The Calcium Sensitizer Levosimendan Improves Human Diaphragm Function

Abstract

Rationale: 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. Objectives: 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 mg/kg bolus followed by 0.1/0.2 mg/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. Measurements and Main Results:The placebo group showed a 9% (P ¼ 0.01) loss of twitch contractility after loaded breathing, whereas no loss in contractility was observed in the levosimendan group. Neuromechanical 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.

The effect of metabolic alkalosis on the ventilatory response in healthy subjects

“…CFdi is a measure for muscle fiber conduction velocity, which is known to decrease during loaded breathing (Doorduin et al, 2012) and fatigue, attributed to many factors including a decreased extracellular sodium concentration which inhibits force development (Fortune and Lowery, 2009;Overgaard et al, 1997). In this study CFdi remains constant, although the administration of sodium bicarbonate resulted in a significant increased plasma sodium concentration, indicating no effect on diaphragm fiber conductivity probability of fatigue of the diaphragm.…”

“…Neuromechanical efficiency (NME) is a specific measure for contractile efficiency of the diaphragm; the ability to generate inspiratory pressure for a given neural respiratory effort (NME = Pdi/EAdi) (Doorduin et al, 2017;Doorduin et al, 2012;Liu et al, 2012). Neuroventilatory efficiency (NVE) defines the tidal volume generated for a given neural respiratory effort (NVE = Vt/EAdi) (Liu et al, 2012).…”

“…The center frequency of the power spectrum of the EAdi signal (CFdi) was used to assess muscle fiber conduction velocity (Doorduin et al, 2012;Sinderby et al, 2001). The CFdi was calculated during 30 s at the start of the HCVR test and 30 s at the last step of P insp CO 2 where all 10 subjects endured the test, both before and after sodium bicarbonate administration.…”

“…A multielectrode esophageal catheter with two balloons (NeuroVent Research Inc, Toronto, Canada) was inserted and positioned, as described previously (Doorduin et al, 2012). The ventilatory response to inhaled CO 2 was assessed by a HCVR test (Nickol et al, 2009;Oren et al, 1991); subjects were seated in upright position with uncast abdomen and wearing a nose clip, breathing through a mouthpiece.…”

Advances in Ventilation — Neurally Adjusted Ventilatory Assist (NAVA)

“…21 One possibility is to quantify the patient' s ability to convert neural demand into tidal ventilation (via a neuro-ventilatory efficiency index) and see whether this can predict failure to wean. 22,23 Monitoring neural demand may one day enable every patient to have a truly individualised weaning programme, tailored according to the relative impact that mobilisation, airway weaning and ventilatory weaning have on their EAdi.…”