Translational Intracerebral Hemorrhage Research: Has Current Neuroprotection Research ARRIVEd at a Standard for Experimental Design and Reporting?

Abstract

One major aim of preclinical intracerebral hemorrhage (ICH) research is to develop and test potential neuroprotectants. Published guidelines for experimental design and reporting stress the importance of clearly and completely reporting results and methodological details to ensure reproducibility and maximize information availability. The current review has two objectives: first, to characterize current ICH neuroprotection research and, second, to analyze aspects of translational design in preclinical ICH studies. Translational design is the adoption and reporting of experimental design characteristics that are thought to be clinically relevant and critical to reproducibility in animal studies (e.g., conducting and reporting experiments according to the STAIR and ARRIVE guidelines, respectively). Given that ICH has no current neuroprotective treatments and an ongoing reproducibility crisis in preclinical research, translational design should be considered by investigators. We conducted a systematic review of ICH research from 2015 to 2019 using the PubMed database. Our search returned 281 published manuscripts studying putative neuroprotectants in animal models. Contemporary ICH research predominantly uses young, healthy male rodents. The collagenase model is the most commonly used. Reporting of group sizes, blinding, and randomization are almost unanimous, but group size calculations, mortality and exclusion criteria, and animal model characteristics are infrequently reported. Overall, current ICH neuroprotection research somewhat aligns with experimental design and reporting guidelines. However, there are areas for improvement. Because failure to consider translational design is associated with inflation of effect sizes (and possibly hindered reproducibility), we suggest that researchers, editors, and publishers collaboratively consider enhanced adherence to published guidelines.

Keywords: Animal models; Experimental design; Experimental reporting; Intracerebral hemorrhage; Neuroprotection; Reproducibility; Systematic review; Translational research.

Fig. 1

Overview of articles revealed from PubMed search and total studies selected for analyses. The inclusion criteria involved intracerebral hemorrhage (ICH) studies that evaluated a neuroprotective or cell-saving therapy. The search criteria included the following terms: “(animal OR rodent OR rat OR mouse)” AND “(intracerebral hemorrhage OR intraparenchymal hemorrhage OR intrastriatal hemorrhage)” NOT “(ischemia OR subarachnoid hemorrhage OR traumatic brain injury OR middle cerebral artery occlusion model)”

Fig. 2

Analysis of experimental design. a Proportion of studies reporting key components of translational design. b Distribution of anesthetic use across all studies analyzed. c Analysis of ICH models used in current ICH research. d Species of animals used in current ICH neuroprotection research. e Sex of animals used in ICH neuroprotection research. f Proportion of studies using animals within particular age groupings

Fig. 3

Assessment of ICH neuroprotection intervention parameters. a Breakdown of treatment administration route across studies. b Evaluation of whether treatment efficacy was shown in a dose-response fashion. c Longest treatment delay in ICH neuroprotection studies

Fig. 4

Analysis of tissue endpoints used in ICH neuroprotection research. a Categorization of endpoints into classes. b Latest timing of injury volume assessment

Fig. 5

Assessment of behavioral endpoints used in ICH neuroprotection research. a Proportion of behavioral endpoint use. Neurological deficit scales are common endpoints in ICH neuroprotection research. b Latest time of behavioral testing for all studies. A majority of studies conduct behavioral testing on or before day 7 post-ICH. c Number of behavioral tasks used per study. About 50% of current ICH neuroprotection research make use of 2 or more behavioral tests per study

Fig. 6

Analysis of largest reported group sizes in experimental ICH research (bin width = 1). Most studies use 6 animals per group as their largest group sizes

Fig. 7

Analysis of most common publication venues for preclinical ICH neuroprotection research. a The top 10 most popular journals from 2015 to 2019 and the number of ICH neuroprotection papers published in each. b Analysis of the top 25 journals that publish ICH neuroprotection research and whether experimental design and reporting in accordance with published guidelines was mandatory, recommended, or not mentioned