Of 452 patients who underwent screening for eligibility, 300 underwent randomization (). Of these 300 patients, the same pattern of protocol noncompletion was observed in each group: 2 because a chest or neck central venous catheter could not be placed and 1 because family members had decided to withdraw support before the research procedure was completed. One patient in the lactate clearance group had the crossover enacted by a physician after all study goals had been met. The ScvO2 value in this patient was normal, so no treatment changes were made. Because the study treatment period had ended, this patient was analyzed in the lactate clearance group for both the intent-to-treat and per-protocol analyses. None were lost to follow-up or voluntarily withdrew from the study, leaving 150 patients in each group for the intent-to-treat analysis and 147 in each group for the per-protocol analysis.
The baseline characteristics of the 2 groups are shown in and in . There were no significant differences between the groups in demographics, comorbid conditions, severity of illness scores, or suspected site of infection. The lungs were the most common source of infection, and 38% of patients had a blood specimen that yielded growth of bacteria, whereas 84% had at least 1 culture specimen that was positive. The median time from emergency department triage to eligibility was 111 minutes (interquartile range [IQR], 56–192 minutes) in the lactate clearance group and 105 minutes (IQR, 60–175 minutes) in the ScvO2 group (P=.67); the median time from eligibility to study entry was 14 minutes (IQR, 1–48 minutes) in the lactate clearance group and 13 minutes (IQR, 1–55 minutes) in the ScvO2 group (P =.72). Prior to enrollment in the study, the mean (SD) amount of intravenous fluid administered was 2.3 L(1.4 L) in the lactate clearance group and 2.4 L (1.4 L) in the ScvO2 group (P =.37).
Patient Demographics and Clinical Characteristicsa
Systemic Inflammatory Response Criteria and Dysfunctional Organ Systems
shows the physiological and severity of illness variables during the first 72 hours of hospitalization. During the first 24 hours, both groups of patients tended to show a trend toward slightly worsening severity of illness in the form of lower systolic blood pressures and higher SOFA scores. The mean initial lactate concentrations were 35.1 mg/dL (3.9 mmol/L) in the lactate clearance group and 37.8 mg/dL (4.2 mmol/L) in the ScvO2 group (P=.39). The mean (SD) lactate concentration measured at 2 hours in the lactate clearance group was 23.4 (23.3) mg/dL (2.6 [2.59] mmol/L) and the median lactate clearance at 2 hours was 40% (IQR, 18%–64%). After the initial 24 hours, survivors in both groups manifested improvements in their physiological and severity of illness scores. We observed that lactate measurements did not worsen over the initial 72 hours (), suggesting that the initial lactate levels were often the most abnormal.
Physiological and Severity of Illness Measurements
There were no differences in the administered treatments through the initial 72 hours of hospitalization as shown in . During the emergency department–based 6-hour resuscitation period, patients received approximately 4.5 L of crystalloid, 221 patients (74%; 95% confidence interval [CI], 68%–79%) required vasopressors for hypotension, and 79 patients (26%; 95% CI, 21%–32%) required mechanical ventilation. Notably, only 29 patients (10%; 95% CI, 7%–14%) required either dobutamine infusion or packed red blood cell transfusion during the initial 6 hours of treatment. Activated protein C administration was only administered in 5 patients (2%; 95% CI, 1%–4%).
Administered Treatments and Resuscitation Goals
Among the 294 (147 per group) patients included in the per-protocol analysis, the central venous pressure goal was achieved in 133 patients (91%; 95% CI, 85%–95%) in the lactate clearance group and 133 (91%; 95% CI, 85%–95%) in the ScvO2 group (P =.99); the mean arterial pressure goal was achieved in 142 patients (97%; 95% CI, 92%–99%) in the lactate clearance group and 142 (97%; 95% CI, 92%–99%) in the ScvO2 group (P=.99); and the lactate clearance goal was met in 139 patients (95%; 95% CI, 90%–98%) in the lactate clearance group and the ScvO2 goal was met in 136 (93%; 95% CI, 87%–96%) patients in the ScvO2 group (P=.67). The median time from patient triage in the emergency department to first antibiotic administration was 115 (IQR, 62–180) minutes in the lactate clearance group and 115 (IQR, 66–170) minutes in the ScvO2 group(P =.98).
The primary and secondary study outcome analysis is outlined in . In the intent-to-treat analysis the inhospital mortality rate was 17% (25 of 150 [95% CI, 11%–24%]) in the lactate clearance group compared with 23% (34 of 150 [95% CI, 17%–30%]) in the ScvO2 group. The difference in these mortality rates was 6% (95% CI, −3% to 15%). The lower limit of this CI is well above the −10% predefined non-inferiority threshold, confirming the primary hypothesis of noninferiority between the lactate clearance and ScvO2 groups for in-hospital mortality. These results did not change substantially in the per-protocol analysis.
Hospital Mortality and Length of Stay
There were no differences in the observed rates of predefined protocol-related serious adverse events between the lactate clearance (9 of 150 [6%; 95% CI, 3%–11%]) and ScvO2 (11 of 150 [7%; 95% CI, 4%–13%]) groups (P=.81).