# Effects of levosimendan on occurrence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a case-control study

Antoine Trinh-Duc, Marc-Antoine Labeyrie, Anaïs Caillard, Wagih Ben Hassen, Alexandre Mebazaa, Benjamin Glenn Chousterman

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Antoine Trinh-Duc, Marc-Antoine Labeyrie, Anaïs Caillard, Wagih Ben Hassen, Alexandre Mebazaa, et al.. Effects of levosimendan on occurrence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a case-control study. Critical Care, 2021, 25 (1), pp.396. 10.1186/s13054-021-03824-x. inserm-05503145

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# Effects of levosimendan on occurrence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a case-control study

Antoine Trinh-Duc<sup>1,2†</sup>, Marc-Antoine Labeyrie<sup>3,4†</sup>, Anaïs Caillard<sup>1,2</sup>, Wagih Ben Hassen<sup>5</sup>, Alexandre Mebazaa<sup>1,2</sup> and Benjamin Glenn Chousterman<sup>1,2* ID</sup>

**Keywords:** Subarachnoid hemorrhage, Cerebral vasospasm, Delayed cerebral ischemia, Levosimendan

Dear Editor,

Delayed cerebral ischemia (DCI) is a common compli-
cation following aneurysmal subarachnoid hemorrhage
(aSAH) contributing to poor prognosis [1]. Macro-vas-
cular dysfunction related to cerebral vasospasm (CVS)
remains the main pathophysiological hypothesis and
therapeutic target of DCI [2]. No preventive treatment
for CVS has yet proven to be effective [3].

Levosimendan, a non-adrenergic calcium-sensitiz-
ing inotrope, has been used to treat neurogenic stress-
induced cardiomyopathy (NSIC) related to aSAH. Only
few cases of patients treated with levosimendan for NSIC
related to aSAH have been reported and have suggested
that levosimendan could be associated with hemody-
namic and neurological improvement [4]. The aim of this
study was to retrospectively evaluate the efficacy of levo-
simendan as a therapy targeting occurrence of CVS in a
cohort of patients admitted in ICU for aSAH.

We retrospectively reviewed the medical records of
patients admitted to the Lariboisière Hospital Surgical
Intensive Care Unit (ICU) (Paris, France) for an aSAH

and treated with levosimendan during the first 48 h
after ICU admission in order to treat neurogenic stress-
induced cardiomyopathy (NSIC) secondary to aSAH
("Levo") defined as an elevation of circulating troponin.
We matched with a 1:2 ratio all Levo patients to patients
that were not treated with levosimendan. Matching was
performed on age, World Federation of Neurosurgical
Societies (WFNS) grade, Fischer grade, need for exter-
nal ventricular derivation (EVD) and severity assessed
by Simplified Acute Physiology Score II (SAPS II). We
excluded patients who died or had treatment withhold-
ing or withdrawal within the first four days following the
bleeding. Levosimendan was administered intravenously
as a continuous infusion over 24 h at a 0.1 µg/kg/min
dose.

The primary endpoint of the study was the rate of
occurrence of CVS defined as vessel narrowing higher
than 50% requiring angioplasty and/or associated with
DCI. DCI was defined according to Vergouwen et al.
[5] Secondary outcomes included occurrence of DCI,
3-month modified Rankin scale (mRS) and variation of
the cerebral arteries diameters between days 5–7 and day
1.

Between January 2018 and May 2020, a total of 652
patients were admitted for aSAH in our institution, and
18 Levo patients and 36 controls could be included in
the study. The characteristics and outcomes of the 54
included patients are presented in Table 1.

