Conditions: Pulmonary Disease, Chronic Obstructive E-cigarettes
Keywords: E-cigarettes COPD
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 12
Healthy volunteers: yes

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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: E-cigarette intervention 2: Sham intervention 3: Hyperpolarized 3-Helium intervention 4: Gadolinium
Intervention descriptions: intervention 1: 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. intervention 2: The "unexposed" condition will be breathing from the study e-cigarette (10 puffs with 30-second inter-puff intervals) with the battery off. intervention 3: 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. intervention 4: 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).

Protocol document:
Prot_SAP_000.pdf: 
 
 
NCT02783768 
 
Study Description 
AAAQ8089 
VAPE-Tox Study 
Version 1.4 5/11/2017 
 
Protocol Title: Ventilation and Pulmonary Endothelium Toxicities (VaPE-Tox) of E-cigarettes: A 
Randomized Crossover Pilot Study 
 
1. Study Purpose and Rationale. 
 
As e-cigarettes become increasingly popular, bolstered by claims that they are relatively safe, 
there is an urgent need for data on the safety of inhalation of e-cigarette vapor. Decades of 
research have demonstrated that the primary site of toxicity of conventional cigarettes is the 
lungs. However, years of exposure are required to affect most standard physiologic measures, 
and e-cigarettes have not been used for long enough to estimate reliably chronic effects. Recent 
advances in non-invasive, radiation-free imaging of the lung, developed in part by our group, 
provide sensitive, specific and reproducible measures to quantify acute pulmonary effects of e-
cigarettes and to predict potential long-term harms. The proposed study employs these 
measures and, thus, may be used to inform regulation. 
 
E-cigarettes may cause acute airway changes due a large number of airway irritants. 
Heated propylene glycol (PG), nicotine, and carbonyls – all commonly found in e-cigarette vapor 
– stimulate vagal C-fibers in the pulmonary epithelium that trigger neuropeptide release, 
inflammation, mucous production, bronchoconstriction, and, potentially, airway remodeling 
leading to chronic lung diseases. Consistent with this, e-cigarette liquid induces airway 
inflammation and hyper-responsiveness in mice and its use, in humans, increases airway 
impedance and peripheral airway resistance by oscillometry. However, e-cigarettes have not 
been proved to reduce lung function, possibly due to the insensitivity of spirometry. 
Hyperpolarized helium (3He) magnetic resonance imaging (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 albuterol and methacholine; and 
to predict pulmonary hospitalizations in persons with COPD. Hence, 3He MRI represents a 
promising but as-yet untested approach to detect, measure, and illustrate acute airway 
effects of e-cigarettes that may predict increased long-term risk of chronic lung disease. 
 
Nicotine and carbonyls such as acrolein have well-established effects on the 
endothelium, suggesting that e-cigarettes may cause acute pulmonary microvascular changes. 
E-cigarette vapor with and without nicotine causes endothelial barrier dysfunction in vitro and, in 
humans, has been associated with decreased exhaled nitric oxide, a major vasodilator and 
regulator of pulmonary microvascular tone.  E-cigarette-related endothelial dysfunction may 
therefore decrease pulmonary microvascular perfusion, which is implicated in the pathogenesis 
of emphysema. Until recently, direct measures of pulmonary microvascular blood flow were 
lacking. Our group has developed an innovative measure of pulmonary microvascular 
blood flow (PMBF) on gadolinium (Gd)-enhanced magnetic resonance imaging (MRI), 
which we found to be markedly abnormal in early chronic obstructive pulmonary disease 
(COPD) and emphysema, and associated with increased endothelial microparticles, a 
marker of endothelial apoptosis; however, PMBF has never been used to assess e-cigarette 
effects. 
 
We therefore propose to test the acute effects of a standardized e-cigarette 
exposure on pulmonary ventilation and perfusion in a randomized crossover design in 10 
young, healthy, e-cigarette users. We hypothesize that e-cigarette exposure will: 


 
 
1. Increase global and regional ventilation defects on 3He-MRI. 
2. Decrease global and regional pulmonary microvascular blood flow. 
 
