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Severe sepsis and septic shock

Severe sepsis and septic shock. Salman Qureshi, MD McGill University Health Centre July 7, 2010 salman.qureshi@mcgill.ca. Severe sepsis and septic shock. Estimated 750,000 cases per year Projected to increase 25% by 2020 (1.1 million cases per year) Average age: 6 th decade

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Severe sepsis and septic shock

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  1. Severe sepsis and septic shock Salman Qureshi, MD McGill University Health Centre July 7, 2010 salman.qureshi@mcgill.ca

  2. Severe sepsis and septic shock • Estimated 750,000 cases per year • Projected to increase 25% by 2020 (1.1 million cases per year) • Average age: 6th decade • 50% are admitted to ICU • 15% require mechanical ventilation • Overall mortality of 30-60% • 10th leading cause of death in USA • Most common cause of death in non-coronary ICU • Annual expenditure of 17 billion dollars Crit Care Med 2001 29:1303

  3. Clinical Vignette I • 40 year old African female living in Montreal • Flu-like symptoms for 2-3 days • Fever, generalized malaise • Onset of sharp right posterior thoracic pain • Presents to outpatient clinic • T=40°C, P=110/min, BP 80/50, R=35/min

  4. Clinical Vignette II • 88 year old female; excellent health prior to admission • Seen in ER for leg pain, swelling • Diagnosed with DVT and cellulitis • Admitted to SSU; treated with IV Cefazolin and LMWH • Respiratory distress, severe hypoxemia, fever, rapid wide complex irregular heart rhythm with profound hypotension

  5. Management questions • What diagnostic tests would be most helpful? • What is the correct choice and timing of antibiotics? • How much colloid or crystalloid should we use to resuscitate the patient? • How will the adequacy of resuscitation be evaluated? • Should we use adjunctive therapies? • Catecholamines or vasopressin • Low-dose corticosteroids • Intensive insulin therapy • Activated protein C • What complications should be anticipated?

  6. Sepsis- what is it?

  7. Sepsis is a syndrome • Current definitions encompass an extraordinarily heterogenous mix of patients: • Different underlying co-morbidities • Variable host immune/inflammatory capabilities • Different types, quantities, and virulence of microorganism (gram positive vs. gram negative bacteria vs. fungal, etc.) • The type and pattern of organ involvement (lung vs. blood vs. peritoneum, etc.)

  8. Incidence of sepsis N Engl J Med 2003 348: 1546

  9. Microbial etiology of sepsis N Engl J Med 2003 348: 1546

  10. Microbial etiology of sepsis • *Gram-positive bacteria 52.1% • Staphylococcus aureus, Streptococcus pneumoniae • Gram-negative bacteria 37.6% • Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa • Polymicrobial infections 4.7% • Anaerobes 1.0% • *Fungi 4.6% • *Greatest relative increase

  11. Need for faster and more precise diagnostic tests • 20-30% of patients with severe sepsis/septic shock have negative blood cultures • Yet, an infection is causal in most of these cases: • Adults have intermittent, low magnitude bacteremia (1-30 CFU/ml) requiring culture of relatively large blood volumes • Blood cultures often sterilized by single dose of antibiotic • Some microorganisms are fastidious • False positive results may result from contaminating skin flora

  12. Real-time PCR for bacteremia • Rapid detection of microbial DNA • Sensitivity: 96.2% • Specificity: 100% • Limit of detection: 40 cfu/ml • Turnaround time: 4 hours • Uses universal primers designed to amplify conserved stretches of DNA from any bacterium • Confirmation of microbial species by nucleotide sequencing is required Exp Biol Med 2005 230:587 J Mol Diag 2005 7:581

  13. Searching for an ideal sepsis marker • Characteristics: • Rapid diagnosis • Stage and prognosticate the disease • Differentiate infectious from non-infectious causes • Differentiate viral from bacterial from fungal infection • Reflect effectiveness of antimicrobials and source control • High sensitivity and specificity • Easy to perform • Low cost

