Restricting fluid therapy in septic shock: Yes or no?

The administration of restrictive, compared with standard, intravenous (IV) fluid therapy to patients with septic shock in the intensive care unit (ICU) did not result in a reduction in mortality risk, according to results of the CLASSIC* trial.

Participants in this international**, open-label trial were 1,554 adults admitted to the ICU who had experienced septic shock within 12 hours of screening and had received ≥1 L of IV fluid in the past 24 hours pre-screening. They were randomized to receive restrictive (n=770) or standard IV fluid therapy (n=784) while in the ICU for a maximum 90 days. The patients in the restrictive- and standard-fluid therapy groups received a median cumulative volume of 1,798 and 3,811 mL of IV fluid, respectively, over the 90-day trial period.

Patients in the restrictive-fluid group could receive IV fluids if they met the following conditions: severe hypoperfusion, mean arterial pressure <50 mm Hg despite vasopressors or inotropics, mottling beyond the kneecap edge, and urinary output <0.1 mL/kg/hour during the first 2 hours post-randomization; as a replacement for fluid loss; correction of dehydration or electrolyte deficiency; or to ensure a daily fluid intake of 1 L. For the standard-fluid therapy group, patients could receive IV fluids if there was improvement in haemodynamic factors, replacement of expected or observed losses or correction of dehydration or electrolyte imbalances, or if ICU protocols recommended maintenance fluid therapy, with no fluid limitations.

The median age of patients was 70–71 years, and 58–60 percent were male. The most common co-existing condition in this cohort was chronic hypertension (45.8 and 46.4 percent in the restrictive- and standard-fluid therapy groups, respectively). About 29 percent were receiving systemic glucocorticoids, and 52.6 and 48.6 percent, respectively, were receiving respiratory support.

At 90 days, incidence of any-cause death did not significantly differ between patients in the restrictive- and standard-fluid therapy groups (42.3 percent vs 42.1 percent; adjusted absolute difference, 0.1 percentage points, 95 percent confidence interval [CI], -4.7 to 4.9; p=0.96). [N Engl J Med 2022;386:2459-2470]

Serious adverse event rates were comparable between the restrictive- and standard-fluid therapy groups (29.4 percent vs 30.8 percent; adjusted absolute difference, -1.7, 99 percent CI, -7.7 to 4.3; p=0.46). This was with respect to incidence of cerebral ischaemia (2.3 percent each), intestinal ischaemia (5.4 percent vs 5.7 percent), and limb ischaemia (2.4 percent vs 2.3 percent). Myocardial ischaemia occurred in 2.1 percent vs 0.8 percent, while severe acute kidney injury occurred in 23.1 percent vs 24.5 percent. Serious adverse reactions to IV crystalloid fluids were reported in 4.1 percent of each group (p=0.95).

At 90 days, patients who received restrictive- vs standard-fluid therapy had a similar number of days alive without life support (median 77 days in each group; p=0.84), and there was no significant difference in the number of days alive and out of hospital (median 21 vs 33 days; p=0.84).

“IV fluids are administered to improve circulation in [patients with septic shock],” said chief investigator Professor Anders Perner from the Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark, and co-authors.

“There’s been much concern among researchers that we sometimes give too much IV fluid treatment, because the excess fluid ends in the organs,” Perner noted. “My personal view is that, on the basis of these results, we should be more restrictive in our use of fluid treatment for patients with severe blood poisoning. These patients have a lot of treatments, and we want to simplify their treatment, provided this doesn’t adversely affect the patients,” he said. [https://www.rigshospitalet.dk/english/news-and-media/news/Pages/2022/june/patients-with-blood-poisoning-do-not-have-to-take-so-much-fluid.aspx, accessed 2 September 2022]

“We haven’t got a final answer to how much fluid they need, but our results will help validate a dose within the framework we’re investigating in the trial. The doses of fluid we examined were safe, but we believe there is a maximum safe dose, and if we exceed this dose the fluid will be harmful for patients,” he concluded.