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

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A Letters to the editor to this article was published on 23 November 2021

A Letters to the editor to this article was published on 03 November 2021

A Response to this article was published on 01 November 2021

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.

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Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful to both research and nursing staffs of the department of Anesthesia and Critical Care Medicine of Laënnec University Hospital.

Funding

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Authors and Affiliations

  1. Service d’Anesthésie-Réanimation, Hôpital Laënnec, Centre Hospitalier Universitaire, 44093, Nantes Cedex 1, France

    Karim Lakhal, Antoine Hivert, Marion Fresco, Vincent Robert-Edan, Pierre-André Rodie-Talbere, Xavier Ambrosi, Bertrand Rozec & Julien Cadiet

  2. Department of Diagnostic and Therapeutic Neuroradiology, University Hospital of Nantes, Nantes, France

    Pierre-Louis Alexandre & Romain Bourcier

  3. 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

    Romain Bourcier & Bertrand Rozec

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Contributions

KL contributed to the conception and design of the study, the collection of clinical data, the statistical analysis, and the drafting and revision of the article. AH contributed to the conception and design of the study, the collection of clinical data, and the drafting and revision of the article. PLA contributed to the collection of radiological data and the revision of the article for its important intellectual content. MF contributed to the collection of clinical data and revision of the article for its important intellectual content. VRE contributed to the collection of clinical data and revision of the article for its important intellectual content. PART contributed to the collection of clinical data and revision of the article for its important intellectual content. XA contributed to the collection of clinical data and revision of the article for its important intellectual content. RB contributed to the interpretation of data and revision of the article for its important intellectual content. BR contributed to the interpretation of data and revision of the article for its important intellectual content. JC contributed to the conception and design of the study and the drafting and revision of the article. All authors approve of the final manuscript.

Corresponding author

Correspondence to Karim Lakhal.

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Conflicts of interest

KL has no conflict of interest in connection with the work submitted. In addition, KL received, during the past 3 years, congress registration fees from Sanofi Aventis (once in 2018), travel fees from Merck Sharp & Dohme (MSD) France (once, in 2017), Gilead Sciences (once, in 2017), pfizer (twice, in 2019 and 2020) and Correvio (twice, in 2020). BR has no conflict of interest in connection with the work submitted. In addition, BR received, during the past 5 years, lecture fees from Fisher&Paykel, Baxter, LFB, Aspen, research grants from Baxter and consulting fees from LFB, Astra Zeneca. None of the other authors has any financial or nonfinancial competing interest in connection with this study.

Ethical Approval/Informed Consent

This research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013). At our institution, intravenous milrinone has been incorporated into routine care several years ago, a dedicated institutional written procedure guiding its use for moderate/severe vasospasms. In patients who were included prospectively (IV milrinone group), consent to use the data for this observational study was obtained from all participants (patients or their next of kin then the patients themselves if they regained capacity) after oral and written reminding of their rights. For patients included retrospectively (historical control cohort), informed consent was waived. Anonymity was respected. This research has been approved by an independent ethical committee (Comité de Protection des Personnes Sud-Ouest & Outre-Mer III, March 2018, N° 2017-A03347-46, amended in march 2019).

Clinical Trials Registration

Ref. NCT 03517670.

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Lakhal, K., Hivert, A., Alexandre, PL. et al. Intravenous Milrinone for Cerebral Vasospasm in Subarachnoid Hemorrhage: The MILRISPASM Controlled Before–After Study. Neurocrit Care 35, 669–679 (2021). https://doi.org/10.1007/s12028-021-01331-z

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