  14. The host response When we sense lipopolysaccharide, we are likely to turn on every defense at our disposal; we will bomb, defoliate, blockade, seal off and destroy all tissue in the area… Pyrogen is released from leukocytes, adding fever to hemorrhage, necrosis and shock. It is a shambles… All this seems unnecessary, panic-driven. There is nothing intrinsically poisonous about endotoxin, but it must look awful, or feel awful, when sensed by cells. -Lewis Thomas N Engl J Med 1972 287: 553

  15. The host response • Severe sepsis and septic shock are thought to be caused by a systemic “dysregulated” inflammatory process. • At present we cannot rapidly measure the patient’s ability to produce an appropriate inflammatory response, as opposed to an excessive or inadequate response. • We also cannot readily measure the adequacy of response nor do we have the tools to interpret this information rapidly and then to appropriately modulate this response to the benefit of our patients. Crit Care Med 2008 36: 964-966

  16. Immunopathogenesis of prolonged sepsis Lancet Infect Dis 2001 1:165

  17. Current paradigm for immunologic response during sepsis N Engl J Med 2003 348:138

  18. Infect Dis Clin N Am 2009 23: 485-401

  19. Surviving Sepsis Campaign • Early goal directed resuscitation during the first 6 hours after recognition (1C) • Administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D) • Recombinant activated protein C with severe sepsis and clinical assessment of high risk for death (2B except 2C for postoperative patients) • Stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C) • Vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure >65 mm Hg (1C) Crit Care Med 2008 36:296

  20. Early goal-directed therapy • Global tissue hypoxia increases during severe sepsis and septic shock and precedes multi-organ failure and death • Goal-directed therapy provided at the earliest stages of severe sepsis and septic shock restores the balance between oxygen supply and demand • Reduced in-hospital mortality (30.5% vs 46.5%) P=0.009 • More fluid, RBC, inotropes in first 6 hours for EGDT • More fluid, RBC, vasopressors, mechanical ventilation, PA catheters (7-72 hours) for standard therapy group N Engl J Med 2001 345:1370

  21. N Engl J Med 2001 345:1370

  22. Chest 2007 132:425 “In this investigation we demonstrate…a 9% absolute and 33% relative mortality reduction of implementing EGDT in ED patients with severe sepsis and septic shock. Our data suggest a number needed to treat of approximately 11 persons.”

  23. Delay in antimicrobial therapy and septic shock mortality • Retrospective review of 2731 septic shock cases • Persistent or recurrent hypotension (MAP <65 mmHg, SBP <90 mm Hg, or drop in SBP >40 mm Hg) despite >2L fluid • Average age 62.7 years; 54.3% males • Overall mortality 56.2% • 77.9% had documented infection • Over the first 6 hours after onset of hypotension, each hour delay in administration of effective antibiotic therapy was associated with a mean increase in mortality of 7.6% • Multivariate analysis showed that time to antimicrobial initiation was the strongest predictor of outcome Crit Care Med 2006 34:1589-1596

  24. Septic shock mortality and antibiotic initiation Average time to antibiotic implementation: 13.51±0.45 hours Median time to antibiotic implementation: 6 hours Crit Care Med 2006 34:1589

  25. Subgroup analysis Crit Care Med 2006 34:1589

  26. Appropriate antimicrobial therapy and septic shock mortality Infect Dis Clin N Am 2009 23: 485-401

  27. Initial antibiotic selection for severe sepsis and septic shock Infect Dis Clin N Am 2009 23: 485-401

  28. Septic shock: The golden hour • In the clinical context, a “golden hour” has been described for therapy of hypovolemic shock due to trauma, cardiogenic shock due to myocardial infarction, and, most recently, obstructive shock due to massive pulmonary embolus • In serious human infections, rapidity of antimicrobial therapy following presentation has been understood to be a critical determinant of outcome for specific conditions including community-acquired pneumonia, ventilator-associated pneumonia, meningitis, bacteremia, and now, septic shock

  29. Vasoactive therapy • Tissue perfusion requires both pressure and flow • Lactic acidosis is a relatively late marker of inadequate tissue perfusion • Vasopressors: increase vascular resistance • Pressure target: MAP >65 mm Hg or SBP >90 mm Hg • Inotropes: increase cardiac contractility • Flow target: Cardiac index >2.2 L/min/m2 or CI that results in a central venous saturation >70% or mixed venous saturation >65% • Vasoactive therapy follows adequate volume expansion

