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Effectiveness of Routine Nebulization of Mucolytics and Bronchodilators During Mechanical Ventilation (Nebulae)

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ClinicalTrials.gov Identifier: NCT02159196
Recruitment Status : Completed
First Posted : June 9, 2014
Last Update Posted : June 16, 2017
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Prof. Dr. Marcus J. Schultz, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Tracking Information
First Submitted Date  ICMJE June 6, 2014
First Posted Date  ICMJE June 9, 2014
Last Update Posted Date June 16, 2017
Study Start Date  ICMJE July 2014
Actual Primary Completion Date March 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2014)
Number of ventilator-free days at day 28 [ Time Frame: day 28 after ICU admission and intubation ]
The number of ventilator-free days (VFDs) is defined as the number of days from day 1 to day 28 after ICU admission and start of mechanical ventilation on which a patient breathes without assistance of the ventilator if the period of unassisted breathing lasted at least 24 consecutive hours. Patients who die or are mechanically ventilated longer than this period are assigned zero ventilator-free days.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 29, 2014)
  • Length of stay [ Time Frame: day 28 and day 90 after ICU admission and intubation ]
    length of stay (ICU and hospital)
  • Mortality [ Time Frame: day 28 and day 90 after ICU admission and intubation ]
    ICU and hospital mortality
  • Pulmonary complications [ Time Frame: daily until detubation or day 28 ]
    Pulmonary complications will include but are not limited to: incidence of Ventilator-associated Pneumonia (VAP); incidence of secondary acute respiratory distress syndrome (ARDS); atelectasis;
  • Side effects [ Time Frame: daily until detubation or day 28 ]
    Side effects of nebulization of mucolytics and/or bronchodilators (due to nebulization itself, or as a result of exposure to the nebulized agents);
Original Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2014)
  • Length of stay [ Time Frame: day 28 and day 90 after ICU admission and intubation ]
    length of stay (ICU and hospital)
  • Mortality [ Time Frame: day 28 and day 90 after ICU admission and intubation ]
    ICU and hospital mortality
  • Pulmonary complications [ Time Frame: daily until detubation or day 28 ]
    Pulmonary complications will include but are not limited to: incidence of Ventilator-associated Pneumonia (VAP); incidence of secundary acute respiratory distress syndrome (ARDS); atelectasis;
  • Side effects [ Time Frame: daily until detubation or day 28 ]
    Side effects of nebulisation of mucolytics and/or bronchodilators (due to nebulisation itself, or as a result of exposure to the nebulized agents);
Current Other Pre-specified Outcome Measures
 (submitted: June 6, 2014)
Health care related costs [ Time Frame: until detubation or day 28 ]
Health care related costs, including costs of ventilation, stay in ICU and/or hospital, cumulative use of sedative drugs and neuromuscular blocking agents, use of tracheostomies, and costs of ventilator-associated pneumonia
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Effectiveness of Routine Nebulization of Mucolytics and Bronchodilators During Mechanical Ventilation
Official Title  ICMJE Effectiveness of Routine Nebulization of Mucolytics and Bronchodilators in Mechanically Ventilated Intensive Care Patients'
Brief Summary

The purpose of this multi-center randomized controlled non-inferiority trial is to determine the effect of a strategy using routine nebulisation of mucolytics and bronchodilators (four times daily) as compared to a strategy using nebulisation of mucolytics or bronchodilators only on clinical indication (i.e. occurrence of persistent thick and tenacious sputum or bronchospasm) in mechanically ventilated intensive care patients. The investigators will examine the effects in terms of ventilator-free days, defined as the number of days alive and free of ventilation at day 28 after start of ventilation.

We hypothesize that a strategy that uses nebulisation of mucolytics or bronchodilators only on clinical indication not to be inferior to a strategy using preventive nebulisation of mucolytics or bronchodilators with regard to the number of ventilator free days in ICU patients at day 28.

Detailed Description

Detailed Description clinical trials.gov:

Design: This will be an investigator-initiated, multi-center, randomized, controlled, parallel two group, non-inferiority trial in intubated and ventilated adult ICU patients. A total of 950 patients in at least six participating centers will be included. Consecutive intubated and ventilated adult intensive care patients with an anticipated ventilation duration of minimal 24 hours will be recruited at ICU admission and onset of ventilation.

