J Head Trauma Rehabil Vol. 30, No. 6, pp. E47–E53 c 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright
An Overview of Acquired Brain Injury Rehabilitation Randomized Controlled Trials Amanda McIntyre, MSc; Shannon Janzen, MSc; Marina Richardson, MSc; Cecilia Kwok, BSc; Robert Teasell, MD, FRCPC Objective: To summarize randomized controlled trials published in the acquired brain injury rehabilitation literature. Setting: N/A. Participants: N/A. Design: Systematic literature review. Main Measures: A total of 143 published randomized controlled trials in acquired brain injury rehabilitation literature from January 1980 to October 2012. Measures were area of research, number of studies, sample size, methodological quality, and country of origin. Results: There were no significant differences in median sample sizes (P = .212; 95% confidence interval [CI], 0.199-0.215) or PEDro scores (P = .492; 95% CI, .491-.510) between 4 research areas in acquired brain injury: sensory-motor, cognitive-communication, medical complications, and psychosocial. Between 1980 and 2012, there was no significant difference in median sample sizes (P = .202; 95% CI, 0.198-0.214). Median PEDro scores did not significantly improve between 1983-1987 (median = 4, interquartile range = 4.5) and 2008-2012 (median = 6, interquartile range = 2; P = .100; 95% CI, 0.093-0.105). Conclusions: This study demonstrates the need for more randomized controlled trials, increased sample sizes, and improved methodological quality to better guide clinical practice for acquired brain injury rehabilitation. Key words: acquired brain injury, randomized controlled trial, rehabilitation
A
CQUIRED BRAIN INJURIES (ABIs), consisting of both traumatic and nontraumatic injuries, are a substantial contributor to death and disability worldwide.1 In 2005, neurological disorders, which included neurological injuries, neuroinfections, and cerebrovascular disease, represented 4.3% of the global burden of disease.1 Traumatic brain injuries (TBIs) are the most common type of ABI (excluding stroke) within which, motor vehicle accidents and falls are the most frequent causes.2 In
Author Affiliations: Lawson Health Research Institute, St. Joseph’s Parkwood Hospital, London, Ontario, Canada (Mss McIntyre, Janzen, Richardson, and Kwok and Dr Teasell); St. Joseph’s Healthcare, St. Joseph’s Parkwood Hospital, London, Ontario, Canada (Dr Teasell); and Department of Physical Medicine and Rehabilitation, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (Dr Teasell). The authors acknowledge the Ontario Neurotrauma Foundation for its support. They also acknowledge the support and collaboration with past and present authors of the Evidence-Based Review of Acquired Brain Injury. The authors declare no conflicts of interest. Corresponding Author: Amanda McIntyre, MSc, Aging, Rehabilitation, & Geriatric Care, Parkwood Hospital, Room B3025, 801 Commissioners Rd E, London, ON N6C 5J1, Canada ([email protected]). DOI: 10.1097/HTR.0000000000000108
developing countries, it is expected that there will be a 65% increase in motor vehicle accidents between 2000 and 2020.3 Furthermore, higher income countries are expected to see an increase in the number of fallrelated TBIs as a result of current aging demographic trends.4 While only 10% of TBIs are deemed moderate to severe,5 these patients access more healthcare services than individuals sustaining mild TBIs.6 Greater injury severity is associated with increased need of treatments of patients and extended rehabilitation costs. Within the first year after an ABI, the mean cost of postacute care for patients in Ontario, Canada, who were discharged to inpatient rehabilitation was $50 030.7 Given the projected increase in the number of neurological injuries and cost of rehabilitation, a comprehensive review of rehabilitation interventions and their effectiveness is important. This type of review offers a foundation for which a highlevel synopsis of the status of research in ABI is possible. In doing so, the areas of research that are heavily represented or underrepresented can be identified, and the strengths and weaknesses of individual studies can be recognized. This synopsis may assist in guiding and prioritizing future research and resources. Therefore, it was our objective to summarize randomized controlled trials (RCTs) published in the ABI rehabilitation literature from January 1980 to October 2012 with respect to area E47
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of research, number of studies, sample size, methodological quality, and country of origin.
TABLE 1 No.
