Systemic Response To Injury

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  • Systemic Response To Injury

    1. 1. SYSTEMIC RESPONSE TO INJURY James Taclin C. Banez, MD, FPSGS, FPCS
    2. 2. <ul><li>Injury (surgery, traumatic & infections): </li></ul><ul><ul><li>Alteration of neuro-endocrine system, metabolic and immunology ----> causes disequilibrium of internal environment & tries to return to homeostasis. </li></ul></ul>
    3. 3. <ul><li>Minor Injuries : is usually followed by functional restoration w/ minimal intervention. </li></ul><ul><li>Major injuries : associated with overwhelming inflammatory response ----> failure to give appropriate intervention ----> multiple organ failure -----> DEATH </li></ul>
    4. 4. Systemic Inflammatory Response Syndrome (SIRS) <ul><li>2 Phases: </li></ul><ul><li>Pro-inflammatory phase: </li></ul><ul><ul><li>Char. By activation of cellular processes designed to restore tissue function & eradicate invading micro-organism. </li></ul></ul><ul><li>Counter-regulatory or anti-inflammatory phase: </li></ul><ul><ul><li>To prevent excessive pro-inflammatory activities and to restore homeostasis </li></ul></ul>
    5. 5. Terminologies Term Definition Infection Identifiable source of microbial insult SIRS Two or more following criteria: - Temp >/= 38C or </= 36C - Heart rate >/= 90 beats/min - Respiratory rate >/= 20 breaths/min or PaCO2 </= 32mmHg or mechanical ventilation - WBC >/= 12,000/ul or </= 4000/ul or >/= 10% band forms Sepsis Identifiable source of infection + SIRS Severe sepsis Sepsis + organ dysfunction Septic shock Sepsis + cardiovascular collapse (requiring vasopressor support)
    6. 6. Central Nervous System Regulation of Inflammation <ul><li>Afferent Signals: </li></ul><ul><li>Circulatory: </li></ul><ul><ul><li>Areas of CNS devoid of bld-brain barrier admit passage of inflammatory mediators (TNF) </li></ul></ul><ul><ul><li>Causing fever, anorexia & depression </li></ul></ul><ul><li>Neural pathways: </li></ul><ul><ul><li>Afferent stimuli to the vagus nerve : </li></ul></ul><ul><ul><li>cytokines – TNF, IL-1 </li></ul></ul><ul><ul><li>Baroreceptors </li></ul></ul><ul><ul><li>Chemoreceptors </li></ul></ul><ul><ul><li>Thermoreceptors </li></ul></ul><ul><ul><li>From the site of injuries </li></ul></ul>
    7. 7. Central Nervous System Regulation of Inflammation <ul><li>Cholinergic Anti-Inflammatory Pathways: </li></ul><ul><li>Acetycholine of parasympathetic: </li></ul><ul><ul><li>reduces tissue macrophage activation </li></ul></ul><ul><ul><li>Reduces tissue macrophage release of inflammatory mediators (TNF alpha, IL1, IL18 & high mobility grp protein (HMG-1), but not the anti-inflammatory cytokine IL10 </li></ul></ul><ul><li>Vagal stimulation reduces HR, increases gut motility, dilates arterioles, causes pupil constriction & regulates inflammation </li></ul>
    8. 8. Systemic Neuro-Endocrine Reflexes <ul><li>Stimuli: </li></ul><ul><ul><li>Effective Circulatory Volume (ECV): </li></ul></ul><ul><ul><ul><li>Sensed by: </li></ul></ul></ul><ul><ul><ul><ul><li>high pressure baroreceptor (aorta, carotid & renal artery) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>low pressure stretch receptors (atrial volume) </li></ul></ul></ul></ul><ul><ul><ul><li>Decreased ECV ---> release of tonic inhibition ---> (+) receptors ----> (+) ACTH, vasopressin , beta-endorphin, E & NE, renin. </li></ul></ul></ul><ul><ul><ul><li>If decrease ECV is < 30% of TBV the neuroendocrine & cardiovascular response can compensate; > 30% ----> DECOMPENSATE (hypotension) </li></ul></ul></ul>
    9. 9. Systemic Neuro-Endocrine Reflexes <ul><li>Stimuli: </li></ul><ul><ul><li>Chemoreceptor Relexes: </li></ul></ul><ul><ul><ul><li>sensed by: a. carotid bodies (inactive) </li></ul></ul></ul><ul><ul><ul><li>b. aortic bodies (inactive) </li></ul></ul></ul><ul><ul><ul><li>stimulation of chemoreceptors: </li></ul></ul></ul><ul><ul><ul><ul><li>decrease oxygen </li></ul></ul></ul></ul><ul><ul><ul><ul><li>increase CO2 and H </li></ul></ul></ul></ul><ul><ul><ul><li>Results to: </li></ul></ul></ul><ul><ul><ul><ul><li>Decrease sympathetic activity (cardiac) & increase in parasympathetic activity. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Increase respiratory rate & decrease cardiac rate and contractility. </li></ul></ul></ul></ul>
    10. 10. Systemic Neuro-Endocrine Reflexes <ul><li>Stimuli: </li></ul><ul><ul><li>Pain & Emotion: </li></ul></ul><ul><ul><ul><li>Pain ---> (+) thalamus & hypothalamus </li></ul></ul></ul><ul><ul><ul><li>Emotion ---> (+) limbic ----> (+) hypothalamus </li></ul></ul></ul><ul><ul><li>Substrate alteration: </li></ul></ul><ul><ul><ul><li>Alteration plasma glucose concentration activates neuroendocrine reflexes thru it’s receptors: </li></ul></ul></ul><ul><ul><ul><ul><li>Hypothalamus -----> pituitary </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Pancreas </li></ul></ul></ul></ul><ul><ul><li>Temperature: </li></ul></ul><ul><ul><ul><li>Changes in core temperature, sensed by the pre-optic area of the hypothalamus ---> alters secretion of several hormones </li></ul></ul></ul>
