Treatment with IV acetaminophen may not improve organ dysfunction in critically ill patients with sepsis: ASTER trial

The study, published in the Journal of the American Medical Association (JAMA), revealed that intravenous (IV) acetaminophen is safe but failed to significantly improve days alive and free of organ support in critically ill patients with sepsis.

"In the RCT of 447 adults, acetaminophen was safe, but there was no meaningful difference in the number of days alive and free of organ support in the acetaminophen arm (20.2 days) versus the placebo arm (19.6 days)," the researchers reported. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

Sepsis, a life-threatening condition triggered by the body's extreme response to an infection, often leads to organ dysfunction and failure. Despite advances in critical care, treatment options for sepsis have remained limited, prompting researchers to explore alternative therapies. Acetaminophen (paracetamol), a widely available over-the-counter medication known for its antipyretic and analgesic properties, emerged as a potential candidate for mitigating the devastating effects of sepsis on organ function.

Acetaminophen has many pharmacological effects that may benefit sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates. Considering this, Lorraine B. Ware, Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues aimed to investigate if acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo.

For this purpose, the researchers conducted a phase 2b randomized, double-blind, clinical trial from 2021 to 2023 with 90-day follow-up. It enrolled adults with sepsis and circulatory or respiratory organ dysfunction in the intensive care unit or emergency department of 40 US academic hospitals within 36 hours of presentation.

Patients were randomized to 1 g of IV acetaminophen every 6 hours or placebo for five days.

The primary endpoint was days alive and free of organ support (vasopressors, mechanical ventilation, and kidney replacement therapy) to day 28. Treatment effect modification was assessed for acetaminophen by pre-randomization plasma cell-free hemoglobin level higher than 10 mg/dL.

The study led to the following findings:

• Of 447 patients enrolled (mean age, 64 years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4), 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) versus placebo (19.6 days).
• Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm, so was the rate of development of acute respiratory distress syndrome within seven days (2.2% versus 8.5% acetaminophen vs placebo).
• There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

The findings showed that treatment of critically ill patients with sepsis with either circulatory or respiratory organ dysfunction with 1 g of IV acetaminophen every 6 hours for five days was safe but did not significantly improve the primary outcome of days alive and free of organ support to day 28, including vasopressors, mechanical ventilation, and kidney replacement therapy.

Reference:

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. Published online May 19, 2024. doi:10.1001/jama.2024.8772