Comparison of Breath-Enhanced and T-Piece Nebulizers in Children With Acute Asthma
Phase: NA
Conditions: Asthma
Sponsor: Seton Healthcare Family

Version date: 30JULY2017 
 
 
Study Title: Comparison of Breath-Enhanded and T-Piece Nebulizers in Children with 
Acute Asthma 
 
NCT 02566902 
 
Document type: IRB approved study protocol 
 
Document date/most recent update: 30 July 2017 
 
Initial IRB approval date: August 28, 2015 
 
IRB Continuing review approval dates: August 16, 2016, August 14, 2017 
 
 
 

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Research Proposal for Review 
Seton Institutional Review Board 
 
I. 
Title 
Comparison of Breath-Enhanced and T-Piece Nebulizers in Children with Acute Asthma 
 
II. 
Investigators (co-investigators), Study Team Members, and Institutional 
Affiliations 
Principal Investigator: 
Matthew Wilkinson, MD 
 
The University of Texas at Austin, Dell Medical School 
 
Dell Children’s Medical Center of Central Texas 
 
Austin, TX 
 
 
Co-Investigators: 
Michael Gardiner, MD 
The University of Texas at Austin, Dell Medical School 
 
Dell Children’s Medical Center of Central Texas 
 
Austin, TX 
 
III. 
Source of Funding 
This study has received funding from the 2014 Scientific, Education and Research 
Foundation of UTSW Austin Research/Fellow Grant (SERF-RG) in the amount of $4997 to 
cover equipment and gift cards for patient enrollment incentive.   
 
The Dell Children’s Medical Center Pediatric Emergency Medicine Fellowship will fund any 
further expenses incurred. 
 
IV. 
Hypothesis, Research Questions, or Goals of the Project 
The objective of this study is to evaluate the efficacy of two different nebulizers.  We 
hypothesize that albuterol delivered with a breath-enhanced nebulizer will lead to 
statistically greater improvement in FEV1 when compared to an equivalent dose delivered 
via a standard t-piece nebulizer. The primary aim will be to study changes in forced 
expiratory volume in one second (FEV1) in patients presenting to an urban pediatric 
emergency department with a moderate to severe acute asthma exacerbation when utilizing 
these two nebulizers.  Secondary aims will include evaluation of hospital admission rates, 
emergency department (ED) length of stay (LOS), changes in asthma severity scores, vital 
sign changes, medication side effects, and total quantity of albuterol given in the ED.  A distal 
aim of the study will be to perform a cost analysis; though we will likely need further clinical 
trials utilizing multiple dose administration in order to accurately analyze cost.    
 
V. 
Background and Significance 
Acute asthma exacerbation is one of the most frequent reasons for children to visit the 
emergency department.  According to the 2011 Centers for Disease Control and Prevention 
National Health Interview Survey, there are 7.1 million children living with a diagnosis of 

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asthma.1 Among the surveyed children, 58% had at least one asthma attack within the prior 
year.1 In 2010, 640,000 children under 15 years old visited an emergency department for 
asthma related reasons.1   The treatment of asthma accounts for a large portion of our 
national healthcare expense with an estimated annual cost of $56 billion, of which children 
account for a significant portion.1 
 
Advances in the ability to safely, effectively, and efficiently treat asthma exacerbations have 
the potential to improve outcomes, patient flow, and the productivity of pediatric emergency 
departments.  Current standard of care treatment of acute asthma includes administration 
of an inhaled short acting β2-agonist (SABA), systemic glucocorticoids, and correction of 
hypoxemia.2 While it has long been accepted that the use of inhaled SABA is efficacious, the 
optimal route of administration has been controversial.  Despite several studies showing that 
metered dose inhalers (MDI) with spacer are likely as effective as nebulizers, ED physicians 
in the United States have been reluctant to change their practice.3-8  
 
Fueled by the ongoing investigation into the ideal mechanism of inhaled SABA delivery, 
nebulizer technology has continued to advance over the past several decades. Studies using 
in-vitro lung models and in-vivo healthy controls have shown newer nebulizer technologies 
to aerosolize more medication with droplet sizes in the ideal respirable range, increasing the 
efficiency of drug delivery and improving lung deposition.9-14   It is unknown whether these 
results will translate into improved clinical outcomes. 
 
