Trial Design and Oversight

Our trial was an investigator-initiated, international, pragmatic, double-blind, parallel-group, randomized, controlled trial that compared intravenous infusions of hydrocortisone with matched placebo in patients with septic shock who were undergoing mechanical ventilation in an intensive care unit (ICU). We conducted the trial in Australia, the United Kingdom, New Zealand, Saudi Arabia, and Denmark.

The trial management committee designed the trial. The trial sponsor (the George Institute for Global Health, Australia) coordinated all the operational processes and conducted all the statistical analyses. Trained research coordinators collected data at each site and entered the information into a Web-based database. Data monitoring and source-data verification were conducted according to a prespecified monitoring plan (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).

Before enrollment was completed, we published the trial protocol (available at NEJM.org) and statistical analysis plan.17,18 Approval from a human research ethics committee was obtained for all the sites before enrollment of the patients. Previous written informed consent or written consent to continue was obtained for all participants, according to the legal requirements in each jurisdiction. The authors vouch for the accuracy and completeness of the data and statistical analyses and for the fidelity of the trial to the protocol.

Neither Pfizer (which supplied hydrocortisone) nor Radpharm Scientific (which supplied placebo) had any input into the design or conduct of the study, data collection, statistical analysis, or writing of the manuscript. Mater Pharmacy Services (Brisbane, Australia) was responsible for acquisition of the drugs and the blinding processes. There was no contractual arrangement between the trial sponsor, the George Institute for Global Health, and either Pfizer or Radpharm Scientific. All contractual arrangements were between Mater Pharmacy Services and the George Institute for Global Health.

Patients

Eligible participants were adults (≥18 years of age) who were undergoing mechanical ventilation, for whom there was a documented or strong clinical suspicion of infection, who fulfilled two or more criteria of the systemic inflammatory response syndrome,19 and who had been treated with vasopressors or inotropic agents for a minimum of 4 hours up to and at the time of randomization. Patients were excluded if they were likely to receive treatment with systemic glucocorticoids for an indication other than septic shock, had received etomidate20 (a short-acting anesthetic agent with adrenal-suppressant properties) during the current hospital admission, were considered to be likely to die from a preexisting disease within 90 days after randomization or had treatment limitations in place, or had met all the inclusion criteria for more than 24 hours. Detailed inclusion and exclusion criteria and the alignment of these criteria with the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)21 are provided in Tables S2A through S2C in the Supplementary Appendix.

Randomization and Trial Regimen

We concealed the randomized trial-group assignments using a minimization algorithm by means of a password-protected, encrypted, Web-based interface. Randomization was stratified according to participating center and according to medical or surgical admission. Surgical admissions were defined as patients being admitted to the ICU from the operating room or the recovery room; all other admissions were considered to be medical admissions.

Patients were assigned to receive an intravenous infusion of hydrocortisone (Pfizer) at a dose of 200 mg per day or matching placebo (Radpharm Scientific). Blinding regarding the trial regimen was ensured by the supply of hydrocortisone and placebo in identical, masked vials. The integrity of the trial-group assignment was confirmed by an independent person who assessed a random sample of hydrocortisone and placebo packs from 10% of the trial population (Table S3A in the Supplementary Appendix). The trial regimen was reconstituted to produce a concentration of 1 mg per milliliter of hydrocortisone or an equivalent volume (in milliliters) of placebo. The trial dose volume was set at 200 ml, which was administered by means of continuous intravenous infusion over a period of 24 hours for a maximum of 7 days or until ICU discharge or death, whichever occurred first. A description of the blinding process and of the preparation and reconstitution of the trial regimen is provided in Table S3B in the Supplementary Appendix.

The patients, treating clinicians, and trial personnel were unaware of the trial-group assignments and sequence. All other aspects of the patients’ care were conducted at the discretion of the treating clinicians.

Outcomes

The primary outcome was death from any cause at 90 days after randomization. Secondary outcomes included death from any cause at 28 days after randomization, the time to the resolution of shock,22 the recurrence of shock, the length of ICU stay, the length of hospital stay, the frequency and duration of mechanical ventilation, the frequency and duration of treatment with renal-replacement therapy, the incidence of new-onset bacteremia or fungemia between 2 and 14 days after randomization, and the receipt of blood transfusion in the ICU. Definitions of the secondary outcomes are provided in Table S4 in the Supplementary Appendix.

Statistical Analysis

We determined that a population of 3800 patients would provide the trial with 90% power to detect an absolute difference of 5 percentage points in 90-day all-cause mortality from an estimated baseline mortality of 33%, at an alpha level of 0.05.6 This calculation allowed for a rate of withdrawal and loss to follow-up of 1%.

The primary-outcome result is presented as the odds ratio for death, with corresponding 95% confidence intervals, analyzed with the use of a logistic-regression model with adjustment for stratification variables, with admission type (medical or surgical) as a fixed effect and trial site as a random effect. Additional sensitivity analyses were performed by adding the following covariates to the main logistic-regression model: sex; age; Acute Physiology and Chronic Health Evaluation (APACHE) II score, assessed on a scale from 0 to 71, with higher scores indicating a higher risk of death23; the time from the onset of shock to randomization; and the use of renal-replacement therapy in the 24 hours before randomization.

The primary outcome was also examined in six prespecified subgroups, which were defined according to the following baseline characteristics: admission type (medical vs. surgical); dose of catecholamine infusions (norepinephrine or epinephrine at a dose of <15 μg per minute vs. ≥15 μg per minute); primary site of sepsis (pulmonary vs. nonpulmonary); sex (male vs. female); APACHE II score (<25 vs. ≥25; a score of ≥25 has been used as a cutoff point to identify patients at a higher risk for death24,25); and the duration of shock according to four intervals of 6 hours each between 0 and 24 hours before randomization (<6 hours, 6 to 12 hours, 12 to 18 hours, or 18 to 24 hours). The secondary binary and continuous outcomes were analyzed with the use of logistic regression and linear regression, respectively, with adjustment for stratification variables. The rate of death in a time-to-event analysis was reported with the use of Kaplan–Meier plots, and differences in survival were tested with the use of a Cox proportional-hazards model26 that included the randomized trial group, admission type, and a random effect for trial site.

The times to the resolution of shock and ventilation and the times to discharge from the ICU and the hospital were analyzed by means of two approaches: with death treated as a competing risk27 and with results described with the use of cumulative incidence function; and as a post hoc analysis with data from patients censored at the time of death and with results described with the use of Kaplan–Meier plots. Differences in the time to event (e.g., resolution of shock, cessation of ventilation, and ICU or hospital discharge) were tested with the use of the same Cox model that was used for the analysis of time to death.

Physiological data were averaged over the period of days 1 to 14 and compared with the use of a repeated-measure, linear mixed model and were presented as overall mean differences with corresponding 95% confidence intervals. Post hoc analyses were performed with the use of a separate calculation of the mean differences over the period of days 1 to 7 (duration of trial regimen) and days 8 to 14. The proportions of patients who had adverse events and serious adverse events were compared with the use of Fisher’s exact test.

All the analyses were conducted on an intention-to-treat basis with no imputation of missing data. For secondary outcomes, a post hoc Holm–Bonferroni procedure was applied to control for multiple testing.28 All the analyses were conducted with the use of SAS software, version 9.4 (SAS Institute).

Two prespecified interim analyses were performed by an independent statistician when 950 patients (25%) and 2500 patients (66%) could be assessed with regard to the primary outcome at 90 days. These analyses were reviewed by an independent data monitoring committee.