Methods: Patients will be randomized to receive either: 'routine nebulisation', i.e. nebulisation of mucolytics and bronchodilators, administered every 6 hours (i.e., 4 times per day) for the complete duration of ventilation, or 'nebulisation on strict clinical indications only', i.e. nebulisation of mucolytics in case of occurrence of persistent thick and tenacious sputum, and only after active humidification is set. Nebulisation of bronchodilators in case of occurrence of bronchospasm and only when signs and symptoms of bronchospasm (wheezing, increased airway pressures, increasing airway resistance, up sloping curve of de end tidal CO2 monitoring) are confirmed. The decision to start nebulisation should be evaluated daily. In case the clinical indication no longer exists, the therapy should be stopped.

Patients will be randomly assigned in a 1:1 ratio to one of both nebulisation strategies within 24 hours after ICU admission and intubation, and only if informed consent is signed by the patient or the patient's legal representative. Randomization will be performed using a dedicated, password protected, SSL-encrypted website. Randomization sequence is generated by a dedicated computer randomization software program using random block sizes and is stratified per center. Due to the nature of the intervention blinding of the caregivers is not possible. Data analysis will be performed blinded for the type of intervention.

Standard care: standard care is provided following local guidelines of the participating centers. Recommendations made for mechanical ventilation: Attending physicians are advised to use lung-protective ventilation strategies, including the use of lower tidal volumes (≤ 6 mL/kg predicted body weight) and/or lower airway pressures (≤ 30 cmH2O). Levels of positive end-expiratory pressure (PEEP) and inspired oxygen (FiO2) are titrated on partial pressure of oxygen (PaO2), preferably using a PEEP/ FiO2-table. If spontaneous ventilation is well tolerated it is used from then till the end of ventilation. Thereafter, weaning from ventilation is performed by stepwise lowering of pressure-support level. Daily assessment of the patient's readiness to wean will be performed.

Monitoring: monitoring of patient safety and reviewing of safety issues is performed by a designated independent Data Safety and Monitoring Board (DSMB). The DSMB watches over the ethics of conducting the study in accordance with the Declaration of Helsinki. All (serious) adverse events (SAE) will be collected by the local investigators and sent in to a designated SAE manager, who presents the events to the DSMB for evaluation.

Interim analysis: An interim analysis for safety will be performed after the first one third (193) and two thirds (388) of the study population, respectively, are included and have completed follow up for the primary outcome. The main concern is the occurrence of tube related incidents in the non-nebulized group, development of ventilator associated pneumonia in the nebulisation group. Serious adverse events (SAEs) such as death, ventilator associated pneumonia, ARDS, new onset ventricular tachyarrhythmia with hemodynamic instability wherefore an intervention is indicated or tube occlusion that are possibly related to study intervention will be compared.

Data collection: Data will be collected at inclusion, daily till day 28 after both ICU admission and intubation and at day 90 after both ICU admission and intubation. Data collection will be performed by an investigator blinded for the randomization group, except on day 90 if the patient is discharged. In that case follow-up will be performed by telephone. Data will be coded by a patient identification number (PIN) of which the code will be kept safe at the local sites. The data will be transcribed by local investigators into an internet based electronic case record form (CRF).

Sample size calculation: Group size calculation is focused on demonstrating non-inferiority. When the sample size in each group is 445 (890 patients in total), an one-sided non-inferiority test (targeted at 0.05) for log-transformed normalized data has 80% power to reject the null hypothesis that the number of ventilator-free days (VFDs) in the intervention group (nebulisation on strict clinical indication) is inferior to the number of VFDs in the control group (routine nebulisation) by a margin of 10% and a coefficient of variation of 0.70, in favor of the alternative hypothesis that the number of VFDs in the intervention group is non-inferior. The choice for a margin of 10% is motivated by what we consider acceptable from a clinical point of view as the maximal acceptable reduction of the ventilator-free period for non-inferiority. Clinically this margin means that an increase of > 10% in the duration of mechanical ventilation will reduce the ventilator free days with > 12 hours (calculated over the mean duration of mechanical ventilation of 5 days) which will be considered inferior, assuming that the data will be analyzed in the log scale using t-test for differences in means at the 5% level. To allow for an anticipated drop out of approximately 5%, a number of 475 (950 in total).