METHODS Study selection The Evidence Based Review of Moderate to Severe Acquired Brain Injury (ERABI; www.abiebr.com) is a comprehensive resource that assesses the evidence for moderate and severe ABI rehabilitation interventions on the basis of all published interventional studies, including non-RCTs and RCTs. The first edition was published in July 2005 with updates annually thereafter. Randomized controlled trials for inclusion in this study were selected from the 8th edition, which encompasses literature published from January 1980 to October 2012. Only RCTs were selected as they are often considered the criterion standard for clinical trials. A detailed description of the search strategy and the inclusion/exclusion criteria used for the ERABI has been published elsewhere8,9 but is summarized here briefly. Articles in English language were located through an extensive search of a variety of databases (eg, PubMed, MEDLINE, EMBASE, CINAHL, and PsycINFO). Two independent reviewers assessed articles for possible inclusion on the basis of the following criteria: 1. Less than 50% of the population consisted of human participants with a moderate (Glasgow Coma Scale score of 9-12) to severe (Glasgow Coma Scale score of 8 or less) TBI; 2. The study design was an RCT; and 3. Rehabilitation interventions were evaluated using a measureable outcome. Studies in which the intervention of interest was provided during acute care and studies with samples comprising more than 50% pediatric patients (85% for 1 key outcome) Intention-to-treat analysis Between-group statistical comparisons reported for at least 1 key outcome Point measures and measures of variability reported for at least 1 key outcome
and then compared scores. Studies that scored 8 to 10 on the PEDro scale were considered to be of “excellent” methodological quality, 6 to 7 of “good” quality, and 4 to 5 of “fair” quality. Scores less than 4 were determined to be of “poor” methodological quality.8,13 Sample sizes extracted from each study represent the individuals who entered the study, regardless of whether they stayed until completion. Analysis For this study, 2 individuals categorized RCTs into 1 of 4 major groups on the basis of the primary outcome assessed in the study. A third individual was available to resolve any discrepancies. The groups included 1. sensory-motor; 2. cognitive-communication; 3. medical complications; and 4. psychosocial. The number of pooled RCTs, categorized by outcome groups, by country of origin, and in combination, was summarized as a count (percentage). The number of RCTs that satisfied each PEDro item was also summarized as a count (percentage). Adherence to each PEDro quality item was analyzed to determine the aspects most or least adhered to. Continuous data, including sample sizes and PEDro scores, were summarized as medians (interquartile range). The Kruskal-Wallis nonparametric 1-way analysis of variance (ANOVA) was used to compare median sample sizes and PEDro scores between groups, with post hoc comparisons using Mann-Whitney tests where appropriate. Statistical significance was defined as P value of less than .05 (95% confidence interval, CI). All analyses were conducted using IBM SPSS Statistics (V. 21; 1989-2012).
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Overview of Acquired Brain Injury Rehabilitation Randomized Controlled Trials RESULTS In total, 143 RCTs were published from January 1980 to October 2012 and included for analysis. Among these RCTs, 125 studies assessed a homogenous brain injury population (ABI 46%, TBI 54%) and 18 studies assessed a mixed population (N = 6, stroke only; N = 2, stroke + other etiologies; N = 6, other etiologies than stroke). The largest portion of RCTs were published by authors from the United States (62.8%), followed by Australia (7.4%). Table 2 reports data on the number of RCTs, median sample sizes, and median PEDro scores for the 4 outcome groups and for all outcome groups combined. A large proportion of RCTs reported on cognitivecommunication (41.9%), with memory (33.3%) and executive functioning (30.0%) receiving the most attention (see Table 3). The majority of studies in the medical complications group assessed nutrition (61.5%). Among sensory-motor RCTs, spasticity was the most widely studied outcome (33.3%), whereas depression and anxiety were the most consistently studied outcomes among psychosocial RCTs (30.3%; Table 3). Almost half of the RCTs (48.0%) scored 4 or 5 on the PEDro scale, which is considered “fair” methodological quality. There were no significant differences in median PEDro scores among the 4 groups (Kruskal-Wallis ANOVA; P = .492; 95% CI, 0.491-0.510). Table 4 shows the percentage of RCTs adhering to each PEDro item by group and in combination. In addition to randomization, the item most consistently adhered to was participant masking (range, 83.3%-96.7%) whereas the item least adhered to was assessor masking (range, 19.2%-375%). Fewer than 50% of all RCTs adhered to the following items: concealed allocation, therapist masking, assessor masking, adequate follow-up, and between-group comparisons. Important differences were noted among the primary outcome
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groups whereby fewer than 50% of RCTs among the cognitive-communication (43.3%), medical complications (46.2%), and psychosocial (27.3%) groups adhered to the item adequate follow-up; conversely, more than 70% adhered to this item in the sensory-motor group. Similar disparities were shown for the item between-group statistical significance whereby fewer than 40% of RCTs from medical complication and psychosocial groups adhered, while all RCTs in the cognitive-communication group adhered to this item. Among the 22 RCTs with a PEDro score of 8 to 10 (rated “excellent”), 13 (59.1%) examined homogenous TBI populations and 45.5% examined pharmacological interventions for either cognitive functioning or depression. Compared with “poor,” “fair,” or “good” quality RCTs collectively, “excellent” RCTs were more likely to have adhered to concealed allocation (20.6% vs 90.1%, respectively), therapist masking (27.3% vs 81.8%, respectively), assessor masking (12.4% vs 86.4%, respectively), and adequate follow-up (38.8% vs 77.3%, respectively). Approximately 32% of all the RCTs were published in the most recent 5 years (2008-2012), with the rate of RCTs published per year increasing from 0.4 in the earliest publication 5-year span (19801985) to 9.2 in the most recent 5-year span (20082012; see Figure 1). There were no significant differences in median sample sizes among the 4 outcome groups (Kruskal-Wallis ANOVA; P = .212; 95% CI, 0.199-0.215). Similarly, there were no significant differences in median sample size between 1980 and 2012 (Kruskal-Wallis ANOVA; P = .202; 95% CI, 0.1980.214; see Figure 2). Over time (1980-2012), median PEDro scores varied significantly (Kruskal-Wallis ANOVA; P = .003; 95% CI, 0.002-0.004; see Figure 3) but did not improve from 1983-1987 (median = 4, interquartile range = 4.5) to 2008-2012 (median = 6,
Characteristics of RCTs for each outcome group (ie, sensory-motor, cognitive-communication, medical complications, and psychosocial) and all RCTs combined TABLE 2
Characteristics
Combined
Sensory/motor
Communication/ cognition
Medical Complications
Psychosocial
No. RCTs (%) Total sample size Median (IQR) PEDro Median (IQR) Scores 1-3 Scores 4-5 Scores 6-7 Scores 8-10
143 (100%) 7193 29 (22)
24 (16.8%) 932 27 (22)
60 (41.9%) 3224 28 (21)
26 (18.2%) 1230 28 (26.8)
33 (23.1%) 1807 32 (45)
5 (2) 6.1% 48.0% 31.1% 14.9%
7 (3) 4.2% 29.2% 41.7% 25.0%
5 (2) 10.0% 50.0% 25.0% 15.0%
5 (3) 3.8% 50.0% 30.8% 15.4%
5 (1) 0.0% 63.6% 24.3% 12.1%
Abbreviations; IQR, interquartile range; PEDro, Physiotherapy Evidence Database scale; RCT, randomized controlled trial.
