Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2018-024521 on 23 March 2019. Downloaded from Prophylactic epinephrine for the prevention of transbronchial lung biopsy-related bleeding in lung transplant recipients (PROPHET) study: a protocol for a multicentre randomised, double-blind, placebo-controlled trial Or Kalchiem-Dekel,1 Aldo Iacono,2 Edward M Pickering,1 Ashutosh Sachdeva,1 Nirav G Shah,1 Mark Sperry,1 Bich-Chieu Tran,1 Robert M Reed 1 To cite: Kalchiem-Dekel O, ABSTRACT Strengths and limitations of this study Iacono A, Pickering EM, et al. Introduction Transbronchial lung biopsy (TBLB) is Prophylactic epinephrine for frequently performed in single-lung and double-lung the prevention of transbronchial ► Randomised, double-blinded, placebo-controlled transplant recipients for evaluation of clinical and lung biopsy-related bleeding multicentre design to ensure unbiased treatment radiological findings as well as routine surveillance for in lung transplant recipients effect measure. acute cellular rejection. While rates of clinically significant (PROPHET) study: a protocol ► Comprehensive data are collected, including vid- for a multicentre randomised, TBLB-related haemorrhage are <1% for all comers, the eo-recording of bronchoscopic procedures, to allow double-blind, placebo- incidence in lung transplant recipients is reported to be independent evaluation by observers blinded to the controlled trial. BMJ Open higher, presumably due to persistent allograft inflammation individual participant data and study arm allocation. 2019;9:e024521. doi:10.1136/ and alterations in allograft blood flow. While routinely Study outcome to be evaluated comprehensively via bmjopen-2018-024521 ► performed by some bronchoscopists, the efficacy and several grading scales by both procedure performer ► Prepublication history for safety profile of prophylactic administration of topical and independent observers. this paper is available online. intrabronchial diluted epinephrine for the prevention of ► The target population of the study, while enriching To view these files, please visit TBLB-related haemorrhage has not been explored in a the outcome of interest, may limit generalisability of http://bmjopen.bmj.com/ the journal online (http:// dx. doi. prospective manner. the findings to other populations. org/ 10. 1136/ bmjopen- 2018- Methods and analysis In this randomised, double-blind, Data informing optimal dose of topical epinephrine 024521). ► placebo-controlled multicentre trial (PROPHET Study), and volume of instillation are lacking. Dose and vol- Received 31 May 2018 single-lung and double-lung transplant adult recipients ume used in this study are based on local expertise Revised 20 February 2019 from participating institutions who are scheduled for and may not necessarily represent optimal values. Accepted 21 February 2019 bronchoscopy with TBLB for clinical indications will be identified. Potential participants who meet inclusion and exclusion criteria and sign an informed consent will study will be published in peer-reviewed scientific journals be randomised to receive either diluted epinephrine or and presented at relevant academic conferences. on October 1, 2021 by guest. Protected copyright. placebo prior to performance of TBLB. The degree of TBLB- Trial registration number NCT03126968; Pre-results. related haemorrhage will be graded by the performing bronchoscopist as well as independent observers. The primary analysis will compare the rates of severe and very INTRODUCTION severe bleeding in participants treated with epinephrine or Flexible bronchoscopy with transbron- placebo. The study will also evaluate the safety profile of chial lung biopsy (TBLB) has become a prophylactic topical epinephrine including the occurrence central diagnostic modality for assessment © Author(s) (or their of serious cardiovascular and haemodynamic adverse of lung allograft function and specifically events. Additional secondary outcomes to be explored employer(s)) 2019. Re-use acute cellular rejection (ACR) following permitted under CC BY-NC. No include rates of non-severe TBLB-related haemorrhage, lung transplantation. Most lung transplant commercial re-use. See rights overall yield of the bronchoscopic procedure and non- and permissions. Published by serious cardiovascular and haemodynamic adverse effects. programmes now perform TBLB for allograft BMJ. Ethics and dissemination The study procedures were function surveillance, new onset symp- For numbered affiliations see reviewed and approved by institutional review boards in toms, ≥10% decrease in forced expiratory end of article. participating institutions. This study is being externally volume over 1 s, assessment of new findings Correspondence to monitored, and a data