A Critical Appraisal of Experimental Intracerebral Hemorrhage Research

Abstract

The likelihood of translating therapeutic interventions for stroke rests on the quality of preclinical science. Given the limited success of putative treatments for ischemic stroke and the reasons put forth to explain it, we sought to determine whether such problems hamper progress for intracerebral hemorrhage (ICH). Approximately 10% to 20% of strokes result from an ICH, which results in considerable disability and high mortality. Several animal models reproduce ICH and its underlying pathophysiology, and these models have been widely used to evaluate treatments. As yet, however, none has successfully translated. In this review, we focus on rodent models of ICH, highlighting differences among them (e.g., pathophysiology), issues with experimental design and analysis, and choice of end points. A Pub Med search for experimental ICH (years: 2007 to 31 July 2011) found 121 papers. Of these, 84% tested neuroprotectants, 11% tested stem cell therapies, and 5% tested rehabilitation therapies. We reviewed these to examine study quality (e.g., use of blinding procedures) and choice of end points (e.g., behavioral testing). Not surprisingly, the problems that have plagued the ischemia field are also prevalent in ICH literature. Based on these data, several recommendations are put forth to facilitate progress in identifying effective treatments for ICH.

Does the Goal Justify the Methods? Harm and Benefit in Neuroscience Research Using Animals

“…The major barriers to translational success identified in these workshops were a lack of rigorous standards and transparency in reporting preclinical studies, similar to what was reported by der Worp (2005) in ischemia stroke research and by MacLellan et al (2012) in intracerebral hemorrhage research. The subsequent published guidelines from these groups outline some of the principles and standards of good study design and report when conducting preclinical trials of candidate therapeutics-e.g., allocation concealment, blinded assessment of outcome, random allocation of subjects to experimental groups, and other methods designed to minimize bias and Type 1 (''false positive'') errors.…”

“…Additionally, there were obvious significant methodological differences between pre-clinical and clinical trials, in that the animals used were generally young and healthy before the experimentally induced stroke, while human patients were often elderly and hypertense (Macleod and Sandercock 2005). The same sort of shortcomings was also identified in studies on intracerebral hemorrhage (MacLellan et al 2012).…”

Hydrogen does not exert neuroprotective effects or improve functional outcomes in rats after intracerebral hemorrhage

“…Firstly, these studies used different experimental models, the blood injection rat model or the collagenase injection mouse model. The blood injection and collagenase injection models are most often used but differ in many aspects (12,(14)(15)(16). Hematoma rapidly accumulates in the brain parenchyma in the clinical setting.…”

Is Gender-specific Therapy Necessary for Patients of Hemorrhagic Stroke?

“…Recent clinical failures call into question whether these models accurately reflect human ICH, and whether they will be useful in successfully translating treatments from the laboratory. 32 Nevertheless, the FC infusion model is currently used for studying sex dimorphic long-term neurological deficits after ICH.…”