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Systemic Response To Injury

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    • 1. SYSTEMIC RESPONSE TO INJURY James Taclin C. Banez, MD, FPSGS, FPCS
    • 2.
      • Injury (surgery, traumatic & infections):
        • Alteration of neuro-endocrine system, metabolic and immunology ----> causes disequilibrium of internal environment & tries to return to homeostasis.
    • 3.
      • Minor Injuries : is usually followed by functional restoration w/ minimal intervention.
      • Major injuries : associated with overwhelming inflammatory response ----> failure to give appropriate intervention ----> multiple organ failure -----> DEATH
    • 4. Systemic Inflammatory Response Syndrome (SIRS)
      • 2 Phases:
      • Pro-inflammatory phase:
        • Char. By activation of cellular processes designed to restore tissue function & eradicate invading micro-organism.
      • Counter-regulatory or anti-inflammatory phase:
        • To prevent excessive pro-inflammatory activities and to restore homeostasis
    • 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. Central Nervous System Regulation of Inflammation
      • Afferent Signals:
      • Circulatory:
        • Areas of CNS devoid of bld-brain barrier admit passage of inflammatory mediators (TNF)
        • Causing fever, anorexia & depression
      • Neural pathways:
        • Afferent stimuli to the vagus nerve :
        • cytokines – TNF, IL-1
        • Baroreceptors
        • Chemoreceptors
        • Thermoreceptors
        • From the site of injuries
    • 7. Central Nervous System Regulation of Inflammation
      • Cholinergic Anti-Inflammatory Pathways:
      • Acetycholine of parasympathetic:
        • reduces tissue macrophage activation
        • Reduces tissue macrophage release of inflammatory mediators (TNF alpha, IL1, IL18 & high mobility grp protein (HMG-1), but not the anti-inflammatory cytokine IL10
      • Vagal stimulation reduces HR, increases gut motility, dilates arterioles, causes pupil constriction & regulates inflammation
    • 8. Systemic Neuro-Endocrine Reflexes
      • Stimuli:
        • Effective Circulatory Volume (ECV):
          • Sensed by:
            • high pressure baroreceptor (aorta, carotid & renal artery)
            • low pressure stretch receptors (atrial volume)
          • Decreased ECV ---> release of tonic inhibition ---> (+) receptors ----> (+) ACTH, vasopressin , beta-endorphin, E & NE, renin.
          • If decrease ECV is < 30% of TBV the neuroendocrine & cardiovascular response can compensate; > 30% ----> DECOMPENSATE (hypotension)
    • 9. Systemic Neuro-Endocrine Reflexes
      • Stimuli:
        • Chemoreceptor Relexes:
          • sensed by: a. carotid bodies (inactive)
          • b. aortic bodies (inactive)
          • stimulation of chemoreceptors:
            • decrease oxygen
            • increase CO2 and H
          • Results to:
            • Decrease sympathetic activity (cardiac) & increase in parasympathetic activity.
            • Increase respiratory rate & decrease cardiac rate and contractility.
    • 10. Systemic Neuro-Endocrine Reflexes
      • Stimuli:
        • Pain & Emotion:
          • Pain ---> (+) thalamus & hypothalamus
          • Emotion ---> (+) limbic ----> (+) hypothalamus
        • Substrate alteration:
          • Alteration plasma glucose concentration activates neuroendocrine reflexes thru it’s receptors:
            • Hypothalamus -----> pituitary
            • Pancreas
        • Temperature:
          • Changes in core temperature, sensed by the pre-optic area of the hypothalamus ---> alters secretion of several hormones
    • 11. Systemic Neuro-Endocrine Reflexes
      • CNS Centers: (hypothalamus)
        • Posterior Hypothalamus:
          • ACTH, sympathetic activity
        • Paraventricular Nucleus:
          • vasopressin, oxytocin & ACTH
        • Ventromedial Nucleus:
          • GH, ACTH
        • Supraoptic Nucleus
          • vasopressin & oxytocin
        • Suprachiasmatic Nucleus:
          • ACTH & gonadotrophin
    • 12. Systemic Neuro-Endocrine Reflexes
      • Efferent Output:
        • Autonomic response:
        • Hormonal response:
          • Hypothalamic – anterior pituitary control
          • Posterior pituitary control
          • Autonomic control
        • Local tissue response:
    • 13. Hormone Response to Injury
      • Hypothalamic regulation
        • CRH
        • TRH
        • GHRH
        • LHRH
      • Anterior Pituitary regulation
        • ACTH – cortisol
        • TSH – T3/T4
        • GH
        • Gonadotrophins
        • Sex hormones
        • Insulin-like growth factor
        • Somatostatin
        • Prolactin
        • Endorphins
      • Posterior Pituitary regulation
        • Vasopressin
        • Oxytocin
      • Autonomic System
        • NE / E
        • Aldosterone
        • Renin-angiotensin system
        • Insulin
        • Glucagon
        • Enkephalins
    • 14.
