Effect of CPAP on 6-Minute Walk Test Outcomes in Patients With ECAC
Effect of CPAP on 6-Minute Walk Test Outcomes in Patients With ECAC
The purpose of this protocol is to perform a prospective, randomized, double-blinded,
 pacebo-controlled clinical trial to determine the influence of a non-invasive positive
 pressure ventilation device on exercise capacity and symptoms in adult patients with ECAC.
 Primary outcome will include the total distance traversed by the study subject during a
 standard 6-minute walk test, and secondary outcomes will include peak flow measurement and
 symptom reporting before and after the exercise testing. The study will focus on the use of
 continuous positive airway pressure (CPAP) device. CPAP is FDA-approved for the treatment of
 various medical conditions, including obstructive sleep apnea and heart failure, but is not
 FDA-approved for the treatment of ECAC. The study will enroll 32 ambulatory study subjects
 with confirmed ECAC at the BIDMC, and each study subject will be monitored for up to 3
 months.
Basal 6MWT performed as a standard of care in these patients will be compared to intervention
 ones to see if there is an improvement of at least 24 meters in their 6MWT distance, then
 both groups will be compared to see if there is a statistically significant difference
 between groups. Subjects, treating physicians and the research fellow performing the 6MWT
 will be blinded to the intervention; the only un-blinded personnel to the intervention will
 be the study coordinator who will be in charge of setting the CPAP before every intervention.

 As part of the standard of care of our institution, patients that are referred due to
 suspicion of ECAC undergo initial PFTs, 6MWT and dynamic CT scan. With this information,
 patients are evaluated in clinic by the interventional pulmonary and thoracic surgery team
 who decide if the patient has the mentioned disease based on the previous testing. To
 corroborate the findings patients with moderate so severe disease are taken into a
 bronchoscopy with dynamic maneuvers as part of the standard of care. Initial bronchoscopic
 examination will be performed as described in the following section "I-Dynamic Bronchoscopy
 Protocol" as part of the standard of care of patients. After initial evaluation, during the
 same intervention, all patients that agree to participate in our study will go through a CPAP
 calibration procedure; in order to determine the adequate pressure to achieve airway patency
 of at least 70% during end exhalation in each individual case. After regular bronchoscopic
 examination, a full face F&P SimplusTM CPAP mask (Fisher & Paykel, Irvine, CA, USA) will be
 placed in all patients to prevent un-blinding the treating physician. The mask will be
 connected to a dual axis swivel adapter (T-adapter) and the bronchoscope will be advanced to
 the nares through the swivel adaptor; air leak will be prevented by the tight disposable cap
 of the swivel adaptor as described by Murgu et al.20

 The calibration process will be performed following the technique first described by Ferguson
 et al10, bronchoscope will be positioned to assess the area with ECAC previously identified
 during regular examination; bronchoscope will be placed in the center of the lumen while
 assuring a constant 1-cm distance between the tip of the bronchoscope and the target area
 being measured, images will be taken during end inspiration and end expiration, gradual
 increases of 1 cmH2O in the CPAP pressure will be made until a 70% or less collapse is seen
 during end expiration by the bronchoscopist. At any given pressure increase the assessment of
 airway collapse will be made in 3 different respiratory cycles, the whole procedure will be
 recorded and posteriorly analyzed using morphometric bronchoscopy (Image J analysis program)
 as described in the "Morphometric Bronchoscopy" section.

 Patient Population Subjects (>18 years of age) with previous diagnosis of ECAC confirmed by
 dynamic CT scan and/or bronchoscopy, who are currently receiving adequate medical therapy
 (Optimal medication doses and interventions defined by Interventional Pulmonary team) for
 comorbidities such as COPD, GERD, asthma, etc and are able to perform a 6 MWT.