This pilot work will provide the experience and data to support subsequent funding 
applications powered to establish definitively the acute pulmonary effects 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 and COPD) with respect to 
ventilation and microvascular perfusion. Furthermore, confirmation of our hypotheses in this 
modest sample would provide important, vivid preliminary data to inform regulatory 
decisions regarding warning labels and public health education.  
 
2. Study Design and Statistical Procedures. 
 
We propose a randomized crossover clinical trial following a run-in period to test the acute 
pulmonary effects of a standardized e-cigarette exposure on 3He-MRI/MRA measures among 
ten young, healthy intermittent e-cigarette users.  
 
Pre-Screening 
Potential participants will be pre-screened for eligibility by trained research assistants via 
telephone. A verbal consent script will be used and an information sheet will be provided. 
Participants found to be eligible on pre-screening will be referred for the first study visit for full 
written informed consent for study procedures and for additional screening (See Figure 1, 
“Consent/Screen”). Screening forms for those who are found to be ineligible (or for those who 
are pre-screened as eligible but do not, for any reason, sign written informed consent at the first 
study visit) will be abstracted, reviewed by the PI, and then discarded in a secure fashion such 
that no PHI is retained.  
 
First Study Visit 
All eligible participants will undergo written informed consent, additional screening procedures, 
and initial evaluation and then be entered into a run-in period to ensure their ability to abstain 
from non-study e-cigarettes and regular cigarettes for the duration of the study (Figure 1). 
 
Randomization 
Participants who are confirmed as adherent after the run-in period will be immediately assigned 
by random number generator in SAS to receive the e-cigarette exposure on days 2-3 or on days 


 
 
6-7, with a 72-hour period between exposed and unexposed conditions. Allocation will be 
concealed until Day 2, when the first experimental exposure is administered. 
Experimental exposure 
 
For the experimental exposure, all participants will use identical, study-provided e-cigarette 
devices; however, these study devices will not be shared between participants. Each device will 
be labeled with the participant number and stored securely between participant uses. After a 
participant completes the study, that participant’s dedicated device will be discarded by 
Environmental Health and Safety.  
 
“Pen-style” e-cigarettes confirmed to be MRI-safe will be used. Cartomizers, batteries, and e-
liquids will be obtained from commercial suppliers. The e-cigarette device will be loaded with 2 
mL of flavorless e-liquid with a ratio of PG to vegetable glycerin of 70:30 and 1.8 mg/dL of 
nicotine. Please see Section 5.3 for additional product details. 
 
Consistent with prior literature, the study e-cigarette exposure will be 10 puffs with 30-second 
inter-puff intervals, as directly observed by a trained research assistant, using the standardized 
e-cigarette. This is anticipated to generate a plasma nicotine concentration of 19 ng/mL, similar 
to 10 puffs of a conventional cigarette. The exposure will be administered under a fume hood 
(Airtech Laminar Flow Workstation, Model ATG 220 UV Therapy Isolation Booth, 
http://www.airtechlaminarflow.com/atg-220.htm) at the enrollment visit in the CTSA and in the 
negative-pressure MRI scanner rooms at two of the four imaging visits. 
 
Blinding 
The “unexposed” condition will be breathing from the study e-cigarette with the battery off (or, if 
this is not feasible, completing the prescribed “puff” maneuvers using only room air). To assess 
the adequacy of blinding, participants will be interviewed at the end of 
study regarding whether they were able to guess correctly their 
allocation assignments. 
 
Imaging 
Gadolinium-enhanced MRI will be performed on days 2 and 6, 
ensuring >48-hour clearance of gadolinium, and 3He-MRI for ventilation 
will be performed on days 3 and 7. 
 
