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Question  Does a resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion implemented early after presentation to the emergency department improve in-hospital mortality among Zambian adults with sepsis and hypotension compared with usual care?

Findings  In this randomized clinical trial that included 209 adults with sepsis and hypotension presenting to an emergency department in Zambia, a 6-hour sepsis protocol emphasizing administration of intravenous fluids, vasopressors, and blood transfusion significantly increased in-hospital mortality compared with usual care (48.1% vs 33.0%, respectively).

Meaning  In resource-limited settings, an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion for adults with sepsis may increase mortality compared with usual care.

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

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Article Information

Corresponding Author: Gordon R. Bernard, MD, School of Medicine, Vanderbilt University, 1161 21st Ave S, Nashville, TN 37232 (gordon.bernard@vanderbilt.edu).

Accepted for Publication: July 21, 2017.

Published Online: September 27, 2017. doi:10.1001/jama.2017.10913

Author Contributions: Dr Andrews had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Andrews, Muchemwa, Kelly, Heimburger, Bernard.

Acquisition, analysis, or interpretation of data: Andrews, Semler, Muchemwa, Lakhi, Heimburger, Mabula, Bwalya, Bernard.

Drafting of the manuscript: Andrews, Semler, Muchemwa, Kelly.

Critical revision of the manuscript for important intellectual content: Andrews, Semler, Muchemwa, Lakhi, Heimburger, Mabula, Bwalya, Bernard.

Statistical analysis: Andrews, Semler.

Obtained funding: Andrews, Bernard.

Administrative, technical, or material support: Andrews, Semler, Lakhi, Heimburger, Mabula, Bwalya, Bernard.

Supervision: Kelly, Heimburger, Bernard.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: Supported in part by grant R24 TW007988 from the National Institutes of Health awarded to the Vanderbilt University International Clinical Research Fellows Program; grant NIH D43 TW001035-11-S1 from the Fogarty International Center awarded to the Vanderbilt University-CIDRZ AIDS International Training and Research Program; and grant UL1 TR000445 from the National Center for Advancing Translational Sciences.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: Presented in part at the European Society of Intensive Care Medicine 30th Annual Congress; September 27, 2017; Vienna, Austria.

Additional Contributions: We thank the individuals working at the microbiology laboratory of Zambia University Teaching Hospital and Eugene Silomba, BS (AIDSRelief Zambia), for their uncompensated contributions to making this trial possible.

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