Prophylactic Topical Epinephrine to Reduce Transbronchial Lung Biopsy-related Hemorrhage in Lung Transplant Recipients: a Prospective Double-blind Placebo-controlled Trial (PROPHylactic Epinephrine in Transbronchial Biopsy [PROPHET] Trial)
Phase: PHASE2
Conditions: Lung Transplant; Complications, Mechanical, Lung Transplant; Complications, Bleeding, Hemoptysis
Sponsor: University of Maryland, Baltimore

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SHORT TITLE: Prophylactic epinephrine and bleeding risk in transbronchial lung biopsies 
 
IDENTIFYING WORDS: Lung transplantation; Fiberoptic bronchoscopy; Transbronchial lung 
biopsy; Topical epinephrine 
 
PRINCIPAL INVESTIGATOR:  
Robert M. Reed MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of 
Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA 
 
ASSOCIATE INVESTIGATORS:   
Nirav G. Shah MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of 
Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA 
 
Edward M. Pickering MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department 
of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA 
 
Aldo Iacono MD, Departments of Medicine and Surgery, R Adams Cowley Shock Trauma Center, 
University of Maryland School of Medicine, Baltimore, Maryland, USA 
 
Ashutosh Sachdeva MBBS, Division of Pulmonary, Critical Care, and Sleep Medicine, Department 
of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA 
 
Bich-Chieu Tran MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of 
Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA 
 
Mark Sperry MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of 
Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA 
 
CLINICAL RESEARCH PROTOCOL
UNIVERSITY OF MARYLAND MEDICAL CENTER, DEPARTMENT OF MEDICINE, DIVISION OF PULMONARY
AND CRITICAL CARE MEDICINE
DATE: 8/23/2024
CLINICAL PROTOCOL NO.: HP-00070208
ClinicalTrials.gov ID:  NCT03126968
TITLE:
Prophylactic topical epinephrine to reduce transbronchial lung biopsy-related 
hemorrhage in lung transplant recipients: a prospective double-blind placebo-controlled trial
(PROPHylactic Epinephrine in Transbronchial biopsy [PROPHET] Trial)

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Or Kalchiem-Dekel MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of 
Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA 
 
William B. Karkowsky MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department 
of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA 
 
Bethany Weiler-Lisowsky MD, Division of Pulmonary, Critical Care, and Sleep Medicine, 
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA 
 
Jennifer Dorsch MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of 
Medicine, University of Maryland School of Medicine, Baltimore, MD, USA 
 
Danielle R. Glick, MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of 
Medicine, University of Maryland School of Medicine, Baltimore, MD, USA 
 
 
 
STUDY RESEARCH CONTACT PERSON 
Robert M. Reed M.D., Division of Pulmonary and Critical Care Medicine, Department of Medicine, 
University of Maryland Medical Center, Baltimore, Maryland, USA 
 
ESTIMATED DURATION OF STUDY: 24 months 
 
TYPE OF PATIENTS: Post-single or double lung transplantation 
 
SUBJECTS OF STUDY:     
Number of participants to be screened: 200  
Number of participants to be enrolled: 100 
Sex:  Male & Female  
 
Age Range: 18 years and above 
 
PROJECT USES IONIZING RADIATION:  Yes, for medically indicated reasons only 
 
PROJECT USES "DURABLE POWER OF ATTORNEY":  No 
 
OFF-SITE PROJECT: No        
 
MULTI-INSTITUTIONAL PROJECT:  No 
 
ClinicalTrials.gov ID:  NCT03126968 
 
 

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Table of Contents 
INTRODUCTION ............................................................................................................................................. 4 
Transbronchial Lung Biopsy ............................................................................................................4 
General Considerations ..................................................................................................................4 
Technique ......................................................................................................................................4 
Hemorrhagic Complications ...........................................................................................................5 
The Role of Transbronchial Lung Biopsies in Lung Transplant Recipients ..........................................7 
Topical Epinephrine for Bleeding Prophylaxis ..................................................................................8 
Potential Adverse effects of Endotracheally- and Endobronchially-Administered Topical Epinephrine
......................................................................................................................................................9 
Study implications ....................................................................................................................................... 10 
Hypothesis ................................................................................................................................................... 11 
Specific aims ................................................................................................................................................ 11 
study Protocol ............................................................................................................................................. 12 
Overview ..................................................................................................................................... 12 
Eligibility Criteria.......................................................................................................................... 12 
Inclusion Criteria .......................................................................................................................... 12 
Exclusion Criteria ......................................................................................................................... 13 
Recruitment Strategy ................................................................................................................... 14 
Patient Evaluation ........................................................................................................................ 15 
Process of Obtaining Informed Consent ........................................................................................ 15 
Initial Evaluation .......................................................................................................................... 16 
Monitoring Subjects and Criteria for Withdrawal of Subjects from the Study ................................. 16 
Study Drug and Placebo Preparation, Packaging, and Randomized Assignment ............................. 16 
Study Group Randomized Assignment .......................................................................................... 17 
Procedure Performance ............................................................................................................... 18 
Outcome Measures ...................................................................................................................... 19 
Primary Efficacy Outcome ............................................................................................................ 19 
Secondary Efficacy Outcomes ....................................................................................................... 20 
Safety Outcomes .......................................................................................................................... 21 
Immediate Post-Procedure Surveillance ....................................................................................... 22 
Long-Term Post-Procedure Surveillance ........................................................................................ 22 
Study Flow (Outpatients) ............................................................................................................. 22 
Study Confidentiality and Privacy ................................................................................................. 24 
Data Documentation .................................................................................................................... 24 
Data Analysis ............................................................................................................................... 25 
Potential Benefits ........................................................................................................................ 26 
Potential Risks and Discomforts ................................................................................................... 26 
Adverse Events Reporting to the IRB ............................................................................................ 27 
Data Monitoring .......................................................................................................................... 27 
References ................................................................................................................................................... 29 
 
 

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INTRODUCTION 
 
Transbronchial Lung Biopsy  
General Considerations 
Transbronchial Lung Biopsy (TBLB) is one of the most important applications of flexible 
bronchoscopy. The procedure, initially introduced by Andersen in 1965 for use via a rigid 
bronchoscope (1), became more widely performed after it was adapted for use with the flexible 
bronchoscope in the early 1970s (2) for the evaluation of localized as well as diffuse pulmonary 
disease. Today, TBLB is regularly performed by 69% of practicing physicians documented in a 
survey of 1,700 North American pulmonary and critical care physicians (3). This indispensable 
procedure, which may be performed under fluoroscopic guidance, constitutes a diagnostic 
alternative to percutaneous transthoracic needle biopsy, thoracoscopy with forceps lung biopsy, 
and thoracotomy with open lung biopsy. Apart from mastering the technique, the bronchoscopist 
must have a thorough understanding of indications, limitations, and immediate complications of 
the TBLB. When properly performed, several studies have established the safety of TBLB in an 
outpatient setting under moderate sedation (4,5).  
Biopsy forceps commonly used for TBLB via the flexible bronchoscope are generally of the order 
of 3 mm or smaller in any given dimension. Because of this restriction in size, tissue samples 
obtained via the transbronchial approach are generally 2–3 mm in any dimension. Despite the 
small size, TBLB provides information regarding pathology that is located beyond the 
cartilaginous airways that may include elements of the small airways of the distal bronchial tree, 
the alveolar space, the vasculature, and lymphatic structures immediately surrounding the alveoli 
(6). Pulmonary diseases that require examination of larger pieces of lung tissue to assess 
heterogeneity or homogeneity of different regions of the involved lung, such as many of the 
idiopathic interstitial lung diseases, are generally not amenable to diagnosis by TBLB and 
consideration of video-assisted thoracoscopic lung biopsy ,which has been shown to have a 
greater diagnostic yield (7,8), should be pursued. With these limitations in mind, TBLB is useful 
for the diagnosis of a variety of infectious, interstitial, and malignant pulmonary diseases, 
including pulmonary infiltrates in the immunocompromised host (9,10), sarcoidosis (11,12), 
eosinophilic lung disease (13,14), drug-induced pneumonitis (15), pulmonary alveolar proteinosis 
(16), lung cancer (17), pulmonary lymphangitic carcinomatosis (18,19), and acute allograft 
rejection in lung transplant recipients (20,21). Absolute contraindications for TBLB include 
inability to obtain informed consent, severe or refractory hypoxemia, uncontrolled 
bronchospasm, and unstable cardiovascular condition, including active ischemia and 
uncontrolled arrhythmia. Relative contraindications include uncorrected coagulopathy, platelet 
count of less than 50 K/μL, severe pulmonary hypertension, uncooperative patient, inability to 
control cough, and lack of resuscitation facilities (22,23).  
 
Technique 
A thorough airway examination usually precedes the TBLB because bleeding after lung biopsy 
may preclude its performance. Adequate control of cough with topical application of lidocaine 

5 
 
and systemic administration of opiates is recommended for optimal biopsy procedure and to 
reduce the risk of pneumothorax (24). 
The choice of biopsy site depends on radiological and fluoroscopic findings. Generally, TBLB is 
not attempted from both lungs during the same bronchoscopic procedure on the same date due 
to risk of bilateral pneumothorax. For selection of the site for the TBLB in the case of diffuse lung 
disease, some providers prefer to perform the biopsy from the dependent parts of the lungs; 
right and left lower lobes (23). In an event of bleeding, the blood is more likely to remain 
contained in this area before spilling into the adjacent lobes (25). The procedure can be 
performed “blindly” or under fluoroscopic guidance when available.  
There is limited information on the optimal number of transbronchial biopsies in various lung 
disease. In general, four to six biopsy specimens are adequate in a majority of patients with 
diffuse lung disease (26). For acute graft rejection surveillance in lung and lung-heart transplant 
recipients, most transplant centers will obtain at least 5 and up to 10 biopsies per procedure 
(20,27). 
 
Hemorrhagic Complications 
TBLB is generally safe, although severe and life threatening procedure-related complications are 
occasionally encountered, most common among them are pneumothorax and procedure-related 
hemorrhage. Significant bleeding related to TBLB has been traditionally attributed to laceration 
of a bronchial artery (28). Established risk factors for clinically significant bleeding following TBLB 
include bleeding diathesis including thrombocytopenia (29), use of antiplatelet and anticoagulant 
medications (30,31), pulmonary hypertension (32), advanced renal failure (33), and immune 
compromised state (34). The propensity to bleed following TBLB was also shown to be related to 
the type of forceps used with some evidence suggesting that bleeding complications are less 
common with alligator forceps as opposed to cup forceps (35,36). According to a recent 
retrospective population-based study from the USA incorporating data from almost 100,000 
patient visits involving TBLB, the overall rate for procedure-related clinically significant 
hemorrhage was 0.58% (37). Another survey from Japan reviewing over 100,000 procedures, 
among them 57,199 forceps biopsies, recorded a bleeding rate of 0.73% (38). Death related to 
airway bleeding in association with bronchoscopic procedures is exceedingly rare (39,40). 
Quantification of TBLB-related bleeding is difficult, subjective, and prone to observer bias. 
Although not formally adopted, several grading systems have been suggested for the purpose of 
quantification of procedure-related hemorrhage. Most published studies use grading systems 
that rely on the amount of mixed blood and bronchial wash fluid in the vacuum suction system 
at the end of the procedure (5,38,41,42). This method may be prone to measurement errors in 
estimation of the actual extent of blood loss during the procedure due to dilution of blood with 
other airway secretions as well as fluid administered via the bronchoscope working channel such 
as saline. A recently published study exploring the safety of percutaneous bronchoscopy-guided 
tracheostomy in thoracic transplantation patients suggested a grading system that classifies 
endobronchial hemorrhage as mild, moderate, or severe based on the most proximal bronchus 
in the bronchial tree obstructed by the bleeding (43). Among the other grading scales described 
in the literature thus far, the one suggested by Herth et al. (44) may have to most clinical 
relevance. This scale grades airway bleeding according to the action implemented by the 

