Prophylactic Topical Epinephrine to Reduce Bleeding in Transbronchial Lung Biopsies

Bleeding Clinical Trial

— PROPHET  

Official 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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03126968
• Other study ID #: HP-00070208
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: July 1, 2017
• Est. completion date: July 2, 2021

Study information

• Verified date: January 2023
• Source: University of Maryland, Baltimore
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Bleeding poses potential for significant complication after transbronchial lung biopsies. The investigators hypothesize that prophylactic intrabronchial instillation of topical epinephrine will reduce the likelihood of bleeding. The investigators plan a double-blind, placebo controlled trial to evaluate this hypothesis.

Description:

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, the investigators 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 50 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, the investigators 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 the investigators' institution comprises an effective means to prevent hemorrhagic complications of TBLB.

HYPOTHESIS

The investigators 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, the investigators 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. This 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: July 2, 2021
• Est. primary completion date: July 2, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male and female subjects, =18 years of age.

• Single- or double-lung transplant recipients scheduled for bronchoscopy with TBLB.

• Willingness to sign an informed consent for study participation.

Exclusion Criteria:

• Age <18 years.

• Pregnancy.

• Inability to understand and provide a written informed consent.

Exclusion criteria for TBLB:

• Platelet count <50 K/microL.

• International normalized ratio (INR) >1.5.

• Known bleeding diathesis.

• Use of prophylactic or therapeutic dose of unfractionated heparin within 6 hours of the procedure.

• Use of prophylactic dose of low molecular weight heparin within 12 hours of the procedure.

• Use of therapeutic dose of low molecular weight heparin within 24 hours of the procedure.

• Use of oral direct thrombin inhibitors or oral factor 10a inhibitors within 48 hours of the procedure.

• Use of clopidogrel, ticlopidine, ticagrelor, or prasugrel within 5 days of the procedure.

• Uremia, defined as estimated glomerular filtration rate (eGFR) =30 mL/min.

• 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.

• An additional synchronous procedure with possible bleeding (bronchoalveolar lavage and endobronchial biopsy allowed).

• 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.

• 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.

Exclusion criteria for application of topical epinephrine:

• Systolic heart failure with an ejection fraction (EF) of <35% as assess by echocardiography performed within one year prior to the procedure.

• Myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, or coronary artery bypass surgery within 6 months prior to the procedure.

• Symptoms and/or ECG findings suggestive of ongoing cardiac ischemia on the day of the procedure.

• Moderate- to severe-grade cardiac valvulopathy as assessed by echocardiography performed within one year prior to the procedure.

• 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.

• Presence of an internal cardioverter/defibrillator.

• History of second or third degree (complete) heart block or sick sinus syndrome.

• 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.

• History of ventricular arrhythmias requiring pharmacologic or electrical cardioversion within the 2 years preceding the procedure.

• Serum potassium of <3.0 mmol/L within the week prior to the procedure.

• Serum glucose level of =300 mg/dL within the week prior to the procedure.

• Any history of critical ischemia related to peripheral arterial disease.

• Persistent resting heart rate (HR) measurement of =120 beats per minute prior to or at the time of the procedure.

• Persistent resting systolic blood pressure (SBP) measurement of =180 mm Hg prior to or at the time of the procedure.

• Persistent resting diastolic blood pressure (DBP) measurement of =110 mm Hg prior to or at the time of the procedure.

• History of acute closed-angle glaucoma within one year of the procedure.

• Diagnosis of pheochromocytoma requiring pharmacologic therapy with an alpha adrenoreceptor blocker at the time of the procedure.

• Diagnosis of thyrotoxicosis requiring pharmacologic therapy with an anti-thyroid agent at the time of the procedure.

Related Conditions & MeSH terms

• Bleeding
• Hemoptysis
• Hemorrhage
• Lung Transplant; Complications
• Lung Transplant; Complications, Mechanical

Intervention

Drug:
• Topical epinephrine
Prophylactic topical epinephrine
• Placebos
Topical placebo (normal saline)

Locations

Country	Name	City	State
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	University of Maryland Medical Center - Midtown Campus	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
University of Maryland, Baltimore

Country where clinical trial is conducted

United States, 

References & Publications (56)

Aboyoun CL, Tamm M, Chhajed PN, Hopkins P, Malouf MA, Rainer S, Glanville AR. Diagnostic value of follow-up transbronchial lung biopsy after lung rejection. Am J Respir Crit Care Med. 2001 Aug 1;164(3):460-3. doi: 10.1164/ajrccm.164.3.2011152. — View Citation