Statistics 
As this is a randomized crossover trial, statistical procedures will 
consist mainly of permutation tests. The proposed study is designed to 
generate preliminary data rather than definitively to confirm or rule out 
acute pulmonary toxicities of e-cigarettes, although the proposed sample may be adequate to 
detect large effects (Table 1). We will have 60% power at an alpha of 5% in two-tailed 
significance testing to detect the 1.02 increase in ventilation defect percentage (VDP) that may 
be predicted based on prior literature showing an approximately 3% FEV1 decline with e-
cigarettes and additionally assuming that prior associations between FEV1 and VDP are linear. 
Based on published associations between secondhand smoke, endothelial microparticle 
concentrations, and pulmonary microvascular measures such as signal intensity (SI) we might 
anticipate a 5% decrement in PMBF from secondhand smoke exposure alone; however, the 
effect is likely to be larger for e-cigarette vapor given its much higher nicotine yield. 
 
3. Study Procedures 


 
 
Pre-screening 
 
After providing verbal consent for participation in the telephone screening questionnaire, which 
will be administered by a trained research assistant or a study investigator, participants will 
answer 18 questions relating to major inclusion/exclusion criteria for ongoing involvement in the 
study (see attached document). 
 
Main study procedures 
All participants will provide written informed consent prior to enrollment using the appropriate, 
approved consent form with signature obtained by one of the investigators or staff listed as such 
in the Personnel section. 
 
The timing of procedures is schematized in Figure 1. The procedures are as follows: 
 
1. Questionnaires: Questionnaires will be administered to all study participants covering 
respiratory symptoms, medical (including exacerbations) history, cigarette/e-cigarette 
use, and MRI and spirometry exclusions (including pregnancy).  
2. Physical Assessment: Blood Pressure will be measured following the MESA 
protocol. Height and Weight will be measured with a scale and stadiometer. Resting 
and exercise oxygen saturation will be measured non-invasively with a pulse 
oximeter. 
3. Phlebotomy: At the enrollment visit and at Imaging Visits 1 and 3, non-fasting venous 
blood samples will be collected to measure creatinine, oxygen tension, complete 
blood count, and serum nicotine. A maximum of 60 ml (4 tablespoons) will be 
collected at a given visit. Samples will also be banked for future analyses. 
4. Urine collection: urine will be collected at all study visits for cotinine measurement 
(uCot) and pregnancy test (uPT) for all women. Urine will also be banked for future 
analyses. 
5. Exhaled carbon monoxide (ExCO): Participants will exhale into a portable monitor, 
which will indicate whether the participant has recently smoked conventional 
cigarettes.  
6. Spirometry (Spiro): All participants will undergo uniform, standardized spirometry at 
the enrollment visit and prior to and after 3He-MRI scanning. Spirometry will be 
performed using a SensorMedics model 1022 rolling-barrel spirometer and/or the 
NDD EasyOne in accordance with American Thoracic Society (ATS) guidelines. 
7. Diffusion Capacity (DLCO) and lung volumes: These non-invasive tests are similar to 
spirometry, but involve less effort. Diffusion capacity may be measured by the 
rebreathing technique in which the participant will be asked to breathe through a 
closed circuit while the flow and volume of inspired and expired gas are measured 
following ATS guidelines. This will be performed at the enrollment visit and before 
and after 3He-MRI scanning by NDD EasyOne Pro. 
8. Exhaled breath condensate (EBC): Participants will be asked to breathe into an EBC 
collection device (Rtube System, Respiratory Research Inc, Charlottesville, VA) for 
up to 10 minutes. EBC will be aliquoted and stored for subsequent analyses.  
9. E-cigarette exposure: This will be completed as described in (2) and (5) at the 
enrollment visit in the CTSA and at two out of the four imaging visits (days 2-3 or 6-7, 
depending on randomization). 
10. Magnetic Resonance Imaging 
a. Ventilation Scan (3He-MRI): this exam will be used to examine the size and 
function of the lungs. For this exam, the participant will lie on a table inside of the 
MRI for about 30 minutes. Before having the MR exam, participants will be asked 


 
 
questions about their medical history and any exclusion criteria. Approximately 
250-400 mL of hyperpolarized 3He mixed with 600-750 mL of nitrogen will be 
inhaled through a one-way valve in one inhalation starting approximately at 
residual volume. After a rest, inhalations may be repeated up to 3 times per 
session. Blood pressure, respiratory rate, pulse and oxygen saturation are 
monitored continuously during MRI procedures.  
b. Perfusion Scan (Gd-MRA): this exam will be used to evaluate pulmonary 
perfusion and cardiac function. For this exam, the participant will lie on a table 
inside of the MRI for about 30 minutes. Before having the MR exam, participants 
will be asked questions about their medical history and any exclusion criteria. 
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). Participants will be coached to achieve and hold in 
expiration (FRC) phase, with several practice attempts prior to scan acquisition.  
 
