Treatment with levosimendan in an experimental model of early ventilator-induced diaphragmatic dysfunction

Vanessa Zambelli; Emma J. Murphy; Paolo Del Vecchio; Laura Rizzi; Roberto Fumagalli; Emanuele Rezoagli; Giacomo Bellani

doi:10.33393/dti.2023.2574

Authors

Vanessa Zambelli School of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy https://orcid.org/0000-0001-8002-5205
Emma J. Murphy LIFE – Health and Bioscience Research Institute, Midwest Campus, Technological University of the Shannon, Limerick - Ireland https://orcid.org/0000-0002-5620-0058
Paolo Del Vecchio School of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy
Laura Rizzi School of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy https://orcid.org/0000-0002-3709-6574
Roberto Fumagalli School of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy and Department of Emergency Medicine, ASST Grande Ospedale Metropolitano Niguarda, Milan - Italy https://orcid.org/0000-0003-0398-1329
Emanuele Rezoagli School of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy and Department of Emergency and Intensive Care, Fondazione IRCCS San Gerardo dei Tintori, Monza - Italy https://orcid.org/0000-0002-4506-7212
Giacomo Bellani School of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy and Department of Emergency and Intensive Care, Fondazione IRCCS San Gerardo dei Tintori, Monza - Italy https://orcid.org/0000-0002-3089-205X

DOI:

https://doi.org/10.33393/dti.2023.2574

Keywords:

Diaphragm contractility, Levosimendan, Mechanical ventilation, Muscle fiber size, Ventilator-induced diaphragmatic dysfunction

Abstract

Introduction: Mechanical ventilation (MV) is a life-saving approach in critically ill patients. However, it may affect the diaphragmatic structure and function, beyond the lungs. Levosimendan is a calcium sensitizer widely used in clinics to improve cardiac contractility in acute heart failure patients. In vitro studies have demonstrated that levosimendan increased force-generating capacity of the diaphragm in chronic obstructive pulmonary disease patients. Thus the aim of this study was to evaluate the effects of levosimendan administration in an animal model of ventilator-induced diaphragmatic dysfunction (VIDD) on muscle contraction and diaphragm muscle cell viability.

Methods: Sprague-Dawley rats underwent prolonged MV (5 hours). VIDD+Levo group received a starting bolus of levosimendan immediately after intratracheal intubation and then an intravenous infusion of levosimendan throughout the study. Diaphragms were collected for ex vivo contractility measurement (with electric stimulation), histological analysis and Western blot analysis. Healthy rats were used as the control.

Results: Levosimendan treatment maintained an adequate mean arterial pressure during the entire experimental protocol, preserved levels of autophagy-related proteins (LC3BI and LC3BII) and the muscular cell diameter demonstrated by histological analysis. Levosimendan did not affect the diaphragmatic contraction or the levels of proteins involved in the protein degradation (atrogin).

Conclusions: Our data suggest that levosimendan preserves muscular cell structure (cross-sectional area) and muscle autophagy after 5 hours of MV in a rat model of VIDD. However, levosimendan did not improve diaphragm contractile efficiency.

Downloads

Download data is not yet available.

References

Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med. 1998;157(1):294-323. PMID:9445314 https://doi.org/10.1164/ajrccm.157.1.9604014 PMID:9445314 DOI: https://doi.org/10.1164/ajrccm.157.1.9604014

Rezoagli E, Laffey JG, Bellani G. Monitoring lung injury severity and ventilation intensity during mechanical ventilation. Semin Respir Crit Care Med. 2022;43(3):346-368. PMID:35896391 https://doi.org/10.1055/s-0042-1748917 PMID:35896391 DOI: https://doi.org/10.1055/s-0042-1748917

Horie S, McNicholas B, Rezoagli E, et al. Emerging pharmacological therapies for ARDS: COVID-19 and beyond. Intensive Care Med. 2020;46(12):2265-2283. PMID:32654006 https://doi.org/10.1007/s00134-020-06141-z PMID:32654006 DOI: https://doi.org/10.1007/s00134-020-06141-z

Powers SK, Wiggs MP, Sollanek KJ, Smuder AJ. Ventilator-induced diaphragm dysfunction: cause and effect. Am J Physiol Regul Integr Comp Physiol. 2013;305(5):R464-R477. PMID:23842681 https://doi.org/10.1152/ajpregu.00231.2013 PMID:23842681 DOI: https://doi.org/10.1152/ajpregu.00231.2013

Gatti S, Abbruzzese C, Ippolito D, et al. Ultrasound versus computed tomography for diaphragmatic thickness and skeletal muscle index during mechanical ventilation. Diagnostics (Basel). 2022;12(11):2890. PMID:36428947 https://doi.org/10.3390/diagnostics12112890PMID:36428947 DOI: https://doi.org/10.3390/diagnostics12112890

Vassilakopoulos T, Petrof BJ. Ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med. 2004;169(3):336-341. PMID:14739134 https://doi.org/10.1164/rccm.200304-489CPPMID:14739134 DOI: https://doi.org/10.1164/rccm.200304-489CP

