ul>
  • 45. Tumor Necrosis Factor <ul><li>Apoptosis - normal fcn of cellular disposal w/o activating the immune/inflammatory system </li></ul><ul><li>2 receptors </li></ul><ul><ul><li>TNFR-1 : inflammation, apoptosis, circulatory shock </li></ul></ul><ul><ul><li>TNFR-2 : no inflammation or shock </li></ul></ul><ul><li>CD95 (Fas) receptor similar structure to TNFR-1 </li></ul><ul><ul><li>Initiates apoptosis </li></ul></ul>
  • 46. Cell Mediated Inflammation <ul><li>Platelets </li></ul><ul><ul><li>Source of eicosanoids and vasoactive mediators </li></ul></ul><ul><ul><li>Clot is a chemoattractant for PMNs/monocytes </li></ul></ul><ul><ul><li>Modulate PMN endothelium adherence </li></ul></ul><ul><ul><li>Migration occurs within 3 hrs of injury </li></ul></ul><ul><ul><ul><li>Mediated by serotonin, PAF, PGE2 </li></ul></ul></ul><ul><li>Eosinophils </li></ul><ul><ul><li>Migrate to parasitic infection and allergen challenge to release cytotoxic granules </li></ul></ul><ul><ul><li>Reside in the GI, lung, and GU tissues </li></ul></ul><ul><ul><li>Activated by IL-3, GM-CSF, IL-5, PAF, and anaphylatoxins C3a and C5a </li></ul></ul>
  • 47. Cell Mediated Inflammation <ul><li>Lymphocytes </li></ul><ul><ul><li>T-helpers produce IL-3, TNF- α , GM-CSF </li></ul></ul><ul><ul><ul><li>TH1: IFN- γ , IL-2, IL-12 </li></ul></ul></ul><ul><ul><ul><li>TH2: IL-4, IL-5, IL-6, IL-9, IL-10, IL-13 </li></ul></ul></ul><ul><ul><ul><li>Severe infection – shift toward more TH2 </li></ul></ul></ul><ul><li>Mast Cells </li></ul><ul><ul><li>First responders to injury </li></ul></ul><ul><ul><li>Produce histamine, cytokines, eicosanoids, proteases, chemokines, TNF- α (stored in granules) </li></ul></ul><ul><ul><li>Cause vasodilation, capillary leakage, and recruit immunocytes </li></ul></ul>
  • 48. Cell Mediated Inflammation <ul><li>Monocytes </li></ul><ul><ul><li>Downregulation of receptor TNFR is clinically and experimentally correlated with CHF, nonsurvival in sepsis </li></ul></ul><ul><li>Neutrophils </li></ul><ul><ul><li>Modulate acute inflammation </li></ul></ul><ul><ul><li>Maturation is stimulated by G-CSF </li></ul></ul><ul><ul><li>Rolling (L-selectin (fast), P-selectin (slow) </li></ul></ul><ul><ul><li>Adhesion/transmigration – ICAM 1, 2, PECAM 1, VCAM 1, CD18 </li></ul></ul>
  • 49. Endothelium-Mediated Injury <ul><li>Neutrophil-Endothelium Interaction </li></ul><ul><ul><li>Increased vascular permeability – facilitate oxygen delivery and immunocyte migration </li></ul></ul><ul><ul><li>Accumulation of neutrophils at injury sites can cause cytotoxicity to vital organs </li></ul></ul><ul><ul><li>Ischemia-reperfusion injury potentiates this response by releasing oxygen metabolites and lysosomal enz. </li></ul></ul><ul><ul><li>Neutrophils – rolling 10-20min (p-selectin), >20min </li></ul></ul>
  • 50. Nitric Oxide <ul><li>Derived from endothelial surfaces responding to Ach, hypoxia, endotoxin, cellular injury, or shear stresses of circulating blood </li></ul><ul><li>T ½ = seconds </li></ul><ul><li>Reduces microthrombosis, mediates protein synthesis in hepatocytes </li></ul><ul><li>Formed from oxidation of L-arginine via NOS (+calmodulin, Ca2+, NADPH) </li></ul>
  • 51. Prostacyclin (PGI2) <ul><li>Endothelium derived in response to shear stress and hypoxia </li></ul><ul><li>Vasodilator </li></ul><ul><li>Platelet deactivation (increases cAMP) </li></ul><ul><li>Clinically used to reduce pulmonary hypertension (especially pediatric) </li></ul>
  • 52. Endothelins <ul><li>Produced as a response to a variety of factors – injury, anoxia, thrombin, IL-1, vasopressin </li></ul><ul><li>ET-1 is a potent vasoconstrictor, 10x more potent than angiotensin II </li></ul>
