Karim Lakhal1, Antoine Hivert2, Pierre-Louis Alexandre3, Marion Fresco2, Vincent Robert-Edan2, Pierre-André Rodie-Talbere2, Xavier Ambrosi2, Romain Bourcier3,4, Bertrand Rozec2,4, Julien Cadiet2. 1. Service d'Anesthésie-Réanimation, Hôpital Laënnec, Centre Hospitalier Universitaire, 44093, Nantes Cedex 1, France. lakhal_karim@yahoo.fr. 2. Service d'Anesthésie-Réanimation, Hôpital Laënnec, Centre Hospitalier Universitaire, 44093, Nantes Cedex 1, France. 3. Department of Diagnostic and Therapeutic Neuroradiology, University Hospital of Nantes, Nantes, France. 4. Institut du Thorax, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université de Nantes, 44093, Nantes, France.
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 vasospasm-related 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 [153-238] 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.
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 vasospasm-related 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 [153-238] 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.