Prophylactic Topical Epinephrine to Reduce Bleeding in Transbronchial Lung Biopsies (PROPHET)

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)

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.

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: 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. 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. 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: The frequency of active measures taken to control pulmonary hemorrhage once it occurred. The proportion of procedures completed as planned in terms of obtaining a predefined target number of biopsy specimens. Comparison between single- and double-lung transplant recipients in terms of prevalence and degree of TBLB-related hemorrhage. 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: Overall duration of the bronchoscopic procedure. The proportion of procedures completed as planned in terms of number of adequate biopsies obtained as assessed by the physician performing the bronchoscopy. 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: The prevalence of clinically significant hemodynamic changes. The prevalence of cardiac adverse events, including conduction abnormalities, arrhythmia, and myocardial ischemia. The prevalence of other vascular adverse events, including stroke, mesenteric ischemia, and critical limb ischemia. Identification of clinical factors associated with an increased or decreased risk of drug-related adverse events.

Study participants who meet inclusion and exclusion criteria and allocated to this arm will be randomized to receive prophylactic endobronchial topical epinephrine in a blinded manner prior to performance of transbronchial lung biopsy.

Study participants who meet inclusion and exclusion criteria and allocated to this arm will be randomized to receive prophylactic endobronchial topical placebo in the form of normal saline in a blinded manner prior to performance of transbronchial lung biopsy.

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.

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.

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.

Number of adequate tissue samples obtained during bronchoscopy as assessed by the performing bronchoscopist.

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.

Any use of hemostatic procedures including balloon tamponade, endobronchial blocker, bronchial artery embolization, emergency surgery.

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 and up to 48 hours following the procedure.

Acute cardiovascular event, including cardiac arrest, new onset chest pain, acute myocardial ischemia, pulmonary edema, acute ischemic stroke, critical limb ischemia, acute mesenteric 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.

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.

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.

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.

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