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Prediction of mortality may improve management and outcomes of patients with sepsis in resource-limited settings. Therefore, we evaluated the ability of a hand-held portable whole-blood lactate (PWBL) analyzer to predict mortality of patients who are admitted to the hospital with severe sepsis.A prospective observational study enrolled 253 patients at a national referral hospital in Uganda. Inclusion criteria required (1) ≥2 systemic inflammatory response syndrome criteria or thermodysregulation, (2) hypotension, and (3) suspected infection. A subset of 72 patients had PWBL and standard laboratory serum lactate measured. The primary measured outcome was in-hospital mortality.Fifty-nine (81.9%) of 72 evaluated patients were infected with human immunodeficiency virus type 1. The in-hospital mortality rate was 25.7% (18 of 70), and the in- and outpatient mortality at 30 days was 41.6% (30 of 72). PWBL was positively associated with in-hospital but not outpatient mortality (P<.001). The receiver operating characteristic area under the curve for PWBL was 0.81 (P<.001). The optimal PWBL concentration for predicting in-hospital mortality (sensitivity, 88.3%; specificity, 71.2%) was ≥4.0 mmol/L. Patients with a PWBL concentration ≥4.0 mmol/L died while in the hospital substantially more often (50.0%) than did those with a PWBL concentration <4.0 mmol/L (7.5%) (odds ratio, 12.3; 95% confidence interval, 3.5-48.9; P<.001). Standard laboratory serum lactate results were inconsistent and less predictive of mortality than were those of PWBL in a multiple logistic regression model.A PWBL concentration ≥4.0 mmol/L predicts with 81% accuracy a 7-fold higher mortality of patients with sepsis than does a PWBL concentration <4.0 mmol/L. PWBL testing would be useful in places where clinical decisions are limited by lack of laboratory infrastructure and poor reliability.