      • HORMONES UNDER ANTERIOR PITUITARY
      • REGULATION
      • CRF – ACTH – Cortisol:
        • (+) CRF – pain, fear, anxiety, angiotensin II, serotonin,
        • acetylcholine & interleukin 1/6
        • ACTH – circardian signals is lost in injury due to pain, anxiety, vasopressin, angiotensin II, E,
        • NE, oxytocins & proinflammatory cytokines
        • Cortisol - elevated in any types of injury, longest in burn pts. (4wks). Actions in injury:
            • potentiates the action of glucagon & E causing hyperglycemia.
            • favors gluconeogenesis; insulin resistance in muscles & adipose tissue.
            • induces protein degradation in the skeletal muscle & releases lactate for hepatic gluconeogenesis
            • potentiates release of FA, triglycerides & glycerol from adipose tissue for energy source
    • 15.
      • CRF – ACTH – Cortisol:
        • Acute adrenal Insufficiency (AAI):
          • Life threatening complication
          • Commonly due to adrenal suppression from exogenous administration of glucocorticoid
          • Manifestation:
            • weakness, n / v, fever & hypotension
            • Hypoglycemia (due to low gluconeogenesis)
            • Hyponatremia & Hyperkalemia (impaired renal tubular reabsorption – due to insufficient aldosterone)
        • Cortisol is an effective immuno-suppressive agents:
          • Caused thymic involution
          • Depressed cell mediated immune response
          • Cause monocyte & neutrophil lose of intracellular bacterial killing
          • It downregulates proinflammatory cytokines production (TNF alpha, IL-1, IL-6); and increases the production of anti-inflammatory mediator IL-10.
    • 16.
      • Growth Hormone:
        • (+) GH is GHRF (-) GH is somatostatin
        • Anabolic for CHON; catabolic for CHO & lipids
        • Stimulatory:
          • Hypoglycemia, decrease ECV, decrease plasma FA & a.a., exercise, STRESS and sleep.
          • Thyroxine, vasopressin, MSH, testosterone, estrogen and alpha adrenergic stimulation.
        • INSULIN like GROWTH FACTOR-1 (Somatomedin C; IGF-1)
          • Partially mediates CHON synthesis properties of GH after injury
          • The liver is the predominant source of IGF-1.
          • Promotes a.a. incorporation & cellular proliferation and attenuates proteolysis in skeletal muscle & liver.
          • In injury: the effects of IGF-1 is inhibited by proinflammatory cytokines (TNF, IL-1 and IL-6). Resulting to (-) nitrogen balance.
    • 17.
      • Macrophage Inhibitory Factor:
        • Produced by:
          • Anterior pituitary gland
          • T lymphocytes at the site of inflammation.
        • Actions:
          • A glucocorticoid antagonist (suppresses the immunosuppresive effects of cortisol).
          • It is a proinflammatory mediator that potentiates gm (-) & (+) septic shock.
      • Endogenous Opiods:
        • Endorphins, enkephalins
        • Elevated after injury & surgery
        • Endorphins ----> attenuate pain perceptions / hypotension
          • Enkephalins ----> HPN, decrease peristalsis and secretion of GIT
    • 18.
      • Thyroid Hormone (T4 / T3):
        • In injury:
          • Low T3
          • (-) TSH release
          • Conversion of T4 – T3 in the target organs are impaired due to cortisol. T4 is converted to an inactive T3 called rT3
      • Gonadotrophins (LHRH/GnRH) & (FSH/LH):
        • Injury, stress or severe illness ----> (-) GRH ----> (-) LH and (-) FSH ---> decrease estrogen and androgen secretions.
        • Causes menstrual irregularities and decrease libido.
