Trial Design and Oversight

In this international, multicenter, parallel-group, superiority, randomized trial, we compared last-tier secondary decompressive craniectomy with continued medical management for refractory intracranial hypertension after TBI. Ethics approval in the United Kingdom was obtained in 2003 from the Cambridgeshire 4 research ethics committee (formerly known as the Eastern multicenter research ethics committee); ethics committees at all other participating institutions also approved the trial.

Because the trial enrolled patients with severe TBI, written informed consent was obtained from the nearest relative or a person who had been designated to give consent on admission of the patient. An independent steering committee and an independent data monitoring and ethics committee reviewed the trial regularly to assess conduct, progress, and safety.

The trial protocol, available with the full text of this article at NEJM.org, was designed in a collaborative fashion by the Divisions of Neurosurgery and Anaesthesia at the University of Cambridge, collaborating clinicians, and the European Brain Injury Consortium. Full details of the protocol have been published previously.11 The investigators vouch for the completeness and accuracy of the data and the analyses and for the fidelity of this report to the trial protocol and the statistical analysis plan.

Participants and Trial Sites

Figure 1. Figure 1. Stages of Therapeutic Management. Agreement for participation was obtained from the nearest relative or a person who had been designated to give consent preemptively on admission of the patient in order to avoid delays in treatment. Randomization was performed after stage 2 if the intracranial pressure was more than 25 mm Hg for 1 to 12 hours. The protocol stages 1 and 2 reflected the therapeutic protocols that were followed in the participating units.

To undergo randomization in the trial, patients had to be between 10 and 65 years of age, have a TBI with an abnormal computed tomographic (CT) scan of the brain, have an intracranial-pressure monitor already in place, and have raised intracranial pressure (>25 mm Hg for 1 to 12 hours, despite stage 1 and 2 measures, as defined below and in Figure 1). Patients who had undergone an immediate operation for evacuation of an intracranial hematoma could be included as long as the operation was not a craniectomy (i.e., the bone flap was replaced at the end of procedure). Patients with bilateral fixed and dilated pupils, bleeding diathesis, or an injury that was deemed to be unsurvivable were excluded. Trial sites were hospitals that provide acute neurosciences care for patients with severe TBI and that have 24-hour neurosurgical services (see the Supplementary Appendix, available at NEJM.org).

Interventions and Randomization

Patients were treated in ICUs according to a protocol that was aimed at maintaining an intracranial pressure of 25 mm Hg or less by applying treatments in a stepwise manner (Figure 1). The initial stage (stage 1) included sedation, analgesia, and head elevation; neuromuscular paralysis was optional. Other targets included a cerebral perfusion pressure (the difference between the mean blood pressure and intracranial pressure) of more than 60 mm Hg, normothermia, normoglycemia, mild hypocapnia (partial pressure of arterial carbon dioxide [PaCO 2 ], 4.5 to 5.0 kPa [34 to 38 mm Hg]), and adequate oxygenation (oxygen saturation, >97%). If the intracranial pressure was not controlled, stage 2 options included ventriculostomy (if an external ventricular drain had not already been inserted for intracranial-pressure monitoring), pharmacologic blood-pressure augmentation, osmotherapy, moderate hypocapnia (PaCO 2 , 4.0 to 4.5 kPa [30 to 34 mm Hg]), and therapeutic hypothermia (not <34°C).

If the intracranial pressure remained above 25 mm Hg for 1 to 12 hours despite these measures, then at stage 3 of the protocol, patients were randomly assigned to undergo decompressive craniectomy with medical therapy or to receive continued medical therapy with the option of adding barbiturates to reduce the intracranial pressure. Patients underwent randomization, in a 1:1 ratio, with the use of permuted blocks of random sizes and with stratification according to trial site. To ensure concealment, the block sizes were not disclosed. Participants underwent randomization with the use of a central telephone randomization service. Concealment of the trial-group assignments was ensured, because the service did not release the randomization code until the patient had reached stage 3 of the protocol.

The surgical treatment was either large unilateral frontotemporoparietal craniectomy (hemicraniectomy), which was recommended for patients with unilateral hemispheric swelling, or bifrontal craniectomy, which was recommended for patients with diffuse brain swelling that affected both hemispheres on imaging studies. The exact type of craniectomy was left to the discretion of the surgeons. Details of the recommended surgical technique are provided in the protocol. In addition, it was recommended that surgery should be performed no later than 4 to 6 hours after randomization.

Patients who were assigned to receive medical treatment alone could undergo a decompressive craniectomy later in case their condition deteriorated further, at the discretion of treating clinicians. Similarly, patients who were assigned to undergo decompressive craniectomy could have barbiturate infusion in case of further deterioration of their condition.

Outcomes

The primary-outcome measure was assessed with the use of the Extended Glasgow Outcome Scale (GOS-E) at 6 months after randomization.12 The GOS-E is a global outcome scale assessing functional independence, work, social and leisure activities, and personal relationships. Its eight outcome categories are as follows: death, vegetative state (unable to obey commands), lower severe disability (dependent on others for care), upper severe disability (independent at home), lower moderate disability (independent at home and outside the home but with some physical or mental disability), upper moderate disability (independent at home and outside the home but with some physical or mental disability, with less disruption than lower moderate disability), lower good recovery (able to resume normal activities with some injury-related problems), and upper good recovery (no problems). Details are provided in the Supplementary Appendix.

