Inducing hypothermia in patients with severe bacterial meningitis offers no clinical benefit and might, in fact, be harmful, according to a clinical trial conducted in France.
Investigators had planned to enroll up to 318 patients in a randomized trial comparing hypothermia treatment to standard care, conducted at 49 intensive care units in France between February 2009 and November 2011. They halted the trial, however, after enrolling the first 98 patients because of concerns by the data and safety monitoring board about excess mortality among those randomized to receive hypothermia treatment, which consisted of a loading dose of 4°C/39°F cold saline and cooling the patient to 32°C/90°F to 34°C/93°F for 48 hours, then passive warming. The trial was led by Dr. Bruno Mourvillier of the Groupe Hospitalier Bichat-Claude Bernard in Paris.
Twenty-five of 49 patients (51%) in the hypothermia group died, compared with 15 of 49 patients (31%) receiving standard care (relative risk, 1.99). Pneumococcal meningitis was diagnosed in 77% of patients. At 3 months, 42 of 49 patients (86%) in the hypothermia group and 36 of 49 patients (74%) in the control group had an unfavorable outcome (RR, 2.17), as gauged by the Glasgow Outcome Scale.
After adjustment for age, scores on the Glasgow Coma Scale at the point of study inclusion, and the presence of septic shock at study inclusion, mortality remained higher in the hypothermia group, but not significantly (hazard ratio, 1.76). However, a post hoc analysis showed a low probability to reach statistical significance in favor of hypothermia by the end of the three original planned stages of the trial.
The study, published online (JAMA 2013 Oct. 8 [doi:10.1001/jama.2013.280506]), was released at the European Society of Intensive Care Medicine’s annual congress in Paris.
Potential mechanisms behind the mortality difference "remain unclear," the authors wrote, noting that they found no difference in nosocomial infections, hemorrhage, cardiovascular effects, or hyperglycemia between the treatment groups. In addition, no significant differences were found in baseline characteristics. All patients received mechanical ventilation and were severely ill, with an average Glasgow Coma Scale rating of 7.
In animal model studies of meningitis, moderate hypothermia has shown favorable effects, such as lowering intracranial pressure and reducing cerebral injury, Dr. Mourvillier and associates noted. They hypothesized that hypothermia would improve functional outcome at 3 months.
"Our trial does not support the use of hypothermia in adults with severe meningitis," they concluded. "Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Our results may have important implications for future trials on hypothermia in patients presenting with septic shock or stroke."
Careful evaluation of safety issues in ongoing trials is needed, they said.
The study was supported by the French Ministry of Health, IST Cardiology, and Covidien. The authors reported no conflicts of interest.