Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis.
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.



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.



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.



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 .).
Intensive Care National Audit and Research Centre, London, United Kingdom
Kathryn M
KM
Rowan
University of Pittsburgh School of Medicine, Pittsburgh
Derek C
DC
Angus
Monash University, Melbourne, VIC, Australia
Michael
M
Bailey
University of Pittsburgh School of Medicine, Pittsburgh
Amber E
AE
Barnato
Monash University, Melbourne, VIC, Australia
Rinaldo
R
Bellomo
Intensive Care National Audit and Research Centre, London, United Kingdom
Ruth R
RR
Canter
University of Leicester, Leicester, United Kingdom
Timothy J
TJ
Coats
University of Sydney, Sydney, Australia
Anthony
A
Delaney
University of Pittsburgh School of Medicine, Pittsburgh
Elizabeth
E
Gimbel
London School of Hygiene and Tropical Medicine, London, United Kingdom
Richard D
RD
Grieve
Intensive Care National Audit and Research Centre, London, United Kingdom
David A
DA
Harrison
Monash University, Melbourne, VIC, Australia
Alisa M
AM
Higgins
Monash University, Melbourne, VIC, Australia
Belinda
B
Howe
University of Pittsburgh School of Medicine, Pittsburgh
David T
DT
Huang
University of Pittsburgh School of Medicine, Pittsburgh
John A
JA
Kellum
Intensive Care National Audit and Research Centre, London, United Kingdom
Paul R
PR
Mouncey
University of Pittsburgh School of Medicine, Pittsburgh
Edvin
E
Music
Monash University, Melbourne, VIC, Australia|University of Adelaide, Adelaide, SA, Australia|Queen Elizabeth Hospital, Adelaide, SA, Australia
Sandra L
SL
Peake
Eli Lilly, Indianapolis
Francis
F
Pike
University of Queensland, Brisbane, Australia
Michael C
MC
Reade
London School of Hygiene and Tropical Medicine, London, United Kingdom
M Zia
MZ
Sadique
University College London, London, United Kingdom
Mervyn
M
Singer
University of Pittsburgh School of Medicine, Pittsburgh
Donald M
DM
Yealy
D000368:Aged; D002316:Cardiotonic Agents / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003362:Cost-Benefit Analysis; D017707:Erythrocyte Transfusion; D005260:Female; D005440:Fluid Therapy; D017052:Hospital Mortality; D006760:Hospitalization / Q000191:economics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D019057:Quality-Adjusted Life Years; D016032:Randomized Controlled Trials as Topic; D012151:Resuscitation / Q000191:economics / Q000379:methods*; D012772:Shock, Septic / Q000401:mortality / Q000628:therapy*; D016019:Survival Analysis; D016896:Treatment Outcome; D014662:Vasoconstrictor Agents / Q000627:therapeutic use*
D002316:Cardiotonic Agents; D014662:Vasoconstrictor Agents