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Septic Shock in 2004

Septic Shock in 2004. Emergency Department Strategies for Reducing Mortality Moritz Haager PGY-3 May 13, 2004. Objectives. Brief review of basic pathophysiology Overview of recent advances in treatment with focus on those most relevant to ED care Initial resuscitation

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Septic Shock in 2004

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  1. Septic Shock in 2004 Emergency Department Strategies for Reducing Mortality Moritz Haager PGY-3 May 13, 2004

  2. Objectives • Brief review of basic pathophysiology • Overview of recent advances in treatment with focus on those most relevant to ED care • Initial resuscitation • Early goal directed therapy • Which fluid? • Which pressor? • Blood transfusions? • Infection & source control • Role of steroids • Ventilatory strategies • Adjunctive pharmacologic therapies • Activated Protein C • Insulin therapy

  3. Epidemiology • Incidence variable but on the rise • ~ 1/1000 – 260/1000 pts days • Larger # of elderly, HIV, chemotherapy, organ transplant, and dialysis pts in addition to diabetics, alcoholics etc • Mortality ranges from 3% for pts w/ no SIRS criteria to 46% for septic shock • Accounts for 215,000 deaths/yr in US = MI deaths or 9.3% of all deaths in 1995 • Annual est cost in US $16.7 billion • Locally ~250 ICU admissions for sepsis per year

  4. Definitions • Old • SIRS • T >38 or <36 • HR > 90 • RR > 20 or PCO2 < 32 • WBC > 12 or < 4 • Too sensitive & simplistic

  5. Latest ACCP/SCCM Consensus Definitions • Infection = invasion of organ system(s) by microorganisms • Sepsis = systemic host response to infection requiring > 1 signs & symptoms of sepsis • Severe sepsis = sepsis w/ organ failure • Septic shock = severe sepsis w/ cardiovascular failure requiring vasoactive medications • Vincent & Jacobs. Curr Opin Infect Dis 16: 309-13. 2003

  6. Vincent & Jacobs. Curr Opin Infect Dis 16: 309-13. 2003

  7. Classifications reflect disease severity Diagnostic category Mortality (%) SIRS criteria none 3 2 7 3 10 4 17 Sepsis 16 Severe sepsis 20 Septic shock 46 • McCoy & Matthews. Drotrecogin Alfa (Recombinant Human Activated Protein C) for the treatment of severe sepsis. Clin Ther 2003; 25: 396-421

  8. PIRO Grading System • P – Predisposing factors • Age, comorbidities, immune status etc • I – Infection • Organism, site(s), degree • R – Response • Degree of host response as judged by clinical & laboratory parameters • O – Organ dysfunction • Degree of organ involvement

  9. Sepsis Etiology • > 90% bacterial etiology • Gram negative ~42% • Gram positive ~34% • Anaerobes ~2-5% • Mixed ~14% • Fungi ~5% • Primarily Candida • More common in ICU setting, immunocompromised pts, steroids, diabetics • Llewelyn & Cohen. Diagnosis of infection in sepsis. Int Care Med. 2001; 27: S10-32 • Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care Med. 2001; 27: S33-48

  10. Sources of Infection • Specific sites: • Respiratory 36% • Blood 20% • Abdomen 19% • Urinary tract 13% • Wounds & Skin 7% • Other 5% • Can be identified in ~92% of pts • Extremely important in choosing Abx • Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care Med. 2001; 27: S33-48

  11. Not all that is febrile & shocky is infectious… • Non-infectious causes of SIRS • Tissue damage • Surgery, trauma, DVT, MI, PE, pancreatitis etc • Metabolic • Thyroid storm, adrenal insufficiency • Malignancy • Tumor lysis syndrome, lymphoma • CNS • SAH • Iatrogenic • Transfusion rxns, anesthetics, NMS etc • Llewelyn & Cohen. Diagnosis of infection in sepsis. Int Care Med. 2001; 27: S10-32

  12. INFLAMMATION PATHOGENS • TNF-α, IL-1, IL-6, IL-7, • Proteases, Leukotrienes, Prostaglandins • Bradykinin, Platelet activating factors • Free oxygen radicals Endotoxins, Exotoxins Direct endothelial invasion SEPSIS TF EXPOSURE ENDOTHELIAL INJURY ANTI-COAGULANT SYSTEM INHIBITON ACTIVATION OF CLOTTING CASCADE FIBRINOLYTIC SYSTEM INHIBITION ↓ AT III, ↓ aPC, ↓ pS ↓ thrombomodulin ↑ PAI-1 PRO-COAGULANT EFFECT MICROVASCULAR THROMBOSIS MULTI ORGAN DYSFUNTION SYNDROME

