Influence of Mechanical Ventilation Modes on the Efficacy of Nebulized Bronchodilator
Influence of Mechanical Ventilation Modes on the Efficacy of Nebulized Bronchodilator
Aerosol therapy is widely used in intensive care in critically ill patients that use
 mechanical ventilation (MV). However, there is a lack of standardization about aerosol
 performance in this group of patients. Thus, this study aims to evaluate the effect of
 nebulization performed in different ventilatory modes on lung function and regional pulmonary
 distribution of critical patients with chronic obstructive pulmonary disease. It is a
 clinical trial, crossover, randomized, controlled and blind. Three interventions with
 bronchodilators will be performed: in the Pressure Controlled Ventilation mode (PCV) with
 positive end expiratory pressure (PEEP) = 85% of autoPEEP, in the PCV mode with PEEP = 15
 cmH2Oand in the Pressure Support Mode (PSV). Pulmonary function data will be evaluated
 through Electrical Impedance Tomography to evaluate the efficacy of the bronchodilator in
 different ventilatory modes.
2. OBJECTIVES

 2.1 Primary

 • To evaluate the influence of mechanical ventilation modes in the efficacy of nebulized
 bronchodilator in ventilator dependent patients with obstructive pulmonary disease.

 2.2 Secondary

 -  To compare regional ventilation distribution through Ventilation Surface Area (VSA) and
 Tidal Impedance Variation (TIV or ∆Z) by electrical impedance tomography (EIT) before,
 immediately after, after 1hour (h), 2h and 3h of nebulized bronchodilator in pressure
 controlled ventilation (PCV) with and without sedative drugs, and during pressure
 support ventilation (PSV).

 -  To compare the peak expiratory flow (PEF), change in End-Expiratory Lung Volume (dEELV),
 Respiratory Compliance (Crs) and Resistance (R), before, immediately after, after 1h, 2h
 and 3h of nebulized bronchodilator by monitoring airway pressure and EIT in ventilator
 modes PCV, with and without sedative drugs and PSV .

 -  To compare the ventilator modes on the VSA, ∆Z, PEF, dEELV and Crs after nebulized
 bronchodilator and the duration of its effects during mechanical ventilation.

 -  To compare two different level of PEEP during nebulized bronchodilator on PCV mode while
 the patient stay with sedative drugs.

 3. METHODS

 3.1 Study design This is a randomized crossover, blinded clinical trial. The randomization
 procedure will be a simple randomization by random number table. In order to improve
 reliability, not transparent sealed envelopes for blind allocation will be used.

 3.2 Local and study period This is a multicenter study that involve the following hospitals:
 Hospital Miguel Arraes - PE and Real Hospital Português de Beneficência em Pernambuco- PE.
 All hospitals are located in the metropolitan region of Recife, Pernambuco, Brazil and the
 study will be conducted from February 2016 to December 2019.

 3.3 Sample The study population consist of patients with obstructive pulmonary disease
 admitted to intensive care unit for MV support who meet the inclusion criteria.

 3.4 Sample size Patients will be identified by a daily telephone calls to the ICUs each
 morning for data collection. Potential candidate patients will be screened for inclusion and
 exclusinon criteria, after the identification of eligible patients. After consent is
 obtained, the research team goes to the ICU to start collecting data. The sample size will be
 calculated by statistical procedures after conducting a pilot study of 10 patients.

 3.5 Technical procedures and tools for data collection

 Prior to starting the intervention, clinical and demographic data will be collected according
 to the evaluation form, ( Appendix 2). After that, patients will be receive each of 4
 interventions, with a minimum of 4 hours between bronchodilator administration to allow for
 washout.

 3.5.1. Intervention Protocol 3.5.1.1. Step 1: Nebulization during Pressure Controlled
 Ventilation (PCV) Mode Initially the patient will be accessed when he still sedated. Two
 intervention will be done with a PCV mode in two different ways and the order of the
 procedures will be randomized.

 One nebulization will be done with a standard PCV mode and parameters will be setted as
 follows: sufficient Δ pressure to maintain the patient's tidal volume (vt) at 6 / kg ideal
 weight, respiratory rate (RR) at 12 bpm, inspiratory time (Ti) up to 1 second, maintain Ti /
 Ttot 0.3 - 0.4 without causing dynamic AutoPEEP, decreasing waveform flow and PEEP level of
 85% from static autoPEEP.

