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Simplified Severe Sepsis Protocol

A Randomized Controlled Trial of Modified Early Goal–Directed Therapy in Zambia*

Andrews, Ben MD; Muchemwa, Levy MBChB; Kelly, Paul MD, FRCP; Lakhi, Shabir MBChB, MMed, MPH; Heimburger, Douglas C. MD, MS, FACP; Bernard, Gordon R. MD

doi: 10.1097/CCM.0000000000000541
Feature Articles

Objective: To assess the efficacy of a simple, goal-directed sepsis treatment protocol for reducing mortality in patients with severe sepsis in Zambia.

Design: Single-center nonblinded randomized controlled trial.

Setting: Emergency department, ICU, and medical wards of the national referral hospital in Lusaka, Zambia.

Patients: One hundred twelve patients enrolled within 24 hours of admission with severe sepsis, defined as systemic inflammatory response syndrome with suspected infection and organ dysfunction

Interventions: Simplified Severe Sepsis Protocol consisting of up to 4 L of IV fluids within 6 hours, guided by jugular venous pressure assessment, and dopamine and/or blood transfusion in selected patients. Control group was managed as usual care. Blood cultures were collected and early antibiotics administered for both arms.

Measurements and Main Results: Primary outcome was in-hospital all-cause mortality. One hundred nine patients were included in the final analysis and 88 patients (80.7%) were HIV positive. Pulmonary infections were the most common source of sepsis. In-hospital mortality rate was 64.2% in the intervention group and 60.7% in the control group (relative risk, 1.05; 95% CI, 0.79–1.41). Mycobacterium tuberculosis complex was isolated from 31 of 82 HIV-positive patients (37.8%) with available mycobacterial blood culture results. Patients in Simplified Severe Sepsis Protocol received significantly more IV fluids in the first 6 hours (2.7 L vs 1.7 L, p = 0.002). The study was stopped early because of high mortality rate among patients with hypoxemic respiratory failure in the intervention arm (8/8, 100%) compared with the control arm (7/10, 70%; relative risk, 1.43; 95% CI, 0.95–2.14).

Conclusion: Factors other than tissue hypoperfusion probably account for much of the end-organ dysfunction in African patients with severe sepsis. Studies of fluid-based interventions should utilize inclusion criteria to accurately capture patients with hypovolemia and tissue hypoperfusion who are most likely to benefit from fluids. Exclusion of patients with severe respiratory distress should be considered when ventilatory support is not readily available.

1Institute for Global Health, Vanderbilt University, Nashville, TN.

2Division of General Internal Medicine and Public Health, Department of Internal Medicine, Vanderbilt University, Nashville, TN.

3Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia.

4Barts and the London School of Medicine, London, United Kingdom.

5Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia.

6Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, TN.

* See also p. 2439.

This work was performed at the University Teaching Hospital and the University of Zambia, School of Medicine in Lusaka, Zambia.

Supported, in part, by the grant R24 TW007988 from the National Institutes of Health Office of the Director and Fogarty International Center through the International Clinical Research Fellows Program at Vanderbilt University.

Dr. Andrews received support for article research from the National Institutes of Health (NIH). His institution received grant support and support for travel from the NIH/Fogarty International Center. Dr. Muchemwa received grant support and support for travel from the NIH/Fogarty International Center and received support for article research from the NIH. Dr. Heimburger received support for travel from and served as board member for Dannon Research Institute and received book royalties from Elsevier. His institution received grant support from the NIH/Fogarty International Center. Dr. Bernard received support for article research from the NIH. His institution received grant support (drug supplies for ARDSnet SAILS trial). The remaining authors have disclosed that they do not have any potential conflicts of interest.

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