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Number of RCTs associated with each primary outcome and main group (ie, sensory-motor, cognitivecommunication, medical complications, and psychosocial) TABLE 3
RCTs Outcome Sensory-motor Spasticity Locomotion Upper limb Aerobic fitness and exercise Visual disturbances and balance Pain Cognitive-communication Memory Executive functioning Attention Processing speed 2+ cognitive elements Communication Medical complications Oral hygiene Nutrition Diabetes mellitus Seizures Fatigue Psychosocial Depression and anxiety Anger, aggression, and agitation Substance abuse Independence and social integration Caregiver burden Life satisfaction
N
%a
8 3 2 5
5.6 2.1 1.4 3.5
3
2.1
3
2.1
20 18 2 2 11 7
14.0 12.6 1.4 1.4 7.7 5.4
1 16 1 5 3
0.7 11.2 0.7 3.5 2.1
10 9
7.0 6.3
4 6
2.8 4.2
3 1
2.1 0.7
Abbreviation: RCT, randomized controlled trial. a Percentages may not sum to 100% due to rounding.
interquartile range = 2; P = .100; 95% CI, 0.093-0.105). There was no improvement in the proportion of RCTs adhering to any one of the PEDro items over time (P > .05). DISCUSSION This study found 143 published RCTs within the ABI rehabilitation literature, spanning a 32-year research period. The number of RCTs in this field published per year has increased, with approximately one-third being published in the last 5 years (2008-2012). Despite the increased number of RCTs and improved methodological quality over time, there were no apparent changes in median sample sizes.
Area of research The greatest emphasis within the literature was on cognitive-communication disorders (41.9%). Cognitive and communication deficits are common consequences of a brain injury, and individuals tend to present with varying degrees of deficit across multiple domains (eg, memory, executive functioning, attention).14 Deficits in cognitive-communication have a strong influence on an individual’s reintegration back into the community, vocational status, and social interactions.14 As a result of an aging population, more people are at a risk of sustaining a brain injury because of falls,4 and the complexity of these cases will be greater due to increased numbers of comorbidities and preexisting cognitive issues (eg, dementia or mild cognitive impairment) among older patients. Compared with other fields, such as stroke rehabilitation,15 the number of RCTs for interventions to improve cognitive-communication issues, given its importance in ABI, still remains small. Psychological disorders such as depression16 and substance abuse17 are also common post-ABI. Despite the prevalence of these conditions, only 33 RCTs have been conducted in this area, half the amount published on cognitive-communication disorders. Undoubtedly, psychosocial aspects interact with all other consequences of ABI and subsequent rehabilitation. Many conditions such as anger, aggression, depression, anxiety, and substance abuse can impede one’s engagement or motivation during the rehabilitation process; as a result, positive outcomes may not endure nor be sustained.18 Successful management of psychosocial issues is more likely to maximize a patient’s opportunity for success and improve quality of life post-ABI. Methodological quality This study found that the PEDro items, assessor masking and between-group analyses, were the items least adhered to. Achieving points for adherence to the quality item does depend not only on implementation during the study process but also on an author’s ability to report on his or her trials.10 In 1996, the CONSORT statement was published to provide guidelines on the reporting of RCTs.19 This may help explain why the methodological quality of RCTs in ABI, as demonstrated by the total PEDro score, has been improving over time, although no one particular item improved. This finding is supported by a recent study performed on a random sample of 200 RCTs from the PEDro online database, which noted that relative adherence to PEDro items had not changed over time.10 De Morton10 suggests that the introduction of the CONSORT statement has not influenced the reporting of clinical trials. It is important to recognize that the PEDro tool does not indicate the absolutely methodological quality of an
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Overview of Acquired Brain Injury Rehabilitation Randomized Controlled Trials
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Percentage of randomized controlled trials adhering to each PEDro tool item by group and in combination TABLE 4
Itema
Total
Sensory/ motor
Cognitivecommunication
Medical complications
Psychosocial
1 2 3 4 5 6 7 8 9 10
100.0 31.5 84.6 93.0 35.7 23.8 44.8 63.6 30.8 80.4
100.0 54.2 87.5 83.3 29.2 37.5 70.8 58.3 54.2 81.7
100.0 25.0 86.7 96.7 30.0 20.0 43.3 68.3 100.0 70.0
100.0 23.1 84.6 92.3 53.8 19.2 46.2 50.0 30.8 84.6
100.0 33.3 78.8 93.9 36.4 24.2 27.3 69.7 39.4 87.9
a See
Table 1 for PEDro item criteria.
Figure 1. Total number of randomized controlled trials (y-axis) published each year between 1980 and 2012 (x-axis).