  • 53. Platelet Activating Factor <ul><li>Phospholipid component of cell membranes, constitutively expressed at low levels </li></ul><ul><li>Released by PMNs, platelets, mast cells, monocytes during acute inflammation </li></ul><ul><li>Further activates PMNs and platelets </li></ul><ul><li>Increases vascular permeability </li></ul><ul><li>PAF antagonists reduce ischemia/reperfusion injury </li></ul>
  • 54. Metabolism During Fasting <ul><li>Comparable to changes seen in acute injury </li></ul><ul><li>Requires 25-40 kcal/kg/day of carbs, protein, fat </li></ul><ul><li>Normal adult body contains 300-400g carbs (glycogen) – 75-100g hepatic, 200-250g muscle (not available systemically due to deficiency of G6P) </li></ul>Mass (kg) Energy (Kcal) Days Available Water 49 0 0 Protein 6 24,000 13 Glycogen 0.2 800 0.4 Fat 15 140,000 78 Total 70.2 164,800 91.4
  • 55. Metabolism During Fasting <ul><li>A healthy 70kg adult will use 180 g /d of glucose to support obligate glycolytic cells (neurons, RBCs, PMNs, renal medulla, skeletal m.) </li></ul><ul><li>Glucagon, Norepi, vasopressin, AngII promote utilization of glycogen stores </li></ul><ul><li>Glucagon, Epi, and cortisol promote gluconeogenesis </li></ul><ul><li>Precursors include lactate (sk.m., rbc, pmn), glycerol, and aa (ala, glutamine) </li></ul>
  • 56. Metabolism of Simple Starvation <ul><li>Lactate is not sufficient for glucose demands </li></ul><ul><li>Protein must be degraded (75 g/d) for hepatic gluconeogenesis </li></ul><ul><li>Proteolysis from decreased insulin and increased cortisol </li></ul><ul><li>Elevated urinary nitrogen (7 -> 30 g/d) </li></ul>
  • 57. Metabolism of Prolonged Starvation <ul><li>Proteolysis is reduced to 20g/d and urinary nitrogen excretion stabilizes to 2-5g/d </li></ul><ul><li>Organs (myocardium, brain, renal cortex, sk.m) adapt to ketone bodies in 2-24 days </li></ul><ul><li>Kidneys utilize glutamine and glutamate in gluconeogenesis </li></ul><ul><li>Adipose stores provide up to 40% calories (approx 160 g FFA and glycerol) </li></ul><ul><ul><li>Stimulated by reduced insulin and increased glucagon and catecholamines </li></ul></ul>
  • 58. Metabolism Following Injury <ul><li>Magnitude of expenditure is proportional to the severity of injury </li></ul><ul><li>Changes in </li></ul><ul><ul><li>Lipid Absorption </li></ul></ul><ul><ul><li>Lipid Oxidation </li></ul></ul><ul><ul><li>Carbohydrate metabolism </li></ul></ul>
  • 59. Lipid Absorption <ul><li>Oxidation of 1g fat = 9 kcal energy </li></ul><ul><li>Dietary lipids require pancreatic lipase and phospholipase to hydrolyze TG into FFA and monoglycerides within the duodenum </li></ul><ul><li>After gut absorption, enterocytes resynthesize TG from monoglycerides + fatty acyl-CoA </li></ul><ul><li>Long chain TG (>12 carbons) enter the circulation as chylomicrons. Shorter FA chains directly enter portal circulation and are transported via albumin </li></ul><ul><li>Under stress, hepatocytes utilize FFA as fuel </li></ul><ul><li>Systemically TG and chylomicrons are used from hydrolysis with lipoprotein lipase (suppressed by trauma and sepsis) </li></ul>
  • 60. Fatty Acid Oxidation <ul><li>FFA + acyl-CoA = LCT are transported across the mitochondrial inner membrane via the carnitine shuttle </li></ul><ul><li>Medium-chain TG (MCT) 6-12 carbons long, freely cross the mitochondrial membrane </li></ul><ul><li>Fatty acyl-CoA undergoes β -oxidation to acetyl-CoA to enter TCA cycle for oxidation to ATP, CO2, and water </li></ul><ul><li>Excess acetyl-CoA is used for ketogenesis </li></ul>