    11. 11. Systemic Neuro-Endocrine Reflexes <ul><li>CNS Centers: (hypothalamus) </li></ul><ul><ul><li>Posterior Hypothalamus: </li></ul></ul><ul><ul><ul><li>ACTH, sympathetic activity </li></ul></ul></ul><ul><ul><li>Paraventricular Nucleus: </li></ul></ul><ul><ul><ul><li>vasopressin, oxytocin & ACTH </li></ul></ul></ul><ul><ul><li>Ventromedial Nucleus: </li></ul></ul><ul><ul><ul><li>GH, ACTH </li></ul></ul></ul><ul><ul><li>Supraoptic Nucleus </li></ul></ul><ul><ul><ul><li>vasopressin & oxytocin </li></ul></ul></ul><ul><ul><li>Suprachiasmatic Nucleus: </li></ul></ul><ul><ul><ul><li>ACTH & gonadotrophin </li></ul></ul></ul>
    12. 12. Systemic Neuro-Endocrine Reflexes <ul><li>Efferent Output: </li></ul><ul><ul><li>Autonomic response: </li></ul></ul><ul><ul><li>Hormonal response: </li></ul></ul><ul><ul><ul><li>Hypothalamic – anterior pituitary control </li></ul></ul></ul><ul><ul><ul><li>Posterior pituitary control </li></ul></ul></ul><ul><ul><ul><li>Autonomic control </li></ul></ul></ul><ul><ul><li>Local tissue response: </li></ul></ul>
    13. 13. Hormone Response to Injury <ul><li>Hypothalamic regulation </li></ul><ul><ul><li>CRH </li></ul></ul><ul><ul><li>TRH </li></ul></ul><ul><ul><li>GHRH </li></ul></ul><ul><ul><li>LHRH </li></ul></ul><ul><li>Anterior Pituitary regulation </li></ul><ul><ul><li>ACTH – cortisol </li></ul></ul><ul><ul><li>TSH – T3/T4 </li></ul></ul><ul><ul><li>GH </li></ul></ul><ul><ul><li>Gonadotrophins </li></ul></ul><ul><ul><li>Sex hormones </li></ul></ul><ul><ul><li>Insulin-like growth factor </li></ul></ul><ul><ul><li>Somatostatin </li></ul></ul><ul><ul><li>Prolactin </li></ul></ul><ul><ul><li>Endorphins </li></ul></ul><ul><li>Posterior Pituitary regulation </li></ul><ul><ul><li>Vasopressin </li></ul></ul><ul><ul><li>Oxytocin </li></ul></ul><ul><li>Autonomic System </li></ul><ul><ul><li>NE / E </li></ul></ul><ul><ul><li>Aldosterone </li></ul></ul><ul><ul><li>Renin-angiotensin system </li></ul></ul><ul><ul><li>Insulin </li></ul></ul><ul><ul><li>Glucagon </li></ul></ul><ul><ul><li>Enkephalins </li></ul></ul>
    14. 14. <ul><li>HORMONES UNDER ANTERIOR PITUITARY </li></ul><ul><li>REGULATION </li></ul><ul><li>CRF – ACTH – Cortisol: </li></ul><ul><ul><li>(+) CRF – pain, fear, anxiety, angiotensin II, serotonin, </li></ul></ul><ul><ul><li>acetylcholine & interleukin 1/6 </li></ul></ul><ul><ul><li>ACTH – circardian signals is lost in injury due to pain, anxiety, vasopressin, angiotensin II, E, </li></ul></ul><ul><ul><li>NE, oxytocins & proinflammatory cytokines </li></ul></ul><ul><ul><li>Cortisol - elevated in any types of injury, longest in burn pts. (4wks). Actions in injury: </li></ul></ul><ul><ul><ul><ul><li>potentiates the action of glucagon & E causing hyperglycemia. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>favors gluconeogenesis; insulin resistance in muscles & adipose tissue. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>induces protein degradation in the skeletal muscle & releases lactate for hepatic gluconeogenesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>potentiates release of FA, triglycerides & glycerol from adipose tissue for energy source </li></ul></ul></ul></ul>
    15. 15. <ul><li>CRF – ACTH – Cortisol: </li></ul><ul><ul><li>Acute adrenal Insufficiency (AAI): </li></ul></ul><ul><ul><ul><li>Life threatening complication </li></ul></ul></ul><ul><ul><ul><li>Commonly due to adrenal suppression from exogenous administration of glucocorticoid </li></ul></ul></ul><ul><ul><ul><li>Manifestation: </li></ul></ul></ul><ul><ul><ul><ul><li>weakness, n / v, fever & hypotension </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hypoglycemia (due to low gluconeogenesis) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hyponatremia & Hyperkalemia (impaired renal tubular reabsorption – due to insufficient aldosterone) </li></ul></ul></ul></ul><ul><ul><li>Cortisol is an effective immuno-suppressive agents: </li></ul></ul><ul><ul><ul><li>Caused thymic involution </li></ul></ul></ul><ul><ul><ul><li>Depressed cell mediated immune response </li></ul></ul></ul><ul><ul><ul><li>Cause monocyte & neutrophil lose of intracellular bacterial killing </li></ul></ul></ul><ul><ul><ul><li>It downregulates proinflammatory cytokines production (TNF alpha, IL-1, IL-6); and increases the production of anti-inflammatory mediator IL-10. </li></ul></ul></ul>
    16. 16. <ul><li>Growth Hormone: </li></ul><ul><ul><li>(+) GH is GHRF (-) GH is somatostatin </li></ul></ul><ul><ul><li>Anabolic for CHON; catabolic for CHO & lipids </li></ul></ul><ul><ul><li>Stimulatory: </li></ul></ul><ul><ul><ul><li>Hypoglycemia, decrease ECV, decrease plasma FA & a.a., exercise, STRESS and sleep. </li></ul></ul></ul><ul><ul><ul><li>Thyroxine, vasopressin, MSH, testosterone, estrogen and alpha adrenergic stimulation. </li></ul></ul></ul><ul><ul><li>INSULIN like GROWTH FACTOR-1 (Somatomedin C; IGF-1) </li></ul></ul><ul><ul><ul><li>Partially mediates CHON synthesis properties of GH after injury </li></ul></ul></ul><ul><ul><ul><li>The liver is the predominant source of IGF-1. </li></ul></ul></ul><ul><ul><ul><li>Promotes a.a. incorporation & cellular proliferation and attenuates proteolysis in skeletal muscle & liver. </li></ul></ul></ul><ul><ul><ul><li>In injury: the effects of IGF-1 is inhibited by proinflammatory cytokines (TNF, IL-1 and IL-6). Resulting to (-) nitrogen balance. </li></ul></ul></ul>