As this is a randomized controlled trial, we expect that randomization in this large study population will sufficiently balance the baseline characteristics. However if imbalance occurs, a Cox proportional hazard model will be used and adjusted accordingly.

The effect of nebulisation on the primary outcome will be investigated in pre-specified subgroups based on humidification method (active or passive), different type of nebulisers and continuous versus breath actuated nebulisation.

Time to event variables: Time to event variables of interest (mortality, extubation, tracheotomy, VAP, ARDS, tube occlusion) are analyzed using Cox regression and visualized by Kaplan-Meier.

If the 95% CI upper bound for inferiority of the nebulized-on-indication group is < 10%, the null hypothesis of inferiority is rejected. If the non-inferiority criterion is satisfied, then superiority for the primary endpoint, the number of ventilator free days will be tested.

Organization: The study is conducted by FP, JB, MJS and SMvdH. SMvdH and FP will lead the project. They provide assistance to the participating clinical sites in trial management, record keeping and data management. Local investigators in each site will perform randomization, supervise data collection and ensure adherence to Good Clinical Practice during the trial.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Respiratory Failure
Intervention  ICMJE
  • Drug: acetylcysteine and salbutamol
    routine nebulisation of a 3 mL-solution of acetylcysteine (fluimucil 100mg/ml) and a 2.5 mL solution containing salbutamol (ventolin 2.5 Nebules 2.5mg/2.5 ml) four times daily
    Other Names:
    • 3 mL fluimucil 100mg/ml
    • 2.5 mL ventolin 2.5 Nebules 2.5mg/2.5 ml
  • Drug: acetylcysteine
    nebulisation of acetylcysteine on strict clinical indications only', i.e. in case of occurrence of persistent thick and tenacious sputum
    Other Name: 3 mL-solution of acetylcysteine (fluimucil 100mg/ml)
  • Drug: salbutamol
    nebulisation of salbutamol on strict clinical indications only', i.e. in case of occurrence of bronchospasm
    Other Name: 2.5 mL salbutamol (ventolin 2.5 Nebules 2.5mg/2.5 ml
Study Arms  ICMJE
  • Active Comparator: acetylcysteine and salbutamol
    Nebulisation of 3 mL-solution of acetylcysteine (fluimucil 100mg/ml, a mucolytic) and a 2.5 mL solution containing salbutamol (ventolin 2.5 Nebules 2.5mg/2.5 ml, a bronchodilator), administered every 6 hours (i.e., 4 times per day) within 24 hours after initiation of ventilation until tracheal extubation.
    Intervention: Drug: acetylcysteine and salbutamol
  • Experimental: acetylcysteine or salbutamol

    Nebulisation on strict clinical indications; nebulisation of 3 mL-solution of acetylcysteine (fluimucil 100mg/ml, a mucolytic) in case of occurrence of persistent thick and tenacious sputum and only after active humidification is set.

    Nebulisation of 2.5 mL solution containing salbutamol (ventolin 2.5 Nebules 2.5mg/2.5 ml, a bronchodilator) in case of occurrence of bronchospasm.

    Interventions:
    • Drug: acetylcysteine
    • Drug: salbutamol
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 29, 2014)
950
Original Estimated Enrollment  ICMJE
 (submitted: June 6, 2014)
580
Actual Study Completion Date  ICMJE June 2017
Actual Primary Completion Date March 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 18 year or older
  • Expected duration of intubation and ventilation > 24 hours
  • Written informed consent

Exclusion Criteria:

  • Age less than 18 years
  • Ventilation before present ICU admission (though short-term ventilation in the emergency room or in the operation room for general anesthesia during surgery is allowed)
  • Suspected or confirmed pregnancy
  • Diagnosed with lung diseases for which inhalation therapy and/or oral steroids are used
  • Diagnoses of: Guillain-Barré syndrome, complete spinal cord lesion or amyotrophic lateral sclerosis, Multiple Sclerosis, Myasthenia Gravis
  • Known allergy for acetylcysteine or salbutamol
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02159196
Other Study ID Numbers  ICMJE Nebulae
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Prof. Dr. Marcus J. Schultz, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study Sponsor  ICMJE Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators  ICMJE ZonMw: The Netherlands Organisation for Health Research and Development
Investigators  ICMJE
Principal Investigator: Marcus J Schultz, Prof Dr MD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
PRS Account Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Verification Date June 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP