Clinical trial NCT02363959
Conditions: Disorder Related to Lung Transplantation Central Airway Stenosis Airway Exudative Plaques Airway Complications Post-Lung Transplantation
Keywords: Hyperbaric Oxygen Lung Transplantation Central Airway Stenosis Airway Exudative Plaques Hyperbaric Oxygen Therapy Post-Lung Transplantation Airway Ischemia Endobronchial Biopsy Bronchoscopy
Sponsor: Duke University
Start date: 2015-02-01; Completion date: 2018-09-30
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the effect of hyperbaric oxygen therapy (HBOT) on airway complications in post-lung transplant recipients with evidence of restricted levels of blood and oxygen in the airway tissue. Study subjects with extensive airway tissue damage in the early post-transplant period will be randomized to HBOT or usual care and followed clinically for 12 months following randomization. The investigators hypothesize that HBOT will decrease the number of airway complications in the treated subjects.

Detailed description:
Hyperbaric oxygen therapy (HBOT) will be performed with the standard HBOT protocol used at Duke for the treatment of compromised grafts and flaps. This is 2 hours of breathing \>99% medical grade oxygen inside an air-pressurized chamber at atmospheric pressure of 2 once a day for 20 sessions. These sessions will be scheduled 3-5 times per week, depending on the availability of the patient and the hyperbaric medicine physician. The HBOT procedure used for this study will be identical to that used for clinical practice in the Duke University Health System Center for Hyperbaric Medicine and Environmental Physiology, including the oxygen that is used in the chamber. Patients will receive treatment through the regular clinical hyperbaric service. These are routine, not special, treatment sessions and they will receive them alongside other Duke University Medical Center patients being treated for other reasons. The medical grade oxygen used is a part of the Duke University Health System Center for Hyperbaric Medicine and Environmental Physiology hyperbaric chamber system.

While the patients randomized to receive usual care will not undergo HBOT, both study groups will receive standard serial bronchoscopies for airway clearance and for the collection of bronchoalveolar lavage fluid for culture data, due to the high rate of infection in lung transplant patients. All subjects will undergo the standard surveillance bronchoscopies every 3 to 4 weeks (x3) for clearance of the exudate from the airway, as well as monitoring progression of the airway abnormalities. As participants in this study, an, endobronchial biopsy of the airway epithelium will be performed at the main carina to collect a sample of recipient epithelium as well as at the first subcarina for each donor lung. Three samples will be collected from each of the biopsy sites. These samples are small (1 to 2 mm) and are thought to have a minimal clinical risk of minor bleeding associated with the procedure. Biopsy will add roughly 3 minutes total to each procedure.

Arms: arm 1: The hyperbaric oxygen therapy (HBOT) will be performed with the standard HBOT protocol used at Duke for the treatment of compromised grafts and flaps. This is 2 hours of breathing \>99% medical grade oxygen inside an air-pressurized chamber at atmospheric pressure of 2 (2 ATA) once a day for 20 sessions. These sessions will be scheduled 3-5 times per week, depending on the availability of the patient and the hyperbaric medicine physician.

During standard bronchoscopies, an endobronchial biopsy of the airway epithelium will be performed. Biopsy will add roughly 3 minutes total to each procedure. arm 2: No hyperbaric oxygen therapy administered, but lung biopsy still completed during standard post-lung transplant bronchoscopies. An endobronchial biopsy of the airway epithelium will be performed. Biopsy will add roughly 3 minutes total to each procedure.
Interventions: intervention 1: Hyperbaric Oxygen Therapy intervention 2: Endobronchial Biopsy of Airway Epithelium
Intervention descriptions: intervention 1: 2 hours of breathing \>99% medical grade oxygen inside an air-pressurized chamber at 2 ATA once a day for 20 sessions. These sessions will be scheduled 3-5 times per week, depending on the availability of the patient and the hyperbaric medicine physician. intervention 2: During standard post-transplantation bronchoscopies, participants in this study will undergo an endobronchial biopsy of the airway epithelium for each donor lung.

