Avoid common mistakes on your manuscript.
Dear Editor,
Aneurysmal subarachnoid hemorrhage (aSAH) is a type of hemorrhagic stroke, which is associated with significant morbidity, and a case fatality of nearly 50% [6, 13, 17, 18]. Early brain injury (EBI) and delayed cerebral ischemia (DCI) are the two main determinants for functional outcome after aSAH. EBI refers to direct mechanical damage to the brain tissue and early pathophysiological changes, including increased intracranial pressure (ICP) and reduced cerebral perfusion. DCI describes a complex of reaction occurring thereafter [20]. Various mechanisms contribute to DCI, including angiographic cerebral vasospasms, microvascular spasm, microthrombosis, cortical spreading depolarization, failure of cerebral autoregulation, and inflammatory responses [20]. The individual importance of each of these pathomechanisms remains to be elucidated and it has been suggested that the etiology of EBI and DCI are linked. However, a unifying theory of these pathophysiological changes has not yet been described. Study of these pathophysiological mechanisms in humans is problematic and thus experimental animal studies have focused on investigating the mechanisms of EBI and potential therapies to either limit or reverse the extent of EBI, to reduce the incidence of DCI and improve functional outcome after aSAH.
Over a period of 15 years until 2014, more than 765 in vivo animal studies analyzed the pathophysiology of experimental aSAH and the effects of (new) therapeutic approaches on prevention of DCI [16]. Various pharmaceutics showed promising results in in vivo animal studies. However, despite the high number of animal studies, different therapeutic approaches, and numerous analyzed pharmaceutics, standard therapies of DCI have barely changed and oral nimodipine remains the only drug to improve neurological outcome in aSAH patients. All other initially promising drugs and approaches have failed to show a benefit in prospective randomized and controlled phase II or III trials. Clazosentan and the CONSCIOUS-1 trails are probably the most prominent examples for a failed translation from bench to bedside. Interestingly, clinical studies frequently showed a positive influence of a drug on vasospasms of large arteries, but did not translate into improved morbidity or mortality [3, 4].
As a consequence of the failed translation from bench to bedside, standards for planning, conducting, and reporting of aSAH animal experiments were proposed in order to align experimental and clinical research. Guidelines for a standardized reporting of animal experiments have successfully been implemented almost a decade ago [8, 9]. These standards included selecting animal models with clinical relevance, accurately calculating sample sizes, and using suitable statistics, standardizing animal treatments, and assessment of blinded outcome parameters [10,11,12, 14,15,16, 19]. Comprehensive meta-analysis and systematic reviews of existing animal data have also been proposed in order to detect effects sizes of treatment, biases, and methodological inadequacies in animal studies [15, 19]. Indeed, new developments and initiatives to improve the quality of systematic reviews of animal studies are likely to improve the translational value of animal research [5].
However, we are not convinced that a standardization and systematic analysis of existing data alone can clarify the failed translation from bench to bedside in aSAH research. Existing experimental aSAH models only partially simulate human conditions for several reasons: intracranial anatomy (e.g., the circle of Willis in rodents) and (patho-) physiology vary significantly between species. Moreover, intrinsic factors such as weight, age, genetic background, metabolism, and hemodynamics contribute to the already existing discrepancy between animal models and human physiology [1, 2]. Even in highly standardized mouse models, DCI-related responses significantly rely on the genetic background of the analyzed mice [1]. Also, pathophysiological responses and mortality rates in mice are significantly affected by the type of model which is used (perforation vs. injection). Mortality rates in most mouse models of DCI after experimental aSAH are significantly lower than human case fatality following aSAH [7].
Furthermore, DCI and EBI are well defined for clinical use but both lack a matching definition which is applicable for experimental aSAH. The clinical definition of DCI: DCI was clinically defined for aSAH patients by a neurological impairment lasting more than one hour which cannot be attributed to other causes [21], is useless for experimental aSAH. Determination of the Glasgow Coma Scale (GCS) to assess neurological deterioration as well as exclusion of other causes of neurological impairment by means of clinical assessment, laboratory testing, and CT or MRI scanning of the brain cannot realistically be performed in experimental aSAH. Moreover, DCI in humans only occurs from the 3rd day after the initial insult, has the highest incidence and severity after 6–8 days, and usually resolves after 12–14 days [4, 22]. In contrast, DCI in experimental animal models is frequently observed before the 3rd day after SAH, e.g., in mice six hours after SAH induction [7]. Therefore, consensus definitions of DCI and EBI, which can be applied to experimental aSAH in animal models, are required.
In summary, future efforts should systematically investigate to what extent aSAH animal models resemble the human condition and how parameters such as the experimental model, animal species, or the genetic background affect EBI- and DCI-related pathophysiological responses. Additionally, consensus definitions of DCI, EBI, and standard outcome measures suitable for experimental aSAH in different species are required.
