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BACKGROUND AND OBJECTIVES: The efficacy of our current approach to incorporating intracranial pressure (ICP) data into pediatric severe traumatic brain injury (sTBI) management is incompletely understood, lacking data from multicenter, prospective, randomized studies. The National Institutes of Health-supported Benchmark Evidence from Latin America-Treatment of Raised Intracranial Pressure-Pediatrics trial will compare outcomes from pediatric sTBI of a management protocol based on ICP monitoring vs 1 based on imaging and clinical examination without monitoring. Because no applicable comprehensive management algorithms for either cohort are available, it was necessary to develop them. METHODS: A consensus conference involving the 21 intensivists and neurosurgeons from the 8 trial sites used Delphi-based methodology to formulate management algorithms for both study cohorts. We included recommendations from the latest Brain Trauma Foundation pediatric sTBI guidelines and the consensus-based adult algorithms (Seattle International Brain Injury Consensus Conference/Consensus Revised Imaging and Clinical Examination) wherever relevant. We used a consensus threshold of 80%. RESULTS: We developed comprehensive management algorithms for monitored and nonmonitored cohort children with sTBI. We defined suspected intracranial hypertension for the nonmonitored group, set minimum number and timing of computed tomography scans, specified minimal age-adjusted mean arterial pressure and cerebral perfusion pressure targets, defined clinical neuroworsening, described minimal requisites for intensive care unit management, produced tiered management algorithms for both groups, and listed treatments not routinely used. CONCLUSION: We will study these protocols in the Benchmark Evidence from Latin America-Treatment of Raised Intracranial Pressure-Pediatrics trial in low- and middle-income countries. Second, we present them here for consideration as prototype pediatric sTBI management algorithms in the absence of published alternatives, acknowledging their limited evidentiary status. Therefore, herein, we describe our study design only, not recommended treatment protocols.

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BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is a major global public health problem. It is a leading cause of death and disability in children and adolescents worldwide. Although increased intracranial pressure (ICP) is common and associated with death and poor outcome after pediatric TBI, the efficacy of current ICP-based management remains controversial. We intend to provide Class I evidence testing the efficacy of a protocol based on current ICP monitor-based management vs care based on imaging and clinical examination without ICP monitoring in pediatric severe TBI. METHODS: A phase III, multicenter, parallel-group, randomized superiority trial performed in intensive care units in Central and South America to determine the impact on 6-month outcome of children aged 1-12 years with severe TBI (age-appropriate Glasgow Coma Scale score ≤8) randomized to ICP-based or non-ICP-based management. EXPECTED OUTCOMES: Primary outcome is 6-month Pediatric Quality of Life. Secondary outcomes are 3-month Pediatric Quality of Life, mortality, 3-month and 6-month Pediatric extended Glasgow Outcome Score, intensive care unit length of stay, and number of interventions focused on treating measured or suspected intracranial hypertension. DISCUSSION: This is not a study of the value of knowing the ICP in sTBI. This research question is protocol-based. We are investigating the added value of protocolized ICP management to treatment based on imaging and clinical examination in the global population of severe pediatric TBI. Demonstrating efficacy should standardize ICP monitoring in severe pediatric TBI. Alternate results should prompt reassessment of how and in which patients ICP data should be applied in neurotrauma care.