Protocol documents:
Prot_SAP_000.pdf: 
April 2015 
 
EFFECT OF HYPERBARIC OXYGEN THERAPY ON THE 
DEVELOPMENT OF AIRWAY STENOSIS IN PATIENTS WITH SEVERE 
AIRWAY EXUDATIVE PLAQUES EARLY AFTER LUNG 
TRANSPLANTATION 
Scott Shofer, Kamran Mahmood, Claude Piantadosi 
NCT02363959 
BACKGROUND: 
Central airway stenosis (CAS) is seen in 8-15% patients after lung transplantation.1,2 
Development of airway stenosis can cause decline in pulmonary function, increased respiratory 
symptoms, increased infections, and occasionally death3. The lungs are unique in containing dual 
circulatory supply from the pulmonary circulation which is reanastomosed during lung 
transplantation, and the bronchial circulation which is not. Perfusion of the large airways is 
thought to occur via retrograde flow from vascular plexus’ between the bronchial and pulmonary 
arterial circulation until new collateral circulation to the bronchial arterial system can develop in 
the weeks following transplantation3. Assessment of large airways perfusion has been 
surprisingly poorly studied, but development of airways ischemia post-transplantation is thought 
to be involved with development of CAS and other airway complications, opportunistic 
infections, particularly fungal infections, and possibly with chronic allograft rejection.1,4   
CAS is managed with balloon dilation followed by airway stent placement for recurrent 
stenosis.4-7  A limited number of  retrospective studies have shown that the treated airway 
complications do not affect survival.1,8  However, these airway complications  prolong 
mechanical ventilation, hospital and ICU length of stay, increase cost, and adversely affect 
quality of life3.  
Patients undergo frequent bronchoscopy in the weeks and months following lung transplantation. 
Many, if not most patients develop some element of necrotic desquamation of the epithelium 
locally referred to as “exudative plaques” or “pseudomembranes”in the large central airways two 
to four weeks after lung transplantation. There is a spectrum of involvement, but prior work 
would suggest that up to 50% of patients who develop the most severe manifestations of these 
plaques go on to develop some form of large airway complication, most commonly CAS9. Our 
local experience supports this observation. There is no established intervention available for 
these patients, however, because airway ischemia is thought to play an important role in this 
process, our group has treated a small group of patients with hyperbaric oxygen therapy (HBOT) 
with anecdotal improvement in the appearance of the airways as well as a perceived reduction in 
frequency and severity of anticipated airway complications in some patients.  


April 2015 
 
HBOT is defined as compression of the body with at least 1.4 atmospheres absolute pressure 
(ATA) of pure oxygen. It is believed to decrease inflammation, control infection, enhance 
perfusion and promote wound healing.10 It is used for treatment of chronic refractory wounds, 
including diabetic, small arterial and radiation-related wounds, as an adjunct to surgical 
reconstruction wounds, flaps or grafts, and chronic osteomyelitis.11-13 It has been shown to 
improve wound healing and decrease the need for limb amputations in diabetic patients. HBOT 
is not necessary or recommended for normal or uncompromised grafts or flaps, but where the 
graft or flap is compromised by hypoxia, ischemia or congestion, HBO2 has been shown to be 
extremely useful in graft salvage (14). Our preliminary experience with HBOT in lung transplant 
patients with severe pseudomembranes has been encouraging. We perceive that use of this 
technique has hastened resolution of the pseudomembranes, improved infectious complications 
and decreased the incidence of CAS.  Based on this preliminary experience we feel systematic 
examination of this approach is warranted. 
 
OBJECTIVES: 
The objective of this study is to evaluate the effect of HBOT on subsequent airway 
complications in lung transplant recipients with evidence of ischemic changes in the large airway 
epithelium. Study subjects with extensive desquamation (exudative plaques) of the large airway 
epithelium in the early post-transplant period will be randomized to HBOT or usual care and 
followed clinically for 12 months following randomization. We hypothesize that HBOT will 
decrease the number of airway complications in the treated subjects. 
 
SUBJECT ENROLLMENT 
Standard post-lung transplantation care includes a bronchoscopy with transbronchial lung biopsy 
at 1 month after surgery. We believe that it is in this early period, when the neovascularization of 
the large airways is thought to occur, that subjects are most likely to benefit from HBOT. 
Patients who are noted  to have extensive exudative plaques (grade 3 or 4) at their 1 month 
bronchoscopy will be referred for a standard follow-up bronchoscopy 2 to 3 weeks later. Should 
the patient show no sign of improvement in their airways, or worsening of the plaques they will 
be considered eligible for enrollment in the study.  
Exclusion Criteria 
Exclusion criteria include: use of mechanical ventilation with FiO2 greater than 40%, use of 
extracorporeal membrane oxygenation, use of inhaled nitric oxide, presence of pneumothorax, 
pregnancy, or inability to provide informed consent. In addition, subjects who are deemed to be 


April 2015 
 
too clinically unstable to be transported safely to the hyperbaric facility by their treating 
physicians will be excluded from enrollment.  
Randomization 
Once subjects are deemed eligible for enrollment, they will be questioned as to their interest in 
participating in the study by the treating physician. Those interested will be approached by the 
study coordinator for informed consent. Once informed consent is obtained, subjects will be 
randomized to usual care or HBOT by selection of a pre-prepared envelope containing the 
randomization assignment. We will target a total enrollment of 40 subjects with 1:1 enrollment 
to either HBOT or usual care. 
Subject Compensation 
Subjects will not be compensated for participation in the study. However, they will not be 
charged for hyperbaric treatment or the research biopsies. The airway and rejection surveillance 
bronchoscopies are part of current standard care in the Duke lung transplant program and are 
continued accordingly in the study. All participants will be recruited at DUHS. 
 