    17. 17. <ul><li>Macrophage Inhibitory Factor: </li></ul><ul><ul><li>Produced by: </li></ul></ul><ul><ul><ul><li>Anterior pituitary gland </li></ul></ul></ul><ul><ul><ul><li>T lymphocytes at the site of inflammation. </li></ul></ul></ul><ul><ul><li>Actions: </li></ul></ul><ul><ul><ul><li>A glucocorticoid antagonist (suppresses the immunosuppresive effects of cortisol). </li></ul></ul></ul><ul><ul><ul><li>It is a proinflammatory mediator that potentiates gm (-) & (+) septic shock. </li></ul></ul></ul><ul><li>Endogenous Opiods: </li></ul><ul><ul><li>Endorphins, enkephalins </li></ul></ul><ul><ul><li>Elevated after injury & surgery </li></ul></ul><ul><ul><li>Endorphins ----> attenuate pain perceptions / hypotension </li></ul></ul><ul><ul><ul><li>Enkephalins ----> HPN, decrease peristalsis and secretion of GIT </li></ul></ul></ul>
    18. 18. <ul><li>Thyroid Hormone (T4 / T3): </li></ul><ul><ul><li>In injury: </li></ul></ul><ul><ul><ul><li>Low T3 </li></ul></ul></ul><ul><ul><ul><li>(-) TSH release </li></ul></ul></ul><ul><ul><ul><li>Conversion of T4 – T3 in the target organs are impaired due to cortisol. T4 is converted to an inactive T3 called rT3 </li></ul></ul></ul><ul><li>Gonadotrophins (LHRH/GnRH) & (FSH/LH): </li></ul><ul><ul><li>Injury, stress or severe illness ----> (-) GRH ----> (-) LH and (-) FSH ---> decrease estrogen and androgen secretions. </li></ul></ul><ul><ul><li>Causes menstrual irregularities and decrease libido. </li></ul></ul><ul><li>Prolactin: </li></ul><ul><ul><li>Produced by anterior pituitary gld and T lymphocytes </li></ul></ul><ul><ul><li>Elevated level after injury in adults not seen in children </li></ul></ul><ul><ul><li>Causes amenorrhea </li></ul></ul>
    19. 19. <ul><li>HORMONES OF AUTONOMIC SYSTEM: </li></ul><ul><li>Catecholamines (E / NE): </li></ul><ul><ul><li>Causes hypermetabolic state following severe injury </li></ul></ul><ul><ul><li>3 – 4fold increase of E & NE in the plasma for 24 – 48 hrs. </li></ul></ul><ul><ul><li>Causes: </li></ul></ul><ul><ul><ul><li>Promotes glycogenolysis, gluconeogenesis, lipolysis and ketogenesis. </li></ul></ul></ul><ul><ul><ul><li>Decreased insulin release & increase glucagon secretion. </li></ul></ul></ul><ul><ul><ul><li>Peripherally, it increases lipolysis in adipose tissue and induces insulin resistance in skeletal muscle </li></ul></ul></ul><ul><ul><ul><li>It inhibit the release of aldosterone. </li></ul></ul></ul><ul><ul><ul><li>Immune function: -- enhances neutrophilia and lymphocytosis </li></ul></ul></ul>
    20. 20. <ul><li>Aldosterone (Mineralocorticoid): </li></ul><ul><ul><li>Released by adrenal zona glomerulosa </li></ul></ul><ul><ul><li>Release is caused by: </li></ul></ul><ul><ul><ul><li>Angiotensin II </li></ul></ul></ul><ul><ul><ul><li>Hyperkalemia </li></ul></ul></ul><ul><ul><ul><li>Aldosterone stimulating factor (ASF) in pituitary </li></ul></ul></ul><ul><ul><ul><li>ACTH (is the most potent stimulant). </li></ul></ul></ul><ul><ul><li>Major function is to maintain intravascular volume by conserving Na & eliminating potassium and H+ in the early distal convoluted tubules of nephron </li></ul></ul>
    21. 21. <ul><li>Renin – Angiotensin: </li></ul><ul><ul><li>Renin in Juxtaglomerular apparatus is released by: </li></ul></ul><ul><ul><ul><li>ACTH, Glucagon, porstagladin, K+, Mg+, and Ca+ </li></ul></ul></ul><ul><ul><ul><li>Baroreceptor – respond to decrease blood pressure </li></ul></ul></ul><ul><ul><ul><li>Macula densa detects changes in chloride concentration. </li></ul></ul></ul><ul><ul><li>Action of angiotensin II: </li></ul></ul><ul><ul><ul><li>Vasoconstrictor </li></ul></ul></ul><ul><ul><ul><li>(+) aldosterone </li></ul></ul></ul><ul><ul><ul><li>(+) ADH </li></ul></ul></ul><ul><ul><ul><li>(+) E </li></ul></ul></ul><ul><ul><ul><li>Increase heart rate and contractility </li></ul></ul></ul>
    22. 22. <ul><li>Glucagon: </li></ul><ul><ul><li>alpha islet cell </li></ul></ul><ul><ul><li>catabolic role </li></ul></ul><ul><ul><li>elevated release after injury </li></ul></ul><ul><li>Insulin: </li></ul><ul><ul><li>Inhibit its release in injury: </li></ul></ul><ul><ul><ul><li>Catecholamine </li></ul></ul></ul><ul><ul><ul><li>Glucagon </li></ul></ul></ul><ul><ul><ul><li>Somatostatin </li></ul></ul></ul><ul><ul><ul><li>Beta endorphins </li></ul></ul></ul><ul><ul><ul><li>IL-1 </li></ul></ul></ul>
    23. 23. <ul><li>Hormones Under Posterior Pituitary Regulation: </li></ul><ul><li>Vasopressin / ADH / Arginine Vasopressin (AVP): </li></ul><ul><ul><li>Causes </li></ul></ul><ul><ul><ul><li>readsorption of H2O in DCT </li></ul></ul></ul><ul><ul><ul><li>Vasoconstriction peripherally </li></ul></ul></ul><ul><ul><ul><li>Stimulates hepatic glycogenolysis & gluconeogenesis </li></ul></ul></ul><ul><ul><li>Elevated plasma osmolality is its major stimulus: </li></ul></ul><ul><ul><li>Location of osmoreceptors: hypothalamus, portal circulation </li></ul></ul>