  13. A tale of 2 theories • Hyperimmune response theory • Sepsis is a state of uncontrolled inflammatory response to infection • Multiple (unsuccessful) trials of anti-inflammatory agents • Hypoimmune response theory • Sepsis leads to immunosuppression through anergic & apoptotic mechanisms • Hotchkiss & Karl. The pathophysiology and treatment of sepsis. N Eng J Med. 2003; 348: 138-50

  14. Clinical Effects • Peripheral vasodilatation & capillary leak • Intravascular volume depletion • Myocardial depression • Hypermetabolic state – global tissue hypoxia • DIC – coagulation > fibrinolysis

  15. Treatment of Septic Shock Antibiotics Surgical Management EGDT Steroids Ventilation rhAPC

  16. Utilize EGDT in 1st 6 hrs Cultures before Abx Source control Aggressive rehydration with colloid or crystalloid Use dopamine or norepinephrine for refractory shock Give stress dose steroids Give rhAPC when appropriate Keep Hb 70-90 Use low TV’s & minimal peak pressure & PEEP vent strategy Use insulin therapy Avoid Supranormal oxygenation Bicarb Dellinger et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004; 32: 858-73 SCCM Guidelines for Treatment of Septic Shock

  17. Early Goal Directed Therapy

  18. SCCM Guidelines • “resuscitation…should not be delayed pending ICU admission.” • Goals of resuscitation in 1st 6 hrs of recognition: (B) • CVP: 8-12 mm Hg (12-15 if ventilated) • MAP: > 65 mm Hg • Urine output: > 0.5 ml/kg/hr • SVO2 > 70% • If unable to attain SVO2 >70% despite above then: • Transfuse to keep Hct > 30% • Dobutamine • Dellinger et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004; 32: 858-73

  19. Rationale behind EGDT • Time is survival: • Goal is to achieve balance b/w O2 delivery & consumption • Standardized approaches to ED Tx have improved outcomes in other Dz (e.g. MI) • Traditional parameters to guide resus (vitals, mental status, urine output) appear to be too insensitive for ongoing tissue hypoxia • Early observational trials found survivors to have hemodynamic parameters that were both higher than non-survivors as well as predicted

  20. Earlier Trials • No consistent benefit from using goal-directed therapy to optimize oxygen delivery in ICU patients • Gattinoni et al. A trial of goal-directed hemodynamic therapy in critically ill patients. N Eng J Med 1995; 333: 1025-32 • Hayes et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Eng J Med 1994; 330: 1717-22 • Yu et al. Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective randomized controlled study. Crit Care Med. 1993; 21: 830-8 • Boyd et al. A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA. 1993; 270: 2699-707 • Tuchschmidt et al. Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest 1992; 102: 216-20 • Shoemaker et al. prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988; 94: 1176-86

  21. Earlier Trials • Limitations: • Heterogeneous study populations • Small sample sizes & wide CI’s • Enrollment after ICU admission • Tended to focus on one intervention in isolation • Most used PA catheters

  22. Rivers et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Eng J Med. 2001; 345: 1368-77 • Prospective RCT of 263 adult pts with sepsis treated either with traditional care or a standardized resuscitation protocol in the ED • All had arterial & central venous lines placed – the EGDT group got a catheter capable of continuous O2 sat measurement • EGDT discontinued once transferred to ICU – all ICU staff blinded to pts assignments • Primary endpoint was mortality

  23. Edwards PreSep Central Venous Oximetry Catheter

  24. EGDT Protocol

  25. Rivers et al. 2001 (cont’d) • Found that EGDT did significantly better • In-hospital mortality 30.5% vs. 46.5%, • ARR 16%, NNT = 6; OR 0.58 (95%CI 0.38 – 0.87) • 60d mortality 44.3% vs. 56.9% • Primarily explained by reduction in sudden CVS collapse deaths (10.3% vs. 21.0%) • Various secondary outcomes (labs & severity scores) significantly better in EGDT group • EGDT pts spent longer time in the ED • EGDT survivors spent less time in hospital than standard Tx survivors (14.6 d vs. 18.4 d) • Baseline SVO2 was 48% despite only 50% ventilated