      • Prolactin:
        • Produced by anterior pituitary gld and T lymphocytes
        • Elevated level after injury in adults not seen in children
        • Causes amenorrhea
    • 19.
      • HORMONES OF AUTONOMIC SYSTEM:
      • Catecholamines (E / NE):
        • Causes hypermetabolic state following severe injury
        • 3 – 4fold increase of E & NE in the plasma for 24 – 48 hrs.
        • Causes:
          • Promotes glycogenolysis, gluconeogenesis, lipolysis and ketogenesis.
          • Decreased insulin release & increase glucagon secretion.
          • Peripherally, it increases lipolysis in adipose tissue and induces insulin resistance in skeletal muscle
          • It inhibit the release of aldosterone.
          • Immune function: -- enhances neutrophilia and lymphocytosis
    • 20.
      • Aldosterone (Mineralocorticoid):
        • Released by adrenal zona glomerulosa
        • Release is caused by:
          • Angiotensin II
          • Hyperkalemia
          • Aldosterone stimulating factor (ASF) in pituitary
          • ACTH (is the most potent stimulant).
        • Major function is to maintain intravascular volume by conserving Na & eliminating potassium and H+ in the early distal convoluted tubules of nephron
    • 21.
      • Renin – Angiotensin:
        • Renin in Juxtaglomerular apparatus is released by:
          • ACTH, Glucagon, porstagladin, K+, Mg+, and Ca+
          • Baroreceptor – respond to decrease blood pressure
          • Macula densa detects changes in chloride concentration.
        • Action of angiotensin II:
          • Vasoconstrictor
          • (+) aldosterone
          • (+) ADH
          • (+) E
          • Increase heart rate and contractility
    • 22.
      • Glucagon:
        • alpha islet cell
        • catabolic role
        • elevated release after injury
      • Insulin:
        • Inhibit its release in injury:
          • Catecholamine
          • Glucagon
          • Somatostatin
          • Beta endorphins
          • IL-1
    • 23.
      • Hormones Under Posterior Pituitary Regulation:
      • Vasopressin / ADH / Arginine Vasopressin (AVP):
        • Causes
          • readsorption of H2O in DCT
          • Vasoconstriction peripherally
          • Stimulates hepatic glycogenolysis & gluconeogenesis
        • Elevated plasma osmolality is its major stimulus:
        • Location of osmoreceptors: hypothalamus, portal circulation
    • 24.
      • Hormones Under Posterior Pituitary Regulation:
      • Vasopressin / ADH / Arginine Vasopressin (AVP):
        • Its release also happens in 10% loss of ECV stimulating the baroreceptor in the left atrium
        • Other stimulus:
          • PAIN
          • Beta adrenergic
          • Angiotensin II
          • Opiods
          • Elevated glucose
    • 25.
      • Oxytocin:
        • Its release caused by SUCKING the nipple
        • Stimulates contraction of mammary gland and uterus during parturition
        • No known function in males
        • Role in injury is unknown
    • 26. Mediators of Inflammation
      • Cytokines:
        • Most potent mediator of the inflammatory response
        • Eradicates invading microorganism and promotes wound healing
        • Overwhelming productions of proinflammatory cytokines can cause:
          • Hemodynamic instability (septic shock)
          • Metabolic derangement (muscle wasting)
        • Can exaggerate to multiple organ failure and death.
        • Inappropriate anti-inflammatory mediator release can lead to immunocompromised and susceptible to overwhelming infection.
    • 27. Mediators of Inflammation
      • Heat Shock Proteins:
        • Intracellular protein modifiers and transporters that protect cells from the deleterious effects of traumatic stress.
        • The following induced its production:
          • Hypoxia
          • Trauma
          • Heavy metals
          • Local trauma
          • Hemorrhage
    • 28. Mediators of Inflammation
      • Reactive Oxygen Metabolites:
        • Oxygen radicals are produced by reduction of oxygen to superoxide anion, and further metabolized to form H2O2 & hydroxyl radicals
        • Causes injury by oxidation of unsaturated fatty acids w/in cell membranes.
        • Activated leukocytes are potent generators for reactive oxygen metabolites.
        • Cells are protected from this metabolite by oxygen scavengers: GLUTATHIONE & CATALASES.