6 
 
operator in order to achieve hemostasis. Despite being the only scale to be implemented in a 
subsequent study (45), it seems that a bias may be introduced into this system by the fact that 
different operators may have different thresholds for implementation of various interventions in 
order to control hemorrhage. Indeed, there is lack of agreement in currently available literature 
as to the best approach to achieve control over the bleeding lung. In general, one school of 
thought supports the wedging technique, first described by Zavala in 1975 (46), where the 
bronchoscope is wedged into the bleeding bronchus in effort to allow enough time for a clot to 
form and at the same time prevent spillage of blood into the rest of the bronchial tree (23). The 
other main school of thought argues for a “back and forth” or “in and out” maneuver that 
includes positioning of the bronchoscope proximal to the bleeding bronchus and suctioning of 
blood as it emerges from the airway in order to avoid coagulation in the airway, which can block 
the suctioning channel and also obscure vision (47).  
As mentioned above, the main danger of TBLB-related bleeding is aspiration of the blood into the 
non-involved bronchial tree rather than exsanguination. Therefore, priority should be given to 
prevention of flooding of the airways with blood. Fortunately, most cases of major airway 
bleeding following TBLB can be managed in the bronchoscopy suite. Apart from positioning the 
bronchoscope in the airway as mentioned above, other measures to achieve hemostasis. These 
include placing the patient in a lateral decubitus position with the bleeding lung in the dependent 
position and application of topical application of 4°C saline (48) and/or vasopressors such as 
cocaine or diluted epinephrine (49,50). The dosing of topical epinephrine for the treatment of 
airway bleeding lacks standardization in terms of dilution and volume of instillation and is based 
mainly on individual operator experience and institutional protocols. Review of the literature 
reveals epinephrine dilution recommendations range from 1:10,000 to 1:100,000 and the volume 
of instillation ranges of 0.5 and up to 20 mL (22,50–52). The British Thoracic Society guidelines 
on diagnostic flexible bronchoscopy suggest small aliquots of 1:10,000 diluted epinephrine (49). 
Topical administration of tranexamic acid as a measure of achieving hemostasis was also 
previously described in case series (53,54). Bleeding refractory to conservative therapies may 
require balloon tamponade with application of an embolectomy balloon catheter via the 
bronchoscope’s working channel (23,49). Inability to control bleeding with those interventions 
should prompt securing the airway with endotracheal intubation. Additionally, selective 
intubation of the non-bleeding lung and application of an endobronchial blocker may be 
considered along with advanced interventions such as selective bronchial artery embolization 
(55,56).  
Local practices in University of Maryland Medical Center (UMMC) for the initial treatment of 
endobronchial bleeding in the bronchoscopy suite includes administration of iced saline in 
aliquots of 5-10 mL followed by 1-2 mL aliquots of 1:10,000 topical epinephrine (0.1-0.2 mg) to a 
maximum of 6 mL (0.6 mg). Additional suggested measures include positioning the patient with 
the bleeding lung in the dependent position and balloon tamponade of the bleeding airway with 
application of a 2-4 FR embolectomy balloon catheter (Edwards Lifesciences®) via the 
bronchoscope’s working channel before attempting more advanced methods to allow 
hemostasis. 
 

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The Role of Transbronchial Lung Biopsies in Lung Transplant Recipients 
Fiberoptic bronchoscopy with multiple TBLB has become the “gold standard” diagnostic modality 
for the assessment of lung allograft function and specifically acute cellular rejection (ACR) 
following lung transplantation. Most lung transplant programs now perform TBLB for graft 
function surveillance, new onset symptoms, ≥10% decrease in FEV1, assessment of a new lung 
infiltrate on chest imaging, or as a follow-up for acute rejection or CMV pneumonitis (57). Acute 
rejection is an established risk factor for the development of bronchiolitis obliterans syndrome 
(BOS), and therefore it has been proposed that early detection and treatment is of paramount 
importance (58). The relatively high incidence of silent rejection or infection in asymptomatic 
patients has lent support for routine surveillance protocols (59,60). Surveillance protocols vary 
widely between transplantation centers since there is little data to guide the frequency of 
surveillance biopsies. The ACR surveillance protocol in UMMC includes routine bronchoscopy 
with TBLB at one-month post-transplant and then every three months for one year. Additional 
bronchoscopies with TBLB are performed based on surveillance TBLB findings, symptoms, or 
results of pulmonary function tests (PFT) (61). As in the general population, the most common 
complications of TBLB in lung transplant recipients are bleeding and pneumothorax. Generally, 
there is evidence that shows a higher propensity for procedure-related bleeding in the post lung 
and heart-lung transplant population. Once again, the recorded rate of clinically significant lung 
hemorrhage is highly dependent of the system adopted for grading of the amount of bleeding. 
In an early study by Chan et al., bronchoscopy data from 83 lung transplant recipients was 
reviewed retrospectively. The rate of clinically significant procedure-related bleeding, defined 
arbitrarily as >50 mL blood loss was 1.9% (62). Scott et al. prospectively evaluated the yield and 
complications of TBLB in 219 procedures on combined heart-lung transplant patients. Blood was 
recovered by suctioning in approximately 44% of procedures, while the rate of >100 mL 
procedure related bleeding was recorded at 12.3% (20). Bjørtuft et al. studied the rate of TBLB-
related bleeding in 104 procedures in 51 patients, 29 of whom were post lung or heart-lung 
transplantation. The rate of clinically significant bleeding, arbitrarily defined is more than 20 mL, 
was 7.7%. No difference in the rate or volume of clinically significant bleeding was observed 
between transplant and non-transplant patients. Interestingly, screening platelet count and 
coagulation tests did not predict bleeding risk in this study (63). A prospective cohort study 
performed at the Johns Hopkins Medical Institutions between 1996 and 1997 evaluated bleeding 
complications among 38 bronchoscopies in 15 lung transplant recipients and compared them to 
659 bronchoscopies in 423 non-transplant patients. In this cohort, lung transplant recipients 
were shown to bleed significantly more, report post-procedure hemoptysis, and have their 
procedure terminated prematurely due to bleeding in comparison to the non-transplant patients. 
Bronchoscopy procedures, including those where TBLB was performed, were significantly longer 
in transplant recipients. In a logistic regression analysis, worse hemoptysis was associated with 
lung transplant status, older age, and longer procedure time. As in prior studies, bleeding risk 
was independent of platelet count, coagulation studies, use of aspirin, and use of 
immunosuppressive medications (64). The relation between risk of bleeding and procedure time 
might reflect a technically challenging procedure or in some cases prolongation of the procedure 
by attempt to control bleeding. Other possible explanations for the increased propensity to bleed 
among lung transplant recipients include an already inflamed lung tissue from infection, ACR, or 
BOS or an increase in blood flow to the transplanted lung, particularly in recipients of single lung 

8 
 
transplants. Evidence from transplantation centers outside the USA correlates with USA reported 
numbers. For example, a study in performed in a single institution in Japan recorded a bleeding 
rate of 11% among 206 procedures on 28 lung transplant recipients (65). Additional relevant 
studies include McWilliams, 2008 (includes additional citations: 1-5) and Smith, 2012. 
 
Topical Epinephrine for Bleeding Prophylaxis 
Epinephrine, also known as adrenalin or adrenaline, is a non-selective agonist of all adrenergic 
receptors, including the major subtypes α1, α2, β1, β2, and β3. β-Adrenergic effects are more 
pronounced at low doses and α1-adrenergic effects at higher doses. The rationale for the use of 
epinephrine for prevention, minimization, and control of superficial bleeding is derived from its 
vasoconstrictive effect on arterioles and capillaries, mediated via activation of α1 receptors on 
blood vessel smooth muscle (66). 
Although adopted by some providers as means to reduced TBLB-related hemorrhage, the use of 
prophylactic instillation of diluted epinephrine into the target bronchus before attempting TBLB 
as means to reduce to occurrence of biopsy-associated bleeding is not established in the medical 
literature. Limited evidence from case series performed in a single institution suggest a beneficial 
effect of prophylactic injection of tranexamic acid into bleeding-prone endobronchial lesions 
such as tumors before attempting endobronchial biopsies (67,68).  
The main body of evidence regarding the efficacy and safety of prophylactic topical epinephrine 
for the prevention of superficial hemorrhage is derived from the surgical literature, specifically 
endoscopic endonasal and sinus surgery, rhinoplasty, and surgical management of burn injuries. 
During functional endoscopic sinus surgery (FESS) and rhinoplasy, common practice involves 
administration of topical vasoconstrictor in the form of 1:1,000 epinephrine-soaked neuropatties 
as well as intranasal injection of a mixed solution of local anesthetic and 1:100,000 epinephrine 
(69). A recent randomized controlled trial comparing cocaine- and epinephrine-soaked 
neuropatties in 37 patients found no significant difference in blood loss with cocaine as compared 
to epinephrine. In this study, no adverse effects associated with cocaine or epinephrine were 
documented (70). A non-randomized trial comparing cocaine with epinephrine in 65 patients 
undergoing rhinoplasty showed similar results (71). The reported rate of cardiovascular 
complications associated with topical epinephrine in this patient population is 0.1% or less 
(72,73) with no deaths reported. In a series of 1,998 patients undergoing endoscopic sinus 
surgery in which 1:1000 diluted topical epinephrine was used for hemostatic purposes, Orlandi 
et al. reported two complications likely associated with the use of topical epinephrine (<0.1%). 
Once case involved ECG changes and the other case involved intraoperative hypertension due to 
inadvertent submucosal injection of the epinephrine solution (73). In a more recent prospective 
series of 19 patients undergoing the same surgery using epinephrine at the same dilution of 
1:1000, there were no documented cases of altered hemodynamics related to topical application 
of epinephrine (74). A study in 10 burn patients undergoing burn wound excision using 1:10000 
diluted epinephrine-soaked gauze wrappings, did not show a significant increase in 
intraoperative serum concentration of epinephrine to indicate systemic absorption (75). 
Nonetheless, a different study in burn patients has demonstrated that tachycardia was more 
common in burn patients undergoing surgery where 1:10,000 epinephrine-soaked gauzes were 
used (76). This finding can be related to the relatively large interface between the applied 

9 
 
epinephrine and inflamed and injured vasculature in the surgical field of burn patients. One study 
reported benefit and a favorable side-effect profile of 1:10,000 epinephrine-soaked gauzes 
applied prophylactically  for hemostasis during laparoscopic cholecystectomy (77). 
 
Potential Adverse effects of Endotracheally- and Endobronchially-Administered Topical 
Epinephrine 
Data concerning the systemic effects of endobronchially administered epinephrine are limited. 
Adverse hemodynamic effects of topical epinephrine are attributed to systemic absorption of 
epinephrine from the airways into the pulmonary and bronchial circulatory systems. Two 
pharmacokinetic studies in a canine model explored blood concentrations of epinephrine after 
administration through the airways. Roberts et al. compared blood concentrations and 
hemodynamic effect of intravenous (IV) versus endotracheal (ET) instillation of epinephrine 
administered in doses of 0.005, 0.03, 0.06, and 0.09 mg/kg diluted in 5 mL of normal saline. The 
authors reported that following ET installation, maximum blood concentrations of epinephrine 
were approximately one-tenth of those achieved with an equal dose administered IV. 
Interestingly, while IV administered epinephrine was rapidly metabolized and cleared, ET 
administration was characterized by a more sustained blood concentration. The same 
relationship between IV and ET administration was observed when comparing pharmacological 
effects with the ET route requiring ten times the IV dose in order to result in a significant increase 
in blood pressure (78). Mazkereth et al. demonstrated significant measurable systemic levels 
when epinephrine in a dose of 0.02 mg/kg diluted in 2 mL of saline was administered into the 
airways using a catheter. More than a 4-fold increase in systemic levels was achieved when 
epinephrine was installed into the distal airways via a catheter as compared with when it was 
administered into the trachea (maximal concentration 8.9±3.2 vs. 2.0±0.4 ng/mL). However, 
neither group demonstrated any significant change in the heart rate, and both had similar, minor 
decreases in blood pressure for 2 to 5 minutes with no significant differences in arterial blood 
gases (79). It is noteworthy that the dose range of epinephrine utilized in the aforementioned 
studies exceeds the dose used for achievement of hemostasis in TBLB-related hemorrhage by a 
factor of 4 to 10. 
The potential of endobronchially administered epinephrine to result in adverse hemodynamic 
effects is well-recognized and dosing recommendations have been made since the 1970s (80). 
Nevertheless, evidence of such adverse effects are scarce and the currently available data are 
mostly derived from cases where epinephrine was administered following iatrogenic bleeding, 
potentially resulting in direct contact of the administered epinephrine with injured blood vessels 
and hence introduction of epinephrine into the systemic circulation. Janjua et al. reported a case 
of coronary vasospasm manifesting as chest pain, ST-segment elevation, and ectopy induced by 
topical administration of 3 mL of 1:10,000 diluted epinephrine during bronchoscopy. It is 
noteworthy that epinephrine was administered into inflamed and friable airways of a lung cancer 
patient for the treatment of bleeding related to endobronchial brushing, potentially augmenting 
the surface area of contact between epinephrine and injured blood vessels. Left heart 
catheterization in this patient revealed mild coronary atherosclerosis and he was discharged 5 
days later following an uneventful hospital course (81). A recent report of two cases implicating 
bronchoscopic administration of epinephrine for TBLB-associated bleeding as the trigger for 

