J. Pridgeon (Correponding author), MHA, W. Videtta, MD, and The NeuroTrauma Research Group
Traumatic Brain Injury (TBI) is a major cause of mortality and disability, both in High Income Countries (HIC) and Low and Middle Income Countries (LMIC). The 1996 Global Burden of Disease Report found Latin America had the highest incidence of intracranial injury worldwide due to high rates of road traffic crashes and to violence1. A recent WHO study projected trauma would be a leading cause of death by the year 20202. TBI accounts for about 85% of all trauma related fatalities3.
The negative consequences of severe TBI are not limited to mortality. The rate of disabilities among survivors is high. Severe brain injury has the potential to impair all major areas of functioning, including various aspects of cognition (eg memory, judgment), physical abilities (e.g. disturbance of balance, ambulation), and to cause behavioral problems such as irritability, lack of initiative, and depression. These deficits, in turn, oftentimes hinder the person with a brain injury from functioning effectively in everyday life (e.g. work, independent living, self care, social relationships)4,5.
Since 2007, the University of Washington (UW), with collaborators from the Oregon Health and Science University, the University of California, San Diego, and Argentina, Bolivia, Ecuador, Colombia, and Brazil have been conducting a Randomized Controlled Trial (RCT) evaluating management of severe TBI using intracranial pressure (ICP) monitoring in the intensive care unit (ICU) at six sites in two countries. In addition an observational study in 5 countries has focused on natural course of recovery and outcome. In the observational study, ICP monitoring varied by site but, overall, was used in a minority of patients. UW Professor Randall Chesnut, MD is Principal Investigator for the overall research program which is funded by an NIH NINDS/Fogarty sponsored grant “Traumatic Brain Injury in Latin America: Lifespan Analysis”. The studies are run in collaboration with Fundacion ALAS (Apoyo al Lesionado Neurologico Agudo – “Support to the Acute Neurological Patient“), and the Latin American Brain Injury Consortium (LABIC).
The project involves 9 centers in 5 countries and examines all severe TBI patients admitted to the hospital, collecting data on demographics, injuries, management, and outcomes. Acute care data collection enables understanding of ICU care and how it impacts outcome in LMIC settings. Outcomes are measured at discharge and 3 and 6 months following injury and include measures of functional outcome, and (in the RCT), neuropsychological outcome using measures translated and normed for Spanish speakers.6,7. The studies use a randomized controlled design and an observational study that provides external validation.
In addition to the ongoing grant, the team has conducted 3 other multinational multi site studies with LABIC investigators. Two were funded by the US and one was sponsored by Fundacion ALAS the Argentine non-profit fiscal and administrative collaborator for LABIC. The purpose of LABIC is to organize and coordinate interactions among Neurointensivists from countries throughout Latin America, provide Neurointensive care education via courses for nurses, physicians, and associated care providers, coordinate Neurointensive Care sections within Latin American national and international conferences (eg Critical Care Conferences, Internal Medicine Conferences, Neurosurgical Conferences), translate important Neurointensive Care documents into Spanish and Portuguese, write and disseminate Neurointensive Care literature to Latin American practitioners, develop national and international research activities and provide a unified voice for interactions with international medical and scientific societies. Current membership includes approximately 300 individuals representing 50 institutions from 12 countries.
The incidence and prevalence of TBI in much of Latin America are not well documented. Although current epidemiological data about TBI in Latin America are rare, the 1996 Global Burden of Disease Report found Latin America to have the highest incidence of intracranial injury in the world due to road traffic accidents and violence6. A prospective, observational study of TBI in Argentina was reported by our group7. In this study, outcomes of a group of TBI subjects were compared to similar study samples in the US. The key findings were: 1) Virtually all patients were discharged from hospital to home due to lack of rehabilitation for TBI; 2) 30% more patients expired in-hospital in the Argentine sample than in the U.S. sample; 3) 53% more of the Argentine patients died of secondary complications than neurological insult. These high rates may be the result of training and staffing differences between HICs and LMICs for hospital wards outside the ICU, as well asresource allocation practices both in and outside the hospital.
Preliminary research in Latin America7 has revealed several important gaps in the ability to understand and treat TBI in those countries. First, the paucity of research in much of Latin America leads to uncertainty about the magnitude of the problem, patient characteristics, treatment methods, and outcomes. Without systematic research in those countries and translating results into practice, poor outcomes will persist. To obtain the needed information, Latin American research capacity needs to be increased. The second gap concerns the applicability of published studies in general, and practice guidelines in particular, in developing countries. Fundamental differences in LMIC trauma care make generalizations from HIC based trauma publications a concern for most TBI management situations in LMICs. We do not know what aspects of the guidelines are either feasible or effective in resource-poor environments. As such, both the ability to follow guidelines as well as the efficacy of those guidelines comes into question. Third, most Latin American countries lack rehabilitation for TBI patients, and neuropsychological assessment is extremely limited. This creates a new population of severely disabled people who are being discharged home without assessment or treatment for their profound deficits and limitations in cognition, language, behavior, physical and psychosocial functioning secondary to their TBI7. Clearly, clinical researchers in Latin America need to generate internally relevant and applicable guidelines for treatment of severe TBI based on their own data. It is possible that under certain circumstances the application of guidelines developed in the U.S. and other HICs could produce more harm than good inasmuch as the research and clinical care infrastructure supporting such studies, including facilities, resources and training, may differ substantially from those available to clinicians in LMICs.