Participants will be asked to abstain from all tobacco products, with the exception of 
the study e-cigarette, from the first until the final study visit (11 days). Of note, 
tobacco product use will not be proscribed during the interval between the pre-
screening telephone call and the first study visit. 
 
4. Results Reports: No clinical reports will be generated for participants; however, a safety read 
will be performed as per CUMC policy. 
 
5. Study Drugs or Devices: 
 
(1) Hyperpolarized helium. IND 123,115 has been obtained from the FDA. The helium gas 
is supplied by Linde Healthcare, 6600 Peachtree Dunwoody Road, Embassy Row 400, 
Suite 300, Atlanta, GA 30328 Phone: Main 678-225-2940. The helium is hyperpolarized 
using the GE polarizer and administered by inhalation, as described in the IND 
application. There will be no charge to participants.  
(2) Dotarem (gadoterate meglumine) will be used as the contrast agent for the Gd-MRA at 
a low dose of 0.03 mmol/kg bodyweight. It will be supplied by Guerbet, 120 West 7th 
Street, Suite 108, Bloomington, IN 47404-3835. Contacts include Toll Free: 877-729-
6679; Phone: 812-333-0059; Fax: 812-333-0084. 
(3) E-cigarette 
o Planned e-cigarette device: We will obtain e-cigarettes from KangerTech 
(Building A1, No 66 West He'xiu road, Fuyong Town, Shenzhen,China; 
sales@kangeronline.com). The model will be the Kanger Top Evod.  
 
Alternate E-cigarette: If e-cigarette #1 is unavailable or there are other 
logistical issues identified, our alternate (highly similar) product will be 
from Halo (Corporate: 7916 Evolutions Way Suite 200, Trinity, Florida 
34655 United States; Manufacturing: 5909 NW 18th Dr., Gainesville, FL. 
32653 United States; Customer Service: (888) 425-6649). We will use the 
“Triton” Variable Voltage Battery (adjustable voltage 3.3-4.8V, 900mAh, 
10 seconds battery cut off time) “Triton” tank with 3.0-3.2 ohm coil.  
o Study e-liquids: study e-cigarettes will be loaded with 2mL of flavorless e-liquid 
with a ratio of PG to vegetable glycerin (VG) of 70:30 and 1.8 mg/dL of nicotine 
(AVAIL Vapor, 820 Southlake Blvd, Richmond, VA 23236, contact Holly Kempf 
Lewis (804) 677-1588). 
 
6. Study Questionnaires: See attached. 


 
 
 
7. Study Subjects: 
 
Inclusion criteria:  Age of 21-35 years at time of enrollment and self-reported voluntary, 
recreational e-cigarette use (>1x/month but <daily). 
 
Exclusion criteria:  any chronic major medical or psychiatric problems including current asthma; 
self-reported heavy snoring/sleep apnea; pre-bronchodilator FEV1 or FVC <80% predicted or 
FEV1/FVC < lower limit of normal58; 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 other illicit drugs, any daily 
medication (including inhalers) except hormonal contraceptives. Persons with an adverse 
symptomatic response to the study e-cigarette exposure (e.g., palpitations, shortness of breath, 
chest pain, headache, dizziness) will also be excluded. 
 
8. Recruitment 
 
Participants will be recruited from the local community and universities via fliers and word of 
mouth. There will be partial co-recruitment with the PI’s related e-cigarette pilot studies 
AAAQ9965 and AAAR2000. Healthy volunteers may be drawn from CUMC/NYP personnel 
including residents/fellows/interns/staff. This latter recruitment will not be coercive as it is 100% 
voluntary and there is no recrimination for non-participation. CUMC/NYP personnel who report 
directly to the PI or co-I will not be recruited. 
 
