Good morning
             Today we discuss the findings of the EUROTHERM3235 study.
Therapeutic hypothermia to reduce intracranial pressure after traumatic brain injury: the Eurotherm3235 RCT
Peter JD Andrews et al
HEALTH TECHNOLOGY ASSESSMENT VOLUME 22 ISSUE 45 AUGUST 2018

Therapeutic hypothermia (TH) has been a tool for trying to optimize outcomes in various situations encountered in neuro critical care.
TBI and Post Cardiac Arrest situations are the two most commonly used cohorts for evaluating TH
EUROTHERM3235 was a multi centre study which attempted to evaluate whether TH between 32-35 C improves outcomes and decreases mortality at 6 months following TBI. In addition, the secondary outcomes studied included benefits related to intra cranial pressure and cost effectiveness.
The covariates ( or sub groups) identified at the beginning of randomization included
1. trial centre
2. aged < 45 years or ≥ 45 years
3. post-resuscitation Glasgow Coma Scale (GCS) motor component score of 1 or 2 or 3–6
4. time from injury < 12 hours or ≥ 12 hours
5. pupils – both reacting or one or neither reacting.

Hypothermia was initiated with 20–30 ml/kg of refrigerated 0.9% saline given intravenously and maintained using the cooling technique available at each centre.
The depth of hypothermia (32–35 °C) was guided by intracranial pressure (ICP), with a higher pressure level warranting a cooler target temperature. TH of 32–35 °C was maintained for at least 48 hours and continued for as long as was necessary to reduce and maintain ICP at < 20 mmHg.
Since initiation of hypothermia could not be blinded, the outcome assessment was done by a blinded researcher.
Screening for inclusion was done up to ten days after the injury.

Inclusion criteria were
Primary closed TBI.
Raised ICP of > 20 mmHg for ≥ 5 minutes after first-line treatments with no obvious reversible cause (e.g. patient position, coughing, inadequate sedation).
≤ 10 days from the initial head injury.
Cooling device or technique available for > 48 hours.
Core temperature of ≥ 36 °C (at the time of randomization).
An abnormal CT scan of the brain, defined as one that shows haematoma, contusion, swelling,
herniation or compressed basal cisterns.

Exclusion criteria were
Patient already receiving TH treatment.
Administration of barbiturate infusion prior to randomisation.
Unlikely to survive for the next 24 hours in the opinion of the ICU consultant or consultant
neurosurgeon treating the patient.
Temperature of ≤ 34 °C at hospital admission.
Pregnancy.

Only centres well versed in ICP management and TH protocols were enrolled. More than half of the eligible centres were in the UK.
A total of 387 participants from 64 centres in 18 countries were randomized.
This study was stopped midway as the steering committee felt that there was possibility of harm with the use of TH. Futility was the outcome predicted.
The odds ratio for unfavorable outcome with TH was 1.69.
The results of the primary analysis were unexpected and showed that participants in the hypothermia
group had significantly poorer outcomes at 6 months (p = 0.04) and a higher mortality rate (p = 0.05) than those treated with standard care alone.
 ICP control also did not differ in the two groups.
At best, a result of futility would be expected if the trial were to continue.
There were signs of harm with the treatment being evaluated.
These signs included increased mortality in participants assigned to the treatment being evaluated and
fewer participants assigned to the treatment being evaluated achieving ‘good recovery’ on the GOSE at the designated outcome assessment point of 6 months after inclusion.

Summary: TH does not appear to be safe in patients being treated for TBI

My views: This is another good physiological concept which has not yielded clinical results. Probably factors other than ICP (and CPP) determine the outcome after TBI