Effects of levosimendan on diaphragm function in mechanically ventilated patients

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. 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 improves contractility of human diaphragm in vitro
(muscle fibers from COPD patient diaphragm) and in vivo (healthy subjects).
Accordingly, levosimendan may appear of value in the treatment of disorders
associated with impaired respiratory muscle function, such as mechanically
ventilated patients.

To determine the effect of levosimendan on diaphragm function in mechanically
ventilated patients.

A double-blind randomized placebo-controlled trial.

Subjects are treated with either levosimendan (continuous levosimendan infusion
of 0.2 µg/kg/min) or placebo for 6 hours. Before treatment and after treatment
patients perform a 30 minute weaning trial.

A specifically designed naso-gastric tube will be inserted for measurement of
the primary outcome parameter. No complications have been reported with the
introduction / use of the dedicated naso-gastric tube. From our clinical
experience, we consider the risks of naso-gastric tube placement minimal,
especially when *high risk patients* are excluded (upper airway / esophageal
pathology, bleeding disorders, hepatic failure) and insertion performed by
well-trained nurses.

A known side effect of levosimendan in patients with cardiogenic shock and
acute heart failure is hypotension due to vasodilation. In the current study
patients with cardiac diseases are excluded, thereby minimizing the risks of
side effects following administration of levosimendan. In our previous study,
that included healthy subjects, no cardiac side effects of levosimendan
administration were reported, despite a high loading dose (40 µg/kg compared to
no bolus in the current study).

A weaning trial is a commonly used method to determine readiness for extubation
and is frequently used on our ICU. The weaning trial will be terminated if
patients have any signs of distress, as acknowledged in clinical protocols.

Blood will be withdrawn from an indwelling arterial catheter already present as
part of routine clinical care. Therefore, no adverse events are anticipated
from blood withdrawal.

The study proposed in the current application will be carried out in
mechanically ventilated patients. Effects of levosimendan on diaphragm function
in vitro and in healthy subjects have been studied and published in high impact
(IF > 10) peer-reviewed medical journals by applicants. Ultimately, we want to
perform a multi-center trial to test whether levosimendan decreases the
duration of mechanical ventilation in critically ill patients. However, first
it should be confirmed that levosimendan indeed improves diaphragm function in
mechanically ventilated patients. Data obtained from this study are an
important step towards innovative pharmacological intervention in patients
failing to wean from mechanical ventilation.