    • 29. Mediators of Inflammation
      • Eicosanoids:
        • Are oxidation derivatives of membrane phospholipid arachidonic acids
        • Secreted by nucleated cells, except lymphocytes
        • 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
    • 30. Mediators of Inflammation
      • Eicosanoids:
        • Actions:
        • PGE 2 increases fluid leakage from bld vessels, inhibit gluconeogenesis and hormone stimulated lipolysis.
        • Leukotrienes are 1000x more potent than histamine promoting capillary leakage, vasoconstriction, bronchoconstriction, neutrophil activation.
        • Products of cyclooxygenase inhibit pancreatic beta cell release of insulin.
    • 31. Mediators of Inflammation
      • Kallikrein-Kinin System:
        • Bradykinin:
          • potent vasodilators
          • Release is caused by hypoxic and ischemic injury
        • Kinins:
          • increase capillary permeability and tissue edema,
          • evoke pain,
          • Inhibit gluconeogenesis
          • increase bronchoconstriction.
          • increase renal vasodilation and reduces renal perfusion pressure ----> (+) renin-angiotensin system.
    • 32. Mediators of Inflammation
      • Serotonin:
        • neurotransmitter (5hydrohytryptamine)
        • tryptophan derivative found in chromaffin cells of the intestine (carcinoid tumors).
        • Vasoconstrictions, bronchoconstriction & platelet aggregations
        • myocardial chronotrope and inotrope
    • 33. Mediators of Inflammation
      • Histamine:
        • Derived from histidine
        • Stored in neurons, skin, gastric mucosa, mast cells basophils and platelets
        • Released is activated by increased calcium levels.
        • 2 receptors:
          • H1 – stimulates bronchoconstriction, intestinal motility, and myocardial contractility
          • H2 – inhibits histamine release
    • 34. Mediators of Inflammation
      • Histamine:
        • Both H1 & H2 receptor activation causes:
          • Hypotension
          • Peripheral pooling of blood
          • Increase capillary permeability
          • Decrease venous return
          • Myocardial failure
        • Elevated in cases of hemorrhagic shock, trauma, thermal injury, endotoxemia and sepsis.
    • 35. Cytokines
      • Usually secreted by immunocytes & other cells
      • Indespensible to tissue healing and immune response generated against microbial invasion
      • Are not stored as preformed molecules and it’s activity is primarily exerted locally w/ cell to cell interaction
      • Their rapid appearance after injury is due to active transcription and translation by the injured or stimulated cells.
      • Direct the inflammatory response to infection, injury and actively promote wound healing
    • 36. CYTOKINES
      • TNF (Tumor Necrosis Factor):
        • Earliest & most potent mediators
        • Monocytes/macrophage and Tcells
        • Actions:
          • Major inducer muscle catabolism & cachexia during stress
          • Coagulation activation
          • Releases prostaglandin E2, platelet activating factor (PAF), glucocorticoid and eicosanoids
          • Initiates of hemodynamic decompensation.
    • 37. CYTOKINES
      • Interleukin-1 (IL-1):
        • Causes:
          • Induces febrile response to injury by stimulating prostaglandin to anterior hypothalamus.
          • Attenuated pain perception by promoting release of beta-endorphins from the pituitary gld.
        • Endogenous IL-1 receptor antagonist (IL-1ra) are also released during injury to auto-regulate IL-1.
    • 38. CYTOKINES
      • Interleukin-2:
        • Promoter of T-lymphocyte proliferation, immunoglobulin production & gut barrier integrity.
    • 39. CYTOKINES
      • Interleukin-4 (IL-4):
        • Produced by activate T-helper lymphocyte.
        • Induces B lymphocyte to produce IgG & IgE impt. for allergy and anthelmintic responses.
        • Potent anti-inflammatory properties , it downgrades the effects of:
          • IL-1
          • TNF-alpha
          • IL-6
          • IL-8
          • Increases macrophage susceptibility to the anti-inflammatory effects of glucocorticoid
    • 40. CYTOKINES
      • Interleukin-6 (IL-6):
        • Produced by all cells & tissues
        • Fnx:
          • It induces neutrophil activation and delay it’s disposal leading to the cells prolonged injurious effect
          • It can also attenuate TNF & IL-1 by promoting the release of soluble tumor necrosis factor receptors and IL-1 receptor antagonists.
