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 24g/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