Combination of Albumin and Cilostazol Improves Outcomes in a Rodent Model of Aneurysmal Subarachnoid Hemorrhage.

Abstract

Background and objectives: Patients recovering from aneurysmal subarachnoid hemorrhage (aSAH) often suffer secondary neurologic injury owing to delayed cerebral ischemia (DCI)-a multifactorial phenomenon. Both albumin and cilostazol have shown efficacy for treating DCI in preclinical and early clinical studies. However, the utility of combining these treatments has not yet been rigorously tested.

Methods: A total of 83 mice, male and female, were randomly divided into five groups as follows: sham; vehicle (0.9% saline); 25% human albumin; cilostazol; and combination 25% human albumin with cilostazol. A total of 11 animals in each group underwent endovascular perforation of the internal carotid artery (ICA) to induce subarachnoid hemorrhage. Daily neuroscores were assessed for each animal, and brain water content was quantified as a surrogate for edema 96 h posthemorrhage. An additional five animals in each group underwent 11.7 T magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) at 96 h to quantify vasospasm.

Results: There was a significant difference in vessel diameter in the left subclavian artery (L SCA; p = 0.014), right subclavian artery (R SCA; p = 0.018), and right internal carotid artery (R ICA; p = 0.026) in the experimental groups with combined treatment outperforming vehicle or either cilostazol or albumin monotherapy. Compared with SAH with vehicle control, treatment with albumin and cilostazol resulted in significantly improved MCA territory pixel intensity (p = 0.017). The treatment groups all had lower brain water contents than the SAH group, most pronounced in the SAH + albumin with cilostazol group compared with the SAH group (p < 0.001). There was a significant overall difference in survival between the groups (p < 0.001), and median neuroscore at all time points in the SAH + combined treatment group, compared with SAH alone; at 24 h (p = 0.036), 48 h (p = 0.001), 72 h (p = 0.001), and 96 h (p = 0.001).

Conclusions: Combination albumin and cilostazol resulted in superior outcomes, including brain water content (edema), large vessel vasospasm, behavioral scores, and survival across brain water content, MRA imaging, 28-point neuroscore, and Kaplan-Meier analysis. These preclinical data support the need for a clinical trial testing this combination therapy.