Ventilation and Pulmonary Endothelium Toxicities of E-cigarettes: A Randomized Crossover Pilot Study (VaPE-Tox)

Ventilation and Pulmonary Endothelium Toxicities (VaPE-Tox) of E-cigarettes: A Randomized Crossover Pilot Study

Determination of the acute pulmonary toxicities of e-cigarettes in young adults is of major public health importance, as e-cigarette vapor contains established toxicants that as hypothesized cause acute damage to the airways and the pulmonary microvasculature that may promote the development of CLD, for which there remain few effective therapies.

The study therefore propose a pilot study using a randomized crossover design in ten healthy young adults to test the acute effects of a standardized e-cigarette exposure on two sensitive, safe, non-invasive imaging measures: (1) ventilation defects on hyperpolarized helium-enhanced magnetic resonance imaging, and (2) pulmonary microvascular blood flow on gadolinium-enhanced pulmonary magnetic resonance angiography.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive; E-cigarettes
• Intervention / Treatment: Device: E-cigarette; Other: Sham; Drug: Hyperpolarized 3-Helium; Drug: Gadolinium

Detailed Description

Magnetic resonance imaging (MRI) and angiography (MRA) measures are promising approaches to detecting and characterizing the anticipated acute pulmonary toxicities of e-cigarettes. Hyperpolarized helium (3He)-enhanced MRI may be more sensitive than spirometry, a global lung function measure, for determination of airway toxicities. 3He-enhanced MRI has been used to demonstrate the extent of ventilation defects in healthy persons with normal spirometry; to measure ventilation changes in asthmatics pre- and post-challenge with bronchodilators and methacholine; and to predict pulmonary hospitalizations in persons with COPD. Meanwhile, until recently, non-invasive measures of pulmonary vascular toxicities were lacking. The investigators have developed an innovative measure of pulmonary microvascular blood flow on gadolinium (Gd)-enhanced MRA, which the investigators found to be markedly abnormal in early chronic obstructive pulmonary disease (COPD) and emphysema, and to be associated with increased endothelial microparticles, a marker of endothelial dysfunction. Nonetheless, neither of these sensitive, non-invasive, repeatable, and reproducible measures has ever been used to assess e-cigarette toxicities.

It is hypothesized that e-cigarette vapor inhalation will result in an acute increase in global and regional ventilation defects and an acute decrease in global and regional pulmonary microvascular perfusion.

This pilot work will provide the experience and data to support subsequent funding applications powered to definitively establish the acute toxicities of e-cigarette vapor of various compositions (e.g., with and without nicotine, with and without flavoring) in persons with and without chronic lung diseases (e.g., asthma) on pulmonary ventilation and microvascular perfusion. Furthermore, confirmation of the hypotheses in this sample would provide important preliminary evidence of e-cigarette pulmonary toxicities to inform interim regulatory decisions, as well as potentially generating vivid images of e-cigarette harms that may be meaningful to the general public and therefore suitable for use in public education campaigns.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• current use of e-cigarettes (>1x/month but <4 days/week)

Exclusion Criteria:

