Effectiveness of Routine Nebulization of Mucolytics and Bronchodilators During Mechanical Ventilation

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.