In the United Kingdom, the trial office in Cambridge mailed the GOS-E questionnaires to surviving participants. If no response was received, a trial team member contacted the patient or a caregiver by telephone to complete the questionnaire. At international sites, local staff were responsible for the above processes. Two trial team investigators, who were unaware of the trial-group assignments, centrally adjudicated outcomes on the basis of the GOS-E questionnaires independently of each other according to a standardized approach.13 Disagreements were resolved by consensus between them or with the consultation of a third trial team investigator who was also unaware of the trial-group assignments.

The secondary outcomes were the following: GOS-E results at 12 and 24 months after randomization; mortality at 6, 12, and 24 months after randomization; quality of life at 6, 12, and 24 months after randomization; Glasgow Coma Scale (GCS) score at discharge from the neurosciences hospital; assessment of intracranial-pressure control; time in the ICU; time to discharge from the neurosciences hospital; and economic evaluation. Quality of life was assessed with the 36-item Short-Form Health Survey in adults and the 10-item Short-Form Health Survey in children. Assessment of intracranial-pressure control included the mean intracranial pressure in the period after randomization, the number of hours with the intracranial pressure above 25 mm Hg in the period after randomization, the intracranial hypertension index 20 (the number of end-hourly measures of intracranial pressure of >20 mm Hg divided by the total number of measurements, multiplied by 100), the intracranial hypertension index 25 (the number of end-hourly measures of intracranial pressure of >25 mm Hg divided by the total number of measurements, multiplied by 100), and the cerebral hypoperfusion index (the number of end-hourly measures of cerebral perfusion pressure of <60 mm Hg divided by the total number of measurements, multiplied by 100). Data on complications and serious adverse events were also collected.

Statistical Analysis

We calculated that a target sample of 400 patients would allow us to detect a treatment effect of 15 percentage points between the two groups (difference in favorable-outcome rate of 45% vs. 60%; see the definition of favorable outcome later in this section) with 80% power at the 5% significance level (two-sided), allowing for a loss to follow-up of up to 15%.11 The analysis was performed according to a statistical analysis plan, which was agreed on without reference to the unblinded data (see the protocol).14

Outcomes were reported in the intention-to-treat population, which was modified to exclude patients who were lost to follow-up or who withdrew consent. Missing outcome data were not imputed. As prespecified in the statistical analysis plan, a sensitivity analysis was performed for the primary-outcome measure in the per-protocol population. The per-protocol population was defined as the patients in the intention-to-treat population who did not have a severe breach of protocol.

The primary-outcome measure was analyzed with an ordinal analysis method that was based on the proportional-odds model.15 The goodness of fit of the unadjusted proportional-odds models was tested with the use of a likelihood-ratio test. The rejection of the proportional-odds model at the 5% significance level indicated a difference in the GOS-E distribution between the two randomized groups. In this situation, the presentation of the results was prespecified to describe the difference in outcomes between the groups, and the groups were compared formally with the use of an unordered chi-square test. For the primary analysis, the GOS-E categories of upper good recovery and lower good recovery were pooled, since a blinded review of the distribution of GOS-E ratings revealed that there were too few patients in these categories for them to be analyzed separately.

In a prespecified sensitivity analysis, we compared the proportion of patients who had an outcome of upper severe disability or better on the GOS-E scale (“favorable outcome”) between the randomized groups, using a chi-square test. Conventionally, the GOS-E scale is dichotomized so that upper severe disability is categorized as being an unfavorable outcome, together with vegetative state and lower severe disability. Patients who are in the category of upper severe disability are largely independent around their homes but need assistance with traveling or shopping, whereas patients who are in the category of lower severe disability live in a supervised facility (care facility) or, if at home, need assistance most of the time. In view of the anticipated high proportion of poor outcomes in this trial population, it was agreed a priori by the trial team and the steering committee that the upper-severe-disability category would be included in the definition of favorable outcome. A similar approach has been followed in some trials of craniectomy for middle-cerebral-artery infarction, in which moderately severe disability (modified Rankin scale score, 4 [unable to walk without assistance and unable to attend to own bodily needs without assistance]) was categorized as a favorable outcome, although most stroke trials conventionally categorize it as unfavorable.16,17

Prespecified exploratory analyses examined the effect of covariate adjustment (age, GCS motor score, pupillary reactivity, and the Marshall grade of the last available prerandomization CT of the brain) on the analyses described above. The duration of ICU stay was analyzed with the use of Kaplan–Meier estimates and log-rank tests. The time to discharge from the neurosciences hospital and the GCS score at discharge from the neurosciences hospital were not analyzed because the data were not collected. Instead, the GCS score at the time of discharge from the ICU was available and was analyzed with the use of the same ordinal method as described above for the GOS-E. All other analyses of categorical data were based on chi-square tests, and analyses of continuous variables were based on Mann–Whitney U tests. The GOS-E ratings at 24 months, quality-of-life data, and the planned economic evaluation have not yet been analyzed.