Outcome and comparative effectiveness research in traumatic brain injury : a methodological perspective

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Although research activity in TBI has expanded rapidly, all these endeavors have not yet resulted in major advances in our understanding of TBI. This thesis addresses two important topics in TBI research. First, outcome following TBI including the prevalence and predictors of psychiatric disorders and post-concussion symptoms. Second, this thesis examines whether comparative effectiveness research (CER) could contribute to evidence generation in TBI, with a focus on current guideline adherence, treatment variation and analytical methods. We found that prevalence rates of post-concussion symptoms and psychiatric disorders varied widely and were dependent on pre-injury factors, patient population, assessment, analysis strategy and the diagnostic criteria used. Etiology of TBI sequelae is complex and multifactorial and includes biological, psychological and social factors that might be difficult to capture in a prediction model. When studying prevalence and predictors of psychiatric disorders and post-concussion symptoms following TBI, the role of misattribution, research setting, attrition and the overlap in symptomatology between post-concussion symptoms and psychiatric disorders should be taken into account. Current evidence underpinning TBI guidelines is weak, and consequently, there is large variation in policy and guideline adherence among neurotrauma centers. This variation provides an opportunity for CER. However, the effect estimate obtained in observational CER studies largely depends on the analytical method used. Since all analytical methods have their strengths and limitations and are based on untestable assumptions, it is important that researchers do not consider one particular analytical method as the most appropriate. Different analytical methods that are reasonable for the research question under study should be used as sensitivity analyses and the results of observational CER studies should be confirmed by high-quality RCTs

Comparing health-related quality of life of Dutch and Chinese patients with traumatic brain injury: Do cultural differences play a role?

Background: There is growing interest in health related quality of life (HRQoL) as an outcome measure in international trials. However, there might be differences in the conceptualization of HRQoL across different socio-cultural groups. The objectives of current study were: (I) to compare HRQoL, measured with the short form (SF)-36 of Dutch and Chinese traumatic brain injury (TBI) patients 1 year after injury and; (II) to assess whether differences in SF-36 profiles could be explained by cultural differences in HRQoL conceptualization. TBI patients are of particular interest because this is an important cause of diverse impairments and disabilities in functional, physical, emotional, cognitive, and social domains that may drastically reduce HRQoL. Methods: A prospective cohort study on adult TBI patients in the Netherlands (RUBICS) and a retrospective cohort study in China were used to compare HRQoL 1 year post-injury. Differences on subscales were assessed with the Mann-Whitney U-test. The internal consistency, interscale correlations, item-internal consistency and item-discriminate validity of Dutch and Chinese SF-36 profiles were examined. Confirmatory factor analysis was performed to assess whether Dutch and Chinese data fitted the SF-36 two factor-model (physical and mental construct). Results: Four hundred forty seven Dutch and 173 Chinese TBI patients were included. Dutch patients obtained significantly higher scores on role limitations due to emotional problems (p < .001) and general health (p < .001), while Chinese patients obtained significantly higher scores on physical functioning (p < .001) and bodily pain (p = .001). Scores on these subscales were not explained by cultural differences in conceptualization, since item- and scale statistics were all sufficient. However, differences among Dutch and Chinese patients were found in the conceptualization of the domains vitality, mental health and social functioning. Conclusions: One year after TBI, Dutch and Chinese patients reported a different pattern of HRQoL. Further, there might be cultural differences in the conceptualization of some of the SF-36 subscales, which has implications for outcome evaluation in multi-national trials

Post-Traumatic Stress Disorder after Civilian Traumatic Brain Injury: A Systematic Review and Meta-Analysis of Prevalence Rates

Post-traumatic stress disorder (PTSD) is a commonly diagnosed psychiatric disorder following traumatic brain injury (TBI). Much research on PTSD and TBI has focused on military conflict settings. Less is known about PTSD in civilian TBI. We conducted a systematic review and meta-analysis on the prevalence of PTSD after mild and moderate/severe TBI in civilian populations. We further aimed to explore the influence of methodological quality and assessment methods. A systematic literature search was performed on studies reporting on PTSD in civilian TBI, excluding studies on military populations. The risk of bias was assessed using the MORE (Methodological evaluation of Observational REsearch) checklist. Meta-analysis was conducted for overall prevalence rates for PTSD with sensitivity analyses for the severity of TBI. Fifty-two studies were included, of which 31 were graded as low risk of bias. Prevalence rates of PTSD in low risk of bias studies varied widely (2.6–36%) with a pooled prevalence rate of 15.6%. Pooled prevalence rates of PTSD for mild TBI (13.5%, 95% confidence interval [CI]: 11.7–15.3; I2 = 2%) did not differ from moderate/severe TBI (11.8, 95% CI: 7.5–16.1; I2 = 63%). Similar rates were reported in studies using different approaches and times of assessment. Although most studies that compared participants with TBI with trauma patients and healthy controls found no difference in prevalence rates of PTSD, a meta-analysis across studies revealed a higher prevalence of PTSD in patients with TBI (odds ratio [OR]: 1.73, 95% CI: 1.21–2.47). This review highlights variability between studies and emphasizes the need for higher-quality studies. Further research is warranted to determine risk factors for the development of PTSD after TBI

Adherence to Guidelines in Adult Patients with Traumatic Brain Injury: A Living Systematic Review.

