E-cigarettes, Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
E-cigarettes, COPD
Brief summary
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.
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.
Interventions
DEVICEE-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.
OTHERSham
The unexposed condition will be breathing from the study e-cigarette (10 puffs with 30-second inter-puff intervals) with the battery off.
DRUGHyperpolarized 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.
DRUGGadolinium
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).
Sponsors
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 35 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary Microvascular Blood Flow (PMBF), Measured on Gadolinium-enhanced MRI, Between E-cigarette Exposed and Unexposed Conditions | After exposure (approximately 30 seconds) | 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. |
| Ventilation Defect Percentage (VDP), Measured on Hyperpolarized 3-helium Enhanced MRI | After exposure (approximately 30 seconds) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lung Function, Measured on Spirometry | After exposure (approximately 30 seconds) | 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. |
| Regional PMBF, Measured on Gadolinium-enhanced MRI | After exposure (approximately 30 seconds) | 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. |
| Cardiac Output, Measured on Cardiac MRI | After exposure (approximately 30 seconds) | 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. |
| Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) | After exposure (approximately 30 seconds) | 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. |
| Regional VDP, Measured on Hyperpolarized 3-helium Enhanced MRI | After exposure (approximately 30 seconds) | Regional VDP in the lower lung was measured on hyperpolarized 3Helium-enhanced MRI after e-cigarette and sham exposures. |
Countries
United States
Participant flow
Pre-assignment details
There were a total of 12 subjects enrolled. 6 subjects were randomized to E-cigarette first, of which 5 completed the full protocol. 5 subjects were randomized to Sham first, all 5 of whom completed the full protocol. 1 subject was consented but not randomized.
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Total |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 5 |
| other Total, other adverse events | 0 / 6 | 0 / 5 |
| serious Total, serious adverse events | 0 / 6 | 0 / 5 |
Outcome results
Primary
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.
Time frame: After exposure (approximately 30 seconds)
Population: Since this study applied a randomized crossover design, participants from both randomization groups (exposure first and sham first) experienced both e-cigarette and sham exposures. In this outcome measure, the same 10 evaluable subjects all had exposure and no exposure at different time periods in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exposed to E-cigarette | Pulmonary Microvascular Blood Flow (PMBF), Measured on Gadolinium-enhanced MRI, Between E-cigarette Exposed and Unexposed Conditions | 74.4 mL(blood)/min/mL(lung) | Standard Deviation 23.9 |
| Unexposed (Sham) | Pulmonary Microvascular Blood Flow (PMBF), Measured on Gadolinium-enhanced MRI, Between E-cigarette Exposed and Unexposed Conditions | 63.1 mL(blood)/min/mL(lung) | Standard Deviation 19.4 |
Comparison: Within-person effects of e-cigarette exposure on pulmonary microvascular blood flow (PMBF) was assessed via mixed models accounting for order effects.~Null hypothesis: e-cigarette exposure is NOT associated with a change in PMBF.~Alternative hypothesis: e-cigarette exposure IS associated with a change in PMBF.~Power calculation: not applicable since this was a pilot/feasibility study.p-value: 0.01295% CI: [4.012, 23.94]Mixed Models Analysis
Primary
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.
Time frame: After exposure (approximately 30 seconds)
Population: A subset of participants were unable to complete the 3-He enhanced MRI due to problems with the helium polarizer and/or scanner (e.g., unable to fit into scanner due to body size). In this outcome measure, 7 out of 11 subjects had evaluable data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exposed to E-cigarette | Ventilation Defect Percentage (VDP), Measured on Hyperpolarized 3-helium Enhanced MRI | 5.5 percentage of total lung volume | Standard Deviation 4.4 |
| Unexposed (Sham) | Ventilation Defect Percentage (VDP), Measured on Hyperpolarized 3-helium Enhanced MRI | 6.6 percentage of total lung volume | Standard Deviation 4.4 |
Secondary
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.
Time frame: After exposure (approximately 30 seconds)
Population: In this outcome measure, 8 subjects had evaluable data for the exposed time period and 7 subjects had evaluable data for the unexposed time period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exposed to E-cigarette | Cardiac Output, Measured on Cardiac MRI | 6197 mL/min | Standard Deviation 1097 |
| Unexposed (Sham) | Cardiac Output, Measured on Cardiac MRI | 6093 mL/min | Standard Deviation 844 |
Secondary
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.
Time frame: After exposure (approximately 30 seconds)
Population: In this outcome measure, the machine broke and only 3 subjects had evaluable data for the exposed time period and 2 subjects had evaluable data for the unexposed time period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exposed to E-cigarette | Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) | 33.65 mL/min/mm Hg | Standard Deviation 3.53 |
| Unexposed (Sham) | Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) | 32.73 mL/min/mm Hg | Standard Deviation 8.69 |
Secondary
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.
Time frame: After exposure (approximately 30 seconds)
Population: In this outcome measure, 7 out of 11 subjects had evaluable data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exposed to E-cigarette | Lung Function, Measured on Spirometry | 4.22 L | Standard Deviation 0.75 |
| Unexposed (Sham) | Lung Function, Measured on Spirometry | 4.08 L | Standard Deviation 1.14 |
Secondary
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.
Time frame: After exposure (approximately 30 seconds)
Population: Data were not analyzed due to unavailable resources and technology because of the pandemic.
Secondary
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.
Time frame: After exposure (approximately 30 seconds)
Population: A subset of participants were unable to complete the 3-He enhanced MRI due to problems with the helium polarizer and/or scanner (e.g., unable to fit into scanner due to body size). In this outcome measure, 7 out of 11 subjects had evaluable data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exposed to E-cigarette | Regional VDP, Measured on Hyperpolarized 3-helium Enhanced MRI | 3.6 percentage of total lung volume | Standard Deviation 2.8 |
| Unexposed (Sham) | Regional VDP, Measured on Hyperpolarized 3-helium Enhanced MRI | 5.8 percentage of total lung volume | Standard Deviation 6.2 |