Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension
Summary by Boris Ladyzhensky MD, 7.9.23
https://www.nejm.org/doi/full/10.1056/NEJMoa2212663
CLOVERS Trial
Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis
Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension
Clinical Hypothesis: A restrictive fluid strategy used during the first 24 hours of resuscitation for sepsis-induced hypotension would lead to lower mortality before discharge home by day 90 than a liberal fluid strategy.
Take Home Message:
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.
There is currently no strong evidence to support one strategy over the other.
As is usually the case, further research is needed.
The administration of vasopressors through peripheral IVs may facilitate earlier use of these agents compared to the traditionally preferred CVC route.
Summary:
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.
Study Design: Multicenter, randomized, un-blinded superiority trial
Methods: Over roughly 4 years, 1563 patients at 60 U.S. centers were enrolled and randomly assigned in a 1:1 ratio to either a restrictive fluid strategy (with early vasopressor use) or a liberal fluid strategy; in each group, the assigned protocol was followed for a period of 24 hours. They sought to detect an absolute between-group difference of 4.5 percentage points in the incidence of death before discharge home by day 90 (the primary outcome), assuming death would occur in 15% of the patients in the liberal fluid group and in 10.5% of those in the restrictive fluid group. Therefore, a total sample of 2320 patients would need to be enrolled in order for the trial to have 90% power at an overall two-sided alpha level of 0.05. In addition, the design incorporated prespecified criteria to stop the trial for efficacy in either group or for futility.
Inclusion criteria: Patients over 18yo with a suspected or confirmed infection (broadly defined as the administration or planned administration of antibiotic agents) and sepsis-induced hypotension (SBP <100 after the administration of ≥1000 ml of intravenous fluid.)
Exclusion criteria: Key exclusion criteria were an elapse of more than 4 hours since the meeting of the criteria for hypotension refractory to the intravenous administration of at least 1 L of fluid, an elapse of more than 24 hours since presentation at the hospital, previous receipt of more than 3 L of intravenous fluid during this episode (including prehospital administration of fluid by emergency medical services), the presence of fluid overload, and severe volume depletion from non-sepsis causes.
Primary outcome: Death from any cause before discharge home by day 90, where home was defined as the same or similar setting to the one where the patient resided before becoming ill.
Secondary outcome: 28-day measures of the number of days free from ventilator use, days free from renal-replacement therapy, days free from vasopressor use, days out of the ICU, and days out of the hospital.
Results: The data and safety monitoring board recommended the halting of the trial for futility at the second interim analysis owing to a lack of between-group differences in the primary and secondary outcomes. 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); The number of reported serious adverse events was similar in the two groups.
Discussion/conclusion:
In this trial involving patients with sepsis-induced hypotension refractory to initial treatment with 1 to 3 L of intravenous fluid, they found that a restrictive fluid strategy (with earlier vasopressor use) did not result in significantly lower (or higher) mortality before discharge home by day 90 than a liberal fluid strategy. There were several limitations to the study, most notably the following:
Due to the nature of the ICU, some patients in the restrictive group received more fluid that intended by the protocol, and vice versa.
Pre-existing conditions were not taken into account, meaning the restrictive or liberal strategies might be best applied to certain patient subgroups over others.
The trial was un-blinded, which could influence the reporting of outcomes and adverse events.
The protocol duration was up to 24h. Longer durations of treatment may have produced different results.
All patients in the trial were diagnosed early after hospital presentation. The findings may not be generalizable to patients who were diagnosed in the later stages of sepsis.