1. To know definitions of SIRS, sepsis, septicshock, MODS To learn basic pathophysiologyBut first, a real case:

2. 86/ Malay/ Lady U/L HPT and IHD Presented to Hospital Tampin A&E on29/4/2012 C/O: Poor oral intake x 2/52 Lethargy x 2/7 Minimal URTI sx Previously ADL independent 3. O/E: Alert, lethargic looking Dehydrated Temp 38.5 Pulse 144 Blood pressure 184/104 Respirations 22 Chest, CV, Abdominalexam normal 4. Laboratory: FBC: WCC 15.48 ( N 45, L 49) / Hb 14.4 / Plt 161 RP: Urea 19.4 / Creat 131 / Na 147 / K 4.6 UFEME: Leu 3+ / Nitrate neg /Blood moderate /Ketone small CXR: Hyperinflated lungs ECG: T inversion leads II, III, avF, v5, v6 5. Diagnosis: Sepsis 2 UTI withdehydration 2 poor oralintake Admitted to Ward 2 Fluid therapy 3 pints over24H Vital signs monitoring CBD Strict IO monitoring Blood c&s, Urine c&s IV Zinacef 750mg stat andTDS Nasal prong 3L/min 6. Day 2: AM rounds: Condition same Tolerating minimal fluid Urine output >30ml/H Spiking temperature PM rounds: Patient appears weak. c/o chestpain started at 8pm BP 96/63 P 130 ECG Sinus tachycardia. ST depression II, III, avF, v4-v6 7. Treated as ACS Started on: S/L GTN 0.5mg stat, and PRN S/c clexane 60mg stat and OD T isordil 10mg BD T aspirin 300mg stat, 100mg OD KIV inotrope 8. VBG:uncompensatedmetabolic acidosis RP:Urea 20/ Creat 120/Na 154 / K 4.3 IVD changed to HSD5 DIL issued to familymembers 9. Explained to family membersregarding patients illcondition: Sepsis Kidney injury ACS In the event of cardiac arrest,family not keen for activeresuscitation DNR issued 10. Day 3: Fever settled Vital signs stable without inotrope Hydration improves, good urine output Seen by dietician and started on RT feeding200cc/3hourly IVD 2 pints HS and 1 pint D5 over 24H 11. Day 4 - Day 7: General condition improving Vital signs stable Hydration status normal, good urine output Completed IV Zinacef Completed S/c Clexane L hand thrombophlebitis On IV Ciprofloxacin 400mg BD Off IVD Cont RT feeding 12. Day 8: Temp 38.7 BP 136/74 P 92 RR 28 32 Sp02 97 under RA L hand thrombophlebitis Chest: bibasal crepitations CXR: pneumonic changes L LZ Cont IV Ciprofloxacin 400mg BD 13. Day 10: GCS E3V4M5 Spiking temp 38 Tolerating RT feeding BP 136/74. P 86. RR 28. Sp02 95-96 under RA Chest bibasal crepts Noted L LL swelling upto calf and knee. Tender calf.Feeble DPA and PTA? L LL DVT 14. Discussed with family members the need for transfer toHTJS for US doppler Family members refused Consented for S/C Clexane DIL reinformed 15. Day 11: General condition ill, gasping BP lowish 90/60 P 113 RR 28 Sp02 95% under NP 3L/min Fluid resuscitation 16. Day 12: (11/5/2012) Patient succumbed to her illness Unresponsive, P not palpable, BP unrecordable at4.10pm No activity on cardiac monitor >15 minutes Pupils fixed dilated 17. DNR as requested by familymembers Informed family members Time of death: 4.25pm Cause of death:Sepsis 2 UTI complicated with: Acute kidney injury Acute coronary syndrome Nosocomial infection 18. Infection: A microbial phenomenoncharacterized by an inflammatoryresponse to the presence ofmicroorganisms or the invasion ofnormally sterile host tissue by thoseorganisms. Bacteremia: The presence of viablebacteria in the blood. 19. Systemic Inflamatory ResponseSyndrome (SIRS): The systemicinflammatory response to a variety ofsevere clinical insults (For example,infection). Sepsis: The systemic inflammatoryresponse to infection. 20. Temperature >38 degrees Celsius or 90 beats per minute. Respiratory rate>20 breaths per minute orPaCO2 12,000/cu mm,10% band forms. 21. Sepsis: Known or suspected infection, plus >2 SIRS Criteria. Severe Sepsis: Sepsis plus >1 organ dysfunction. MODS. Septic Shock. 22. Septic Shock: Sepsis induced withhypotension despite adequateresuscitation along with the presence ofperfusion abnormalities which mayinclude, but are not limited to lacticacidosis, oliguria, or an acute alterationin mental status. 23. Multiple Organ Dysfunction Syndrome(MODS): The presence of altered organfunction in an acutely ill patient such thathomeostasis cannot be maintainedwithout intervention. 