Guidelines aim to improve the quality of medical care and reduce treatment variation. The extent to which guidelines are adhered to in the field of traumatic brain injury (TBI) is unknown. The objectives of this systematic review were to (1) quantify adherence to guidelines in adult patients with TBI, (2) examine factors influencing adherence, and (3) study associations of adherence to clinical guidelines and outcome. We searched EMBASE, MEDLINE, Cochrane Central, PubMed, Web of Science, PsycINFO, SCOPUS, CINAHL, and grey literature in October 2014. We included studies of evidence-based (inter)national guidelines that examined the acute treatment of adult patients with TBI. Methodological quality was assessed using the Research Triangle Institute item bank and Quality in Prognostic Studies Risk of Bias Assessment Instrument. Twenty-two retrospective and prospective observational cohort studies, reported in 25 publications, were included, describing adherence to 13 guideline recommendations. Guideline adherence varied considerably between studies (range 18-100%) and was higher in guideline recommendations based on strong evidence compared with those based on lower evidence, and lower in recommendations of relatively more invasive procedures such as craniotomy. A number of patient-related factors, including age, Glasgow Coma Scale, and intracranial pathology, were associated with greater guideline adherence. Guideline adherence to Brain Trauma Foundation guidelines seemed to be associated with lower mortality. Guideline adherence in TBI is suboptimal, and wide variation exists between studies. Guideline adherence may be improved through the development of strong evidence for guidelines. Further research specifying hospital and management characteristics that explain variation in guideline adherence is warranted

Prehospital Trauma Care among 68 European Neurotrauma Centers: Results of the CENTER-TBI Provider Profiling Questionnaires

The first hour following traumatic brain injury (TBI) is considered crucial to prevent death and disability. It is, however, not established yet how the prehospital care should be organized to optimize recovery during the first hour. The objective of the current study was to examine variation in prehospital trauma care across Europe aiming to inform comparative effectiveness analyses on care for neurotrauma patients. A survey on prehospital trauma care was sent to 68 neurotrauma centers from 20 European countries participating in the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. The survey was developed using literature review and expert opinion and was pilot tested in 16 centers. All participants completed the questionnaire. Advanced life support was used in half of the centers (n = 35; 52%), whereas the other centers used mainly basic life support (n = 26; 38%). A mobile medical team (MMT) could be dispatched 24/7 in most centers (n = 66; 97%). Helicopters were used in approximately half of the centers to transport the MMT to the scene (n = 39; 57%) and the patient to the hospital (n = 31, 46%). Half of the centers used a stay-and-play approach at the scene (n = 37; 55%), while the others used a scoop-and-run approach or another policy. We found wide variation in prehospital trauma care across Europe. This may reflect differences in socio-economic situations, geographic differences, and a general lack of strong evidence for some aspects of prehospital care. The current variation provides the opportunity to study the effectiveness of prehospital interventions and systems of care in comparative effectiveness research

Prehospital Trauma Care among 68 European Neurotrauma Centers: Results of the CENTER-TBI Provider Pr

The first hour following traumatic brain injury (TBI) is considered crucial to prevent death and disability. It is, however, not established yet how the prehospital care should be organized to optimize recovery during the first hour. The objective of the current study was to examine variation in prehospital trauma care across Europe aiming to inform comparative effectiveness analyses on care for neurotrauma patients. A survey on prehospital trauma care was sent to 68 neurotrauma centers from 20 European countries participating in the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. The survey was developed using literature review and expert opinion and was pilot tested in 16 centers. All participants completed the questionnaire. Advanced life support was used in half of the centers (n = 35; 52%), whereas the other centers used mainly basic life support (n = 26; 38%). A mobile medical team (MMT) could be dispatched 24/7 in most centers (n = 66; 97%). Helicopters were used in approximately half of the centers to transport the MMT to the scene (n = 39; 57%) and the patient to the hospital (n = 31, 46%). Half of the centers used a stay-and-play approach at the scene (n = 37; 55%), while the others used a scoop-and-run approach or another policy. We found wide variation in prehospital trauma care across Europe. This may reflect differences in socio-economic situations, geographic differences, and a general lack of strong evidence for some aspects of prehospital care. The current variation provides the opportunity to study the effectiveness of prehospital interventions and systems of care in comparative effectiveness research