9. Informed consent and eligibility 
 
Since the exclusion criteria for the VAPE-Tox Study are few but cannot be fully determined prior 
to the first study visit (Day -3), the participant will come into the clinic and first sign the informed 
consent and HIPAA forms. Participants will be invited to the Clinical and Translational Science 
Awards (CTSA) research suite, where they will be confirmed to meet all inclusion/exclusion 
criteria via questionnaires, exhaled CO (exCO), pre-bronchodilator spirometry, serum creatinine 
assay, urine pregnancy test for women, and a practice session for the study e-cigarette 
exposure under observation by a trained research assistant, before being asked to abstain 
completely from non-study e-cigarette use for the duration of the study. Eligibility will be 
confirmed by the PI in writing. 
Adherent participants, defined on Day 0 as no interim self-reported e-cigarette use, <=10 ppm 
exhaled CO (exCO), and urine cotinine (uCot) <100 ng/mL, will continue immediately with 
randomization. 
 
10. Confidentiality of Study Data 
 
The consent form signed by the participant will provide written assurance that all individual data 
collected in the study will be kept confidential to the extent provided by the Privacy Act of 1974.  
Any personal identifiers will be maintained on limited-access, secure servers and never put on 
endpoint devices so that confidential data are not released. 
Participants will be informed that: (1) the only people who will know that they are 
research participants are members of the research team and, if appropriate, their physicians or 
health care providers; (2) no individual identifying information about them will be disclosed to 
others, except if required by law; and (3) when the results of the study are published or 


 
 
discussed in conferences, no information will be included that would reveal their identity. 
 
Data identified by study ID and acrostic only may be transferred to the MESA COPD 
Reading Centers (John Hopkins University, University of Iowa, Hannover University, University 
of Wisconsin, Northwestern University). Coded research data will be stored on password-
protected, secure servers hosted by the Division of General Medicine and certified by CUMC IT 
the CUMC Radiology PACS, and in locked filing cabinets in General Medicine, and potentially 
on endpoint devices that will, in all cases, be encrypted. 
Identifiable data will be stored in the General Medicine Server described above and in 
locked filing cabinets in separately partitioned drives/cabinets. The linking file will be similarly 
protected with limited access. 
 
11. Potential Risks 
 
There are no direct risks or discomforts from participation in the questionnaire, anthropometry, 
blood pressure, oxygen saturation, urine collection, or exhaled breath condensate. The only 
possible risk from these components involves the social-psychological risk for the individual 
resulting from the inadvertent disclosure of confidential medical information.  
 
Potential risks posed by the proposed study exposures and procedures are as follows: 
1. E-cigarette use:  
a. Nicotine exposure: Side effects from products that contain nicotine can include 
sweating, lightheadedness, dizziness, nausea, and nervousness. These effects 
are unlikely in individuals who use nicotine-containing products regularly, but are 
more likely to occur in non-regular users. Regardless, these effects are transient 
and long-term adverse effects are not expected based upon the study exposure. 
Nicotine is also an addictive substance, therefore exposure to nicotine 
theoretically carries a risk of promoting addition; however, in the amounts and 
manner administered in the study, this is very unlikely to occur.  
b. Propylene glycol exposure: propylene glycol is contained in most e-cigarette 
liquids, and will make up 70% of the study e-cigarette liquid. It is often used to 
make "theater fog" and is considered relatively safe, but it has occasionally been 
associated with shortness of breath or bronchospasm, especially in people with a 
history of asthma. 
c. Unknown risks: The effects of e-cigarette use remain mostly unknown, which is 
the major motivation for this study. We are only recruiting young, healthy, adults 
who have already made the decision to use e-cigarettes intermittently, despite 
this uncertainty. A safety board will be monitoring the study. 
2. Claustrophobia: A minority of individuals may be subject to psychological risks if they 
develop previously unknown claustrophobia inside the magnet. Claustrophobic episodes 
can be psychologically traumatic to participants; however, the trauma ceases upon 
removal of the subject from the scanner and does not have any known lasting effects.  
3. Magnet risks: All MRI studies involve exposure to magnetic field strength, rate of change 
of magnetic field gradients, and RF power exposure within guidelines recommended by 
the Food and Drug Administration. 
4. Risks relating to gadolinium contrast:  
a. Nephrogenic Systemic Fibrosis (NSF) is a rare fibrosing condition of the skin 
and organs that has been reported in association with gadolinium contrast agents 
and severe renal failure (GRF < 30 ml/min/1.73 m2). No reported cases have 
occurred above this level in patients with chronic renal impairment. Acute onset 
renal failure, hepatorenal syndrome, peri-hepatic transplant or kidney transplant 
represent additional risk factors. The clinical course of NSF is progressive and 