RCT. As described earlier, reporting practices and standards can heavily influence the final PEDro score that a study receives. In addition, some items are difficult or impossible to achieve. For example, in drug trials, true placebo interventions can be easily administered. Comparatively, it may be impossible for therapists to blind participants from behavioral interventions. Blinding was considered when the person in question (subject, therapist, or assessor) did not know which group the subject had been allocated to, and it could be expected that they were unable to distinguish between the treatments given to different groups. The large number of studies
Figure 2. Median (interquartile range) sample sizes (y-axis) for each year between 1980 and 2012 (x-axis) for all randomized controlled trials combined.
Figure 3. Median ( interquartile range) PEDro scores (y-axis) for each year between 1980 and 2012 (x-axis) for all randomized controlled trials combined.
with placebo (cognitive-communication and psychosocial) and sham (motor) control groups likely explains to the high rate of adherence for participant blinding (93%) observed in this study. Sample size Our finding that median sample sizes did not improve over time has been confirmed by Dickinson et al20 The authors examined an earlier subset of literature for the quality and size of RCTs in all stages of head injury and similarly found no trend over time for sample size. Furthermore, they noted that very few studies were powered well enough for statistically significant findings to consistently emerge.20 Applying the authors’ same parameters (α = .05; 80% power; baseline risk = 0.2), none of the trials included in this study would be able to reliably detect absolute risk of death and disability. In a recent study by Latif et al,21 authors reported that 57.3% of articles in a 2008 sample of physical medicine and rehabilitation RCTs performed sample size calculations. Although this proportion has increased since 1998 (3.8%), Latif et al21 stated that it is still not adequate given current publication guidelines. www.headtraumarehab.com
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These findings are concerning given that in ABI research, where the number of trials is limited, single studies are often used to show evidence for or against certain treatments. The issue of small sample sizes suggests the need for multicentered trials or standardization of data collection to allow for pooling of study results; these efforts are currently underway.22 An alternative solution may be that trials recruit individuals with mixed populations.
the 21st century. A previous review of rehabilitation literature for moderate to severe ABI found that only 27.6% of articles were RCTs.8 Promisingly, the gap in the quantity and quality of brain injury research is being acknowledged and becoming a focus through the International Initiative for Traumatic Brain Injury Research,24 a collaborative project involving the multiple countries in an “effort to coordinate and harmonize clinical research activities across the full spectrum of TBI injuries.”
Geographical origin
CONCLUSIONS
Each year, approximately $80 million of investigatordriven resources are supported by the National Institutes of Health for TBI research in the United States.23 This may help explain why 62.8% of the authorship for the RCTs included in this study originated in the United States. Regardless, the limited number and quality of brain injury rehabilitation RCTs is surprising. To improve awareness for research in the area, ABI needs strong advocates. Awareness for ABI is increasing as a result of the recent attention paid to young athletes injured while playing competitive sports (eg, hockey and football) and US veterans returning from war zones in
Since just 143 RCT have been published on the rehabilitation of moderate to severe brain injury, there is a considerable need for greater focus on this common and complex disorder. Moreover, the quantity of RCTs is in sharp contrast with the 1063 available for stroke rehabilitation using similar inclusion criteria and time period.15 Median sample sizes were small and PEDro scores were low among all of the outcome groups. Larger studies with improved methodological quality are imperative to properly evaluate the effectiveness of interventions and establish evidence-based practices in ABI rehabilitation.
REFERENCES 1. World Health Organization. Neurological Disorders: Public Health Challenges. Geneva, Switzerland: World Health Organization; 2006. 2. Tagliaferri F, Compagnone C, Korsic M, Servadei F, Kraus J. A systematic review of brain injury epidemiology in Europe. Acta Neurochir (Wien). 2006;148(3):255–268; discussion 268. 3. Peden M, Scurfield R, Sleet D, et al. Summary: World Report on Road Traffic Injury Prevention. Geneva, Switzerland: World Health Organization; 2004. 4. Roozenbeek B, Maas AI, Menon DK. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol. 2013;9(4):231–236. 5. Brown AW, Elovic EP, Kothari S, Flanagan SR, Kwasnica C. Congenital and acquired brain injury. 1. Epidemiology, pathophysiology, prognostication, innovative treatments, and prevention. Arch Phys Med Rehabil. 2008;89(3 suppl 1): S3–S8. 6. Prang KH, Ruseckaite R, Collie A. Healthcare and disability service utilization in the 5-year period following transportrelated traumatic brain injury. Brain Inj. 2012;26(13–14): 1611–1620. 7. Chen A, Bushmeneva K, Zagorski B, Colantonio A, Parsons D, Wodchis WP. Direct cost associated with acquired brain injury in Ontario. BMC Neurol. 2012;12:76. 8. Teasell R, Bayona N, Marshall S, et al. A systematic review of the rehabilitation of moderate to severe acquired brain injuries. Brain Inj. 2007;21(2):107–112. 9. Teasell RW, Marshall S, Cullen N, et al. Evidence-Based Review of Moderate to Severe Acquired Brain Injury. 8th ed. London, Ontario, Canada: Brain Injury Association of Canada. 2012. 10. de Morton NA. The PEDro scale is a valid measure of the methodological quality of clinical trials: a demographic study. Aust J Physiother. 2009;55(2):129–133.