  26. Rivers et al. 2001 (cont’d) • Differences in EGDT group • More fluid early (4.9 L vs. 3.5L) • More transfusions (64.1% vs. 18.5%) • More inotropic support (13.7% vs. 0.8%) • Less use of pulmonary artery catheters later in ICU stay (18% vs. 31.9%)

  27. Controversies • Conflicts with earlier studies showing lack of benefit from using hemodynamic goals • Hayes et al. N Eng J Med 1995; 330: 1717-22 • Gattinoni et al. N Eng J Med 1995; 333: 1025-32 • Different time points – all prior studies in ICU setting • More heterogeneous patient populations

  28. Controversies • Transfusion practice • How does this fit with the TRICC trial? • Need for IJ or SC lines • Which part of protocol accounts for benefit? • How will this affect department flow

  29. Supporting data • Retrospective study of pediatric sepsis • Early normalization of vitals associated with >9 fold improved odds of survival • Odds of mortality increase >2-fold with every hour of ongoing shock • Only 45% of pts were adequately fluid resuscitated • Han et al. Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome

  30. Supporting data • Success of hemodynamic optimization appears time-dependent • Meta-analysis of ICU pts • Studies instituting PAC goal-directed therapy later than 12 hrs or after onset of organ failure failed to show benefit • Studies that intervened early found to result in significant mortality reduction of 23% (95%CI 16-30) • Kern et al. Meta-analysis of hemodynamic optimization in high-risk patients. Crit Care Med 2002; 30: 1686-92

  31. Fluids in Sepsis

  32. SCCM Guidelines • No evidence for choosing colloid over crystalloids (Grade C) • Administer crystalloids as 500-1000 cc over 30 mins & repeat prn based on response (E) • Administer colloids at 300-500 cc over 30 mins & repeat prn based on response (E)

  33. Crystalloids or colloids? • Controversial • Many heterogeneous studies • No evidence for superiority of one over other, but trend towards increased mortality w/ colloids • Choi et al. Crystalloids vs. colloids in fluid resuscitation: A systematic review. Crit Care Med. 1999; 27: 200-10 • Shierhout & Roberts. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: A systematic review of randomized trials. BMJ. 1998; 316: 961-4 • Crystalloids • Cheaper, easily available, less risk of anaphylactoid rxns, resuscitate intra- & extravascular space

  34. VasopressorsJust need a little squeeze..

  35. SCCM Guidelines • Should be used when • shock refractory to fluid resuscitation • Life-threatening hypotension (E) • Dopamine or norepinephrine are 1st line agents (D) • ‘Renal dose’ dopamine does not work & should not be used (B) • Invasive BP monitoring & central IV lines should be placed as soon as possible (E) • Vasopressin may be considered as a 2nd line agent in refractory shock (E) • Dobutamine may be considered in refractory shock felt to be due to low cardiac output (E)

  36. Does “renal dose” dopamine work? • NO!! • DBRCT multicenter trial of 328 ICU pts randomized to placebo or dopamine at 2ug/kg/min • No difference in mortality, peak serum creatinine, need for renal replacement Tx, rise in serum creatinine, or length of stay • ANZICS clinical trials group. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomized trial. Lancet. 2000; 356: 2139-43

  37. Norepinephrine or Dopamine 1st in septic shock? • Tons of animal data; very few clinical studies • Decreased mortality w/ norepinephrine vs. dopamine in one NON-randomized trial • Theoretical benefits w/ norepinephrine • Less tachycardia • No effect on HPA or cerebral perfusion pressure • Increased GFR • Decreased lactate levels • Improved splanchnic blood flow • Vincent & de Backer. Crit Care 2003; 7: 6-8 • On the other hand dopamine is quickly available and familiar • Bottom line = either will do as an initial pressor

  38. Transfusion

  39. Why do sick pts become anemic? • 95% of ICU pts are anemic by day 3 of ICU stay • Mechanisms • Phlebotomy = 65 ml/day on average • Underproduction anemia • Blunted erythropoietin response secondary to inflammatory cytokine production • Abnormal iron metabolism due to immune activation • Low iron levels & elevated ferritin • Corwin et al. Transfusion practice in the critically ill. Crit Care Med 2003; 31(S): S668-71