Newer generation nebulizers include breath-actuated and breath-enhanced nebulizers.  
Breath-actuated nebulizers function via a piston-activation, which initiates nebulization only 
during patient inhalation, enhancing medication delivery and reducing waste.  The 
drawbacks of breath-actuated nebulizers include their high cost, significantly longer 
nebulization times, and occasional non-activation when a patient is unable to generate 
significant inspiratory force to initiate nebulization, which is a significant problem in the 
pediatric population.14,15 Breath-enhanced nebulizers, on the other hand, continuously 
nebulize medication and gain their advantage via an aerosol holding chamber and a one-way 
valve system that directs exhaled air away from the nebulizer chamber.  This technology 
minimizes medication loss upon exhalation, and allows nebulized aerosol to build up in the 
chamber prior to the next breath cycle, thus delivering a bolus dose of medication on 
inhalation.12-14 
 
Newer technology nebulizers have not been widely accepted into clinical practice largely due 
to healthcare comfort with existing practices, lack of clinical trials evaluating efficacy in sick 
patients, and concerns regarding the cost of these newer nebulizers.   Despite the benefits 
that have been demonstrated in healthy subjects and lung models, few studies have 
evaluated these newer technology nebulizers in pediatric patients presenting with acute 
asthma exacerbations.  One randomized controlled trial of pediatric patients demonstrated 
decreased symptom scores, respiratory rates, and lower admission rates with the use of 
breath-actuated nebulizers compared to t-piece nebulizers.15 We were only able to identify 
one study which analyzed spirometry data in pediatric patients with newer nebulizer 
technologies.16 In this study, patients receiving inhaled terbutaline showed greater FEV1 
improvement using a breath-actuated device as compared to a constant flow nebulizer.   

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To our knowledge, the efficacy of breath-enhanced compared to t-piece nebulizers on airway 
obstruction as determined by spirometry has not been evaluated in children with acute 
asthma.  There is an ongoing study at our institution (principal investigator is Dr. Wilkinson) 
that is evaluating ED LOS in pediatric asthma patients when placed on a breath-enhanced 
versus t-piece nebulizer treatment pathway.  Dr. Wilkinson’s study is not evaluating FEV1 or 
other spirometric data to measure airway obstruction or the efficacy of a single treatment.  
Measurement of FEV1 has been used throughout other asthma literature as a reliable 
measure of airway obstruction and effectiveness of treatment in patients with acute 
asthma.16-19 FEV1 measurement has been recommended by the National Heart, Lung, and 
Blood Institute (NHLBI) as a means of assessing the degree of airway obstruction, and 
response to therapy in acute asthma.2 In their 2007 guidelines, the NHLBI recommended 
routine FEV1 measurements in all patients presenting for acute asthma exacerbations, as this 
measure is a more reliable indicator of severity of exacerbations than severity of symptoms.2 
Additionally, FEV1 is more useful than peak expiratory flow (PEF) due to the ability to 
evaluate flow-volume loops and distinguish poor effort and restrictive lung diseases from 
asthma-related obstruction.20-22 For all of these reasons, we feel it is pertinent to study this 
breath-enhanced nebulizer technology in relation to clinical spirometric data in order to 
demonstrate clinical efficacy. 
 
VI. 
Research Method, Design, and Proposed Statistical Analysis 
This study will be a blinded observer, randomized, controlled trial comparing breath-
enhanced nebulizer albuterol therapy with nebulized albuterol administered via a t-piece 
nebulizer.   
 