    • 41. CYTOKINES
      • Interleukin-8 (IL-8):
        • Activity is similar to IL-6
        • Biomarker for the risk of multiple organ failure
        • Does not produced hemodynamic instability but is a chemoattractant and activator of neutrophil
    • 42. CYTOKINES
      • Interleukin-10 (IL-10):
        • It reduces TNF-alpha
        • Attenuate systemic inflammatory response and reduces mortality during septic peritonitis
        • Associated w/ increased bacterial load & mortality
    • 43. CYTOKINES
      • Interleukin-12 (IL-12):
        • Primary role in cell-mediated immunity & promotes differentiation of T H 1 cells.
        • Inducing an inflammatory response for 48hrs, independently from TNF & IL-1.
        • Promotes neutrophil & coagulation activation
        • Toxicity is synergistic w/ IL-2 .
    • 44. CYTOKINES
      • Interleukin-13 (IL-13):
        • Structural & functional similarities w/ IL-4
        • Modulate macrophage function
        • Inhibit nitric oxide production & the expression of proinflammatory cytokines and enhance production of IL-1ra
        • It attenuates leukocyte interaction w/ activated endothelial surfaces
    • 45. CYTOKINES
      • Interleukin-15 (IL-15):
        • Potent autocrine regulatory properties.
        • Possess similar bioactivity in promoting lymphocyte activation & proliferation
        • Induces IL-8 production .
      • Interleukin-18 (IL-18):
        • Formerly interferon (IFN)-y-inducing factor
        • Proinflammatory cytokine
        • Structurally similar to IL-1beta & functionally similar to IL-12.
    • 46. CYTOKINES
      • Interferon-y:
        • Produced by Helper T lymphocytes when activated by bacterial antigens, IL-2, IL-12, IL-18
        • Can also induce production of IL-2, IL-12, IL-18
        • Elevated for as long as 8 days.
        • Can activate circulating and tissue macrophage
        • Alveolar macrophage activation may induce acute lung inflammation after major surgery or trauma.
    • 47. CYTOKINES
      • Granuloctye-Macrophage Colony-Stimulating Factor (GMC-SF):
        • Delays apoptosis of macrophages and neutrophils; contribute to organ injury (ARDS)
        • Promote maturation and recruitment of functional leukocytes needed for normal inflammatory cytokine response & potentially in wound healing.
    • 48. Cell-Mediated Inflammatory Response
      • Platelets:
        • Clot formed at the site of injury releases inflammatory mediators w/c serves as the principal chemo-attractant for neutrophils and monocytes.
        • Migration of platelets & neutrophils through the vascular endothelium occurs w/in 3 hrs of injury and mediated by:
          • Serotonin
          • Platelet-activating factor
          • Prostaglandin E2
    • 49. Cell-Mediated Inflammatory Response
      • Lymphocytes & T-cell Immunity:
        • Injury associated w/ Acute impairment of cell-mediated immunity and macrophage funct ion
        • 2 subgroups of T-helper lymphocytes:
          • T H 1
          • T H 2
    • 50. Cell-Mediated Inflammatory Response
      • Eosinophils:
        • Migrate to inflammed endothelium and release cytoplasmic granules that are cytotoxic
        • It preferentially migrate to sites of parasitic infection and allergy
        • Resides in GIT, lung and genitourinary tissues
        • Major activators:
          • IL-3
          • IL-5
          • Platelet-activating factor
          • Complement anaphylatoxins C3a and C5a
    • 51. Cell-Mediated Inflammatory Response
      • Mast Cells:
        • When activated it produce:
          • Histamine
          • Cytokines (IL-3, IL4, IL-5, IL-6, IL-10, IL-13, IL-14 & migration-inhibitory factor (MIF).
          • Eicosanoids
          • Proteases
          • Chemokines
    • 52. Cell-Mediated Inflammatory Response
      • Mast Cells:
        • Immediate results:
          • Vasodilation
          • Recruitment of other immunocytes
          • Capillary leakage
        • TNF-alpha secreted rapidly by this cell bec. of its abundant source
    • 53. Cell-Mediated Inflammatory Response
      • Monocytes:
        • There is down regulation in monocyte and neutrophil TNFR expression
        • 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
      • Neutrophils:
        • Inflammatory mediators from site of injury induces neutrophil adherence to the injured tissue.
