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.

Figure 1

Summary of search strategy and selection of intracerebral hemorrhage (ICH) studies.

Figure 2

Summary of recent practices in experimental intracerebral hemorrhage (ICH) studies. The collagenase and blood infusion models are most frequently used (A). The majority of studies use male animals whereas females are rarely used (B). Most studies model ICH in rats and mice (C). Measurement of physiological variables during and especially after ICH surgery is limited (D).

Figure 3

Analysis of intracerebral hemorrhage (ICH) study design. Many studies failed to report characteristics such as mortality rate, the number of and reason for excluded animals, blinding, or random assignment. None of the studies conducted a power analysis.

Figure 4

Frequency of end points used in intracerebral hemorrhage (ICH) studies. The most common end points were behavioral outcome and edema.

Figure 5

Behavioral tests used to assess functional outcome following intracerebral hemorrhage (ICH). The neurological deficit score (NDS) was used most frequently, whereas tests of skilled reaching and cognition were rarely used (A). Other tests (e.g., ladder) were used but at a very small frequency. Timing of the latest behavioral assessment in ICH studies is shown in panel B. Few studies assessed functional outcome beyond 8 weeks after ICH.