and safety monitoring committee on chest imaging or as a follow-up for acute 1 Dr Robert M Reed; has been assembled to monitor patient safety and to rejection or cytomegalovirus pneumonitis. rreed@ som. umaryland. edu evaluate the efficacy of the intervention. The results of this For ACR surveillance in lung and lung–heart Kalchiem-Dekel O, et al. BMJ Open 2019;9:e024521. doi:10.1136/bmjopen-2018-024521 1 Open access BMJ Open: first published as 10.1136/bmjopen-2018-024521 on 23 March 2019. Downloaded from transplant recipients, most transplant centres will obtain such as tranexamic acid.17 18 Dosing of topical epineph- at least 5 and up to 10 biopsies per procedure.2 3 The rine for treatment of airway bleeding lacks standardisa- frequency and period of time over which surveillance tion. Recommendations regarding epinephrine dilution biopsies are obtained is debatable and based on local range between 1:10 000 and 1:100 000 and recommended expertise within transplant institutions. volumes of instillation vary between 0.5 mL and 20 mL TBLB is generally safe, although severe and life-threat- in different publications.16 19–21 Our local practice for ening procedure-related complications are occasionally the initial treatment of endobronchial bleeding includes encountered. Most common among them are pneumo- administration of iced saline in aliquots of 2–10 mL thorax and haemorrhage. Large population-based studies followed by 1–2 mL aliquots of 1:10 000 topical epineph- have established the overall rate of TBLB-related haem- rine (0.1–0.2 mg) to a maximum of 6 mL (0.6 mg). orrhage, defined arbitrarily as recovery of ≥50 mL of Although adopted by some providers as means to bloody fluid, at 0.58%–0.73%.4 5 Death related to airway reduced TBLB-related haemorrhage, the use of prophy- bleeding in association with bronchoscopic procedures is lactic instillation of diluted epinephrine into the target exceedingly rare.5 6 Evidence suggests a higher propen- bronchus before attempting TBLB is not established in sity for TBLB-related bleeding in the lung and heart–lung the literature. The main body of evidence regarding the transplant population. In a population of lung–heart efficacy and safety of prophylactic topical epinephrine transplant patients, Scott et al2 recorded a 12.6% rate for the prevention of haemorrhage is derived from the of >100 mL procedure-related bleeding. In another surgical literature, specifically endoscopic endonasal and prospective study, Diette et al7 recorded higher rates sinus surgery, rhinoplasty and surgical management of of bronchoscopy-related haemorrhage, postprocedure burn injuries.22–25 haemoptysis and early termination of a procedure due The potential for endobronchially administered to bleeding in lung transplant patients when compared epinephrine to result in adverse haemodynamic effects with non-transplant controls. Possible reasons posited to is well recognised, and dosing recommendations have explain the greater propensity to bleed among lung trans- been made since the 1970s.26 Nevertheless, evidence of plant recipients include an already inflamed lung tissue such adverse effects is scarce. Janjua et al27 reported a case from infection, ACR or bronchiolitis obliterans, as well as of coronary vasospasm manifesting as chest pain, ST-seg- an increase in blood flow to the transplanted lung, partic- ment elevation and ectopy induced by topical adminis- ularly in recipients of single lung transplants.7 tration of 3 mL of 1:10 000 diluted epinephrine during Quantification of TBLB-related bleeding is difficult, bronchoscopy. In this case, epinephrine was adminis- subjective and prone to bias. Many investigators use tered into inflamed and friable airways of a lung cancer grading systems that rely on the amount of mixed blood patient for the treatment of established bleeding, poten- and bronchial wash fluid in the vacuum suction system tially augmenting the area of contact between epineph- 5 8–10 at the end of the procedure. This method may be rine and injured blood vessels. More recently, two cases http://bmjopen.bmj.com/ prone to measurement errors in estimation of the actual of ventricular fibrillation possibly induced by broncho- extent of blood loss during the procedure due to dilu- scopic administration of epinephrine for TBLB-related tion of blood with other airway secretions as well as fluids bleeding were reported.28–30 In both cases, arrhythmia administered via the bronchoscope channel. Pilarczyk et occurred with bronchoscopic instillation of epinephrine al11 suggested a grading system that classifies endobron- as a therapeutic measure in response to bleeding and via chial haemorrhage based on the most proximal bronchus a catheter that was positioned distally in the bronchial in