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.

BackgroundCationic arginine-rich peptides (CARPs) have demonstrated neuroprotective and/or behavioural efficacy in ischemic and hemorrhagic stroke and traumatic brain injury models. Therefore, in this study we investigated the safety and neuroprotective efficacy of the CARPs poly-arginine-18 (R18; 18-mer of arginine) and its D-enantiomer R18D given in the acute bleeding phase in an intracerebral hemorrhage (ICH) model.MethodsOne hundred and fifty-eight male Sprague-Dawley rats received collagenase-induced ICH. Study 1 examined various doses of R18D (30, 100, 300, or 1000 nmol/kg) or R18 (100, 300, 1000 nmol/kg) administered intravenously 30 minutes post-collagenase injection on hemorrhage volume 24 hours after ICH. Study 2 examined R18D (single intravenous dose) or R18 (single intravenous dose, plus 6 daily intraperitoneal doses) at 300 or 1000 nmol/kg commencing 30 minutes post-collagenase injection on behavioural outcomes (Montoya staircase test, and horizontal ladder test) in the chronic post-ICH period. A histological assessment of tissue loss was assessed using a Nissl stain at 28 days after ICH.ResultsWhen administered during ongoing bleeding, neither R18 or R18D exacerbated hematoma volume or worsened functional deficits. Lesion volume assessment at 28 days post-ICH was not reduced by the peptides; however, animals treated with the lower R18D 300 nmol/kg dose, but not with the higher 1000 nmol/kg dose, demonstrated a statistically increased lesion size compared to saline treated animals.ConclusionOverall, both R18 and R18D appeared to be safe when administered during a period of ongoing bleeding following ICH. Neither peptide appears to have any statistically significant effect in reducing lesion volume or improving functional recovery after ICH. Additional studies are required to further assess dose efficacy and safety in pre-clinical ICH studies.

Intracerebral hemorrhage (ICH) accounts for 10–15% of all strokes and leaves most survivors with impairments. Fever, a rise in the thermoregulatory set point, complicates ICH. This review summarizes ICH fever studies and employs meta-analytic techniques to explore the relationship between fever and ICH. We discuss methodological considerations for future studies and provide an overview of mechanisms by which fever, and its treatment, may impact ICH. We searched the PubMed database using the following terms: ((fever OR hyperthermia) AND (intracerebral hemorrhage OR intraparenchymal hemorrhage OR intracerebral haemorrhage OR intraparenchymal haemorrhage)). Our search returned 727 studies, of which 21 were included in our final analysis, consisting of 19 clinical, and two preclinical, studies. We conducted a meta-analysis on the clinical data to quantify how fever is related to mortality, functional outcomes, and intraventricular hemorrhage. Analysis of clinical studies suggested that fever causes an increased risk of mortality but does not appear to be associated with poor outcomes among survivors, making it difficult to ascertain the extent of harm caused by post-ICH fever or the benefits of its treatment. Perhaps these inconsistencies stem from variable fever definitions, and temperature measurement and fever treatment protocols. Additionally, the lack of mechanistic data in clinical studies coupled with preclinical studies showing no harmful effects of moderate bouts of hyperthermia raise concerns about the direct contribution of hyperthermia and fever in post ICH outcome. Overall, the significance of temperature increases after ICH is unclear, making this an important area for future research.

Therapeutic hypothermia (TH) has applications dating back millennia. In modern history, however, TH saw its importation into medical practice where investigations have demonstrated that TH is efficacious in ischemic insults, notably cardiac arrest and hypoxic‐ischemic encephalopathy. As well, studies have been undertaken to investigate whether TH can provide benefit in focal stroke (i.e., focal ischemia and intracerebral hemorrhage). However, clinical studies have encountered various challenges with induction and maintenance of post‐stroke TH. Most clinical studies have attempted to use body‐wide cooling protocols, commonly hindered by side effects that can worsen post‐stroke outcomes. Some of the complications and difficulties with systemic TH can be circumvented by using local hypothermia (LH) methods. Additional advantages include the potential for lower target temperatures to be achieved and faster TH induction rates with LH. This systematic review summarizes the body of clinical and preclinical LH focal stroke studies and raises key points to consider for future LH research. We conclude with an overview of LH neuroprotective mechanisms and a comparison of LH mechanisms with those observed with systemic TH. Overall, whereas many LH studies have been conducted preclinically in the context of focal ischemia, insufficient work has been done in intracerebral hemorrhage. Furthermore, key translational studies have yet to be done in either stroke subtype (e.g., varied models and time‐to‐treat, studies considering aged animals or animals with co‐morbidities). Few clinical LH investigations have been performed and the optimal LH parameters to achieve neuroprotection are unknown.

