Study Patients

Figure 1. Figure 1. Enrollment and Outcomes. AIDS denotes acquired immunodeficiency syndrome, EGDT early, goal-directed therapy, and EQ-5D European Quality of Life–5 Dimensions.

Table 1. Table 1. Characteristics of the Patients at Baseline.

From February 16, 2011, to July 24, 2014, we screened 6192 patients at 56 sites (including 29% that are teaching hospitals), which resulted in the enrollment of 1260 patients (Tables S1 and S2 and Fig. S2 and S3 in the Supplementary Appendix). Four patients requested complete withdrawal and five were ineligible, which left 1251 patients in the initial analysis (625 in the EGDT group and 626 in the usual-care group). Eight patients withdrew before 90 days, which left 1243 patients in the analysis of outcomes (623 in the EGDT group and 620 in the usual-care group) (Figure 1, and Table S3 in the Supplementary Appendix). The two study groups were well matched at baseline (Table 1, and Table S4 in the Supplementary Appendix).

The criterion for refractory hypotension was met in 338 patients (54.1%) in the EGDT group and 348 patients (55.6%) in the usual-care group, and the criterion for hyperlactatemia was met in 409 patients (65.4%) and 399 patients (63.7%), respectively. The intravenous-fluid volume before randomization was similar in the two groups, as were median times from presentation at the emergency department until inclusion criteria were met and until randomization. Only about two thirds of patients in either group were deemed likely to be admitted to the ICU from the emergency department if they were not enrolled in the study; those deemed unlikely to be admitted were less severely ill. The sites of infection (most commonly lung) were well balanced in the two groups. All patients received antimicrobial drugs before randomization.

Adherence to the Protocol

Table 2. Table 2. Interventions Delivered during and after the 6-Hour Intervention Period.

Most patients in the EGDT group underwent timely insertion of a central venous catheter capable of continuous ScvO 2 monitoring. Two catheters that were inserted in error in the usual-care group were not used for monitoring ScvO 2 (Table 2, and Table S5 in the Supplementary Appendix). In the EGDT group, reasons for failure of insertion were as follows: patient no longer met inclusion criteria or met exclusion criteria (22 patients), there was a lapse in the process of care (lack of equipment, staff, beds, communication, or error) (20 patients), there were technical difficulties or problems with a patient (18 patients), there was a decision by a clinician (9 patients), or the patient declined to have a catheter inserted but did not withdraw from the trial (5 patients); in 4 patients, no reason was provided, and 2 patients died before catheter insertion. The mean (±SD) first ScvO 2 value recorded (at hour 1) was 70±12% (Fig. S4 in the Supplementary Appendix). Standard central venous catheters were not mandated but were placed in 50.9% of the patients in the usual-care group, and ScvO 2 was measured from aspirated blood samples in 6 patients. Arterial catheters were also not mandated but were placed in most patients.

EGDT was stopped prematurely in 21 patients (median time to cessation, 3 hours) because active treatment was withdrawn (9 patients), the patient was no longer considered to have sepsis (5 patients), or EGDT was terminated in error (3 patients); in addition, 1 patient was transferred to an operating room, 1 patient declined treatment, and no reason was provided for 2 patients. Among the 35 patients who died within 6 hours (17 in the EGDT group and 18 in the usual-care group), 5 in the EGDT group and 6 in the usual-care group had withdrawal of active treatment. Adherence to EGDT ranged from 86 to 95%, depending on the method of assessment (Fig. S5 in the Supplementary Appendix).

Intervention Period

During the 6-hour intervention period, patients in the EGDT group received more intravenous fluids than did patients in the usual-care group (Table 2). Hourly fluid volume decreased over the 6 hours, but patients in the usual-care group received a larger initial volume (Fig. S6 in the Supplementary Appendix). Crystalloids were administered more frequently than colloids in the two groups. More patients in the EGDT group than in the usual-care group received vasopressors and dobutamine. Although more patients in the EGDT group received red-cell transfusions, larger volumes were transfused in the usual-care group. During the 6-hour intervention period, administration of platelets and fresh-frozen plasma was similar in the two groups, although the volume of each was higher in the EGDT group (Table 2). At 6 hours, values for central venous pressure, mean arterial pressure, systolic blood pressure, and hemoglobin were similar in the two groups among patients in whom they were measured, which happened with greater frequency in the EGDT group (Table S6 in the Supplementary Appendix).