Randomized Control Trial
For over 30 years HIC academic medical communities have believed that directly monitoring ICP is required for successful TBI management. However, with respect to improving patient outcomes, the efficacy of basing treatment on monitored ICP values has never been tested in a Class I RCT. In other countries most clinicians assess ICP indirectly based on clinical signs or neuroimaging results, and use ICP management protocols. Even in the United States ICP monitoring is not consistently used in managing severe TBI patients8. The question is whether treatment informed by ICP monitoring is superior to that based on indirect assessment of ICP. Therefore, this is an important question for resource-rich as well as resource-limited environments. Such a trial could not proceed where ICP monitoring had become a standard of care because it would require withholding established (although not rigorously proven) practice from some subjects. However, it could be performed in countries or hospitals where ICP monitoring was available (via ventriculostomy) but not practiced since the trial would involve providing (instead of withholding) more sophisticated treatment tools for some patients.
The purpose of this 5-year project is to test the effect of ICP monitor-based management of patients with severe TBI on outcomes at hospital discharge and at 3 and 6 months after injury. This randomized controlled trial is being conducted in 6 centers; 4 in Bolivia and 2 in Ecuador. The study hypotheses include 1) patients with severe TBI whose acute care treatment is managed using ICP monitors will have significantly lower mortality and better neuropsychological and functional recovery at 6 months post injury than those managed with the standard protocol, and 2) adding ICP monitoring to TBI patient care will minimize secondary complications and decrease ICU length of stay.
Subjects: To be included, patients had to arrive at the study hospital within 24 hours of injury and have a Glasgow Coma Scale score (GCS) of 3-8 at admission or deteriorate to that level within 24 hours. After eligibility is determined and consent obtained from family members within 24 hours of injury, they are randomized into an ICP arm or standard care arm. If consent was not obtained within this time frame patients were not entered into the study. Outcomes at 3 and 6 months are assessed by examiners blinded to group membership.
Measures: A broad range of measures are collected on each patient including:
1) Acute data: Demographics, injury and its severity, vital signs, other treatments, CTs, other surgeries etc.
2) Outcome data: At 3 months after injury subjects are evaluated on a measure reflecting functional limitations in everyday life using the Glasgow Outcome Scale Extended (GOSE)9. At 6 months after injury the battery includes, in addition to the GOSE, tests that examine important neuropsychological constructs sensitive to the integrity of brain functions, including TBI. Tests in this battery were based both on the literature and the UW investigators’ prior TBI work. Test selection considerations included: 1) they cover different aspects of functioning that are clinically relevant and likely to be affected by brain injury; 2) the measures possess good psychometric properties with respect to sensitivity, validity, and reliability; 3) the measures are appropriate for use with a broad spectrum of brain injury severity and likely to be responsive to treatment effects directed at improving outcome and; 4) most importantly, the measures have been translated, adapted and validated for use with Spanish speakers12. The neuropsychological constructs examined included working memory, speed of information processing, memory and learning, executive functions, and motor speed and dexterity.
Patient accession ended in 2011 and follow up data are now being collected. Importantly, overall study recruitment goals were met and follow up will conclude by mid-2012. The six-month follow up rate was 96% - remarkable for any RCT and a testament to the determination of the Latin American investigators and outcomes examiners to demonstrate they could successfully conduct a challenging RCT that can generate Class I evidence.
The outcome from severe TBI in Latin America has not been previously described using a prospective multicenter, multinational study approach. Therefore, we conducted a pilot Traumatic Coma Data Bank (TCDB) from seven centers in five countries in South America as a model to better understand outcomes in severe TBI in low to middle income countries (LMICs). Between 2008 and 2010, we enrolled and prospectively studied 226 patients with severe TBI to 6 months using the Extended Glasgow Outcome Scale (GOS-E). These were in addition to the patients enrolled in the RCT.
Results: Early (14 day) mortality is 17%, remarkably similar to modern outcomes in high income countries (HIC), despite resource limitations including very rare use of ICP monitoring. However, unique to this population, there is a “delayed” mortality, representing about 33% of the deaths that brings the six-month figure to 26%, appreciably higher than what has been seen in recent studies from HIC. Most of these later deaths were related to systemic complications rather than the neurologic causes of death that predominated in the first 14 days. Complications included pneumonia and other infections, pressure sores, deep vein thrombosis and pulmonary embolism; all are consistent with reduced levels of care following ICU discharge, and represent a productive area for further research and intervention.
We also discovered a previously undescribed but common (15%) group of sTBI patients whose ICU admission is delayed 24+ hours or eliminated due to ICU bed unavailability. Study hospitals varied with regard to their triage systems to refer patients when no ICU bed was available, and some facilities varied with respect to this practice.