Comparative Effectiveness of Surgery for Traumatic Acute Subdural Hematoma in an Aging Population

Analysis and support of clinical decision makin

Variation in Blood Transfusion and Coagulation Management in Traumatic Brain Injury at the Intensive Care Unit: A Survey in 66 Neurotrauma Centers Participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Study

Our aim was to describe current approaches and to quantify variability between European intensive care units (ICUs) in patients with traumatic brain injury (TBI). Therefore, we conducted a provider profiling survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The ICU Questionnaire was sent to 68 centers from 20 countries across Europe and Israel. For this study, we used ICU questions focused on 1) hemoglobin target level (Hb-TL), 2) coagulation management, and 3) deep venous thromboembolism (DVT) prophylaxis. Seventy-eight participants, mostly intensivists and neurosurgeons of 66 centers, completed the ICU questionnaire. For ICU-patients, half of the centers (N = 34; 52%) had a defined Hb-TL in their protocol. For patients with TBI, 26 centers (41%) indicated an Hb-TL between 70 and 90 g/L and 38 centers (59%) above 90 g/L. To treat trauma-related hemostatic abnormalities, the use of fresh frozen plasma (N = 48; 73%) or platelets (N = 34; 52%) was most often reported, followed by the supplementation of vitamin K (N = 26; 39%). Most centers reported using DVT prophylaxis with anticoagulants frequently or always (N = 62; 94%). In the absence of hemorrhagic brain lesions, 14 centers (21%) delayed DVT prophylaxis until 72 h after trauma. If hemorrhagic brain lesions were present, the number of centers delaying DVT prophylaxis for 72 h increased to 29 (46%). Overall, a lack of consensus exists between European ICUs on blood transfusion and coagulation management. The results provide a baseline for the CENTER-TBI study, and the large between-center variation indicates multiple opportunities for comparative effectiveness research

Apolipoprotein E epsilon 4 (APOE-ε4) genotype is associated with decreased 6-month verbal memory performance after mild traumatic brain injury

Introduction: The apolipoprotein E (APOE) ε4 allele associates with memory impairment in neurodegenerative diseases. Its association with memory after mild traumatic brain injury (mTBI) is unclear. Methods: mTBI patients (Glasgow Coma Scale score 13–15, no neurosurgical intervention, extracranial Abbreviated Injury Scale score ≤1) aged ≥18 years with APOE genotyping results were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study. Cohorts determined by APOE-ε4(+/−) were assessed for associations with 6-month verbal memory, measured by California Verbal Learning Test, Second Edition (CVLT-II) subscales: Immediate Recall Trials 1–5 (IRT), Short-Delay Free Recall (SDFR), Short-Delay Cued Recall (SDCR), Long-Delay F

Comparative effectiveness of surgery in traumatic acute subdural and intracerebral haematoma: study protocol for a prospective observational study within CENTER-TBI and Net-QuRe

INTRODUCTION: Controversy exists about the optimal treatment for patients with a traumatic acute subdural haematoma (ASDH) and an intracerebral haematoma/contusion (t-ICH). Treatment varies largely between different regions. The effect of this practice variation on patient outcome is unknown. Here, we present the protocol for a prospective multicentre observational study aimed at comparing the effectiveness of different treatment strategies in patients with ASDH and/or t-ICH. Specifically, the aims are to compare (1) an acute surgical approach to an expectant approach and (2) craniotomy to decompressive craniectomy when evacuating the haematoma. METHODS AND ANALYSIS: Patients presenting to the emergency room with an ASDH and/or an t-ICH are eligible for inclusion. Standardised prospective data on patient and injury characteristics, treatment and outcome will be collected on 1000 ASDH and 750 t-ICH patients in 60-70 centres within two multicentre prospective observational cohort studies: the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) and Neurotraumatology Quality Registry (Net-QuRe). The interventions of interest are acute surgery, defined as surgery directly after the first CT at presentation versus late or no surgery and craniotomy versus decompressive craniectomy. The primary outcome measure is the Glasgow Outcome Score-Extended at 6 months. Secondary outcome measures include in-hospital mortality, quality of life and neuropsychological tests. In the primary analysis, the effect of treatment preference (eg, proportion of patients in which the intervention under study is preferred) per hospital will be analysed with random effects ordinal regression models, adjusted for casemix and stratified by study. Such a hospital-level approach reduces confounding by the indication. Sensitivity analyses will includ