Pham T, Heunks L, Bellani G, et al. Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study. Lancet Respir Med. 2023 Jan 20:S2213-2600(22)00449-0. https://doi.org/10.1016/S2213-2600(22)00449-0. Epub ahead of print. PMID: 36693401. DOI: https://doi.org/10.1016/S2213-2600(22)00449-0

Giani M, Rezoagli E, Grassi A, et al. Low skeletal muscle index and myosteatosis as predictors of mortality in critically ill surgical patients. Nutrition. 2022;101:111687. PMID:35700589 https://doi.org/10.1016/j.nut.2022.111687 PMID:35700589 DOI: https://doi.org/10.1016/j.nut.2022.111687

Knisely AS, Leal SM, Singer DB. Abnormalities of diaphragmatic muscle in neonates with ventilated lungs. J Pediatr. 1988;113(6):1074-1077. PMID:3142983 https://doi.org/10.1016/S0022-3476(88)80585-7 PMID:3142983 DOI: https://doi.org/10.1016/S0022-3476(88)80585-7

Powers SK, Kavazis AN, Levine S. Prolonged mechanical ventilation alters diaphragmatic structure and function. Crit Care Med. 2009;37(10)(suppl):S347-S353. PMID:20046120 https://doi.org/10.1097/CCM.0b013e3181b6e760 PMID:20046120 DOI: https://doi.org/10.1097/CCM.0b013e3181b6e760

Shanely RA, Van Gammeren D, Deruisseau KC, et al. Mechanical ventilation depresses protein synthesis in the rat diaphragm. Am J Respir Crit Care Med. 2004;170(9):994-999. PMID:15297271 https://doi.org/10.1164/rccm.200304-575OC PMID:15297271 DOI: https://doi.org/10.1164/rccm.200304-575OC

Tobin MJ, Laghi F, Jubran A. Narrative review: ventilator-induced respiratory muscle weakness. Ann Intern Med. 2010;153(4):240-245. PMID:20713792 https://doi.org/10.7326/0003-4819-153-4-201008170-00006 PMID:20713792 DOI: https://doi.org/10.7326/0003-4819-153-4-201008170-00006

Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev. 2008;88(4):1243-1276. PMID:18923182 https://doi.org/10.1152/physrev.00031.2007 PMID:18923182 DOI: https://doi.org/10.1152/physrev.00031.2007

Andrade FH, Reid MB, Westerblad H. Contractile response of skeletal muscle to low peroxide concentrations: myofibrillar calcium sensitivity as a likely target for redox-modulation. FASEB J. 2001;15(2):309-311. PMID:11156946 https://doi.org/10.1096/fj.00-0507fje PMID:11156946 DOI: https://doi.org/10.1096/fj.00-0507fje

Pollesello P, Ovaska M, Kaivola J, et al. Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C. A molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study. J Biol Chem. 1994;269(46):28584-28590. Erratum in: J Biol Chem. 1995 Feb 10;270. 6.: 2880. PMID: 7961805. https://doi.org/10.1016/S0021-9258(19)61945-9 PMID:7961805 DOI: https://doi.org/10.1016/S0021-9258(19)61945-9

Haikala H, Kaivola J, Nissinen E, Wall P, Levijoki J, Lindén IB. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol. 1995;27(9):1859-1866. PMID:8523447 https://doi.org/10.1016/0022-2828(95)90009-8 PMID:8523447 DOI: https://doi.org/10.1016/0022-2828(95)90009-8

van Hees HW, Dekhuijzen PN, Heunks LM. Levosimendan enhances force generation of diaphragm muscle from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179(1):41-47. PMID:18990676 https://doi.org/10.1164/rccm.200805-732OCPMID:18990676 DOI: https://doi.org/10.1164/rccm.200805-732OC

Follath F, Cleland JGF, Just H, et al; Steering Committee and Investigators of the Levosimendan Infusion versus Dobutamine (LIDO) Study. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002;360(9328):196-202. https://doi.org/10.1016/S0140-6736(02)09455-2 PMID:12133653 DOI: https://doi.org/10.1016/S0140-6736(02)09455-2

Sareila O, Korhonen R, Auvinen H, et al. Effects of levo- and dextrosimendan on NF-kappaB-mediated transcription, iNOS expression and NO production in response to inflammatory stimuli. Br J Pharmacol. 2008;155(6):884-895. PMID:19002103 https://doi.org/10.1038/bjp.2008.328PMID:19002103 DOI: https://doi.org/10.1038/bjp.2008.328

Schellekens WJ, van Hees HW, Linkels M, et al. Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice. Crit Care. 2015;19(1):69. PMID:25888356 https://doi.org/10.1186/s13054-015-0798-8 PMID:25888356 DOI: https://doi.org/10.1186/s13054-015-0798-8

Díaz L, Zambrano E, Flores ME, et al. Ethical considerations in animal research: the principle of 3R’s. Rev Invest Clin. 2020;73(4):199-209. PMID:33090120 https://doi.org/10.24875/RIC.20000380 PMID:33090120 DOI: https://doi.org/10.24875/RIC.20000380