    24. 24. <ul><li>Hormones Under Posterior Pituitary Regulation: </li></ul><ul><li>Vasopressin / ADH / Arginine Vasopressin (AVP): </li></ul><ul><ul><li>Its release also happens in 10% loss of ECV stimulating the baroreceptor in the left atrium </li></ul></ul><ul><ul><li>Other stimulus: </li></ul></ul><ul><ul><ul><li>PAIN </li></ul></ul></ul><ul><ul><ul><li>Beta adrenergic </li></ul></ul></ul><ul><ul><ul><li>Angiotensin II </li></ul></ul></ul><ul><ul><ul><li>Opiods </li></ul></ul></ul><ul><ul><ul><li>Elevated glucose </li></ul></ul></ul>
    25. 25. <ul><li>Oxytocin: </li></ul><ul><ul><li>Its release caused by SUCKING the nipple </li></ul></ul><ul><ul><li>Stimulates contraction of mammary gland and uterus during parturition </li></ul></ul><ul><ul><li>No known function in males </li></ul></ul><ul><ul><li>Role in injury is unknown </li></ul></ul>
    26. 26. Mediators of Inflammation <ul><li>Cytokines: </li></ul><ul><ul><li>Most potent mediator of the inflammatory response </li></ul></ul><ul><ul><li>Eradicates invading microorganism and promotes wound healing </li></ul></ul><ul><ul><li>Overwhelming productions of proinflammatory cytokines can cause: </li></ul></ul><ul><ul><ul><li>Hemodynamic instability (septic shock) </li></ul></ul></ul><ul><ul><ul><li>Metabolic derangement (muscle wasting) </li></ul></ul></ul><ul><ul><li>Can exaggerate to multiple organ failure and death. </li></ul></ul><ul><ul><li>Inappropriate anti-inflammatory mediator release can lead to immunocompromised and susceptible to overwhelming infection. </li></ul></ul>
    27. 27. Mediators of Inflammation <ul><li>Heat Shock Proteins: </li></ul><ul><ul><li>Intracellular protein modifiers and transporters that protect cells from the deleterious effects of traumatic stress. </li></ul></ul><ul><ul><li>The following induced its production: </li></ul></ul><ul><ul><ul><li>Hypoxia </li></ul></ul></ul><ul><ul><ul><li>Trauma </li></ul></ul></ul><ul><ul><ul><li>Heavy metals </li></ul></ul></ul><ul><ul><ul><li>Local trauma </li></ul></ul></ul><ul><ul><ul><li>Hemorrhage </li></ul></ul></ul>
    28. 28. Mediators of Inflammation <ul><li>Reactive Oxygen Metabolites: </li></ul><ul><ul><li>Oxygen radicals are produced by reduction of oxygen to superoxide anion, and further metabolized to form H2O2 & hydroxyl radicals </li></ul></ul><ul><ul><li>Causes injury by oxidation of unsaturated fatty acids w/in cell membranes. </li></ul></ul><ul><ul><li>Activated leukocytes are potent generators for reactive oxygen metabolites. </li></ul></ul><ul><ul><li>Cells are protected from this metabolite by oxygen scavengers: GLUTATHIONE & CATALASES. </li></ul></ul>
    29. 29. Mediators of Inflammation <ul><li>Eicosanoids: </li></ul><ul><ul><li>Are oxidation derivatives of membrane phospholipid arachidonic acids </li></ul></ul><ul><ul><li>Secreted by nucleated cells, except lymphocytes </li></ul></ul><ul><ul><li>Not stored w/in cells but are synthesized rapidly upon stimulation by hypoxic injury, tissue injury, endotoxin, NE, vasopressin angiotensin II, bradykinin, serotonin, acetylcholine, cytokines and histamine </li></ul></ul>
    30. 30. Mediators of Inflammation <ul><li>Eicosanoids: </li></ul><ul><ul><li>Actions: </li></ul></ul><ul><ul><li>PGE 2 increases fluid leakage from bld vessels, inhibit gluconeogenesis and hormone stimulated lipolysis. </li></ul></ul><ul><ul><li>Leukotrienes are 1000x more potent than histamine promoting capillary leakage, vasoconstriction, bronchoconstriction, neutrophil activation. </li></ul></ul><ul><ul><li>Products of cyclooxygenase inhibit pancreatic beta cell release of insulin. </li></ul></ul>
    31. 31. Mediators of Inflammation <ul><li>Kallikrein-Kinin System: </li></ul><ul><ul><li>Bradykinin: </li></ul></ul><ul><ul><ul><li>potent vasodilators </li></ul></ul></ul><ul><ul><ul><li>Release is caused by hypoxic and ischemic injury </li></ul></ul></ul><ul><ul><li>Kinins: </li></ul></ul><ul><ul><ul><li>increase capillary permeability and tissue edema, </li></ul></ul></ul><ul><ul><ul><li>evoke pain, </li></ul></ul></ul><ul><ul><ul><li>Inhibit gluconeogenesis </li></ul></ul></ul><ul><ul><ul><li>increase bronchoconstriction. </li></ul></ul></ul><ul><ul><ul><li>increase renal vasodilation and reduces renal perfusion pressure ----> (+) renin-angiotensin system. </li></ul></ul></ul>
    32. 32. Mediators of Inflammation <ul><li>Serotonin: </li></ul><ul><ul><li>neurotransmitter (5hydrohytryptamine) </li></ul></ul><ul><ul><li>tryptophan derivative found in chromaffin cells of the intestine (carcinoid tumors). </li></ul></ul><ul><ul><li>Vasoconstrictions, bronchoconstriction & platelet aggregations </li></ul></ul><ul><ul><li>myocardial chronotrope and inotrope </li></ul></ul>
    33. 33. Mediators of Inflammation <ul><li>Histamine: </li></ul><ul><ul><li>Derived from histidine </li></ul></ul><ul><ul><li>Stored in neurons, skin, gastric mucosa, mast cells basophils and platelets </li></ul></ul><ul><ul><li>Released is activated by increased calcium levels. </li></ul></ul><ul><ul><li>2 receptors: </li></ul></ul><ul><ul><ul><li>H1 – stimulates bronchoconstriction, intestinal motility, and myocardial contractility </li></ul></ul></ul><ul><ul><ul><li>H2 – inhibits histamine release </li></ul></ul></ul>