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BACKGROUND AND OBJECTIVES: Our Phase-I parallel-cohort study suggested that managing severe traumatic brain injury (sTBI) in the absence of intracranial pressure (ICP) monitoring using an ad hoc Imaging and Clinical Examination (ICE) treatment protocol was associated with superior outcome vs nonprotocolized management but could not differentiate the influence of protocolization from that of the specific protocol. Phase II investigates whether adopting the Consensus REVised Imaging and Clinical Examination (CREVICE) protocol improved outcome directly or indirectly via protocolization. METHODS: We performed a Phase-II sequential parallel-cohort study examining adoption of the CREVICE protocol from no protocol vs a previous protocol in patients with sTBI older than 13 years presenting ≤24 hours after injury. Primary outcome was prespecified 6-month recovery. The study was done mostly at public South American centers managing sTBI without ICP monitoring. Fourteen Phase-I nonprotocol centers and 5 Phase-I protocol centers adopted CREVICE. Data were analyzed using generalized estimating equation regression adjusting for demographic imbalances. RESULTS: A total of 501 patients (86% male, mean age 35.4 years) enrolled; 81% had 6 months of follow-up. Adopting CREVICE from no protocol was associated with significantly superior results for overall 6-month extended Glasgow Outcome Score (GOSE) (protocol effect = 0.53 [0.11, 0.95], P = .013), mortality (36% vs 21%, HR = 0.59 [0.46, 0.76], P < .001), and orientation (Galveston Orientation and Amnesia Test discharge protocol effect = 10.9 [6.0, 15.8], P < .001, 6-month protocol effect = 11.4 [4.1, 18.6], P < .005). Adopting CREVICE from ICE was associated with significant benefits to GOSE (protocol effect = 0.51 [0.04, 0.98], P = .033), 6-month mortality (25% vs 18%, HR = 0.55 [0.39, 0.77], P < .001), and orientation (Galveston Orientation and Amnesia Test 6-month protocol effect = 9.2 [3.6, 14.7], P = .004). Comparing both groups using CREVICE, those who had used ICE previously had significantly better GOSE (protocol effect = 1.15 [0.09, 2.20], P = .033). CONCLUSION: Centers managing adult sTBI without ICP monitoring should strongly consider protocolization through adopting/adapting the CREVICE protocol. Protocolization is indirectly supported at sTBI centers regardless of resource availability.

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BACKGROUND: Most patients with severe traumatic brain injury (sTBI) in low- or-middle-income countries and surprisingly many in high-income countries are managed without intracranial pressure (ICP) monitoring. The impact of the first published protocol (Imaging and Clinical Examination [ICE] protocol) is untested against nonprotocol management. OBJECTIVE: To determine whether patients treated in intensive care units (ICUs) using the ICE protocol have lower mortality and better neurobehavioral functioning than those treated in ICUs using no protocol. METHODS: This study involved nineteen mostly public South American hospitals. This is a prospective cohort study, enrolling patients older than 13 years with sTBI presenting within 24 h of injury (January 2014-July 2015) with 6-mo postinjury follow-up. Five hospitals treated all sTBI cases using the ICE protocol; 14 used no protocol. Primary outcome was prespecified composite of mortality, orientation, functional outcome, and neuropsychological measures. RESULTS: A total of 414 patients (89% male, mean age 34.8 years) enrolled; 81% had 6 months of follow-up. All participants included in composite outcome analysis: average percentile (SD) = 46.8 (24.0) nonprotocol, 56.9 (24.5) protocol. Generalized estimating equation (GEE) used to account for center effects (confounder-adjusted difference [95% CI] = 12.2 [4.6, 19.8], P = .002). Kaplan-Meier 6-month mortality (95% CI) = 36% (30%, 43%) nonprotocol, 25% (19%, 31%) protocol (GEE and confounder-adjusted hazard ratio [95% CI] = .69 [.43, 1.10], P = .118). Six-month Extended Glasgow Outcome Scale for 332 participants: average Extended Glasgow Outcome Scale score (SD) = 3.6 (2.6) nonprotocol, 4.7 (2.8) protocol (GEE and confounder-adjusted and lost to follow-up-adjusted difference [95% CI] = 1.36 [.55, 2.17], P = .001). CONCLUSION: ICUs managing patients with sTBI using the ICE protocol had better functional outcome than those not using a protocol. ICUs treating patients with sTBI without ICP monitoring should consider protocolization. The ICE protocol, tested here and previously, is 1 option.

