A State-of-the-Science Overview of Randomized Controlled Trials Evaluating Acute Management of Moderate-to-Severe Traumatic Brain Injury

Abstract

Moderate-to-severe traumatic brain injury (TBI) remains a major global challenge, with rising incidence, unchanging mortality and lifelong impairments. State-of-the-science reviews are important for research planning and clinical decision support. This review aimed to identify randomized controlled trials (RCTs) evaluating interventions for acute management of moderate/severe TBI, synthesize key RCT characteristics and findings, and determine their implications on clinical practice and future research. RCTs were identified through comprehensive database and other searches. Key characteristics, outcomes, risk of bias, and analysis approach were extracted. Data were narratively synthesized, with a focus on robust (multi-center, low risk of bias, n > 100) RCTs, and three-dimensional graphical figures also were used to explore relationships between RCT characteristics and findings. A total of 207 RCTs were identified. The 191 completed RCTs enrolled 35,340 participants (median, 66). Most (72%) were single center and enrolled less than 100 participants (69%). There were 26 robust RCTs across 18 different interventions. For 74% of 392 comparisons across all included RCTs, there was no significant difference between groups. Positive findings were broadly distributed with respect to RCT characteristics. Less than one-third of RCTs demonstrated low risk of bias for random sequence generation or allocation concealment, less than one-quarter used covariate adjustment, and only 7% employed an ordinal analysis approach. Considerable investment of resources in producing 191 completed RCTs for acute TBI management has resulted in very little translatable evidence. This may result from broad distribution of research effort, small samples, preponderance of single-center RCTs, and methodological shortcomings. More sophisticated RCT design, large multi-center RCTs in priority areas, increased focus on pre-clinical research, and alternatives to RCTs, such as comparative effectiveness research and precision medicine, are needed to fully realize the potential of acute TBI research to benefit patients.

Severe traumatic brain injury: targeted management in the intensive care unit

“…Improved characterisation of mechanisms might also offer new goals for neuroprotective drug development. However, translational failure of a few biologically and experimentally well founded inter ventions 118 suggests that uncharacterised patient factors are still a major stumbling block in terms of tailoring aggressive treatments to maximise benefit and minimise harm at an individual level. Despite the wealth of data, stratification of patients into subgroups with more homogeneous pathophysiology, disease course, and expected outcome is still at an early stage.…”

The Glasgow Outcome Scale — 40 years of application and refinement

“…A state-of-the-science overview published in 2016 identified >180 randomized controlled trials published since 1980 in which interventions for managing acute head injury were compared 56 , and the GOS or GOSE was the clinician-reported index of outcome in more than two thirds of these trials. 56 Twenty-six of these RCTs, were defined as methodologically robust and the GOS/GOSE was used in 23. The analysis in many of these studies was based on outcome dichotomization, and the criterion for efficacy was a shift from unfavourable outcomes to favourable outcomes.…”

“…Emotional distress continues to be associated with poor functional outcome many years after injury 74 , and GOS measures correlate closely with emotional distress and QoL as measured with generic QoL assessments, such as the SF-36, and with the Quality of Life After Brain Injury (QOLIBRI) measure, which is specific for patients with head injury. 35,56 The strength of the association between these measures indicates excellent validity of the clinician rating scales in relation to patient-reported outcomes. The direction of any causal relationship between subjective wellbeing and global function remains to be clarified, and is an important issue for understanding how patients can adjust to the effects of head injury.…”

Outcome assessment after traumatic brain injury

“…We, therefore, welcome their recommendation to continue concurrent use of the GOS and GOSE. In a recent overview these scales showed significant differences in outcome in 29% of 112 different RCTs in which they were used as an end point 5 . Moreover, the GOS has proved effective in follow up in middle and low income countries where, as the Lancet commission importantly emphasise, 90% of deaths due to TBI occur.…”