References
D’Abbondanza JA, Ai J, Lass E, Wan H, Brathwaite S, Tso MK, et al. Robust effects of genetic background on responses to subarachnoid hemorrhage in mice. J Cereb Blood Flow Metab. 2015. https://doi.org/10.1177/0271678X15612489.
D’Abbondanza JA, Lass E, Ai J, Loch Macdonald R. Mouse genetic background is associated with variation in secondary complications after subarachnoid hemorrhage. Acta Neurochir Suppl. 2015;120:29–33. https://doi.org/10.1007/978-3-319-04981-6_5.
Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2011;31:1443–51. https://doi.org/10.1038/jcbfm.2011.7.
Hijdra A, Van Gijn J, Stefanko S, Van Dongen KJ, Vermeulen M, Van Crevel H. Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: clinicoanatomic correlations. Neurology. 1986;36:329–33.
Hooijmans CR, Ritskes-Hoitinga M. Progress in using systematic reviews of animal studies to improve translational research. PLoS Med. 2013;10:e1001482. https://doi.org/10.1371/journal.pmed.1001482.
Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke. 1997;28:660–4.
Kamp MA, Lieshout JH, Dibue-Adjei M, Weber JK, Schneider T, Restin T, et al. A systematic and meta-analysis of mortality in experimental mouse models analyzing delayed cerebral ischemia after subarachnoid hemorrhage. Transl Stroke Res. 2017. https://doi.org/10.1007/s12975-016-0513-3.
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8:e1000412. https://doi.org/10.1371/journal.pbio.1000412.
Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG, National Centre for the Replacement R, et al. Animal research: reporting in vivo experiments--the ARRIVE guidelines. J Cereb Blood Flow Metab. 2011;31:991–3. https://doi.org/10.1038/jcbfm.2010.220.
Lapchak PA, Zhang JH. Data standardization and quality management. Transl Stroke Res. 2018;9:4–8. https://doi.org/10.1007/s12975-017-0531-9.
Lapchak PA, Zhang JH. Translational stroke research guideline projections: the 20/20 standards. Transl Stroke Res. 2018;9:9–12. https://doi.org/10.1007/s12975-017-0534-6.
Lapchak PA, Zhang JH, Noble-Haeusslein LJ. RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Transl Stroke Res. 2013;4:279–85. https://doi.org/10.1007/s12975-012-0209-2.
Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: population-based study and systematic review. Neurology. 2010;74:1494–501. https://doi.org/10.1212/WNL.0b013e3181dd42b3.
Marbacher S. Animal models for the study of subarachnoid hemorrhage: are we moving towards increased standardization? Transl Stroke Res. 2016;7:1–2. https://doi.org/10.1007/s12975-015-0442-6.
Marbacher S. Can quality improvement tools overcome the translational roadblock-the vital influence of the researcher. Transl Stroke Res. 2017;8:203–5. https://doi.org/10.1007/s12975-017-0524-8.
Marbacher S, Gruter B, Schopf S, Croci D, Nevzati E, D’Alonzo D, et al. Systematic review of in vivo animal models of subarachnoid hemorrhage: species, standard parameters, and outcomes. Transl Stroke Res. 2018. https://doi.org/10.1007/s12975-018-0657-4.
Stegmayr B, Eriksson M, Asplund K. Declining mortality from subarachnoid hemorrhage: changes in incidence and case fatality from 1985 through 2000. Stroke. 2004;35:2059–63. https://doi.org/10.1161/01.STR.0000138451.07853.b6.
Steiger HJ, Beez T, Beseoglu K, Hanggi D, Kamp MA. Perioperative measures to improve outcome after subarachnoid hemorrhage-revisiting the concept of secondary brain injury. Acta Neurochir Suppl. 2015;120:211–6. https://doi.org/10.1007/978-3-319-04981-6_36.
Suzuki H, Nakano F. To improve translational research in subarachnoid hemorrhage. Transl Stroke Res. 2018;9:1–3. https://doi.org/10.1007/s12975-017-0546-2.
van Lieshout JH, Dibue-Adjei M, Cornelius JF, Slotty PJ, Schneider T, Restin T, et al. An introduction to the pathophysiology of aneurysmal subarachnoid hemorrhage. Neurosurg Rev. 2017. https://doi.org/10.1007/s10143-017-0827-y.
Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010;41:2391–5. https://doi.org/10.1161/STROKEAHA.110.589275.
Weir B, Grace M, Hansen J, Rothberg C. Time course of vasospasm in man. J Neurosurg. 1978;48:173–8. https://doi.org/10.3171/jns.1978.48.2.0173.
Acknowledgments
We thank Christiane von Saß for careful reading of the manuscript.
Funding
This study is supported by MKMD grants from The Netherlands Organization for Health Research and Development (ZonMw Grand Numbers 114024130 and 114024137).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Ethical Approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Kamp, M.A., Steiger, HJ. & van Lieshout, J.H. Experimental Aneurysmal Subarachnoid Hemorrhage: Tiding Over. Transl. Stroke Res. 11, 1–3 (2020). https://doi.org/10.1007/s12975-019-00726-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12975-019-00726-7