Early, Goal-Directed Therapy for Septic Shock — A Patient-Level Meta-Analysis
Open accessAbstract
BACKGROUND: After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS: We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics. RESULTS: We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS: In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158 .).
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In the PROCESS, ARISE, and PROMISE trials, the average volume of fluid received pre-randomisation was in the range of 30 ml/kg, suggesting 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-randomisation 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 [67]
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References 20 · Cited by 600
Research works printed but not linked: 1
- [9]9. resuscitation for severe sepsis and septic shock: methodology of ProCESS, ARISE, and ProMISe. Intensive Care Med 2013; 39: 1760-75.
- Authors
- The PRISM Investigators
- Affiliations
- Intensive Care National Audit & Research Centre (GB)
- Corresponding author
- The PRISM Investigators
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-06-08
- Volume
- 376
- Issue
- 23
- Pages
- 2223-2234
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2625233900
- Cited by
- 600
- References
- 20
- Citations by year
- 2026: 39 · 2025: 49 · 2024: 61 · 2023: 54 · 2022: 63 · 2021: 57 · 2020: 74 · 2019: 80 · 2018: 78 · 2017: 45
- FWCI
- 59.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
- Funders
- Bristol-Myers Squibb
- Pfizer
- University of Pittsburgh
- Intensive Care Foundation
- National Institute for Health and Care Research (07/37/47)
- Monash University
- National Institutes of Health (GM076659)
- Medical Research Council
- Health Technology Assessment Programme (07/37/47)
- National Health and Medical Research Council (491075, 1021165)
- National Institute of General Medical Sciences (P50GM076659, GM076659)
- 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
- early goal-directed therapy, septic shock, 90-day mortality, usual care, treatment effect heterogeneity, subgroup analysis, intensive care utilization, cardiovascular support, hospital costs, vasopressors, fluid resuscitation, ProCESS trial, ARISE trial, PROMISE trial, individual patient data
- MeSH terms
- Aged, Cardiotonic Agents, Combined Modality Therapy, Cost-Benefit Analysis, Female, Fluid Therapy, Hospitalization, Humans, Infusions, Intravenous, Male, Middle Aged, Resuscitation, Shock, Septic, Vasoconstrictor Agents, Survival Analysis, Randomized Controlled Trials as Topic, Treatment Outcome, Hospital Mortality, Practice Guidelines as Topic, Erythrocyte Transfusion, Quality-Adjusted Life Years
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