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Globally, intracranial pressure (ICP) monitoring use in severe traumatic brain injury (sTBI) is inconsistent and susceptible to resource limitations and clinical philosophies. For situations without monitoring, there is no published comprehensive management algorithm specific to identifying and treating suspected intracranial hypertension (SICH) outside of the one ad hoc Imaging and Clinical Examination (ICE) protocol in the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST:TRIP) trial. As part of an ongoing National Institutes of Health (NIH)-supported project, a consensus conference involving 43 experienced Latin American Intensivists and Neurosurgeons who routinely care for sTBI patients without ICP monitoring, refined, revised, and augmented the original BEST:TRIP algorithm. Based on BEST:TRIP trial data and pre-meeting polling, 11 issues were targeted for development. We used Delphi-based methodology to codify individual statements and the final algorithm, using a group agreement threshold of 80%. The resulting CREVICE (Consensus REVised ICE) algorithm defines SICH and addresses both general management and specific treatment. SICH treatment modalities are organized into tiers to guide treatment escalation and tapering. Treatment schedules were developed to facilitate targeted management of disease severity. A decision-support model, based on the group's combined practices, is provided to guide this process. This algorithm provides the first comprehensive management algorithm for treating sTBI patients when ICP monitoring is not available. It is intended to provide a framework to guide clinical care and direct future research toward sTBI management. Because of the dearth of relevant literature, it is explicitly consensus based, and is provided solely as a resource (a "consensus-based curbside consult") to assist in treating sTBI in general intensive care units in resource-limited environments.

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OBJECTIVE: While existing guidelines support the treatment of intracranial hypertension in severe traumatic brain injury (TBI), it is unclear when to suspect and initiate treatment for high intracranial pressure (ICP). The objective of this study was to derive a clinical decision rule that accurately predicts intracranial hypertension. METHODS: Using Delphi methods, the authors identified a set of potential predictors of intracranial hypertension and a clinical decision rule a priori by consensus among a group of 43 neurosurgeons and intensivists who have extensive experience managing severe TBI without ICP monitoring. To validate these predictors, the authors used data from a Latin American trial (n = 150; BEST TRIP). To report on the performance of the rule, they calculated sensitivity, specificity, and positive and negative predictive values with 95% confidence intervals. In a secondary analysis, the rule was validated using data from a North American trial (n = 131; COBRIT). RESULTS: The final predictors and the clinical decision rule were approved by 97% of participants in the consensus working group. The predictors are divided into major and minor criteria. High ICP would be considered suspected in the presence of 1 major or ≥ 2 minor criteria. Major criteria are: compressed cisterns (CT classification of Marshall diffuse injury [DI] III), midline shift > 5 mm (Marshall DI IV), or nonevacuated mass lesion. Minor criteria are: Glasgow Coma Scale (GCS) motor score ≤ 4, pupillary asymmetry, abnormal pupillary reactivity, or Marshall DI II. The area under the curve for the logistic regression model that contains all the predictors was 0.86. When high ICP was defined as > 22 mm Hg, the decision rule performed with a sensitivity of 93.9% (95% CI 85.0%-98.3%), a specificity of 42.3% (95% CI 31.7%-53.6%), a positive predictive value of 55.5% (95% CI 50.7%-60.2%), and a negative predictive value of 90% (95% CI 77.1%-96.0%). The sensitivity of the clinical decision rule improved with higher ICP cutoffs up to a sensitivity of 100% when intracranial hypertension was defined as ICP > 30 mm Hg. Similar results were found in the North American cohort. CONCLUSIONS: A simple clinical decision rule based on a combination of clinical and imaging findings was found to be highly sensitive in distinguishing patients with severe TBI who would suffer intracranial hypertension. It could be used to identify patients who require ICP monitoring in high-resource settings or start ICP-lowering treatment in environments where resource limitations preclude invasive monitoring.Clinical trial registration no.: NCT02059941 (clinicaltrials.gov).