Ahmad M, Livingston DR, Golish JA, Mehta AC, Wiedemann HP. The safety of outpatient transbronchial biopsy. Chest. 1986 Sep;90(3):403-5. doi: 10.1378/chest.90.3.403. — View Citation

Andersen HA, Fontana RS, Sanderson DR, Harrison EG Jr. Transbronchoscopic lung biopsy in diffuse pulmonary disease: results in 300 cases. Med Clin North Am. 1970 Jul;54(4):951-9. No abstract available. — View Citation

Baz MA, Layish DT, Govert JA, Howell DN, Lawrence CM, Davis RD, Tapson VF. Diagnostic yield of bronchoscopies after isolated lung transplantation. Chest. 1996 Jul;110(1):84-8. doi: 10.1378/chest.110.1.84. — View Citation

Berbescu EA, Katzenstein AL, Snow JL, Zisman DA. Transbronchial biopsy in usual interstitial pneumonia. Chest. 2006 May;129(5):1126-31. doi: 10.1378/chest.129.5.1126. — View Citation

Cazzadori A, Di Perri G, Todeschini G, Luzzati R, Boschiero L, Perona G, Concia E. Transbronchial biopsy in the diagnosis of pulmonary infiltrates in immunocompromised patients. Chest. 1995 Jan;107(1):101-6. doi: 10.1378/chest.107.1.101. — View Citation

Chan CC, Abi-Saleh WJ, Arroliga AC, Stillwell PC, Kirby TJ, Gordon SM, Petras RE, Mehta AC. Diagnostic yield and therapeutic impact of flexible bronchoscopy in lung transplant recipients. J Heart Lung Transplant. 1996 Feb;15(2):196-205. — View Citation

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. 2003 Feb;22(2):195-7. doi: 10.1016/s1053-2498(02)00462-x. — View Citation

Diette GB, Wiener CM, White P Jr. The higher risk of bleeding in lung transplant recipients from bronchoscopy is independent of traditional bleeding risks: results of a prospective cohort study. Chest. 1999 Feb;115(2):397-402. doi: 10.1378/chest.115.2.397. — View Citation

Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, Mandal S, Martin J, Mills J, Navani N, Rahman NM, Wrightson JM, Munavvar M; British Thoracic Society Bronchoscopy Guideline Group. British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE. Thorax. 2013 Aug;68 Suppl 1:i1-i44. doi: 10.1136/thoraxjnl-2013-203618. No abstract available. — View Citation

Fernandez-Cossio S, Rodriguez-Dinten MJ, Gude F, Fernandez-Alvarez JM. Topical Vasoconstrictors in Cosmetic Rhinoplasty: Comparative Evaluation of Cocaine Versus Epinephrine Solutions. Aesthetic Plast Surg. 2016 Oct;40(5):637-44. doi: 10.1007/s00266-016-0673-2. Epub 2016 Jun 29. — View Citation

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. — View Citation

Flick MR, Wasson K, Dunn LJ, Block AJ. Fatal pulmonary hemorrhage after transbronchial lung biopsy through the fiberoptic bronchoscope. Am Rev Respir Dis. 1975 Jun;111(6):853-6. doi: 10.1164/arrd.1975.111.6.853. — View Citation

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. doi: 10.1164/arrd.1980.122.5.721. — View Citation

Glanville AR. The role of surveillance bronchoscopy post-lung transplantation. Semin Respir Crit Care Med. 2013 Jun;34(3):414-20. doi: 10.1055/s-0033-1348466. Epub 2013 Jul 2. — View Citation

GOGERTY JH, STRAND HA, OGILVIE AL, DILLE JM. Vasopressor effects of topical epinephrine in certain dental procedures. Oral Surg Oral Med Oral Pathol. 1957 Jun;10(6):614-22. doi: 10.1016/s0030-4220(57)80009-7. No abstract available. — View Citation

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. doi: 10.1378/chest.99.3.562. — View Citation

Higgins TS, Hwang PH, Kingdom TT, Orlandi RR, Stammberger H, Han JK. Systematic review of topical vasoconstrictors in endoscopic sinus surgery. Laryngoscope. 2011 Feb;121(2):422-32. doi: 10.1002/lary.21286. Epub 2011 Jan 13. — View Citation

Hopkins PM, Aboyoun CL, Chhajed PN, Malouf MA, Plit ML, Rainer SP, Glanville AR. Prospective analysis of 1,235 transbronchial lung biopsies in lung transplant recipients. J Heart Lung Transplant. 2002 Oct;21(10):1062-7. doi: 10.1016/s1053-2498(02)00442-4. — View Citation

