In Reply: Development of a Randomized Trial Comparing ICP-Monitor-Based Management of Severe Pediatric Traumatic Brain Injury to Management Based on Imaging and Clinical Examination Without ICP Monitoring-Study Protocol

To the Editor:

The letter from Nielsen et al¹ questioning the propriety of our current randomized control trial (RCT) on intracranial pressure (ICP) monitor–guided treatment of severe traumatic brain injury (TBI) in children (the BELA TRIPP Trial^2,3) allows us to reiterate the ethical and scientific considerations that we encountered surrounding our previous, similar adult investigation (the BEST TRIP trial⁴) and addressed.^5,6 Early editions of the Brain Trauma Foundation guidelines stated that a randomized ICP monitoring trial was necessary but ethically unlikely⁷ because it would involve withholding monitoring in half of our patients with TBI, all of whom would generally be monitored. Our situational naïveté was exposed when our Latin American colleagues in developing a prospective observational TBI research project proposed turning that proposal into an ICP RCT, as doing it at their centers meant adding monitoring to patients who would otherwise not be monitored. Their proposal led us to realize that the “scientific ethics” surrounding this issue were universally consistent but the “visceral ethics” appeared situational (permissive in their environment; prohibitive in ours). The study design passed review by the National Institute of Neurological Disorders and Stroke, the Fogarty Institute, the University of Washington, and the ethics/Institutional Review Board committees at each of our study sites and was completed in 2012.⁴

That trial demonstrated no difference between ICP monitor-based care and care based on imaging and clinical examination (ICE) without monitoring. This demonstrated to our low-and-middle-income countries (LMIC) colleagues that they could accomplish effective TBI care in their practice environments and also provided a management algorithm to guide them in this task. Further research into the performance of an elaborated ICE protocol (COnsensus Revised ICE—CREVICE) has now provided a treatment protocol with proven efficacy.^8,9 These LMIC-specific results are direct benefits of their participation in the BEST TRIP trial study.

Clearly, the BEST TRIP trial was actually conceived by our Latin American colleagues. Our team, based in a high income country (HIC), certainly provided funding access and scientific experience, allowing the study to be successfully accomplished, but the concept of performing the RCT to determine the potential value of adding ICP monitoring to their practices (eg, redirecting limited resources) and the widespread LMIC-focused study-related benefits outlined herein reflect the LMIC-centric nature of this research. BEST TRIP was not (and BELA TRIPP is not) an HIC-focused project performed in LMICs for inappropriate reasons. It is an LMIC-focused investigation and, therefore, should be done in resource-limited countries.

A common question is how the BEST TRIP results relate to children with pediatric TBI younger than 13 years having been excluded. Consideration of performing a pediatric trial led to a feasibility and ethics conference with Latin American pediatric neurotrauma practitioners in Buenos Aires in December 2014. The participants strongly supported the study, and many desired to participate.

In writing the BELA TRIPP Trial application, our sensitivity to propriety questions prompted us to involve 2 ethicists from the University of Washington's Institute of Translational Health Sciences-Regulatory Support and Bioethics Core and the Treuman Katz Center for Pediatric Bioethics at Seattle Children's Hospital (Benjamin Wilfond, MD and Katheryn Porter, PhD). They reviewed the proposal presubmission and continue to work with the team.

BEST TRIP benefited our LMIC-based research colleagues and has withstood post hoc ethical challenges based on the arguments outlined above. We have thoroughly attempted to preemptively address possible ethical conflicts with BELA TRIPP. We do not believe the trial design to be unprincipled. However, the question of whether centers in HICs should be concomitantly involved requires further comment. The recent Brain Trauma Foundation Pediatric Traumatic Brain Injury Guidelines update reaffirmed the lack of solid evidence that ICP monitor-based management improves long-term outcome, affirming scientific equipoise. However, the same “visceral-equipoise” angst encountered in BEST TRIP plagues the issue of withholding ICP monitoring in pediatric patients to form a nonmonitored cohort at centers routinely employing monitoring. The empiric nature of scientific equipoise renders it universal; visceral equipoise is clearly situational. It is implausible to organize a study involving HIC centers reluctant to follow the research protocol. Notably, despite frequent discussion of replicating BEST TRIP in HICs, nothing has been formally proposed. Similar to BEST TRIP, BELA TRIPP is primarily focused at optimizing pediatric TBI care and hospital resource allocation in LMICs. Therefore, we do not consider the lack of HIC centers as prejudicial or compromising to the value and focus of the project. Although the results will be of academic interest in HICs, they will be of direct practical, beneficial value in LMICs. Ergo, respecting the clinical zeitgeist existing at academic pediatric trauma centers and the LMIC-centric focus of the research, we are proceeding with BELA TRIPP exclusively in Latin American LMIC centers.

We agree with the closing statement by Nielsen et al¹ about protecting “the most vulnerable children in LMICs,” but we believe that it is specifically not applicable to BELA TRIPP because it is inconsistent with the trial's design. The underlying scientific equipoise applies universally, regardless of the visceral equipoise-related issues present in HIC centers, and the study is directly focused on LMIC-centric questions. Although we agree with many of their concepts, we believe their arguments do not apply to the BELA TRIPP trial when considered in light of the issues that we have covered here. We thank them for this opportunity to discuss this issue in a public forum.

Funding

This study received funding from the Eunice Kennedy Shriver National Institute on Child Health and Human Development (NICHD), and the Fogarty International Center of the National Institutes of Health (NIH) (5R01-HD060570; ClinicalTrials.gov Identifier: NCT05566431).

Disclosures

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.