Therapeutic hypothermia (TH) has been shown to be effective in improving outcomes in adults and neonates with hypoxic-ischemic encephalopathy. The theory is that TH can diminish the secondary injury by decreasing the brain’s metabolic demands, the amount of inflammation and lipid peroxidation, and the excitotoxicity that occurs with brain injuries. Because of these effects , as well as successful studies in animal models, attempts have been made to use TH to improve outcomes in patients who have sustained traumatic brain injury (TBI). However, clinical trials have not definitively shown any improvement in clinical outcomes. The design of the Cool Kids trial altered some of the parameters used in the previous phase 3 trials – specifically, starting the cooling process earlier and continuing it for longer – in hopes of bolstering outcomes.
In this phase 3, multicenter, randomized controlled trial, reported in the June issue of The Lancet Neurology, Adelson and colleagues recruited TBI patients younger than 18 years who had a Glasgow Coma Scale score between 3 and 8 (with a motor component less than 6) and who were available for randomization within 6 hours of the injury. Those that met inclusion criteria were randomly assigned in a 1:1 ratio and were stratified by site and age to either the hypothermia or normothermia group.
Patients in the hypothermia group were rapidly cooled to 34-35 °C using iced saline, then surface cooled to 32-33°C for 48 hours. Next, they were slowly rewarmed by 0.5-1°C every 12-24 hours. If the intracranial pressures (ICPs) were greater than 20 mm Hg during the rewarming, an additional 24 hours of cooling was instituted, after which rewarming was reinstituted regardless of ICP. Patient temperatures in the normothermic group were maintained between 36.5°C and 37.5°C. Other therapies used in the management of TBI were based on pediatric guidelines. The primary outcome was mortality at 3 months after injury. Secondary outcome measures included Glasgow Outcome Scale scores, Glasgow Outcome Scale–Extended Pediatric scores (both at 3 months after injury), number of interventions to maintain appropriate ICP (using a mean pediatric intensity level of therapy score), and serious adverse events.
Because of slow accrual and concerns about safety data from a previous pediatric TH trial, a futility analysis was done and the trial was stopped early. Seventy-seven patients had been recruited: 39 in the hypothermia group and 38 in the normothermia group. Baseline characteristics between the two groups were similar. The primary outcome of mortality within 3 months did not differ between the groups. Likewise, no differences were detected in the two Glasgow Outcome Scale scores. Although the normothermic group underwent decompressive craniectomy (DC) more commonly than the hypothermic group, there were no differences between the groups in the pediatric intensity level of therapy scores. Finally, no differences were seen in the number of serious adverse events.
The authors cited a number of limitations to the study. Despite consensus by the investigators to a step-wise management of these TBI patients, some variations in practice did occur, namely the increased use of DC in normothermic patients. Additionally, tracking daily patterns of ICP means may have explained the lack of difference in level of therapy scores. More importantly, the authors acknowledge the possibility that TH may have a positive effect on a particular type of TBI pathology – i.e., diffuse injury versus surgically evacuated hematomas – a factor which could not be tested in this cohort. Future testing of this hypothesis will be difficult, as researchers will have trouble arguing clinical equipoise, given the lack of positive findings in any phase 3 TH trial.
This Concise Critical Appraisal is authored by SCCM member Daniel E. Sloniewsky, MD. Each installment highlights journal articles most relevant to the critical care practitioner. Daniel Sloniewsky is an Associate Professor in the Department of Pediatrics at the Stony Brook Long Island Children’s Hospital in Stony Brook, NY, where he is board certified in Pediatrics and Pediatric Critical Care. He completed his Fellowship training at Children’s Memorial Hospital and Northwestern University in Chicago. His major interests are in acute pediatric pulmonary disease, transfusion medicine and ethics. He is also actively involved in resident education, Pediatric Advanced Life Support and Pediatric FCCS instruction.