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For Septic Shock, Another Toss-up Between Emphasizing Vasopressors Vs Fluids

SAN FRANCISCO — For sepsis-induced hypotension, a restrictive fluid strategy with earlier vasopressor use didn’t impact mortality compared with liberal fluids, the CLOVERS trial showed.

The restrictive strategy had its intended effect, reducing median IV fluids administered over 24 hours by 2,134 mL in favor of more vasopressor use compared with the liberal fluids strategy among 1,563 patients refractory to initial treatment with 1 to 3 L of IV fluid, according to Nathan I. Shapiro, MD, MPH, of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston.

However, all-cause, 90-day mortality before discharge home differed by less than a percentage point between the two strategies (14.0% restrictive vs 14.9% liberal fluid strategy, P=0.61), he reported at the Society of Critical Care Medicine Critical Care Congress. The findings were simultaneously published online in the New England Journal of Medicine.

“The results of the CLOVERS trial suggest that for the types of patients enrolled in this trial, the prioritization of either a vasopressor-predominant or fluid-predominant approach resulted in similar patient-centered outcomes,” Shapiro and colleagues concluded.

The findings concurred with those of the CLASSIC trial, in which a restrictive fluid protocol had no impact on 90-day all-cause mortality compared with a standard, more liberal fluid approach among septic shock patients already admitted to the ICU after initial resuscitation with 1 L of fluids.

One difference between the trials was patient population, with CLOVERS enrolling almost exclusively patients who presented to a hospital emergency department (ED) with sepsis (about two-thirds thereafter being admitted to the ICU), whereas most patients in CLASSIC came to the ICU from a hospital ward (34%) or the operating room (23%).

CLOVERS also excluded patients for whom the treatment approach could be clearly guided by clinical circumstances. Clinicians had to approve patient participation, so those with extremes of volume overload or volume depletion deemed not eligible for randomization would not have been enrolled, the researchers noted.

The results wouldn’t be generalizable to such patients, they added, although the enrolled population was broadly representative of patients who present to the ED with sepsis-induced hypotension.

No patient characteristics predicted better outcomes with one strategy versus another.

The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial included 1,563 adults (age about 60; less than half female; predominantly white) seen at 60 U.S. centers who were enrolled within 4 hours of meeting criteria for sepsis-induced hypotension (<100 mm Hg systolic) refractory to initial treatment with 1 to 3 L of IV fluid. They were randomly assigned to a fluid strategy administered open label for 24 hours.

In the restrictive fluid protocol, the primary treatment prioritized vasopressors. After patients got up to 2 L of fluid, including what was given prerandomization, then the norepinephrine dose was adjusted to achieve a mean arterial pressure of at least 65 mm Hg, with a second vasopressor added if needed. Rescue fluids were given for specified indications indicative of severe intravascular volume depletion, with a preference for 500 mL boluses.

In the liberal fluid protocol, patients got an initial liter of isotonic crystalloid after randomization, then another liter if not yet volume replete based on clinical signs and if heart rate and blood pressure didn’t normalize. Additional fluid boluses were given if triggered clinically, such as due to tachycardia. If still meeting criteria, “rescue vasopressors” were allowed.

While pre-randomization strategies were similar between groups (median 2,050 mL fluid and about 20% getting vasopressors), that quickly changed after randomization. In the first 6 hours on the protocol, the restrictive group got a median of 500 mL of fluid compared with 2,300 mL in the liberal group; by 24 hours, the groups averaged 1,267 and 3,400 mL, respectively.

Vasopressors showed the same pattern, with 59% versus 37% of the patients getting them. They were also started a mean of 1.4 hours earlier and used for a mean of 4.2 hours longer over the first 24 hours in the restrictive fluids group.

Protocol adherence was nearly 100% in both groups.

None of the secondary endpoints showed an advantage to one strategy over the other, including number of days free from organ-support therapy, from renal-replacement therapy, from vasopressor use, or out of the ICU or hospital at 28 days.

Serious adverse events (AEs) likewise were similar between groups overall, although there were fewer involving fluid overload or pulmonary edema in the restrictive fluid group (both 0 vs 3 cases).

Limitations included the potential for bias in ascertainment and reporting of AEs and that “potentially important subgroups (including patients with specific coexisting conditions for which data were not collected in this trial)” were not assessed.

“Finally, we evaluated patients with sepsis-induced hypotension that was recognized early after hospital presentation,” Shapiro’s group noted. “These findings may not be generalizable to patients with delayed recognition of sepsis-induced hypotension or who are in the later phases of care.”


The trial was funded by the National Heart, Lung, and Blood Institute.

Shapiro disclosed relationships with Diagnostic Robotics, Inammatix, Prenosis, and Rapid Pathogen Screening.

Primary Source

New England Journal of Medicine

Source Reference: Shapiro NI, et al “Early restrictive or liberal fluid management for sepsis-induced hypotension” N Engl J Med 2023; DOI: 10.1056/NEJMoa2212663.

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