Effects of levosimendan on diaphragm contractility in healthy subjects

Mechanical ventilation offers essential ventilatory support during acute
respiratory failure. Unfortunately, mechanical ventilation is associated with
risks and complications and therefore, physicians aim to wean patients from the
ventilator as soon as the underlying reason for respiratory failure has
resolved. However, 20 - 30 % of intubated patients are difficult to wean from
mechanical ventilation, resulting in increased morbidity, mortality and health
care costs. The respiratory muscles drive ventilation with the diaphragm as the
most important inspiratory muscle. The capacity of the diaphragm of critically
ill patients is impaired by ICU-acquired muscle weakness. The combination of an
increased load imposed on the respiratory muscles and a reduced capacity to
generate pressure results in weaning failure. No specific intervention is
available to improve strength of the respiratory muscles in critically ill
patients.
Levosimendan is a relatively new drug that improves cardiac contractility in
patients with heart failure. Its main mechanism of action is enhanced binding
of calcium to the myocardial contractile proteins. Recent data from our lab
showed that levosimendan also improves in vitro contractility of human
respiratory muscle fibers. The effect of levosimendan on respiratory muscle in
vivo has not been studied. If levosimendan indeed does improve respiratory
muscle contractility in vivo, it may be useful in patients with impaired
contractility of the respiratory muscles, such as weaning failure patients.

The primary objective of this proof of principle study is to determine the
effect of levosimendan on the strength and endurance of the diaphragm in
healthy subjects. The secondary objective is to gain insight in the neural
activation and efficiency of contraction of the diaphragm during unloaded and
loaded breathing.

A double blind randomized parallel trial in healthy subjects.

Subjects are treated with either levosimendan or placebo. Diaphragm strength
and endurance is determined by measuring transdiaphragmatic pressure (Pdi)
during magnetic stimulation of the phrenic nerves. Electrical activity of the
diaphragm (Edi) is measured by esophageal electromyography. Diaphragm muscle
contractile efficiency is expressed as the Edi / Pdi ratio. Diaphragm
efficiency is measured before and after a loading dose of levosimendan (or
placebo), and subsequently, before and after loaded inspiratory breathing in
the presence of levosimendan (or placebo).

Subjects will visit our ICU research unit once for approximately 6 hours. After
informed consent, physical examination, electrocardiography and
echocardiography are performed by an experienced clinician. Several studies
have shown the safety of levosimendan in healthy subjects. No severe adverse
events were reported in any study. Positioning of the esophageal catheter is
associated with temporary discomfort, but is not painful. The presence of the
catheter during the experiment may result in mild discomfort. No complications
have been reported with the introduction / use of this soft small bore
catheter. Magnetic stimulation of the phrenic nerve is not painful, but
co-contraction could be encountered as uncomfortable. Therefore, stimulation
intensity is gradually increased to let the subject get acquinted with the
stimulus intensity. No adverse affects of magnetic stimualtion have been
reported by other researchers. Subjects have no clinical benefits in
participating in this study. A modest financial compensation is available