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Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Experimental-Clinical Disconnect and the Unmet Need

Abstract

Background

Delayed cerebral ischemia (DCI) is among the most dreaded complications following aneurysmal subarachnoid hemorrhage (SAH). Despite advances in neurocritical care, DCI remains a significant cause of morbidity and mortality, prolonged intensive care unit and hospital stay, and high healthcare costs. Large artery vasospasm has classically been thought to lead to DCI. However, recent failure of clinical trials targeting vasospasm to improve outcomes has underscored the disconnect between large artery vasospasm and DCI. Therefore, interest has shifted onto other potential mechanisms such as microvascular dysfunction and spreading depolarizations. Animal models can be instrumental in dissecting pathophysiology, but clinical relevance can be difficult to establish.

Methods

Here, we performed a systematic review of the literature on animal models of SAH, focusing specifically on DCI and neurological deficits.

Results

We find that dog, rabbit and rodent models do not consistently lead to DCI, although some degree of delayed vascular dysfunction is common. Primate models reliably recapitulate delayed neurological deficits and ischemic brain injury; however, ethical issues and cost limit their translational utility.

Conclusions

To facilitate translation, clinically relevant animal models that reproduce the pathophysiology and cardinal features of DCI after SAH are urgently needed.

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Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by Grants from the Japanese Heart Foundation/Bayer Yakuhin Research Grant Abroad, NIH (P01NS055104, R01NS102969, R25NS065743, and KL2TR002542), the Foundation Leducq, the Heitman Foundation, the Ellison Foundation, the Brain Aneurysm Foundation’s Timothy P. Susco and Andrew David Heitman Foundation Chairs of Research, the Aneurysm and AVM Foundation, and the American Heart Association (18POST34030369).

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FO collected, analyzed the data, and wrote manuscript; DYC analyzed the data and wrote manuscript; MS edited the manuscript; CA conceived the study, analyzed the data, and wrote the manuscript.

Correspondence to Fumiaki Oka.

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The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Oka, F., Chung, D.Y., Suzuki, M. et al. Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Experimental-Clinical Disconnect and the Unmet Need. Neurocrit Care 32, 238–251 (2020). https://doi.org/10.1007/s12028-018-0650-5

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Keywords

  • Subarachnoid hemorrhage
  • Delayed cerebral ischemia
  • Animal models