STUDY PROCEDURES 
Hyperbaric Therapy 
The HBOT will be performed with the standard HBOT protocol used at Duke for the treatment 
of compromised grafts and flaps. This is 2 hours of breathing >99% medical grade oxygen inside 
an air-pressurized chamber at 2 ATA once a day for 20 sessions. These sessions will be 
scheduled 3-5 times per week, depending on the availability of the patient and the hyperbaric 
medicine physician. The HBOT procedure used for this study will be identical to that used for 
clinical practice in the Duke University Health System Center for Hyperbaric Medicine and 
Environmental Physiology, including the oxygen that is used in the chamber. Patients will 
receive treatment through the regular clinical hyperbaric service. These are routine, not special, 
treatment sessions and they will receive them alongside other Duke University Medical Center 
patients being treated for other reasons. The medical grade oxygen used is a part of the Duke 
University Health System Center for Hyperbaric Medicine and Environmental Physiology 
hyperbaric chamber system.  
The patients sign the standard Duke informed consent for the administration of HBOT inside the 
chamber. The primary risks, which each occur in less than 10% of patients, are middle ear 
barotrauma from the changes in barometric pressure (resolves in a few days) and temporary near-
sightedness that may occur after 20 to 30 sessions, and resolves in 2-3 months, but which can 
rarely leave some persistent myopia that requires a change in eyeglass prescription. The other 


April 2015 
 
risks are very rare (<1%) and include oxygen-induced convulsions, and pneumothorax, and there 
is a very remote chance of mechanical or electrical failure in the chamber resulting in a fire.  
Airway Surveillance 
While the patients randomized to receive usual care will not undergo HBOT, both study groups 
will receive standard serial bronchoscopies for airway clearance and for the collection of 
bronchoalveolar lavage fluid for culture data, due to the high rate of infection in lung transplant 
patients. All subjects will undergo the standard surveillance bronchoscopies every 3 to 4 weeks 
(x3) for clearance of the exudate from the airway, as well as monitoring progression of the 
airway abnormalities. Additional bronchoscopies will be performed as clinically indicated. 
Following the completion of the airway surveillance, subjects will revert to the standard rejection 
surveillance schedule of bronchoscopy every 3 months for the first year post-transplant.  
At each surveillance bronchoscopy, subjects will have the standard bronchoalveolar lavage 
performed for detection of infectious agents. Due to the high evidence of airway infections in 
patients with severe exudative plaques, a lavage is performed during each bronchoscopy as a part 
of standard practice to collect microbiologic data. As participants in this study, an, endobronchial 
biopsy of the airway epithelium will be performed at the main carina to collect a sample of 
recipient epithelium as well as at the first subcarina for each donor lung. Three samples will be 
collected from each of the biopsy sites. These samples are small (1 to 2 mm) and are thought to 
have a minimal clinical risk of minor bleeding associated with the procedure. Biopsy will add 
roughly 3 minutes total to each procedure. These samples will be used for mRNA extraction to 
detect expression of genes associated with response to tissue hypoxia. 
Measurements and Data Collection 
Primary outcomes: Need for airway stent placement and rate of acute rejection in the 12 months 
of observation as determined by transbronchial lung biopsy. 
Secondary outcomes: Include development of airway stenosis, need for balloon bronchoplasty, 
development of clinically significant pulmonary infection as defined by initiation of 
antimicrobials to treat the suspected organism, development of airway dehiscence following 
enrollment in the study, development of bronchiolitis obliterans syndrome, and bronchial 
epithelial gene expression.  
Additional clinical data to be collected will include spirometric data, frequency of 
hospitalization, hospital days, ICU days, mechanical ventilation days, need for tracheostomy, and 
survival.  
 