  30. Catecholamines I • Norepinephrine • Strong a1 agonist; weak b agonist; initial agent of choice for low BP in septic shock • 1-20 ug/minute IV • Phenylephrine • Pure a agonist; does not induce tachycardia • 20-200 ug/minute IV infusion; 100-200 ug IV bolus lasts ~2-3 minutes • Epinephrine • Potent b1> b2 agonist, a1 agonist; arrythmogenic; associated wtih lactic acidosis • 1-10 ug/minute IV

  31. Catecholamines II • Dopamine • Chemical precursor of epinephrine and norepinephrine • Dose dependent renal/mesenteric vasodilation, b1, a1 effects; arrythmogenic • 2.5-10 ug/kg/minute IV infusion • Dobutamine • Inotrope; raises heart rate and contractility • b1 and b2 agonist with variable effect on BP • 2.5-10 ug/kg/minute IV infusion

  32. Milrinone • Non-catecholamine • Potent stimulator of cardiac contractility • Improved right and left heart function • Pulmonary > systemic vasodilation • Lowers pulmonary artery pressure • Systemic hypotension • Loading dose 50 ug/kg bolus IV • Infusion 0.25-0.75 ug/kg/minute IV • Duration of action: 4 hours

  33. Vasopressin • Non-catecholamine; stimulates specific receptors • Useful as catecholamine-sparing agent in refractory hypotension • Mesenteric vasoconstriction at higher dose • 0.01-0.04 Units/minute IV infusion • Up to 40 Unit bolus IV in ACLS protocol

  34. Vasopressin and septic shock trial (VASST) • Randomized, multicenter, controlled trial involving 778 patients with septic shock • Evaluation of low-dose vasopressin (0.01 to 0.03 U per minute) added to norepinephrine vs. norepinephrine alone • No difference in the primary end point of 28-day mortality (35% and 39%, respectively; P = 0.26) or 90-day mortality (43.9% and 49.6%, respectively; P = 0.11) • Patients with less severe septic shock (those with a requirement for 5 to 14 μg of norepinephrine per minute at baseline) had a significant reduction in mortality with vasopressin therapy (26.5% vs. 35.7%, P = 0.05) N Engl J Med 2008 358:877

  35. VASST: caveats • Low overall mortality; high risk patients excluded (acute ischemic heart disease or CHF) • Catecholamine alone achieved a mean BP of 72 mm Hg • Study participants were not truly refractory to catecholamines • Vasopressin was used a catecholamine sparing agent • Average time from meeting entry criteria and infusion of study drug was 12 hours • past the window for early goal-directed therapies

  36. Sepsis: a prothrombotic state Host defense that aims to contain microbes/inflammation Uncontrolled systemic microvascular thrombosis contributes to multiple organ dysfunction N Engl J Med 1999 340: 207

  37. Activated Protein C (APC): anticoagulant properties N Engl J Med 2001 344:699

  38. Activated Protein C • An endogenous protein that is converted from it inactive precursor by an endothelial thrombin-thrombomodulin complex • APC levels fall during severe sepsis; associated with increased mortality • Inhibits thrombosis: Antagonizes factor Va and VIIIa • Promotes fibrinolysis: Inhibits expression of plasminogen activator inhibitor-1 • Anti-inflammatory: Reduces monocyte cytokine release

  39. Randomized trials of APC in sepsis • PROWESS trial (N Engl J Med 2001 344:699) • 6.1% absolute mortality reduction for sepsis-induced organ dysfunction associated with a clinical assessment of high risk of death (APACHE II ≥25 or multiple organ failure) • ADDRESS trial (N Engl J Med 2005; 353:1332) • Not recommended for adults with a low risk of death (APACHE II<20) • ENHANCE open-label trial (CCM 2005 33:2266 ) • Some evidence that earlier administration (<24h) is beneficial

