CLOVERS

Population

• Patients with sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid, randomized within 4 hours of meeting criteria.

Intervention

Restrictive fluid strategy prioritizing vasopressors and lower intravenous fluid volumes for 24 hours.

Comparator

Liberal fluid strategy prioritizing higher intravenous fluid volumes before vasopressor use for 24 hours.

Key results

• Death before discharge home by day 90: 14.0% with restrictive fluids vs 14.9% with liberal fluids; estimated difference -0.9 percentage points (95% CI -4.4 to 2.6; p=0.61).
• The restrictive group received less intravenous fluid during the 24-hour protocol (difference of medians -2134 ml; 95% CI -2318 to -1949).
• The restrictive group had earlier, more prevalent, and longer vasopressor use.
• Reported serious adverse events were similar in the two groups.

Harms

• The number of reported serious adverse events was similar in the two groups.

Practice impact

• Either an early-vasopressor or a liberal-fluid strategy is acceptable after the first 1 to 3 liters in sepsis-induced hypotension.

Applicability

• Most applicable to adults with sepsis-induced hypotension who have already received 1 to 3 liters of intravenous fluid and are being resuscitated over the next 24 hours.

Limitations

• The trial was unblinded and compared two active resuscitation strategies after initial fluid had already been given.
• It does not define the first-liter strategy or fluid choice before randomization.
• Five patients in the restrictive group and four in the liberal group had primary-outcome data censored as lost to follow-up.

Common misinterpretations

• CLOVERS does not say fluids are unnecessary; both arms had already received 1 to 3 liters, and the liberal arm then received substantially more fluid.
• A negative mortality result is not proof that early vasopressors are safer or more dangerous than more fluid.