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Original Investigation | Caring for the Critically Ill Patient

Induced Hypothermia in Severe Bacterial Meningitis:  A Randomized Clinical Trial

Bruno Mourvillier, MD1; Florence Tubach, MD, PhD2; Diederik van de Beek, MD, PhD3; Denis Garot, MD4; Nicolas Pichon, MD5; Hugues Georges, MD6; Laurent Martin Lefevre, MD7; Pierre-Edouard Bollaert, MD8; Thierry Boulain, MD9; David Luis, MD10; Alain Cariou, MD11; Patrick Girardie, MD12; Riad Chelha, MD13; Bruno Megarbane, MD, PhD14; Arnaud Delahaye, MD15; Ludivine Chalumeau-Lemoine, MD16 ; Stéphane Legriel, MD17; Pascal Beuret, MD18 ; François Brivet, MD19; Cédric Bruel, MD20; Fabrice Camou, MD21; Delphine Chatellier, MD22; Patrick Chillet, MD23; Bernard Clair, MD24; Jean-Michel Constantin, MD25; Alexandre Duguet, MD26; Richard Galliot, MD27; Frédérique Bayle, MD28; Hervé Hyvernat, MD29; Kader Ouchenir, MD30; Gaetan Plantefeve, MD31; Jean-Pierre Quenot, MD32; Jack Richecoeur, MD33; Carole Schwebel, MD34; Michel Sirodot, MD35; Marina Esposito-Farèse, PhD2; Yves Le Tulzo, MD, PhD36; Michel Wolff, MD1
[+] Author Affiliations
1Réanimation Médicale et Infectieuse, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Bichat-Claude Bernard, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
2Département d’Epidémiologie et Recherche Clinique, Assistance Publique-Hôpitaux de Paris Hopital Bichat, INSERM, CIE 801, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
3Department of Neurology, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
4Service de Réanimation Médicale, Centre Hospitalier Universitaire de Tours–Hôpital Bretonneau, Tours, France
5Réanimation Medico-Chirurgicale, Centre Hospitalier Universitaire Dupuytren, Limoges Cedex, Cedex, France
6Réanimation Polyvalente et Maladies Infectieuses, Centre Hospitalier Universitaire de Tourcoing, Tourcoing, France
7Centre Hospitalier Departemental Les Oudaries, Service de Réanimation Polyvalente, La Roche-sur-Yon, France
8Centre Hospitalier Universitaire de Nancy, Hopital Central, Service de Réanimation Médicale, Nancy, France
9Service de Réanimation Polyvalente, Centre Hospitalier Regional Orléans, Orléans, France
10Service de Réanimation Médico-Chirurgicale, Centre Hospitalier Universitaire Jean Verdier, Assistance Publique-Hôpitaux de Paris, Bondy, France
11Service de Réanimation Médicale, Paris, France, Centre Hospitalier Universitaire Cochin-Saint-Vincent de Paul-Site Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France
12Service de Réanimation Polyvalente, Centre Hospitalier Regional Universitaire de Lille-Hôpital Roger Salengro, Lille, France
13Service de Réanimation Polyvalente, Centre Hospitalier Intercommunal André Grégoire Montreuil, Montreuil, France
14Service de Réanimation Médicale et Toxicologique, Centre Hospitalier Universitaire Lariboisière Assistance Publique-Hôpitaux, Paris, France
15Service de Réanimation Polyvalente, Centre Hospitalier, Rodez, France
16 Service de Réanimation Médico-Chirurgicale, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Tenon, Paris, France
17Service de Réanimation, Centre Hospitalier de Versailles, Le Chesnay, France
18 Service de Réanimation Médico-Chirurgicale, Centre Hospitalier, Roanne, Fance
19Réanimation Médicale Centre Hospitalier Universitaire Antoine Beclère, Assistance Publique-Hôpitaux de Paris, Clamart, France
20Service de Réanimation Polyvalente, Groupe Hospitalier Paris Saint-Joseph, Paris, France
21Réanimation Médicale, Hôpital Saint André, Centre Hospitalier Universitaire, Bordeaux, France
22Service de Réanimation Medicale, Centre Hospitalier Universitaire , Poitiers, France
23Service de Réanimation Polyvalente, Centre Hospitalier, Châlons-en-Champagne, France
24Service de Réanimation Médico-Chirurgicale, Assistance Publique-Hôpitaux de Paris, Garches, France
25Service de Réanimation Adultes and USC, Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France
26Service de Pneumologie et Réanimation Médicale, Centre Hospitalier Universitaire La Pitié-Salpêtrière Assistance Publique-Hôpitaux de Paris, Paris, France
27Réanimation Polyvalente, Hôpital Foch, Suresnes, France
28Service de Réanimation Médicale et Respiratoire, Centre Hospitalier Universitaire Hôpital de la Croix Rousse, Lyon, France
29Service de Réanimation Médicale, Hôpital de l’Archet, Nice, France
30Réanimation Polyvalente, Les Hôpitaux de Chartres, Chartres, France
31Service de Réanimation Polyvalente, Centre Hospitalier, d'Argenteuil, France
32Service de Réanimation Médicale, Centre Hospitalier Universitaire, Dijon, France
33Service de Réanimation Médico-Chirurgicale, CH René Dubos, Pontoise, France
34Service de Réanimation Médicale, Centre Hospitalier Universitaire Hôpital A. Michallon, La Tronche, France
35Service de Réanimation Polyvalente, Centre Hospitalier de la Région d’Annecy, Pringy, France
36Service de Réanimation Médicale et Infectieuse, Centre Hospitalier Universitaire Hôpital Pontchaillou, Rennes, France
JAMA. 2013;310(20):2174-2183. doi:10.1001/jama.2013.280506.
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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  clinicaltrials.gov Identifier: NCT00774631

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Figures

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Figure 1.
Flow Diagram of Patients

GCS indicates Glasgow Coma Scale.aOther reasons for exclusion were pregnancy, positive cryptococcal test result, brain abscess, or complications requiring therapeutic hypothermia, such as cardiac arrest. Patients were also excluded if the physician in charge decided to limit life support, if the patient had no medical insurance, or if the individual was included in another interventional study. Among these 7 excluded, 2 patients were missed.

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Figure 2.
Body Temperature of Patients With Severe Meningitis During First 48 Hours After Randomization Between Hypothermia and Standard Therapy
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Figure 3.
Three-Month Scores on Glasgow Outcome Scale of Patients With Severe Bacterial Meningitis Treated With Hypothermia or Standard Therapy
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Figure 4.
Kaplan-Meier Estimates of Survival of Patients With Severe Bacterial Meningitis Treated With Hypothermia or Standard Therapy

Three-month survival curves were compared with a univariate Cox proportional hazards regression model.

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