SIRS, Sepsis, and MODS Claudio Martin, MSc, MD Programme in Critical Care University of Western Ontario London, Ontario, Canada Objectives • To know definitions of SIRS, sepsis, septic shock, MODS • To become familiar with the epidemiology of sepsis • To learn basic pathophysiology (inflammation, cardiovascular physiology) of SIRS and sepsis But first, a real case: Case presentation • 43-year-old male • Flu-like symptoms for 1 day • In ER – Temp 39.5 – Pulse 130 – Blood pressure 70/30 – Respirations 32 – Petechial rash – Chest, CV, Abdominal exam normal Case presentation - 2 • Laboratory – pH 7.29, PaO2 82, PaCO2 29 • Investigations pending – Blood, urine cultures • Orally intubated and placed on mechanical ventilation • Central venous catheter inserted – Cefotaxime 2 g iv – Normal saline 2 litres initially, repeated • Admitted to ICU Case presentation - 3 • In ICU: – Noradrenaline started to support blood pressure – Additional fluid (saline and pentastarch) given based on low CVP – Pulmonary artery catheter inserted to aid further hemodynamic management • Despite therapy patient remained anuric – Continuous venovenous hemofiltration initiated Case presentation - 4 • Early gram stain on blood revealed gram negative rods • Patient started on: – Hydrocortisone 100 mg iv q8h – Recombinant activated protein C 24g/kg/hour for 96 hours – Enrolled in RCT (double-blind) of vasopressin vs norepinephrine for BP support – Enteral nutrition via nasojejunal feeding tube – Prophylaxis for stress ulcers, deep venous thromboses Case Presentation - Resolution • Patient gradually stabilized and improved with complete resolution of organ dysfunction over 5 days • Final cultures confirmed diagnosis as meningococcemia Infection: Part of a bigger picture • Infection: – Presence of organisms in a closed space or location where not normally found Infection Adapted from: Bone RC et al. Chest. 1992;101:1644-55. Opal SM et al. Crit Care Med. 2000;28:S81-2. SIRS: Systemic Inflammatory Response Syndrome • SIRS: A clinical response arising from a nonspecific insult manifested by 2 of the following: – Temperature 38°C or 36°C – HR 90 beats/min – Respirations 20/min – WBC count 12,000/mL or 4,000/mL or >10% immature neutrophils Adapted from: Bone RC et al. Chest. 1992;101:1644-55. Opal SM et al. Crit Care Med. 2000;28:S81-2. Sepsis: More Than Just Inflammation • Sepsis: – Known or suspected infection – SIRS criteria Adapted from: Bone RC et al. Chest. 1992;101:1644-55. Severe Sepsis: Acute Organ Dysfunction • Severe Sepsis = Sepsis with signs of acute organ dysfunction in any of the following systems: – Cardiovascular (septic shock) – Renal – Respiratory – Hepatic – Hemostasis – CNS – Unexplained metabolic acidosis Adapted from: Bone RC et al. Chest. 1992;101:1644-55. Sepsis: A Complex Disease Adapted from: Bone RC et al. Chest. 1992;101:1644-55. Opal SM et al. Crit Care Med. 2000;28:S81-2. Jargon 2002: PIRO Infection Inflammation Physiologic Biochemical Severe Sepsis Specific Organ Severity Predisposition • Pre-existing disease – Cardiac, Pulmonary, Renal – HIV • Age (extremes of age) • Gender (males) • Genetics – TNF polymorphisms (TNF promoter high secretor genotype) Response • Physiology – Heart rate – Respiration – Fever – Blood pressure – Cardiac output – WBC – Hyperglycemia • Markers of Inflammation – TNF – IL-1 – IL-6 – Procalcitonin – PAF Organ Dysfunction • • • • • • • • • • Lungs Kidneys CVS CNS PNS Coagulation GI Liver Endocrine Skeletal Muscle Adult