Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial

Abstract

Importance: The effect of an early resuscitation protocol on sepsis outcomes in developing countries remains unknown.

Objective: To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care.

Design, setting, and participants: Randomized clinical trial of 212 adults with sepsis (suspected infection plus ≥2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013.

Interventions: Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (≥65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management.

Main outcomes and measures: The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors.

Results: Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001).

Conclusions and relevance: Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations.

Trial registration: clinicaltrials.gov Identifier: NCT01663701.

Figure 1.. Screening, Randomization, and Follow-up of Patients Through the Trial

^aDefined as a noninvasively measured arterial oxygen saturation of less than 90% and a respiratory rate greater than 40 breaths per minute.

Figure 2.. Kaplan-Meier Plot of the Probability of Survival Until Day 28 After Enrollment

Vital status was known through study day 28 for 194 patients (94.2%). The median duration of follow-up was 28 days (interquartile range, 28-28 days) in both study groups. Vertical ticks on the curves indicate censoring due to loss to follow-up after hospital discharge.

Figure 3.. Risk of In-hospital Mortality by Subgroup for Patients Treated With the Sepsis Protocol vs Usual Care

The sepsis protocol increased the overall absolute risk of in-hospital mortality by 15.1% (95% CI, 2.0%-28.3%) compared with usual care. ^aObjective assessment of the level of consciousness (range, 3 [deep unconsciousness] to 15 [normal level of consciousness]). ^bA severity score and mortality estimation tool (range, 0-217; higher values indicate higher risk of in-hospital mortality). ^cMeasured above the clavicle with the patient positioned at 45°. For example, because most patients in the trial had depleted volume levels, the median jugular venous pressure was around 2 cm H₂O below the clavicle or −2 cm H₂O.