• any chronic medical or major psychiatric problems including current asthma
• self-reported heavy snoring/sleep apnea
• pre-bronchodilator FEV1 or FVC <80% predicted or FEV1/FVC < lower limit of normal
• MRI exclusions (pregnancy, claustrophobia, metal in body, gadolinium allergy, eGFR <60 mL/min/1.73m2)
• MRI scan with contrast within the last 12 months or planned MRI with contrast in the next 6 months
• use of any of the following in the prior 30 days: any conventional cigarettes, marijuana >10 days, any illicit drugs, any medication or inhalers (excluding hormonal contraceptives)
• binge drinking (≥5 alcoholic beverages over 2 hours) over the prior two weeks
• adverse symptomatic response to the study e-cigarette exposure (e.g., palpitations, shortness of breath, chest pain, headache, dizziness)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: E-cigarette first; Participants will undergo the e-cigarette exposure prior to the first two MRI measures, and then they will undergo the sham exposure prior to the last two MRI measures. The two MRIs performed under both experimental exposures (e-cigarette and sham) will be enhanced by (1) gadolinium and then (2) hyperpolarized 3-helium.	Device: E-cigarette; The study e-cigarette exposure will be 10 puffs with 30-second inter-puff intervals, as directly observed by a trained research assistant, using a standardized e-cigarette. Cartomizers, batteries, and e-liquids will be obtained from commercial suppliers. The e-cigarette device will be loaded with 1 mL of flavorless e-liquid with a ratio of PG to vegetable glycerin of 70:30 and 1.8 mg/dL of nicotine.; Other: Sham; The "unexposed" condition will be breathing from the study e-cigarette (10 puffs with 30-second inter-puff intervals) with the battery off.; Drug: Hyperpolarized 3-Helium; Hyperpolarized 3-Helium will be used as an experimental contrast agent for the Ventilation MRIs performed twice per participant in both experimental arms. Approximately 250-600 mL of hyperpolarized 3He mixed with 300-750 mL nitrogen will be inhaled through a one-way valve in one inhalation starting approximately at residual volume.; Other Names: 3-He; Drug: Gadolinium; Gadolinium contrast will be injected into the antecubital vein through an 18-20 gauge IV. The type of gadolinium will be 0.03 mmol/kg bodyweight of dotarem (gadoterate meglumine).; Other Names: Gd
Experimental: Sham first; Participants will undergo the sham exposure prior to the first two MRI measures, and then they will undergo the e-cigarette exposure prior to the last two MRI measures. The two MRIs performed under both experimental exposures (e-cigarette and sham) will be enhanced by (1) gadolinium and then (2) hyperpolarized 3-helium.	Device: E-cigarette; The study e-cigarette exposure will be 10 puffs with 30-second inter-puff intervals, as directly observed by a trained research assistant, using a standardized e-cigarette. Cartomizers, batteries, and e-liquids will be obtained from commercial suppliers. The e-cigarette device will be loaded with 1 mL of flavorless e-liquid with a ratio of PG to vegetable glycerin of 70:30 and 1.8 mg/dL of nicotine.; Other: Sham; The "unexposed" condition will be breathing from the study e-cigarette (10 puffs with 30-second inter-puff intervals) with the battery off.; Drug: Hyperpolarized 3-Helium; Hyperpolarized 3-Helium will be used as an experimental contrast agent for the Ventilation MRIs performed twice per participant in both experimental arms. Approximately 250-600 mL of hyperpolarized 3He mixed with 300-750 mL nitrogen will be inhaled through a one-way valve in one inhalation starting approximately at residual volume.; Other Names: 3-He; Drug: Gadolinium; Gadolinium contrast will be injected into the antecubital vein through an 18-20 gauge IV. The type of gadolinium will be 0.03 mmol/kg bodyweight of dotarem (gadoterate meglumine).; Other Names: Gd

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary Microvascular Blood Flow (PMBF), Measured on Gadolinium-enhanced MRI, Between E-cigarette Exposed and Unexposed Conditions	PMBF will be measured on gadolinium-enhanced MRI after e-cigarette and sham exposures. There were four days between the measurements of PMBF (e-cigarette) and PMBF (sham). PMBF is measured in mL(blood)/min/mL(lung volume). Lower PMBF has been observed in adults with COPD and emphysema.	After exposure (approximately 30 seconds)
Ventilation Defect Percentage (VDP), Measured on Hyperpolarized 3-helium Enhanced MRI	VDP will be measured on hyperpolarized 3Helium-enhanced MRI after e-cigarette and sham exposures. Due to limitations of prior qualitative/visual assessments of MRI, we developed and validated a new deep learning approach to the precise measurement of ventilation defects and report the percent non-fully ventilated lung using this method.	After exposure (approximately 30 seconds)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional PMBF, Measured on Gadolinium-enhanced MRI	Regional PMBF (ie, in the right versus left, upper versus lower lobes) will be measured on gadolinium-enhanced MRI after e-cigarette and sham exposures.	After exposure (approximately 30 seconds)
Regional VDP, Measured on Hyperpolarized 3-helium Enhanced MRI	Regional VDP in the lower lung was measured on hyperpolarized 3Helium-enhanced MRI after e-cigarette and sham exposures.	After exposure (approximately 30 seconds)
Lung Function, Measured on Spirometry	Lung function will be measured on spirometry. Two participants had only one valid FEV1 measure, and one participant had no valid FEV1 measures. Hence, 3 participants (2 in "E-cigarette first" and 1 in "Sham first") were not analyzed. The analysis combines the groups in order to separate the effects of randomization group (order) and exposure.	After exposure (approximately 30 seconds)
Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)	DLCO will be measured. There was a malfunction of the machine used to measure the DLCO. Hence, only one participant had paired DLCO values and 3 had unpaired measures.	After exposure (approximately 30 seconds)
Cardiac Output, Measured on Cardiac MRI	Cardiac output will be measured on cardiac MRI. In the "E-cigarette first" arm, 2 participants did not have 2 valid measures of CO (one pair was missing, one was invalid). In the "Sham first" arm, 3 participants had one invalid measure of CO. The analysis combines the groups in order to separate the effects of randomization group (order) and exposure.	After exposure (approximately 30 seconds)

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Elizabeth Oelsner, MD, MPH, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Actual): July 24, 2018
• Study Completion (Actual): July 24, 2018

Study Registration Dates

• First Submitted: May 24, 2016
• First Submitted That Met QC Criteria: May 24, 2016
• First Posted (Estimate): May 26, 2016

Study Record Updates

• Last Update Posted (Actual): October 22, 2020
• Last Update Submitted That Met QC Criteria: September 29, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: COPD; E-cigarettes
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: AAAQ8089

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes