Subgroup Analysis and Covariate Adjustment in Randomized Clinical Trials of Traumatic Brain Injury: A Systematic Review

Neurosurgery ◽  
2005 ◽  
Vol 57 (6) ◽  
pp. 1244-1253 ◽  
Author(s):  
Adrían V. Hernández ◽  
Ewout W. Steyerberg ◽  
Gillian S. Taylor ◽  
Anthony Marmarou ◽  
J Dik F. Habbema ◽  
...  
2021 ◽  
Author(s):  
Adam T Biggs ◽  
Lanny F Littlejohn ◽  
Hugh M Dainer

ABSTRACT Introduction Hyperbaric oxygen therapy (HBOT) is a commonly used treatment for a variety of medical issues, including more than a dozen currently approved uses. However, there are alternative proposed uses that have significant implications among an active duty military or veteran population as treatments for PTSD, mild traumatic brain injury (mTBI), and traumatic brain injury (TBI). These applications have seen a recent groundswell of support from the operator and veteran communities, raising the visibility of using HBOT for alternative applications. The current review will cover the existing evidence regarding alternative uses of HBOT in military medicine and provide several possibilities to explain the potential conflicting evidence from empirical results. Materials and Methods There were no inclusion or exclusion criteria for articles addressing currently approved HBOT uses as covered under the military health system. These references were provided for comparison and illustration as needed. For alternative HBOT uses, the review focuses explicitly upon three alternative uses in PTSD, mTBI, and TBI. The review addresses any piece of case study evidence, observational data, quasi-experimental design, or randomized-controlled trial that explored any or a combination of these issues within an active duty population, a veteran population, or a civilian population. Results The existing medical evidence does not support a consensus viewpoint for these alternative uses of HBOT. Based on the literature review, there are four competing positions to explain the lack of consistency among the empirical results. These possibilities are described in no particular order. First, an explanation suggests that the results are because of placebo effects. The combination of participant expectations and subjective symptom reporting creates the potential that reported improvements are because of placebo rather than casual mechanisms. Second, another position suggests that experiments have utilized sham conditions which induced therapeutic benefits. If sham conditions have actually been weakened active treatment conditions, rather than placebo controls, it could explain the lack of observed significant differences in randomized clinical trials. Third, there has been a substantial amount of heterogeneity both in the symptoms treated and the treatments applied. This heterogeneity could explain the inconsistency of the data and the difficulty in reaching a consensus viewpoint. Fourth, the HBOT treatments may actively treat some tangential medical issue the patient is having. The treatment would thus promote an environment of healing without directly treating either PTSD, mTBI, or TBI, and the reduction in orthogonal medical issues facilitates a pathway to recovery by reducing tangential medical problems. Conclusions The mixed empirical evidence does not support recommending HBOT as a primary treatment for PTSD, mTBI, or TBI. If applied under the supervision of a licensed military medical professional, the consistently safe track record of HBOT should allow it to be considered as an alternative treatment for PTSD, mTBI, or TBI once primary treatment methods have failed to produce a benefit. However, the evidence does warrant further clinical investigation with particular emphasis on randomized clinical trials, better placebo controls, and a need to develop a consistent treatment protocol.


2018 ◽  
Vol 15 (4) ◽  
pp. 398-412 ◽  
Author(s):  
Guillaume Leblanc ◽  
Amélie Boutin ◽  
Michèle Shemilt ◽  
François Lauzier ◽  
Lynne Moore ◽  
...  

Background Most deaths following severe traumatic brain injury follow decisions to withdraw life-sustaining therapies. However, the incidence of the withdrawal of life-sustaining therapies and its potential impact on research data interpretation have been poorly characterized. The aim of this systematic review was to assess the reporting and the impact of withdrawal of life-sustaining therapies in randomized clinical trials of patients with severe traumatic brain injury. Methods We searched Medline, Embase, Cochrane Central, BIOSIS, and CINAHL databases and references of included trials. All randomized controlled trials published between January 2002 and August 2015 in the six highest impact journals in general medicine, critical care medicine, and neurocritical care (total of 18 journals) were considered for eligibility. Randomized controlled trials were included if they enrolled adult patients with severe traumatic brain injury (Glasgow Coma Scale ≤ 8) and reported data on mortality. Our primary objective was to assess the proportion of trials reporting the withdrawal of life-sustaining therapies in a publication. Our secondary objectives were to describe the overall mortality rate, the proportion of deaths following the withdrawal of life-sustaining therapies, and to assess the impact of the withdrawal of life-sustaining therapies on trial results. Results From 5987 citations retrieved, we included 41 randomized trials (n = 16,364, ranging from 11 to 10,008 patients). Overall mortality was 23% (range = 3%–57%). Withdrawal of life-sustaining therapies was reported in 20% of trials (8/41, 932 patients in trials) and the crude number of deaths due to the withdrawal of life-sustaining therapies was reported in 17% of trials (7/41, 884 patients in trials). In these trials, 63% of deaths were associated with the withdrawal of life-sustaining therapies (105/168). An analysis carried out by imputing a 4% differential rate in instances of withdrawal of life-sustaining therapies between study groups yielded different results and conclusions in one third of the trials. Conclusion Data on the withdrawal of life-sustaining therapies are incompletely reported in randomized controlled trials of patients with severe traumatic brain injury. Given the high proportion of deaths due to the withdrawal of life-sustaining therapies in severe traumatic brain injury patients, and the potential of this medical decision to influence the results of clinical trials, instances of withdrawal of life-sustaining therapies should be systematically reported in clinical trials in this group of patients.


2014 ◽  
Vol 121 (3) ◽  
pp. 653-664 ◽  
Author(s):  
Weijun Peng ◽  
Zhihua Xing ◽  
Jingjing Yang ◽  
Yang Wang ◽  
Weihao Wang ◽  
...  

Object Erythropoietin (EPO) shows promise as a neuroprotective agent in animal models of traumatic brain injury (TBI). However, clinical trials of the efficacy of EPO treatment in patients with TBI yield conflicting results. The authors conducted a systematic review and meta-analysis to assess the effect of EPO in experimental animal models of TBI, the goal being to inform the design of future clinical trials. Methods The authors identified eligible studies by searching PubMed, Web of Science, MEDLINE, Embase, and Google Scholar in October 2013. Data were pooled using the random-effects model, and results were reported in terms of standardized mean difference. Statistical heterogeneity was examined using both I2 and chi-square tests, and the presence of small study effects was investigated with funnel plots and Egger tests. In-depth analyses were performed for lesion volume and neurobehavioral outcome, and the studies' methodological quality was also evaluated. Results Of a total of 290 studies, 13 found an effect of EPO on lesion volume and neurobehavioral outcome. Overall, the methodological quality of the studies was poor, and there was evidence of statistical heterogeneity among the publications as well as small-study effects. However, in-depth analyses showed statistically significant findings in favor of a beneficial effect of EPO after TBI. Conclusions Despite limitations of this systematic review that may have influenced the findings, the authors conclude that EPO might be beneficial in treating experimental TBI in terms of reducing lesion volume and improving neurobehavioral outcome. However, this review also indicates that more well-designed and well-reported animal studies are needed.


Brain Injury ◽  
2019 ◽  
Vol 34 (2) ◽  
pp. 149-159 ◽  
Author(s):  
Bhanu Sharma ◽  
David Allison ◽  
Patricia Tucker ◽  
Donald Mabbott ◽  
Brian W. Timmons

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