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.
To test the hypothesis that induced hypothermia improves outcome in patients with severe
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.
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
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.
clinicaltrials.gov Identifier: NCT00774631