    34. 34. Mediators of Inflammation <ul><li>Histamine: </li></ul><ul><ul><li>Both H1 & H2 receptor activation causes: </li></ul></ul><ul><ul><ul><li>Hypotension </li></ul></ul></ul><ul><ul><ul><li>Peripheral pooling of blood </li></ul></ul></ul><ul><ul><ul><li>Increase capillary permeability </li></ul></ul></ul><ul><ul><ul><li>Decrease venous return </li></ul></ul></ul><ul><ul><ul><li>Myocardial failure </li></ul></ul></ul><ul><ul><li>Elevated in cases of hemorrhagic shock, trauma, thermal injury, endotoxemia and sepsis. </li></ul></ul>
    35. 35. Cytokines <ul><li>Usually secreted by immunocytes & other cells </li></ul><ul><li>Indespensible to tissue healing and immune response generated against microbial invasion </li></ul><ul><li>Are not stored as preformed molecules and it’s activity is primarily exerted locally w/ cell to cell interaction </li></ul><ul><li>Their rapid appearance after injury is due to active transcription and translation by the injured or stimulated cells. </li></ul><ul><li>Direct the inflammatory response to infection, injury and actively promote wound healing </li></ul>
    36. 36. CYTOKINES <ul><li>TNF (Tumor Necrosis Factor): </li></ul><ul><ul><li>Earliest & most potent mediators </li></ul></ul><ul><ul><li>Monocytes/macrophage and Tcells </li></ul></ul><ul><ul><li>Actions: </li></ul></ul><ul><ul><ul><li>Major inducer muscle catabolism & cachexia during stress </li></ul></ul></ul><ul><ul><ul><li>Coagulation activation </li></ul></ul></ul><ul><ul><ul><li>Releases prostaglandin E2, platelet activating factor (PAF), glucocorticoid and eicosanoids </li></ul></ul></ul><ul><ul><ul><li>Initiates of hemodynamic decompensation. </li></ul></ul></ul>
    37. 37. CYTOKINES <ul><li>Interleukin-1 (IL-1): </li></ul><ul><ul><li>Causes: </li></ul></ul><ul><ul><ul><li>Induces febrile response to injury by stimulating prostaglandin to anterior hypothalamus. </li></ul></ul></ul><ul><ul><ul><li>Attenuated pain perception by promoting release of beta-endorphins from the pituitary gld. </li></ul></ul></ul><ul><ul><li>Endogenous IL-1 receptor antagonist (IL-1ra) are also released during injury to auto-regulate IL-1. </li></ul></ul>
    38. 38. CYTOKINES <ul><li>Interleukin-2: </li></ul><ul><ul><li>Promoter of T-lymphocyte proliferation, immunoglobulin production & gut barrier integrity. </li></ul></ul>
    39. 39. CYTOKINES <ul><li>Interleukin-4 (IL-4): </li></ul><ul><ul><li>Produced by activate T-helper lymphocyte. </li></ul></ul><ul><ul><li>Induces B lymphocyte to produce IgG & IgE impt. for allergy and anthelmintic responses. </li></ul></ul><ul><ul><li>Potent anti-inflammatory properties , it downgrades the effects of: </li></ul></ul><ul><ul><ul><li>IL-1 </li></ul></ul></ul><ul><ul><ul><li>TNF-alpha </li></ul></ul></ul><ul><ul><ul><li>IL-6 </li></ul></ul></ul><ul><ul><ul><li>IL-8 </li></ul></ul></ul><ul><ul><ul><li>Increases macrophage susceptibility to the anti-inflammatory effects of glucocorticoid </li></ul></ul></ul>
    40. 40. CYTOKINES <ul><li>Interleukin-6 (IL-6): </li></ul><ul><ul><li>Produced by all cells & tissues </li></ul></ul><ul><ul><li>Fnx: </li></ul></ul><ul><ul><ul><li>It induces neutrophil activation and delay it’s disposal leading to the cells prolonged injurious effect </li></ul></ul></ul><ul><ul><ul><li>It can also attenuate TNF & IL-1 by promoting the release of soluble tumor necrosis factor receptors and IL-1 receptor antagonists. </li></ul></ul></ul>
    41. 41. CYTOKINES <ul><li>Interleukin-8 (IL-8): </li></ul><ul><ul><li>Activity is similar to IL-6 </li></ul></ul><ul><ul><li>Biomarker for the risk of multiple organ failure </li></ul></ul><ul><ul><li>Does not produced hemodynamic instability but is a chemoattractant and activator of neutrophil </li></ul></ul>
    42. 42. CYTOKINES <ul><li>Interleukin-10 (IL-10): </li></ul><ul><ul><li>It reduces TNF-alpha </li></ul></ul><ul><ul><li>Attenuate systemic inflammatory response and reduces mortality during septic peritonitis </li></ul></ul><ul><ul><li>Associated w/ increased bacterial load & mortality </li></ul></ul>
    43. 43. CYTOKINES <ul><li>Interleukin-12 (IL-12): </li></ul><ul><ul><li>Primary role in cell-mediated immunity & promotes differentiation of T H 1 cells. </li></ul></ul><ul><ul><li>Inducing an inflammatory response for 48hrs, independently from TNF & IL-1. </li></ul></ul><ul><ul><li>Promotes neutrophil & coagulation activation </li></ul></ul><ul><ul><li>Toxicity is synergistic w/ IL-2 . </li></ul></ul>
    44. 44. CYTOKINES <ul><li>Interleukin-13 (IL-13): </li></ul><ul><ul><li>Structural & functional similarities w/ IL-4 </li></ul></ul><ul><ul><li>Modulate macrophage function </li></ul></ul><ul><ul><li>Inhibit nitric oxide production & the expression of proinflammatory cytokines and enhance production of IL-1ra </li></ul></ul><ul><ul><li>It attenuates leukocyte interaction w/ activated endothelial surfaces </li></ul></ul>
    45. 45. CYTOKINES <ul><li>Interleukin-15 (IL-15): </li></ul><ul><ul><li>Potent autocrine regulatory properties. </li></ul></ul><ul><ul><li>Possess similar bioactivity in promoting lymphocyte activation & proliferation </li></ul></ul><ul><ul><li>Induces IL-8 production . </li></ul></ul><ul><li>Interleukin-18 (IL-18): </li></ul><ul><ul><li>Formerly interferon (IFN)-y-inducing factor </li></ul></ul><ul><ul><li>Proinflammatory cytokine </li></ul></ul><ul><ul><li>Structurally similar to IL-1beta & functionally similar to IL-12. </li></ul></ul>
