Induced hypothermia in severe bacterial meningitis: a randomized clinical trial

Bruno Mourvillier, Florence Tubach, Diederik van de Beek, Denis Garot, Nicolas Pichon, Hugues Georges, Laurent Martin Lefevre, Pierre-Edouard Bollaert, Thierry Boulain, David Luis, Alain Cariou, Patrick Girardie, Riad Chelha, Bruno Megarbane, Arnaud Delahaye, Ludivine Chalumeau-Lemoine, Stéphane Legriel, Pascal Beuret, François Brivet, Cédric Bruel, Fabrice Camou, Delphine Chatellier, Patrick Chillet, Bernard Clair, Jean-Michel Constantin, Alexandre Duguet, Richard Galliot, Frédérique Bayle, Hervé Hyvernat, Kader Ouchenir, Gaetan Plantefeve, Jean-Pierre Quenot, Jack Richecoeur, Carole Schwebel, Michel Sirodot, Marina Esposito-Farèse, Yves Le Tulzo, Michel Wolff
JAMA: the Journal of the American Medical Association 2013 November 27, 310 (20): 2174-83

IMPORTANCE: Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia.

OBJECTIVE: To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis.

DESIGN, SETTING, AND PATIENTS: An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized.

INTERVENTIONS: Hypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care.

MAIN OUTCOMES AND MEASURES: Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients.

RESULTS: After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977).

CONCLUSIONS AND RELEVANCE: Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke.

TRIAL REGISTRATION: Identifier: NCT00774631.

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