The study site will be the Dell Children’s Medical Center Emergency Department, an urban 
pediatric ED with approximately 80,000 visits per year, of which than 3000 visits are due to 
asthma related issues.  The patient population will include children with previously 
diagnosed asthma, aged ≥ 6 years to < 18 years old, presenting to our pediatric ED with 
breathing difficulty or cough, and found to have an initial FEV1 less than 70% predicted based 
on NHANES III study data (moderate to severe exacerbation). 2,15,23 Patients will be excluded 
from the study if they have no clinical evidence of exacerbation by asthma scoring (PAS score 
of 0), have preexisting chronic lung disease besides asthma, have congenital heart disease, 
have neuromuscular disease, have a suspected intrathoracic foreign body, have an allergy or 
other contraindication to a study medication, or have severe breathing difficulty requiring 
immediate resuscitation. 
 
 
 
 
 
 
 
 
Subject Eligibility: 
Inclusion: 

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1. Age ≥ 6 years and < 18 years 
2. History of physician diagnosed asthma 
3. Presenting to ED with acute asthma exacerbation 
4. Parent or guardian speaks English or Spanish. 
Exclusion: 
1. PAS score of 0 
2. Initial FEV1 greater than 70% predicted 
3. Patient unable to perform acceptable initial spirometry 
4. Pregnancy or breast-feeding 
5. Immediate resuscitation required 
6. Chronic lung disease (other than asthma) 
7. Congenital heart disease 
8. Neuromuscular disease 
9. Suspected intrathoracic foreign body 
10. Allergy or other contraindication to study medication 
 
Subjects will be identified in triage and will be screened and enrolled by a member of the 
study team (P1).  A research nurse will be available for 6-8 hours per day to serve as the 
primary enrolling personnel during these hours.  Additionally, each of the pediatric 
emergency medicine fellows and several pediatric emergency medicine attending physicians 
will be trained and certified for enrollment, and will enroll subjects during evenings, nights, 
and weekends.  We anticipate having study personnel available at a minimum of 18 hours 
per day for enrollment.  The P1 personnel will assess the potential subject and screen 
potential subjects for inclusion and exclusion criteria as detailed above.  As a part of 
screening, the P1 personnel will perform baseline spirometry measurements prior to 
consent.  Spirometry is a minimal risk procedure that is performed as standard of care in 
many emergency departments nationwide (either as spirometry, or PEF measurements).  
Performing spirometry prior to consent will expedite screening, and for children who have 
FEV1 greater than 70% predicted or those unable to perform acceptable spirometry, this will 
allow them to be excluded and their asthma treated more promptly.  This will avoid excluded 
children having to undergo consent prior to being excluded and receiving treatment for their 
acute asthma.  Consent will be obtained from the parent or guardian of all patients, and 
assent obtained from patients who are at least 7 years of age.  If required prior to study 
enrollment, supplemental oxygen may be administered to maintain oxygen saturation > 90% 
if there is evidence of hypoxemia on continuous pulse-oximetry.  If there is a delay of greater 
than 15 minutes due to the consent process, a unit dose (2.5mg) of albuterol may be given 
with a standard t-piece nebulizer up to 3 times as needed.  Patients requiring this unit dose 
of albuterol will still be eligible for enrollment so long as they meet enrollment criteria 
following this therapy. Following consent, the P1 personnel will record an initial set of vital 
signs (temperature, heart rate, respiratory rate, blood pressure, and peripheral pulse 
oximetry), and record baseline asthma scores using multiple previously validated asthma 
severity scores (PAS and PASS).24,25 At this point, study patients will be randomized to 
receive treatment with either the experimental (breath-enhanced) or control (t-piece) 
nebulizer.  Randomization will be performed with a computerized randomization process.  
Pre-assigned opaque envelopes will be used in order to conceal randomized assignments, 
preventing any knowledge of patient assignment to the enrolling personnel.  A second 

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member of the study team (P2) will open the subject’s randomized folder that will dictate 
the appropriate therapy arm. P2 will administer a single 5mg dose of albuterol via the 
appropriate nebulizer as determined by randomization.  P1 will be blinded to the treatment 
arm, whereas P2 will not be blinded.  Following 15 minutes of therapy - sufficient time for 
both treatment arms to be complete - P1 will perform a post-treatment assessment of the 
subject including a repeat set of vital signs, pulse-oximetry, asthma scoring, and spirometry 
measurements.    
 