10 
 
ventricular fibrillation has generated discussion regarding the safety of this technique (82–84). It 
is worth noting that these episodes of arrhythmias occurred with bronchoscopic instillation of 
epinephrine by a catheter which was positioned in close proximity to a bleeding vessel as well as 
the thin alveolar-capillary interface which allows more systemic absorption than the more 
proximal airways. It seems that the volume of diluents used has as much of a significant role on 
determining the magnitude of systemic absorption of epinephrine as the absolute dose 
administered. In one interesting canine study, 1 mg of epinephrine diluted in 10 mL of normal 
saline administered endotracheally, resulted in higher mean plasma epinephrine concentrations 
when compared with the same dose administered in 1 mL of saline (85). These results lend 
support to the theory maintaining that a more distal delivery of epinephrine results in more 
systemic absorption with a larger volume of instillation likely resulting in carriage of more 
epinephrine into the pulmonary absorption areas. Unfortunately, there is no study comparing 
different concentrations and/or volumes of installation for bronchoscopic administration of 
epinephrine for hemostatic control following TBLB, let alone prophylactic use of topical 
epinephrine for bleeding prevention or minimization. It is possible that bronchoscopically 
delivered epinephrine after the onset of bleeding would not reach the source of bleeding due to 
dilutional effect and therefore would be of limited or no benefit. However, as pulmonary 
organogenesis occurs by branching morphogenesis, proximal administration may vasoconstrict 
the vessels feeding the injured vasculature, thus decreasing flow and promoting hemostasis. 
 
STUDY IMPLICATIONS 
The role of prophylactic topical epinephrine in improving hemostasis and prevention of clinically-
significant pulmonary hemorrhage has never been studied formally in the past, despite its 
common use by pulmonologists performing bronchoscopic TBLB. Lung transplant recipients 
undergo multiple bronchoscopies and TBLBs for surveillance and evaluation of ACR as well as 
lung infection, especially during the first year post-transplantation. This population may have a 
predilection to TBLB-related bleeding and may benefit from measures to reduce the frequency 
and magnitude of this relatively common complication. 
 
In the PROPHET trial, we intend to assess the degree of biopsy-related bleeding, measures taken 
to control bleeding, and potential effects of bleeding on completion of the intended procedure 
in 100 bronchoscopy procedures performed on single and double lung transplant recipients, 
randomized to prophylactic topical epinephrine versus placebo (normal saline). The study 
participant, physician performing the TBLB, and independent observer reviewing the procedure 
recording will all be blinded to the randomization. Further use of measures to control bleeding 
that occurs during the procedure as well as the decision to complete the procedure as planned 
or to abort it prematurely will be left to the discretion of the performer. In this way, we aim to 
elucidate a potential role of topical epinephrine in the prevention of TBLB-related airway 
bleeding in lung transplant recipients and assess whether the dose and volume of instillation 
used in our institution comprises an effective means to prevent hemorrhagic complications of 
TBLB. 

11 
 
 
HYPOTHESIS 
We hypothesize that prophylactic instillation of topical epinephrine prior to performance of TBLB 
will decrease the frequency and extent of biopsy-related hemorrhage as well as result in fewer 
procedures being aborted earlier than intended due to bleeding complications as well as shorter 
overall procedure time due to the preventive effect on bleeding. Concomitantly, we hypothesize 
that the instillation of topical epinephrine will not be associated with a serious adverse event 
profile in comparison to placebo. 
 
SPECIFIC AIMS 
 
In this randomized-controlled double blind placebo controlled clinical trial post-lung transplant 
patients scheduled to receive bronchoscopy with TBLB as part of their routine standard of care 
will be randomized to receive a fixed dose and volume of topical endobronchial epinephrine 
versus matching volume of placebo which will be instilled into the target biopsy airway prior to 
performance of TBLB. Our study will specifically aim at providing the following information: 
 
Aim 1: Demonstrate the feasibility of assessments of bleeding related to TBLB, including: 
1. The degree of TBLB-related bleeding using a standardized grading scale used by the 
physician performing the procedure to quantify the degree of procedure-related 
bleeding. 
2. The degree of TBLB-related bleeding using a standardized grading scale used by two 
independent observers blinded to patient data and study drug assignment who will 
review a video recording of the procedure to quantify the degree of procedure-related 
bleeding. 
3. The magnitude of inter-observer variability in grading TBLB-related hemorrhage 
based on review of video recording of the procedure.  
 
Aim 2: Evaluate the hypothesis that prophylactic administration of topical epinephrine results in 
reductions in TBLB-related hemorrhage in lung transplant recipients, including: 
1. The frequency of active measures taken to control pulmonary hemorrhage once it 
occurred.  
2. The proportion of procedures completed as planned in terms of obtaining a 
predefined target number of biopsy specimens. 
3. Comparison between single- and double-lung transplant recipients in terms of 
prevalence and degree of TBLB-related hemorrhage. 
4. Identification of clinical factors associated with an increased or decreased risk of 
procedure-related hemorrhage. 
 
Aim 3: Evaluate the hypothesis that prophylactic administration of topical epinephrine affects 
the overall efficiency of bronchoscopy with TBLB performance, including:  
1. Overall duration of the bronchoscopic procedure. 

12 
 
2. The proportion of procedures completed as planned in terms of number of adequate 
biopsies obtained as assessed by the physician performing the bronchoscopy. 
3. The proportion of procedures resulting in acquisition of adequate biopsy samples that 
allows proper pathologic evaluation of assignment of a pathologic diagnosis. 
 
Aim 4: Explore the hypothesis that instillation of our prespecified dose and volume of topical 
epinephrine into the target biopsy airway is not associated with an adverse event profile that is 
significantly different from placebo, including: 
1. The prevalence of clinically significant hemodynamic changes. 
2. The prevalence of cardiac adverse events, including conduction abnormalities, 
arrhythmia, and myocardial ischemia. 
3. The prevalence of other vascular adverse events, including stroke, mesenteric 
ischemia, and critical limb ischemia. 
4. Identification of clinical factors associated with an increased or decreased risk of drug-
related adverse events. 
 
 
STUDY PROTOCOL  
Overview 
The PROPHET trial is a prospective randomized double-blind placebo-controlled pilot study. 
During the study period, we intend to recruit post single or double lung transplantation patients 
expected to undergo bronchoscopy with TBLB as a part of their routine post-transplantation care. 
Study participants who meet inclusion and exclusion criteria will be randomized to receive 
prophylactic endobronchial topical epinephrine or placebo in a blinded manner prior to 
performance of TBLB. Bleeding complications of TBLB will then be assessed by the bronchoscopist 
at the time of the procedure and subsequently by two independents reviewers who will observe 
a video recording of the procedure. The bronchoscopist as well as the reviewers will be blinded 
to the study drug assignment. Additionally, patients will be monitored for potential adverse 
events associated with topical epinephrine instillation. In this trial, we intend to include a total 
of 100 procedures in the final analysis. The first 40 procedures will serve as a pilot for proof of 
concept, refinement of the protocol, and interim analysis of data for safety outcomes. 
 
Eligibility Criteria 
 
Inclusion Criteria 
1. Male and female subjects, ≥18 years of age. 
2. Single- or double-lung transplant recipients scheduled for bronchoscopy with TBLB. 
3. Willingness to sign an informed consent for study participation. 
 

13 
 
Exclusion Criteria 
1. Age <18 years. 
2. Pregnancy. 
3. Inability to understand and provide a written informed consent. 
4. Exclusion criteria for TBLB 
4.1. 
Platelet count <50 K/microL. 
4.2. 
International normalized ratio (INR) >1.5. 
4.3. 
Known bleeding diathesis. 
4.4. 
Use of prophylactic or therapeutic dose of unfractionated heparin within 
6 hours of the procedure. 
4.5. 
Use of prophylactic dose of low molecular weight heparin within 12 hours 
of the procedure. 
4.6. 
Use of therapeutic dose of low molecular weight heparin within 24 hours 
of the procedure. 
4.7. 
Use of oral direct thrombin inhibitors or oral factor 10a inhibitors within 
48 hours of the procedure. 
4.8. 
Use of clopidogrel, ticlopidine, ticagrelor, or prasugrel within 5 days of the 
procedure. 
4.9. 
Uremia, defined as estimated glomerular filtration rate (eGFR) ≤30 
mL/min. 
4.10. 
Moderate to severe pulmonary hypertension as defined by a mean 
pulmonary artery pressure of >40 mm Hg on right heart catheterization or an 
estimated pulmonary artery systolic pressure of >62 mm Hg on transthoracic 
echocardiography, both performed within 1 year of the procedure. 
4.11. 
An 
additional 
synchronous 
procedure 
with 
possible 
bleeding 
(bronchoalveolar lavage and endobronchial biopsy allowed), unless the additional 
procedure is to be performed following TBLB. 
4.12. 
Decompensated liver cirrhosis, defined as the presence of clinically 
significant ascites, clinical evidence of esophageal or gastric varices, or history of 
bleeding from gastric or esophageal varices. 
4.13. 
Prior history of TBLB-related airway bleeding requiring admission to the 
hospital or advanced measures to achieve hemostasis, including endotracheal 
intubation, bronchial blocker application, bronchial artery embolization, or 
surgical intervention. 
5. Exclusion criteria for application of topical epinephrine: 
5.1. 
Systolic heart failure with an ejection fraction (EF) of <35% as assess by 
echocardiography performed within one year prior to the procedure. 
5.2. 
Myocardial infarction, acute coronary syndrome, percutaneous coronary 
intervention, or coronary artery bypass surgery within 6 months prior to the 
procedure. 
5.3. 
Symptoms and/or ECG findings suggestive of ongoing cardiac ischemia on 
the day of the procedure. 
5.4. 
Moderate- to severe-grade cardiac valvulopathy as assessed by 
echocardiography performed within one year prior to the procedure. 

14 
 
5.5. 
Inadequately controlled supraventricular arrhythmia, including atrial 
fibrillation, atrial flutter, and atrio-ventricular node re-entrant tachycardia 
(AVNRT) as revealed by ECG or cardiac monitoring at the time of the procedure. 
5.6. 
Presence of an internal cardioverter/defibrillator. 
5.7. 
History of second or third degree (complete) heart block or sick sinus 
syndrome. 
5.8. 
Baseline ECG or cardiac monitoring revealing frequent occurrence (≥10 
events per minute) of atrial or ventricular ectopy documented prior to or at the 
time of the procedure. 
5.9. 
History of ventricular arrhythmias requiring pharmacologic or electrical 
cardioversion within the 60 days preceding the procedure. 
5.10. 
Serum potassium of <3.0 mmol/L within the week prior to the procedure. 
5.11. 
Serum glucose level of ≥300 mg/dL within the week prior to the procedure. 
5.12. 
Any history of critical ischemia related to peripheral arterial disease. 
5.13. 
Persistent resting heart rate (HR) measurement of ≥120 beats per minute 
prior to or at the time of the procedure. 
5.14. 
Persistent resting systolic blood pressure (SBP) measurement of ≥180 mm 
Hg prior to or at the time of the procedure. 
5.15. 
Persistent resting diastolic blood pressure (DBP) measurement of ≥110 
mm Hg prior to or at the time of the procedure. 
5.16. 
History of acute closed-angle glaucoma within one year of the procedure. 
5.17. 
Diagnosis of pheochromocytoma requiring pharmacologic therapy with an 
alpha adrenoreceptor blocker at the time of the procedure. 
5.18. 
Diagnosis of thyrotoxicosis requiring pharmacologic therapy with an anti-
thyroid agent at the time of the procedure. 
 