 


April 2015 
 
TREATMENT ARM CROSSOVER 
Should patients enrolled in the usual care arm develop airway complications such as airway 
stenosis, dehiscence, or airway malacia, or if the patient fails to improve their exudative plaque 
score over the period of observation, they may be offered hyperbaric therapy with continued 
collection of clinical data. Subjects will be eligible for crossover therapy between 8 and 12 
weeks after the initial study bronchoscopy. 
There are two criteria for a patient to qualify for HBOT crossover treatment. The first criterion is 
the development of an airway complication, most likely airway stenosis requiring intervention. 
This is clinically defined by our group as an airway that is no longer traversable with a 
therapeutic (6.4mm OD) bronchoscope. Other complications are airway dehiscence or malacia 
(excessive loss of structural integrity). The second criterion is failure of the airway exudate to 
improve in score severity during the 8 week observation period. This is measured using the 
scoring system outlined in Table 1. 
 
RISK/BENEFIT ASSESSMENT 
It is currently unknown if treatment of patients with severe exudative plaques in the early post-
lung tranplant period with HBOT will prevent development of large airway complications. Our 
limited anecdotal experience suggests it may improve outcomes. The risks of the procedure are 
small and detailed above. The potential benefits are significant since airway stenosis can lead to 
worse allograft function, increased infections, and occasionally death. Subjects randomized to 
usual care will be at usual risk of airway complications. Given the clinical equipoise regarding 
HBOT treatment in lung transplant, we feel this is an ethical treatment decision for this patient 
population.    
 
COST TO THE SUBJECT 
There will be no additional costs to the subject over usual care. The hyperbaric treatment will be 
provided at no charge to the subjects. 
 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
Data analysis will be performed by the primary investigators. Categorical data will be analyzed 
using Fisher’s exact test given the small sample size, while continuous data will be assessed for 
statistical significance with Student’s t-test. Our prior work with airway stenosis in lung 
transplant recipients documented a 15% rate of stenosis in all transplant patients. Our clinical 
experience suggests a rate 2 to 4-fold higher in patients with severe ischemic desquamation of 


April 2015 
 
the large airways. Experience with HBOT in this population is limited, but rates of significant 
airway stenosis may be as low as 10% after therapy. Sample size calculations using a 60% 
stenosis rate in the usual care group, a 10% stenosis rate in the HBOT group with a p-value of 
0.05 suggest that a sample of 14 subjects/group will have an 80% power to detect statistical 
significance. We will target a total of 40 subjects to allow for subject withdrawal and loss due to 
the development of critical illness in this tenuous population. Intention to treat analysis will be 
used for all patients based on initial randomization, with subgroup analysis for the crossover 
patients for airway stent placement. All biologic samples will be collected by week 6, prior to 
any patient crossover events. 
 
DATA and SAFETY MONITORING 
Data will be stored on a secured Access database located on the PIN station “U” drive in an 
secured folder. All subject entries will be de-identified using a study assigned identification 
number. The key to the study identifiers will be kept in a locked file cabinet in the study 
coordinators office. Database use will be limited to the primary investigators, co-investigators, 
and the study coordinator.  
Primary risks are related to bronchoscopy with minimal risk of bleeding related to the 
endobronchial lung biopsy, and some discomfort from the bronchoscopy itself which is part of 
usual post-transplant care. Additional risks of hyperbaric treatment are detailed above and very 
rare.  Any adverse events that occur during the study will be immediately reported to the IRB.  
Table 1. Pseudomembrane Scoring System 
Stage 
Definition 
Stage 0 
No exudate 
Stage 1 
Limited to anastomosis 
Stage 2 
Anastomosis to upper lobe orifice, including 
medial bronchus intermedius 
Stage 3 
Involvement of the lower lobe orifice  
Stage 4 
Covers all visible airways 
 
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Shofer SL, Wahidi MM, Davis WA, et al. Significance of and risk factors for the development of 
central airway stenosis after lung transplantation. Am J Transplant 2013;13:383-9. 
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Thistlethwaite PA, Yung G, Kemp A, et al. Airway stenoses after lung transplantation: incidence, 
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4. 
Dutau H, Cavailles A, Sakr L, et al. A retrospective study of silicone stent placement for 
management of anastomotic airway complications in lung transplant recipients: short- and long-term 
outcomes. J Heart Lung Transplant 2010;29:658-64. 


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Nunley D, Gal A, Vega D, perlino C, Smith P, Lawrence E. Saprophytic fungal infections and 
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Faglia E, Favales F, Aldeghi A, et al. Adjunctive systemic hyperbaric oxygen therapy in 
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Saber AA, Yahya KZ, Rao A, et al. A new approach in the management of chronic nonhealing 
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Maynor ML, Moon RE, Camporesi EM, et al. Chronic osteomyelitis of the tibia: treatment with 
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