11. Moseley AM, Herbert RD, Sherrington C, Maher CG. Evidence for physiotherapy practice: a survey of the Physiotherapy Evidence Database (PEDro). Aust J Physiother. 2002;48(1):43–49. 12. Maher CG, Sherrington C, Herbert RD, Moseley AM, Elkins M. Reliability of the PEDro scale for rating quality of randomized controlled trials. Phys Ther. 2003;83(8):713–721. 13. Foley NC, Teasell RW, Bhogal SK, Speechley MR. Stroke rehabilitation evidence-based review: methodology. Top Stroke Rehabil. 2003;10(1):1–7. 14. McAllister TW. Neurobehavioral sequelae of traumatic brain injury: evaluation and management. World Psychiatry. 2008;7(1): 3–10. 15. McIntyre A, Richardson M, Janzen S, Hussein N, Teasell R. The evolution of stroke rehabilitation randomized controlled trials. Int J Stroke. 2014;9(6):789–792. 16. Bombardier CH, Fann JR, Temkin NR, Esselman PC, Barber J, Dikmen SS. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA. 2010;303(19):1938–1945. 17. West SL. Substance use among persons with traumatic brain injury: a review. NeuroRehabilitation. 2011;29(1):1–8. 18. van den Broek MD. Why does neurorehabilitation fail? J Head Trauma Rehabil. 2005;20(5):464–473. 19. Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA. 1996;276(8):637–639. 20. Dickinson K, Bunn F, Wentz R, Edwards P, Roberts I. Size and quality of randomised controlled trials in head injury: review of published studies. BMJ. 2000;320(7245):1308–1311. 21. Abdul Latif L, Daud Amadera JE, Pimentel D, Pimentel T, Fregni F. Sample size calculation in physical medicine and rehabilitation: a systematic review of reporting, characteristics, and results
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Overview of Acquired Brain Injury Rehabilitation Randomized Controlled Trials in randomized controlled trials. Arch Phys Med Rehabil. 2011;92(2): 306–315. 22. Maas AI, Harrison-Felix CL, Menon D, et al. Common data elements for traumatic brain injury: recommendations from the interagency working group on demographics and clinical assessment. Arch Phys Med Rehabil. 2010;91(11): 1641–1649.
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23. European Commission. The international initiative for traumatic brain injury research (InTBIR). http://ec.europa.eu/ research/health/medical-research/brain-research/internationalinitiative_en.html. Accessed July 23, 2014. 24. Canadian Institutes of Health Research. Research in traumatic brain injury. http://www.cihr-irsc.gc.ca/e/45665.html. Accessed July 23, 2014.
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An Overview of Acquired Brain Injury Rehabilitation Randomized Controlled Trials Amanda McIntyre, MSc; Shannon Janzen, MSc; Marina Richardson, MSc; Cecilia Kwok, BSc; Robert Teasell, MD, FRCPC Objective: To summarize randomized controlled trials published in the acquired brain injury rehabilitation literature. Setting: N/A. Participants: N/A. Design: Systematic literature review. Main Measures: A total of 143 published randomized controlled trials in acquired brain injury rehabilitation literature from January 1980 to October 2012. Measures were area of research, number of studies, sample size, methodological quality, and country of origin. Results: There were no significant differences in median sample sizes (P = .212; 95% confidence interval [CI], 0.199-0.215) or PEDro scores (P = .492; 95% CI, .491-.510) between 4 research areas in acquired brain injury: sensory-motor, cognitive-communication, medical complications, and psychosocial. Between 1980 and 2012, there was no significant difference in median sample sizes (P = .202; 95% CI, 0.198-0.214). Median PEDro scores did not significantly improve between 1983-1987 (median = 4, interquartile range = 4.5) and 2008-2012 (median = 6, interquartile range = 2; P = .100; 95% CI, 0.093-0.105). Conclusions: This study demonstrates the need for more randomized controlled trials, increased sample sizes, and improved methodological quality to better guide clinical practice for acquired brain injury rehabilitation. Key words: acquired brain injury, randomized controlled trial, rehabilitation
A
CQUIRED BRAIN INJURIES (ABIs), consisting of both traumatic and nontraumatic injuries, are a substantial contributor to death and disability worldwide.1 In 2005, neurological disorders, which included neurological injuries, neuroinfections, and cerebrovascular disease, represented 4.3% of the global burden of disease.1 Traumatic brain injuries (TBIs) are the most common type of ABI (excluding stroke) within which, motor vehicle accidents and falls are the most frequent causes.2 In
Author Affiliations: Lawson Health Research Institute, St. Joseph’s Parkwood Hospital, London, Ontario, Canada (Mss McIntyre, Janzen, Richardson, and Kwok and Dr Teasell); St. Joseph’s Healthcare, St. Joseph’s Parkwood Hospital, London, Ontario, Canada (Dr Teasell); and Department of Physical Medicine and Rehabilitation, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (Dr Teasell). The authors acknowledge the Ontario Neurotrauma Foundation for its support. They also acknowledge the support and collaboration with past and present authors of the Evidence-Based Review of Acquired Brain Injury. The authors declare no conflicts of interest. Corresponding Author: Amanda McIntyre, MSc, Aging, Rehabilitation, & Geriatric Care, Parkwood Hospital, Room B3025, 801 Commissioners Rd E, London, ON N6C 5J1, Canada ([email protected]). DOI: 10.1097/HTR.0000000000000108
developing countries, it is expected that there will be a 65% increase in motor vehicle accidents between 2000 and 2020.3 Furthermore, higher income countries are expected to see an increase in the number of fallrelated TBIs as a result of current aging demographic trends.4 While only 10% of TBIs are deemed moderate to severe,5 these patients access more healthcare services than individuals sustaining mild TBIs.6 Greater injury severity is associated with increased need of treatments of patients and extended rehabilitation costs. Within the first year after an ABI, the mean cost of postacute care for patients in Ontario, Canada, who were discharged to inpatient rehabilitation was $50 030.7 Given the projected increase in the number of neurological injuries and cost of rehabilitation, a comprehensive review of rehabilitation interventions and their effectiveness is important. This type of review offers a foundation for which a highlevel synopsis of the status of research in ABI is possible. In doing so, the areas of research that are heavily represented or underrepresented can be identified, and the strengths and weaknesses of individual studies can be recognized. This synopsis may assist in guiding and prioritizing future research and resources. Therefore, it was our objective to summarize randomized controlled trials (RCTs) published in the ABI rehabilitation literature from January 1980 to October 2012 with respect to area E47
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
E48
JOURNAL OF HEAD TRAUMA REHABILITATION/NOVEMBER–DECEMBER 2015
of research, number of studies, sample size, methodological quality, and country of origin.