Recruitment Strategy 
Recruitment for the proposed clinical trial will follow the well-established procedures at UMMC. 
Patients will be recruited from the daily clinical practice of the study investigators as well as the 
patient cohort being followed and treated by the lung transplantation service in our institution. 
As a referral center for lung transplantation in the state of Maryland as well as the surrounding 
states, UMMC care for a large number of post-lung transplantation patients who are likely to 
meet inclusion and exclusion criteria. Based on our experience with regard to our local practice 
over past years, we are fairly confident we have access to adequate numbers of patients and 
procedures in order to complete recruitment. This provides reasonable assurance that a 
sufficient number of participants should be able to be recruited and a sufficient number of 
procedures should be able to be recorded for this trial as well as speaks to its clinical and scientific 
relevance as its conduct will provide important information in the role of prophylactic 
epinephrine as means to prevent pulmonary and airway bleeding in lung transplant recipients 
undergoing bronchoscopic TBLB. 
 

15 
 
Potential PROPHET Trial participants will be screened from the pool of post-lung transplantation 
patients followed in UMMC and requiring TBLB, based on standards of care at our institution. 
Common indications for bronchoscopy with random TBLB sampling of the lung allograft include 
surveillance for acute graft rejection over the first post-transplantation year; evaluation of 
potential graft dysfunction based on clinical judgment (increased shortness of breath, worsening 
cough, decline in pulse oximetry), decline in the forced expiratory volume in one second (FEV1) 
or average forced expiratory flow at 25-75 percent of the forced vital capacity (FEF25-75%) as 
demonstrated by serial standardized spirometry, or radiological evidence; and tissue acquisition 
for suspected chronic graft rejection or bronchiolitis obliterans syndrome when the patient is a 
non-surgical candidate or a less invasive modality for tissue acquisition is desired before the 
decision regarding more invasive surgical modalities is made. A common indication for 
bronchoscopy with targeted TBLB sampling of the lung allograft or the native lung in single-lung 
transplant recipients is evaluation of focal parenchymal lung findings observed in radiologic 
studies and suspected for infectious, inflammatory, toxic, or a malignant process. 
 
Patient Evaluation 
Patients will undergo all study related procedures, including screening, informed consent, initial 
evaluation, and study intervention, during the hospital encounter scheduled for their 
bronchoscopy and TBLB.  
 
Process of Obtaining Informed Consent 
Informed Consent will be performed on the day of study recruitment. Eligible PROPHET Study 
patients will be discretely approached by one of the study investigators who will explain in 
layman’s language the aims, methods, potential benefits, and hazards associated with 
participation in the PROPHET trial. Details of the protocol will be discussed with the potential 
participant at the time of scheduling the bronchoscopy procedure, ensuring adequate time for 
consideration of the protocol (>24 hours from initial discussion). These individuals will then be 
approached with the informed consent form. Whenever possible, the informed consent form will 
be given to the potential participants in advance. The risks, benefits, and alternative will be 
discussed so that the decision to participate in the study will be made independently by the 
candidate. Only a well-trained clinical coordinator, the principal investigator, or an associate 
investigator from the Division of Pulmonary and Critical Care Medicine in UMMC will obtain 
consent. The consent will be obtained using and Institutional Review Board (IRB) approved 
consent document.  
Any potential participants who cannot consent for themselves will be excluded from the study, 
as defined by the exclusion criteria (see above). This includes anyone who will be, or will have 
been, in a stressful, painful, or drugged condition before or during the consent process or 
otherwise lacks the mental capacity to consent for themselves. We will not obtain consent from 
Legally Authorized Representatives (LARs). We will not enroll minors. 
Lung transplantation recipients undergo multiple bronchoscopic procedures in the post-
transplantation period. Hence, it is very likely that a patient who is eligible for participation in the 

16 
 
study will undergo more than one bronchoscopy with TBLB during the study period. In this 
instance, a separate informed consent will be obtained for each individual procedure.  
 
Initial Evaluation 
Any potential PROPHET participants who meet initial screening criteria and are anticipated to 
undergo bronchoscopy with TBLB will undergo a thorough chart review conducted by a member 
of the research team. Demographics, past medical history and comorbid conditions, indication 
for lung transplant, indication for bronchoscopy with TBLB and possible concurrent procedure(s), 
prior complications related to bronchoscopy or TBLB, current and active medications, most 
recent pulmonary function tests, and most recent report of echocardiogram will be reviewed to 
ensure inclusion and exclusion criteria are met. Recent laboratory data including complete blood 
count, comprehensive metabolic panel, coagulation studies, and 12-lead electrocardiogram will 
be reviewed following our institutional standard protocol for bronchoscopy.  
On the day of procedure, as per our institutional procedural protocol, participants will have 
intake vital signs obtained. Recent history and physical examinations dated within 30 days of 
procedure will be reviewed or obtained if not available. Participants will be monitored under 
telemetry starting with this intake period, during and approximately an hour after conclusion of 
procedure unless procedural complication merit additional closer monitoring.  
 
Monitoring Subjects and Criteria for Withdrawal of Subjects from the Study 
Before and after the procedure, on the procedure day, study participants will be monitored in 
the UMMC endoscopy peri-procedure suite (for outpatients) or in the admitting unit (for 
inpatients). An on-call pulmonary physician will be available to assist with any immediate issues. 
During the procedure, study participants will be monitored by the UMMC bronchoscopy suite 
nursing staff, the performing bronchoscopist, and any additional physicians participating in the 
procedure. We do not anticipate problems requiring withdrawal of patients from the PROPHET 
study once enrolled, other than by the patient’s request. In the event a study subject elects to be 
withdrawn from the study and requests their data to be withdrawn as well, we will comply. 
 
Study Drug and Placebo Preparation, Packaging, and Randomized Assignment 
The dosing of topical epinephrine for the purpose of airway bleeding prophylaxis is not 
standardized and based mainly on operator preference and in some cases local policies. The 
UMMC does not have a formal policy regarding the prophylactic use of epinephrine in TBLB. 
Treatment of airway bleeding with topical epinephrine once it has occurred is also controversial 
in terms of dilution and volume of instillation and, again, is based mainly on individual operator 
practice and institutional protocols. Dilution ratio ranges from 1:1,000 to 1:100,000 and volume 
of instillation ranges from 1 to 20 mL in different reports published across the medical literature 
(22,50–52). The only guidelines addressing this practice are the British Thoracic Society (BTS) 
guidelines on Diagnostic Flexible Bronchoscopy, which suggest using “small aliquots of 1:10,000 
diluted epinephrine” (49).  

17 
 
For the PROPHET study, we decided to adopt the recommendation made by the BTS regarding 
the dilution. Regarding the volume of instillation, we chose a volume of 2 mL based on the 
common local practice in UMMC. It is standard practice during a bronchoscopy for a cup of saline 
and a cup of 1:10,000 diluted epinephrine to be prepared by the bronchoscopy suite support 
staff. Syringes for administration of both are included with the cups so to permit administration. 
Our plan for randomization simply takes these syringes that are already available and on the 
bronchoscopy cart as standard practice and applies a two-step randomization process to ensure 
team blinding.  
On day of procedure, a diluted 1:10,000 epinephrine syringe will be prepared by a member of 
the research team who will not be involved in the allocation of the study drug. To allow for the 
possibility that biopsies possibly will be performed from separate airways, two milliliters of 
1:10,000 concentration of epinephrine along with 8 ml of ambient air will be drawn into a two 
syringes (“study drug”). Two separate syringes will be made with 2 ml of sterile saline and 8 ml 
of ambient air (“placebo”). The two sets of syringes will be labeled “A” or “B” based on an electric 
coin toss for randomization. A record of the coded syringes and their content will be documented 
in a unique database separate from the study database. In order not to breach blinding, lot 
numbers for both Epinephrine and saline aliquots will be documented in each study participant’s 
CRF without disclosing which letter was assigned to each aliquot. 
As described below, the next step is for a second team member to randomly select one set of 
labeled syringes without the first study team member knowing which was selected, and then log 
the selection. As such, the team remains blinded and only when the two logs are later merged 
will drug assignment be unblinded. 
 
 
Study Group Randomized Assignment 
To eliminate bias, two randomization and blinding processes will be employed: in preparing and 
labeling the sets syringes (as described above) and in choosing of the set of syringes at the time 
of the procedure. Those two separate processes will be performed by different members of the 
research team, each of them blinded to the results of the other procedure:  
 
1. Two syringes will be prepared with the study drug (1:10,000 dilution of epinephrine) and 
two will be prepared with placebo (sterile saline). The syringes will be randomly labeled 
“A” and “B” based on a computerized electric coin toss and documented in a separate 
database as described above. This will be done by a member of the research team who 
will not be participating in the procedure and therefore blinded to the second 
randomization (syringe selection).  
2. The syringes will be delivered to the procedure room prior to the procedure. At this time, 
the research team member who is responsible for the syringes will leave the room prior 
to the second randomization point.  
3. The bronchoscopist or his/her assistant who is blinded to the drug and placebo 
preparation process will randomly choose “A” or “B” based again on a computerized 
electric coin toss.  
4. The chosen set of syringes will be recorded as part of the study database.  

18 
 
 
Procedure Performance 
1. Bronchoscopy will be performed in the controlled environment of the UMMC dedicated 
bronchoscopy suite under moderate sedation. The bronchoscopy suite in UMMC is routinely 
staffed by a nurse and a respiratory therapist in addition to the bronchoscopist and any 
trainees assisting with the procedure.  
2. In addition to informed consent for participation in the study protocol, a formal UMMC 
informed consent for the performance of fiberoptic bronchoscopy, bronchoscopy-related 
procedures, and use of moderate sedation will be obtained.  
3. Per local protocol, peri-procedurally and during the procedure, the patient’s heart rate, 
electrocardiography rhythm strip, respiratory rate, and oxygen saturation will be monitored 
continuously. Blood pressure will be repeatedly measured every 3 minutes. Up to 6 liters of 
supplemental oxygen via nasal cannula will be given in order to maintain an oxygen saturation 
of >92%. A defibrillator as well as a resuscitation drugs and equipment are available at all 
times in the bronchoscopy suite.  
4. Patient will undergo the procedure in the supine position on an adjustable bed. 
Premedication will be performed per local protocol, including inhalation of 5 mL of 4% 
lidocaine via a nebulizer. Gurgling of 2 to 4 mL of 2% liquid lidocaine (20-40 mg) for upper 
airway anesthesia may also be applied depending on the performing bronchoscopist’s 
preference. Moderate sedation will be achieved with a combination of midazolam (maximal 
dose of 6 mg per procedure) and fentanyl (maximal dose of 300 mcg per procedure). 
Laryngeal and lower airway anesthesia during the procedure will be obtained with the use of 
2 mL aliquots of 2% liquid lidocaine up to a cumulative liquid lidocaine dose of 400 mg. A bite 
block will be used for procedures performed through the transoral approach. For the 
transnasal approach, 2% viscous lidocaine will be applied with a cotton swab to the chosen 
nostril and nasal passage to allow easy advancement of the bronchoscope.  
5. Bronchoscopy will be performed with an Olympus BF-1T160 or BF-1TH190 (Olympus, Tokyo, 
Japan) video bronchoscope under fluoroscopic guidance (OEC 9900 Elite Mobile C-arm, GE 
Healthcare, Chicago, Illinois, United States).  
6. For the purpose of independent post-procedure analysis, the entire procedure from insertion 
of the bronchoscope into the airways until its final retraction will be video-recorded on DVD 
media and individually labeled without disclosing study arm assignment. DVDs will be stored 
with other individual patient study documents for later review. Access to the stored DVDs will 
be provided only to the PROPHET study research team. 
7. Prior to biopsy performance 2 mL of 1:10,000 diluted epinephrine followed by 8 mL of 
ambient room air or 2 mL of sterile saline solution followed by 8 mL of ambient room air as 
described in “Study Drug and Placebo Preparation” will be instilled into the target airway by 
the bronchoscopist. This process may be repeated once, should the performing 
bronchoscopist choose to perform additional biopsy passes through a different airway. If 
choose to do so, the same study drug will be instilled into both airways. Any additional 
biopsies performed, will be done without airway instillation of study drug. 
8. Biopsies will be performed using brand bronchoscopic biopsy forceps as preferred by the 
procedure performer. For ACR, aim will be to obtain 5 to 8 adequate biopsies, preferably from 