Our conclusion from the Observational Study was that TBI outcome in LMICs appears different enough from to that in HICs to call into question the applicability of epidemiological or treatment studies from HICs to LMICs.
In addition to supporting research, The Fogarty Institute mission is to build research capacity in LMICs. Study investigators received didactic training in research methodology and active mentoring and oversight of their work as part of the trial. Some collaborators received direct experience in running a study and providing training and monitoring of the personnel at the sites. Institutional capacity was enhanced through sites participation in establishing internationally-recognized Ethics Committee certification and conducting annual IRB reviews with certification to the UW Human Subjects Division. Research administrative experience was also an important part of building independent, self-sustaining, and productive research centers. Consistent with establishing durable research capacity, several core investigators have formed a clinical research organization (Centro de Infomatica y Investigaciones Clinica [CIIC]) in the interest of supporting future research (TBI and other) in Latin America.
Annual All Team Meetings provided Latin American Investigators and outcomes examiners the opportunity to present individual center results to the combined group, clarify procedures, troubleshoot problems, give constructive feedback, propose research questions and design protocols for future studies. Investigators and outcomes examiners are now being encouraged to generate publications and independent grant applications as a next step in developing research capacity. The future expansion of LABIC to include post acute care professionals such as rehabilitation, educational re-entry and community based providers could have a positive effect on both TBI care and research.
Traumatic Brain Injury is a major cause of mortality and disability, both in HIC and LMICs. TBI accounts for about 85% of all trauma related fatalities. Despite a lack of tradition in Latin American countries, 9 institutions in 5 countries have conducted two studies during 5 years. In the Observational Study, TBI outcome in LMICs appears different enough from that in HICs to call into question the applicability of epidemiological or treatment studies from HICs to LMICs. The guidelines developed in The guidelines developed in HIC are applicable in only a few centers in Latin America. We believe that systematic research in Latin American and translation of results into practice could improve patient outcome.. Latin American research capacity needs to increase in order to realize this goal.
- Puvanachandra P, Hyder A. Traumatic brain injury in Latin America and the Caribbean: a call for research. Salud Publica de Mexico. 2008;50(S-1): S3-S5.
- World Health Organization. Neurological Health Disorders and Public Health Challenges. ISBN 92 4 156336 2, 2006.
- Puvanachandra P., Hyder A. The Burden of Traumatic Brain Injury in Asia: A call for research. Pak J Neurol Sci 2009; 4(1):27-32
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- Cherner, M, Suarez, P, Lazzaretto, D, Artiola I Fortuny, L, Rivera Mindt, M, Marcotte, T, Grant, I, Heaton, R & the HNRC Group. (2007). Demographically corrected norms for the Brief Visuospatial Memory Test-Revised and Hopkins Verbal Learning Test-Revised in Monolingual Spanish Speakers from the U.S. – Mexico Border Region. Archives of Clinical Neuropsychology, 22 (3), 343-353.
- Cherner M, Suárez P, Rivera Mindt M, Taylor M, Lazzaretto D, Grant I, Artiola i Fortuny L, Heaton R & the HNRC Group (2010). Demographically Adjusted Norms for the Paced Auditory Serial Addition Task (PASAT) in Spanish. JINS 16(S1), 114.
- Murray CJL , Lopez AD.Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997; 349: 1498–1450.
- Rondina C, Videtta W, Petroni G, Lujan S, Schoon P, Mori LB, Matkovich J, Carney N, & Chesnut R. Mortality and morbidity from moderate to severe traumatic brain injury in Argentina. J Head Trauma Rehabil2005;20(4):368-376.
- Ghajar J, Hariri RJ, Narayan JK, Iacono LA, Firlik K, Patterson RH. Survey of critical care management of comatose, head-injured patients in the United States. Critical Care Medicine, 2005;23(3):560-567.
- Wilson J.T. Pettigrew L.E. Teasdale G.M. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J. Neurotrauma 1998;15:573–585.
- Artiola i Fortun L Hermosillo Romo D, Heaton RK, Pardee III, RE. Manual de Normas Y Procedimientos Para La Bateria Neuropsicolog. Psychology Press.
NIH/NINDS R01 NS058302; Integra Life Sciences; Mr. Richard Adler with Adler Giersch PS and Mr. Mike Nelson with Nelson Langer Engle, PLLC.
The NeuroTrauma Research Group:
- Latin America Investigators:
- G. Petroni, S. Lujan, C. Rondina, F. Rondina (Hospital de Emergencias, Dr. Clemente Alvarez, Rosario, Argentina).
- W. Videtta (Prof. A. Posadas National Hospital, Buenos Aires, Argentina)
- United States Investigators:
- R. Chesnut (PI), N. Temkin, S. Dikmen, J. Machamer, J. Barber, J. Pridgeon, K. Chaddock, J. Celix (University of Washington, Seattle, Washington).
- N. Carney, A. Huddleston (Oregon Health Sciences University, Portland, Oregon).
- M. Cherner, T. Hendrix (University of California, San Diego).