Early protocolized care has become the standard since the 2001 trial by Rivers et al, which demonstrated 16% greater survival when patients with severe sepsis or septic shock were treated with a six-hour protocol of early, aggressive goal-directed therapy (EGDT). However, it is unclear which elements of the Rivers protocol are most beneficial. The Protocolized Care for Early Septic Shock (ProCESS) investigators, led by Derek Angus from the University of Pittsburgh, performed a multicenter trial comparing alternative resuscitation strategies for patients with septic shock.
The ProCESS trial was conducted at 31 hospitals in the United States. Central venous oxygen saturation (ScvO2) monitoring equipment was provided by Edwards Lifesciences, but the company did not have any other role in the study. Patients were recruited in the emergency department; they had to be at least 18 years of age and had to meet diagnostic criteria for septic shock (i.e., refractory hypotension, two or more criteria for systemic inflammatory response syndrome, sepsis suspected according to the treating physician). Patients were randomly assigned in a 1:1:1 ratio to EGDT, protocol-based standard-therapy interventions, or usual care. All elements of the original Rivers study (fluids, dobutamine, vasopressors, packed red-cell transfusions, and placement of a ScvO2 catheter) were included in EGDT. Protocol-based therapy recommended less aggressive measures than EGDT, such as a lower hemoglobin threshold (7.5 g/dL), no requirement for a ScvO2 catheter, and use of systolic blood pressure and shock index to address fluid status and hypoperfusion. Patients in the usual-care group were treated by bedside providers who directed all care under no study protocol. The primary outcome of interest was in-hospital death. Secondary outcomes included additional long-term survival outcomes, duration of organ failures and other intensive care unit needs. All patients were analyzed in the groups to which they were randomized. Physicians and clinicians were not blinded to the treatment. Lead investigators could not act as the treating physician in the usual-care group.
Four hundred and thirty-nine patients were enrolled in the EGDT group, 446 in the protocol-based standard-therapy group, and 456 in the usual-care group. All groups were well matched according to demographic and clinical variables. Compliance was high in both protocol groups; 11.9% had protocol violations in the EGDT group and 4.4% had violations in the standard-therapy group. Patients in the protocol groups received a greater amount of fluid overall initially and overall compared to the usual-care group at 72 hours. More vasopressors were used in both of the protocol groups (54.9% in EGDT, 52.2% in standard therapy) compared to the usual-care group (44.1%). The 60-day in-hospital mortality for the combined protocol-based groups did not differ significantly from that in the usual-care group (relative risk, 1.04; 95% confidence interval, 0.82-1.31; P=0.83). Acute renal failure was higher in the standard-therapy group (6%) compared to the EGDT group (3.1%) and the usual-care group (2.8%; P=0.04). More patients in the EGDT group were admitted to intensive care units compared to the other groups. There were no significant differences in other secondary outcomes between the groups. Reported adverse events did not differ significantly across the study groups.
In this study, where adherence to two different protocols was relatively high, there was no difference in mortality rates. This study was not a direct replication of the study by Rivers et al, although elements of modern sepsis care — early recognition of sepsis, early antibiotic administration, steroids, initial fluid administration, and other intensive care unit interventions — were present in all three groups. The 60-day mortality in the participating hospitals was fairly low (18% to 21%), perhaps indicating that the standard of care for sepsis at these centers was already high. In this study, the use of ScvO2 catheters is called into question, since patients in the EGDT did not have better outcomes when these catheters were used to guide therapy. Readers are encouraged to review an excellent editorial by Craig M. Lilly, as well as the vibrant and insightful online discussions related to this study at the EMCrit and ALiEM blogs.
Samuel M. Galvagno Jr., DO, PhD, is editor of Concise Critical Care Appraisal. An assistant professor at the University of Maryland, R Adams Cowley Shock Trauma Center, he is board certified in anesthesiology, critical care medicine and public health.