Andrews PJ, Sinclair HL, Rodriguez A, Harris BA, Battison CG, Rhodes JK, et al
. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med
2015; [Epub ahead of print].
Use of hypothermia in medical practice dates back to the ancient Greek physicians
who used it in patients of haemorrhage and trauma. In current medical practice, therapeutic
hypothermia is largely used as a neuroprotectant in patients of out-of-hospital cardiac
arrest and neonatal hypoxic-ischaemic encephalopathy. Its role in patients of traumatic
brain injury (TBI) is conflicting. A meta-analysis in 2008 found a trend towards better
outcome with hypothermia in TBI, if cooling was maintained for more than 48 h.[1] Eurotherm3235 (The European Study of Therapeutic Hypothermia [32–35°C] for intracranial
pressure [ICP] reduction after TBI) was designed keeping in mind the lessons learnt
from the past and to overcome the fallacies of previous trials.
It was a multicenter, randomised controlled trial that tested titrated therapeutic
hypothermia to standard management to control raised ICP on patient outcome. The treatment
options for raised ICP were stratified into three stages. Stage 1 interventions included
mechanical ventilation, head elevation, analgesia ± muscle paralysis and intravenous
fluids with/without inotropes to maintain a mean arterial pressure of ≥80 mmHg. It
also permitted ventriculostomy with or without cerebrospinal fluid drainage/surgical
removal of space-occupying lesions. Stage 2 treatment options included hyper-osmolar
therapy and inotropes to maintain a cerebral perfusion pressure (CPP) ≥60 mmHg ± therapeutic
hypothermia. Use of barbiturates was not allowed at this stage. Patients not responding
to Stage 2 methods were treated with Stage 3 interventions including barbiturate therapy
and decompressive craniectomy. All patients admitted to Intensive Care Unit (ICU)
after TBI with ICP monitoring in place were screened. Two thousand four hundred and
ninety eight patients from 55 centres in 18 countries were assessed for eligibility
for inclusion in the trial, of which 387 patients from 47 centres were randomised.
The trial included adult patients with primary closed TBI with an abnormal computed
tomography scan of brain and an ICP >20 mmHg for ≥5 min resistant to Stage 1 therapy.
The core temperature ≥36°C at the time of randomisation. Enrolment of patients was
initially allowed for upto 72 h after injury but was increased to 10 days after injury,
after the pilot phase, to include those with evolving brain swelling. An upper age
limit of 65 years was also removed after the pilot phase to include older patients.
Patients already receiving therapeutic hypothermia or barbiturate infusion, those
unlikely to survive for next 24 h, temperature ≤34°C at hospital admission and pregnant
were excluded. Patients randomised to control group received standard care whereas
those randomised to study group received therapeutic hypothermia in addition to standard
Stage 2 treatment to control raised ICP. Induction of hypothermia was done with 20–30
ml/kg of refrigerated 0.9% saline given over 20–30 min and maintained with the cooling
technique available at the centre. Hypothermia was continued for a minimum of 48 h
or as long as required to maintain ICP <20 mmHg. Guideline was provided for detection
and treatment of shivering. Rewarming at a rate of 0.25°C/h was considered after a
minimum period of 48 h if ICP was <20 mmHg, or if Stage 3 therapy was required. Outcome
assessment was done using the Extended Glasgow Outcome Scale at 6 months. Other variables
studied were 6 months mortality rate, ICP control, incidence of pneumonia and other
serious adverse events (bleeding, cardiovascular instability, thermal burns, CPP <50
mmHg), length of ICU and hospital stay, modified Oxford Handicap Scale at 1 month,
discharge or death and economics. The trial initially aimed to enrol a total of 1800
patients which was reduced to 600 patients after the pilot phase, but, recruitment
had to be stopped in October 2014 for safety concerns. The study found that Stage
3 interventions were required in 54% and 44% patients in control and study group,
respectively. Stage 2 treatment failure was seen less frequently in hypothermia group.
Barbiturate infusion was used more frequently in the control group but not in patients
who underwent decompressive craniectomy. A worse outcome was observed in the study
group at 6 months (adjusted common odds ratio 1.53, P = 0.04). A favourable outcome occurred in 25.7% and 36.5% patients in hypothermia
and control group, respectively (P = 0.03). Serious adverse events occurred more often in hypothermia group (33 events
vs. 10 events). There was no significant difference based on the time from injury
to initiation of hypothermia (<12 h vs. ≥12 h). The authors concluded that in patients
of TBI with intracranial hypertension, use of therapeutic hypothermia along with standard
care did not result in improved outcome than with standard care alone though there
is a risk of bias since the trial was stopped early due to safety concerns.
Although therapeutic hypothermia has been studied in TBI earlier, none of the trials
so far have been able to establish its neuroprotective role with certainty. Its ability
to reduce ICP is known but improvement in patient outcome has not been established
so far. A Cochrane meta-analysis (2009) of 23 trials concluded that there is no evidence
that hypothermia is beneficial in TBI. It reduced unfavourable outcomes in low-quality
trials only.[2] A more recent systematic review by Crossley et al., suggested that therapeutic hypothermia may be beneficial in TBI, but again, the
majority of trials included were of low quality.[3] In a recent trial by Maekawa et al. compared prolonged mild therapeutic hypothermia (32–34°C) for ≥ 72 h and slower
rewarming (<1°C/day) with fever control (35.5–37°C). They found no significant difference
in the likelihood of poor neurological outcome between the two groups.[4] With conflicting evidence still continuing, the debate about the effectiveness of
therapeutic hypothermia in TBI is likely to continue. The choice of this treatment
modality in TBI largely remains individual and dependent on familiarity with cooling
techniques, local expertise and protocols.
