Ventilation and Pulmonary Endothelium Toxicities of E-cigarettes: A Randomized Crossover Pilot Study
Condition: Pulmonary Disease, Chronic Obstructive; E-cigarettes
MeSH terms: Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Early Phase 1

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.
    

Intervention name(s): E-cigarette; Sham; Hyperpolarized 3-Helium; Gadolinium
Intervention type(s): Device; Other; Drug; Drug
Intervention description(s): 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.; The "unexposed" condition will be breathing from the study e-cigarette (10 puffs with 30-second inter-puff intervals) with the battery off.; 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.; 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 intervention name(s): 3-He; Gd
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Other
Keywords: E-cigarettes; COPD