 
 
may be fatal. The incidence in the high risk population (severe renal failure, stage 
4-5, transplant, dialysis) is 2-6%.  
b. Allergy: there is a risk of allergic reaction after the gadolinium injection, with a 
less than one in 300,000 chance that this will be severe. Metallic taste in mouth, 
tingling in the arm, nausea, or headache occurs in less than 1% of people.  
c. Discomfort: Insertion of the needle to inject contrast may cause minor pain, 
bruising and/or infection at the injection site. 
d. Deposition in brain tissue: Gadolinium has recently been reported to deposit in 
a dose-dependent manner in the brain, although the significance of this is 
unknown and there is no evidence of harm.  
5. Risks relating to hyperpolarized helium contrast: 
a. Transient desaturation: Although generally proved to be well-tolerated, 
hyperpolarized helium inhalation and the subsequent breath-hold maneuver have 
been found, in a subset of subjects, to cause a mean transient decrease of 4% in 
oxygen saturation, with recovery occurring within one minute.  
b. Discomfort: mild lightheadedness and headache have also been reported after 
3He inhalation, although these resolved during or immediately after imaging 
sessions. 
6. Spirometry: This is a non-invasive test that involves minimal risks, such as precipitating 
coughing or mild, transient dizziness. 
 
For regular users of conventional or e-cigarettes, or other tobacco products, there is a risk of 
some discomfort during abstinence from e-cigarettes and nicotine during the study. Side effects 
from tobacco/nicotine abstinence can include irritability, anxiety and restlessness, excessive 
hunger, difficulty concentrating, and sleep disturbance. Though these potential side effects have 
not been characterized in e-cigarettes users, they are common abstinence symptoms in 
cigarette smokers. Though uncomfortable, these feelings are not medically dangerous. 
 
The only alternative to agreeing to participate is to decline to participate. 
 
12. Protections Against Risk 
 
In addition to continuous monitoring by trained research assistants during all study procedures, 
the following specific protections will be provided against the potential risks posed by the 
proposed study procedures.  
 
1. Anthropometry, blood pressure and pulse oximetry: There are no direct risks or 
discomforts from participation in the anthropometry, blood pressure or pulse oximetry to 
measure oxygen saturation. 
2. Questionnaires: There is minimal risk related to questionnaires, this involves the social-
psychological risk from the inadvertent disclosure of confidential medical information. We 
guard against this by maintaining study information identified by study number only in a 
filing system separate from the name and address files. 
3. Phlebotomy: The risks associated with blood collection are minimal and include the 
potential to feel a little pain or get a bruise at the place where the blood is drawn. It is 
possible, but not likely, that there may be swelling or bleeding at the site. 
4. EBC testing is non-invasive and involves minimal risks. 
5. Spirometry: Spirometry is non-invasive and involves minimal risks. Spirometry can 
induce shortness of breath, coughing or chest tightness, and may cause the participant 
to feel lightheaded. It is very rarely complicated by syncope. No bronchodilators will be 
administered.  


