BACKGROUND AND OBJECTIVE:Therapeutic hypothermia is now the standard of care for hypoxic-ischemic encephalopathy. Treatment should be started early, and it is often necessary to transfer the infant to a regional NICU for ongoing care. There are no large studies reporting outcomes from infants cooled passively compared with active (servo-controlled) cooling during transfer. Our goal was to review data from a regional transport service, comparing both methods of cooling.
METHODS:This was a retrospective observational study of 143 infants referred to a regional NICU for ongoing therapeutic hypothermia. Of the 134 infants transferred, the first 64 were cooled passively, and 70 were subsequently cooled after purchase of a servo-controlled mattress. Key outcome measures were time to arrival at the regional unit, temperature at referral and arrival at the regional unit, and temperature stability during transfer.
RESULTS:The age cooling was started was significantly shorter in the actively cooled group (46 [0–352] minutes vs 120 [0–502] minutes;P<.01). The median (range) stabilization time (153 [60–385] minutes vs 133 [45–505] minutes;P= .04) and age at arrival at the regional unit (504 [191–924] minutes vs 452 [225–1265]) minutes;P= .01) were significantly shorter in the actively cooled group. Only 39% of infants passively cooled were within the target temperature range at arrival to the regional unit compared with 100% actively cooled.
CONCLUSIONS:Servo-controlled active cooling has been shown to improve temperature stability and is associated with a reduction in transfer time.
On the basis of mixed results from previous trials, we assessed whether therapeutic hypothermia for 48-72 h with slow rewarming improved mortality in children after brain injury.
In this phase 3, multicenter, multinational, randomised controlled trial, we included patients with severe traumatic brain injury who were younger than 18 years and could be enrolled within 6 h of injury. We used a computer-generated randomisation sequence to randomly allocate patients (1:1; stratified by site and age [<6 years, 6-15 years, 16-17 years]) to either hypothermia (rapidly cooled to 32-33°C for 48-72 h, then rewarmed by 0·5-1·0°C every 12-24 h) or normothermia (maintained at 36·5-37·5°C). The primary outcome was mortality at 3 months, assessed by intention-to-treat analysis; secondary outcomes were global function at 3 months after injury using the Glasgow outcome scale (GOS) and the GOS-extended pediatrics, and the occurrence of serious adverse events. Investigators assessing outcomes were masked to treatment. This trial is registered with ClinicalTrials.gov, number NCT00222742.
The study was terminated early for futility after an interim data analysis on data for 77 patients (enrolled between Nov 1, 2007, and Feb 28, 2011): 39 in the hypothermia group and 38 in the normothermia group. We detected no between-group difference in mortality 3 months after injury (6 [15%] of 39 patients in the hypothermia group vs two [5%] of 38 patients in the normothermia group; p=0·15). Poor outcomes did not differ between groups (in the hypothermia group, 16 [42%] patients had a poor outcome by GOS and 18 [47%] had a poor outcome by GOS-extended paediatrics; in the normothermia group, 16 [42%] patients had a poor outcome by GOS and 19 [51%] of 37 patients had a poor outcome by GOS-extended paediatrics). We recorded no between-group differences in the occurrence of adverse events or serious adverse events.
Hypothermia for 48 h with slow rewarming does not reduce mortality of improve global functional outcome after paediatric severe traumatic brain injury.
The authors hypothesized that cooling before evacuation of traumatic intracranial hematomas protects the brain from reperfusion injury and, if so, further hypothesized that hypothermia induction before or soon after craniotomy should be associated with improved outcomes.
The National Acute Brain Injury Study: Hypothermia I (NABIS:H I) was a randomized multicenter clinical trial of 392 patients with severe brain injury treated using normothermia or hypothermia for 48 hours with patients reaching 33°C at 8.4 ± 3 hours after injury. The National Acute Brain Injury Study: Hypothermia II (NABIS:H II) was a randomized, multicenter clinical trial of 97 patients with severe brain injury treated with normothermia or hypothermia for 48 hours with patients reaching 35°C within 2.6 ± 1.2 hours and 33°C within 4.4 ± 1.5 hours of injury. Entry and exclusion criteria, management, and outcome measures in the 2 trials were similar.
In NABIS:H II among the patients with evacuated intracranial hematomas, outcome was poor (severe disability, vegetative state, or death) in 5 of 15 patients in the hypothermia group and in 9 of 13 patients in the normothermia group (relative risk 0.44, 95% CI 0.22–0.88; p = 0.02). All patients randomized to hypothermia reached 35°C within 1.5 hours after surgery start and 33°C within 5.55 hours. Applying these criteria to NABIS:H I, 31 of 54 hypothermia-treated patients reached a temperature of 35°C or lower within 1.5 hours after surgery start time, and the remaining 23 patients reached 35°C at later time points. Outcome was poor in 14 (45%) of 31 patients reaching 35°C within 1.5 hours of surgery, in 14 (61%) of 23 patients reaching 35°C more than 1.5 hours of surgery, and in 35 (60%) of 58 patients in the normothermia group (relative risk 0.74, 95%, CI 0.49–1.13; p = 0.16). A meta-analysis of 46 patients with hematomas in both trials who reached 35°C within 1.5 hours of surgery start showed a significantly reduced rate of poor outcomes (41%) compared with 94 patients treated with hypothermia who did not reach 35°C within that time and patients treated at normothermia (62%, p = 0.009).
Induction of hypothermia to 35°C before or soon after craniotomy with maintenance at 33°C for 48 hours thereafter may improve outcome of patients with hematomas and severe traumatic brain injury. Clinical trial registration no.: NCT00178711.