A randomized trial of protocol-based care for early septic shock.
Open accessAbstract
BACKGROUND: In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary. METHODS: In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support. RESULTS: We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support. CONCLUSIONS: In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. (Funded by the National Institute of General Medical Sciences; ProCESS ClinicalTrials.gov number, NCT00510835.).
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Early detection and appropriate treatment of sepsis are associated with a significant mortality benefit in hospitalized patients.
“Early detection and appropriate treatment of sepsis have been associated with a significant mortality benefit in hospitalized patients.1,2,3”
From External validation of a widely implemented proprietary sepsis prediction model in hospitalized patients (2021) · cites this paper as [2]
The paper’s introductory passage reports a prior emergency-department study in which a 6-hour treatment protocol significantly reduced mortality among patients with severe sepsis or septic shock. But the ProCESS Discussion says its own trial found no mortality advantage for protocol-based resuscitation over bedside care, and that it did not assess settings where septic shock was not recognized promptly. The source therefore supports a narrower treatment finding, not the broader claim about early detection and treatment in hospitalized patients. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn the PROCESS, ARISE and PROMISE trials, the average volume of fluid received pre-randomization was in the range of 30 mL/kg, suggesting that this fluid volume has been adopted in routine clinical practice.
“In the PROCESS (64), ARISE (65) and PROMISE (66) trials, the average volume of fluid received pre-randomization was also in the range of 30 mL/kg, suggesting that this fluid volume has been adopted in routine clinical practice (67).”
From Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. (2021) · cites this paper as [64]
The observed reductions compare favorably with other sepsis intervention studies.
“The observed reductions in ICU length of stay (1.8 days), mechanical ventilation duration (2.3 days), and 28-day mortality (5.7%) are clinically meaningful and compare favorably with other sepsis intervention studies22,23.”
From Machine learning predicts sepsis deterioration trajectories. (2026) · cites this paper as [23]
The model has a 38% greater mortality reduction than Yealy et al.
“Supplementary Table 8 benchmarks our model against prior studies, demonstrating a 2.1-fold longer lead time than Seymour et al16and a 38% greater mortality reduction than Yealy et al.23.”
From Machine learning predicts sepsis deterioration trajectories. (2026) · cites this paper as Yealy et al.23
The Results > Outcomes passage reports no significant mortality reduction with protocol-based care compared with usual care (19.5% versus 18.9%). The paper does not assess the citing authors’ model or provide a 38% comparison, so its findings cannot verify the claimed benchmark. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe four largest sepsis resuscitation trials administered moderate to large fluid volumes during the first 72 hours.
“The four largest clinical trials in sepsis resuscitation used moderate to large amounts of fluids in the first 72 h.”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [64]
In the ProCESS, ARISE, and ProMISe trials, approximately 7-8 L of fluids were administered in the usual care groups, with a reported low mortality rate.
“ProCESS[64], ARISE [65] and ProMISe [66] administered approximately 7–8 L in the usual care groups with a reported low mortality rate.”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [64]
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- Authors
- The ProCESS Investigators
- Affiliations
- University of Pittsburgh Medical Center (US)
- Corresponding author
- The ProCESS Investigators
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-05
- Volume
- 370
- Issue
- 18
- Pages
- 1683-1693
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4101700
- OpenAlex
- W2104415072
- Cited by
- 2,414
- References
- 23
- Citations by year
- 2026: 81 · 2025: 90 · 2024: 101 · 2023: 129 · 2022: 124 · 2021: 179 · 2020: 193 · 2019: 183 · 2018: 213 · 2017: 292 · 2016: 329 · 2015: 332 · 2014: 158 · 2013: 4 · 2012: 1
- FWCI
- 280.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000005)
- National Institute of General Medical Sciences (P50GM076659)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Hemodynamic Monitoring and Therapy
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Abdominal Surgery and Complications
- Keywords
- septic shock, early goal-directed therapy, protocol-based care, sepsis resuscitation, in-hospital mortality, vasopressors, inotropic agents, blood transfusion, central venous pressure monitoring, emergency department, organ support, usual care comparison, 60-day mortality, 90-day mortality
- MeSH terms
- Adult, Aged, Anti-Bacterial Agents, Blood Transfusion, Cardiotonic Agents, Clinical Protocols, Combined Modality Therapy, Emergency Service, Hospital, Female, Fluid Therapy, Humans, Male, Middle Aged, Resuscitation, Shock, Septic, Vasoconstrictor Agents, Hospital Mortality, Outcome Assessment, Health Care
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