Neurocardiac protection with milrinone for restoring acute cerebral hypoperfusion and delayed ischemic injury after experimental subarachnoid hemorrhage

Background and purpose Acute cerebral hypoperfusion following subarachnoid hemorrhage (SAH) is highly related to the pathogenesis of delayed cerebral ischemia (DCI), but the therapeutic option is poorly available. This study aimed to clarify the effect of milrinone (MIL) on cerebral blood flow (CBF) and related outcomes after experimental SAH. Methods Twenty-seven male C57BL/6 mice were assigned to either sham surgery (SAH-sham; n = 6), SAH induced by endovascular perforation (control; n = 10), or SAH followed by cardiac support with intravenous MIL (n = 11) performed 1.5-h after SAH induction. CBF, neurobehavioral function, occurrence of DCI were assessed by MR-continuous arterial spin labeling, daily neurological score testing, and diffusion- and T2-weighted MR images on days 1 and 3, respectively. Results Initial global CBF depression was notable in mice of control and MIL groups as compared to the SAH-sham group (P < 0.05). MIL raised CBF in a dose-dependent manner (P < 0.001), resulted in lower incidence of DCI (P = 0.008) and better recovery from neurobehavioral decline than control (P < 0.001). The CBF values on day 1 predicted DCI with a cut-off of 42.5 ml/100 g/min (82% specificity and 83% sensitivity), which was greater in mice treated with MIL than those of control (51.7 versus 37.6 ml/100 g/min; P < 0.001). Conclusion MIL improves post-SAH acute hypoperfusion that can lead to the prevention of DCI and functional worsening, acting as a neurocardiac protective agent against EBI.