Study Design and Oversight

From October 5, 2008, to April 23, 2014, we conducted this prospective, randomized, parallel-group trial in 51 tertiary care and nontertiary care metropolitan and rural hospitals. Most centers were in Australia or New Zealand, with 6 centers in Finland, Hong Kong, and the Republic of Ireland (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).24 Participating institutions did not have sepsis-resuscitation protocols at the time of site selection, and usual care did not include resuscitation guided by measurement of the central venous oxygen saturation (ScvO 2 ).25 The ARISE study was one of three collaborative, harmonized studies, along with the ProCESS trial10 and the Protocolized Management in Sepsis (ProMISe) trial (Current Controlled Trials number, ISRCTN36307479), designed to address the effectiveness of EGDT.24

The study protocol was approved by the ethics committee at Monash University, which was the coordinating center, and at each participating institution. The protocol and statistical analysis plan are available at NEJM.org. Prior informed written consent or delayed consent was obtained from all patients or their legal surrogates. The trial was overseen by an independent data and safety monitoring committee. ScvO 2 monitors were loaned to participating sites by Edwards Lifesciences, which had no other role in the conduct of the study.

Study Population

Patients 18 years of age or older who met the eligibility criteria within 6 hours after presentation to the emergency department were assessed for enrollment. Eligibility criteria were a suspected or confirmed infection, two or more criteria for a systemic inflammatory response26 (see the Methods section in the Supplementary Appendix), and evidence of refractory hypotension or hypoperfusion. Refractory hypotension was defined as a systolic blood pressure of less than 90 mm Hg or a mean arterial pressure of less than 65 mm Hg after an intravenous fluid challenge of 1000 ml or more administered within a 60-minute period. Hypoperfusion was defined as a blood lactate level of 4.0 mmol per liter or more. Randomization was required within 2 hours after fulfillment of the final inclusion criterion. The initiation of the first dose of intravenous antimicrobial therapy was mandated before randomization. The study exclusion criteria are provided in the Methods section in the Supplementary Appendix.

Randomization

Eligible patients were randomly assigned in a 1:1 ratio to receive either EGDT or usual care for 6 hours. Randomization was stratified according to study center with the use of a permuted-block method and was performed by means of a centralized telephone interactive voice-response system that was accessible 24 hours a day. Because of the nature of the intervention, all patients and clinicians involved in their care were aware of study-group assignments.

Study Treatments

For patients in the usual-care group, decisions about the location of care delivery, investigations, monitoring, and all treatments were made by the treating clinical team. ScvO 2 measurement was not permitted during the 6-hour intervention period. Data were collected regarding insertion of invasive monitoring devices, intravenous-fluid resuscitation, vasoactive support, red-cell transfusion, mechanical ventilation, and other supportive therapy.

For patients in the EGDT group, the intervention was provided by a study team trained in EGDT delivery. Both the care providers and location of delivery were dependent on local resources. Thus, investigators used EGDT implementation models based in the emergency department, the intensive care unit (ICU), or both. A multifaceted intervention was used to standardize EGDT delivery across sites.24 Details of EGDT implementation, personnel, and location are provided in Table S1 and Fig. S1 in the Supplementary Appendix.

In the EGDT group, an arterial catheter and a central venous catheter capable of continuous ScvO 2 measurement (Edwards Lifesciences) were inserted within 1 hour after randomization. The resuscitation algorithm was based on the original EGDT algorithm11 and was followed until 6 hours after randomization (Fig. S1 in the Supplementary Appendix).

Study Outcomes

The primary study outcome was death from any cause within 90 days after randomization. Secondary and tertiary outcomes included survival time from randomization to 90 days; mortality in the ICU; mortality at 28 days; in-hospital mortality at 60 days; cause-specific mortality at 90 days27; length of stay in the emergency department, ICU, or elsewhere in the hospital; receipt and duration of mechanical ventilation, vasopressor support, or renal-replacement therapy; destination at the time of discharge (for surviving inpatients); limitation of therapy (e.g., do-not-resuscitate order) at the time of death (for nonsurvivors); and adverse events.

Statistical Analysis

All analyses were conducted according to a statistical analysis plan that was reported previously.28 The sample-size calculation was based on an assumed in-hospital rate of death in the usual-care group of 28%,25,29 with an increment of 10 percentage points (38%) for the rate of death at 90 days.8,30 Thus, an enrollment of 1600 patients would have a power of 85 to 90% (at a two-sided alpha level of 0.05) to detect an absolute risk reduction of 7.6 percentage points (or a relative risk reduction of 20%) in the EGDT group, with allowance for a plausible range of loss to follow-up. One interim analysis was planned and performed after the enrollment of 50% of the patients, with the use of a two-sided, symmetric O'Brien–Fleming design and a two-sided P value of 0.005; this analysis was reviewed by the independent data and safety monitoring committee.

All analyses were conducted according to the intention-to-treat principle. No assumptions were made for missing or unavailable data. We report continuous variables as means (±SD) or medians and interquartile ranges, and categorical variables as proportions. We used Student's t-test or the Wilcoxon rank-sum test to analyze between-group differences, as appropriate. Fisher's exact test was used for categorical variables, including the primary outcome. Absolute and relative risk differences with 95% confidence intervals for all-cause mortality at 90 days are reported. Additional sensitivity analyses were performed with the use of multivariable logistic regression adjusted for predefined baseline covariates: country, age, score on the Acute Physiology and Chronic Health Evaluation II (APACHE II), systolic blood pressure (<90 mm Hg or ≥90 mm Hg), and presence or absence of invasive mechanical ventilation. We used the Kaplan–Meier method to calculate survival time from randomization to 90 days and the log-rank test to perform between-group comparisons. We used Cox proportional-hazards models adjusted for the previously specified baseline covariates to calculate hazard ratios with 95% confidence intervals. Values for length of hospital stay and duration of organ support were log-transformed and analyzed with the use of linear regression and are reported as ratios with 95% confidence intervals.

We conducted subgroup analyses for the primary outcome for predefined variables: country, age (<65 years or ≥65 years), APACHE II score (<25 or ≥25), presence or absence of invasive mechanical ventilation, presence or absence or refractory hypotension, lactate level (<4.0 mmol per liter or ≥4.0 mmol per liter), and intravenous fluid administration (<20 ml per kilogram of body weight or ≥20 ml per kilogram). Subgroup analyses were performed with the use of logistic regression, with heterogeneity determined on the basis of interaction between treatment and subgroup. Odds ratios with 95% confidence intervals for death at 90 days are presented in a forest plot.

All analyses were performed with the use of SAS software, version 9.3 (SAS Institute). A two-sided P value of 0.05 or less was considered to indicate statistical significance, except for the primary outcome, for which a P value of 0.0491 or less was used.