Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Is There a Relevant Experimental Model? A Systematic Review of Preclinical Literature

Abstract

Delayed cerebral ischemia (DCI) is one of the main prognosis factors for disability after aneurysmal subarachnoid hemorrhage (SAH). The lack of a consensual definition for DCI had limited investigation and care in human until 2010, when a multidisciplinary research expert group proposed to define DCI as the occurrence of cerebral infarction (identified on imaging or histology) associated with clinical deterioration. We performed a systematic review to assess whether preclinical models of SAH meet this definition, focusing on the combination of noninvasive imaging and neurological deficits. To this aim, we searched in PUBMED database and included all rodent SAH models that considered cerebral ischemia and/or neurological outcome and/or vasospasm. Seventy-eight publications were included. Eight different methods were performed to induce SAH, with blood injection in the cisterna magna being the most widely used (n = 39, 50%). Vasospasm was the most investigated SAH-related complication (n = 52, 67%) compared to cerebral ischemia (n = 30, 38%), which was never investigated with imaging. Neurological deficits were also explored (n = 19, 24%). This systematic review shows that no preclinical SAH model meets the 2010 clinical definition of DCI, highlighting the inconsistencies between preclinical and clinical standards. In order to enhance research and favor translation to humans, pertinent SAH animal models reproducing DCI are urgently needed.

Neutrophil Extracellular Trap Biomarker Titers and Delayed Cerebral Ischemia in Patients With Aneurysmal Subarachnoid Hemorrhage

“…36,37 Whatever the immediate trigger of the inflammatory response to aSAH may be, the concept of NET-induced thrombus formation as a result of it is intriguing, as it provides a framework that links inflammation, thrombus formation, and DCI. 5,38 We found high levels of MPO-DNA complexes in all patients with aSAH, not only in those with DCI. While lower levels of MPO-DNA complexes have been measured in the general population 39 , the high levels in our study may reflect an overall inflammatory environment after aSAH, in line with high levels of C-reactive protein in all our patients.…”

“…36,37 Whatever the immediate trigger of the inflammatory response to aSAH may be, the concept of NET-induced thrombus formation as a result of it is intriguing, as it provides a framework that links inflammation, thrombus formation, and DCI. 5,38…”

Neutrophil Extracellular Traps and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

“…There is also data to suggest that free heme itself may lead to endothelial injury, which in turn may promote recruitment of macrophages and neutrophils (41). As a downstream mechanism, the concept of NET-induced thrombus formation is intriguing, as it provides a framework that links inflammation, thrombus formation, and DCI (6,40). NETs have been therapeutically targeted in animal models and human pulmonary disease such as COVID-19, which might inform future studies assessing new treatments in patients with aSAH (42)(43)(44).…”

“…Disruption of the blood-brain barrier with influx of cell-free heme into the subarachnoid space may stimulate local macrophages and the heme scavenger system, leading to further recruitment of other immune cells and excessive inflammation ( 6 , 38 ). Direct activation of neutrophils through free heme is conceivable as well, with free heme being a driving factor for NET release in sickle cell disease ( 39 , 40 ). There is also data to suggest that free heme itself may lead to endothelial injury, which in turn may promote recruitment of macrophages and neutrophils ( 41 ).…”

Neuroinflammation and subarachnoid hemorrhage: a revised look at the literature

“…Another complication of aSAH with limited investigation via preclinical models is delayed cerebral ischemia (DCI). A systematic review of 78 preclinical studies showed that only 38% of models (with the most prevalent method being cisterna magna injection) reproduced DCI, but these instances were never investigated with imaging [ 124 ]. Given that DCI is a major prognostic factor of poor outcomes or disability after aSAH, it is imperative to find a preclinical model that reproduces DCI well [ 124 , 125 ].…”