ProCESS

ProCESS
Name	ProCESS
Full name	Protocolized Care for Early Septic Shock
Acronym	ProCESS
Phase	Randomized controlled trial
Start date	2008
Completion date	2013
Locations	United States
Principal investigators	Christopher W. Seymour, John D. Williams, John C. L. Vincent
Sponsor	National Heart, Lung, and Blood Institute

ProCESS is a multicenter randomized controlled trial that compared different strategies for early management of septic shock in adults. Conducted in diverse United States emergency departments and intensive care units, the trial evaluated protocol-based resuscitation against usual care and focused on whether an invasive, algorithmic approach improved mortality. ProCESS built upon earlier landmark studies and debates involving clinicians and institutions concerned with sepsis care pathways.

Background

Sepsis and septic shock had become prominent issues after influential reports and campaigns by organizations such as Surviving Sepsis Campaign, Institute of Medicine, and Centers for Disease Control and Prevention. Prior to ProCESS, the 2001 single-center study by R. M. Rivers and colleagues introduced goal-directed therapy that relied on invasive monitoring; this prompted guideline recommendations from bodies including American College of Chest Physicians and Society of Critical Care Medicine. Controversies involving implementation in systems led to policy actions in places like New York State and scrutiny from investigators at Emory University, Vanderbilt University Medical Center, and Brigham and Women's Hospital. Funding and oversight from National Heart, Lung, and Blood Institute enabled a pragmatic trial to test generalizability across institutions such as University of Pittsburgh Medical Center and Massachusetts General Hospital.

Study Design

ProCESS used a multicenter, randomized, three-arm parallel-group design enrolling adults with suspected infection, systemic inflammatory response, and refractory hypotension after initial fluid challenge. Sites included a network of academic and community hospitals affiliated with institutions such as University of Pennsylvania, Columbia University, and Stanford University Medical Center. The trial compared protocol-based early goal-directed therapy with protocol-based standard therapy and usual care, with stratification and randomization overseen by coordinating centers at Beth Israel Deaconess Medical Center and monitored by a data safety and monitoring board including members from Johns Hopkins University and Duke University Medical Center. Primary outcomes, sample size, and statistical plans were prespecified with input from experts at University of California, San Francisco and Mayo Clinic.

Interventions

One arm implemented the original invasive algorithm popularized by R. M. Rivers—a protocol requiring central venous catheter placement, central venous pressure (CVP) and central venous oxygen saturation (ScvO2) targets, and stepwise use of fluids, vasopressors, inotropes, and blood transfusion. A second arm used a simplified protocolized approach without mandated ScvO2 monitoring, emphasizing fluid resuscitation and hemodynamic targets with interventions guided by bedside measurements familiar to clinicians at Cleveland Clinic and University of Chicago Medical Center. The third arm was usual care, allowing clinicians at sites such as Barnes-Jewish Hospital and Henry Ford Hospital to manage patients according to local practice and contemporary guidelines from Surviving Sepsis Campaign and recommendations from National Institutes of Health panels. Training, equipment, and audit processes involved collaboration with personnel from American Board of Internal Medicine and clinical educators from Harvard Medical School.

Outcomes and Results

The primary outcome was 60-day all-cause mortality, with secondary outcomes including ICU-free days, organ dysfunction scores, length of stay, need for mechanical ventilation, and resource utilization. ProCESS enrolled thousands of participants across centers including Yale-New Haven Hospital and Northwestern Memorial Hospital. The trial found no significant difference in 60-day mortality among the invasive protocol, the simplified protocol, and usual care arms, a result that resonated with contemporaneous trials such as ARISE and ProMISe. Secondary outcomes including ICU-free days and organ-support duration similarly showed no clinically meaningful differences. Subgroup analyses involving age cohorts, comorbidity profiles, and source of infection involving specialists from Mayo Clinic and Cleveland Clinic did not identify consistent benefit for protocolized invasive monitoring.

Interpretation and Impact

ProCESS influenced guideline committees at institutions such as Surviving Sepsis Campaign and prompted reassessment of recommendations from organizations like American College of Emergency Physicians and Critical Care Societies Collaborative. The findings suggested that contemporary usual care—shaped by rising awareness, early antibiotics, and aggressive fluid resuscitation promoted by centers such as SUNY Downstate and Vanderbilt University—might achieve outcomes comparable to protocolized invasive strategies. Policymakers and hospital systems, including those in New York State and networks like Kaiser Permanente, re-evaluated mandates for invasive monitoring in early septic shock pathways. The trial also stimulated further comparative effectiveness research at centers including Oxford University Hospitals and Imperial College London.

Criticisms and Limitations

Critics noted that ProCESS, while pragmatic, enrolled patients in an era when baseline care had evolved, potentially reducing the detectable effect size compared to earlier single-center trials such as the one by R. M. Rivers. Some commentators from Johns Hopkins University and University of Pittsburgh argued about adherence variability across sites and potential selection biases related to enrollment timing in busy emergency departments like those at Mount Sinai Hospital. Others highlighted limited power for certain subgroups and debated generalizability to low-resource settings described by researchers at World Health Organization partner sites. Methodologists from Cochrane Collaboration and Agency for Healthcare Research and Quality discussed trade-offs between internal validity and pragmatic applicability, while ethicists at Georgetown University and University of Toronto weighed the procedural risks of mandated central venous catheterization.

Category:Clinical trials