 
 
6. E-cigarette exposure: We will only recruit young, healthy, current e-cigarette using 
adults. Since these subjects choose to use e-cigarettes recreationally, it is reasonable to 
infer that they have determined independently that they are willing to accept the mostly 
unknown risks associated with e-cigarette vapor. Nonetheless, we will mitigate any 
potential risks associated with the standardized study exposure – which will employ 
short-term exposure to publicly available e-cigarette products containing a standardized 
e-liquid with moderate nicotine content and without flavorings – by requiring a monitored 
“test run” of the study e-cigarette exposure at the enrollment visit. All persons with an 
adverse response (e.g., palpitations, shortness of breath, chest pain, headache, 
dizziness) will be excluded. We will also provide symptomatic and hemodynamic 
monitoring throughout the study procedures. 
7. Claustrophobia: We include severe, known claustrophobia as a contraindication to 
participation in this project 
8. Magnet risks: All subjects will be screened to exclude those with contraindications to 
MR, including those with pacemakers, aneurysm clips, cochlear implants or other 
implanted electronic devices. Subjects with a history of occupational exposure to small 
metallic projectiles will also be excluded. The MR scanner areas at the sites are 
equipped with standard medical emergency equipment for a hospital-based MR center. 
9. Gadolinium contrast:  
a. Nephrogenic Systemic Fibrosis (NSF): Participants with high-risk conditions 
will be excluded. GFR will be measured within two weeks of imaging, and GFR < 
60 ml/min/1.73 m2 will be the cutoff for exclusion in this study. 
b. Deposition in brain tissue: We will mitigate against this risk by using a low dose 
of gadolinium (0.03 mmol/kg) and a type of gadolinium that is not believed to be 
associated with this problem.  
10. Hyperpolarized helium contrast: Medical grade 3He is hyperpolarized and mixed with 
inert nitrogen gas using a commercial polarizer (manufactured by GE Healthcare). 3He-
enhanced MRI has been performed in over a thousand patients by 2008 and probably 
another 1000 since then. Since all of the inhaled 3He is expired, it is well-tolerated by 
health controls and patients with severe lung disease alike. The major risk is transient 
hypoxemia following inhalation of the gas. The mean change in SpO2 in a series of 100 
subjects (controls, smokers, and severe COPD) was 0 +/- 2%, with a range from -4 to 
6%, although occasionally (<5%) a significant desaturation is observed (Lutey, 
Radiology 2008). These have all been asymptomatic and without sequelae, to our 
knowledge. Other minor symptoms reported after inhalation of 3He include occasional 
(<5%) cough, lightheadedness and headache (similar to spirometry). We have obtained 
an IND from the FDA and its production at CUMC to be used in this process. 
 
Potential problems and adverse events will be monitored and evaluated as per the Data Safety 
Monitoring Plan, which includes a DSMB. 
 
12. Plan for Incidental Findings 
The imaging may reveal subclinical findings that require further testing or interventions, which 
may be harmful, costly or cause distress.  
 
The MRI protocols are designed for research purposes and do not necessarily provide standard 
clinical information on, for example, cardiac structure or function. The information obtained is 
specific to particular protocols, such that specific regions of the heart or lungs may be visualized 
with poor or no visualization of other regions of these organs or of the chest or other parts of the 
body. 
 


 
 
MRI of the lungs yields generally low-resolution images of the large airways and airspaces, 
respectively. Only large abnormalities (e.g., large bronchiogenic cancer) would be detected. 
 
Dr Prince, co-I (Dept of Radiology, CUMC and WCMC), will read all scans in a timely fashion for 
participants. 
 
IFs of Clinical Significance will be communicated to the participants verbally and in writing. 
Major abnormalities (eg carcinoma) will be reported; subtle alternations of unknown clinical 
significance (eg regional lack of ventilation in a patient without respiratory symptoms) will not. 
 
13. Potential Benefits 
 
Three are no direct benefits to participants expected from this study except for the feeling of 
being involved in an important study. The societal benefits from the information on the 
relationship between e-cigarette vapor inhalation and pulmonary ventilation and microvascular 
perfusion are potentially large. 
 
15. Alternatives: None. 
 
16. Data Safety and Monitoring Plan 
 
Please see attached document and proposed Data Safety and Monitoring Board (DSMB) roster. 
 
17. IND Holder Responsibilities