 Tracheobronchomalacia Evaluation CT Central Airway Protocol: All patients will be imaged
 according to our standard low dose CT central airway protocol21, which includes imaging
 during end-inspiratory and continuous dynamic expiratory phases. A multidetector row, helical
 CT scanner (LightSpeed; GE Medical Systems; Milwaukee, WI; or Aquilion; Toshiba America
 Medical Systems; Tustin, CA) which includes 4, 8, 16, and 64 detector-row systems will be
 used. Helical scanning will be performed in the cranio-caudal dimension during both
 respiratory phases. An experienced thoracic radiologist will review the CT images on a
 picture archiving and communication system (PACS) [Path-Speed, General Electric Medical
 Systems]. Using a computerized tracing tool in our PACS system, the inner wall of the airway
 will be hand traced at the level of maximal collapse in dynamic expiratory images to
 calculate the cross-sectional area of the airway (mm2). At the same level on end-inspiration
 images, the cross-sectional area of the airway lumen will be determined by using the same
 method. The percentage of luminal collapse between both respiratory phases will be calculated
 using the following formula= [1 - (Aee/Aei)],) X100, where Aee is luminal area at end
 expiration and Aei is luminal area at end inspiration. Mild ECAC is diagnosed if the percent
 of luminal collapse during dynamic expiration is 70-80%, moderate from 80-90% and severe
 >90%.

 I-Dynamic Bronchoscopy Protocol All patients who are enrolled for the study will undergo
 bronchoscopy under minimal sedation using intravenous midazolam and fentanyl to allow
 spontaneous respiration. Lidocaine (1%, 20 ml), will be delivered by atomizer to the
 posterior oropharynx until the gag reflex is suppressed. The larynx, vocal cords,
 aryepiglottic folds and entire tracheobronchial tree will be irrigated with 1% lidocaine in
 2-ml aliquots delivered through the bronchoscope during the procedure. An Olympus BF P180
 video bronchoscope (Olympus America, Melville, NY) with a 4.9-mm outer diameter and 2.0-mm
 working channel will be used to minimize any stenting effect. The bronchoscope will be
 introduced into the proximal trachea at the level of the cricoid. At that point, patients
 will be instructed to take a deep breath, hold it and then blow it out (forced expiratory
 maneuver). Maneuver will be done at the following six sites: proximal trachea at the level of
 the cricoid; mid-trachea 5 cm proximal to the carina; distal trachea 2 cm proximal to the
 carina; right main stem bronchus at the right tracheobronchial angle; bronchus intermedius
 and left main bronchus at the left tracheobronchial angle. The maneuver will be repeated
 three times to ensure maximal airway narrowing during exhalation. All bronchoscopies will be
 video recorded and reviewed after the procedure to assess the degree of airway collapse. Mild
 ECAC is defined as a collapse 70-80%, moderate 80-90% and severe >90% of the airway during
 exhalation. This is standard of care for patients with EDAC.

 After collapse degree is assessed trough forced expiratory maneuver, a nasal CPAP device
 (Define model) will be used in the patient, forced expiratory maneuvers will be repeated with
 different CPAP configurations until a 70% or less airway collapse is achieved. Calibration at
 which 70% airway collapse is achieved will be recorded and posteriorly used as the CPAP
 volume for the second 6MWT.

 Morphometric bronchoscopy Cross-sectional area (CSA) of the airway will be calculated after
 the procedure by using the Image J analysis program (available free of charge at
 http://rsb.info.nih.gov/ij/) using two different measurement techniques as it was described
 by Murgu et al.22 The graphical measurement method uses color levels within the image to
 identify an appropriate region to be measured. Images are imported into Image J and a color
 balance window is opened (Image > Adjust > Color Balance). The histogram is then set to RGB
 color. The minimum and maximum bars are adjusted so that the resulting line corresponds to
 the highest point of the histogram. Only red, yellow, white, and black colors then remain.
 The black area, which represents the region to be measured for CSA, is selected using a wand
 tool. Using the region of interest (ROI) Manager (Analyze > Tools > ROI Manager) the selected
 area is then calculated in pixels. The manual measurement method requires that the operator
 selects the area to be measured by first opening the image using Image J. Using the polygon
 selections tool, the area of interest is then selected, and the ROI manager is used as in the
 graphical method.

