Cilostazol decreases duration of spreading depolarization and spreading ischemia after aneurysmal subarachnoid hemorrhage

Abstract

Objective: Traditionally, angiographic vasospasm (aVS) has been thought to cause delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, successful treatment of aVS alone does not result in improved neurological outcome. Therefore, there may be other potential causes of poor neurological outcome, including spreading depolarization (SD). A recent study showed beneficial effects of cilostazol on DCI and neurological outcome. The present prospective clinical trial and experimental study focused on effects of cilostazol on SDs. Methods: Fifty aSAH patients were treated with clip ligation and randomly assigned to a cilostazol (n = 23) or control group (n = 27). Effects of cilostazol on DCI, aVS, and SDs, measured with subdural electrodes, were examined. The effect of cilostazol on SD-induced perfusion deficits (spreading ischemia) was assessed in an aSAH-mimicking model. Results: There was a trend for less DCI in the cilostazol group, but it did not reach our threshold for statistical significance (13.0% vs 40.0%, odds ratio = 0.266, 95% confidence interval [CI] = 0.059-1.192, p = 0.084). However, the total SD-induced depression duration per recording day (22.2 vs 30.2 minutes, β = −251.905, 95% CI = −488.458 to −15.356, p = 0.043) and the occurrence of isoelectric SDs (0 vs 4 patients, β = −0.916, 95% CI = −1.746 to −0.085, p = 0.037) were significantly lower in the cilostazol group. In rats, cilostazol significantly shortened SD-induced spreading ischemia compared to vehicle (Student t test, difference = 30.2, 95% CI = 5.3-55.1, p = 0.020). Interpretation: Repair of the neurovascular response to SDs by cilostazol, as demonstrated in the aSAH-mimicking model, may be a promising therapy to control DCI.

Correlates of Spreading Depolarization, Spreading Depression, and Negative Ultraslow Potential in Epidural Versus Subdural Electrocorticography

“…Thereafter, a relative oligemia to 135 (IQR: 76–182) % occurred (Figure 2A). The typical pattern of SI (Dreier et al, 1998; Dreier, 2011; Sugimoto et al, 2018) was not observed in any of the SDs under hypoxia that preceded the terminal one.…”

“…These typically occur following non-spreading depression of activity after onset of anoxia/severe ischemia, and thus historically are termed ‘anoxic SD’ (van Harreveld, 1946; Leão, 1947; Bures and Buresova, 1957; Marshall, 1959). However, SD can transform into intermediate and persistent types even in well-nourished tissue by the mechanism of SI, which reflects inverse neurovascular coupling (Dreier et al, 1998, 2001; Dreier, 2011; Sugimoto et al, 2018). Here, we observed SI in response to terminal SD in two out of four hypoxic animals in which the terminal SD preceded the CA.…”

Electroencephalography, Hospital Complications, and Longitudinal Outcomes After Subarachnoid Hemorrhage

“…Neurophysiologic changes have previously been proposed as one pathway contributing to DCI progression [27] and new or worsening EAs are representative of poor cerebral metabolism [9][10][11][12] and have been shown to predict DCI [4,5]. Furthermore, these EEG abnormalities have previously been linked to cortical spreading depolarizations [10][11][12], which themselves have been associated with DCI and subsequent poor outcome [13,28,29]. Prior literature illustrates that new or worsening EAs are strongly co-linear with subsequent DCI, which is likely an in-hospital complication intermediate in the chain of events leading to poor outcome, rather than a confounder [6].…”

Spreading Depolarizations and Subarachnoid Hemorrhage

“…They also showed that volume expansion with IV fluids and nimodipine, a calcium channel blocker used clinically to prevent DCI, could antagonize spreading ischemia through effects on the microcirculation [55]. In collaboration with other investigators in a clinical-translational paper, they found that the phosphodiesterase-3 inhibitor cilostazol could decrease the duration of spreading ischemia in their rat model of SAH and SDs [57]. Finally, a different group targeted SDs using valproate and found that valproate mitigated injury from induced SD in an endovascular perforation model of SAH [56].…”