19 
 
the lateral subsegment of either the right or left lower lobes to allow optimal visualization 
and minimize forshortening under fluoroscopy as well as to avoid as much as possible spillage 
of blood into uninvolved lung segments in the event of biopsy-related hemorrhage as 
described above. For the evaluation of radiological findings, aim will be to obtain 4 to 8 
adequate biopsy specimens from an involved segment in one of the lungs based on imaging. 
All bronchoscopies will be performed by an experienced bronchoscopist. 
9. The following data will be recorded with regard to the performance of the procedure: 
9.1. Patient study-arm assignment – recorded in a separate database. 
9.2. Indication for bronchoscopy with TBLB. 
9.3. Target number of TBLB specimens and target lobe and segment. 
9.4. Name and dosages of all medications administered to the patient in the hospital during 
the day of the procedure, including medications frequently administered during 
bronchoscopy such as topical anesthetic agents, sedation and analgesia agents, and 
hemostatic agents. Study drug vs. placebo administration will be recorded as described 
previously under “Randomization” and “Study Drug and Placebo Preparation and 
Packaging”. 
9.5. Supplemental oxygen requirements which exceed patient’s baseline requirements 
during or following the procedure. 
9.6. Any hemodynamic, cardiac, or respiratory events as recorded by telemetry in the 
procedure suite and/or in the recovery suite following the procedure. 
9.7. Bronchoscope model, including outer diameter and inner diameter of working channel. 
9.8. Date and time of scope insertion and completion of the procedure as defined by the 
performing bronchoscopist. 
9.9. Biopsy forceps brand, including outer diameter, open forceps diameter, and type of 
forceps (round cup, oval cup, alligator, impaling needle). 
9.10. 
Fluoroscopy time. 
9.11. 
Number of forceps passes. 
9.12. 
Total number of acquired biopsy specimens; Specimen distribution across 
laboratories (anatomic pathology, microbiology, other laboratory). 
9.13. 
Lobe and segment of each biopsy specimen. 
9.14. 
Any medical intervention performed in the bronchoscopy suite or in the recovery 
suite for stabilization of the patient’s medical condition during or following the 
procedure, including hemostasis, management of cardiac events, and management of 
respiratory events. 
 
Outcome Measures 
Primary Efficacy Outcome 
The primary efficacy outcome of the PROPHET Study is the prevalence of major hemorrhage as 
defined by two independent reviewers who will review the procedure video while blinded to the 
individual patient information, study drug assignment, and any procedure related data not 
recorded on video. Hemorrhage will be graded according to a grading system suggested by 

20 
 
Pilarczyk et al. (43) and modified in accordance with the PROPHET Study scientific question as 
follows: 
 
Grade 
Description 
No hemorrhage 
 
No hemorrhage 
Minor 
Endobronchial hemorrhage resulting in segmental or more distal bronchus 
blood spillage 
Intermediate 
Endobronchial hemorrhage resulting in lobar bronchus blood spillage 
Major 
Endobronchial hemorrhage resulting in mainstem bronchus, more 
proximal blood spillage, or spillage into the uninvolved lung 
 
Secondary Efficacy Outcomes 
1. Occurrence of no, minor, or intermediate bleeding as defined by the independent 
reviewer. 
2. Likert scale grading of bleeding by independent observer on a scale of 1 to 5: 
 
1 
2 
3 
4 
5 
Much less than 
usual for TBLB
Less than usual 
for TBLB
Usual for TBLB 
More than usual 
for TBLB 
Much more than 
usual for TBLB
 
3. Intra-procedural grading by the performing bronchoscopist according to procedure-
related outcome as described    by Ernst et al. and Herth et al. (31,44): 
 
Grade 
Description 
No hemorrhage 
No hemorrhage 
Mild 
Any bleeding originating from the biopsy target airway requiring 
wedging of the bronchoscope or “in and out” motion in order to 
achieve hemostasis 
Moderate 
Any bleeding originating from the biopsy target airway requiring in 
addition to maneuvering the bronchoscope application of iced 
saline or topical epinephrine or placing the patient with the 
bleeding lung in the dependent position 
Severe 
Any bleeding originating from the biopsy target airway requiring, 
in addition to the above-mentioned maneuvers, early termination 
of the procedure or necessitating application of balloon 
tamponade, endotracheal intubation, application of a bronchial 
blocker, or use of other invasive measures to achieve hemostasis, 
such as bronchial artery embolization or surgical intervention 
 
4. Number of forceps passes performed. 
5. Number of adequate tissue samples obtained. 

21 
 
6. Early termination of the procedure due to bleeding complication, defined as non-
achievement of the target number of tissue samples as designated by the performing 
bronchoscopist prior to the procedure related to hemorrhage. 
7. Duration of the procedure from first bronchoscope insertion to last bronchoscope 
withdrawal. 
8. Total volume of iced saline used during the procedure. 
9. Total dose of unblended topical epinephrine used during the procedure. 
10. Any use of hemostatic procedures including balloon tamponade, endobronchial blocker, 
bronchial artery embolization, emergency surgery. 
11. Any use of devices or procedures with intention of securing the airway including oral 
airway, 
nasal 
airway, 
laryngeal mask, 
endotracheal intubation, emergency 
cricothyroidotomy, and emergency tracheostomy. 
12. Unplanned admission to the hospital or escalation in level of care within 48 hours of the 
procedure. 
13. Pathologic diagnosis achieved. 
 
Safety Outcomes 
The safety of topical epinephrine administration and potential instillation-related adverse events 
will be derived from clinical monitoring, vital signs, and ECG recordings during and immediately 
following the procedure as well as from any clinical, laboratory, or radiologic investigations 
performed during or following the procedure. Complications deemed related to topical 
epinephrine administration and comprise the study safety outcomes include: 
1. All-cause mortality within 3 hours of instillation of the study drug. 
2. Acute cardiovascular event, including cardiac arrest, new onset chest pain, acute 
myocardial ischemia, pulmonary edema, acute ischemic stroke, critical limb ischemia, 
acute mesenteric ischemia, occurring within 30 minutes of instillation of the study drug. 
3. Acute closed angle glaucoma within 30 minutes of the instillation of the study drug. 
4. New onset ECG changes suggestive of myocardial ischemia, including ST segment changes 
(defined: ≥1 mm ST segment elevation or ≥3 mm ST segment depression in ≥2 precordial 
or limb ECG leads that correspond together to one of the cardiac walls), new onset 
ventricular tachycardia, significant increase (≥10 per minute) in occurrence of ventricular 
ectopic beats, new onset supraventricular arrhythmia, new onset bundle branch block, 
and new onset 2nd or 3rd degree atrioventricular block, all occurring within 30 minutes of 
the instillation of the study drug. 
5. Significant change in heart rate (defined as heart rate of >120 bpm and/or increase by 
≥30 bpm above the baseline or heart rate <60 bpm and/or ≥30 bpm below the baseline) 
as recorded within 30 minutes of the instillation of the study drug. 
6. Significant change in systolic blood pressure (defined as increase in systolic blood 
pressure >180 mm Hg and/or ≥40 mm Hg above the baseline; increase in diastolic blood 
pressure >110 mm Hg and/or ≥20 mm Hg above the baseline; or fall in systolic blood 
pressure <90 mm Hg and/or ≥20 mm Hg below the baseline) as recorded within 30 
minutes of the instillation of the study drug. 
 

22 
 
Please refer to the section titled “Adverse Events Reporting and Data Monitoring” for further 
elaboration regarding reporting adverse events to the study monitoring committee. Please refer 
to the section titled “Adverse Events Reporting to the IRB” for further elaboration regarding 
reporting adverse events to the IRB. 
 
Immediate Post-Procedure Surveillance 
Following retraction of the bronchoscope, fluoroscopy will be performed while the patient is still 
on the bronchoscopy bed in order to try and identify early pneumothorax. The patient will then 
be transferred for recovery in the UMMC endoscopy peri-procedure suite or in the admitting 
unit. A chest radiograph will be obtained to identify late pneumothorax within two hours of the 
termination of the procedure or later if late symptoms suggestive of pneumothorax appear. Also, 
a repeat ECG will be obtained within two hours of the termination of the procedure or earlier if 
symptoms suggestive of cardiac arrhythmia, ischemia, or conduction abnormality appear. The 
patient will also be assessed by a clinician to evaluate for signs and symptoms of pneumothorax 
or significant pulmonary hemorrhage on the same day of the procedure. Patients will be 
instructed not the drink or eat in the 2 hours following the procedure and if stable for discharge 
from the hospital on the same day of the procedure, to be driven to their place of residence by 
an escort. Patients will also be instructed to call if they had any hemoptysis, dyspnea, chest pain, 
or wished to ask questions.  
 
Long-Term Post-Procedure Surveillance 
A follow-up telephone call will be performed by one of the study investigators 24 to 48 hours 
following the bronchoscopic procedure. Patients will be requested to report any ill-effects of the 
procedure and will be specifically asked about sore throat, fever, chills, hemoptysis, dyspnea, and 
chest pain. Symptomatic patients will be managed as deemed appropriate according to clinical 
judgment and the UMMC bronchoscopy suite guidelines. Management options include 
reassurance, prescription of appropriate medication, referral to the primary care physician, 
referral to the lung transplantation clinic, or referral to a local or the UMMC emergency room. 
Emergency situations may arise in which it is necessary to unmask treating physicians, emergency 
department personnel, clinic personnel, or the patient to the assigned treatment. Situations that 
require unmasking are expected to be rare. Since epinephrine has a short half-life it will probably 
be already eliminated from the study participant’s circulation by the time they are seen by a 
provider for possible study drug-related side effect. It is possible, however, that emergency 
personnel or treating physicians might feel it is necessary to know the medication that participant 
was taking to decide upon a rational course of treatment, or to ensure that other medications 
are not given that might adversely interact with epinephrine. In such cases the treating medical 
personnel should call the PI for study unmasking. In that event, an Unmasking Report for the 
event must be completed. 
 
Study Flow (Outpatients) 
Time Frame 
Study Procedure(s) 

23 
 
Days -30 to -1 
1. Identification of potential study participants from the pool of 
lung transplant recipients considered for TBLB within the 
coming month in UMMC according to inclusion and exclusion 
criteria. 
2.  Description of study rational, aims, methods, potential 
benefits, and potential hazards by one of the study 
investigators during the routine phone call performed for the 
purpose of procedure coordination, allowing time for 
consideration. 
Day 0, time -2 to -1 
hours 
1. Patient admission to UMMC endoscopy peri-procedure suite. 
2. Anthropometric data, vital signs, baseline ECG, and routine 
laboratory tests will be obtained per local protocol. 
3. Patient’s medical record including past medical history, 
comorbidities, indication for current bronchoscopic TBLB, and 
ancillary studies (labs, ECG, echocardiography, imaging) will be 
again reviewed by one of the study investigators to confirm that 
the potential participant meets inclusion and exclusion criteria. 
4. Recent (previous 30 days) history and physical exam will be 
reviewed and/or performed and recorded if absent. 
5. Participant related data will be documented in the CRF. 
6. Study protocol will be again described in detail by one of the 
study investigators and informed consent will be obtained. 
Day 0, Time -1 to 0 
hours 
1. Study drug preparation and randomization will be performed in 
a blinded manner. 
Day 0, time 0 
1. Study procedure will be performed in the UMMC bronchoscopy 
suite as described above. 
2. Procedure related data will be documented in the CRF. 
Day 0, time 0 to +3 
1. Upon completion of the procedure, the study participant will 
return to the UMMC endoscopy peri-procedure suite. 
2. Vital signs will be obtained and patient will be monitored.  
3. Chest radiograph will be obtained within 2 hours of study 
completion. 
4. Additional studies (laboratory, imaging, etc.) will be obtained 
on an individual basis based to emerging need. 
5. Any therapeutic measures, including hospital admission, will be 
performed according to emerging needs. 
6. Study participant will be interviewed and examined by one of 
the study investigators who participated in the procedure. 
Initial outcomes and results will be reported to the participant. 
7. Study participant will be discharged home according to local 
policy unless emerging conditions require their admission to the 
hospital. 