TABLE 1 No.
METHODS Study selection The Evidence Based Review of Moderate to Severe Acquired Brain Injury (ERABI; www.abiebr.com) is a comprehensive resource that assesses the evidence for moderate and severe ABI rehabilitation interventions on the basis of all published interventional studies, including non-RCTs and RCTs. The first edition was published in July 2005 with updates annually thereafter. Randomized controlled trials for inclusion in this study were selected from the 8th edition, which encompasses literature published from January 1980 to October 2012. Only RCTs were selected as they are often considered the criterion standard for clinical trials. A detailed description of the search strategy and the inclusion/exclusion criteria used for the ERABI has been published elsewhere8,9 but is summarized here briefly. Articles in English language were located through an extensive search of a variety of databases (eg, PubMed, MEDLINE, EMBASE, CINAHL, and PsycINFO). Two independent reviewers assessed articles for possible inclusion on the basis of the following criteria: 1. Less than 50% of the population consisted of human participants with a moderate (Glasgow Coma Scale score of 9-12) to severe (Glasgow Coma Scale score of 8 or less) TBI; 2. The study design was an RCT; and 3. Rehabilitation interventions were evaluated using a measureable outcome. Studies in which the intervention of interest was provided during acute care and studies with samples comprising more than 50% pediatric patients (85% for 1 key outcome) Intention-to-treat analysis Between-group statistical comparisons reported for at least 1 key outcome Point measures and measures of variability reported for at least 1 key outcome
and then compared scores. Studies that scored 8 to 10 on the PEDro scale were considered to be of “excellent” methodological quality, 6 to 7 of “good” quality, and 4 to 5 of “fair” quality. Scores less than 4 were determined to be of “poor” methodological quality.8,13 Sample sizes extracted from each study represent the individuals who entered the study, regardless of whether they stayed until completion. Analysis For this study, 2 individuals categorized RCTs into 1 of 4 major groups on the basis of the primary outcome assessed in the study. A third individual was available to resolve any discrepancies. The groups included 1. sensory-motor; 2. cognitive-communication; 3. medical complications; and 4. psychosocial. The number of pooled RCTs, categorized by outcome groups, by country of origin, and in combination, was summarized as a count (percentage). The number of RCTs that satisfied each PEDro item was also summarized as a count (percentage). Adherence to each PEDro quality item was analyzed to determine the aspects most or least adhered to. Continuous data, including sample sizes and PEDro scores, were summarized as medians (interquartile range). The Kruskal-Wallis nonparametric 1-way analysis of variance (ANOVA) was used to compare median sample sizes and PEDro scores between groups, with post hoc comparisons using Mann-Whitney tests where appropriate. Statistical significance was defined as P value of less than .05 (95% confidence interval, CI). All analyses were conducted using IBM SPSS Statistics (V. 21; 1989-2012).
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Overview of Acquired Brain Injury Rehabilitation Randomized Controlled Trials RESULTS In total, 143 RCTs were published from January 1980 to October 2012 and included for analysis. Among these RCTs, 125 studies assessed a homogenous brain injury population (ABI 46%, TBI 54%) and 18 studies assessed a mixed population (N = 6, stroke only; N = 2, stroke + other etiologies; N = 6, other etiologies than stroke). The largest portion of RCTs were published by authors from the United States (62.8%), followed by Australia (7.4%). Table 2 reports data on the number of RCTs, median sample sizes, and median PEDro scores for the 4 outcome groups and for all outcome groups combined. A large proportion of RCTs reported on cognitivecommunication (41.9%), with memory (33.3%) and executive functioning (30.0%) receiving the most attention (see Table 3). The majority of studies in the medical complications group assessed nutrition (61.5%). Among sensory-motor RCTs, spasticity was the most widely studied outcome (33.3%), whereas depression and anxiety were the most consistently studied outcomes among psychosocial RCTs (30.3%; Table 3). Almost half of the RCTs (48.0%) scored 4 or 5 on the PEDro scale, which is considered “fair” methodological quality. There were no significant differences in median PEDro scores among the 4 groups (Kruskal-Wallis ANOVA; P = .492; 95% CI, 0.491-0.510). Table 4 shows the percentage of RCTs adhering to each PEDro item by group and in combination. In addition to randomization, the item most consistently adhered to was participant masking (range, 83.3%-96.7%) whereas the item least adhered to was assessor masking (range, 19.2%-375%). Fewer than 50% of all RCTs adhered to the following items: concealed allocation, therapist masking, assessor masking, adequate follow-up, and between-group comparisons. Important differences were noted among the primary outcome
