Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension

Abstract

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.).

Figure 1.. Fluid and Vasopressor Administration Protocols in the Restrictive Fluid Group and the Liberal Fluid Group.

Panel A shows the instructions for intravenous (IV) fluid and vasopressor administration in the restrictive fluid group, and Panel B the instructions in the liberal fluid group. In both trial groups, all protocol assessments, such as frequency of vital-sign monitoring, lactic acid measurements, and echocardiographic interventions, were performed at the discretion of the clinical team. The restrictive fluid protocol suggested norepinephrine as the primary vasopressor and epinephrine as a second vasopressor; neither was required. The restrictive fluid protocol defined “echocardiographic or hemodynamic evidence of extreme hypovolemia” as a maximal diameter of the inferior vena cava (IVC) of less than 5 mm, an empty left ventricle on echocardiography (e.g. left ventricular end diastolic area index, <5.5 cm² per square meter of body-surface area), or stroke-volume increase of more than 30% in response to a passive leg raise, fluid challenge, or positive-pressure breaths. KVO denotes keep vein open, and MAP mean arterial pressure. The liberal fluid protocol instructed that patients receiving vasopressors should have the dose adjusted down or vasopressors discontinued, as feasible. The protocol included an instruction that care team members could use any available “measured assessment” they chose (e.g. echocardiography, IVC measurement, or central venous pressure measurement) or any type of “clinical assessment” of volume status to trigger use of additional fluids. If a patient had manifestations of fluid overload, fluids were to be halted. The liberal fluid protocol also expressly permitted the use of vasopressors after the administration of 5 liters of total fluid.

Figure 2.. Subgroup Analysis for the Primary Outcome.

The primary outcome was death from any cause before discharge home by day 90. Estimates were from Kaplan–Meier curves. Confidence intervals have not been adjusted for multiplicity and may not be used for hypothesis testing. Race and ethnic group were reported by the patients or their legal representative. Sequential Organ Failure Assessment (SOFA) scores range from 0 to 20, with higher scores indicating greater severity. For the purposes of subgroup analysis, subgroups were assessed in quartiles, with quartile 1 including patients with a SOFA score of 0 or 1, quartile 2 those with a score of 2, quartile 3 those with a score of 3 to 5, and quartile 4 those with a score of 6 or higher. (In the trial, the highest SOFA score observed was 16.) ICU denotes intensive care unit.