24 
 
Day +1 to +2 
1. Study participant will be contacted by phone by one of the 
study investigators to inquire regarding any ill-effects of the 
procedure. 
Day 0 to +30 
1. 30-day all-cause mortality will be recorded. 
2. Pathologic diagnosis will be recorded. 
Day 0 and forth 
1. Study video DVD will be reviewed and graded by two blinded 
independent observers. 
 
 
Study Confidentiality and Privacy 
Data Documentation 
1. All study participants’ data will be anonymized and assigned a unique 5-character study 
identification number consisting of the first letter of the participants’ last name, the first 
digit, and the last 3 digits of their UMMC medical record number. In a potential case 
where two different patients will be assigned the same study identification number, the 
first and last 4 digits of the UMMC medical record number will be assigned to both 
patients.  
2. Individual PROPHET Study participant data will be collected in a designated study paper 
Case Report Form (CRF). Any information identified as Protected Health Information (PHI) 
will be kept separate from the participants CRF in a secure environment at UMMC 
accessible only to study staff allowed access to PHI. Each study participant CRF will also 
include the DVD media used for recording the bronchoscopy procedure.  
3. All study collected data will be incorporated into computerized databases. Databases will 
be located behind UMMC network firewall on a UMMC server and accessible only under 
the following conditions: 
3.1 
A workstation physically present in UMMC and physically connected to the 
network. 
3.2 
Granted system access to database server. 
3.3 
Granted password to the database folder(s). 
3.4 
Granted password to the database item(s). 
4. Computerized databases in use for the PROPHET study will include: 
4.1 
Patient identifier and study drug assignment. This database will be accessible to 
investigators involved in study drug marking and blinded to the procedure and 
outcomes. 
4.2 
All other study participant data collected as described above. This database will 
be accessible to investigators blinded to study drug assignment. 
5. All study investigators will be trained and instructed not to export data to a standalone 
file, whether on laptops, hard drives, thumb drives, CDs, or any other media. 
 

25 
 
Data Analysis 
Sample Size and Power Calculations 
Formal power calculations are not possible as studies of this kind have not been previously 
performed and an aim of the study is to develop new bleeding assessment tools.  As such, the 
first 40 procedures will provide data intended to show feasibility as well as to inform more refined 
power calculations. Numbers are based primarily on feasibility.  
Limitation of study participants to transplant recipients is anticipated to improve study power.  
In a relatively recent population-based study performed in the USA, Tukey et al. reviewed almost 
100,000 patient visits involving TBLB and reported an overall rate for procedure-related clinically 
significant hemorrhage of 0.58% (37). In a second large survey from Japan, Asano et al. reviewed 
over 100,000 procedures, among them 57,199 forceps biopsies, and recorded a bleeding rate of 
0.73% (38).  These low rates of bleeding likely reflect both insensitive thresholds to define 
bleeding as well as a lower risk population than that of lung transplant recipients. 
Bleeding risk in lung transplantation patients seems to be higher than that of the general 
population, although one must bear in mind the following caveats: (1) most of the currently 
published literature is retrospective and observational in nature; (2) lung transplant recipients 
studies mostly involve small patient populations; and (3) in most studies to date, the definition 
of clinically-significant bleeding was based on the amount of bloody fluid collected in the suction 
container during the procedure. This quantification method is prone to much bias since this fluid 
is a mixture of blood, airway secretions, and lavage fluid, and thus may over-estimated the true 
volume of blood loss. Also, the volume of blood loss considered clinically relevant varies across 
published studies and affects to a great extent on the reported rate of clinically-significant 
bleeding. The most prominent lung transplant studies examining the prevalence of TBLB-related 
bleeding are summarized in the table below: 
 
Study 
Number of 
procedures 
Prevalence 
of clinically 
significant 
hemorrhage 
(%) 
Definition of clinically significant 
hemorrhage 
Reference 
Scott et al.
219 
12.3 
>100 mL blood loss 
(20) 
Chan et al. 
83 
1.9 
>50 mL blood loss 
(62) 
Bjørtuft et al. 
29 
7.7 
>20 mL blood loss 
(63) 
Inoue et al. 
206 
11 
Not defined 
(65) 
Chhajed et al. 
363 
4 
≥100 mL blood loss 
(86) 
Diette et al.
15 
44.5 
>25 mL blood loss 
(87) 
Hopkins et al. 
1,235 
4 
>100 mL blood loss 
(88) 
McWilliams et 
al. 
353 
13 
>50 mL blood loss 
 
Smith et al. 
2,111 
0.5 
>30 mL blood loss 
 

26 
 
 
 
 
 
 
 
 
 
 
Data are expressed as means with standard deviations, medians with interquartile 
range, percentages, and proportions as appropriate. Continuous outcome variables 
were visually examined for normality and outliers using histograms and scatter plots. 
The normal distribution was assessed with the Shapiro-Wilk test. Continuous variables 
were compared with the Student’s t-test for normally distributed data with similar 
variance and the Mann-Whitney tests for non-normally distributed data. Proportions 
were compared using Chi-squared or Fisher’s exact tests as appropriate. Statistical 
significance was set at P<0.05. All statistical analyses were performed based on original
assigned groups and using Stata software, version 14 (Stata Corp LLC).
Potential Benefits
We hypothesize that prophylactic instillation of topical epinephrine prior to TBLB will reduced
procedure-related hemorrhage, leading to lower rate of prematurely aborted procedure due to
bleeding complications and higher yield of intended biopsies. The participants may, therefore,
have direct benefit from participation if prophylactic topical epinephrine reduces the rate of
procedure related hemorrhage in TBLB therefore avoiding early termination of procedure and
more intended biopsies taken providing a higher diagnostic yield.
No financial reimbursements or incentive for participating in the PROPHET study will be provided.
Potential Risks and Discomforts
The decision to perform bronchoscopy with TBLB will be based on clinical indications as a part of
each study participant standard of care and not as a part of the research. Potential risks and
discomfort of the bronchoscopy and TBLB themselves are no more than what the participant
would undergo as a part of their post-transplantation bronchoscopy. These risks include
hemorrhage related to the procedural maneuvers, respiratory distress, pneumothorax (i.e.
collapsed lung). These complications are rare (less than <1% of all bronchoscopies) and can be
expected in any bronchoscopy and TBLB. An experienced bronchoscopist and a well-trained staff
such as ours are well trained to handle these potential complications in the controlled
environment of the bronchoscopy suite. Bronchoscopic procedures performed in the UMMC
bronchoscopy suite are usually performed under conscious sedation. Potential risks and
discomforts of conscious sedation for our study participants are no more than what the
participant would undergo for their post-transplantation bronchoscopy. Conscious sedation is
generally safe, but can cause nausea and vomiting, ineffective ventilation resulting from airway
obstruction or respiratory depression, causing hypoxia, hypercarbia, or aspiration associated
with loss of protective airway reflexes, as well as cardiovascular complications including
hypotension and arrhythmia. Drug overdose and drug reactions are a constant possibility in
patients undergoing conscious sedation.
The potential risks of epinephrine are well described in cases of sufficient systemic absorption of
the drug. Most serious complications are arrhythmias and hemodynamic compromise and tend
to occur in a dose dependent manner. Most complications seen are in the setting of existing
bleeding from procedural maneuvers. Topical epinephrine, in these situations, is instilled in
airways with damaged mucosa and blood vessels. There is direct communication between the
airway and blood vessels allowing for more direct absorption of epinephrine leading to higher
concentration of epinephrine in the blood stream and therefore systemic complications. There is
no reported data of the incidence rate of complications arising from epinephrine in the setting
of topical prophylactic use, but it is expected to have lower rate of systemic absorption. In rare

27 
 
cases of complications, our staff is well trained and the procedure room is equipped to treat these 
potential complications of epinephrine. 
Research related risk to the patient will also be loss of confidentiality. Loss of confidentiality is 
unlikely to occur as all data will be accessed and stored securely only by members of the research 
team. All patient data will be incorporated into a central database. Patients will be assigned with 
a unique identification number. The database will be maintained behind University of Maryland 
firewall in a password-protected folder on the I: drive. The database file will also be password 
protected. Any limited physical data will be kept in a locked cabinet with only keys available to 
research team members. Confidential data will not be shared. 
  
Adverse Events Reporting to the IRB  
All adverse events occurring during the study, including those observed by or reported to the 
research team, will be recorded. Serious unanticipated problems, defined as complications 
thought to be likely related to the study drug administration and require some intervention, will 
be reported to the IRB as soon as possible but not more than 5 business days after the PI first 
learns of the event. For example, a brief arrhythmia that requires no intervention will not be 
reported within 5 business days, while an arrhythmia requiring drug or electrical shock 
administration will be reported within 5 business days. Likewise, any serious protocol deviations 
will be reported to the IRB as soon as possible but not more than 7 business days after the PI first 
learns of the event. Not serious unanticipated problems will be reported to the IRB as soon as 
possible but not more than 14 business days after the PI first learns of the event. Not serious 
protocol deviations will only be reported to the IRB (within 14 business days after the PI first 
learns of the deviation) if they represent a departure from UMMC policies for the conduct of 
human subject research, adversely affect the health care of subject(s), or compromise the 
interpretation or integrity of the research. Not serious protocol deviations that result from 
normal subject scheduling variations or technical issues associated with sampling that do not 
impact the health of the subject or interpretation of the study data will not be reported. 
Adverse events that are clearly not related to the study procedures, such as those that occur 
prior to initiation of study-related procedures, will not be reported to the IRB. Adverse events 
that are expected and thought to be related to the natural history of lung transplantation and its 
comorbidities will not be reported to the IRB. 
Expected adverse events (sore throat, cough, mild hemoptysis, low-grade fever, non-life-
threatening allergic reactions) that do not require intervention will not be reported to the IRB. 
All other adverse events will be reported in aggregate at the time of continuing review. 
Deaths will be reported to the IRB within 7 business days after the PI first learns of the event.  
 
Data Monitoring 
There will be interim analysis of data for safety and all adverse events. These analyses will be 
done by an independent physician reviewer after a pilot period of 40 procedures or 10 major 
bleeding events, whichever occurs first. Thereafter, safety analysis will be performed and 
reviewed at a minimum of every 6 months.  

28 
 
All adverse events including known complications and unexpected adverse events of the 
bronchoscopy and TBLB and medications administered will be recorded as part of our data 
monitoring. Reportable event including but not limited to unanticipated problems, protocol 
deviation, any change in subject’s status will generate a report. The report will include subject 
identification, date of event, date the PI became aware of the event, description of event, date 
the event resolved if applicable, type of harm if any experienced by the participant, relationship 
harm to the event and date the report was submitted to the IRB and other regulatory authorities. 
 
