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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Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021; 49:e1063-e1143. The 93 recommendations do not depart dramatically from the 2017 guidelines. Includes additional guidance on timing of antibiotics in patients with possible sepsis without shock and lower suspicion of sepsis.
PMID: 34605781


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but subsequently compared only hydrocortisone-fludrocortisone to placebo in 1,241 patients after drotrecogin was withdrawn from the market in 2011.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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Kumar A, Roberts D, Wood KE et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006; 34: 1589-1596.  This landmark retrospective cohort study of 2,731 patients helped establish septic shock as a medical emergency.  Effective antimicrobial administration within the first hour of documented hypotension was associated with increased survival to hospital discharge. Each hour of delay in antimicrobial administration was associated with an average decrease in survival of 7.6%. This study demonstrated the need for timely antibiotics in septic shock, which was later confirmed in multiple other studies.
PMID: 16625125

Kyriazopoulou E, Liaskou-Antoniou L, Adamis G, et al. Procalcitonin to reduce long-term infection-associated adverse events in sepsis: a randomized trial. Am J Respir Crit Care Med. 2021; 203:202-210. Multicenter trial of 266 septic patients, of whom 61% had pneumonia and 7% septic shock, found the procalcitonin-guided group had reduced median antibiotic duration by 5 days and reduced subsequent risk of a composite of infection or death from C. difficile colitis and MDR organisms (7.2 vs 15.2%). Surprisingly, the procalcitonin-guided group also had lower 28-day mortality (15.2 vs 28.2%).
PMID: 32757963
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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.
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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The National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network. Early restrictive or liberal fluid management for sepsis-induced hypotension. N Engl J Med. 2023; 388: 499-510. An unblinded multicenter superiority trial assigned 1563 patients with sepsis-induced hypotension to a restrictive fluid strategy (prioritizing vasopressors) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids) for 24 hours. The majority of patients were enrolled from the emergency department, and both groups received 2L of fluid prior to randomization. 2L less fluid was administered overall in the restrictive fluid group. All-cause mortality before discharge home by day 90 was similar between groups as were adverse events. Notably, this trial was halted early for futility. An additional important note is that 500 patients received vasopressors via peripheral catheters with no significant complications, adding to growing literature suggestive of safety of this practice.
PMID: 36688507

Meyhoff TS, Hjortrup PB, Wetterslev J, et al; CLASSIC Trial Group. Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med. 2022; 386:2459-2470. There is concern that excessive fluid resuscitation worsens outcomes in septic shock. This RCT of over 1,500 patients found no difference in 90-day mortality or adverse events with use of a restrictive fluid strategy.  Of note, both groups had received 3 liters of fluid on average prior to enrollment and the difference between restrictive and usual care was only 2 liters following enrollment. One concern raised is that the usual care arm was more restrictive than typical practice.
PMID: 35709019

***For discussion of crystalloid fluid choice in septic shock, refer to Nephrology Critical Care.

Adjunctive Therapy:

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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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

Hemodynamic Monitoring:

Vincent JL, Joosten A, Saugel B. Hemodynamic monitoring and support. Crit Care Med. 2021; 49:1638-1650.
This review provides historical and contemporary perspectives on hemodynamic monitoring methods in critically-ill patients, including evidence supporting, or not supporting, their use.
PMID: 34269718