title: The calcium sensitizer levosimendan improves human diaphragm function.
abstract: BACKGROUND
  Acquired diaphragm muscle weakness is a key feature in several chronic conditions, including chronic obstructive pulmonary disease, congestive heart failure, and difficult weaning from mechanical ventilation. No drugs are available to improve respiratory muscle function in these patients. Recently, we have shown that the calcium sensitizer levosimendan enhances the force-generating capacity of isolated diaphragm fibers.
  
  
  OBJECTIVE
  To investigate the effects of the calcium sensitizer levosimendan on in vivo human diaphragm function.
  
  
  METHODS
  In a double-blind, randomized, crossover design, 30 healthy subjects performed two identical inspiratory loading tasks. After the first loading task, subjects received levosimendan (40 μg/kg bolus followed by 0.1/0.2 μg/kg/min continuous infusion) or placebo. Transdiaphragmatic pressure, diaphragm electrical activity, and their relationship (neuromechanical efficiency) were measured during loading. Magnetic phrenic nerve stimulation was performed before the first loading task and after bolus administration to assess twitch contractility. Center frequency of diaphragm electrical activity was evaluated to study the effects of levosimendan on muscle fiber conduction velocity.
  
  
  RESULTS
  The placebo group showed a 9% (P=0.01) loss of twitch contractility after loaded breathing, whereas no loss in contractility was observed in the levosimendan group. Neuro-mechanical efficiency of the diaphragm during loading improved by 21% (P<0.05) in the levosimendan group. Baseline center frequency of diaphragm electrical activity was reduced after levosimendan administration (P<0.05).
  
  
  CONCLUSIONS
  The calcium sensitizer levosimendan improves neuromechanical efficiency and contractile function of the human diaphragm. Our findings suggest a new therapeutic approach to improve respiratory muscle function in patients with respiratory failure.
authors.affiliation: Radboud University Nijmegen Medical Centre, Department of Critical Care Medicine, Geert Grooteplein zuid 10, 6525 GA Nijmegen, The Netherlands.
authors.forename: Jonne
authors.initials: J
authors.lastname: Doorduin
authors.forename: Christer A
authors.initials: CA
authors.lastname: Sinderby
authors.forename: Jennifer
authors.initials: J
authors.lastname: Beck
authors.forename: Dick F
authors.initials: DF
authors.lastname: Stegeman
authors.forename: Hieronymus W H
authors.initials: HW
authors.lastname: van Hees
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.forename: Leo M A
authors.initials: LM
authors.lastname: Heunks
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D003964:Diaphragm / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D018908:Muscle Weakness / Q000517:prevention & control*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D012129:Respiratory Function Tests; D000077464:Simendan; D055815:Young Adult
chemical_list: D006835:Hydrazones; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D000077464:Simendan