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

Abstract

Background: Intravenous (IV) milrinone, in combination with induced hypertension, has been proposed as a treatment option for cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). However, data on its safety and efficacy are scarce. Methods:This was a controlled observational study conducted in an academic hospital with prospectively and retrospectively collected data. Consecutive patients with cerebral vasospasm following aSAH and treated with both IV milrinone (0.5 µg/kg/min −1 , as part of a strict protocol) and induced hypertension were compared with a historical control group receiving hypertension alone. Multivariable analyses aimed at minimizing potential biases. We assessed (1) 6-month functional disability (defined as a score between 2 and 6 on the modified Rankin Scale) and vasospasmrelated brain infarction, (2) the rate of first-line or rescue endovascular angioplasty for vasospasm, and (3) immediate tolerance to IV milrinone.Results: Ninety-four patients were included (41 and 53 in the IV milrinone and the control group, respectively). IV milrinone infusion was independently associated with a lower likelihood of 6-month functional disability (adjusted odds ratio [aOR] = 0.28, 95% confidence interval [CI] = 0.10-0.77]) and vasospasm-related brain infarction (aOR = 0.19, 95% CI 0.04-0.94). Endovascular angioplasty was less frequent in the IV milrinone group (6 [15%] vs. 28 [53%] patients, p = 0.0001, aOR = 0.12, 95% CI 0.04-0.38). IV milrinone (median duration of infusion, 5 [2-8] days) was prematurely discontinued owing to poor tolerance in 12 patients, mostly (n = 10) for "non/hardly-attained induced hypertension" (mean arterial blood pressure < 100 mmHg despite 1.5 µg/kg/min −1 of norepinephrine). However, this event was similarly observed in IV milrinone and control patients (n = 10 [24%] vs. n = 11 [21%], respectively, p = 0.68). IV milrinone was associated with a higher incidence of polyuria (IV milrinone patients had creatinine clearance of 191 ml/min −1 ) and hyponatremia or hypokalemia, whereas arrhythmia, myocardial ischemia, and thrombocytopenia were infrequent.Conclusions: Despite its premature discontinuation in 29% of patients as a result of its poor tolerance, IV milrinone was associated with a lower rate of endovascular angioplasty and a positive impact on long-term neurological and radiological outcomes. These preliminary findings encourage the conduction of confirmatory randomized trials.

Nimodipine vs. Milrinone – Equal or Complementary Use? A Retrospective Analysis

“…It reduces the amount of calcium available for the contraction of vascular smooth muscle cells. The increase of second messengers in cell functions may bring along a broad range of side effects (21)(22)(23). In our retrospective analysis, 1 mg milrinone provoked a self-limiting cardiac arrhythmia in one patient, similar to the case report of Vimala et al (23).…”

“…In our retrospective analysis, 1 mg milrinone provoked a self-limiting cardiac arrhythmia in one patient, similar to the case report of Vimala et al ( 23 ). In former studies, polyuria, hypokalemia, and hyponatremia were expected adverse effects ( 5 , 22 ). Myocardial ischemia and thrombocytopenia were infrequent.…”

Early management of patients with aneurysmal subarachnoid hemorrhage in a hospital with neurosurgical/neuroendovascular facilities: a consensus and clinical recommendations of the Italian Society of Anesthesia and Intensive Care (SIAARTI)—part 2

“…Milrinone, possessing a mechanism of action for the reversal of cerebral vasospasm as well as potentially antiinflammatory effects, has been identified as a promising therapeutic agent for DCI [22]. Several recent preliminary studies showed a potential benefit of milrinone for the management of DCI-related vasospasm and encourage the conduction of confirmatory randomized trials [23][24][25]. Awaiting more data from well-powered studies, we are unable to provide any recommendation regarding the utilization of milrinone in case of DCI related to refractory vasospasm.…”

Hemodynamic response and clinical outcome following intravenous milrinone plus norepinephrine–based hyperdynamic hypertensive therapy in patients suffering secondary cerebral ischemia after aneurysmal subarachnoid hemorrhage

“…These authors did not see a substantial difference in outcome between the two strategies. In contrast, Lakhal et al reported from their monocentric historical comparison significantly lower rates of brain infarction and poor clinical outcome using intravenous milrinone in combination with induced hypertension, compared to induced hypertension alone [ 14 ].…”