 Finally to provide an objective measurement in our patients, a collapsibility index (CI) will
 be calculated: difference in airway lumen size between end inspiration and end expiration: CI
 = (CSAinspir - CSAexpir)/(CSAinspire x 100%). Then measurements obtained for each patient
 during 3 respiratory cycles will be compared to discard that there is any significant
 statistical difference between them.

 Six Minute Walk Test The 6MWT is a test that requires a 100-ft hallway but no exercise
 equipment or advanced training for technicians. It evaluates the global and integrated
 responses of all the systems involved during exercise, including the pulmonary and
 cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular
 units, and muscle metabolism. Testing will be performed by the study personnel in a
 controlled environment. Supplies such as oxygen, sublingual nitroglycerine, aspirin, and
 albuterol (metered dose inhaler or nebulizer) will be available. The distance walked will be
 reported in meters. Data from both groups will be compared in order to verify if CPAP has a
 positive impact on exercise capacity in these patients. Since subjects have never used CPAP
 before and are not used to the device a 10 minute Run-in period will be allowed in which the
 CPAP will be placed while the patient is seating to allow he/she to get used to the sensation
 generated by the machine, at this time the study personnel will also look for air leaks that
 could compromise the results of the study. Either a regular CPAP or a sham-CPAP will be used
 for the Run-in period depending on the result of the randomization; this will be done to
 avoid the patient noticing the difference between this period and the 6 MWT which could
 happen if only regular CPAP was used.

 Sham-CPAP The Sham-CPAP will be created following the methods of Farre et al23 And Rodway et
 al.24 An enlarged air leak incorporated into the exhalation valve will be positioned between
 the mask and the CPAP tubing, allowing airflow resistance of the exhalation port to be almost
 eliminated by increasing its area, thereby virtually cancelling positive pressure. Also an
 orifice restrictor in the CPAP circuit will be connected between the CPAP unit and the tubing
 in order to load the blower with the same airflow resistance as in true CPAP. These changes
 allow the ventilator operating noise and the airflow through the exhalation port remain
 unchanged, which are crucial to a CPAP placebo.

 Enrollment CPAP naïve patients with a diagnosis of ECAC will be informed about the trial and
 if interested will be recruited for our randomized controlled study. Patients who meet the
 inclusion criteria by the principle investigator or co-investigators will be approached
 during an office visit to our Chest Disease Clinic at BIDMC
Inclusion Criteria:

 -  Patient with a diagnosis of ECAC either via bronchoscopy or CT Scan

 -  Age > 18 years

 -  Patients that will undergo a diagnostic or therapeutic bronchoscopy as part of their
 standard of care

 -  Patients with a baseline 6 MWT

 -  Patients that have never used CPAP devices in the past

 Exclusion Criteria:

 -  Patients with poorly-controlled respiratory comorbidities (asthma, COPD, obstructed
 sleep apnea, GERD, relapsing polychondritis)

 -  No evidence for acute respiratory tract infection, or respiratory tract infection
 within the prior 3 weeks

 -  Resting bradycardia (<50 beats/min), frequent multifocal PVCs, complex ventricular
 arrhythmia, sustained SVT

 -  Dysrhythmia that might pose a risk during exercise or training

 -  Any disease or condition that interferes with completion of initial or follow-up
 assessments

 -  Subject has co-morbidities that may significantly reduce subject's ability to improve
 exercise capacity (e.g., severe arthritis, planned knee surgery) or baseline
 limitation on 6MWT is not due to dyspnea.

 -  Subject has an inability to walk >140m (150 yd) in 6 minutes

 -  Subject has an inability to tolerate bronchoscopy under moderate sedation or general
 anesthesia.

 -  Subject has a known sensitivity to drugs required to perform bronchoscopy.