    46. 46. CYTOKINES <ul><li>Interferon-y: </li></ul><ul><ul><li>Produced by Helper T lymphocytes when activated by bacterial antigens, IL-2, IL-12, IL-18 </li></ul></ul><ul><ul><li>Can also induce production of IL-2, IL-12, IL-18 </li></ul></ul><ul><ul><li>Elevated for as long as 8 days. </li></ul></ul><ul><ul><li>Can activate circulating and tissue macrophage </li></ul></ul><ul><ul><li>Alveolar macrophage activation may induce acute lung inflammation after major surgery or trauma. </li></ul></ul>
    47. 47. CYTOKINES <ul><li>Granuloctye-Macrophage Colony-Stimulating Factor (GMC-SF): </li></ul><ul><ul><li>Delays apoptosis of macrophages and neutrophils; contribute to organ injury (ARDS) </li></ul></ul><ul><ul><li>Promote maturation and recruitment of functional leukocytes needed for normal inflammatory cytokine response & potentially in wound healing. </li></ul></ul>
    48. 48. Cell-Mediated Inflammatory Response <ul><li>Platelets: </li></ul><ul><ul><li>Clot formed at the site of injury releases inflammatory mediators w/c serves as the principal chemo-attractant for neutrophils and monocytes. </li></ul></ul><ul><ul><li>Migration of platelets & neutrophils through the vascular endothelium occurs w/in 3 hrs of injury and mediated by: </li></ul></ul><ul><ul><ul><li>Serotonin </li></ul></ul></ul><ul><ul><ul><li>Platelet-activating factor </li></ul></ul></ul><ul><ul><ul><li>Prostaglandin E2 </li></ul></ul></ul>
    49. 49. Cell-Mediated Inflammatory Response <ul><li>Lymphocytes & T-cell Immunity: </li></ul><ul><ul><li>Injury associated w/ Acute impairment of cell-mediated immunity and macrophage funct ion </li></ul></ul><ul><ul><li>2 subgroups of T-helper lymphocytes: </li></ul></ul><ul><ul><ul><li>T H 1 </li></ul></ul></ul><ul><ul><ul><li>T H 2 </li></ul></ul></ul>
    50. 50. Cell-Mediated Inflammatory Response <ul><li>Eosinophils: </li></ul><ul><ul><li>Migrate to inflammed endothelium and release cytoplasmic granules that are cytotoxic </li></ul></ul><ul><ul><li>It preferentially migrate to sites of parasitic infection and allergy </li></ul></ul><ul><ul><li>Resides in GIT, lung and genitourinary tissues </li></ul></ul><ul><ul><li>Major activators: </li></ul></ul><ul><ul><ul><li>IL-3 </li></ul></ul></ul><ul><ul><ul><li>IL-5 </li></ul></ul></ul><ul><ul><ul><li>Platelet-activating factor </li></ul></ul></ul><ul><ul><ul><li>Complement anaphylatoxins C3a and C5a </li></ul></ul></ul>
    51. 51. Cell-Mediated Inflammatory Response <ul><li>Mast Cells: </li></ul><ul><ul><li>When activated it produce: </li></ul></ul><ul><ul><ul><li>Histamine </li></ul></ul></ul><ul><ul><ul><li>Cytokines (IL-3, IL4, IL-5, IL-6, IL-10, IL-13, IL-14 & migration-inhibitory factor (MIF). </li></ul></ul></ul><ul><ul><ul><li>Eicosanoids </li></ul></ul></ul><ul><ul><ul><li>Proteases </li></ul></ul></ul><ul><ul><ul><li>Chemokines </li></ul></ul></ul>
    52. 52. Cell-Mediated Inflammatory Response <ul><li>Mast Cells: </li></ul><ul><ul><li>Immediate results: </li></ul></ul><ul><ul><ul><li>Vasodilation </li></ul></ul></ul><ul><ul><ul><li>Recruitment of other immunocytes </li></ul></ul></ul><ul><ul><ul><li>Capillary leakage </li></ul></ul></ul><ul><ul><li>TNF-alpha secreted rapidly by this cell bec. of its abundant source </li></ul></ul>
    53. 53. Cell-Mediated Inflammatory Response <ul><li>Monocytes: </li></ul><ul><ul><li>There is down regulation in monocyte and neutrophil TNFR expression </li></ul></ul><ul><ul><li>In none surviving pts w/ severe sepsis and failed to recover, an immediate reduction in monocyte surface TNFR expression was observed, while surviving pts have normal or near normal receptor levels </li></ul></ul><ul><li>Neutrophils: </li></ul><ul><ul><li>Inflammatory mediators from site of injury induces neutrophil adherence to the injured tissue. </li></ul></ul><ul><ul><li>It’s function is mediated by vast array of intracellular granules that are chemotactic or cytotoxic to local tissue & invading microorganisms. </li></ul></ul>
    54. 54. Endothelium-Mediated Injury <ul><li>Neutrophil-Endothelium Interaction: </li></ul><ul><ul><li>Inc. vascular permeability during inflammation is intended to facilitate O2 delivery and immunocyte migration to the site of injury. </li></ul></ul><ul><ul><li>However accumulation & infiltration of leukocytes (neutrophil) contribute to the cytotoxicity of vital tissue ---> MOF. </li></ul></ul><ul><ul><li>Ischemia/reperfusion injury potentiates this response by: </li></ul></ul><ul><ul><ul><li>unleashing oxygen metabolites </li></ul></ul></ul><ul><ul><ul><li>Lysosomal enzymes that degrade tissue basal membranes </li></ul></ul></ul><ul><ul><ul><li>Cause microvascular thrombosis </li></ul></ul></ul><ul><ul><ul><li>Activate myeloperoxidases. </li></ul></ul></ul>
    55. 55. Endothelium-Mediated Injury <ul><li>Recruitment of circulating neutrophils to endothelial surfaces is mediated by actions of adhesive molecules called SELECTINS (L,P,E) </li></ul>
