This randomized controlled trial compared outcomes for patients with traumatic brain injury (TBI) and intracranial hypertension who received therapeutic hypothermia (32-35°C) plus standard care versus standard care alone. The trial was stopped early due to higher mortality in the hypothermia group. At 6 months, functional outcomes as measured by the GOSE were worse in the hypothermia group. While hypothermia successfully controlled intracranial pressure, it did not result in improved outcomes compared to standard care alone and was associated with higher mortality.

1. MACQUARIE NEUROSURGERY JOURNAL CLUB
14/04/16
14/04/16
Dr Michael Mulcahy

2. MACQUARIE NEUROSURGERY
JOURNAL CLUB
Andrews PJ, Sinclair HL, Rodriguez A, Harris BA, Battison CG, Rhodes JK, Murray GD;
Eurotherm3235 Trial Collaborators.
Hypothermia for Intracranial Hypertension after Traumatic
Brain Injury
The New England Journal of Medicine, Dec 2015, volume 373, issue 25, pp2403-12.

3. Authors
• Chief investigator: Professor Peter Andrews, Western General Hospital,
Edinburgh
• 6 co-authors and 154 Eurotherm3235 collaborators
• Funded by National Institute for Health Research Health Technology
Assessment program (UK Department of Health)
• Pilot phase funded by The European Society
of Intensive Care Medicine
• Trial sponsors: University of Edinburgh and
NHS Lothian

4. Disclosures
•International committee of medical journal editors (ISMJE) disclosure form
•P.Andrews reported lecturing fees from Bard and Integra LifeSciences
•J.Rhodes reported lecturing fees from Bard

5. Study Relevance
• TBI is underrepresented in medical research compared with other health
problems
• There is little evidence supporting the common interventions to treat
intracranial hypertension
• General observation of ICP reduction associated with hypothermia
• Trend towards benefit for hypothermia in low quality trials, but…

6. Study Relevance

7. Study Relevance
•Meta-analyses have been inconsistent due to variability in the RCTs
•Examples:
- presence of intracranial hypertension
- ICP or CT as inclusion criteria
- duration of cooling
- rate of re-warming
- use of barbiturates

8. Originality
•Raised ICP only
•Duration of hypothermia
•Rapid induction of hypothermia
•Slow rewarming

9. Study Hypothesis
• Patients treated with therapeutic hypothermia (32-35o
C) have reduced morbidity
and mortality rates compared to those receiving standard care alone after TBI.
• Primary outcome: GOSE score at 6 months
• Secondary outcomes:
• 6 month mortality rate
• ICP control
• Incidence of pneumonia
• Length of stay in ICU and hospital
• MOHS
• Correlation between MOHS at discharge and GOSE at 6 months

10. Study Protocol

11. Study Design
• RCT
• Interventional
• Pragmatic
• Multi-centre (25 UK centres, 39 elsewhere)
• Open-label

12. Study Design

13. Study Design
Hypothermia:
• initiated with 20-30ml/kg refrigerated 0.9% saline given intravenously
• maintained using cooling systems available
• maintained for at least 48hours
• Depth (from 32-35 degrees) is guided by ICP
• If stage 3 treatments required, hypothermia is terminated
Follow up:
• Participants are sent the GOSE questionnaire by post at 6 months
• Letter is also sent to the person who gave consent for the trial

14. Study Design
Inclusion criteria:
• ? to 65
• primary closed TBI
• raised ICP >20mmHg for >5min after first line treatments with no obvious
reversible cause
• <72 hours from initial head injury
• cooling devices or techniques available for >48hours
• core temperature >36o
C at time of randomisation
• abnormal CT

15. Study Design
Inclusion criteria:
• ? to 65
• primary closed TBI
• raised ICP >20mmHg for >5min after first line treatments with no obvious
reversible cause
• <72 hours from initial head injury
• cooling devices or techniques available for >48hours
• core temperature >36o
C at time of randomisation
• abnormal CT

16. Study Design
Exclusion criteria
• already receiving therapeutic hypothermia
• administration of barbiturate prior to randomisation
• unlikely to survive for the next 24 hours
• temperature <34o
C
• pregnancy

17. Population

18. Internal Validity
Sample size/power
• Aimed to detect an absolute decrease in poor outcome of 7%
• 80% power
• Two groups of 815 would detect a decrease in poor outcome from 60% to
53%
• Aimed for two groups of 900 (loss to follow up)
• However…

19. Internal Validity
Sample size/power
• After the pilot, this was revised to a total sample size of 600
• Using a dichotomous analysis of GOSE, this would give 81% power to
detect an absolute reduction of 12% (60 to 48%)
• Using an ordinal analysis of GOSE scores with covariate adjustment leads
to a trial of 600 being equivalent to 1000 that assessed a binary outcome
• This will give 80% power at the 5% significance (two sided) to detect an
absolute reduction in poor outcome of 9% (from 60% to 51%)

20. Internal Validity
Randomisation
• Used either a central internet based randomisation service, or a telephone
randomisation service
• Minimisation, stratified by:
• trial centre
• age < or > 45
• post-resuscitation GCS motor component 1-2 or 3-6
• time from injury < or > 12 hours
• pupils: both reacting or 1 or neither reacting

21. Internal Validity
Blinding
• Investigators were not blinded
• Primary outcome data assessment was blinded

22. Internal Validity
Statistical Analysis
• SAS software, version 9.3
• Intention-to-treat analysis
• Ordinal logistic regression to analyse the 6 month GOSE score
• Covariates: age; post-resuscitation GCS; time from injury (<12 or >12);
pupillary response
• The eight points of the GOSE were collapsed to 6 (death was pooled with
a vegetative state and lower severe disability)
• Strict p<0.01 was used for covariate analysis

23. Results

24. Results (Primary Outcome)
• At 6 months, GOSE scores were unfavourable for the hypothermia group
• The trial was stopped early by the independent steering committee

25. Results

26. Results
Adverse events and mortality
•33 events in hypothermia group, 10 events in control group

27. Results
Adverse events
•33 events in hypothermia group, 10 events in control group
Unadjusted hazard ratio for death at 6 months: OR 1.45 (1.01 to 2.10) p=0.047Unadjusted hazard ratio for death at 6 months: OR 1.45 (1.01 to 2.10) p=0.047

28. Results
Intracranial pressure
• Mean daily ICP similar
• First occurrence of failure to
control ICP: 57 cases in
hypothermia group, 84 in control
group
• Therefore, more frequent use of
stage 3 treatments: 102 of 189
(54.0%) v. 84 of 192 (43.8%)
• No difference in decompressive
craniotomy

29. External Validity/generalisability
• Are the results of this trial important?
• Not representative of the TBI population.
• Feasible intervention, but utilised appropriately
• TBI up to 10 days?
• Trial stopped early
• Intention to treat
• 6 month follow up
2498 screened
1742 raised ICP
387 included

30. Discussion/Conclusion
• Hypothermia did not result in better outcomes
• The trial was stopped early due to safety concerns
• Hypothermia plus standard care successfully controlled ICP. This was not
statistically significant when compared to standard care alone.
• Unrepresentative population
• Difficult to isolate the impact of one intervention in a pragmatic trial
• Other stage 2 interventions were not measured, and benefits or harms of these
are unknown
• Hypothermia may have an effect on patients with higher ICP
• Barbiturates may be a confounding factor
• Non-blinding may lead to more adverse event reporting in the intervention group