Intravenous milrinone for treatment of delayed cerebral ischaemia following subarachnoid haemorrhage: a pooled systematic review

Small trials have demonstrated promising results utilising intravenous milrinone for the treatment of delayed cerebral ischaemia (DCI) after subarachnoid haemorrhage (SAH). Here we summarise and contextualise the literature and discuss the future directions of intravenous milrinone for DCI. A systematic, pooled analysis of literature was performed in accordance with the PRISMA statement. Methodological rigour was analysed using the MINORS criteria. Extracted data included patient population; treatment protocol; and clinical, radiological, and functional outcome. The primary outcome was clinical resolution of DCI. Eight hundred eighteen patients from 10 single-centre, observational studies were identified. Half (n = 5) of the studies were prospective and all were at high risk of bias. Mean age was 52 years, and females (69%) outnumbered males. There was a similar proportion of low-grade (WFNS 1–2) (49.7%) and high-grade (WFNS 3–5) (50.3%) SAH. Intravenous milrinone was administered to 523/818 (63.9%) participants. Clinical resolution of DCI was achieved in 375/424 (88%), with similar rates demonstrated with intravenous (291/330, 88%) and combined intra-arterial-intravenous (84/94, 89%) therapy. Angiographic response was seen in 165/234 (71%) receiving intravenous milrinone. Hypotension (70/303, 23%) and hypokalaemia (31/287, 11%) were common drug effects. Four cases (0.5%) of drug intolerance occurred. Good functional outcome was achieved in 271/364 (74%) patients. Cerebral infarction attributable to DCI occurred in 47/250 (19%), with lower rates in asymptomatic spasm. Intravenous milrinone is a safe and feasible therapy for DCI. A signal for efficacy is demonstrated in small, low-quality trials. Future research should endeavour to establish the optimal protocol and dose, prior to a phase-3 study.