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BACKGROUND: Severe traumatic brain injury (sTBI) is a significant global health problem disproportionately affecting low- and middle-income countries (LMICs). Management of intracranial hypertension in sTBI is crucial to survival and optimal recovery. Practitioners in high-income countries routinely use intracranial pressure (ICP) monitors although their usefulness has been questioned. ICP monitors are usually unavailable in LMICs. No consensus-based/tested protocols or literature exists for sTBI treatment without ICP monitoring. METHODS: Investigators developed serial SurveyMonkey surveys for Latin American neurointensivists and neurosurgeons to determine current practice. These clinicians had extensive routine ongoing experience in sTBI without ICP monitoring. Surveys were administered and analyzed before/during/after a 2015 Buenos Aires consensus conference. Investigators identified areas of convergence blinded from colleagues' responses. A 47-clinician task force, representing 15 countries, who routinely manage patients with sTBI without monitors developed consensus-based treatment guidelines during a 3-day facilitated conference. RESULTS: Elements were added to the protocol at an 80% agreement threshold. Follow-on surveys resolved remaining elements to 97% agreement. The protocol addresses both tapering (on improvement) and neuroworsening. Staged treatment options were identified, plus unique clinical practice issues. This process introduced a research method to a large multidisciplinary group of LMIC clinicians. This report describes the process used to develop an LMIC-specific protocol that is transferable to other diseases/injuries. The protocol is being tested in 5 LMICs. CONCLUSIONS: We derived consensus-based guidelines for sTBI treatment without ICP monitoring, and introduced a research method to a large multidisciplinary group of LMIC clinicians naive to such methods.

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The imaging and clinical examination (ICE) algorithm used in the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST TRIP) randomized controlled trial is the only prospectively investigated clinical protocol for traumatic brain injury management without intracranial pressure (ICP) monitoring. As the default literature standard, it warrants careful evaluation. We present the ICE protocol in detail and analyze the demographics, outcome, treatment intensity, frequency of intervention usage, and related adverse events in the ICE-protocol cohort. The 167 ICE protocol patients were young (median 29 years) with a median Glasgow Coma Scale motor score of 4 but with anisocoria or abnormal pupillary reactivity in 40%. This protocol produced outcomes not significantly different from those randomized to the monitor-based protocol (favorable 6-month extended Glasgow Outcome Score in 39%; 41% mortality rate). Agents commonly employed to treat suspected intracranial hypertension included low-/moderate-dose hypertonic saline (72%) and mannitol (57%), mild hyperventilation (adjusted partial pressure of carbon dioxide 30-35 mm Hg in 73%), and pressors to maintain cerebral perfusion (62%). High-dose hyperosmotics or barbiturates were uncommonly used. Adverse event incidence was low and comparable to the BEST TRIP monitored group. Although this protocol should produce similar/acceptable results under circumstances comparable to those in the trial, influences such as longer pre-hospital times and non-specialist transport personnel, plus an intensive care unit model of aggressive physician-intensive care by small groups of neurotrauma-focused intensivists, which differs from most high-resource models, support caution in expecting the same results in dissimilar settings. Finally, this protocol's ICP-titration approach to suspected intracranial hypertension (vs. crisis management for monitored ICP) warrants further study.