Inoue M, Minami M, Wada N, Nakagiri T, Funaki S, Kawamura T, Shintani Y, Okumura M. Results of surveillance bronchoscopy after cadaveric lung transplantation: a Japanese single-institution study. Transplant Proc. 2014 Apr;46(3):944-7. doi: 10.1016/j.transproceed.2013.10.055. — View Citation

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. 2010 Apr;17(2):117-21. doi: 10.1097/LBR.0b013e3181dc9920. — View Citation

Jain P, Sandur S, Meli Y, Arroliga AC, Stoller JK, Mehta AC. Role of flexible bronchoscopy in immunocompromised patients with lung infiltrates. Chest. 2004 Feb;125(2):712-22. doi: 10.1378/chest.125.2.712. — View Citation

Janjua M, Badshah A, Allen SA. Images in cardiology. Epinephrine-induced ST elevation: a case of endobronchial topical epinephrine-induced coronary vasospasm. Heart. 2009 Apr;95(8):656. doi: 10.1136/hrt.2008.161646. No abstract available. — View Citation

Khoo KL, Lee P, Mehta AC. Endobronchial epinephrine: confusion is in the air. Am J Respir Crit Care Med. 2013 May 15;187(10):1137-8. doi: 10.1164/rccm.201209-1682LE. No abstract available. — View Citation

Korkmaz H, Yao WC, Korkmaz M, Bleier BS. Safety and efficacy of concentrated topical epinephrine use in endoscopic endonasal surgery. Int Forum Allergy Rhinol. 2015 Dec;5(12):1118-23. doi: 10.1002/alr.21590. Epub 2015 Jul 8. — View Citation

Kukafka DS, O'Brien GM, Furukawa S, Criner GJ. Surveillance bronchoscopy in lung transplant recipients. Chest. 1997 Feb;111(2):377-81. doi: 10.1378/chest.111.2.377. — View Citation

Kuster GG, Fischer B. Pharmacologic hemostasis in laparoscopy: topical epinephrine facilitates cholecystectomy. Am Surg. 1993 May;59(5):281-4. — View Citation

Lee P, Mehta AC, Mathur PN. Management of complications from diagnostic and interventional bronchoscopy. Respirology. 2009 Sep;14(7):940-53. doi: 10.1111/j.1440-1843.2009.01617.x. — View Citation

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. doi: 10.5858/2007-131-407-TBIITP. — View Citation

Mall W, Abel H. Topical application of epinephrine during bronchoscopy in barbiturate-halothane-anaesthesia and its influence on cardiac action. Bronchopneumologie. 1978 Jul-Aug;28(4):311-6. — View Citation

Marquez-Martin E, Vergara DG, Martin-Juan J, Flacon AR, Lopez-Campos JL, Rodriguez-Panadero F. Endobronchial administration of tranexamic Acid for controlling pulmonary bleeding: a pilot study. J Bronchology Interv Pulmonol. 2010 Apr;17(2):122-5. doi: 10.1097/LBR.0b013e3181dc8c17. — View Citation

Matthay RA, Farmer WC, Odero D. Diagnostic fibreoptic bronchoscopy in the immunocompromised host with pulmonary infiltrates. Thorax. 1977 Oct;32(5):539-45. doi: 10.1136/thx.32.5.539. — View Citation

Mazkereth R, Paret G, Ezra D, Aviner S, Peleg E, Rosenthal T, Barzilay Z. Epinephrine blood concentrations after peripheral bronchial versus endotracheal administration of epinephrine in dogs. Crit Care Med. 1992 Nov;20(11):1582-7. doi: 10.1097/00003246-199211000-00017. — View Citation

Orlandi RR, Warrier S, Sato S, Han JK. Concentrated topical epinephrine is safe in endoscopic sinus surgery. Am J Rhinol Allergy. 2010 Mar-Apr;24(2):140-2. doi: 10.2500/ajra.2010.24.3454. — View Citation

Papin TA, Lynch JP 3rd, Weg JG. Transbronchial biopsy in the thrombocytopenic patient. Chest. 1985 Oct;88(4):549-52. doi: 10.1378/chest.88.4.549. — View Citation

Papp AA, Uusaro AV, Ruokonen ET. The effects of topical epinephrine on haemodynamics and markers of tissue perfusion in burned and non-burned patients requiring skin grafting. Burns. 2009 Sep;35(6):832-9. doi: 10.1016/j.burns.2008.10.001. Epub 2009 May 30. — View Citation

Paret G, Vaknin Z, Ezra D, Peleg E, Rosenthal T, Vardi A, Mayan H, Barzilay Z. Epinephrine pharmacokinetics and pharmacodynamics following endotracheal administration in dogs: the role of volume of diluent. Resuscitation. 1997 Aug;35(1):77-82. doi: 10.1016/s0300-9572(96)01091-x. — View Citation

