The pooled results of three randomized trials indicate no overall benefit from early goal-directed therapy for septic shock.
While some observational studies have suggested that early, goal-directed therapy (EGDT) helps reduce mortality from septic shock, three multicenter trials—ProCESS, ARISE, and ProMISe—showed no benefit from this therapy.
Pooling the Data
To gain a better understanding of the treatment effect of EGDT, David T. Huang, MD, MPH, and colleagues conducted a prospective, individual patient-level meta-analysis, which combined data from all three trials that were used to determine the effect of EGDT compared with usual care on outcomes and to compare the effect of EGDT across pre-specified patient and care-delivery subgroups. Results of the research, dubbed the Protocolized Resuscitation in Sepsis Meta-Analysis (PRISM) study, were published in The New England Journal of Medicine.
“After the ProCESS, ARISE, and ProMISe trials were published and showed no benefit from EGDT, residual questions still remained,” says Dr. Huang. “In particular, published editorials wondered if EGDT might still be beneficial in the most severely ill, and if the lack of benefit over usual care seen in ProCESS, ARISE, and ProMISe was because usual care now appeared to include aggressive early fluid resuscitation.”
For the study, entry criteria, intervention protocols, outcomes, resource-use measures, and data collection were harmonized across the three trials, with all analyses specified before unblinding. Once the trials were complete, data were pooled— excluding the protocol-based standard-therapy group from the ProCESS trial—and residual differences were resolved. The primary outcome was 90-day mortality, and secondary outcomes included 1-year survival, organ support, and hospitalization costs. Dr. Huang and colleagues tested for treatment-by-subgroup interactions for 16 patient characteristics and six care-delivery characteristics.
No Evidence of Benefit
Among 3,723 patients at 138 hospitals in seven countries, mortality at 90 days was similar for EGDT (24.9%) and usual care (25.4%). EGDT was associated with greater mean use of intensive care (5.3 vs 4.9 days) and cardiovascular support (1.9 vs 1.6 days) than was usual care. 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.
Duration of stay in the intensive care unit (first admission and total days) and receipt of cardiovascular support (both percentage of patients and duration) were greater in the EGDT group than in the usual-care group. There was no significant difference in the duration of survival to 1 year between the group that received EGDT and the group that received usual care (Figure).
“We found no evidence of benefit overall or in any subgroup, including subgroups with the highest severity of illness, using multiple definitions of illness severity,” says Dr. Huang. “We also found that while there was considerable variation in usual care intensity—defined as site propensity to administer vasopressors and intravenous fluids in usual care—there was no evidence of benefit at sites providing less aggressive resuscitation in usual care.”
Dr. Huang also points out that every patient in these three trials had early recognition and treatment, (with early lactate screening, IV fluids, and antibiotics), which could help explain part of their findings in the general advances in sepsis care. “The PRISM study did not test whether early recognition was better than late, nor whether prompt care was better than delayed,” Dr. Huang adds. “We therefore believe PRISM does not undermine efforts to promote sepsis awareness, diagnose early, and treat early, and we all agree on the need for early recognition and care of sepsis.”
Dr. Huang says that future research should be directed toward novel therapies and diagnostics, including better phenotyping of sepsis given the heterogeneity of sepsis, and embedding clinical research into routine clinical care to provide faster, better answers for patients and clinicians (ie, a “learning healthcare system”).
Rowan K, Angus D, Huang D. Early, Goal-Directed Therapy for Septic Shock — A Patient-Level Meta-Analysis. N Engl J Med. 2017;376:2223-223. Available at: www.nejm.org/doi/full/10.1056/NEJMoa1701380#t=article