<footnote>*Correspondence: benjamin.chousterman@aphp.fr</footnote>

<footnote>†Antoine Trinh-Duc and Marc-Antoine Labeyrie have contributed equally</footnote>

<footnote n="1">¹ Department of Anesthesiology and Critical Care, DMU Parabol, FHU PROMICE, APHP.Nord, Lariboisière Hospital, 2 rue Ambroise Paré, 75010 Paris, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
<table><caption>**Table 1** Characteristics, management and outcome for levosimendan cases and non-levosimendan controls</caption><thead><tr><th></th><th>Cases ("Levo")<sup>a</sup><br>(n = 18)</th><th>Controls<sup>b</sup><br>(n = 36)</th><th>P-value</th><th>Odds-Ratio</th></tr></thead><tbody><tr><td><strong>Patients characteristics</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Age—median (IQR)—years</td><td>61 (50–70)</td><td>61,5 (52–68)</td><td>0.63</td><td></td></tr><tr><td>Female—No (%)</td><td>15 (83.3)</td><td>30 (83.3)</td><td>1.00</td><td></td></tr><tr><td>Arterial hypertension—No (%)</td><td>6 (33.3)</td><td>17 (47.2)</td><td>0.39</td><td></td></tr><tr><td>Smoking—No (%)</td><td>10 (55.6)</td><td>10 (27.8)</td><td>0.07</td><td></td></tr><tr><td>Diabetes—No (%)</td><td>0 (0)</td><td>1 (2.8)</td><td>1.00</td><td></td></tr><tr><td>Stroke history—No (%)</td><td>2 (11.1)</td><td>4 (11.1)</td><td>1.00</td><td></td></tr><tr><td>SAPS 2—median (IQR)</td><td>60 (43; 65)</td><td>49 (40; 57)</td><td>0.15</td><td></td></tr><tr><td>SOFA—median (IQR)</td><td>8 (7; 11)</td><td>6 (2; 9)</td><td>0.03</td><td></td></tr><tr><td><strong>Characteristic of SAH</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>WFNS grade—median (IQR)</td><td>5 (4; 5)</td><td>4 (4; 5)</td><td>0.43</td><td></td></tr><tr><td>Fischer grade—median (IQR)</td><td>4 (4; 4)</td><td>4 (4; 4)</td><td>0.48</td><td></td></tr><tr><td>Coiling—No (%)</td><td>16 (88.9)</td><td>32 (88.9)</td><td>1.00</td><td></td></tr><tr><td>External ventricular drainage—No (%)</td><td>7 (38.9)</td><td>23 (63.9)</td><td>0.09</td><td></td></tr><tr><td>Decompressive craniectomy—No (%)</td><td>2 (11.1)</td><td>3 (8.3)</td><td>1.00</td><td></td></tr><tr><td><strong>Cardiac impairment<sup>c</sup></strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Cardiac troponin peak—median (IQR)—ng/L</td><td>3999<br>(2210; 7382)</td><td>821<br>(40; 4532)</td><td>0.007</td><td></td></tr><tr><td>BNP peak—median (IQR)—ng/L</td><td>1122<br>(762; 1718)</td><td>138<br>(65; 937)</td><td>0.001</td><td></td></tr><tr><td><strong>Outcome</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Cerebral vasospasm—No (%)</td><td>5 (27.8)</td><td>24 (66.7)</td><td>0.009</td><td>0.199<br>[0.0443; 0.766]</td></tr><tr><td>Delayed cerebral ischemia—No (%)</td><td>0 (0)</td><td>7 (19.4)</td><td>0.08</td><td>NA</td></tr><tr><td>MRS at 3 months ≤ 3—No (%)</td><td>11 (61.1)</td><td>18 (50)</td><td>0.57</td><td>1.558<br>[0.4331; 5.922]</td></tr><tr><td>Death at 3 months—No (%)</td><td>1 (5.6)</td><td>9 (25)</td><td>0.14</td><td>0.181<br>[0.004; 1.516]</td></tr></tbody></table>

Characteristics of patients are compared with Mann–Whitney U test for quantitative variables and Fisher's exact test for categorical variables

BNP, B-type natriuretic peptide; MRS, modified Rankin score; NA, not available; SAPS2, Simplified Acute Physiology Score 2; SOFA, Sepsis-related Organ Failure Assessment; WFNS, World Federation of Neurosurgical Societies

Considering the primary outcome of the study, the rate of CVS was lower in patients treated with levosimendan compared to the control group (5/18 (28%) vs 24/36 (67%), respectively, *p* = 0.009).

There was no brain infarction related to CVS in the Levo group, but the difference with the control did not reach statistical significance (0/18 (0%) vs 7/36 (19%) for the Levo vs control groups, respectively, *p* = 0.08).

