Meta-analysis of pre-clinical studies of early decompression in acute spinal cord injury:a battle of time and pressure

The use of early decompression in the management of acute spinal cord injury (SCI) remains contentious despite many pre-clinical studies demonstrating benefits and a small number of supportive clinical studies. Although the pre-clinical literature favours the concept of early decompression, translation is hindered by uncertainties regarding overall treatment efficacy and timing of decompression.We performed meta-analysis to examine the pre-clinical literature on acute decompression of the injured spinal cord. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of (i) the reporting of efficacy of decompression at various time intervals (ii) number of animals and (iii) the mean outcome and variance in each group. Random effects meta-analysis was used and the impact of study design characteristics assessed with meta-regression.Overall, decompression improved behavioural outcome by 35.1% (95%CI 27.4-42.8; I(2)=94%, p<0.001). Measures to minimise bias were not routinely reported with blinding associated with a smaller but still significant benefit. Publication bias likely also contributed to an overestimation of efficacy. Meta-regression demonstrated a number of factors affecting outcome, notably compressive pressure and duration (adjusted r(2)=0.204, p<0.002), with increased pressure and longer durations of compression associated with smaller treatment effects. Plotting the compressive pressure against the duration of compression resulting in paraplegia in individual studies revealed a power law relationship; high compressive forces quickly resulted in paraplegia, while low compressive forces accompanying canal narrowing resulted in paresis over many hours.These data suggest early decompression improves neurobehavioural deficits in animal models of SCI. Although much of the literature had limited internal validity, benefit was maintained across high quality studies. The close relationship of compressive pressure to the rate of development of severe neurological injury suggests that pressure local to the site of injury might be a useful parameter determining the urgency of decompression

A systematic review of exercise training to promote locomotor recovery in animal models of spinal cord injury

In the early 1980s experiments on spinalized cats showed that exercise training on the treadmill could enhance locomotor recovery after spinal cord injury (SCI). In this review, we summarize the evidence for the effectiveness of exercise training aimed at promoting locomotor recovery in animal models of SCI. We performed a systematic search of the literature using Medline, Web of Science, and Embase. Of the 362 studies screened, 41 were included. The adult female rat was the most widely used animal model. The majority of studies (73%) reported that exercise training had a positive effect on some aspect of locomotor recovery. Studies employing a complete SCI were less likely to have positive outcomes. For incomplete SCI models, contusion was the most frequently employed method of lesion induction, and the degree of recovery depended on injury severity. Positive outcomes were associated with training regimens that involved partial weight-bearing activity, commenced within a critical period of 1-2 weeks after SCI, and maintained training for at least 8 weeks. Considerable heterogeneity in training paradigms and methods used to assess or quantify recovery was observed. A 13-item checklist was developed and employed to assess the quality of reporting and study design; only 15% of the studies had high methodological quality. We recommend that future studies include control groups, randomize animals to groups, conduct blinded assessments, report the extent of the SCI lesion, and report sample size calculations. A small battery of objective assessment methods including assessment of over-ground stepping should also be developed and routinely employed. This would allow future meta-analyses of the effectiveness of exercise interventions on locomotor recovery

Line graph exploring the relationship between compressive duration and compressive pressure.

<p>(A) The association between the duration of compression producing severe neurological injury and the compressive pressure in those studies in which there was an initial injury to the spinal cord followed by compression. The data demonstrates a close correlation and again obeys a power law relationship (y = 829.06x^-0.459) with a linear distribution on a log-log plot of the variables (upper inset). (B) Power law (y = 144.62x^-0.248) relationship between compressive pressure and duration in studies employing an initial injury to the spinal cord followed by narrowing of the spinal canal to induce compression. These models had lower estimated pressures and longer durations of compression were necessary to produce paraplegia.</p

Meta-regression of functional (neurobehavioral) improvement versus compressive pressure (p=0.004).

<p>The size of each point reflects the precision of each comparison.</p

Effect size and 95% confidence intervals of the neurobehavioural assessments in the 79 experiments included in meta-analysis.

<p>The reference line represents the overall effect size of 35.1% with the gray shaded bar the 95% confidence intervals (27.5-42.8) of the global estimate.</p

Flow diagram depicting the number of publications initially identified, number of records following removal of duplicates and exclusions, and the final number of publications included for analysis.

<p>Image adapted from: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). <i>P</i>referred <i>R</i>eporting <i>I</i>tems for <i>S</i>ystematic Reviews and <i>M</i>eta-<i>A</i>nalyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi: 10.1371/journal. pmed1000097.</p

Effect of reported study blinding on effect size.

<p>The shaded gray bar represents the 95% confidence limits of the global estimate. The vertical error bars represent the 95% confidence intervals for the individual estimates. The width of each bar reflects the log of the number of animals contributing to that comparison.</p

Evidence of publication bias demonstrated by (A) Egger regression analysis of early decompression experiments.

<p>The 95% confidence intervals of the regression line do not include the origin, suggesting the presence of a significant publication bias. (B) Funnel plot showing the data in black and the additional missing studies suggested by trim and fill in red. The red vertical line indicates the possible global estimate in the absence of publication bias.</p

The change in effect size with (A) Region of injury, (B) Method of compression (Clip = aneurysm clip), (C) Neurobehavioural score (NDS = Neurologic deficit score; Olby = Olby score; Tarlov = Tarlov scale; Multiple = ≥2 behavioural tests; Motor = Motor test; BBB = Basso Beattie Bresnahan scale).

<p>The shaded gray bar represents the 95% confidence limits of the global estimate. The vertical error bars represent the 95% confidence intervals for the individual estimates. The width of each bar reflects the log of the number of animals contributing to that comparison. Each stratification accounts for a significant proportion of the heterogeneity observed between studies. (D) Meta-regression of functional neurobehavioural improvement versus the time of final assessment (p=0.046). The size of each point reflects the precision of each comparison.</p