    56. 56. Endothelium-Mediated Injury <ul><li>Nitric Oxide: </li></ul><ul><ul><li>Formed from oxidation of L-arginine </li></ul></ul><ul><ul><li>Derived from endothelial surfaces </li></ul></ul><ul><ul><li>Cells that produces this subs: </li></ul></ul><ul><ul><ul><li>Neutrophil </li></ul></ul></ul><ul><ul><ul><li>monocytes </li></ul></ul></ul><ul><ul><ul><li>Renal cells </li></ul></ul></ul><ul><ul><ul><li>Kupffer cells </li></ul></ul></ul><ul><ul><ul><li>Cerebellar neurons </li></ul></ul></ul><ul><ul><li>Action: </li></ul></ul><ul><ul><ul><li>Maintain normal smooth muscle relaxation </li></ul></ul></ul><ul><ul><ul><li>Reduce thrombosis by reducing platelet adhesions and aggregation </li></ul></ul></ul><ul><ul><ul><li>Mediates protein synthesis in hepatocyte </li></ul></ul></ul>
    57. 57. Endothelium-Mediated Injury <ul><li>Prostacyclin: </li></ul><ul><ul><li>Induces vaso-relaxation and platelet deactivation by increasing cAMP </li></ul></ul><ul><li>Endothelins: </li></ul><ul><ul><li>Formed by vascular endothelial cells in response to: </li></ul></ul><ul><ul><ul><li>Injury </li></ul></ul></ul><ul><ul><ul><li>Thrombin </li></ul></ul></ul><ul><ul><ul><li>Transforming growth factor-B (TGF-B) </li></ul></ul></ul><ul><ul><ul><li>IL-1 </li></ul></ul></ul><ul><ul><ul><li>Angiotensin II </li></ul></ul></ul><ul><ul><ul><li>Vasopressin </li></ul></ul></ul><ul><ul><ul><li>Catecholamine </li></ul></ul></ul><ul><ul><ul><li>Anoxia </li></ul></ul></ul><ul><ul><li>Action: </li></ul></ul><ul><ul><ul><li>The MOST POTENT vasoconstriction (10 x more angiotensin II) </li></ul></ul></ul><ul><ul><ul><li>Vasoconstriction is reversed by acetylcholine </li></ul></ul></ul>
    58. 58. Endothelium-Mediated Injury <ul><li>Platelet-Activating Factor: </li></ul><ul><ul><li>Released by neutrophils, platelets, mast cells and monocytes </li></ul></ul><ul><ul><li>It activate neutrophils and platelets and increase vascular permeability. </li></ul></ul><ul><li>Atrial Natriuretic Peptides: </li></ul><ul><ul><li>Released by atrial tissue, gut, kidney, brain, adrenal glds and endothelium </li></ul></ul><ul><ul><li>Actions: </li></ul></ul><ul><ul><ul><li>Vasodilator and induce fluid and electrolyte excretion </li></ul></ul></ul><ul><ul><ul><li>Inhibits aldosterone secretion </li></ul></ul></ul><ul><ul><ul><li>Prevent reabsorption of sodium </li></ul></ul></ul>
    59. 59. END OF FIRST PART
    60. 60. Metabolic Changes and Nutritional Management of Surgical Patients James Taclin C. Banez, MD, FPSGS, FPCS
    61. 61. Majority of surgical patients: <ul><li>well nourished / healthy </li></ul><ul><li>uncomplicated major surgical procedure </li></ul><ul><li>has sufficient fuel reserve </li></ul><ul><li>can withstand brief period of catabolic insult and starvation of 7 days </li></ul><ul><ul><li>Postoperatively: </li></ul></ul><ul><ul><ul><li>can resume normal oral intake </li></ul></ul></ul><ul><ul><ul><li>supplemental diet is not needed </li></ul></ul></ul>
    62. 62. Surgical Patients that Needs Nutritional Support <ul><li>To shorten the postoperative recovery phase and minimize the number of complications: </li></ul><ul><ul><li>Chronically debilitated from their diseases or malnutrition. </li></ul></ul><ul><ul><li>Suffered severe trauma, sepsis or surgical complications </li></ul></ul>
    63. 63. Metabolic Changes in Surgical Patients <ul><li>Metabolic events brought about by STIMULI : </li></ul><ul><ul><li>Injury </li></ul></ul><ul><ul><li>Starvation </li></ul></ul><ul><li>Metabolic response is directed to restore: </li></ul><ul><ul><li>Homeostasis </li></ul></ul><ul><ul><li>Repair </li></ul></ul>
    64. 64. Metabolic Response to Starvation <ul><li>HYPOGLYCEMIA – is primary stimulus </li></ul><ul><li>Hormonal Changes: increase cortisol, catecholamines, glucagon, growth hormones </li></ul><ul><li>Primary gluconeogenic precursors by the liver & kidney: </li></ul><ul><li>a. lactate b. glycerol c. amino acid (alanine & glutamine) </li></ul>
    65. 65. <ul><li>Proteolysis increase due to increase CORTISOL ------> inc. urinary nitrogen first 4 days of starvation (8-12g/day = 6.25g of muscle/g of nitrogen). </li></ul>
    66. 66. <ul><li>Protein catabolism for gluconeogenesis primarily comes from SKELETAL muscle, but in pure starvation other organs are involved </li></ul><ul><li>In liver. CHON loss is selective; spare enzymes for gluconeogenesis and lipolysis. </li></ul><ul><li>In pancreas and GIT, enzymes for digestion and protein for regeneration of epithelium is involved -> PARADOXICAL FOOD INTOLERANCE </li></ul>
    67. 67. <ul><li>Rapid proteolysis of body CHON cannot proceed at 75 g/day for long, or else patient will die immediately RANDLE EFFECT. </li></ul><ul><ul><li>decrease urinary excretion of nitrogen 2 – 4 gm/day due to keto-adaptation of the brain </li></ul></ul><ul><ul><li>decrease protein degeneration and major source of energy is FAT (90%) </li></ul></ul>
    68. 68. Metabolism of Injured Patient <ul><li>PHASES: </li></ul><ul><li>Catabolic phase (Ebb, Adrenergic-Corticoid): </li></ul><ul><ul><li>immediately following surgery or trauma </li></ul></ul><ul><ul><li>characterized w/ hyperglycemia, increase secretion of urinary nitrogen beyond the level of starvation </li></ul></ul><ul><ul><li>caused by increase glucagon, glucocorticoid, catecholamines and decrease insulin </li></ul></ul><ul><ul><li>tries to restore circulatory volume and tissue perfusion </li></ul></ul>