Patients randomized to the “control” arm will receive therapy with our standard ED 
nebulizer, the Hudson RCI® Micro Mist® nebulizer (Teleflex Medical®, Research Triangle 
Park, NJ).  The treatment will be preferentially administered with a mouthpiece. Patients 
unable or unwilling to use a mouthpiece (as determined by the P2) will receive therapy with 
a simple mask (Hudson RCI®, Teleflex Medical®, Research Triangle Park, NJ).  
 
Patients randomized to the “experimental” arm will receive therapy with a NebuTech® 
HDN®, Breath-Enhanced High Density Jet Nebulizer (Salter Labs®, Arvin, CA).  Treatments 
will be preferentially administered with a mouthpiece. Patients unable or unwilling to use a 
mouthpiece (as determined by the P2) will receive therapy with a mask.  The NebuTech® 
HDN® allows for a proprietary vented mask, which still utilizes the breath-enhanced features 
of the system (I-GuardTM Valved Aerosol Delivery System, Salter Labs®, Arvin, CA).   
 
Spirometry measurements will be taken using a handheld spirometer which has been 
validated in healthy controls (NDD EasyOne®).26 In keeping with the most recent American 
Thoracic Society guidelines, participants will asked to perform a minimum of 3 and 
maximum of 8 forced expiratory maneuvers in order to obtain 3 adequate samples as 
determined by the device.27 Based on prior data, more than 8 attempts at spirometry may 
result in patient fatigue which will artificially decrease the patient’s performance on lung 
function testing27.  The highest recorded FEV1 will be used for analysis.  Flow-volume loops 
will be evaluated by a pulmonologist in order to assess adequacy of spirometry 
measurements for all patients, and those with inadequate loops will be excluded from FEV1 
analysis.  The pulmonologist involved will be blinded to therapy arm. 
 
A member of the research team will collect baseline data from the subject’s guardian.  Data 
will be recorded on a standardized form and will include subject demographics (including 
age, ethnicity, primary care provider), baseline home therapies, and assessment of baseline 
asthma severity, nature and duration of current symptoms, and treatments prior to ED 
arrival.  Following the post-treatment assessment, the P1 (blinded) study personnel will be 
asked to predict which nebulizer was utilized in the study, in order to evaluate adequacy of 
blinding. 
 
Following completion of the experimental stage as detailed above, patients will be released 
to receive standard of care therapy as determined by the assigned attending ED physician.  
We anticipate that the majority of patients will receive care according to the DCMC ED 
asthma pathway, including administration of inhaled ipratropium bromide and an oral 
systemic glucocorticoid.  However, some patients may be treated off of the ED pathway, and 
variability in subsequent therapy is possible.  Data will be recorded on a standardized form 

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regarding subsequent therapy through the remainder of the patients’ ED course.  Patients 
who are admitted to the hospital will be treated according to the standard of care as 
determined by the inpatient attending physician. Following disposition from the ED, no 
further data will be obtained from patients. 
 
Sample Size 
Treatment groups will be analyzed on an intention-to-treat basis.  The primary outcome for 
this study is change in FEV1 from initial presentation to reassessment.  By evaluating data 
from previously performed studies,16,18 we have conducted a sample size calculation using 
an estimated baseline initial FEV1 of 55% predicted, and an estimated 10% FEV1 
improvement with standard of care.  The calculations were performed using STATA 13 
statistical software (StataCorp, LP, College Station, TX). In order to detect an improvement 
differential of 5% (absolute) between treatment arms, with a power of 0.80 and alpha of 
0.05, we will need 64 patients enrolled in each arm.  It has been shown previously that as 
few as 35%-65% of patients with severe asthma exacerbations are able to successfully 
perform peak expiratory flow or spirometry.22,28 However other studies have not had 
significant difficulty with pediatric subjects performing spirometry.15 Several of these 
studies evaluated patients as young as 5 years old.  Due to the inconsistency of data, and the 
fact that we will be enrolling patients 6 years and older, we estimate that with sufficient 
coaching, approximately 60% of patients in this study will be able to successfully complete 
interpretable spirometry.  Based on this, we will need to enroll 213 patients in order to 
obtain interpretable data on 128 patients.  We will perform ongoing flow-volume loop 
analysis of obtained data in order to adjust our total enrollment goal based on the percentage 
of subjects with interpretable data sets. 
 