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BACKGROUND: Intracranial-pressure monitoring is considered the standard of care for severe traumatic brain injury and is used frequently, but the efficacy of treatment based on monitoring in improving the outcome has not been rigorously assessed. METHODS: We conducted a multicenter, controlled trial in which 324 patients 13 years of age or older who had severe traumatic brain injury and were being treated in intensive care units (ICUs) in Bolivia or Ecuador were randomly assigned to one of two specific protocols: guidelines-based management in which a protocol for monitoring intraparenchymal intracranial pressure was used (pressure-monitoring group) or a protocol in which treatment was based on imaging and clinical examination (imaging-clinical examination group). The primary outcome was a composite of survival time, impaired consciousness, and functional status at 3 months and 6 months and neuropsychological status at 6 months; neuropsychological status was assessed by an examiner who was unaware of protocol assignment. This composite measure was based on performance across 21 measures of functional and cognitive status and calculated as a percentile (with 0 indicating the worst performance, and 100 the best performance). RESULTS: There was no significant between-group difference in the primary outcome, a composite measure based on percentile performance across 21 measures of functional and cognitive status (score, 56 in the pressure-monitoring group vs. 53 in the imaging-clinical examination group; P=0.49). Six-month mortality was 39% in the pressure-monitoring group and 41% in the imaging-clinical examination group (P=0.60). The median length of stay in the ICU was similar in the two groups (12 days in the pressure-monitoring group and 9 days in the imaging-clinical examination group; P=0.25), although the number of days of brain-specific treatments (e.g., administration of hyperosmolar fluids and the use of hyperventilation) in the ICU was higher in the imaging-clinical examination group than in the pressure-monitoring group (4.8 vs. 3.4, P=0.002). The distribution of serious adverse events was similar in the two groups. CONCLUSIONS: For patients with severe traumatic brain injury, care focused on maintaining monitored intracranial pressure at 20 mm Hg or less was not shown to be superior to care based on imaging and clinical examination. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01068522.).

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BACKGROUND: Although in the developed world the intracranial pressure (ICP) monitor is considered the standard of care for patients with severe traumatic brain injury (TBI), its usefulness to direct treatment decisions has never been tested rigorously. OBJECTIVE: The primary focus was to conduct a high-quality, randomized, controlled trial to determine whether ICP monitoring used to direct TBI treatment improves patient outcomes. By providing education, equipment, and structure, the project will enhance the research capacity of the collaborating investigators and will foster the collaborations established during earlier studies. METHODS: Study centers were selected that routinely treated ICP based on clinical examination and computed tomography imaging using internal protocols. We randomized patients to either an ICP monitor group or an imaging and clinical examination group. Treatment decisions for the ICP monitor group are guided by ICP monitoring based on established guidelines. Treatment decisions for the imaging and clinical examination group are made using a single protocol derived from those previously being used at those centers. EXPECTED OUTCOMES: There are 2 study hypotheses: (1) patients with severe TBI whose acute care treatment is managed using ICP monitors will have improved outcomes and 2) incorporating ICP monitoring in the care of patients with severe TBI will minimize complications and decrease length of intensive care unit stay. DISCUSSION: This clinical trial tests the effectiveness of a management protocol based on technology considered pivotal to brain trauma treatment in the developed world: the ICP monitor. A randomized, controlled trial of ICP monitoring has never been performed-a critical gap in the evidence base that supports the role of ICP monitoring in TBI care. As such, the results of this randomized, controlled trial will have global implications regardless of the level of development of the trauma system.

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In patients with severe traumatic brain injury (TBI), the influence on important outcomes of the use of information from intracranial pressure (ICP) monitoring to direct treatment has never been tested in a randomized controlled trial (RCT). We are conducting an RCT in six trauma centers in Latin America to test this question. We hypothesize that patients randomized to ICP monitoring will have lower mortality and better outcomes at 6-months post-trauma than patients treated without ICP monitoring. We selected three centers in Bolivia to participate in the trial, based on (1) the absence of ICP monitoring, (2) adequate patient accession and data collection during the pilot phase, (3) preliminary institutional review board approval, and (4) the presence of equipoise about the value of ICP monitoring. We conducted extensive training of site personnel, and initiated the trial on September 1, 2008. Subsequently, we included three additional centers. A total of 176 patients were entered into the trial as of August 31, 2010. Current enrollment is 81% of that expected. The trial is expected to reach its enrollment goal of 324 patients by September of 2011. We are conducting a high-quality RCT to answer a question that is important globally. In addition, we are establishing the capacity to conduct strong research in Latin America, where TBI is a serious epidemic. Finally, we are demonstrating the feasibility and utility of international collaborations that share resources and unique patient populations to conduct strong research about global public health concerns.

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