Is intracranial pressure monitoring still required in the management of severe traumatic brain injury? Ethical and methodological considerations on conducting clinical research in poor and low-income countries.

Abstract

Long-term disabilities suffered by patients with severe traumatic brain injury (TBI) are a continuous challenge for health care systems and a burden for patients, their families, and the community in terms of suffering, disability, and monetary cost.[13,19] Approximately 50% of TBI comatose patients with an abnormal computed tomography (CT) scan also have high intracranial pressure (ICP).[22] Death, vegetative state, and severe disability are the expected outcomes in patients with persistent high ICP not controlled by medical and/or surgical treatment. As high ICP cannot be estimated reliably by clinical examination or even sequential imaging, ICP monitoring has been considered a necessary tool for its diagnosis and management. After decades of ongoing debate about how and when to monitor ICP, a consensus was finally reached in 1995 with the publication of the first evidence-based guidelines (EBGs) for the management of severe TBI in adults, developed under the sponsorship of the Brain Trauma Foundation (BTF).[3] Three consecutive versions of these guidelines have established–as a level II recommendation–that ICP should be monitored in “all salvageable patients with a severe TBI and an abnormal CT scan”.[3,30] BTF guidelines are endorsed by most scientific societies worldwide and they have been translated into many languages and disseminated and applied in the United States, Europe, South America, China, and Japan, thus defining the core principles for managing severe TBI. In keeping with the guidelines, care centered on ICP management is the standard for patients with severe TBI in both developed countries and those developing countries that can afford their costly management. A few studies have shown that good adherence to the BTF guidelines improve outcomes and reduce the cost of the acute care.[12,16,24,26] The recent publication of the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST TRIP) trial in the New England Journal of Medicine (NEJM) changed this calm scenario unexpectedly, particularly because some of the investigators coauthoring the paper were also active contributors to recent versions of the BTF guidelines.[7] This randomized clinical trial (RCT), which enrolled 324 patients in 6 hospitals in Bolivia and Ecuador, reported as its main conclusion that ICP-based management increased the 6-month favorable outcome only by a marginal and nonsignificant 5% difference when compared with patients for whom care was guided with serial CTs and clinical examination.[7] Despite some clarifications by the principal investigator,[6] the main message conveyed by this trial is that ICP monitoring does not make an outcome difference when managing TBI.[14] Consequently, the debate of whether or not ICP should be monitored has been effectively resuscitated and it is receiving wide media coverage and generating more heat than light among clinicians.[14] Some neurosurgeons and intensivists would even like to have a moratorium until class I evidence is obtained for ICP monitoring. BEST TRIP is a good example of research that has no practical relevance to the health needs of the host country, but it is apparently important to the foreign sponsors and researchers and therefore it provides a good opportunity to raise the issues of double standards, external validity, exploitation of vulnerable populations, the role of personal and clinical equipoise, and the value of biomedical research itself. There is a growing ethical concern for the obvious and hidden risks of conducting certain clinical trials in poor and low-income countries. These trials are frequently funded by pharmaceutical or medical device companies and approved by prestigious regulatory bodies that are based in Western Europe or the United States, countries where some of the trial designs and medical practices employed in these poorer countries would never be permissible.[8]