Study Design

The study was a multicenter, parallel-group trial, with randomized assignment to intracranial-pressure monitoring (the pressure-monitoring group) or imaging and clinical examination (the imaging–clinical examination group). Randomization was stratified according to study site, severity of injury, and age. The study was started at three Bolivian hospitals (for details, see the Supplementary Appendix, available with the full text of this article at NEJM.org); an additional Bolivian hospital and two Ecuadorian hospitals were subsequently recruited to increase enrollment. All six sites had ICUs staffed with intensivists, 24-hour computed tomographic (CT) services and neurosurgery coverage, and high volumes of patients with trauma.

Eligibility

All patients presenting with traumatic brain injury were screened for eligibility on admission at the study hospitals. To be included in the study, patients had to be 13 years of age or older and have a score on the Glasgow Coma Scale (GCS) of 3 to 8 (with a score on the GCS motor component of 1 to 5 if the patient was intubated) or a higher score on admission that dropped to the specified range within 48 hours after injury. (The GCS ranges from 3 to 15, with higher scores indicating higher levels of consciousness; the motor score ranges from 1 to 6.) Patients with a GCS score of 3 and bilateral fixed and dilated pupils and those with an injury believed to be unsurvivable were excluded. The complete list of inclusion and exclusion criteria has been reported previously8 and is available in the Supplementary Appendix. Informed consent was obtained for all participants.

Group Assignments and Interventions

Randomization sequences were computer-generated by a data-center biostatistician and were stratified according to site, severity of injury (GCS score of 3 to 5, or GCS motor score of 1 to 2 if the patient was intubated, vs. GCS score of 6 to 8, or GCS motor score of 3 to 5 if the patient was intubated), and age (<40 years vs. ≥40 years), with a block size of 2 or 4 (see the Supplementary Appendix).

The study was conducted in accordance with the protocol (available at NEJM.org), which specified that three CT scans be obtained (at baseline, 48 hours, and 5 to 7 days) and standard supportive care provided for each patient, with care to include mechanical ventilation, sedation, and analgesia. Non-neurologic problems were managed aggressively in both groups.

Patients randomly assigned to the pressure-monitoring group had an intraparenchymal monitor placed as soon as possible and were treated to maintain an intracranial pressure of less than 20 mm Hg, in accordance with the guidelines for the management of severe traumatic brain injury4-7 (for more information see the description of treatment protocols in the Supplementary Appendix). Drainage of cerebrospinal fluid required ventriculostomy placement. The care for patients randomly assigned to the imaging–clinical examination group was provided in accordance with a protocol based on the pretrial standard for care at the three original participating hospitals (see the Supplementary Appendix). In the absence of intracranial mass lesions requiring surgery, signs of intracranial hypertension on imaging or clinical examination were treated first with hyperosmolar therapies with the use of protocol-specified doses on a fixed schedule of administration, optional mild hyperventilation (at a partial pressure of arterial carbon dioxide of 30 to 35 mm Hg), and optional ventricular drainage. Continuing edema prompted consideration of the administration of high-dose barbiturates. Additional treatments were required for patients with “neuroworsening,”9 persistent edema, or clinical signs of intracranial hypertension. (More information on the interventions provided and on operational definitions — including the definition of neuroworsening — is available in the Supplementary Appendix.)

Outcomes

The primary outcome, assessed within 6 months after the study onset, was a composite of 21 components: measures of survival (survival time, counted as 1 component), duration and level of impaired consciousness (time to follow commands, sum of errors on the orientation questions from the Galveston Orientation and Amnesia Test [GOAT] on discharge from the hospital — 2 components), functional status and orientation 3 months after injury (assessed with the use of the Extended Glasgow Outcome Scale [GOS-E], the Disability Rating Scale, and GOAT — 3 components), and functional and neuropsychological status 6 months after injury (15 components). The battery of tests included measures of mental status, working memory, information-processing speed, episodic memory and learning, verbal fluency, executive function, and motor dexterity (information on the range and direction of scores for each measure is provided in Table S2 in the Supplementary Appendix). Trained examiners who were unaware of the group assignments administered the tests at 3 and 6 months. Data quality and monitoring are discussed in the Supplementary Appendix.

For the primary outcome, each participant's percentile was determined separately for each of the 21 measures; the overall outcome was the average of the 21 percentiles10 (on a scale from 0 to 100, with lower percentiles representing worse outcomes); for details, see the outcomes section in the Supplementary Appendix. Protocol-specified secondary outcomes were the length of stay in the ICU (measured as the total number of days in the ICU and the number of days in the ICU on which the patient received at least one brain-specific treatment) and systemic complications. Brain-specific treatments were those directed at intracranial hypertension and included the administration of hyperosmolar agents and pressors and the use of hyperventilation but excluded ventilation, sedation, and analgesia. Additional, post hoc secondary outcomes were the hospital length of stay, the number of days of mechanical ventilation, treatment with high-dose barbiturates or decompressive craniectomy, and therapeutic intensity (for details, see the Supplementary Appendix). For some analyses focused specifically on interventions for intracranial hypertension, we defined the duration of therapy as the number of days from injury until the last brain-specific treatment. Data for patients who survived for more than 1 day after the last brain-specific treatment (collectively referred to as the brain-treatment survivors subgroup) were also analyzed. We integrated brain-specific treatments by summing the number of treatments delivered per hour over the course of the treatment interval.

Study Oversight

The study was approved by the institutional review board at the University of Washington and the ethics committees at all study centers. All authors vouch for the accuracy and completeness of the data and data analyses and for the fidelity of this report to the study protocol. Integra Life Sciences donated the catheters used in monitoring intracranial pressure and provided additional unrestricted support for this project. Integra had no role in the design or conduct of the study, the data analysis, or the writing of the manuscript.

Statistical Analysis

The planned sample size of 324 was determined by means of simulation to provide 80% power to detect an increase of 10 percentage points in the percentage of patients with a good outcome or with moderate disability according to the GOS-E (odds ratio with imaging and clinical examination vs. pressure monitoring, 1.5), and a corresponding improvement on other measures (see the Supplementary Appendix). One planned interim efficacy analysis was conducted when half the participants had undergone the 6-month assessment.

The primary hypothesis was tested with the use of the blocked Wilcoxon test,11 with blocking on stratification factors, and a two-sided significance level of 0.05. We obtained odds ratios and confidence intervals from a logistic proportional-odds model, accounting for the same factors (see the Supplementary Appendix).10 This analysis was supplemented by similar analyses of individual measures and composite analyses of subgroup measures. Cox models were used to analyze survival. A significance level of 0.01 was used to test secondary hypotheses. The main analyses included data on all participants randomly assigned to a treatment group (intention-to-treat population). Sensitivity analyses included analyses restricted to patients who survived, those who received the assigned treatment, and those who survived for at least 24 hours after receiving brain-specific treatments.