After the Intervention Period

Between 6 and 72 hours, the numbers of patients in the two groups receiving intravenous fluids were similar, but patients in the usual-care group received larger volumes. More patients in the EGDT group received intravenous colloids, but overall volumes were similar in the two groups. The number of patients receiving intravenous crystalloids was similar in the two groups, but volumes were larger in the usual-care group. The number of patients receiving red-cell transfusions was higher in the EGDT group, but volumes were larger in the usual-care group. The use of vasopressors and dobutamine remained higher in the EGDT group. Although the numbers of patients receiving platelets and fresh-frozen plasma were similar in the two groups, the volume of platelets was larger in the EGDT group, whereas the volume of fresh-frozen plasma was higher in the usual-care group (Table 2, and Table S7 in the Supplementary Appendix). At 72 hours, physiological, biochemical, and SOFA values were similar in the two groups (Table S8 in the Supplementary Appendix).

Primary Outcome

Table 3. Table 3. Study Outcomes.

Mortality at 90 days was not significantly different in the two groups, with deaths reported in 184 of 623 patients (29.5%) in the EGDT group versus 181 of 620 patients (29.2%) in the usual-care group, with an unadjusted relative risk in the EGDT group of 1.01 (95% CI, 0.85 to 1.20; P=0.90), for an absolute risk reduction of −0.3 percentage points (95% CI, −5.4 to 4.7). After adjustment for baseline characteristics, the odds ratio was 0.95 (95% CI, 0.74 to 1.24; P=0.73) (Table 3). Sensitivity analyses for patients with a missing primary outcome (2 in the EGDT group and 6 in the usual-care group) showed relative risks ranging from 0.99 to 1.03. There was no evidence of a learning-curve effect (P=0.56). In the adherence-adjusted analysis, the relative risk was 1.02 (95% CI, 0.78 to 1.32; P=0.90) (Table S9 and Fig. S7 in the Supplementary Appendix).

Secondary Outcomes

Figure 2. Figure 2. Kaplan–Meier Survival Estimates. Shown is the probability of survival for patients with severe sepsis receiving early, goal-directed therapy (EGDT) and those receiving usual care at 90 days.

The mean SOFA score at 6 hours, the proportion of patients receiving advanced cardiovascular support, and the median length of stay in the ICU were significantly greater in the EGDT group than in the usual-care group. No other secondary outcomes were significantly different (Table 3, and Table S10 in the Supplementary Appendix). There was no significant difference in the duration of survival between the two groups (P=0.63 by the log-rank test; adjusted hazard ratio, 0.94, 95% CI, 0.79 to 1.11; P=0.46) (Figure 2). Mean EQ-5D scores and QALYs were similar in the two groups. The average cost was higher in the EGDT group (£12,414 [U.S. $17,647]) than in the usual-care group (£11,424 [U.S. $16,239]), but the difference was not significant (P=0.26) (Table 3, and Tables S11 through S16 and Fig. S8 in the Supplementary Appendix). The incremental net benefit for EGDT as compared with usual care was negative and similar across prespecified subgroups and alternative scenarios that were considered in sensitivity analyses (Tables S17 and S18 and Fig. S9 in the Supplementary Appendix). The probability that EGDT was cost-effective was below 20% (Fig. S10 in the Supplementary Appendix).

Subgroup Analyses

There was no significant difference regarding the effect of EGDT according to prespecified subgroups as defined by the degree of protocolized care used in the usual-care group, age, MEDS score, SOFA score, or time from presentation at the emergency department to randomization (P=0.39 to 0.72 for interaction) (Table S9 and Fig. S11 in the Supplementary Appendix).

Serious Adverse Events

At least one serious adverse event was reported in 30 patients (4.8%) in the EGDT group and 26 patients (4.2%) in the usual-care group (P=0.58) (Table 3, and Table S19 in the Supplementary Appendix). Four serious adverse events were reported as being related to EGDT (two cases of pulmonary edema and one of arrhythmia, which were deemed to be probably related, and one case of myocardial ischemia, which was deemed to be definitely related), as compared with four events (in three patients) related to usual care (two cases of pneumothorax and one case of pulmonary edema, which were deemed to be probably related, and one case of ventricular fibrillation, which was deemed to be definitely related).