There was no association between levosimendan administration and mRS at 3 months (OR 1.56 [0.43;5.92]; *p* = 0.56) neither for mortality at 3 months (OR 0.18 [0.00; 1.52]; *p* = 0.14).

Regarding evolution of vessels diameters, we observed a slight increase in the median cerebral

arteries diameters between D0 and D5–7 (0.03 mm (IQR [−0.01; 0.06])) in the Levo group, while cerebral arteries showed signs of vasospasm with a decreasing diameter in the control group (−0.47 mm (IQR [−0.51; −0.24]) (*p* = 0.002; Fig. 1). Characteristics of the patients included in this analysis did not differ.

We found an association between the administration of levosimendan and a reduced incidence of CVS. Our study presents several limitations including its retrospective and non-randomized design that may induce several biases. Cardiac impairment was more frequent in the Levo group, since NSIC is associated with occurrence of CVS [6]; this argues in favor of a positive impact of levosimendan.

<footnote><sup>a</sup> No missing data</footnote>

<footnote><sup>b</sup> Missing data: arterial hypertension status for one patient, smoking status for one patient, diabetes status for one patient, stroke history for one patient, SOFA for six patients, type of aneurysmal securization for one patient, cardiac troponin peak for four patients, BNP peak for ten patients, use of norepinephrine for two patients</footnote>
<figure><img src="image_4.png" /><figcaption>**Fig. 1** Mean vessels diameters variations between day 1 and days 5–7 in levosimendan treated vs control patients. Quantitative analysis of cerebral arteries diameters in patients who had vessel imaging (CT or angiography) at admission and at days 5–7 in nine levosimendan-treated patients and 18 controls. Vessels narrowing was more pronounced in controls compared to levosimendan-treated patients (P = 0.004)</figcaption></figure>

Our results suggest that levosimendan could represent a therapeutic candidate for early prevention of cerebral vasospasm secondary to aSAH.

**Acknowledgements**

The authors are in debt to Prof. Etienne Gayat for his help regarding data analysis and manuscript drafting.

**Authors' contributions**

ATD and MAL collected the data, analyzed the data and drafted the manuscript. AC and GBH collected the data, analyzed the data and made critical revision to the manuscript. AM analyzed the data and made critical revision to the manuscript. BGC analyzed the data, supervised the work and drafted the manuscript. All authors read and approved the final manuscript.

**Funding**

This study was not funded.

**Availability of data and materials**

Data are available upon request to corresponding author.

**Declarations**

**Ethics approval and consent to participate**

This research is a single-centre retrospective case-control study of patients admitted to the Lariboisière Hospital Surgical Intensive Care Unit (ICU) (Paris, France) for an aSAH. The study was approved by an ethics committee (Comité d'éthique de la Recherche en Anesthésie-Réanimation (CERAR) no. IRB

00010254-2018-062 and Commission Nationale Informatique et Liberté (CNIL) (no. 2173692)).

**Consent for publication**

All authors approved the content of the manuscript and its publication.

**Competing interests**

BGC was a member of an advisory board for Roche Diagnostic; AM received speaker's honoraria from Abbott, Novartis, Orion, Roche and Servier and fees as a member of the advisory board and/or steering committee from Cardiorentis, Adrenomed, MyCartis, Neurotronik and Sphingotec. EG received research grant from Sphingotec and consultancy fees from Magnisense and Roche Diagnostics. All other authors have nothing to disclose.

**Author details**

¹Department of Anesthesiology and Critical Care, DMU Parabol, FHU PROMICE, APHP-Nord, Lariboisière Hospital, 2 rue Ambroise Paré, 75010 Paris, France. ²INSERM U942 MASCOT, Université de Paris, Paris, France. ³Department of Interventional Neuroradiology, Hopital Lariboisière, Paris, France. ⁴EA 7334 REMES, Université de Paris, Paris, France. ⁵UMR 1266, Department of Neurora-diology, GHU Paris, Université de Paris, INSERM, Paris, France.

Received: 27 September 2021 Accepted: 11 November 2021

Published online: 16 November 2021

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3. Li K, Barras CD, Chandra RV, Kok HK, Maingard JT, Carter NS, et al. A review of the management of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. World Neurosurg. 2019;126:513–27.

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