Procedural and Methodological Quality in Preclinical Stroke Research–A Cohort Analysis of the Rat MCAO Model Comparing Periods Before and After the Publication of STAIR/ARRIVE

Abstract

The translation of preclinical stroke research into successful human clinical trials remains a challenging task. The first Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for preclinical research and several other guidelines were published to address these challenges. Most guidelines recommend the use of physiological monitoring to detect the occurrence of undesired pathologies such as subarachnoid hemorrhage and to limit the variability of the infarct volume and–therefore-homogenize the experimental result for complete reporting particularly with respect to transparency and methodological rigor. From the years 2009 and 2019, 100 published articles each using a rat stroke model were analyzed to quantify parameters related to anesthesia, physiological monitoring, stroke model type, ischemia verification, and overall study quality over time. No significant difference in the frequency of cerebral blood flow (CBF) measurements over time (28/34% for 2009/2019) was found. Notably, significantly fewer studies reported temperature, blood pressure, and blood gas monitoring data in 2019 compared to 2009. On the other hand, an increase in general study quality parameters (e.g., randomization, reporting of approval) was seen. In conclusion, the frequency of periinterventional monitoring has decreased over time. Some general methodological quality aspects, however, partially have increased. CBF measurement–the gold standard for ischemia verification-was applied rarely. Despite the growing recognition of current guidelines such as STAIR and ARRIVE (both widely approved in 2019) reporting, methods and procedures mostly do not follow these guidelines. These deficits may contribute to the translational failure of preclinical stroke research in search for neuroprotective therapies.

Secondary Ischemia Assessment in Murine and Rat Preclinical Subarachnoid Hemorrhage Models: A Systematic Review

“…In line with experimental ischemic stroke experiments, sophisticated neurovascular monitoring such as CBF and intracerebral pressure measurements plays a crucial role in detecting the severity of the induced pathology while ruling out associated complications (such as ischemia). 32 …”

Elastin‐like polypeptide delivery of anti‐inflammatory peptides to the brain following ischemic stroke

“…3,12 Preclinical studies have shown that inhibiting inflammation both locally and systemically can reduce tissue damage and improve neurological outcome following ischemic stroke. [13][14][15] However, these studies have not led to translation to the human population for a number of reasons, including a lack of rigor and reproducibility in preclinical experimental stroke research, 16,17 lack of delivery of the therapeutic to the infarct and ischemic penumbra, 18,19 and the unknown optimal treatment window following ischemia and reperfusion, 20 as well as many technical factors. The formation, and subsequent modifications, of the Stroke Therapy Academic Industry Roundtable (STAIR) guidelines aim to increase translation of stroke therapeutics to the patient population by correcting for many of the technical limitations of prior studies.…”

Relevance of Sham Control Group in Preclinical Animal Studies of Cerebral Ischemia

“…There are numerous reasons for translational failure in preclinical stroke research conditioned by the experimental setting itself, such as the generation of a plausible hypothesis, the methodological quality of the experimental procedure and the analysis of the results (ideally double-blinded). In order to improve the quality of preclinical studies, the STAIR (Stroke Therapy Academic Industry Roundtable) and ARRIVE (Animal Research: Reporting of in vivo Experiments) guidelines were published [5, 6]. Among the recommendations described, the importance of including a sham group stands out [7].…”