 Other nebulization will be done also in PCV mode with same parameters, but the level of PEEP
 will be increased to 15 cmH2O. Between this two interventions will be given 4 hours for
 washout.

 After this, we will talk to the medical staff to interrupt sedation, will be given 3 hour for
 wash out to start de Step 2.

 3.5.1.2. Step 2: Nebulization During Pressure Support Ventilation (PSV) With a clinical
 progression of the patient, a 4th evaluation will be done on the first day when the patient
 achieve PSV mode. In this ventilation mode the patient will control the Ti, Ttot, RR and
 inspiratory flow so it will be set only one Δ pressure for the patient to support a Vt of 6
 ml/kg. The lowest minimum value of Δ P is 10 cmH2O and the end of inspiratory phase will be
 determined by a decrease at 25% of the patient peak inspiratory flow.

 3.5.2 Nebulization Protocol

 Nebulized bronchodilator drugs will be Salbutamol Sulfate (aerolin nebulis) and ipratropium
 bromide (atrovent) diluted in a saline solution (saline 0.9%) in 3 ml. The vibrating Mesh
 nebulizer (Aeroneb Pro-X, Galway, Ireland) will be placed in the inspiratory circuit of the
 MV immediately before 'Y' piece using a 22 mm T adapter. The nebulizer is operated by an
 electric controller connected mains power. The vibrating Mesh produces aerosol with an
 average particle size of 5 μm and will remain on continuously until the end of nebulization.

 If a heat moisture exchanger (HME) is used during mechanical ventilation, it must be removed
 from between the nebulizer and airway before nebulization so that it does not filter out and
 reduce aerosol delivered.

 3.5.3 Evaluation by Electrical Impedance Tomography. TIE is a tool of obtaining transverse
 plane image of any section of the human body by means of low-power electric current. The
 image is obtained from the electric current or potential detected on the surface of the
 evaluated area, where each "pixel" image is its impedance or resistivity. Thus, when used in
 thoracic follow-up, the EIT is able to evaluate the aeration and ventilation of the patient
 through the following variables: distribution of regional lung ventilation by Tidal Impedance
 Variation (ΔZ), Ventilation Surface Area (VSA), Percentage of Recruitable Lung (PRLV), Change
 in End-Expiratory Lung Volume (dEELV) and Respiratory Compliance (Crs) .

 Initially, to evaluate the acute pulmonary impact of nebulizer bronchodilator on different
 ventilatory modes, EIT will be be performed before and immediately after the aerosol
 administration and repeated with each ventilation mode. Furthermore, the duration of
 nebulization effect will be evaluated by performing EIT after 1, 2 and 3h in each ventilation
 mode. There will be a > 4 hour washout between bronchodilator administrations.

 An impedance tomography (ENLIGHTER, Timpel, Brazil) will be used with the patient in supine
 position with a bed elevation of 45◦, so a belt with 32 electrodes will be applied to the
 chest, in the position corresponding to the 4th - 5th intercostal space on a shaved skin.
 Electrodes have to be positioned for reading electrocardiograms and a flow sensor that should
 be attached to the endotracheal tube. After this procedures recording data starts for 3
 minutes.

 For image acquisition, harmless electrical currents (5-8 nA, 125 KHz) will be injectates
 through electrode pairs in rotating sequence, and the potential differences Will be captured
 in other non injetantes electrode. Variations in thoracic impedance will be evaluated through
 a LabView software (National Instruments, USA) and the data is recorded in separate files for
 patients for further analysis.
Inclusion Criteria:

 Patients with asthma or chronic obstructive pulmonary disease (COPD) Invasive mechanical
 ventilation Hemodynamically stable

 Exclusion Criteria:

 Prescribed metered dose inhaler (MDI) or intravenous bronchodilators Undrained pneumothorax
 Bronchopleural fistula Chest trauma Tracheoesophageal fistula Tracheal granulomas Tracheal
 stenosis PEEP dependence

 Contraindicated disconnection of the MV

 Endotracheal tube diameter less than 7.5

 Do not make part of the protocol of daily sedation

 No regular ventilatory drive when with out sedation

 Do not reach a minimum tidal volume 6 ml/kg with a maximum peak pressure (PIP) of 35 cmH2O
 (centimeter of water) during MV.

 Do not use the same MV modes that will be tested in this study