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groups whereby fewer than 50% of RCTs among the cognitive-communication (43.3%), medical complications (46.2%), and psychosocial (27.3%) groups adhered to the item adequate follow-up; conversely, more than 70% adhered to this item in the sensory-motor group. Similar disparities were shown for the item between-group statistical significance whereby fewer than 40% of RCTs from medical complication and psychosocial groups adhered, while all RCTs in the cognitive-communication group adhered to this item. Among the 22 RCTs with a PEDro score of 8 to 10 (rated “excellent”), 13 (59.1%) examined homogenous TBI populations and 45.5% examined pharmacological interventions for either cognitive functioning or depression. Compared with “poor,” “fair,” or “good” quality RCTs collectively, “excellent” RCTs were more likely to have adhered to concealed allocation (20.6% vs 90.1%, respectively), therapist masking (27.3% vs 81.8%, respectively), assessor masking (12.4% vs 86.4%, respectively), and adequate follow-up (38.8% vs 77.3%, respectively). Approximately 32% of all the RCTs were published in the most recent 5 years (2008-2012), with the rate of RCTs published per year increasing from 0.4 in the earliest publication 5-year span (19801985) to 9.2 in the most recent 5-year span (20082012; see Figure 1). There were no significant differences in median sample sizes among the 4 outcome groups (Kruskal-Wallis ANOVA; P = .212; 95% CI, 0.199-0.215). Similarly, there were no significant differences in median sample size between 1980 and 2012 (Kruskal-Wallis ANOVA; P = .202; 95% CI, 0.1980.214; see Figure 2). Over time (1980-2012), median PEDro scores varied significantly (Kruskal-Wallis ANOVA; P = .003; 95% CI, 0.002-0.004; see Figure 3) but did not improve from 1983-1987 (median = 4, interquartile range = 4.5) to 2008-2012 (median = 6,
Characteristics of RCTs for each outcome group (ie, sensory-motor, cognitive-communication, medical complications, and psychosocial) and all RCTs combined TABLE 2
Characteristics
Combined
Sensory/motor
Communication/ cognition
Medical Complications
Psychosocial
No. RCTs (%) Total sample size Median (IQR) PEDro Median (IQR) Scores 1-3 Scores 4-5 Scores 6-7 Scores 8-10
143 (100%) 7193 29 (22)
24 (16.8%) 932 27 (22)
60 (41.9%) 3224 28 (21)
26 (18.2%) 1230 28 (26.8)
33 (23.1%) 1807 32 (45)
5 (2) 6.1% 48.0% 31.1% 14.9%
7 (3) 4.2% 29.2% 41.7% 25.0%
5 (2) 10.0% 50.0% 25.0% 15.0%
5 (3) 3.8% 50.0% 30.8% 15.4%
5 (1) 0.0% 63.6% 24.3% 12.1%
Abbreviations; IQR, interquartile range; PEDro, Physiotherapy Evidence Database scale; RCT, randomized controlled trial.
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Number of RCTs associated with each primary outcome and main group (ie, sensory-motor, cognitivecommunication, medical complications, and psychosocial) TABLE 3
RCTs Outcome Sensory-motor Spasticity Locomotion Upper limb Aerobic fitness and exercise Visual disturbances and balance Pain Cognitive-communication Memory Executive functioning Attention Processing speed 2+ cognitive elements Communication Medical complications Oral hygiene Nutrition Diabetes mellitus Seizures Fatigue Psychosocial Depression and anxiety Anger, aggression, and agitation Substance abuse Independence and social integration Caregiver burden Life satisfaction
N
%a
8 3 2 5
5.6 2.1 1.4 3.5
3
2.1
3
2.1
20 18 2 2 11 7
14.0 12.6 1.4 1.4 7.7 5.4
1 16 1 5 3
0.7 11.2 0.7 3.5 2.1
10 9
7.0 6.3
4 6
2.8 4.2
3 1
2.1 0.7
Abbreviation: RCT, randomized controlled trial. a Percentages may not sum to 100% due to rounding.
interquartile range = 2; P = .100; 95% CI, 0.093-0.105). There was no improvement in the proportion of RCTs adhering to any one of the PEDro items over time (P > .05). DISCUSSION This study found 143 published RCTs within the ABI rehabilitation literature, spanning a 32-year research period. The number of RCTs in this field published per year has increased, with approximately one-third being published in the last 5 years (2008-2012). Despite the increased number of RCTs and improved methodological quality over time, there were no apparent changes in median sample sizes.
