Date Published: January 25, 2017
Publisher: Public Library of Science
Author(s): Aurelie Thomas, Johann Detilleux, Paul Flecknell, Charlotte Sandersen, Giuseppe Pignataro.
Numerous studies using rats in stroke models have failed to translate into successful clinical trials in humans. The Stroke Therapy Academic Industry Roundtable (STAIR) has produced guidelines on the rodent stroke model for preclinical trials in order to promote the successful translation of animal to human studies. These guidelines also underline the importance of anaesthetic and monitoring techniques. The aim of this literature review is to document whether anaesthesia protocols (i.e., choice of agents, mode of ventilation, physiological support and monitoring) have been amended since the publication of the STAIR guidelines in 2009. A number of articles describing the use of a stroke model in adult rats from the years 2005 and 2015 were randomly selected from the PubMed database and analysed for the following parameters: country where the study was performed, strain of rats used, technique of stroke induction, anaesthetic agent for induction and maintenance, mode of intubation and ventilation, monitoring techniques, control of body temperature, vascular accesses, and administration of intravenous fluids and analgesics. For each parameter (stroke, induction, maintenance, monitoring), exact chi-square tests were used to determine whether or not proportions were significantly different across year and p values were corrected for multiple comparisons. An exact p-test was used for each parameter to compare the frequency distribution of each value followed by a Bonferroni test. The level of significant set at < 0.05. Results show that there were very few differences in the anaesthetic and monitoring techniques used between 2005 and 2015. In 2015, significantly more studies were performed in China and significantly fewer studies used isoflurane and nitrous oxide. The most striking finding is that the vast majority of all the studies from both 2005 and 2015 did not report the use of ventilation; measurement of blood gases, end-tidal carbon dioxide concentration, or blood pressure; or administration of intravenous fluids or analgesics. The review of articles published in 2015 showed that the STAIR guidelines appear to have had no effect on the anaesthetic and monitoring techniques in rats undergoing experimental stroke induction, despite the publication of said guidelines in 2009.
According to the World Health Organisation, stroke remains the second most common cause of death in high-income countries . One in four cases of stroke is fatal within a year in the UK, and the quality of life of stroke survivors is likely to be significantly impaired as over half of them are left with a disability . Preclinical research aims to improve diagnosis and treatment of stroke patients, as reflected by the publication of hundreds of research papers every year. The principle underlying experimental stroke studies is relatively straightforward. Firstly, a focal cerebral ischemia is inflicted on rodents [3,4,5]. Secondly, some treatment is administered, and thirdly the infarct sizes are compared within treatment groups. There are nonetheless a near-infinite number of methodological variants, and little consensus regarding the ideal methodology to be used in experiments of this kind. Often studies involving animal models of acute cerebral ischemia fail to translate into human stroke treatments. Despite around 600 treatments having been reported as effective in preclinical studies , clinically proven treatment options are scarce, which suggests that further refinements may be required for rodent models to produce data relevant to human medicine.
The initial search delivered 426 hits for 2005 and 465 hits for 2015. Both sets of search results were screened for relevance and eligibility. All references corresponding to studies written in languages other than English were excluded (n = 20 for 2005, n = 11 for 2015). Remaining references were continually randomly selected and screened for inclusion/exclusion criteria until 200 publications (n = 100 for 2005, n = 100 for 2015) had been retained for further analysis. The number of papers rejected for various reasons is given in detail in Fig 1.
Overall this review shows that anaesthetic techniques and their reporting for experimental stroke studies in rats have not changed significantly over the last ten years, despite the release of relevant guidelines in 2009 .
In conclusion, this study suggests that despite the publication of rodent-specific guidelines for models of stroke, anaesthetic modalities were similar in 2015 to those in 2005. Non-binding guidelines alone are unlikely to trigger practical and efficient changes in the way laboratory animals are anaesthetised. The intrinsic nature of the guidelines as well as the inability to implement suggested changes in research institutions may be causal factors. In particular, the practical expertise required for the application of research guidelines may not be readily available.