A 35-year-old man is admitted to the intensive care unit (ICU) in septic shock after surgery for a perforated appendix. According to a recent study comparing fluid administration strategies in ICU patients in septic shock, which of the following outcomes is MOST likely if this patient is administered a restrictive fluid strategy as opposed to a standard fluid strategy?

  • □ (A) Similar risk of 90-day mortality
  • □ (B) Higher risk of acute kidney injury
  • □ (C) Lower risk of intestinal ischemia

Sepsis remains a top cause of mortality worldwide. The Surviving Sepsis Campaign has published recommendations for the treatment of sepsis and septic shock. The most recent publication in 2021 retained the rating of strong for some recommendations, such as the use of vasopressor support to maintain a mean arterial pressure (MAP) of 65 mm Hg or greater. Other recommendations had their ratings downgraded; for example, the recommendation regarding the use of a 30-mL/kg intravenous (I.V.) crystalloid fluid bolus within the first three hours for the treatment of sepsis-induced hypotension was downgraded from strong to weak because of a low quality of evidence.

As a response to the low quality and quantity of evidence for the ideal fluid administration in patients diagnosed with sepsis, the Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care Trial (CLASSIC) was conducted. This international, open-label, randomized trial sought to follow patients 18 years and older who were admitted to the ICU with the diagnosis of septic shock. A patient needed to meet each of the following criteria to meet the definition of septic shock:

  • Suspected infection, confirmed infection, or positive blood culture
  • Ongoing vasopressor or inotropic support required to maintain a MAP of 65 mm Hg or greater
  • Serum lactate level of 2 mmol/L or higher within three hours of admission
  • Receipt of at least 1 L of I.V. fluids in the 24 hours immediately prior to screening for study inclusion.

A total of 1,545 patients were randomized, with 764 patients in the restrictive group and 781 in the standard fluid group. The restrictive group received I.V. fluids only if there were signs of severe hypoperfusion, defined as any of the following criteria:

  • MAP below 50 mm Hg despite vasopressor or inotrope infusion
  • Serum lactate of 4 mmol/L or greater
  • Urine output less than 0.1 mL/kg/h within the first two hours of randomization
  • Mottling beyond the kneecap.

If patients in the restrictive group showed any signs of hypoperfusion, they received a 250- to 500-mL I.V. bolus of crystalloid, followed by reassessment. Patients in the restrictive group also were able to receive IV fluids to replace documented fluid loss, such as gastrointestinal or wound blood loss. They could also receive I.V. fluids to correct dehydration and electrolyte deficiencies and to ensure a total of 1 L of fluids each 24 hours, inclusive of medications and total parenteral nutrition, if enteral administration was contraindicated.

The standard fluid group had no upper limit of I.V. fluid administration as long as there was improvement in patient hemodynamics. Patients also received I.V. fluids to replace expected or observed losses in accordance with existing ICU protocols. For both groups, isotonic crystalloid was suggested for administration unless a large amount of ascites was removed during paracentesis, for which albumin could be administered.

Both groups remained in the ICU for a median of five days after randomization. Excluding medications and nutrition, the restrictive group received a daily median volume of 1,798 mL of fluids, whereas the standard fluid group received 3,811 mL of fluids while in the ICU. The median cumulative volume of all fluids administered in the ICU for the restrictive and standard fluid groups was 10,433 mL and 12,747 mL, respectively. The I.V. protocol was violated in 162 patients (21.5%) in the restrictive group and 101 patients (13.0%) in the standard fluid group.

The primary outcome of the trial was 90-day mortality. Death within 90 days was not found to be different between the groups, occurring in 323 of 764 patients (42.3%) in the restrictive group and 329 of 781 patients (42.1%) in the standard fluid group (95% CI, –4.7 to 4.9).

Secondary outcomes included the following:

  • Serious adverse events, defined as ischemic events (cerebral, cardiac, limb, or intestinal) or new severe acute kidney injury
  • Serious adverse reactions to the I.V. fluids
  • Days alive at 90 days without life support (e.g., mechanical ventilation, renal replacement therapy, vasopressor or inotrope administration)
  • Days alive and out of the hospital at 90 days.

After 90 days, one or more serious adverse events occurred in 221 patients (29.4%) in the restrictive group and 238 patients (30.8%) in the standard fluid group (99% CI, –7.7 to 4.3). Specifically, cerebral ischemia occurred in 17 patients (2.3%) in the restrictive group and 18 patients (2.3%) in the standard fluid group, whereas intestinal ischemia occurred in 41 patients (5.4%) in the restrictive group and 44 patients (5.7%) in the standard fluid group. Severe acute kidney injury occurred in 173 patients (23.1%) in the restrictive group and 189 patients (24.5%) in the standard fluid group. After I.V. fluid administration, a serious adverse reaction occurred in 31 patients (4.1%) in the restrictive group and 32 patients (4.1%) in the standard fluid group (99% CI, –2.8 to 2.6); most of these reactions were severe hypernatremia, severe hyperchloremic acidosis, or generalized tonic-clonic seizures. All other secondary outcomes were also not found to be different between the two groups.

In conclusion, this trial investigated restrictive versus liberal fluid strategies in patients with septic shock and found no differences in 90-day mortality, serious adverse events, or serious reaction to I.V. fluids administered.

Answer A