Respiratory Distress Syndrome Acute Tubular Necrosis Shock Metabolic encephalopathy Critical Illness Polyneuropathy Disseminated Intravascular Coagulopathy Gastroparesis and ileus Cholestasis Adrenal insufficiency Rhabdomyolysis Specific therapy exists Magnitude of the Problem • Estimated 215,000 deaths from US 1995 data • High cost for management (ICU care, diagnostic testing, drugs) – Estimated 20 day LOS; $22,000 cost • Represents 9.3% of all deaths • Equals deaths after acute myocardial infarction Sepsis: Defining a Disease Continuum Infection/ Trauma SIRS A clinical response arising from a nonspecific insult, including 2 of the following: – Temperature ≥38oC or ≤36oC – HR ≥90 beats/min – Respirations ≥20/min – WBC count ≥12,000/mm3 or ≤4,000/mm3 or >10% immature neutrophils Sepsis Severe Sepsis SIRS with a presumed or confirmed infectious process SIRS = systemic inflammatory response syndrome. Bone et al. Chest. 1992;101:1644. Sepsis: Defining a Disease Continuum Infection/ Trauma SIRS Sepsis Severe Sepsis Shock • Sepsis with ≥1 sign of organ failure – Cardiovascular (refractory hypotension) – Renal – Respiratory – Hepatic – Hematologic – CNS – Unexplained metabolic acidosis Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207. Epidemiology of Sepsis The International Cohort Study Infection Sepsis Severe Sepsis Septic Shock Percent of cases within each category 18 28 24 30 35% mortality 8353 patients with LOS > 24h 4277 infections (2696 on admission) Alberti, Int Care Med 2002 Sources of Sepsis The International Cohort Study Severe Sepsis Septic Shock Respiratory 66 53 Abdomen 9 20 Bacteremia 14 16 Urinary 11 11 Multiple - - Microbiology of Sepsis The International Cohort Study Severe Sepsis Septic Shock Gram-positive 44 40 Gram-negative 47 47 Fungal 9 13 Polymicrobial - - Pathogenesis of SIRS/MODS Preoperative Illness Trauma or Operation Tissue Injury optimal oxygen delivery and support Recovery Excessive Inflammatory Response Inadequate Resuscitation SIRS/MODS Initiation of Inflammatory Response From Wheeler & Bernard, NEJM 1999 Homeostasis Is Unbalanced in Severe Sepsis Carvalho AC, Freeman NJ. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5:223-8; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44. Coagulation and Fibrinolysis Bernard, GR. NEJM 2001;344;10:699-709 Pathogenesis of SIRS/MODS Preoperative Illness Trauma or Operation Tissue Injury optimal oxygen delivery and support Recovery Excessive Inflammatory Response Inadequate Resuscitation SIRS/MODS Regulation of oxygen delivery Normal Abnormal Cardiac output BP=CO * SVR Cardiac Output regional distribution regional distribution Intra Organ Distribution Intra Organ Distribution Microcirculation Microcirculation QO2 = Flow * O2 content Oxygen Delivery • Delivery:Demand mismatch • Diffusion limitation (edema) Oxygen Consumption H+ H+ I Q NADH + H+ H+ Cytc III H+ H+ IV 1/2 O2 + H+ H2O NAD+ ADP + Pi •Pyruvate Dehydrogenase (PDH) activity decreased •Decreased delivery of Acetyl CoA to TCA cycle •Mitochondrial dysfunction ATP Severe Sepsis: The Final Common Pathway Endothelial Dysfunction and Microvascular Thrombosis Hypoperfusion/Ischemia Acute Organ Dysfunction (Severe Sepsis) Death Severe Sepsis: Management of Our Case Endothelial Dysfunction and Microvascular Thrombosis rhAPC Corticosteroids Hypoperfusion/Ischemia Fluids Vasopressors Acute Organ Dysfunction (Severe Sepsis) CVVHF Enteral nutrition Death Survival
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