Critical & Organ Care · 2001
Rivers Early Goal-Directed Therapy for Sepsis
Early Goal-Directed Therapy (EGDT) in severe sepsis and septic shock
Sepsis management in the 1990s was supportive and largely reactive. Clinicians gave fluids, started vasopressors when blood pressure fell, and treated the source. There was no widely accepted protocol that defined what resuscitation should look like in the first hours, and mortality from severe sepsis and septic shock remained in the range of 40 to 50% at most centers. Emanuel Rivers, an emergency physician at Henry Ford Hospital in Detroit, hypothesized that correcting tissue oxygen delivery deficits before organ dysfunction became established, rather than after admission to the ICU, could change outcomes.
Rivers and colleagues randomized 263 patients presenting to the Henry Ford emergency department with severe sepsis or septic shock to a six-hour protocolized resuscitation bundle or to standard care. The bundle targeted specific physiologic endpoints in sequence: central venous pressure of 8 to 12 mmHg through fluid loading, mean arterial pressure of 65 mmHg or above with vasopressors, and central venous oxygen saturation of at least 70% achieved through packed red cell transfusion or dobutamine as needed. In-hospital mortality was 30.5% in the EGDT group versus 46.5% in controls. The paper appeared in the New England Journal of Medicine in 2001 and generated immediate wide adoption.
The Surviving Sepsis Campaign, launched in 2002, translated EGDT into international guidelines and into sepsis bundles that hospitals were encouraged to implement. Central venous catheters for ScvO2 monitoring became a standard part of early sepsis care in many institutions. The protocol gave structure to what had been variable, physician-dependent resuscitation, and the substantial mortality reduction in the original trial gave clinicians a clear rationale for front-loading aggressive treatment.
Three multicenter trials published between 2014 and 2015 tested EGDT against usual care in larger populations. ProCESS, led by Derek Angus at the University of Pittsburgh, enrolled 1,341 patients. ARISE enrolled 1,600 patients at 51 sites in Australia and New Zealand. ProMISe enrolled 1,260 patients across 56 NHS hospitals in England. Taken together, the three trials randomized more than 4,200 patients and none found a mortality benefit for protocolized EGDT compared with usual care, which by then had incorporated early antibiotics, fluids, and careful hemodynamic attention without the rigid ScvO2 targets.
The divergence between the original result and the replication trials was debated extensively. The most plausible explanation was that usual care had improved substantially in the intervening decade, narrowing the gap that EGDT had originally exploited. The Surviving Sepsis guidelines were revised to retain early antibiotics and fluid resuscitation while removing mandated central venous monitoring targets for ScvO2. The episode entered the literature on trial design as a clear illustration of how single-center trials of complex interventions can overestimate treatment effects when usual care in the control arm is of lower quality than what becomes standard practice by the time replication is attempted.
Key People
- Emanuel Rivers — Emergency physician at Henry Ford Hospital; designed and led the EGDT trial
- Derek Angus — Principal investigator of the ProCESS trial that challenged EGDT
- Rinaldo Bellomo — Principal investigator of the ARISE trial; University of Melbourne intensivist
N Engl J Med. 2001
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