        • It’s function is mediated by vast array of intracellular granules that are chemotactic or cytotoxic to local tissue & invading microorganisms.
    • 54. Endothelium-Mediated Injury
      • Neutrophil-Endothelium Interaction:
        • Inc. vascular permeability during inflammation is intended to facilitate O2 delivery and immunocyte migration to the site of injury.
        • However accumulation & infiltration of leukocytes (neutrophil) contribute to the cytotoxicity of vital tissue ---> MOF.
        • Ischemia/reperfusion injury potentiates this response by:
          • unleashing oxygen metabolites
          • Lysosomal enzymes that degrade tissue basal membranes
          • Cause microvascular thrombosis
          • Activate myeloperoxidases.
    • 55. Endothelium-Mediated Injury
      • Recruitment of circulating neutrophils to endothelial surfaces is mediated by actions of adhesive molecules called SELECTINS (L,P,E)
    • 56. Endothelium-Mediated Injury
      • Nitric Oxide:
        • Formed from oxidation of L-arginine
        • Derived from endothelial surfaces
        • Cells that produces this subs:
          • Neutrophil
          • monocytes
          • Renal cells
          • Kupffer cells
          • Cerebellar neurons
        • Action:
          • Maintain normal smooth muscle relaxation
          • Reduce thrombosis by reducing platelet adhesions and aggregation
          • Mediates protein synthesis in hepatocyte
    • 57. Endothelium-Mediated Injury
      • Prostacyclin:
        • Induces vaso-relaxation and platelet deactivation by increasing cAMP
      • Endothelins:
        • Formed by vascular endothelial cells in response to:
          • Injury
          • Thrombin
          • Transforming growth factor-B (TGF-B)
          • IL-1
          • Angiotensin II
          • Vasopressin
          • Catecholamine
          • Anoxia
        • Action:
          • The MOST POTENT vasoconstriction (10 x more angiotensin II)
          • Vasoconstriction is reversed by acetylcholine
    • 58. Endothelium-Mediated Injury
      • Platelet-Activating Factor:
        • Released by neutrophils, platelets, mast cells and monocytes
        • It activate neutrophils and platelets and increase vascular permeability.
      • Atrial Natriuretic Peptides:
        • Released by atrial tissue, gut, kidney, brain, adrenal glds and endothelium
        • Actions:
          • Vasodilator and induce fluid and electrolyte excretion
          • Inhibits aldosterone secretion
          • Prevent reabsorption of sodium
    • 59. END OF FIRST PART
    • 60. Metabolic Changes and Nutritional Management of Surgical Patients James Taclin C. Banez, MD, FPSGS, FPCS
    • 61. Majority of surgical patients:
      • well nourished / healthy
      • uncomplicated major surgical procedure
      • has sufficient fuel reserve
      • can withstand brief period of catabolic insult and starvation of 7 days
        • Postoperatively:
          • can resume normal oral intake
          • supplemental diet is not needed
    • 62. Surgical Patients that Needs Nutritional Support
      • To shorten the postoperative recovery phase and minimize the number of complications:
        • Chronically debilitated from their diseases or malnutrition.
        • Suffered severe trauma, sepsis or surgical complications
    • 63. Metabolic Changes in Surgical Patients
      • Metabolic events brought about by STIMULI :
        • Injury
        • Starvation
      • Metabolic response is directed to restore:
        • Homeostasis
        • Repair
    • 64. Metabolic Response to Starvation
      • HYPOGLYCEMIA – is primary stimulus
      • Hormonal Changes: increase cortisol, catecholamines, glucagon, growth hormones
      • Primary gluconeogenic precursors by the liver & kidney:
      • a. lactate b. glycerol c. amino acid (alanine & glutamine)
    • 65.
      • Proteolysis increase due to increase CORTISOL ------> inc. urinary nitrogen first 4 days of starvation (8-12g/day = 6.25g of muscle/g of nitrogen).
    • 66.
      • Protein catabolism for gluconeogenesis primarily comes from SKELETAL muscle, but in pure starvation other organs are involved
      • In liver. CHON loss is selective; spare enzymes for gluconeogenesis and lipolysis.
      • In pancreas and GIT, enzymes for digestion and protein for regeneration of epithelium is involved -> PARADOXICAL FOOD INTOLERANCE
    • 67.
