Milrinone for refractory cerebral vasospasm with delayed cerebral ischemia

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>Intravenous (IV) milrinone is a promising option for the treatment of cerebral vasospasm with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, data remain limited on the efficacy of treating cases that are refractory to standard therapy with IV milrinone. The aim of this study was to determine predictors of refractory vasospasm/DCI despite treatment with IV milrinone, and to analyze the outcome of rescue therapy with intraarterial (IA) milrinone and/or mechanical angioplasty.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>The authors conducted a retrospective cohort study of all patients with aSAH admitted between 2010 and 2016 to the Montreal Neurological Institute and Hospital. Patients were stratified into 3 groups: no DCI, standard therapy, and rescue therapy. The primary outcome was frequency of DCI-related cerebral infarction identified on neuroimaging before hospital discharge. Secondary outcomes included functional outcome reported as modified Rankin Scale (mRS) score, and segment reversal of refractory vasospasm.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>The cohort included 322 patients: 212 in the no DCI group, 89 in the standard therapy group, and 21 in the rescue therapy group. Approximately half (52%, 168/322) were admitted with poor-grade aSAH at treatment decision (World Federation of Neurosurgical Societies grade III–V). Among patients with DCI and imaging assessing severity of vasospasm, 62% (68/109) had moderate/severe radiological vasospasm on DCI presentation. Nineteen percent (21/110) of patients had refractory vasospasm/DCI and were treated with rescue therapy. Targeted rescue therapy with IA milrinone reversed 32% (29/91) of the refractory vasospastic vessels, and 76% (16/21) of those patients experienced significant improvement in their neurological status within 24 hours of initiating therapy. Moderate/severe radiological vasospasm independently predicted the need for rescue therapy (OR 27, 95% CI 8.01–112). Of patients with neuroimaging before discharge, 40% (112/277) had developed new cerebral infarcts, and only 21% (23/112) of these were vasospasm-related. Overall, 65% (204/314) of patients had a favorable functional outcome (mRS score 0–2) assessed at a median of 4 months (interquartile range 2–8 months) after aSAH, and there was no difference in functional outcome between the 3 groups (p = 0.512).</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>The aggressive use of milrinone was safe and effective based on this retrospective study cohort and is a promising therapy for the treatment of vasospasm/DCI after aSAH.</jats:p></jats:sec>

Intravenous Milrinone for Cerebral Vasospasm in Subarachnoid Hemorrhage: The MILRISPASM Controlled Before–After Study

“…A few published reports addressed the effects of intraarterial and/or IV milrinone as treatment for vasospasm [14,26,28]. Fewer articles reported its safety.…”

“…Fewer articles reported its safety. These reports mostly consist in single-center case report/series including from 1 to 110 patients, most of them being retrospective [14,26,28]. For several reasons, a comparison of results across studies is tricky.…”

“…For several reasons, a comparison of results across studies is tricky. First, milrinone modalities of IV infusion markedly vary from one study to another with respect to dosage (ranging from 0.5 [29] to 2.5 µg/kg/min −1 [26]), duration (from a few days to 2 weeks [15,16,30]) and combination or not with prior intraarterial administration [14]. The dose of IV milrinone we administered (0.5 µg/kg/min −1 possibly incremented progressively to 1.5 µg/kg/min −1 ) was the one used in the hallmark case series by Fraticelli et al [15] and lies Fig.…”

“…Vasospasm detection relied on thorough clinical examinations, at least daily transcranial color-coded duplex Doppler of middle cerebral arteries (combining a dynamic approach [25] to the commonly retained velocity thresholds [2]). Vasospasm was confirmed by computed tomography (CT) angiography and classified as mild (arterial narrowing of < 25% as compared with the reference CT angiography), moderate (25-50%), and severe (> 50%) [26].…”

The Role of Urine F2-isoprostane Concentration in Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Haemorrhage—A Poor Prognostic Factor

“…The most plausible theory on the pathogenesis suggests that the subarachnoid blood acts as a nidus of reactive oxygen species (ROS) and inflammatory factors, which promote the peroxidation of membrane lipids of endothelial cells and proliferation of smooth muscles cells leading to DCI [ 7 ]. Current guidelines recommend only oral nimodipine, which improve the neurologic outcomes, albeit not counteracting the DCI itself [ 8 ]; the research on a new drug is ongoing [ 9 ].…”