Effects of Levosimendan on Diaphragm Function in Mechanically Ventilated Patients

Study Overview
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Brief Summary
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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.We hypothesize that levosimendan could improve respiratory muscle function in mechanically ventilated patients commencing a CPAP trial.

Official Title
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Effects of Levosimendan on Diaphragm Function in Mechanically Ventilated Patients

Conditions
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Muscle Weakness Conditions, Weaning Failure

Intervention / Treatment
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* Drug: Levosimendan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: mechanical ventilation > 3 days informed consent able to sustain a CPAP trial for 30 minutes PaO2/FiO2 ratio > 200 mmHg ventilatory settings: positive end expiratory pressure <= 10 cmH2O, pressure support <= 10 cmH2O Exclusion Criteria: pre-existent muscle disease (congenital or acquired) or diseases/disorders known to be associated with myopathy including auto-immune diseases pre-existent cardiac disease (based on history, electrocardiography and transthoracic echocardiography) upper airway/esophageal pathology (i.e. recent surgery, esophageal varices, diaphragmatic hernia) phrenic nerve lesions pregnancy, breast feeding severe renal failure (serum creatinine > 150 umol/L) severe hepatic failure recent (within 5 days) nasal bleeding systolic blood pressure < 120 mmHg

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levosimendan<br>Levosimendan 0.2 ug/kg/min intravenous for a single 7 hours. | Drug: Levosimendan<br> <br> * Other names: Simdax;|
| Placebo Comparator: Placebo<br>Similar coloured placebo intravenous for a single 7 hours | Drug: Placebo<br>* Similar coloured placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuro-mechanical efficiency of the diaphragm | The primary outcome measure is the neuro-mechanical efficiency(i.e. the ratio of diaphragm electrical activity and transdiaphragmatic pressure) of the diaphragm during a continuous positive airway pressure (CPAP) trial. | Artefact-free periode in the last 10 minutes of each CPAP trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuro-ventilatory efficiency of the diaphragm | A secondary outcome measure is the neuro-ventilatory efficiency (i.e. the ratio of diaphragm electrical activity and tidal volume) during a continuous positive airway pressure (CPAP) trial. | Artefact-free periode in the last 10 minutes of each CPAP trial | 
| Oxygen consumption (VO2) | A secondary outcome measure is the oxygen consumption during a continuous positive airway pressure (CPAP) trial. | Artefact-free periode in the last 10 minutes of each CPAP trial | 
| Partial pressure of oxygen in arterial blood (PaO2) | A secondary outcome measure is the PaO2 at the end of a continuous positive airway pressure (CPAP) trial. | Last minute of the 30 minute CPAP trial | 
| Accessory respiratory muscle activity | To determine the effects of levosimendan on accessory respiratory muscle function, ventilator settings are adapted after the last CPAP-trial. | Measured during a one hour protocol after the second CPAP trial. | 
| Carbon dioxide production (VCO2) | A secondary outcome measure is the carbon dioxide production during a continuous positive airway pressure (CPAP) trial. | Artefact-free periode in the last 10 minutes of each CPAP trial | 
| Partial pressure of carbon dioxide in arterial blood (PaCO2) | A secondary outcome measure is the PaCO2 at the and of a continuous positive airway pressure (CPAP) trial. | Last minute of the 30 minute CPAP trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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levosimendan, diaphragm function, mechanically ventilated patients, neuro-mechanical efficiency