 
 
 

29 
 
REFERENCES 
1.  
Andersen HA, Harrison EGJ. Transbronchoscopic lung biopsy in diffuse pulmonary 
disease. Trans Annu Meet Am Bronchoesophagol Assoc. 1965;45:84–91.  
2.  
Fletcher EC, Levin DC. Flexible fiberoptic bronchoscopy and fluoroscopically guided 
transbronchial biopsy in the management of solitary pulmonary nodules. West J Med. 
1982 Jun;136(6):477–83.  
3.  
Prakash UB, Offord KP, Stubbs SE. Bronchoscopy in North America: the ACCP survey. 
Chest [Internet]. 1991 Dec;100(6):1668–75. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/1959412 
4.  
Ahmad M, Livingston DR, Golish JA, Mehta AC, Wiedemann HP. The safety of outpatient 
transbronchial biopsy. Chest. 1986 Sep;90(3):403–5.  
5.  
Hernandez Blasco L, Sanchez Hernandez IM, Villena Garrido V, de Miguel Poch E, Nunez 
Delgado M, Alfaro Abreu J. Safety of the transbronchial biopsy in outpatients. Chest. 
1991 Mar;99(3):562–5.  
6.  
Leslie KO, Gruden JF, Parish JM, Scholand MB. Transbronchial biopsy interpretation in the 
patient with diffuse parenchymal lung disease. Arch Pathol Lab Med. 2007 
Mar;131(3):407–23.  
7.  
Berbescu EA, Katzenstein A-LA, Snow JL, Zisman DA. Transbronchial biopsy in usual 
interstitial pneumonia. Chest. 2006 May;129(5):1126–31.  
8.  
Poletti V, Ravaglia C, Buccioli M, Tantalocco P, Piciucchi S, Dubini A, et al. Idiopathic 
pulmonary fibrosis: diagnosis and prognostic evaluation. Respiration. 2013;86(1):5–12.  
9.  
Matthay RA, Farmer WC, Odero D. Diagnostic fibreoptic bronchoscopy in the 
immunocompromised host with pulmonary infiltrates. Thorax. 1977 Oct;32(5):539–45.  
10.  
Cazzadori A, Di Perri G, Todeschini G, Luzzati R, Boschiero L, Perona G, et al. 
Transbronchial biopsy in the diagnosis of pulmonary infiltrates in immunocompromised 
patients. Chest. 1995 Jan;107(1):101–6.  
11.  
Gilman MJ, Wang KP. Transbronchial lung biopsy in sarcoidosis. An approach to 
determine the optimal number of biopsies. Am Rev Respir Dis. 1980 Nov;122(5):721–4.  
12.  
Pinsker KL, Kamholz SL. Diagnosis of sarcoidosis by transbronchial lung biopsy. Vol. 79, 
Chest. UNITED STATES; 1981. p. 123–4.  
13.  
Housini I, Tomashefski JFJ, Cohen A, Crass J, Kleinerman J. Transbronchial biopsy in 
patients with pulmonary eosinophilic granuloma. Comparison with findings on open lung 
biopsy. Arch Pathol Lab Med. 1994 May;118(5):523–30.  
14.  
Matsuse H, Shimoda T, Fukushima C, Matsuo N, Sakai H, Takao A, et al. Diagnostic 
problems in chronic eosinophilic pneumonia. J Int Med Res. 1997;25(4):196–201.  
15.  
Romagnoli M, Bigliazzi C, Casoni G, Chilosi M, Carloni A, Dubini A, et al. The role of 
transbronchial lung biopsy for the diagnosis of diffuse drug-induced  lung disease: a case 
series of 44 patients. Sarcoidosis, Vasc Diffus lung Dis  Off J WASOG /  World Assoc 

30 
 
Sarcoidosis Other Granulomatous Disord. 2008 Sep;25(1):36–45.  
16.  
Goldstein LS, Kavuru MS, Curtis-McCarthy P, Christie HA, Farver C, Stoller JK. Pulmonary 
alveolar proteinosis: clinical features and outcomes. Chest. 1998 Nov;114(5):1357–62.  
17.  
Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis 
and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-
based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e142S–65S.  
18.  
Aranda C, Sidhu G, Sasso LA, Adams F V. Transbronchial lung biopsy in the diagnosis of 
lymphangitic carcinomatosis. Cancer. 1978 Oct;42(4):1995–8.  
19.  
Torrington KG, Hooper RG. Diagnosis of lymphangitic carcinomatosis by transbronchial 
lung biopsy. South Med J. 1978 Dec;71(12):1487–8.  
20.  
Scott JP, Fradet G, Smyth RL, Mullins P, Pratt A, Clelland CA, et al. Prospective study of 
transbronchial biopsies in the management of heart-lung and  single lung transplant 
patients. J Heart Lung Transplant. 1991;10(5 Pt 1):626–7.  
21.  
Glanville AR. The role of bronchoscopic surveillance monitoring in the care of lung 
transplant recipients. Semin Respir Crit Care Med. 2006;27(5):480–91.  
22.  
Ernst A. Introduction to bronchoscopy [Internet]. 1st ed. Cambridge University Press; 
2009. 176 p. Available from: 
http://www.cambridge.org/us/academic/subjects/medicine/respiratory-
medicine/introduction-bronchoscopy?format=HB 
23.  
Mehta A, Prasoon J. Interventional Bronchoscopy A Clinical Guide [Internet]. Humana 
Press; 2013. 262 p. Available from: http://www.springer.com/us/book/9781627033947 
24.  
Talmage EA. Safe combined general and topical anesthesia for laryngoscopy and 
bronchoscopy. South Med J [Internet]. 1973 Apr [cited 2016 Sep 2];66(4):455–9. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/4575235 
25.  
Zavala DC. Transbronchial biopsy in diffuse lung disease. Chest. 1978 May;73(5 
Suppl):727–33.  
26.  
Descombes E, Gardiol D, Leuenberger P. Transbronchial lung biopsy: an analysis of 530 
cases with reference to the number of samples. Monaldi Arch chest Dis = Arch Monaldi 
per le Mal del torace  / Fond Clin del Lav IRCCS [and] Ist di Clin Tisiol e Mal Appar Respir 
Univ di Napoli, Second ateneo. 1997 Aug;52(4):324–9.  
27.  
Kukafka DS, O’Brien GM, Furukawa S, Criner GJ. Surveillance bronchoscopy in lung 
transplant recipients. Chest [Internet]. 1997 Feb [cited 2016 Sep 2];111(2):377–81. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/9041985 
28.  
Cordasco EMJ, Mehta AC, Ahmad M. Bronchoscopically induced bleeding. A summary of 
nine years’ Cleveland clinic experience and review of the literature. Chest. 1991 
Oct;100(4):1141–7.  
29.  
Papin TA, Lynch JP, Weg JG. Transbronchial biopsy in the thrombocytopenic patient. 
Chest [Internet]. 1985 Oct [cited 2016 Sep 2];88(4):549–52. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/4042705 

31 
 
30.  
Brickey DA, Lawlor DP. Transbronchial biopsy in the presence of profound elevation of 
the international normalized ratio. Chest [Internet]. 1999;115(6):1667–71. Available 
from: http://dx.doi.org/10.1378/chest.115.6.1667 
31.  
Ernst A, Eberhardt R, Wahidi M, Becker HD, Herth FJF. Effect of routine clopidogrel use 
on bleeding complications after transbronchial  biopsy in humans. Chest. 2006 
Mar;129(3):734–7.  
32.  
Morris MJ, Peacock MD, Mego DM, Johnson JE, Anders GT. The Risk for Hemorrhage 
from Bronchoscopic Lung Biopsy Due to Pulmonary Hypertension in Interstitial Lung 
Disease. J Bronchol [Internet]. 1998 Apr [cited 2016 Sep 3];5(2):117–21. Available from: 
http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00128594
-199804000-00006 
33.  
Mehta NL, Harkin TJ, Rom WN, Graap W, Addrizzo-Harris DJ. Should Renal Insufficiency 
Be a Relative Contraindication to Bronchoscopic Biopsy? J Bronchol [Internet]. 2005 Apr 
[cited 2016 Sep 2];12(2):81–3. Available from: 
http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00128594
-200504000-00005 
34.  
Jain P, Sandur S, Meli Y, Arroliga AC, Stoller JK, Mehta AC. Role of flexible bronchoscopy 
in immunocompromised patients with lung infiltrates. Chest [Internet]. 2004 Feb [cited 
2016 Sep 2];125(2):712–22. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/14769756 
35.  
Jabbardarjani H, Eslaminejad A, Mohammadtaheri Z, Kiani A, Arab A, Masjedi MR. The 
effect of cup versus alligator forceps on the results of transbronchial lung biopsy. J 
Bronchology Interv Pulmonol [Internet]. 2010 Apr [cited 2016 Sep 2];17(2):117–21. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/23168725 
36.  
Sehgal IS, Bal A, Dhooria S, Agrawal P, Gupta N, Ram B, et al. A Prospective Randomized 
Controlled Trial Comparing the Efficacy and Safety of Cup vs Alligator Forceps for 
Performing Transbronchial Lung Biopsy in Patients With Sarcoidosis. Chest [Internet]. 
2016 Jun [cited 2016 Sep 2];149(6):1584–6. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/27287583 
37.  
Tukey MH, Wiener RS. Population-based estimates of transbronchial lung biopsy 
utilization and complications. Respir Med. 2012 Nov;106(11):1559–65.  
38.  
Asano F, Aoe M, Ohsaki Y, Okada Y, Sasada S, Sato S, et al. Deaths and complications 
associated with respiratory endoscopy: a survey by the Japan Society for Respiratory 
Endoscopy in 2010. Respirology. 2012 Apr;17(3):478–85.  
39.  
Asano F, Aoe M, Ohsaki Y, Okada Y, Sasada S, Sato S, et al. Deaths and complications 
associated with respiratory endoscopy: a survey by the Japan Society for Respiratory 
Endoscopy in 2010. Respirology. 2012 Apr;17(3):478–85.  
40.  
Flick MR, Wasson K, Dunn LJ, Block AJ. Fatal pulmonary hemorrhage after transbronchial 
lung biopsy through the fiberoptic bronchoscope. Am Rev Respir Dis [Internet]. 1975 Jun 
[cited 2016 Sep 2];111(6):853–6. Available from: 

32 
 
http://www.ncbi.nlm.nih.gov/pubmed/1137250 
41.  
Ibrahim AS, Allangawi MH, Sattar HA, Mobyed HS, Almohammed AA. Indications, 
diagnostic yields and complications of transbronchial biopsy over 5  years in the State of 
Qatar. Saudi Med J. 2005 Apr;26(4):641–5.  
42.  
Chhajed PN, Aboyoun C, Malouf MA, Hopkins PM, Plit ML, Glanville AR. Risk factors and 
management of bleeding associated with transbronchial lung biopsy in lung transplant 
recipients. J Heart Lung Transplant [Internet]. 2003 Feb [cited 2016 Sep 1];22(2):195–7. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/12581769 
43.  
Pilarczyk K, Carstens H, Heckmann J, Lubarski J, Marggraf G, Jakob H, et al. Safety and 
Efficiency of Percutaneous Dilatational Tracheostomy With Direct Bronchoscopic 
Guidance for Thoracic Transplant Recipients. Respir Care. 2016;61(2).  
44.  
Herth FJF, Becker HD, Ernst A. Aspirin does not increase bleeding complications after 
transbronchial biopsy. Chest [Internet]. 2002;122(4):1461–4. Available from: 
http://dx.doi.org/10.1378/chest.122.4.1461 
45.  
Ernst A, Eberhardt R, Wahidi M, Becker HD, Herth FJF. Effect of routine clopidogrel use 
on bleeding complications after transbronchial biopsy in humans. Chest [Internet]. 
2006;129(3):734–7. Available from: http://dx.doi.org/10.1378/chest.129.3.734 
46.  
Zavala DC. Diagnostic fiberoptic bronchoscopy: Techniques and results of biopsy in 600 
patients. Chest [Internet]. 1975 Jul [cited 2016 Sep 3];68(1):12–9. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/168036 
47.  
Glanville AR. The role of surveillance bronchoscopy post-lung transplantation. Semin 
Respir Crit Care Med [Internet]. 2013 Jun [cited 2016 Sep 2];34(3):414–20. Available 
from: http://www.ncbi.nlm.nih.gov/pubmed/23821514 
48.  
Sahebjami H. Letter: Iced saline lavage during bronchoscopy. Chest [Internet]. 1976 Jan 
[cited 2016 Aug 29];69(1):131–2. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/1244274 
49.  
Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, et al. British Thoracic 
Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE. 
Thorax [Internet]. 2013 Aug [cited 2016 Aug 24];68 Suppl 1:i1–44. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/23860341 
50.  
Lee P, Mehta AC, Mathur PN. Management of complications from diagnostic and 
interventional bronchoscopy. Respirology [Internet]. 2009 Sep [cited 2016 Aug 
31];14(7):940–53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19740256 
51.  
Shah P. Atlas of Flexible Bronchoscopy. 1st ed. CRC Press; 2011. 256 p.  
52.  
Prakash UB. Bronchoscopy. 1st ed. Raven Pr; 1994. 547 p.  
53.  
Solomonov A, Fruchter O, Zuckerman T, Brenner B, Yigla M. Pulmonary hemorrhage: A 
novel mode of therapy. Respir Med [Internet]. 2009 Aug [cited 2016 Sep 2];103(8):1196–
200. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19251406 
54.  
Márquez-Martín E, Vergara DG, Martín-Juan J, Flacón AR, Lopez-Campos JL, Rodríguez-