24. Lungs Adult Respiratory Distress Syndrome Kidneys Acute Tubular Necrosis CVS Shock CNS Metabolic encephalopathy PNS Critical Illness Polyneuropathy Coagulation Disseminated Intravascular GICoagulopathy Liver Gastroparesis and ileus Endocrine Cholestasis Skeletal Muscle Adrenal insufficiency RhabdomyolysisSpecific therapy exists 25. Adapted from: Bone RC et al. Chest. 1992;101:1644-55.Opal SM et al. Crit Care Med. 2000;28:S81-2. 26. Infection/TraumaSIRSSepsis Severe SepsisA clinical response arisingSIRS with a presumed or from a nonspecific insult, confirmed infectious including 2 of theprocess following: Temperature 38oC or36oC HR 90 beats/min Respirations 20/min WBC count12,000/mm3 or 4,000/mm3 or >10%immature neutrophils SIRS = systemic inflammatory response syndrome. Bone et al. Chest. 1992;101:1644. 27. Infection/ TraumaSIRSSepsis Severe Sepsis Sepsis with 1 sign of organ failure Cardiovascular (refractoryhypotension) Renal Respiratory Shock Hepatic Hematologic CNS Unexplained metabolic acidosisBone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207. 28. InfectionPhysiologicInflammationBiochemical Severe Sepsis Specific OrganSeverity 29. Pre-existing disease Cardiac, Pulmonary, Renal HIV Age (extremes of age) Gender (males) Genetics TNF polymorphisms (TNF promoter highsecretor genotype) 30. Physiology Markers of Heart rate Inflammation Respiration TNF Fever IL-1 Blood pressure IL-6 Cardiac output Procalcitonin WBC Hyperglycemia 31. Fever. Leukocytosis. Tachypnea. Tachycardia. Reduced Vascular Tone. Organ Dysfunction. 32. Hemodynamic Alterations Hyperdynamic State (Warm Shock) Tachycardia. Elevated or normal cardiac output. Decreased systemic vascular resistance. Hypodynamic State (Cold Shock) Low cardiac output. 33. Myocardial Depression. Altered Vasculature. Altered Organ Perfusion. Imbalance of O2 delivery andConsumption. Metabolic (Lactic) Acidosis. 34. Stage 1. In response to injury /infection, the local environment producescytokines. Stage 2. Small amounts of cytokinesare released into the circulation: Recruitment of inflammatory cells. 35. Stage 3. Failure to controlinflammatory cascade: Loss of capillary integrity. Stimulation of Nitric Oxide Production. Maldistribution of microvascular blood flow. Organ injury and dysfunction. 36. Bacterial Endotoxin TNF- Interleukin-1 Interleukin-6 Interleukin-8 Platelet Activating Factor (PAF) Interferon-Gamma Prostaglandins Leukotrienes Nitric Oxide 37. Interleukin-10 PGE2 Protein C Interleukin-6 Interleukin-4 Interleukin-12 Lipoxins GM-CSF TGF IL-1RA 38. Answer: Organ Failure 39. Knaus, et al. (1986):Direct correlation between number of organ systems failedand mortality.Mortality Data:#OF D1 D2D3 D4 D5 D6D71 22% 31%34% 35%40%42% 41%2 52% 67%66% 62%56%64% 68%3 80% 95%93% 96%100100 100%% % 40. Multiple Organ Dysfunction (MODS) andMultiple Organ Failure (MOF) result fromdiffuse cell injury / death resulting incompromised organ function. Mechanisms of cell injury / death: Cellular Necrosis (ischemic injury). Apoptosis. Leukocyte-mediated tissue injury. Cytopathic Hypoxia 41. Cytokine production leads to massive productionof endogenous vasodilators. Structural changes in the endothelium result inextravasation of intravascular fluid intointerstitium and subsequent tissue edema. Plugging of select microvascular beds withneutrophils, fibrin aggregates, and microthrombiimpair microvascular perfusion. Organ-specific vasoconstriction. 42. Infection Inflammatory EndothelialVasodilation MediatorsDysfunctionHypotensionMicrovascular PluggingVasoconstriction Edema Maldistribution of Microvascular Blood Flow IschemiaCell Death Organ Dysfunction 43. Loss of Sympathetic Responsiveness: Down-regulation of adrenergic receptornumber and sensitivity, possible altered signaltransduction. Vasodilatory Inflammatory Mediators. Endotoxin has direct vasodilatory effects. Increased Nitric Oxide Production. 44. Vasoactive Intestinal Peptide Bradykinin Platelet Activating Factor Prostanoids Cytokines Leukotrienes Histamine NO 45. Decreased red cell deformability in inflammatory states. Microvascular sequestration of activated leukocytes andplatelets. Sepsis is a Procoagulant State. The extrinsic pathway may be activated in sepsis by upregulation of Tissue Factor on monocytes or endothelial cells. Fibrinolysis appears to be inhibited in sepsis by upregulation of Plasminogen Activator Inhibitor. A variety of pathways result in reduced Protein C activity in sepsis. 