Sepsis / Septic Shock


Singer M, Deutschman C, Seymour C, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016; 315:801-10. An update of the 2001 definition, Sepsis-3 defines sepsis as “life-threatening organ dysfunction caused by a dysregulated host response to infection”. Sepsis-3 uses the retrospectively validated “qSOFA” score (altered mentation, SBP < 100 mmHg, respiratory rate > 22) to identify patients outside of the ICU for risk of death or prolonged ICU stay. In the ICU they recommend using a SOFA score increase of at least 2 to identify organ dysfunction. They also disavow the much-maligned SIRS criteria as a method for identifying septic patients. Criticism of this update includes over-reliance on qSOFA score, which had not been prospectively validated prior to publication.

PMID: 26903338

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Rhodes A, Evans LE, Alhazzani W et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017; 45:486-552.

PMID: 28098591

Hydrocortisone therapy

Venkatesh B, Finfer S, Cohen J et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018; 378:797-808. From 2013 - 2017, the ADRENAL trial randomized 3,800 patients with septic shock receiving mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day via continuous infusion) or placebo for 7 days or until death or ICU discharge. There was no difference in 90-day mortality (near 28% for both groups). The steroid group spent less time on vasopressors but duration of ICU stay and days free of mechanical ventilation did not differ.

PMID: 29347874

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Annane D, Renault A, Brun-Buisson C et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018; 378:809-818. The APROCCHSS trial initially randomized patients to various combinations of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), and placebo but subsequently compared only hydrocortisone-fludrocortisone to placebo in 1,241 patients after drotrecogin was withdrawn from the market in 2011. The steroid group had lower 90-day mortality (43% vs 49%, p = 0.03) and had fewer days on vasopressors but days of mechanical ventilation did not differ significantly. The role of mineralocorticoid in improving outcomes is unclear. Concerns raised about this trial include long duration of enrollment and high observed mortality in both groups.

PMID: 29490185

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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 following large RCTs found that, compared to early goal-directed therapy, management that does not include continuous central venous O2 monitoring, require central venous pressure monitoring, and entailed less frequent blood transfusions and inotrope use nonetheless produced equivalent outcomes, even without the use of protocolized resuscitation. These results will likely result in modification of future sepsis guidelines.

ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014; 370:1683-93.

PMID: 24635773

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ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014; 371:1496-506.

PMID: 25272316

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Mouncey PR, Osborn TM, Power GS, et al for the ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. New Engl J Med 2015; 372: 1301-1311.

PMID: 25776532

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***For discussion of fluid choice in septic shock, refer to Semler et al under Nephrology Critical Care.

Adjunctive Therapy

Marik PE, Khangoora V, Rivera R et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017; 151:1229-38. A retrospective, single center study of 47 patients with severe sepsis or septic shock found lower hospital mortality in the treatment group (8.5% vs 40.4%). The results, as well as the limitations in the study design, have created a lot of buzz. However, results from a larger confirmatory RCT published in 2020 (Fujii T et al, JAMA 2020; 323:423-31) did not show benefit and the results of additional trials are anticipated in 2020.

PMID: 27940189

Albumin for Fluid Resuscitation

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. In approximately 7000 unselected ICU patients requiring volume administration—including trauma, sepsis, and most other diagnoses—a randomized, blinded study of albumin versus saline found no difference in the primary outcome of 28-day mortality or in secondary outcomes. However, in a subgroup analysis of approximately 1200 patients with severe sepsis, there was a trend toward decreased mortality in the albumin group (relative risk 0.87, p=0.06).

PMID: 15163774

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Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014; 370:1412-21. Multicenter open-label RCT randomized 1,818 patients to daily 20% albumin to maintain a serum albumin > 3 gm/dl plus crystalloids vs. crystalloids alone for the duration of their ICU stay and found no difference in mortality. The albumin group had shorter duration of vasopressor support but duration of mechanical ventilation or need for renal replacement therapy did not differ.

PMID: 24635772

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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

Also see “Ultrasound in the ICU”


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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Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017; 377:419-30. Noteworthy for being the basis for recent FDA approval of a new class of vasopressor. ATHOS-3 trial randomized 321 patients with vasodilatory shock receiving > 0.2 μg/kg/min of norepinephrine or comparable dose of another vasopressor to either angiotensin II or placebo. The primary endpoint was increase in mean arterial pressure of 10 mm Hg or attaining MAP of 75 mmHg at 3 hours without increase in baseline pressor. Angiotensin II achieved this endpoint in 69% vs. 23% for placebo (OR 7.95) but had no effect on 28 day mortality.

PMID: 28528561

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***See also Cardiology Critical Care

Fluid Responsiveness

Teboul JL, Monnet X, Chemla D, et al. Arterial pulse pressure variation with mechanical ventilation. Am J Respir Crit Care Med. 2019;199:22-31. Concise review of use of pulse pressure variation to assess for fluid responsiveness in mechanically ventilated patients including potential pitfalls.

PMID: 30138573

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