A History of the Sepsis Trials

This month’s critical care mini-fellowship discussion was about the article, “Timing of Vasopressors in Septic Shock” as well as a review of the recent PROCESS, ARISE and PROMISE trials.

Overall mortality rates in septic shock improved significantly from the 1990s to 2012 which coincides with several changes of practice including the Surviving Sepsis Campaign and the Rivers trial.

In 2001, Rivers found that “Early Goal-directed Therapy (EGDT) decreased the risk of mortality among patients with severe sepsis or septic shock. In the EGDT arm, in-hospital mortality was 30.5% compared to 46.5% for the standard therapy group (P.009, NNT=6). Rivers recommended a strict sequential protocol for patients in the ED prior to their ICU admission including placement of a central line with a CVP goal of 8-12 mmHg achieved with intravenous fluid boluses, a MAP > 65mmHg achieved with pressors if necessary, Scv02 > 70% achieved with blood transfusions if necessary to bring hematocrit up to 30 and urine output greater than 0.5mg/kg/hour.

The PROCESS trial in 2014 was the first of the three studies to compare the effectiveness of EGDT to usual care and found no difference in mortality at the time of follow-up between treatment arms. Critics of this trial note that the study centers were disproportionately academic centers where using lactate to monitor sepsis was already “usual care.” The results of PROCESS are echoed by the ARISE and PROMISE trials. But before we put EGDT out to the pasture, we should consider what “usual care” for septic shock has become to modern ED physicians. According to these data, early recognition and treatment with antibiotics along with aggressive fluid resuscitation with or without pressors were not significantly different between the study arms suggesting that even without strict protocols, ED physicians’ “usual care” and EGDT are quite similar nowadays.  These data also suggest that some of  EGDT such as mandated Sv02 monitoring and CVC do not confer mortality benefits to patients and can therefore be safely left up to the physician’s discretion.

Finally,”Timing of Vasopressor Initiation and Mortality in Septic Shock” was a well-powered cohort study that looked at whether early correction of MAP to > 65 mmHg with vasopressors was associated with improved survival in septic shock. We were intrigued by the hypothesis of this paper and its large sample size (6,514 patients) of sick (mean APACHE score 26.1) patients, however were underwhelmed by its conclusion. The authors trended mortality by each hour of delay to the start of pressors. The median time to vasopressor initiation was 3 hours. There was no significance in the OR for survival by time to pressors until 14 hours! Secondary outcomes were not significant, including hospital length of stay, duration of pressor therapy and of duration of ventilator support. While the results of this study are unlikely to change practice management (nobody is going to wait 13 hour to start pressors in septic shock), it does raise the interesting question as to whether a mild permissive hypotension, for example, MAP 60-65, may be adequate to maintain organ perfusion in patients with relative contraindications for aggressive inotrope therapy (such as CAD) or aggressive fluid resuscitation (CHF).

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wendyrollerblades

Senior EM Resident at SUNY Downstate / Kings County Hospital, EM/Critical Care Blogger, Medical Student Education Curriculum Co-Chair, has a blackbelt in "keepin' it real"

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