46. Endothelial cell expression of Selectinsand ICAM / ELAM is upregulated in Sepsisdue to inflammatory activation. Selectins bind carbohydrate ligands on thesurfaces of PMNs. ICAM bind Integrins on the surfaces of PMNs. The Selectins initiate a weak bond betweenthe PMN and the endothelial cell causingPMNs to tumble along the vessel wall. 47. Binding of leukocytes to ICAM leads totransmigration of PMNs into interstitium. Transmigration disrupts normal cell-celladhesions resulting in increased vascularpermeability and tissue edema. Vascular permeability is also increasedby several types of inflammatorycytokines. 48. A physiologic process of homeostatically-regulated programmed cell death toeliminate dysfunctional or excessive cells. A number of inflammatory cytokines, NO,low tissue perfusion, oxidative injury, LPS, andglucocorticoids all are known to increaseapoptosis in endothelial and parenchymalcells. Levels of circulating sfas (circulatingapoptotic receptor) and nuclear matrixprotein (general cell death marker) are bothelevated in MODS. 49. Transmigration and release of elastaseand other degradative enzymes candisrupt normal cell-cell connectionsand normal tissue architecturerequired for organ function. Reactive oxygen species cause directcellular DNA and membrane damageand induce apoptosis. 50. A defect of cellular oxygen utilization. May be due to activation of PARP (poly-ADP-ribosylpolymerase-1). Oxidative DNA damage activates PARP whichconsumes intracellular and mitochondrialNAD+. NAD+ depletion leads to impaired respirationand a shift to anaerobic metabolism. Affected cells may suspend normal cell-specific activities in favor of preservation ofcell viability. 51. Optimize Organ Perfusion Expand effective blood volume. Hemodynamic monitoring. 52. Optimize Organ Perfusion Pressors may be necessary. Compensated Septic Shock: Phenylephrine Norepinephrine Dopamine Vasopressin Uncompensated Septic Shock: Epinephrine Dobutamine + Phenylephrine / Norepinephrine 53. Control Infection Source Drainage Surgical Radiologically-guided Culture-directed antimicrobial therapy Support of reticuloendothelial system Enteral / parenteral nutritional support Minimize immunosuppressive therapies 54. Support Dysfunctional Organ Systems Renal replacement therapies (CVVHD, HD). Cardiovascular support (pressors, inotropes). Mechanical ventilation. Transfusion for hematologic dysfunction. Minimize exposure to hepatotoxic andnephrotoxic therapies. 55. Modulation of Host Response Targeting Endotoxin Anti-endotoxin monoclonal antibody failed to reduce mortality in gram negative sepsis. Neutralizing TNF Excellent animal data. Large clinical trials of anti-TNFmonoclonal antibodies showed a verysmall reduction in mortality (3.5%). 56. Modulation of Host Response IL-1 Antagonism Three randomized trials: Only 5% mortality improvement. PAF-degrading enzyme Great phase II trial. Phase III trial stopped due to no demonstrable efficacy. NO Antagonist (LNMA) Increased mortality (? Pulmonary Hypertension). 57. Modulation of Host Response Antithrombin III No therapeutic effect. Subset of patients with effect when concomitantheparin not given. Activated Protein C (Drotrecogin alpha /Xigris) Statistically significant 6% reduction in mortality. Well-conducted multicenter trial (PROWESS). FDA-approved for use in reduction of mortality insevere sepsis (sepsis with organ failure). 58. Modulation of Host ResponseCorticosteroids Multiple studies from 1960s 1980s: Not helpful, possibly harmful. Annane, et al. (2002): 10% mortality reduction in vasopressor-dependent septic shock (relative adrenal insufficiency, ACTH nonresponders). 59. Components: Early Recognition Early Goal-Directed Therapy Monitoring Resuscitation Pressor / Inotropic Support Steroid Replacement Recombinant Activated Protein C Source Control Glycemic Control Nutritional Support Adjuncts: Stress Ulcer Prophylaxis, DVT Prophylaxis, Transfusion, Sedation, Analgesia, Organ Replacement