  • 61. Carbohydrate Metabolism <ul><li>Carbohydrates + pancreatic intestinal enzymes yield dimeric units (sucrase, lactase, maltase) </li></ul><ul><li>Intestinal brush border disaccharidases break them into simple hexose units which are transported into the intestinal mucosa </li></ul><ul><li>Glucose and galactose are absorbed via a sodium dependent active transport pump </li></ul><ul><li>Fructose absorption via facilitated diffusion </li></ul>
  • 62. Carbohydrate Metabolism <ul><li>1g carbohydrate = 4 kcal energy </li></ul><ul><li>IV/parenteral nutrition 3.4 kcal/g dextrose </li></ul><ul><li>In surgical patients dextrose administration is to minimize muscle wasting </li></ul><ul><li>Glucose can be utilized in a variety of pathways – phosphorylation to G6P then glycogenesis or glycogenolysis, pyruvic acid pathway, or pentose shunt </li></ul>
  • 63. Protein and Amino Acid Metabolism <ul><li>Average adult protein intake 80-120 g/day </li></ul><ul><ul><li>every 6 g protein yields 1 g nitrogen </li></ul></ul><ul><ul><li>1g protein = 4 kcal energy </li></ul></ul><ul><li>Following injury, glucocorticoids increase urinary nitrogen excretion (>30g/d), peak at 7d, persist 3-7 wks </li></ul>
  • 64. Nutrition in the Surgical Patient <ul><li>Nutritional assessment to determine the severity of deficiencies/excess </li></ul><ul><li>Wt loss, chronic illnesses, dietary habits, quality/quantity of food, social habits, meds </li></ul><ul><li>Physical exam – loss of muscle/adipose tissue, organ dysfunction </li></ul><ul><li>Biochemical – Cr excretion, albumin, prealbumin, total lymphocyte count, transferrin </li></ul>
  • 65. Surgical Nutrition <ul><li>Support the requirements for protein synthesis </li></ul><ul><li>Nonprotein calorie : nitrogen ratio = 150:1 </li></ul><ul><li>A lower rate of 80-100:1 may be beneficial in some critically ill or hypermetabolic patients </li></ul><ul><li>Basal Energy Expenditure (BEE): </li></ul><ul><li>men = 66.47 + 13.75(W) + 5(H) – 6.76(A) kcal/d </li></ul><ul><li>women = 655.1 + 9.56(W) + 1.85(H) – 4.68 (A) kcal/d </li></ul><ul><li>W= wt in kg, H= Ht in cm, A= age in years </li></ul>
  • 66. Enteral Feeding <ul><li>Less expensive and risks than parenteral </li></ul><ul><li>Reduced intestinal atrophy </li></ul><ul><li>44% reduction in infections over parenteral in the critically ill </li></ul><ul><li>Healthy patients without malnutrition undergoing uncomplicated surgery can tolerate 10 d of maintenance IV fluids only before significant protein catabolism begins </li></ul>
  • 67. Initiation of Enteral Feeding <ul><li>Immediately after adequate fluid resuscitation (UOP) </li></ul><ul><li>Not absolute prerequisites: presence of bowel sounds, passage of flatus or stool </li></ul><ul><li>Gastric residuals of >200ml in 4-6 hrs or abdominal distention requires cessation/lowering the rate </li></ul>
  • 68. Enteral Formulas <ul><li>Low-residue isotonic </li></ul><ul><ul><li>caloric density 1.0kcal/ml, 1500-1800 ml/day </li></ul></ul><ul><ul><li>Provide carbs, protein, lytes, water, fat, water sol vitamins, calorie:Nitrogen of 150:1. </li></ul></ul><ul><ul><li>No fiber bulk = minimum residue </li></ul></ul><ul><ul><li>Standard for stable patients with an intact GI tract </li></ul></ul><ul><li>Isotonic with fiber </li></ul><ul><ul><li>Soluble and insoluble fiber (soy) </li></ul></ul><ul><ul><li>Delay GI transit time and reduce diarrhea </li></ul></ul><ul><ul><li>Not contraindicated in the critically ill </li></ul></ul>
  • 69. Enteral Formulas <ul><li>Immune-Enhancing </li></ul><ul><ul><li>Glutamine, argenine, omega-3 FA, nucleotides, beta-carotene. </li></ul></ul><ul><ul><li>Benefits not consistent in trials </li></ul></ul><ul><ul><li>Expensive </li></ul></ul><ul><li>Calorie-Dense </li></ul><ul><ul><li>1.5-2 kcal/ml, higher osmolality (ok for intragastric feeding) </li></ul></ul><ul><ul><li>for fluid restriction/inability to tolerate larger volumes </li></ul></ul><ul><li>High-Protein </li></ul><ul><ul><li>Isotonic and nonisotonic available </li></ul></ul><ul><ul><li>calorie:Nitrogen ratio of 80-120:1 </li></ul></ul>
