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Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension
, Nathan I Shapiro1, Ivor S Douglas1
1From the Department of Emergency Medicine, Beth Israel Deaconess Medical Center-Harvard Medical School (N.I.S.), the Biostatistics Center (D.H., W.H., P.L.) and the Department of Medicine (K.O., N.R., B.T.T.), Massachusetts General Hospital, and the Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center (D.T.), Boston, and the Department of Medicine, Baystate Medical Center, Springfield (J.S.S.) - all in Massachusetts; the Department of Medicine, Denver Health Medical Center, Denver (I.S.D.), and the Department of Emergency Medicine, University of Colorado School of Medicine, Aurora (A.A.G.) - both in Colorado; the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore (R.G.B., T.J.I.); the Department of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Murray, and the Department of Medicine, University of Utah, Salt Lake City - both in Utah (S.M.B., C.K.G.); the Ohio State University Wexner Medical Center, Columbus (M.C.E.); the Department of Medicine, Montefiore Medical Center, Bronx, NY (M.N.G.); the Department of Medicine, Oregon Health and Science University, Portland (C.L.H., A.K.); the Department of Emergency Medicine, University of Mississippi Medical Center, Jackson (A.E.J.); the Department of Medicine, University of California, San Francisco, Medical Center, San Francisco (K.D.L.); the Department of Emergency Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC (C.D.M.); the Department of Surgery, University of Michigan Medical School, Ann Arbor (P.K.P.); the Departments of Medicine (T.W.R., M.W.S.) and Emergency Medicine (W.H.S.), Vanderbilt University Medical Center, Nashville; and the Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh (D.M.Y.).
Background:
Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited.
Methods:
In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed.
Results:
A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups.
Conclusions:
Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).
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