DOI: 10.60645/bdc-5l11-b920
title: Prevention and Early Treatment of Acute Lung Injury (PETAL) Acetaminophen in Sepsis: Targeted Therapy to Enhance Recovery (ASTER) (PETAL ASTER-BioLINCC)

description: 
**Data Access NOTE**: Please refer to the &#8220;Authorized Access&#8221; section below for information about how access to the data from this accession differs from many other dbGaP accessions. 

Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL ASTER include plasma, urine and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. 

**Objectives: **To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis participants 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 participants 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 participants with elevated plasma cell-free hemoglobin, and small clinical trials have had positive sepsis participant 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 participants 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 participants with sepsis and respiratory or circulatory organ dysfunction. 

**Participants: **A total of 447 participants were enrolled and randomized, 227 to the acetaminophen arm and 220 to the placebo arm. Data from 40 participants who were randomized to the Vitamin C arm, which was stopped early (see Design section below), is also included.

**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.

Participants 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. Participants 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 participants. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.