  • 70. Enteral Formulas <ul><li>Elemental </li></ul><ul><ul><li>Contain predigested nutrients, small peptides </li></ul></ul><ul><ul><li>Limited complex carbs and fat (long/med chains) </li></ul></ul><ul><ul><li>Easily absorbed, but limited long term use </li></ul></ul><ul><ul><li>High osmolality = slow infusion or diluted </li></ul></ul><ul><ul><li>Expensive </li></ul></ul><ul><li>Renal-Failure </li></ul><ul><ul><li>Lower fluid volume, K, phos, and Mg </li></ul></ul><ul><ul><li>Essential aa, high calorie : nitrogen ratio, no vitamins </li></ul></ul>
  • 71. Enteral Formulas <ul><li>Pulmonary-Failure </li></ul><ul><ul><li>Fat content is increased to 50% of total calories </li></ul></ul><ul><ul><li>Reduces CO2 production and ventilation burden </li></ul></ul><ul><li>Hepatic-Failure </li></ul><ul><ul><li>50% of aa are branched chains (Leu, Ile, Val) </li></ul></ul><ul><ul><li>Potentially reverses encephalopathy </li></ul></ul><ul><ul><li>Controversial, no clear benefits in trials </li></ul></ul>
  • 72. Enteral Access <ul><li>Nasogastric Tube - requires intact mental status and laryngeal reflexes to reduce aspiration </li></ul><ul><ul><li>Difficult to place, requires radiographic confirmation </li></ul></ul><ul><ul><li>If required >30 d, convert to PEG </li></ul></ul><ul><ul><li>Problems: clogging, kinking, inadvertent removal </li></ul></ul><ul><li>Percutaneous Endoscopic Gastrostomy – </li></ul><ul><ul><li>Impaired swallowing/obstruction, major facial trauma </li></ul></ul><ul><ul><li>Contraindications: ascites, coagulophathy, gastric varices, gastric neoplasm, lack of suitable location </li></ul></ul><ul><ul><li>Tubes can be use for 12-24 mos </li></ul></ul><ul><ul><li>Requires endoscopic transillumination of abdominal wall and passage of catheter into an insufflated stomach </li></ul></ul><ul><ul><li>Complications in 3% of cases: infection, peritonitis, aspiration/pneumonia, leaks, dislodgement, bowel perforation, enteric fistulas, bleeding </li></ul></ul>
  • 73. Percutaneous Endoscopic Gastrostomy-Jejunostomy <ul><li>Feeding administered past the pylorus </li></ul><ul><li>Cannot tolerate gastric feedings/signif aspiration </li></ul><ul><li>Passes a catheter through an existing PEG past the pylorus into the duodenum </li></ul><ul><li>Long term malfunction >50% due to retrograde tube migration into the stomach, kinking, clogging </li></ul>
  • 74. Direct Percutaneous Endoscopic Jejunostomy <ul><li>Same technique as PEG placement but requires an enteroscope/colonscope to reach the jejunum </li></ul><ul><li>Less malfunction than PEG-J </li></ul><ul><li>Kinking/clogging reduced by placing larger caliber catheters </li></ul>
  • 75. Surgical Gastrostomy and Jejunostomy <ul><li>With complex abdominal trauma/laparatomy there may be an opportunity for placement </li></ul><ul><li>Contraindication: distal obstruction, severe intestinal wall edema, radiation enteritis, inflammatory bowel disease, ascites, severe immunodeficiency, bowel ischemia </li></ul><ul><li>Adverse effects: abdominal/bowel distention, cramps, pneumotosis intestinalis, small bowel necrosis </li></ul>
  • 76. Parenteral Nutrition <ul><li>Continuous infusion of hyperosmolar carbs, proteins, fats and other nutrients through a catheter into the SVC </li></ul><ul><li>Optimal > 100-150 kcal/g nitrogens </li></ul><ul><li>Higher rates of infection compared to enteral </li></ul><ul><li>Studies with parenteral nutrition and complete bowel rest results in increased stress hormone and inflammatory responses </li></ul>