Statistical Analysis 
The primary outcome of change in FEV1 will be compared between the two groups using a 
two-tailed t-test, or non-parametric equivalent if the data is non-normally distributed.  
Baseline group characteristics will be summarized in a table with means and standard 
deviations for continuous data, percentages for categorical data, and medians with 
interquartile ranges for ordinal data. 
 
Secondary outcomes for this study will include hospital admission rates, emergency 
department (ED) length of stay (LOS), changes in asthma severity scores, vital sign changes, 
medication side effects, and total quantity of albuterol given in the ED.  Analysis of these 
variables will be completed using appropriate statistical analysis depending on the nature of 
the data (t-test for continuous, chi square of Fisher’s exact test for categorical, and Mann-
Whitney U test for ordinal). Non-parametric tests will be used when appropriate. 
 
Finally, if significant baseline differences in the groups occur, linear multivariable regression 
analysis of the primary endpoint will be performed to adjust for potential confounders. 
 
 
VII. 
Human Subject Interactions 
a. Sources of Potential Participants 

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Subjects will be screened for enrolment if they present to the DCMC ED with signs of an acute 
asthma exacerbation. The nursing staff at triage, as well as Pediatric Emergency Medicine 
study personnel will identify potential research subjects.  In addition, a full time research RN 
will be available to assist with identification and enrollment of potential subjects, if funding 
allows as mentioned above. Subjects that meet all inclusion and exclusion criteria and 
consent to participate will be enrolled. 
 
b. Procedure for Recruitment of Participants 
All patients who have physician-diagnosed asthma will be triaged upon arrival to the 
emergency department, and will be evaluated by a triage nurse.  Upon identification of a 
patient with previously diagnosed asthma who is presenting with breathing difficulty or 
cough, the triage nurse will contact study personnel, either in the form of the research nurse 
(if available) or other study personnel who are available within the ED. Additionally, 
research personnel may identify subjects through periodic monitoring of the ED tracking 
board from the research office. Study personnel will approach the parent or guardian for 
potential study enrollment.  As a part of screening for inclusion and exclusion criteria, study 
personnel will briefly explain the nature of the research project and perform baseline 
spirometry measurement prior to obtaining informed consent.  Performance of this minimal 
risk study is considered by many to be standard of care in acute asthma, and will expedite 
screening of patients if performed prior to consent. 
 
c. Procedure of Obtaining Informed Consent 
Potential subjects and their parent or guardian will have the nature of the research study as 
well as potential risks and benefits of enrollment explained by study personnel.  Consent will 
be obtained from the parent or guardian of all subjects, and assent obtained from subjects 
who are at least 7 years of age.  A consent form written in English or Spanish will be provided 
to the parent/guardian based on their preferred language.  A Spanish interpreter will be 
utilized as needed to answer questions and ensure clear understanding of expectations after 
enrollment.  Subjects and parents will be given adequate time to consider enrollment, and 
questions will be encouraged and answered prior to enrollment.  
 
d. Research Protocol 
It will be explained to subjects and guardians that if enrolled in the study, that study 
participation will involve receiving an albuterol therapy with either the control or 
experimental nebulizer, assigned randomly, and performing follow-up spirometry testing 
after treatment.  It will be explained that all of these therapies will occur within the DCMC 
ED, and will take approximately 20 minutes from start to finish. Subjects will be informed 
that if medically necessary, other treatments will be given, and that following participation, 
that standard of care treatment for their condition will be performed.  A detailed description 
of the research protocol is provided in section VI above. 
 
e. Timeline 
This study is expected to begin enrollment in July 2015 and run through June 2017, though 
target dates may need to be adjusted based on ongoing analysis of enrollment rate, as well 
as the percentage of patients able to successfully provide spirometry data. Data cleaning and 
analysis will be completed by August 2017. The target abstract completion data is November 

