Effects of Levosimendan on Diaphragm Function in Mechanically Ventilated 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.We hypothesize that levosimendan could improve respiratory muscle function in mechanically ventilated patients commencing a CPAP trial.

Study Overview

• Status: Unknown
• Conditions: Weaning Failure; Muscle Weakness Conditions
• Intervention / Treatment: Drug: Levosimendan; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 42
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500HB
      • Recruiting
      • Radboud University Nijmegen Medical Centre
      • Contact: Leo MA Heunks, MD, PhD; Phone Number: 024-3617273; Email: l.heunks@ic.umcn.nl
      • Contact: Jonne Doorduin, MSc; Phone Number: 024-3617273; Email: j.doorduin@ic.umcn.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Levosimendan; Levosimendan 0.2 ug/kg/min intravenous for a single 7 hours.	Drug: Levosimendan; Other Names: Simdax
PLACEBO_COMPARATOR: Placebo; Similar coloured placebo intravenous for a single 7 hours	Drug: Placebo; Similar coloured placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Medical Center Nijmegen
• Collaborators: Orion Corporation, Orion Pharma
• Investigators: Principal Investigator: Leo Heunks, MD, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (ANTICIPATED): May 1, 2016
• Study Completion (ANTICIPATED): May 1, 2016

Study Registration Dates

• First Submitted: September 21, 2012
• First Submitted That Met QC Criteria: November 1, 2012
• First Posted (ESTIMATE): November 4, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): June 10, 2015
• Last Update Submitted That Met QC Criteria: June 9, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: levosimendan; diaphragm function; mechanically ventilated patients; neuro-mechanical efficiency
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Weakness; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Simendan
• Other Study ID Numbers: Levo2