Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial

Abstract

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates.

Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo.

Design, setting, and participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation.

Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days.

Main outcome and measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL.

Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

Conclusions and relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients.

Trial registration: ClinicalTrials.gov Identifier: NCT04291508.

Figure 1.. Patient Screening, Enrollment, and Follow-up

Patients could have more than 1 reason for exclusion. ^aInitially, 448 patients were randomized to acetaminophen plus vitamin C: 228 to receive acetaminophen active; 220 pooled placebo; 40 vitamin C active. On June 15, 2022, the vitamin C arm of the trial was stopped after enrolling 79 participants due to external clinical trial data for vitamin C (see the Methods section). ^bDefined as receiving 1 or more doses of the assigned study drug.

Figure 2.. Survival and Days Alive, and Free of Organ Support to Day 28

A, Survival and the proportion of patients without organ support over the first 28 days after randomization. Organ support included mechanical ventilation, vasopressors, and renal replacement therapy. Probabilities are shown for the 441 patients with complete 28-day follow-up. B, The primary outcome was days alive and free of organ support, including mechanical ventilation, vasopressors, and renal replacement therapy to day 28. Non-White racial groups are plotted together due to small numbers in individual racial groups. The P value for overall between-group difference was derived by t test and the P values for subgroup interaction by analysis of variance.

Figure 3.. Change of Total Sequential Organ Failure Assessment (SOFA) Scores From Enrollment to Day 7 by Treatment Arm

Data are reported as mean (dots), median (bars), IQR (boxes), and values falling within 1.5 × IQR (whiskers). Changes in total SOFA score from enrollment were compared each day by t test. P values for days 2 through 4 are P < .05. GCS indicates Glasgow Coma Scale.