  40. Adrenal Insufficiency • Waterhouse R. Case of suprarenal apoplexy. Lancet 1911;1:577 • Large randomized trials of high dose corticosteroid therapy have been negative • In critical illness, a state of relative adrenal insufficiency may develop that is associated with persistent catecholamine dependence • Cortisol is a permissive factor for catecholamine action Am J Respir Crit Care Med 2006 174:1319

  41. Prognostic Stratification Baseline cortisol 250 ug cosyntropin 28 day mortality (nmol/L) (ACTH) < 940 > 250 26% > 940 > 250 67% < 940 < 250 > 940 < 250 82% Overall mortality 58% (51-65) Median survival 17 days (14-27) JAMA 2000 283: 1038

  42. Low dose steroid trial • 300 patients in 19 ICUs in France • Cosyntropin (ACTH) test performed on all • Randomized to placebo vs: • 50 mg hydrocortisone iv q6h x 7days • 50 ug fludrocortisone po od x 7 days • 7% absolute reduction in mortality among ACTH non-responders treated with steroids (p=0.02) • No significant difference in 28 day mortality in ACTH responders: trend towards increased mortality JAMA 2002 288: 262

  43. Corticosteroid Therapy of SepticShock (CORTICUS) study • 499 patients with septic shock and hypotension for >1 hour after adequate fluid resuscitation • Randomized to hydrocortisone 200 mg/d for 5 days with tapering over 6 days vs. placebo; no fludrocortisone • Findings: • Faster reversal of shock in hydrocortisone group • No overall mortality difference at 28 days (RR of death 1.09; 95% CI 0.84-1.41) regardless of cosyntropin response • Increased incidence of superinfection, including new episodes of sepsis or septic shock in the hydrocortisone group • Only 35% power to detect 20% mortality difference N Engl J Med 2008 358:111

  44. Controversy over cortisol • Free cortisol, rather than the protein-bound fraction, is responsible for the physiologic function of the hormone • More than 90 percent of circulating cortisol in human serum is bound to proteins • corticosteroid- binding globulin: high affinity low capacity • albumin: low affinity high capacity • Alterations in the binding proteins could affect measured concentrations of serum total cortisol and, thus, the interpretation of tests used to assess adrenal function N Engl J Med 2004 350:1629-38

  45. Intensive insulin therapy • Tight glycemic control (4.4-6.1 mmol/L) conferred a 3.4% absolute mortality benefit among patients in a surgical intensive care unit (N Engl J Med 2001 345:1359) • 42% relative mortality reduction among patients in ICU >5 days • Single centre study with liberal use of parenteral calories • Significant increase in hypoglycemia <2.2 mmol/L • Follow-up study in 3 medical ICUs did not show an overall mortality benefit (N Engl J Med 2006 354: 449) • Subgroup analyses demonstrated less acute renal injury and shorter duration of mechanical ventilation • Mortality benefit for patients in ICU >3 days, but difficult to accurately predict who will be in this group at ICU admission

  46. VISEP: Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis • Terminated early; no mortality benefit or difference in organ failure scores at 28 or 90 days • Severe hypoglycemia was reported in 17.1% of the intensive-therapy group and 4.1% of the conventional-therapy group (P<0.001) • Hypoglycemia was an independent risk factor for death from any cause- but could be a marker of poor outcome rather than causal N Engl J Med 2008 358:125

  47. NICE-SUGAR trial • Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) • Large open-label RCT (6104 patients) comparing insulin therapy targeting glucose range of 4.5-6.0 mmol/L vs. 8.0-10.0 mmol/L • Higher mortality at day 90 in intensive glucose control group (27.5% vs 24.9%; p=0.02) • No significant differences in ICU or hospital LOS or rates of organ dysfunction • Current recommendation is a target glucose range of 8.0-10.0 mmol/L in ICU N Engl J Med 2009 360:1283-97

  48. Clinical Vignette I • 40 year old African female living in Montreal • Flu-like symptoms for 2-3 days • Fever, generalized malaise • Onset of sharp right posterior thoracic pain • Presents to outpatient clinic • T=40°C, P=110/min, BP 80/50, R=35/min

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