  40. What should be the transfusion threshold? • SCCM Guidelines • Transfuse to keep Hb > 70 g/L unless extenuating circumstances (e.g. CAD) (B) • Based on TRICC trial • Rivers et al. 2001 • Transfuse to keep hematocrit at least 30%

  41. TRICC Trial • Multicenter RCT of 838 ICU pts w/ Hb <90 • Randomized to • Liberal strategy • Transfusion threshold 100 g/L – aim for 100 -120g/L • Restrictive strategy (study group) • Transfusion threshold 70 g/L – aim for 70 – 90 g/L • Primary outcome • All cause mortality at 30 days • Herbert et al. A multicenter, randomized, controlled trial of transfusion requirements in critical care. N Eng J Med. 1999; 340: 409-17

  42. TRICC Trial • Results • No difference in 30d mortality • ARR 4.6% (95%CI -0.84 – 10.2%) • No difference in 60d mortality • No difference in mortality in sepsis sub-group • Less sick pts (APACHE II score <20) did better with restrictive strategy • ARR 7.4% (95%CI 1.0 – 13.6%) • Conclusion • Restrictive strategy equivalent to, and possibly better than keeping Hb > 100 g/L

  43. Why the TRICC trial does not contradict Rivers et al • Different patient population • Euvolemic pts • Enrolled within 72 hrs of ICU admission • Only 6% had Dx of sepsis, and only 26.5% had any infection at all

  44. Antibiotic TreatmentThe war against bugs

  45. SCCM Guidelines • Draw appropriate cultures first • Give antibiotics within 1 hr of recognition of septic syndrome • Antibiotics should be broad-spectrum & chosen to cover most likely organisms based on presentation & local resistance patterns • Arrange for further diagnostic studies to rule out surgically correctable foci of infection once appropriate

  46. Fatal Error • “Autopsy studies in persons who died in the intensive care unit show that failure to diagnose and appropriately treat infections with antibiotics or surgical drainage is the most common avoidable error” • Hotchkiss & Karl. The pathophysiology and treatment of sepsis. N Eng J Med. 2003; 348: 138-50

  47. Do Antibiotics make a difference? • Animal models indicate progressive increase in mortality w/ each hour of delay to Abx • Few prospective RCT’s – most outcome data based on retrospective analyses • ARR 16 – 26% when initial Abx were appropriate • Virtually all studies in ICU setting • Prospective cohort study of 406 pts w/ sepsis found inadequate initial Abx Tx significantly increased risk of death in non-surgical sepsis (OR 8.15; 95%CI 1.98-33.5) • Adequate Tx dec’d risk of death in surgical sepsis (OR 0.37, 95%CI 0.18-0.77) • Garnacho-Montero et al. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 2003; 31: 2742-51

  48. Mono- or Combination Therapy? • Combination Tx: theoretical advantages • Broadens spectrum • Synergism • Decreases emergence of resistant strains • No good studies to document improved outcomes • Paucity of relevant data and adequately powered studies • Bochd, Glauser, & Calandra. Antibiotics in sepsis. Int Care Med. 2001; 27: S33-48

  49. Mono- or Combination Therapy? • Meta-analysis • 64 RCT’s (7586 pts) of monotherapy vs. Beta-lactam & aminoglycosides combo • No difference in all-cause mortality, treatment failure, or resistance development • Lack of benefit consistent in all subgroups analyzed • Significant increased nephrotoxicity w/ combo Tx NNH 15 (14-17) • Paul et al. Beta-lactam monotherapy versus beta-lactam aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomized trials. BMJ 2004; 238: 668

  50. Undifferentiated febrile shocky pt w/ no focus Ceftriaxone Respiratory Ceftriaxone + macrolide or resp quinolone Urinary tract Gentamicin or quinolone Meningitis Ceftriaxone +/- vancomycin +/- ampicillin Intraabdominal Ancef + flagyl + gentamicin (24 hr dosing) Ceftriaxone + flagyl Pip-tazo Carbapenem Necrotizing fasciitis IVIG + penicillin + clindamycin + surgery Dr. Dan Gregson personal communication Local ID recommendations: Quick reference guide

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