Sepsis / Septic Shock
Guidelines
Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296-327. This update of the 2004 guidelines utilized a new approach for grading the evidence underlying recommendations. Noteworthy changes include elimination of the cosyntropin stim test and downgrading the recommendation to “weak” for hydrocortisone in patients with persistent shock and for activated protein C in patients with severe sepsis.
PMID: 18158437
Hydrocortisone therapy
Annane D, Sebile V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288; 862-71. Placebo-controlled RCT of 300 septic patients found the subgroup of patients failing to respond to 250 mcg cosyntropin but receiving 50mg HC q6 and 50mcg fludrocortisone qd had significantly reduced morality compared to the non-responders given placebo (53% vs. 63%). No benefit was seen in giving steroid to corticotropin-responsive patients. The statistical methods used in reporting outcomes, as well as the high mortality compared to other trials in septic shock patients, are concerns raised about this study.
PMID: 12186604
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Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358:111-24. RCT (N = 499) found no 28-day mortality benefit to “physiologic” doses of hydrocortisone administered within 72 hours of sepsis onset, independent of the response to a corticotropin stim test. Difficulty with patient recruitment and lower than expected mortality led to the study having a power of < 35% to detect a 20% reduction in relative risk of death.
PMID: 18184957
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Activated protein C
Bernard GR, Vincent JL, Laterre PE, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709. Large, phase III multicenter RCT found patients randomized to APC had an absolute mortality reduction of 6%, but may have a greater risk of bleeding.
PMID: 11236773
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Abraham E, Laterre PF, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005; 353:1332-41. Multi-center RCT (N= 2613) of placebo vs. DrotAA (24 mg/kg/hr x 96 hours) found an increased incidence of serious bleeding complications without mortality benefit with use of DrotAA. The authors conclude DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.
PMID: 16192478
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Early resuscitation
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-77. This RCT of 263 patients found benefit from early (in E.D.) aggressive resuscitation (in-hospital mortality of 30% in the goal-directed group compared to 46% in the standard therapy group). The intervention arm was noteworthy for prn use of blood transfusion and/or inotropes to maintain central venous O2 sat >70%. Authors speculate the earlier aggressiveness accounts for better outcomes than previous studies of goal-directed hemodynamic optimization.
PMID: 11794169
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Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized controlled trial. JAMA 2010; 303:739-46. This randomized trial of 300 patients found protocol-driven resuscitation based on lactate clearance to be as effective as resuscitation based on continuous ScVO2 monitoring. Of note, the use of inotropes and red blood cell transfusion was similar between groups and substantially less than in the EGDT study above.
PMID: 20179283
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The Safe Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247-56. A high-quality study involving 6997 patients assigned to receive albumin or saline found no difference in 28-day mortality, single or multiple organ dysfunction, days spent in ICU, days spent in the hospital, mechanical ventilation days, and days spent on renal replacement therapy. Although the debate over the use of crystalloids vs. colloids will likely rage on, these results make a strong case against the routine use of colloids given the added expense.
PMID: 15163774
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Durairaj L, Schmidt GA. Fluid therapy in resuscitated sepsis: less is more. Chest 2008;133:252-63. Thoughtful review of fluid management after the first six hours of early goal directed therapy. There are figures and examples demonstrating both static and dynamic measurements for evaluating the patient’s fluid status and the likelihood of the patient being “fluid responsive.”
PMID: 18187750
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Hemodynamic Monitoring
Connors AF, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. JAMA 1996;276:889-897. This famous prospective cohort study found worse outcome with use of PACs in the critically ill, instantly becoming a source of enormous controversy.
PMID: 8782638
Richard C, Warszawski J, Anguel N, et al. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2003;290:2713-20. This multicenter study of 676 patients with common indications for PA catheter placement in the MICU found neither harm nor benefit with catheter placement. Management based on catheter-derived data was at the discretion of the attending physician rather than by protocol. In the control arm, 78% of patients underwent echocardiography.
PMID: 14645314
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Vasopressors
Russel JA, Walley KR, Singer J, et al. VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87. Large scale randomized blinded study of low dose vasopressin added to norepinephrine versus norepinephrine alone in septic shock. No significant differences in overall mortality or serious adverse events were identified; however post hoc analysis suggested possible 28 and 90 day mortality benefit in a subset of patients with less severe septic shock.
PMID: 18305265
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DeBacker D, Biston P, Devriendt J, et al. SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. . N Engl J Med. 2010;362:779-89. Large multicenter RCT of 1679 patients with shock of any etiology, demonstrated equal mortality and significantly fewer arrhythmias with norepinephrine as first line vasopressor. Subgroup of those with cardiogenic shock had higher mortality with dopamine. Concerns raised have included heterogeneity of shock physiologies included, restricted fluid resuscitation protocol, and open label use of norepinephrine after conservative max doses of study drug. However, this study adds valuable evidence to our currently limited understanding of comparative merits of pressors.
PMID: 20200382
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***See also Ventilator-Associated Pneumonia and Cardiology Critical Care