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2017, followed by manuscript writing and submission.   DCMC ED sees approximately 3000 
visits for asthma annually.  With research staff available at a minimum of 18 hours per day, 
we expect to have no issue achieving adequate enrollment for this study within a two-year 
period. 
 
f. Privacy and Confidentiality of Participants 
Study subjects will be assigned a unique identification number to protect their 
confidentiality through the course of the study period.  A list linking subjects and identifiers 
will be maintained in a locked cabinet behind a locked door in the research office. Subject 
identity will remain strictly confidential and will only be accessible by the research team, 
unless disclosure is required by law. 
 
g. Confidentiality of Research Data 
Throughout the duration of the study, an electronic database will be maintained in a secure, 
password-protected, firewalled shared drive with access restricted to the research staff 
working directly on data analysis.  Paper records including data collection forms containing 
patient identifiers, copies of a patient’s medical chart, or other records containing protected 
health information (PHI), will be maintained in a study folder identified by study ID numbers.  
These folders will be kept in a locked cabinet located in a locked, badge-controlled facility.  
Once the database has been compiled and completed, PHI will be removed such that the only 
link between the study ID number and the patient will be a key, which will be stored 
separately from the study database.  Data stored on the internal memory of the handheld 
spirometer will only be identified by the patient’s study ID number without other PHI.  All 
patient identifiers will be removed following data collection and analysis.  All study records 
will be maintained at least as long as required by law.  The data from this study may be 
published, but subject identities will not be disclosed. 
 
h. Research Resources 
Research personnel will consist of Pediatric Emergency Medicine (PEM) Fellowship faculty, 
PEM fellows, and the PEM Fellowship research nurse/coordinator. All of the research efforts 
of these people are reimbursed through the standard academic pay mechanism of the 
fellowship. No additional resources will be required. Equipment costs will be covered by the 
SERF grant. Any additional costs will be covered by the PEM Fellowship seed fund (if 
needed). 
 
VIII. 
Potential Risks and Alternatives 
There is a potential risk to patients of loss of confidentiality.  This risk is minimized utilizing 
the methods described above.  If the experimental nebulizer shows decreased efficacy 
compared to the control arm, subjects may experience less bronchodilation, and 
subsequently may require more subsequent doses of albuterol, or other adjunctive 
therapies.  There is no reason to believe that patients in the experimental group will 
experience greater discomfort than those patients in the control group. 
 
Data and safety Monitoring: 
This study involves 2 FDA approved nebulizers that have been used clinically for decades. 
The medication doses are similar to those used by children in the home setting. For these 

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reasons this study is considered very low risk and equivalent to the ED standard of care for 
non-study patients.  Despite this, a Data and Safety Monitoring Plan will be in place for 
ongoing evaluation of the safety of this study.   The DSMP will consist of the PI (Dr. 
Wilkinson) and the Co-I (Dr. Gardiner) reviewing any reported adverse events within 24 
hours of occurrence. Additionally, at the midpoint of the study (subject #107), there will be a 
scheduled interim analysis. During this analysis we will analyze group difference with 
regards to adverse event and admission rates. If, during either of these reviews, new 
information is discovered that would change the risk profile of the study, enrollment will be 
suspended and the IRB will be notified to help determine a course of action. 
 
 
IX. 
Potential Benefits 
The potential benefit of this trial is the possibility of a better understanding of the effect of 
breath-enhanced nebulizer technology on the treatment of acute asthma.  Additionally, if we 
are able to demonstrate significant benefit of this new technology, this may enhance the 
treatment of future pediatric patients with asthma, at home or in the emergency department.  
The potential benefit of this study to the individual study patient is largely unknown.  
Patients who are randomized to the experimental arm of the study may experience greater 
bronchodilation due to improved medication delivery; however, this benefit is likely minimal 
given that this study is evaluating only a single dose of albuterol. 
 
X. 
Sites or Agencies involved in the research project 
Research activities will be carried out exclusively at Dell Children’s Medical Center. 
 
XI. 
Review by another IRB 
Not applicable. 
 
XII. 
Citations 
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