Area of research The greatest emphasis within the literature was on cognitive-communication disorders (41.9%). Cognitive and communication deficits are common consequences of a brain injury, and individuals tend to present with varying degrees of deficit across multiple domains (eg, memory, executive functioning, attention).14 Deficits in cognitive-communication have a strong influence on an individual’s reintegration back into the community, vocational status, and social interactions.14 As a result of an aging population, more people are at a risk of sustaining a brain injury because of falls,4 and the complexity of these cases will be greater due to increased numbers of comorbidities and preexisting cognitive issues (eg, dementia or mild cognitive impairment) among older patients. Compared with other fields, such as stroke rehabilitation,15 the number of RCTs for interventions to improve cognitive-communication issues, given its importance in ABI, still remains small. Psychological disorders such as depression16 and substance abuse17 are also common post-ABI. Despite the prevalence of these conditions, only 33 RCTs have been conducted in this area, half the amount published on cognitive-communication disorders. Undoubtedly, psychosocial aspects interact with all other consequences of ABI and subsequent rehabilitation. Many conditions such as anger, aggression, depression, anxiety, and substance abuse can impede one’s engagement or motivation during the rehabilitation process; as a result, positive outcomes may not endure nor be sustained.18 Successful management of psychosocial issues is more likely to maximize a patient’s opportunity for success and improve quality of life post-ABI. Methodological quality This study found that the PEDro items, assessor masking and between-group analyses, were the items least adhered to. Achieving points for adherence to the quality item does depend not only on implementation during the study process but also on an author’s ability to report on his or her trials.10 In 1996, the CONSORT statement was published to provide guidelines on the reporting of RCTs.19 This may help explain why the methodological quality of RCTs in ABI, as demonstrated by the total PEDro score, has been improving over time, although no one particular item improved. This finding is supported by a recent study performed on a random sample of 200 RCTs from the PEDro online database, which noted that relative adherence to PEDro items had not changed over time.10 De Morton10 suggests that the introduction of the CONSORT statement has not influenced the reporting of clinical trials. It is important to recognize that the PEDro tool does not indicate the absolutely methodological quality of an
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Overview of Acquired Brain Injury Rehabilitation Randomized Controlled Trials
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Percentage of randomized controlled trials adhering to each PEDro tool item by group and in combination TABLE 4
Itema
Total
Sensory/ motor
Cognitivecommunication
Medical complications
Psychosocial
1 2 3 4 5 6 7 8 9 10
100.0 31.5 84.6 93.0 35.7 23.8 44.8 63.6 30.8 80.4
100.0 54.2 87.5 83.3 29.2 37.5 70.8 58.3 54.2 81.7
100.0 25.0 86.7 96.7 30.0 20.0 43.3 68.3 100.0 70.0
100.0 23.1 84.6 92.3 53.8 19.2 46.2 50.0 30.8 84.6
100.0 33.3 78.8 93.9 36.4 24.2 27.3 69.7 39.4 87.9
a See
Table 1 for PEDro item criteria.
Figure 1. Total number of randomized controlled trials (y-axis) published each year between 1980 and 2012 (x-axis).
RCT. As described earlier, reporting practices and standards can heavily influence the final PEDro score that a study receives. In addition, some items are difficult or impossible to achieve. For example, in drug trials, true placebo interventions can be easily administered. Comparatively, it may be impossible for therapists to blind participants from behavioral interventions. Blinding was considered when the person in question (subject, therapist, or assessor) did not know which group the subject had been allocated to, and it could be expected that they were unable to distinguish between the treatments given to different groups. The large number of studies
Figure 2. Median (interquartile range) sample sizes (y-axis) for each year between 1980 and 2012 (x-axis) for all randomized controlled trials combined.
Figure 3. Median ( interquartile range) PEDro scores (y-axis) for each year between 1980 and 2012 (x-axis) for all randomized controlled trials combined.
with placebo (cognitive-communication and psychosocial) and sham (motor) control groups likely explains to the high rate of adherence for participant blinding (93%) observed in this study. Sample size Our finding that median sample sizes did not improve over time has been confirmed by Dickinson et al20 The authors examined an earlier subset of literature for the quality and size of RCTs in all stages of head injury and similarly found no trend over time for sample size. Furthermore, they noted that very few studies were powered well enough for statistically significant findings to consistently emerge.20 Applying the authors’ same parameters (α = .05; 80% power; baseline risk = 0.2), none of the trials included in this study would be able to reliably detect absolute risk of death and disability. In a recent study by Latif et al,21 authors reported that 57.3% of articles in a 2008 sample of physical medicine and rehabilitation RCTs performed sample size calculations. Although this proportion has increased since 1998 (3.8%), Latif et al21 stated that it is still not adequate given current publication guidelines. www.headtraumarehab.com
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These findings are concerning given that in ABI research, where the number of trials is limited, single studies are often used to show evidence for or against certain treatments. The issue of small sample sizes suggests the need for multicentered trials or standardization of data collection to allow for pooling of study results; these efforts are currently underway.22 An alternative solution may be that trials recruit individuals with mixed populations.
the 21st century. A previous review of rehabilitation literature for moderate to severe ABI found that only 27.6% of articles were RCTs.8 Promisingly, the gap in the quantity and quality of brain injury research is being acknowledged and becoming a focus through the International Initiative for Traumatic Brain Injury Research,24 a collaborative project involving the multiple countries in an “effort to coordinate and harmonize clinical research activities across the full spectrum of TBI injuries.”
Geographical origin
CONCLUSIONS
Each year, approximately $80 million of investigatordriven resources are supported by the National Institutes of Health for TBI research in the United States.23 This may help explain why 62.8% of the authorship for the RCTs included in this study originated in the United States. Regardless, the limited number and quality of brain injury rehabilitation RCTs is surprising. To improve awareness for research in the area, ABI needs strong advocates. Awareness for ABI is increasing as a result of the recent attention paid to young athletes injured while playing competitive sports (eg, hockey and football) and US veterans returning from war zones in
Since just 143 RCT have been published on the rehabilitation of moderate to severe brain injury, there is a considerable need for greater focus on this common and complex disorder. Moreover, the quantity of RCTs is in sharp contrast with the 1063 available for stroke rehabilitation using similar inclusion criteria and time period.15 Median sample sizes were small and PEDro scores were low among all of the outcome groups. Larger studies with improved methodological quality are imperative to properly evaluate the effectiveness of interventions and establish evidence-based practices in ABI rehabilitation.
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