SIRS Sepsis and MODS Claudio Martin MSc MD

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 – p. H 7. 29, Pa. O 2 82, Pa. CO 2 • • 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 venous hemofiltration initiated

Case presentation - 4 • Early gram stain on blood revealed gram negative rods • Patient started on: – Hydrocortisone 100 mg iv q 8 h – 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: S 81 -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/m. L or 4, 000/m. L or >10% immature neutrophils Adapted from: Bone RC et al. Chest. 1992; 101: 1644 -55. Opal SM et al. Crit Care Med. 2000; 28: S 81 -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: S 81 -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 Ø Adult Respiratory Distress Syndrome Ø Acute Tubular Necrosis Ø Shock Ø Metabolic encephalopathy Ø Critical Illness Polyneuropathy Ø Disseminated Intravascular Coagulopathy Ø Gastroparesis and ileus Ø Cholestasis Ø Adrenal insufficiency Ø Rhabdomyolysis üSpecific 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 ≥ 38 o. C or ≤ 36 o. C – HR ≥ 90 beats/min – Respirations ≥ 20/min – WBC count ≥ 12, 000/mm 3 or ≤ 4, 000/mm 3 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 > 24 h 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 BP=CO * SVR Cardiac output Cardiac Output regional distribution Intra Organ Distribution Microcirculation QO 2 = Flow * O 2 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 O 2 + H+ H 2 O NAD+ ADP + Pi • Pyruvate Dehydrogenase (PDH) activity decreased • Decreased delivery of Acetyl Co. A 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 rh. APC Corticosteroids Hypoperfusion/Ischemia Fluids Vasopressors Acute Organ Dysfunction (Severe Sepsis) CVVHF Enteral nutrition Death Survival