MACQUARIE NEUROSURGERY JOURNAL CLUB 14/04/16

Dr Michael Mulcahy

MACQUARIE NEUROSURGERYJOURNAL 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.

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

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

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…

Study Relevance

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

Originality

•Raised ICP only

•Duration of hypothermia

•Rapid induction of hypothermia

•Slow rewarming

Study Hypothesis

• Patients treated with therapeutic hypothermia (32-35oC) 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

Study Protocol

Study Design

• RCT

• Interventional

• Pragmatic

• Multi-centre (25 UK centres, 39 elsewhere)

• Open-label

Study Design

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

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 >36oC at time of randomisation

• abnormal CT

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 >36oC at time of randomisation

• abnormal CT

Study Design

Exclusion criteria

• already receiving therapeutic hypothermia

• administration of barbiturate prior to randomisation

• unlikely to survive for the next 24 hours

• temperature <34oC

• pregnancy

Population

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…

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%)

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

Internal Validity

Blinding

• Investigators were not blinded

• Primary outcome data assessment was blinded

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

Results

Results (Primary Outcome)

• At 6 months, GOSE scores were unfavourable for the hypothermia group

• The trial was stopped early by the independent steering committee

Results

Results

Adverse events and mortality

•33 events in hypothermia group, 10 events in control group

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=0.047

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

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

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