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Reversing Cholinergic Bronchoconstriction by Common Inotropic Agents: A Randomized Experimental Trial on Isolated Perfused Rat Lungs

Fodor, Gergely H. MD, PhD*; Bayat, Sam MD, PhD*; Babik, Barna MD, PhD; Habre, Walid MD, PhD; Peták, Ferenc PhD, DSc§

doi: 10.1213/ANE.0000000000003502
Critical Care and Resuscitation: Original Laboratory Research Report
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BACKGROUND: The ability of inotropic agents to alter airway reactivity and lung tissue mechanics has not been compared in a well-controlled experimental model. Therefore, we compared the potential to alter lung tissue viscoelasticity and bronchodilator effects of commonly used inotropic agents in an isolated perfused rat lung model.

METHODS: After achieving steady state lung perfusion, sustained bronchoconstriction was induced by acetylcholine (ACh). Isolated rat lungs were then randomly allocated to 6 groups treated with either saline vehicle (n = 8) or incremental concentrations of inotropes (adrenaline, n = 8; dopamine, n = 7; dobutamine, n = 7; milrinone, n = 8; or levosimendan, n = 6) added to the whole-blood perfusate. Airway resistance (Raw), lung tissue damping (G), and elastance were measured under baseline conditions, during steady-state ACh-induced constriction and for each inotrope dose.

RESULTS: No change in Raw was observed after addition of the saline vehicle. Raw was significantly lower after addition of dopamine (maximum difference [95% CI] of 29 [12–46]% relative to the saline control, P = .004), levosimendan (58 [39–77]%, P < .001), and adrenaline (37 [21–53]%, P < .001), whereas no significant differences were observed at any dose of milrinone (5 [−12 to 22]%) and dobutamine (4 [−13 to 21]%). Lung tissue damping (G) was lower in animals receiving the highest doses of adrenaline (difference: 22 [7–37]%, P = .015), dobutamine (20 [5–35]%, P = .024), milrinone (20 [6–34]%, P = .026), and levosimendan (36 [19–53]%, P < .001) than in controls.

CONCLUSIONS: Although dobutamine and milrinone did not reduce cholinergic bronchoconstriction, they reversed the ACh-induced elevations in lung tissue resistance. In contrast, adrenaline, dopamine, and levosimendan exhibited both potent bronchodilatory action against ACh and diminished lung tissue damping. Further work is needed to determine whether these effects are clinically relevant in humans.

From the *Unit for Anesthesiological Investigations, Department of Anesthesiology, Pharmacology and Intensive Care, University of Geneva, Geneva, Switzerland

Department of Anesthesiology and Intensive Care, University of Szeged, Szeged, Hungary

Unit for Anesthesiological Investigations, Department of Anesthesiology, Pharmacology and Intensive Care, University of Geneva and Pediatric Anesthesia Unit, Geneva Children’s Hospital, Geneva, Switzerland

§Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary.

Published ahead of print 25 April 2018.

Accepted for publication April 25, 2018.

Funding: This study was funded by a research grant from the University Hospitals of Geneva, Switzerland; the Swiss National Science Foundation Grant (32003B_169334); and a Hungarian Basic Research Council Grant (OTKA-NKFIH K115253).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Ferenc Peták, PhD, DSc, Department of Medical Physics and Informatics, University of Szeged, 9 Koranyi fasor, H-6720, Szeged, Hungary. Address e-mail to petak.ferenc@med.u-szeged.hu.

Copyright © 2018 International Anesthesia Research Society
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