Objectives

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

Background

Acetaminophen (paracetamol) has many effects that can be beneficial in sepsis treatment, including analgesia, antipyresis, cyclooxygenase-2 inhibition, as well as a potent and specific hemoprotein reduction that can block hemoglobin-induced oxidation of lipids and other substrates. The majority of sepsis patients experience elevated circulating cell-free hemoglobin levels, which is associated with development of organ dysfunction including acute respiratory distress syndrome (ARDS) and death.

Acetaminophen has been found in observational studies to be associated with improved survival in critically ill sepsis patients with elevated plasma cell-free hemoglobin, and small clinical trials have had positive sepsis patient outcomes such as reduced plasma biomarkers of lipid peroxidation and improved kidney function. However, a large, randomized trial of acetaminophen administration for treatment of fever in patients with suspected infection did not show a mortality benefit. The NHLBI PETAL Network initiated ASTER as a larger phase trial to examine the utility of plasma cell-free hemoglobin level as a biomarker for future sepsis trials and whether acetaminophen would increase the number of days alive and free of organ support for patients with sepsis and respiratory or circulatory organ dysfunction.

Participants

Eligible participants were 18 years or older with sepsis defined as clinical evidence of a known or suspected infection with antibiotics administration planned. Participants must have had either (1) hypotension defined as the need for any vasopressor after administration of at least 1 L of intravenous fluid or (2) respiratory failure defined by mechanical ventilation, noninvasive ventilatory support at any level, or greater than or equal to 6 L/min of supplemental oxygen. Eligible participants could be enrolled if they were admitted (or planned to be admitted) to a study site intensive care unit (ICU) within 36 hours of presentation to the emergency department or presentation to any acute care hospital. Demographic and clinical data were collected from the medical record for prespecified subgroup analysis, including sex, race, ethnicity, COVID-19 status, and receipt of acetaminophen between hospital presentation and randomization. A total of 447 participants were enrolled and randomized, 227 to the acetaminophen arm and 220 to the placebo arm.

Design

ASTER was a phase 2b multicenter, randomized, double-blind trial. The study originally had a 3-arm platform trial in which participants were randomized 1:1:1 to treatment with intravenous acetaminophen, vitamin C, or a common placebo. The vitamin C arm of the trial was stopped after enrolling 79 participants due to external clinical trial data for vitamin C.

Patients randomized to the acetaminophen arm received acetaminophen at the dose of 1 g in 100 mL diluent (or 15 mg/kg if actual body weight was <50 kg) every 6 hours intravenously for 5 days for a total of 20 doses. Patients randomized to placebo received an identical appearing intravenous infusion of 100 mL of 5% dextrose in water every 6 hours for 5 days. In both arms, the study drug was discontinued prior to 120 hours, if one of the following occurred, (1) discharge from the study hospital, (2) discharge from the ICU, (3) withdrawal from the study, or (4) death. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were monitored on study day 0, and days 2 through 5 . New measured values of AST or ALT greater than or equal to 10 times the upper limit of normal on any measurement prompted permanent discontinuation of the study drug. The primary efficacy variable was days alive and free of any organ support (dialysis, assisted ventilation, and vasopressors) out to day 28.

Conclusions

Intravenous acetaminophen was considered to be safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

Ware LB, Files DC, Fowler A, et al. Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial. JAMA. 2024;332(5):390-400. doi:10.1001/jama.2024.8772

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