Isoflurane postconditioning with cardiac support promotes recovery from early brain injury in mice after severe subarachnoid hemorrhage

Abstract Aims Neurocardiac dysfunction is a life-threatening systemic consequence of subarachnoid hemorrhage (SAH) that contributes to triggering delayed cerebral ischemia (DCI). This study aimed to determine the impact of dobutaminecardiac support during isoflurane postconditioningon pos t -SAH DCI. Main methods Male C57BL/6 mice were subjected to SAH, SAH plus isoflurane postconditioning, or SAH plus isoflurane postconditioningwith dobutamine. Severity of SAH was graded from 1 to 4 (mild, 1–2; severe, 3–4) based on T2*-weighted magnetic resonance imaging (MRI). Cardiac output (CO) measured by transthoracic pulsed wave Doppler-echocardiographywas titrated at a supra-normal level with intravenous dobutamineinfusion. Neurological function was examined daily by neurological score and Rotarod tests. DCI was analyzed 3 days later by determining new infarction on diffusion-weighted MRI. In a separate experiment, mice were pretreated with hypoxia-inducible factor (HIF) inhibitor 2-methoxyestradiol(2ME2). Key findings Clinically relevant CO depression was notable in severe SAH grade mice, in which dobutamineCO management combined with isoflurane postconditioningshowed earlier and improved functional recovery than postconditioningwith single isofluraneinhalation. Incidence of infarction and volumes on day 3 reduced significantly in this subgroup. All of the effects during preconditioning were attenuated by 2ME2 pretreatment. Significance Isoflurane postconditioningunder dobutaminecardiac support improves recovery from SAH-induced early brain injury, leading to reduced DCI resultant from severe experimental SAH. These results indicate the importance of neuro-cardiac protection, in which HIF may be acting as a critical mediator, as a promising therapeutic approach to SAH.