33 
 
Panadero F. Endobronchial administration of tranexamic Acid for controlling pulmonary 
bleeding: a pilot study. J Bronchology Interv Pulmonol [Internet]. 2010 Apr [cited 2016 
Sep 2];17(2):122–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23168726 
55.  
Shigemura N, Wan IY, Yu SCH, Wong RH, Hsin MKY, Thung HK, et al. Multidisciplinary 
management of life-threatening massive hemoptysis: a 10-year experience. Ann Thorac 
Surg [Internet]. 2009 Mar [cited 2016 Aug 24];87(3):849–53. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/19231404 
56.  
Yendamuri S. Massive Airway Hemorrhage. Thorac Surg Clin [Internet]. 2015 Aug [cited 
2016 Aug 24];25(3):255–60. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/26210922 
57.  
Aboyoun CL, Tamm M, Chhajed PN, Hopkins P, Malouf MA, Rainer S, et al. Diagnostic 
value of follow-up transbronchial lung biopsy after lung rejection. Am J Respir Crit Care 
Med [Internet]. 2001 Aug 1 [cited 2016 Aug 26];164(3):460–3. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/11500350 
58.  
Vitulo P, Cremaschi P, Arbustini E, Volpato G, Volpini E, Martinelli L, et al. Surveillance 
transbronchial biopsy in the diagnosis of acute lung rejection in heart and lung and lung 
transplant recipients. Monaldi Arch chest Dis = Arch Monaldi per le Mal del torace / Fond 
Clin del Lav IRCCS [and] Ist di Clin Tisiol e Mal Appar Respir Univ di Napoli, Second ateneo 
[Internet]. 1996 Feb [cited 2016 Aug 26];51(1):12–5. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/8901314 
59.  
Trulock EP, Ettinger NA, Brunt EM, Pasque MK, Kaiser LR, Cooper JD. The role of 
transbronchial lung biopsy in the treatment of lung transplant recipients. An analysis of 
200 consecutive procedures. Chest [Internet]. 1992 Oct [cited 2016 Aug 26];102(4):1049–
54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1327662 
60.  
Baz MA, Layish DT, Govert JA, Howell DN, Lawrence CM, Davis RD, et al. Diagnostic yield 
of bronchoscopies after isolated lung transplantation. Chest [Internet]. 1996 Jul [cited 
2016 Aug 26];110(1):84–8. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/8681672 
61.  
Timofte I, Terrin M, Barr E, Sanchez P, Kim J, Reed R, et al. Belatacept for renal rescue in 
lung transplant patients. Transpl Int [Internet]. 2016 Apr [cited 2016 Aug 31];29(4):453–
63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26678245 
62.  
Chan CC, Abi-Saleh WJ, Arroliga AC, Stillwell PC, Kirby TJ, Gordon SM, et al. Diagnostic 
yield and therapeutic impact of flexible bronchoscopy in lung transplant recipients. J 
Heart Lung Transplant [Internet]. 1996 Feb [cited 2016 Aug 26];15(2):196–205. Available 
from: http://www.ncbi.nlm.nih.gov/pubmed/8672524 
63.  
Bjørtuft, Brosstad F, Boe J. Bronchoscopy with transbronchial biopsies: Measurement of 
bleeding volume and evaluation of the predictive value of coagulation tests. Eur Respir J. 
1998;12(5):1025–7.  
64.  
Diette GB, Wiener CM, White P. The higher risk of bleeding in lung transplant recipients 
from bronchoscopy is independent of traditional bleeding risks: Results of a prospective 

34 
 
cohort study. Chest [Internet]. 1999;115(2):397–402. Available from: 
http://dx.doi.org/10.1378/chest.115.2.397 
65.  
Inoue M, Minami M, Wada N, Nakagiri T, Funaki S, Kawamura T, et al. Results of 
surveillance bronchoscopy after cadaveric lung transplantation: a Japanese single-
institution study. Transplant Proc [Internet]. 2014 Apr [cited 2016 Aug 31];46(3):944–7. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/24767387 
66.  
GOGERTY JH, STRAND HA, OGILVIE AL, DILLE JM. Vasopressor effects of topical 
epinephrine in certain dental procedures. Oral Surg Oral Med Oral Pathol [Internet]. 
1957 Jun [cited 2016 Sep 1];10(6):614–22. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/13441276 
67.  
Zamani A. Bronchoscopic intratumoral injection of tranexamic acid: a new technique for 
control of biopsy-induced bleeding. Blood Coagul Fibrinolysis [Internet]. 2011 Jul [cited 
2016 Sep 2];22(5):440–2. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/21577092 
68.  
Zamani A. Bronchoscopic intratumoral injection of tranexamic acid to prevent excessive 
bleeding during multiple forceps biopsies of lesions with a high risk of bleeding: a 
prospective case series. BMC Cancer [Internet]. 2014 [cited 2016 Sep 2];14:143. Available 
from: http://www.ncbi.nlm.nih.gov/pubmed/24581173 
69.  
Higgins TS, Hwang PH, Kingdom TT, Orlandi RR, Stammberger H, Han JK. Systematic 
review of topical vasoconstrictors in endoscopic sinus surgery. Laryngoscope [Internet]. 
2011 Feb [cited 2016 Sep 4];121(2):422–32. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/21271600 
70.  
Valdes CJ, Bogado M, Rammal A, Samaha M, Tewfik MA. Topical cocaine vs adrenaline in 
endoscopic sinus surgery: a blinded randomized controlled study. Int Forum Allergy 
Rhinol [Internet]. 2014 Aug [cited 2016 Sep 4];4(8):646–50. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/24678064 
71.  
Fernández-Cossío S, Rodríguez-Dintén MJ, Gude F, Fernández-Álvarez JM. Topical 
Vasoconstrictors in Cosmetic Rhinoplasty: Comparative Evaluation of Cocaine Versus 
Epinephrine Solutions. Aesthetic Plast Surg [Internet]. 2016 Jun 29 [cited 2016 Sep 1]; 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/27357633 
72.  
Korkmaz H, Yao WC, Korkmaz M, Bleier BS. Safety and efficacy of concentrated topical 
epinephrine use in endoscopic endonasal surgery. Int Forum Allergy Rhinol [Internet]. 
2015 Dec [cited 2016 Sep 1];5(12):1118–23. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/26152362 
73.  
Orlandi RR, Warrier S, Sato S, Han JK. Concentrated topical epinephrine is safe in 
endoscopic sinus surgery. Am J Rhinol Allergy [Internet]. [cited 2016 Sep 1];24(2):140–2. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/20338114 
74.  
Gunaratne DA, Barham HP, Christensen JM, Bhatia DDS, Stamm AC, Harvey RJ. Topical 
concentrated epinephrine (1:1000) does not cause acute cardiovascular changes during 
endoscopic sinus surgery. Int Forum Allergy Rhinol. 2016 Feb;6(2):135–9.  

35 
 
75.  
Missavage AE, Bush RL, Kien ND, Reilly DA. The effect of clysed and topical epinephrine 
on intraoperative catecholamine levels. J Trauma. 1998 Dec;45(6):1074–8.  
76.  
Papp AA, Uusaro A V, Ruokonen ET. The effects of topical epinephrine on 
haemodynamics and markers of tissue perfusion in burned and non-burned patients 
requiring skin grafting. Burns [Internet]. 2009 Sep [cited 2016 Sep 1];35(6):832–9. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/19481869 
77.  
Kuster GG, Fischer B. Pharmacologic hemostasis in laparoscopy: topical epinephrine 
facilitates cholecystectomy. Am Surg [Internet]. 1993 May [cited 2016 Sep 1];59(5):281–
4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8489094 
78.  
Roberts JR, Greenberg MI, Knaub MA, Kendrick Z V, Baskin SI. Blood levels following 
intravenous and endotracheal epinephrine administration. JACEP [Internet]. 1979 Feb 
[cited 2016 Sep 1];8(2):53–6. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/439542 
79.  
Mazkereth R, Paret G, Ezra D, Aviner S, Peleg E, Rosenthal T, et al. Epinephrine blood 
concentrations after peripheral bronchial versus endotracheal administration of 
epinephrine in dogs. Crit Care Med [Internet]. 1992 Nov [cited 2016 Sep 2];20(11):1582–
7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1424703 
80.  
Mall W, Abel H. Topical application of epinephrine during bronchoscopy in barbiturate-
halothane-anaesthesia and its influence on cardiac action. Bronchopneumologie 
[Internet]. [cited 2016 Aug 29];28(4):311–6. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/92354 
81.  
Janjua M, Badshah A, Allen SA. Images in cardiology. Epinephrine-induced ST elevation: a 
case of endobronchial topical epinephrine-induced coronary vasospasm. Heart 
[Internet]. 2009 Apr [cited 2016 Sep 1];95(8):656. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/19329720 
82.  
Steinfort DP, Herth FJF, Eberhardt R, Irving LB. Potentially fatal arrhythmia complicating 
endobronchial epinephrine for control of iatrogenic bleeding. Am J Respir Crit Care Med 
[Internet]. 2012 May 1 [cited 2016 Aug 29];185(9):1028–30. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/22550217 
83.  
Khoo KL, Lee P, Mehta AC. Endobronchial epinephrine: confusion is in the air. Am J Respir 
Crit Care Med [Internet]. 2013 May 15 [cited 2016 Sep 2];187(10):1137–8. Available 
from: http://www.ncbi.nlm.nih.gov/pubmed/23675717 
84.  
Steinfort DP, Herth FJF, Eberhardt R, Irving LB. Reply: Endobronchial epinephrine: 
confusion is in the air. Am J Respir Crit Care Med [Internet]. 2013 May 15 [cited 2016 Sep 
2];187(10):1138. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23675719 
85.  
Paret G, Vaknin Z, Ezra D, Peleg E, Rosenthal T, Vardi A, et al. Epinephrine 
pharmacokinetics and pharmacodynamics following endotracheal administration in dogs: 
the role of volume of diluent. Resuscitation [Internet]. 1997 Aug [cited 2016 Sep 
2];35(1):77–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9259064 
86.  
Chhajed PN, Aboyoun C, Malouf MA, Hopkins PM, Plit ML, Glanville AR. Risk factors and 

36 
 
management of bleeding associated with transbronchial lung biopsy in lung transplant 
recipients. J Heart Lung Transplant [Internet]. 2003 Feb [cited 2016 Sep 3];22(2):195–7. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/12581769 
87.  
Diette GB, Wiener CM, White P. The higher risk of bleeding in lung transplant recipients 
from bronchoscopy is independent of traditional bleeding risks: results of a prospective 
cohort study. Chest [Internet]. 1999 Feb [cited 2016 Aug 26];115(2):397–402. Available 
from: http://www.ncbi.nlm.nih.gov/pubmed/10027438 
88.  
Hopkins PM, Aboyoun CL, Chhajed PN, Malouf MA, Plit ML, Rainer SP, et al. Prospective 
analysis of 1,235 transbronchial lung biopsies in lung transplant recipients. J Heart Lung 
Transplant [Internet]. 2002 Oct [cited 2016 Aug 26];21(10):1062–7. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/12398870