Pinsker KL, Kamholz SL. Diagnosis of sarcoidosis by transbronchial lung biopsy. Chest. 1981 Jan;79(1):123-4. doi: 10.1378/chest.79.1.123b. No abstract available. — View Citation

Poletti V, Ravaglia C, Buccioli M, Tantalocco P, Piciucchi S, Dubini A, Carloni A, Chilosi M, Tomassetti S. Idiopathic pulmonary fibrosis: diagnosis and prognostic evaluation. Respiration. 2013;86(1):5-12. doi: 10.1159/000353580. Epub 2013 Jun 26. — View Citation

Prakash UB, Offord KP, Stubbs SE. Bronchoscopy in North America: the ACCP survey. Chest. 1991 Dec;100(6):1668-75. doi: 10.1378/chest.100.6.1668. — View Citation

Roberts JR, Greenberg MI, Knaub MA, Kendrick ZV, Baskin SI. Blood levels following intravenous and endotracheal epinephrine administration. JACEP. 1979 Feb;8(2):53-6. doi: 10.1016/s0361-1124(79)80036-2. — View Citation

Sahebjami H. Letter: Iced saline lavage during bronchoscopy. Chest. 1976 Jan;69(1):131-2. doi: 10.1378/chest.69.1.131b. No abstract available. — View Citation

Sehgal IS, Bal A, Dhooria S, Agrawal P, Gupta N, Ram B, Aggarwal AN, Behera D, Agarwal R. 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. 2016 Jun;149(6):1584-6. doi: 10.1016/j.chest.2016.03.025. No abstract available. — View Citation

Shigemura N, Wan IY, Yu SC, Wong RH, Hsin MK, Thung HK, Lee TW, Wan S, Underwood MJ, Yim AP. Multidisciplinary management of life-threatening massive hemoptysis: a 10-year experience. Ann Thorac Surg. 2009 Mar;87(3):849-53. doi: 10.1016/j.athoracsur.2008.11.010. — View Citation

Solomonov A, Fruchter O, Zuckerman T, Brenner B, Yigla M. Pulmonary hemorrhage: A novel mode of therapy. Respir Med. 2009 Aug;103(8):1196-200. doi: 10.1016/j.rmed.2009.02.004. Epub 2009 Feb 28. — View Citation

Steinfort DP, Herth FJ, Eberhardt R, Irving LB. Potentially fatal arrhythmia complicating endobronchial epinephrine for control of iatrogenic bleeding. Am J Respir Crit Care Med. 2012 May 1;185(9):1028-30. doi: 10.1164/ajrccm.185.9.1028. No abstract available. — View Citation

Steinfort DP, Herth FJ, Eberhardt R, Irving LB. Reply: Endobronchial epinephrine: confusion is in the air. Am J Respir Crit Care Med. 2013 May 15;187(10):1138. doi: 10.1164/rccm.201301-0123LE. No abstract available. — View Citation

Talmage EA. Safe combined general and topical anesthesia for laryngoscopy and bronchoscopy. South Med J. 1973 Apr;66(4):455-9. doi: 10.1097/00007611-197304000-00015. No abstract available. — View Citation

Timofte I, Terrin M, Barr E, Sanchez P, Kim J, Reed R, Britt E, Ravichandran B, Rajagopal K, Griffith B, Pham S, Pierson RN 3rd, Iacono A. Belatacept for renal rescue in lung transplant patients. Transpl Int. 2016 Apr;29(4):453-63. doi: 10.1111/tri.12731. Epub 2016 Feb 8. — View Citation

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. 1992 Oct;102(4):1049-54. doi: 10.1378/chest.102.4.1049. — View Citation

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. 2014 Aug;4(8):646-50. doi: 10.1002/alr.21325. Epub 2014 Mar 26. — View Citation

Vitulo P, Cremaschi P, Arbustini E, Volpato G, Volpini E, Martinelli L, Fracchia C, Rossi A. Surveillance transbronchial biopsy in the diagnosis of acute lung rejection in heart and lung and lung transplant recipients. Monaldi Arch Chest Dis. 1996 Feb;51(1):12-5. — View Citation

Yendamuri S. Massive Airway Hemorrhage. Thorac Surg Clin. 2015 Aug;25(3):255-60. doi: 10.1016/j.thorsurg.2015.04.009. Epub 2015 Jun 12. — View Citation

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. 2014 Mar 1;14:143. doi: 10.1186/1471-2407-14-143. — View Citation

