A 70-year-old woman with sepsis presents for urgent cystoscopy and stenting. She has already received 1 L of crystalloid fluid, but her systolic blood pressure is currently less than 100 mm Hg and her lactate level is greater than 4 mmol/L. According to a recent trial that compared early restrictive fluid management to liberal fluid management in patients with sepsis-induced hypotension, which of the following strategies was MOST likely associated with a mortality benefit at 90 days?

  • □ (A) Early restrictive fluid management
  • □ (B) Liberal fluid management
  • □ (C) No difference between strategies

The role of goal-directed fluid therapy in septic shock continues to evolve. Recent studies have found that usual care is associated with similar outcomes compared with early goal-directed therapy in septic shock. One of the major differences between the two strategies is the volume of fluid patients receive before the initiation of vasopressors. Over time, clinical practice has changed such that vasopressors are administered earlier in the course of treating septic shock. Investigators of the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial partnered with the National Heart, Lung, and Blood Institute Prevention and the Early Treatment of Acute Lung Injury Clinical Trials Network to conduct an unblinded superiority trial at 60 centers in the United States to determine whether early use of vasopressors improves 90-day mortality in patients with septic shock.

Patients who were not experiencing clinical manifestations of fluid overload were randomized within four hours after they met criteria for septic shock and were hemodynamically refractory to the administration of 1 to 3 L of crystalloid. A total of 1,563 patients were enrolled: 782 in the restrictive fluid (early vasopressor) group and 781 in the liberal fluid group. In the restrictive fluid group, the early use of vasopressors was prioritized; norepinephrine was titrated to a goal mean arterial pressure of greater than 65 mm Hg, and no additional fluid boluses were administered except 500-mL fluid boluses up to a maximum of 2 L under certain conditions (severe hypotension, refractory hypotension while receiving norepinephrine, rising lactate level, sinus heart rate >130 beats/min, extreme hypovolemia). The liberal fluid protocol consisted of an additional 2-L isotonic crystalloid bolus at randomization followed by 500-mL fluid boluses based on clinical triggers, such as tachycardia, with rescue vasopressors permitted for prespecified indications (severe hypotension, lactate >4 mmol/L, fluid overload, >5 L of total fluid administered). The study protocol was followed for 24 hours after randomization.

The primary outcome of the study was the rate of all-cause mortality before discharge home by day 90. Home was defined as the living arrangement before admission, such that if a patient came from a private residence and was discharged to a rehabilitation facility, they were still followed for up to 90 days or when they returned to the private residence. All-cause mortality before discharge home by day 90 was not found to be different between the two treatment groups: 14.0% in the restrictive fluid group versus 14.9% in the liberal fluid group (95% CI, –4.4 to 2.6). Secondary outcomes, including mean number of days free from organ support therapy (24.0 vs. 23.6), ventilator use (23.4 vs. 22.8), or renal replacement therapy (24.1 vs. 23.9) and number of serious adverse events (21 vs. 19), were also not found to be different between the restrictive fluid group and the liberal fluid group. The total median amount of fluid administered during the 24 hours after randomization was 1,267 mL in the restrictive group and 3,400 mL in the liberal group, resulting in a mean difference of –2,134 mL (95% CI, –2,318 to –1,949 mL). Notably, norepinephrine was initiated earlier and used for a longer duration in the restrictive fluid group.

It should be noted that the study patients were treated based only on prespecified protocol targets (i.e., mean arterial pressure, lactate level, urine output, and heart rate), and modalities such as central venous pressure, pulse pressure variation, and esophageal Doppler monitoring were not used in this study.

In summary, a recent multicenter study that investigated the combination of early restrictive fluid management and vasopressor use compared with liberal fluid administration found no difference in 90-day all-cause mortality in patients with septic shock.

Answer: C