    69. 69. Metabolism of Injured Patient <ul><li>PHASES: </li></ul><ul><li>Early anabolic phase (flow, corticoid-withdrawal): </li></ul><ul><ul><li>tissue perfusion has been restored, may last for days to months depending on: </li></ul></ul><ul><ul><ul><li>severity of injury </li></ul></ul></ul><ul><ul><ul><li>previous health </li></ul></ul></ul><ul><ul><ul><li>medical intervention </li></ul></ul></ul><ul><ul><li>sharp decline in nitrogen excretion </li></ul></ul><ul><ul><li>nitrogen balance is positive (4g/day) indicating synthesis of CHON and there is a rapid and progressive gain in weight and muscular strength </li></ul></ul>
    70. 70. Metabolism of Injured Patient <ul><li>PHASES: </li></ul><ul><li>Late anabolic phase: </li></ul><ul><ul><li>several months after injury </li></ul></ul><ul><ul><li>occurs once volume deficit have been restored </li></ul></ul><ul><ul><li>slower re-accumulation of CHON </li></ul></ul><ul><ul><li>re-accumulation of body fat </li></ul></ul>
    71. 71. Metabolism of Injured Patient <ul><li>Carbohydrate Metabolism in Injured Patient: </li></ul><ul><li>Hyperglycemia = proportional to the severity of injury </li></ul><ul><ul><li>Importance: </li></ul></ul><ul><ul><ul><li>Homeostatic significance </li></ul></ul></ul><ul><ul><ul><li>Ready source of energy to the brain </li></ul></ul></ul><ul><ul><ul><li>Adequate delivery </li></ul></ul></ul><ul><ul><li>Caused by: </li></ul></ul><ul><ul><ul><li>Increased catecholamine (primarily), cortisol, glucagon, GH, vasopressin, angiotensin II, somatostatin and decrease insulin. </li></ul></ul></ul>
    72. 72. Metabolism of Injured Patient <ul><li>Carbohydrate Metabolism: </li></ul><ul><li>Hyperglycemia: </li></ul><ul><ul><li>Caused by: </li></ul></ul><ul><ul><ul><li>Increased catecholamine (primarily), cortisol, glucagon, GH, vasopressin, angiotensin II, somatostatin and decrease insulin. </li></ul></ul></ul><ul><ul><ul><li>Gluconeogenesis in liver and kidney and impaired peripheral uptake of glucose </li></ul></ul></ul>
    73. 73. Metabolism of Injured Patient <ul><li>Carbohydrate Metabolism: </li></ul><ul><li>Hyperglycemia: </li></ul><ul><ul><li>Insulin resistance: </li></ul></ul><ul><ul><ul><li>During the Ebb phase there is reduction in beta cell sensitivity to glucose due to Catecholamine, somatostatin and reduced pancreatic blood flow </li></ul></ul></ul><ul><ul><ul><li>Resistance to exogenous administration on insulin in both EBB and early FLOW phases </li></ul></ul></ul><ul><ul><ul><li>In middle and late Flow phase, beta cell sensitivity return to normal and it’s level is higher, but hyperglycemia persist because of continuous gluconeogenesis </li></ul></ul></ul>
    74. 74. Metabolism of Injured Patient <ul><li>Carbohydrate Metabolism: </li></ul><ul><li>Glucose metabolism in wounded tissue : </li></ul><ul><ul><li>Increase glucose uptake and lactate production because of anaerobic glycolysis due to local tissue hypoxia </li></ul></ul><ul><ul><li>(+) insulin insensitivity </li></ul></ul>
    75. 75. Metabolism of Injured Patient <ul><li>Lipid metabolism: </li></ul><ul><ul><li>primary source of energy </li></ul></ul><ul><ul><li>Best stimulus for hormone-sensitive lipase is CATECHOLAMINE </li></ul></ul><ul><ul><li>RANDLE EFFECT is not present </li></ul></ul>
    76. 76. Metabolism of Injured Patient <ul><li>Protein Metabolism: </li></ul><ul><ul><li>Nitrogen urine excretion 30-50g/day due to proteolysis ; 20% utilized for energy (calories) the rest for gluconeogenesis by liver and kidney (cortisol, glucagon, catecholamine). </li></ul></ul><ul><ul><li>Primary source of protein is the skeletal muscle and the visceral organs are spared. </li></ul></ul><ul><ul><li>Ketoadaptation is inhibited ----> gluconeogenesis persist ---> proteolysis persist (INTERLEUKIN I). </li></ul></ul><ul><ul><li>The degree and duration (-) nitrogen balance is related to severity of injury . The net CHON catabolism depends on the age, sex and physical condition of the patient (> in young, healthy and male) </li></ul></ul><ul><ul><li>(-) nitrogen balance can be reduced by high caloric nitrogen supplement </li></ul></ul>
    77. 77. <ul><li>Traumatized Man </li></ul>
    78. 78. <ul><li>Injury of any type is associated with: </li></ul><ul><li>Immobilization </li></ul><ul><li>Starvation </li></ul><ul><li>Repair </li></ul><ul><ul><li>the first two are associated with reduction in energy requirement. While the third is associated w/ increase energy requirement </li></ul></ul><ul><li>The amount of energy produced in injured pt. is not optimum, to supply necessary energy for the repair due to: </li></ul><ul><ul><li>reduced or absent nutritional intake </li></ul></ul><ul><ul><li>significant reduction of energy charge and ATP content during shock, hypoxia, sepsis, ischemia and wound -  anaerobic metabolism </li></ul></ul>
    79. 79. <ul><li>REE (Resting energy expenditure) by Harris and Benedict: </li></ul><ul><li>(MEN) 66.47 + 13.75 (W) + 5.0 (H) – 6.76 (A) </li></ul><ul><li>= Kcal/day </li></ul><ul><li>(Female) 65.51 + 9.56 (W) + 1.85 (H) – 4.68 (A) </li></ul><ul><li>= Kcal/day </li></ul><ul><li>Fever: increase resting energy expenditure of approximately 7% for each degree of F of fever. </li></ul>

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