  • 77. Parenteral Nutrition Rationale <ul><li>Seriously ill patients with malnutrition, sepsis or surgery/trauma when use of the GI tract for feeding is not possible </li></ul><ul><ul><li>Short bowel syndrome after massive resection </li></ul></ul><ul><ul><li>Prolonged paralytic ileus (>7 days) </li></ul></ul><ul><ul><li>Severe intestinal malabsorption </li></ul></ul><ul><ul><li>Functional GI disorders – esophageal dyskinesia </li></ul></ul><ul><ul><li>Etc. </li></ul></ul>
  • 78. Total Parenteral Nutrition <ul><li>Central parenteral nutrition, aka TPN </li></ul><ul><li>Requires access to a large diameter vein </li></ul><ul><li>Dextrose content is high (15-25%) </li></ul>
  • 79. Peripheral Parenteral Nutrition <ul><li>Lower osmolality </li></ul><ul><li>Reduced dextrose (5-10%) </li></ul><ul><li>Protein (3%) </li></ul><ul><li>Not appropriate for severe malnutrition due to need for larger volumes of some nutrients </li></ul><ul><li>Shorter periods, < 2 wks </li></ul>
  • 80. Parenteral Nutrition <ul><li>Dextose 15-25% </li></ul><ul><li>Amino acids 3-5% </li></ul><ul><li>Vitamins (Vit K is not included) </li></ul><ul><li>Lipid emulsions to prevent essential FA deficiency (10-15% of calories) </li></ul><ul><li>Prepared by the pharmacy from commercially available kits </li></ul><ul><li>If prolonged – supplement trace minerals </li></ul><ul><ul><li>Zinc (eczematous rash), copper (microcytic anemia), chromium (glucose intolerance) </li></ul></ul>
  • 81. Parenteral Nutrition <ul><li>Insulin supplement to insure glucose tolerance </li></ul><ul><li>IV fluids/electrolytes if high fluid losses </li></ul><ul><li>Freq. monitor fluid status, vital signs, UOP, electrolytes, BUN, and LFTs. Glucose q6h </li></ul>
  • 82. Complications <ul><li>Hyperglycemia – pt with impaired glc tolerance or high infusion rate </li></ul><ul><ul><li>Tx- volume replacement, correct electrolytes, insulin </li></ul></ul><ul><ul><li>Avoid by monitoring daily fluid balance, glc, & lytes </li></ul></ul><ul><li>Overfeeding – results in CO2 retention and respiratory insufficiency </li></ul><ul><li>Hepatic steatosis </li></ul><ul><li>Cholestasis and gallstones </li></ul><ul><li>Hepatic abnormalities – serum transaminase, alk phos and bilirubin </li></ul><ul><li>Intestinal - atrophy from disuse, bacterial overgrowth, reduced lymphoid tissue and IgA production, impaired gut immunity </li></ul>
  • 83. Special Formulations <ul><li>Glutamine and Arginine </li></ul><ul><ul><li>Glutamine – nonessential aa, comprises 66% of free amino acids </li></ul></ul><ul><ul><li>During stress glu is depleted and shunted as a fuel source to visceral organs and tumors </li></ul></ul><ul><ul><li>Inconclusive data for benefits of increased supplementation </li></ul></ul><ul><ul><li>Arginine – nonessential aa, promotes net nitrogen retention and protein synthesis in the critically ill/injured. Benefits still under investigation. </li></ul></ul><ul><li>Omega-3 Fatty Acids </li></ul><ul><ul><li>Canola or fish oil. Displaces omega-6 FAs, theoretically reducing pro-inflammatory responses </li></ul></ul><ul><li>Nucleotides </li></ul><ul><ul><li>? Increase cell proliferation, DNA synthesis, T Helper cell function </li></ul></ul>
  • 84. References <ul><li>The material in this presentation was directly adapted from: </li></ul><ul><li>E. Lin, S. E. Calvano, and S. F. Lowry. Chapter 1. Systemic Response to Injury and Metabolic Support. In Schwartz's Principles of Surgery, 8 th ed. F. C. Brunicardi, D. K. Andersen , T. R. Billiar, D. L. Dunn, J. G. Hunter, R. E. Pollock, eds. McGraw-Hill Professional, 2004. </li></ul>

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