Zamani A. Bronchoscopic intratumoral injection of tranexamic acid: a new technique for control of biopsy-induced bleeding. Blood Coagul Fibrinolysis. 2011 Jul;22(5):440-2. doi: 10.1097/MBC.0b013e328346efb7. — View Citation

Zavala DC. Diagnostic fiberoptic bronchoscopy: Techniques and results of biopsy in 600 patients. Chest. 1975 Jul;68(1):12-9. doi: 10.1378/chest.68.1.12. — View Citation

* Note: There are 56 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major hemorrhage as defined by two independent reviewers.	The primary efficacy outcome of the PROPHET Study is the prevalence of major hemorrhage during bronchoscopy 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 the following grading system: No hemorrhage.; Minor hemorrhage - Endobronchial hemorrhage resulting in segmental or more distal bronchus blood spillage.; Intermediate hemorrhage - Endobronchial hemorrhage resulting in lobar bronchus blood spillage.; Major hemorrhage - Endobronchial hemorrhage resulting in mainstem bronchus, more proximal blood spillage, or spillage into the uninvolved lung.	Primary outcome is defined as hemorrhage occurring up to 30 minutes after withdrawal of the bronchoscope and deemed related to transbronchial lung biopsy.
Secondary	Occurrence of no, minor, or intermediate bleeding as defined by the independent reviewer.	Prevalence of no-, minor, or intermediate hemorrhage during bronchoscopy 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.	This outcome is defined as hemorrhage occurring during the bronchoscopic procedure and deemed related to transbronchial lung biopsy and up to 30 minutes following withdrawal of the bronchoscope.
Secondary	Intra-procedural hemorrhage grading by the performing bronchoscopist	Intra-procedural hemorrhage will be graded by the performing bronchoscopist according to the following scale: No hemorrhage.; Mild hemorrhage - Any bleeding originating from the biopsy target airway requiring wedging of the bronchoscope or "in and out" motion in order to achieve hemostasis.; Moderate hemorrhage - 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 hemorrhage - 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.	This outcome will be analyzed at the time of procedure performance and up to 48 hours following the procedure.
Secondary	Number of forceps passes performed	Number of biopsy forceps passes performed during bronchoscopy.	This outcome will be analyzed at the time of procedure performance.
Secondary	Number of adequate tissue samples obtained	Number of adequate tissue samples obtained during bronchoscopy as assessed by the performing bronchoscopist.	This outcome will be analyzed at the time of procedure performance.
Secondary	Early termination of the procedure	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.	This outcome will be analyzed at the time of procedure performance.
Secondary	Duration of the procedure	Duration of the procedure from first bronchoscope insertion to last bronchoscope withdrawal.	Duration of the procedure from first bronchoscope insertion to last bronchoscope withdrawal.
Secondary	Total volume of iced saline used	Total volume (mL) of iced saline used during the procedure.	This outcome will be analyzed at the time of procedure performance.
Secondary	Total dose of unblended topical epinephrine used	Total dose (mg) of unblended topical epinephrine used during the procedure.	This outcome will be analyzed at the time of procedure performance.
Secondary	Any use of hemostatic measures	Any use of hemostatic procedures including balloon tamponade, endobronchial blocker, bronchial artery embolization, emergency surgery.	This outcome will be analyzed at the time of procedure performance.
Secondary	Any use of devices or procedures with intention of securing the airway	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.	This outcome will be analyzed at the time of procedure performance.
Secondary	Unplanned admission to the hospital.	Unplanned admission to the hospital.	This outcome will be analyzed at the time of procedure performance and up to 48 hours following the procedure.
Secondary	Pathologic diagnosis achieved.	Biopsy resulting in acquisition of a specimen which allows a viable pathologic diagnosis.	Up to 30 days post-procedure.
Secondary	All-cause mortality	All-cause mortality	Within 3 hours on instillation of study drug.
Secondary	Acute cardiovascular event	Acute cardiovascular event, including cardiac arrest, new onset chest pain, acute myocardial ischemia, pulmonary edema, acute ischemic stroke, critical limb ischemia, acute mesenteric ischemia.	Within 30 minutes of instillation of the study drug.
Secondary	Acute closed angle glaucoma	Acute closed angle glaucoma	Within 30 minutes of instillation of the study drug.
Secondary	New onset ECG changes suggestive of myocardial ischemia	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.	Within 30 minutes of instillation of the study drug.
Secondary	Significant change in heart rate	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.	Within 30 minutes of instillation of the study drug.
Secondary	Significant change in systolic blood pressure	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.	Within 30 minutes of instillation of the study drug.