Trial Design and Oversight

The European Study of Therapeutic Hypothermia (32–35°C) for Intracranial Pressure Reduction after Traumatic Brain Injury (the Eurotherm3235 Trial) aimed to recruit 600 patients who had a traumatic brain injury. The first patient was enrolled in November 2009, and the trial was stopped early in October 2014 for participant safety.

The trial protocol was developed by the first, second, fourth, and last authors in consultation with an international advisory board. The trial was conducted and reported with fidelity to the study protocol. Full details of the trial protocol have been published previously,22 and the protocol is available with the full text of this article at NEJM.org. After the pilot phase of the trial, the inclusion criteria and power calculation were refined as described below. The authors vouch for the accuracy and completeness of the data and analyses. Data were gathered by investigators at the trial sites (see the Supplementary Appendix, available at NEJM.org).

Ethical approval was obtained from the Scotland A Research Ethics Committee, the Bradford Research Ethics Committee, and ethics committees in another 14 countries. Owing to the incapacitated state of the potential participants, it was not possible to obtain consent directly from them. Written informed consent was therefore sought from each eligible patient’s nearest relative or person designated to give consent. Early consent was obtained when possible to prevent a delay between a rise in intracranial pressure and potential randomization.

An independent steering committee and independent data and safety monitoring committee reviewed the trial regularly, assessing conduct, progress, and safety (see the Supplementary Appendix). Trial recruitment was stopped on the advice of the data and safety monitoring committee after its ninth meeting (Table S11 in the Supplementary Appendix).

Participants

All patients admitted to the ICU after a traumatic brain injury who had intracranial-pressure monitoring in place were screened. Eligible patients were believed to be of legal age for consent. Other inclusion criteria were a primary, closed traumatic brain injury; an intracranial pressure of more than 20 mm Hg for at least 5 minutes after stage 1 treatments (Figure 1), with no obvious reversible cause; an initial head injury that had occurred no more than 10 days earlier; the availability of a cooling device or technique for more than 48 hours; a core temperature of at least 36°C (at the time of randomization); and an abnormal computed tomographic scan of the brain. Patients who were already receiving therapeutic hypothermia or who were unlikely to survive for the next 24 hours were excluded. Other exclusion criteria were the administration of barbiturate infusion before randomization, a temperature of 34°C or less at hospital admission, and pregnancy.

The inclusion criteria were changed in January 2012, on the basis of the pilot-phase findings,23 to remove an upper age limit (previously 65 years) and to increase the time from injury from 72 hours to 10 days. These changes allowed the enrollment of older patients and those with evolving brain swelling.

ICUs in hospitals that provide specialist neurologic treatment for traumatic brain injury were recruited (25 centers in the United Kingdom and 39 elsewhere). Evidence of expertise with intracranial-pressure monitoring and therapeutic cooling were necessary.

Data Collection

An online case-report form (Lincoln, Paris) was used for collection of data (Fig. S8 in the Supplementary Appendix), including baseline demographic information and data on completion of stage 1 interventions; intracranial pressure and temperature at randomization; intracranial pressure, mean arterial pressure, cerebral perfusion pressure, and temperature measured hourly on days 1 through 7; failure of stage 2 therapy to control intracranial pressure; new pneumonia; and functional outcome. This trial was pragmatic, with a focus on patient-oriented outcomes; therefore, we did not collect data on which stage 2 therapies were delivered to patients.5

Randomization and Study Treatment

Participants were randomly assigned to standard care (control group) or therapeutic hypothermia plus standard care (intervention group). Randomization was performed with the use of a minimization procedure to balance assignments according to center, age, Glasgow Coma Scale (GCS) motor score, time from injury, and pupillary response. The online case-report form ensured minimization (with a random element) and concealment of allocation to study groups. The trial had an open-label design, with patients, families, and treating clinicians aware of the study-group assignments. Scoring of the primary outcome measure (described below) was blinded.

According to the study protocol, hypothermia was induced by a bolus of intravenous, refrigerated 0.9% sodium chloride (20 to 30 ml per kilogram of body weight) and thereafter maintained with the usual cooling technique of each site. Guidelines were provided for induction and maintenance of hypothermia, rewarming, and detection and treatment of shivering in the intervention group (Fig. S1, S2, and S3 in the Supplementary Appendix).

Core temperature in the hypothermia group was reduced by the minimum required to maintain an intracranial pressure of 20 mm Hg or less (in keeping with guidelines of the Brain Trauma Foundation24), within the limits of 32 to 35°C. Stage 2 treatments were added if hypothermia failed to control intracranial pressure. Stage 3 treatments were used for patients whose intracranial pressure was not controlled by hypothermia and all other stage 2 treatments.

Hypothermia was maintained for at least 48 hours in the intervention group and continued for as long as necessary to control intracranial pressure. Rewarming was considered after 48 hours at a rate of 0.25°C per hour, provided that intracranial pressure was 20 mm Hg or less. The control group also received stage 2 and 3 treatments but without hypothermia (Figure 1).

