1. The Calcium Sensitizer Levosimendan Improves Human Diaphragm Function Jonne Doorduin, Christer A. Sinderby, Jennifer Beck, Dick F. Stegeman, Hieronymus W. H. van Hees, Johannes G. van der Hoeven, and Leo M. A. Heunks Am J Respir Crit Care Med 2012;185(1):90-5. R3 이민혜

2. Introduction Impaired force generation of the respiratory muscles : ex, COPD, CHF, pulmonary hypertension, patients on mechanical ventilation Pathophysiology of diaphragm dysfunction  muscle fiber atrophy  contractile protein dysfunction COPD : reduced sensitivity of the contractile proteins to calcium Calcium sensitivity  reduced in the diaphragm of animal models of CHF  prolonged mechanical ventilation Levosimendan  Clinically used calcium sensitizer  Acute HF : Enhance cardiac contractility  Vasodilatory properties  Mediated by the opening the ATP-sensitive potassium (KATP) channels

3. Introduction Hypothesis :  Levosimendan improves contractile function of the human diaphragm in vivo through calcium sensitizing  Levosimendan would decrease muscle fiber conduction velocity of the diaphragm through its effects on KATP channels in diaphragm fibers Double-blind, placebo–controlled, crossover design in healthy subjects performing inspiratory loading tasks

4. Methods Enrolled 30 healthy volunteers  Placebo, n=13 vs. levosimendan, n=14 Multielectrode esophageal catheter  Diaphragm electromyographic activity (EMGdi)  Esophageal pressure(Pes)  Gastric pressure (Pga)  Transdiaphragmatic pressure (Pdi) = Pga – Pes Magnetic stimulation and maximal inspiratory effort  Cervical magnetic stimulation of the phrenic nerve : Twitch Pdi (Pditw)  Compound muscle action potential of the diaphragm (CMAPdi)  Maximal voluntary Pdi (Pdimax) : mean Pdi in the first second during a maximal inspiratory effort

5. Methods Inspiratory loading task  Sitting in upright position  Breathed through a mouthpiece while wearing a nose clip  Intermittent inspiratory maneuvers of 10 seconds against a closed valve (near isometric contractions) followed by 7 seconds of unloaded breathing  Total loading task duration was 10minutes

6. Methods

7. Results No significant difference in Pditw and Pdimax between the placebo and the levosimendan groups before study medication. On average, loaded breathing in subjects receiving placebo resulted in significant reductions in Pditw(-9+3%; P=0.01) and Pdimax(-5+3%; P<0.05).

8. Results

10. Baseline center frequency of diaphragm electrical activity was reduced after levosimendan administration (P<0.05)

11. Results Neuromechanical efficiency of the diaphragm : 21% improved

12. Conclusion Calcium sensitizer levosimendan : Improves contractile function and neuromechanical efficiency of the human diaphragm  New therapeutic approach for patients with acute respiratory muscle dysfunction