Study Design

We conducted an investigator-initiated, prospective, parallel-group, blinded, randomized, controlled trial. The management committee (made up of all the authors) designed the trial, which was endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group. The George Institute for Global Health (Sydney) and the Medical Research Institute of New Zealand (Wellington) provided subsidized project management and on-site monitoring of data quality for this study. The protocol, which was reported before enrollment commenced13 and is available with the full text of this article at NEJM.org, was approved by the New Zealand Multi-region Ethics Committee and by each participating institution. Written informed consent before randomization or delayed consent was obtained from each patient or a legal surrogate, unless an institutional ethics committee approved a waiver of consent (e.g., in the event that a patient died before informed consent could be obtained from a surrogate decision maker). The authors vouch for the accuracy and completeness of the data and analyses and for the fidelity of this report to the protocol.

Patients

Patients 16 years of age or older with a temperature of 38°C or higher within 12 hours before enrollment and who were receiving antimicrobial therapy for a known or suspected infection were eligible for inclusion. Among the exclusion criteria were acute brain disorders and liver dysfunction that contraindicated the use of acetaminophen. A full list of exclusion criteria is provided in Table S1 in the Supplementary Appendix, available at NEJM.org.

Randomization and Study Drugs

Eligible patients were randomly assigned, in a 1:1 ratio, to receive either an infusion containing 1 g of intravenous acetaminophen (Perfalgan, Bristol-Myers Squibb) or an infusion of 5% dextrose in water, every 6 hours. The study medications were packaged in indistinguishable 100-ml glass bottles. Randomization was performed with the use of an encrypted Web-based system involving block randomization with a block size of six and was stratified according to participating center. Investigators were unaware of the randomization block size.

Patients continued to receive the study drug until 28 days after enrollment or until the occurrence of one of the prespecified cessation criteria: discharge from the ICU, resolution of fever as defined by a prespecified algorithm (Fig. S1 in the Supplementary Appendix), cessation of antimicrobial therapy, death, or the development of a contraindication to the study drug.

Rescue physical cooling was permitted if the body temperature rose to 39.5°C or higher. The use of open-label acetaminophen was permitted after the course of study medication was completed. The use of other treatments to reduce body temperature was restricted by the protocol (see the Supplementary Appendix).

Outcome Measures

The primary outcome measure was ICU-free days to day 28.14 ICU-free days is a composite outcome combining mortality and ICU length of stay. The number of ICU-free days was calculated as 28 minus the number of days or part-days spent in the ICU during the first 28 days after randomization (excluding any days of ICU readmission); patients who died were assigned the worst possible outcome of zero ICU-free days.14

Secondary outcomes, within a 90-day follow-up period, were all-cause mortality at day 28 and day 90; survival time (number of days alive) from randomization until day 90; ICU and hospital length of stay; and hospital-free days, days free from mechanical ventilation, days free from inotropes or vasopressors, days free from renal-replacement therapy, and days in the ICU that were free from support. To be deemed free from support in the ICU, a patient was required to be free from mechanical ventilation, inotropes or vasopressors, and renal-replacement therapy for an entire calendar day and had to remain free from such supports until discharge from the ICU. Patients who died were assigned zero days for all outcome measures involving freedom from support or hospital-free days.

Physiological- and laboratory-related outcome variables were mean and maximum axillary temperature; the proportion of patients who stopped the study drug owing to the development of liver dysfunction; mean serum C-reactive protein (CRP) levels measured in the ICU on days 1, 3, 5, and 7; the proportion of patients in the ICU with a serum creatine kinase level of more than 5000 units on days 1, 3, 5, or 7; and highest serum creatinine level in the ICU during the first 7 days after randomization.

The primary outcome was examined in four prespecified subgroups defined according to the following prerandomization criteria: the presence or absence of septic shock (defined as sepsis-induced hypotension despite adequate fluid resuscitation), the use or nonuse of aspirin, the presence or absence of high fever (defined as a temperature of ≥39°C in the 12 hours before enrollment), and the location of infection acquisition (community, hospital, or ICU). Full details of the study design can be found in the protocol.

Statistical Analysis

The statistical analysis plan was reported before the interim analysis was conducted.15 On the basis of an inception cohort study16, we assumed a mean control value of 16.0±9.2 ICU-free days. With this assumption and allowing for a 15% inflation in sample size to account for the use of a rank-based test15 and an additional 5% inflation to account for loss to follow-up, we calculated that a sample size of 700 patients would provide 80% power to detect an absolute difference of 2.2 ICU-free days at 28 days after randomization, at an alpha level of 0.05.

All analyses were conducted on an intention-to-treat basis with masking to study-group assignments. We defined the intention-to-treat population as all enrolled patients except those who withdrew consent for use of data. We made no imputation for missing values. For the primary analysis comparing ICU-free days between study groups, we used a Wilcoxon rank-sum test and present results as point estimates of absolute difference, using 96.2% confidence intervals to account for the interim efficacy analysis conducted after enrollment of 233 patients. Point estimates of absolute difference that are provided are the median of all paired differences between observations in the two groups, calculated with the use of the Hodges–Lehmann method.17

The risk of death at day 28 and day 90 was estimated by means of Poisson regression and is presented as a relative risk with 95% confidence intervals. For mortality at day 28 and day 90, adjusted analyses were performed with the use of multivariate Poisson regression. Prespecified covariates were age, ICU admission source, and Acute Physiology and Chronic Health Evaluation (APACHE) II score.18 We compared survival times to day 90 using log-rank tests and present these as Kaplan–Meier curves and used a Cox proportional-hazards model to calculate hazard ratios for death. ICU and hospital length of stay were compared in the overall study groups and, as prespecified, among survivors and nonsurvivors separately.

For the prespecified subgroups, we performed a proportional-odds analysis with the number of ICU-free days categorized as 0 to 7 days, 8 to 14 days, 15 to 21 days, or 22 to 27 days. This facilitated a formal test for subgroup heterogeneity with an interaction term. All analyses were conducted with the use of SAS statistical software, version 9.3 (SAS Institute). Two-sided P values of less than 0.05 were considered to indicate statistical significance, except in the case of the primary outcome, for which a P value of 0.0379 or less was used.19

Study results were initially reviewed by the management committee, whose members were unaware of the study-group assignments. Post hoc analyses were performed to further evaluate the effects of the study drugs on temperature and the use of cointerventions that might have affected body temperature before the study-group assignments were unmasked. Additional details of statistical analyses and post hoc analyses are available in the Supplementary Appendix.