Outcomes

The primary outcome measure was the score on the Extended Glasgow Outcome Scale (GOS-E) at 6 months after injury.25,26 The eight-point scale assesses the effects of traumatic brain injury on function in major areas of life. A GOS-E score of 1 indicates death, 2 indicates a vegetative state, 3 or 4 indicates severe disability, 5 or 6 indicates moderate disability, and 7 or 8 indicates good recovery (Table S2 in the Supplementary Appendix). The GOS-E questionnaire (Fig. S4 in the Supplementary Appendix) was sent by mail to surviving participants from the trial office in Edinburgh. When this was not possible, a local staff member contacted the patient by telephone to complete the questionnaire. An investigator who was unaware of the study-group assignments scored all outcomes according to the standardized approach (Fig. S4 in the Supplementary Appendix). The manually calculated scores were automatically checked in the trial database with the use of a specially developed algorithm. An independent expert was consulted in the few cases in which adjudication was needed.

Secondary outcomes were 6-month mortality, lack of intracranial-pressure control (failure of all stage 2 therapies to control intracranial pressure to ≤20 mm Hg), incidence of pneumonia during days 1 through 7 after randomization, length of ICU stay, and grade on the modified Oxford Handicap Scale (MOHS; a score of 0 indicates no symptoms, 1 minor symptoms, 2 some restriction, 3 dependent, 4 fully dependent, and 5 death) (Table S3 in the Supplementary Appendix)27 at 28 days or discharge from an acute-care hospital (whichever came first).

Data were collected on serious adverse events, including bleeding, cardiovascular instability, thermal burns, and a cerebral perfusion pressure of less than 50 mm Hg. Data on other adverse events were not collected, because many untoward events are expected in patients with traumatic brain injury who are admitted to the ICU.

Statistical Analysis

As a result of the internal pilot phase, the sample size for the full trial was reduced from 1800 to 600 patients.23 Two factors contributed to this decision: our original sample size may have underestimated the possible benefit of hypothermia because, unlike participants in most previous trials, participants in the Eurotherm3235 Trial had evidence of brain swelling (raised intracranial pressure); and we showed that an enhanced cooling intervention could be delivered, as described by Peterson et al.28 These data therefore informed the revised power calculation.

Using an ordinal analysis of the GOS-E scores together with covariate adjustment (primary efficacy analysis), we were able to increase the statistical efficiency of the analysis,29,30 so that a trial involving 600 patients would have power equivalent to that of a trial involving 1000 patients that assessed a binary outcome. We calculated that with such an analysis, the study would have the equivalent of 80% power to detect a rate of unfavorable outcome (GOS-E score of 1 to 4) that was 9 percentage points lower with hypothermia than with standard care (51% vs. 60%), at the 5% significance level (two-sided).

All analyses were performed with SAS software, version 9.3 (SAS Institute). Analyses were performed on an intention-to-treat basis, incorporating all patients who underwent randomization and for whom outcome data were available, with patients evaluated according to their assigned intervention.

For the primary analysis, the distribution of the 6-month GOS-E scores between the two groups (hypothermia vs. control) was compared with the use of ordinal logistic regression30 and with adjustment for the following baseline covariates: age (included as a continuous variable, with the use of a linear term in the regression model), postresuscitation GCS motor score (1 or 2 [no or extensor response] vs. 3 to 6 [flexion or better response]) (Table S1 in the Supplementary Appendix), time from injury (<12 hours vs. ≥12 hours), and pupillary response (both reacting vs. one reacting vs. neither reacting; included as an unordered categorical variable in the regression model).

For this analysis, we collapsed the eight-point GOS-E to six categories by pooling death with a vegetative state and lower severe disability. This ensured that the analysis would not favor an intervention that reduced mortality at the expense of increasing the proportion of severely disabled survivors.

Prespecified subgroups for the primary analysis were defined on the basis of the baseline covariates described above, the location of the center (United Kingdom vs. elsewhere), and the volume of the center (≥10 vs. <10 patients). We performed these analyses by including an interaction term between intervention and the relevant covariate in the ordinal logistic-regression model; a stricter level of statistical significance (P<0.01) was used owing to their exploratory nature.

MOHS grades were analyzed in the same way as GOS-E scores, but we collapsed the six grades to four categories by grouping dependent, fully dependent, and death (Table S9B in the Supplementary Appendix). In the analysis of the between-group difference in mortality, Cox proportional-hazards regression was used to estimate the intervention effect.

Other continuous outcomes were tested with an analysis of covariance; for binary outcomes, logistic regression was used. Intracranial pressure, core temperature, mean arterial pressure, and cerebral perfusion pressure on days 1 through 7 were analyzed post hoc with the use of a linear model, with study days as repeated measurements with a compound-symmetry covariance matrix. All these analyses used the same covariates as were prespecified for GOS-E scores together with the baseline value of the relevant variable.