EUROTHERM

Andrews 2015

Hypothermia had poorer outcome and mortality

In patients with traumatic brain injury (TBI), does hypothermia (32-35°C) and standard care compared to standard care alone reduce death and major disability at 6 months after injury?
Multi-centre, multi-country RCT with a weighted recruitment to increase UK population
Centralised randomisation with minimisation procedure to balance centre, age, GCS motor score, time from injury and pupillary response
Appropriate concealment of allocation until inclusion
Open-label – patients, families and treating clinicians aware
Outcome assessor blinded
Pilot trial period with subsequent adjustment of inclusion criteria and target sample size
Powered at 80% to detect a 9% absolute reduction in the rate of unfavourable outcomes from an expected incidence of 60% in the standard care group with 0.05 two-sided alpha significance level, if 600 patients were included

This was initially 1800, but this was adjusted after the pilot trial period identified a higher incidence of pathology with raised intracranial pressure in the study population and a change in the statistical method (ordinal analysis of outcome measure rather than binomial)

The inclusion criteria was changed during the study to remove an upper age limit (previously 65 years) and to increase the time from injury from 72 hours to 10 days
Early termination risks bias (tends to over estimate effect magnitude) however remaining results collected after termination did not show regression toward the mean suggesting this is not the case in this trial
Loss of outcome data for 10 cases (given fragility index was 3, these 10 could have changed the result significantly)
Lack of data on additional Stage 2 therapies limits opportunity to draw new hypotheses – it could be that some other Stage 2 therapy caused the harm / benefit effect seen in this trial and that hypothermia was not the causal therapy
In patients with elevated intracranial pressure after TBI, therapeutic hypothermia, in addition to standard treatment, results in a greater risk of death and worse neurological outcomes in survivors compared to standard measures