Background: As not all ischemic stroke patients benefit from currently available treatments, there is considerable need for neuroprotective co-therapies. Therapeutic hypothermia is one such co-therapy, but numerous issues have hampered its clinical use (e.g., pneumonia risk with whole-body cooling). Some problems may be avoided with brain-specific methods, such as intra-arterial selective cooling infusion (IA-SCI) into the arteries supplying the ischemic tissue.Objective: Our research question was about the efficacy of IA-SCI in animal middle cerebral artery occlusion models. We hypothesized that IA-SCI would be beneficial, but translationally-relevant study elements may be missing (e.g., aged animals).Methods: We completed a systematic review of the PubMed database following the PRISMA guidelines on May 21, 2020 for animal studies that administered IA-SCI in the peri-reperfusion period and assessed infarct volume, behavior (primary meta-analytic endpoints), edema, or blood-brain barrier injury (secondary endpoints). Our search terms included: “focal ischemia” and related terms, “IA-SCI” and related terms, and “animal” and related terms. Nineteen studies met inclusion criteria. We adapted a methodological quality scale from 0 to 12 for experimental design assessment (e.g., use of blinding/randomization, a priori sample size calculations).Results: Studies were relatively homogenous (e.g., all studies used young, healthy animals). Some experimental design elements, such as blinding, were common whereas others, such as sample size calculations, were infrequent (median methodological quality score: 5; range: 2–7). Our analyses revealed that IA-SCI provides benefit on all endpoints (mean normalized infarct volume reduction = 23.67%; 95% CI: 19.21–28.12; mean normalized behavioral improvement = 35.56%; 95% CI: 25.91–45.20; mean standardized edema reduction = 0.95; 95% CI: 0.56–1.34). Unfortunately, blood-brain barrier assessments were uncommon and could not be analyzed. However, there was substantial statistical heterogeneity and relatively few studies. Therefore, exploration of heterogeneity via meta-regression using saline infusion parameters, study quality, and ischemic duration was inconclusive.Conclusion: Despite convincing evidence of benefit in ischemic stroke models, additional studies are required to determine the scope of benefit, especially when considering additional elements (e.g., dosing characteristics). As there is interest in using this treatment alongside current ischemic stroke therapies, more relevant animal studies will be critical to inform patient studies.

Localized brain hypothermia (HYPO) can be achieved by infusing cold saline into the carotid artery of animals and patients. Studies suggest that HYPO improves behavioral and histological outcomes in focal ischemia models. Given that ischemic stroke and intracerebral hemorrhage (ICH) share pathophysiological overlap, we tested whether cold saline infusion is safe and neuroprotective when given during collagenase-induced ICH. Eighty-five adult male Sprague-Dawley rats were used. Experiment 1 investigated brain and body temperature changes associated with a cold saline infusion paradigm that was scaled from patients according to brain weight and blood volume (3 mL/ 20-minute infusion). Experiment 2 determined whether HYPO aggravated bleeding volume. Experiment 3 investigated if cerebral edema or elemental concentrations were altered by HYPO. We also collected core body temperature and activity data through telemetry. Experiment 4 investigated whether behavioral outcomes (e.g., skilled reaching) and tissue loss were influenced by HYPO. Our HYPO protocol decreased the ipsilateral striatal temperature by *0.20°C (p < 0.001), with no other effects. HYPO did not affect hematoma volume (p = 0.64), cerebral edema (p = 0.34), or elemental concentrations (p = 0.49) at 24 hours post-ICH. Although ICH caused persistent behavioral impairments, HYPO did not improve behavioral outcomes (measured by a neurological deficit scale, cylinder, and the staircase test; p > 0.05 for all). Brain tissue loss was not different between groups on day 28 post-ICH (p = 0.90). Although cold saline infusion appears to be safe in the acute post-ICH period, there was no evidence that this therapy improved outcome. However, our treatment protocol was relatively mild and additional interventions might help improve efficacy. Finally, our findings may also speak to the safety of this cooling approach in focal ischemia where hemorrhagic transformation is a risk; future studies on this issue are needed.

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