Innes CA, Wagstaff AJ. Levosimendan: a review of its use in the management of acute decompensated heart failure. Drugs. 2003;63(23):2651-2671. PMID:14636085 https://doi.org/10.2165/00003495-200363230-00009 PMID:14636085 DOI: https://doi.org/10.2165/00003495-200363230-00009

Zambelli V, Sigurtà A, Rizzi L, et al. Angiotensin-(1-7) exerts a protective action in a rat model of ventilator-induced diaphragmatic dysfunction. Intensive Care Med Exp. 2019;7(1):8. PMID:30659381 https://doi.org/10.1186/s40635-018-0218-x PMID:30659381 DOI: https://doi.org/10.1186/s40635-018-0218-x

Papp Z, Agostoni P, Alvarez J, et al. Levosimendan efficacy and safety: 20 years of SIMDAX in clinical use. J Cardiovasc Pharmacol. 2020;76(1):4-22. PMID:32639325 https://doi.org/10.1097/FJC.0000000000000859 PMID:32639325 DOI: https://doi.org/10.1097/FJC.0000000000000859

Girardis M, Bettex D, Bojan M, et al. Levosimendan in intensive care and emergency medicine: literature update and expert recommendations for optimal efficacy and safety. J Anesth Analg Crit Care. 2022;2(1):1-22. https://doi.org/10.1186/s44158-021-00030-7 DOI: https://doi.org/10.1186/s44158-021-00030-7

Hooijman PE, Beishuizen A, de Waard MC, et al. Diaphragm fiber strength is reduced in critically ill patients and restored by a troponin activator. Am J Respir Crit Care Med. 2014;189(7):863-865. PMID:24684359 https://doi.org/10.1164/rccm.201312-2260LEPMID:24684359 DOI: https://doi.org/10.1164/rccm.201312-2260LE

Doorduin J, Sinderby CA, Beck J, et al. The calcium sensitizer levosimendan improves human diaphragm function. Am J Respir Crit Care Med. 2012;185(1):90-95. PMID:21960535 https://doi.org/10.1164/rccm.201107-1268OC PMID:21960535 DOI: https://doi.org/10.1164/rccm.201107-1268OC

Roesthuis L, van der Hoeven H, Sinderby C, et al. Effects of levosimendan on respiratory muscle function in patients weaning from mechanical ventilation. Intensive Care Med. 2019;45(10):1372-1381. PMID:31576436 https://doi.org/10.1007/s00134-019-05767-yPMID:31576436 DOI: https://doi.org/10.1007/s00134-019-05767-y

Zambelli V, Rizzi L, Delvecchio P, et al. Hexarelin modulates lung mechanics, inflammation, and fibrosis in acute lung injury. Drug Target Insights. 2021;15:26-33. PMID:34871336 https://doi.org/10.33393/dti.2021.2347 PMID:34871336 DOI: https://doi.org/10.33393/dti.2021.2347

Nieminen MS, Buerke M, Cohen-Solál A, et al. The role of levosimendan in acute heart failure complicating acute coronary syndrome: a review and expert consensus opinion. Int J Cardiol. 2016;218:150-157. PMID:27232927 https://doi.org/10.1016/j.ijcard.2016.05.009PMID:27232927 DOI: https://doi.org/10.1016/j.ijcard.2016.05.009

Schellekens WJ, van Hees HW, Vaneker M, et al. Toll-like receptor 4 signaling in ventilator-induced diaphragm atrophy. Anesthesiology. 2012;117(2):329-338. PMID:22722577 https://doi.org/10.1097/ALN.0b013e3182608cc0 PMID:22722577 DOI: https://doi.org/10.1097/ALN.0b013e3182608cc0

Dres M, Demoule A. Diaphragm dysfunction during weaning from mechanical ventilation: an underestimated phenomenon with clinical implications. Crit Care. 2018;22(1):73. PMID:29558983 https://doi.org/10.1186/s13054-018-1992-2 PMID:29558983 DOI: https://doi.org/10.1186/s13054-018-1992-2

Testelmans D, Maes K, Wouters P, et al. Rocuronium exacerbates mechanical ventilation-induced diaphragm dysfunction in rats. Crit Care Med. 2006;34(12):3018-3023. PMID:17012910 https://doi.org/10.1097/01.CCM.0000245783.28478.AD PMID:17012910 DOI: https://doi.org/10.1097/01.CCM.0000245783.28478.AD

Testelmans D, Maes K, Wouters P, Powers SK, Decramer M, Gayan-Ramirez G. Infusions of rocuronium and cisatracurium exert different effects on rat diaphragm function. Intensive Care Med. 2007;33(5):872-879. PMID:17361387 https://doi.org/10.1007/s00134-007-0584-4PMID:17361387 DOI: https://doi.org/10.1007/s00134-007-0584-4

Hraiech S, Forel JM, Papazian L. The role of neuromuscular blockers in ARDS: benefits and risks. Curr Opin Crit Care. 2012;18(5):495-502. PMID:22941207 https://doi.org/10.1097/MCC.0b013e328357efe1 PMID:22941207 DOI: https://doi.org/10.1097/MCC.0b013e328357efe1