A Randomized Trial of Protocol-Based Care for Early Septic Shock

Published - Written by Daniela Lamas

Over a decade ago, a trial revolutionized how patients with septic shock are treated in the early hours of their hospital stay.

In 2001, with the premise that existing interventions in septic shock occur too late in a patient’s course, Emanuel Rivers and colleagues reported that patients treated in the emergency department with a protocol called ‘early goal directed therapy’ (EGDT) were significantly more likely to survive than those treated with the standard of care at the time.

“EGDT saves lives” became the key commandment of emergency care for patients in septic shock. The protocol’s mandates – specifically central venous catheterization and monitoring of invasively obtained oxygen saturation measurements to guide intravenous fluids, blood transfusions, vasopressors and inotropic medications – were incorporated into hospital protocols and sepsis campaigns worldwide.

But in the years since, follow-up studies have called certain aspects of this protocol into question. For instance, while Rivers recommended blood transfusion to a hematocrit goal of 30, more recent studies have suggested that such high goals might actually be harmful. More recently, researchers demonstrated that trending blood tests like lactate levels might be just as good a gauge of resuscitation as the numbers taken from an invasively placed central venous catheter.  Clearly, EGDT demonstrated that early attention to patients in septic shock is key. But a question remained: Do we really need to follow each component of Rivers’ initial protocol to save lives from septic shock?

According to a study published in this week’s issue of NEJM, we don’t. To address this question, researchers randomly assigned over 1300 patients with septic shock to one of three groups, which would determine their management for the first six hours of their hospital stay. One third of the patients were managed according to an EGDT protocol based on the Rivers study.  A second group would be managed with a different algorithm– termed protocol-based standard therapy –based on standard of care as described by intensive care and emergency physicians worldwide. That protocol differed from the Rivers protocol in that it relied more on clinical judgment of volume status instead of invasive monitoring. For example, patients would receive fluid based on clinical parameters rather than to target a goal number, and would undergo central line placement only if their caregivers did not think they could be managed with peripheral IVs. Blood transfusions were targeted to a hemoglobin goal of 7.5 grams/deciliter.  The third group would receive ‘usual care’ at their institution, without prompts or protocols. All other aspects of management – like antibiotic administration and mechanical ventilation – were left to the discretion of the medical team.

Patients randomly assigned to protocol-based standard therapy received the greatest amount of IV fluid during the first 6 hours, 3.3 liters, compared to 2.3 liters in the usual care group and 2.8 liters in the EGDT group. While greater than 90 percent of patients in the EGDT therapy group had a central line placed in the first six hours, just over half of the other groups underwent this procedure. Invasively obtained oxygen saturations were monitored in nearly all of the patients randomly assigned to EGDT, but in fewer than five percent of the patients in the other two groups. Finally, patients randomly assigned to EGDT were more likely to receive blood transfusions and dobutamine than either of the other two groups.

Did the difference seen in Rivers’ trial hold up? While treatment differed between groups, mortality did not. At sixty days, 21 percent of patients in the EGDT group had died, 18.2 percent of the protocol-based standard therapy group and 18.9 percent of the group receiving usual care. These mortality rates were all significantly lower than the 47 and the 31 percent mortality seen in the usual care  and intervention arms of Rivers’ trial.  There was no mortality difference between groups at ninety days or one year, nor was there any difference in whether patients were discharged home or to rehab facilities.

In an accompanying editorial, Craig Lilly notes that these results should not be interpreted to say that protocols have no role in the treating septic shock. Instead, he notes, the similar outcomes between groups – including those who received usual care at their institutions – is a testament to the lasting power of Rivers’ results in disseminating the key role of early diagnosis and treatment for patients in septic shock. Perhaps invasive interventions like central lines aren’t necessary for all patients, but timely attention to the patient’s fluid status, quick dosing of antibiotics and determination of when to start vasopressors are. This trial, Lilly concludes, “identifies early recognition of sepsis, early administration of antibiotics, early adequate volume resuscitation, and clinical assessment of the adequacy of circulation as the elements we should focus on to save lives.”

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