      • Rapid proteolysis of body CHON cannot proceed at 75 g/day for long, or else patient will die immediately RANDLE EFFECT.
        • decrease urinary excretion of nitrogen 2 – 4 gm/day due to keto-adaptation of the brain
        • decrease protein degeneration and major source of energy is FAT (90%)
    • 68. Metabolism of Injured Patient
      • PHASES:
      • Catabolic phase (Ebb, Adrenergic-Corticoid):
        • immediately following surgery or trauma
        • characterized w/ hyperglycemia, increase secretion of urinary nitrogen beyond the level of starvation
        • caused by increase glucagon, glucocorticoid, catecholamines and decrease insulin
        • tries to restore circulatory volume and tissue perfusion
    • 69. Metabolism of Injured Patient
      • PHASES:
      • Early anabolic phase (flow, corticoid-withdrawal):
        • tissue perfusion has been restored, may last for days to months depending on:
          • severity of injury
          • previous health
          • medical intervention
        • sharp decline in nitrogen excretion
        • nitrogen balance is positive (4g/day) indicating synthesis of CHON and there is a rapid and progressive gain in weight and muscular strength
    • 70. Metabolism of Injured Patient
      • PHASES:
      • Late anabolic phase:
        • several months after injury
        • occurs once volume deficit have been restored
        • slower re-accumulation of CHON
        • re-accumulation of body fat
    • 71. Metabolism of Injured Patient
      • Carbohydrate Metabolism in Injured Patient:
      • Hyperglycemia = proportional to the severity of injury
        • Importance:
          • Homeostatic significance
          • Ready source of energy to the brain
          • Adequate delivery
        • Caused by:
          • Increased catecholamine (primarily), cortisol, glucagon, GH, vasopressin, angiotensin II, somatostatin and decrease insulin.
    • 72. Metabolism of Injured Patient
      • Carbohydrate Metabolism:
      • Hyperglycemia:
        • Caused by:
          • Increased catecholamine (primarily), cortisol, glucagon, GH, vasopressin, angiotensin II, somatostatin and decrease insulin.
          • Gluconeogenesis in liver and kidney and impaired peripheral uptake of glucose
    • 73. Metabolism of Injured Patient
      • Carbohydrate Metabolism:
      • Hyperglycemia:
        • Insulin resistance:
          • During the Ebb phase there is reduction in beta cell sensitivity to glucose due to Catecholamine, somatostatin and reduced pancreatic blood flow
          • Resistance to exogenous administration on insulin in both EBB and early FLOW phases
          • 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
    • 74. Metabolism of Injured Patient
      • Carbohydrate Metabolism:
      • Glucose metabolism in wounded tissue :
        • Increase glucose uptake and lactate production because of anaerobic glycolysis due to local tissue hypoxia
        • (+) insulin insensitivity
    • 75. Metabolism of Injured Patient
      • Lipid metabolism:
        • primary source of energy
        • Best stimulus for hormone-sensitive lipase is CATECHOLAMINE
        • RANDLE EFFECT is not present
    • 76. Metabolism of Injured Patient
      • Protein Metabolism:
        • 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).
        • Primary source of protein is the skeletal muscle and the visceral organs are spared.
        • Ketoadaptation is inhibited ----> gluconeogenesis persist ---> proteolysis persist (INTERLEUKIN I).
        • 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)
        • (-) nitrogen balance can be reduced by high caloric nitrogen supplement
    • 77.
      • Traumatized Man
    • 78.
      • Injury of any type is associated with:
      • Immobilization
      • Starvation
      • Repair
        • the first two are associated with reduction in energy requirement. While the third is associated w/ increase energy requirement
      • The amount of energy produced in injured pt. is not optimum, to supply necessary energy for the repair due to:
        • reduced or absent nutritional intake
        • significant reduction of energy charge and ATP content during shock, hypoxia, sepsis, ischemia and wound -  anaerobic metabolism
    • 79.
      • REE (Resting energy expenditure) by Harris and Benedict:
      • (MEN) 66.47 + 13.75 (W) + 5.0 (H) – 6.76 (A)
      • = Kcal/day
      • (Female) 65.51 + 9.56 (W) + 1.85 (H) – 4.68 (A)
      • = Kcal/day
      • Fever: increase resting energy expenditure of approximately 7% for each degree of F of fever.
    • 80.  

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