Clovers Trial:

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Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension | New England Journal of Medicine (nejm.org)

Summary:

The Clovers trial was a multicenter study with 60 centers in the United States enrolling patients for a total of 1563 patients. Inclusion criteria include sepsis induced hypotension and septic shock. A large number of patients did not require pressors at all and responded to fluid alone. Mortality was about 15% overall, consistent with a population that was not as sick as the CLASSIC trial. The restrictive group received a total median of 3.3 Liters of initial fluid resuscitation, compared to 5.5 Liters in the liberal resuscitation group.

• Population: 1563 patients with hypotension or septic shock, Randomized to 2 groups.

• Intervention: Restrictive fluid administration with earlier vasopressor use, in the first 24 hrs.

• Control: Liberal fluid administration.

• Outcome: No difference in 90-day mortality. No difference in secondary outcomes.

• Type of Question: Therapy

• Type of Study: RCT.

  
  

Risk of Bias is small. Very well-done study. Blinding of clinicians was unfeasible, as they had to follow pre-specified protocols. Co-interventions are not specified except for pressors; however, they are part of the intervention and therefore expected to be significantly different in both groups.

Clinical Significance:

Benefit: There is no difference in mortality at 90 days when using more fluid and less vasopressors vs less fluid and more vasopressors within the ranges used in the study. What's important is most likely achieving a MAP goal and maintaining organ function.

Also, the study showed no statistical or clinically significant difference in days free of organ support, renal replacement therapy, ventilator use or days out of ICU or out of the hospital. Post hoc analysis showed a reduction of 8.1% admissions to the ICU in the liberal fluid resuscitation group.

Harms: Vasopressors are not as dangerous in higher doses as previously feared.

Context: Previous data has shown fluid given in distributive shock is short lived, blood pressure and cardiac output improvements last approximately 30 minutes and are gone by the 1-hour mark. Most fluid goes to the extracellular compartment and only a small fraction remains intravascular. Observational data in the past has shown a dose-response increased mortality with larger amounts of fluid given (quantities beyond what these studies looked at)

Mostly Settled Science.

Likelihood of data changing in the future - unlikely.

For more information on this topic, refer to CLASSIC trial.