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Electronic Cigarettes—A Narrative Review for Clinicians

Published:February 28, 2015DOI:https://doi.org/10.1016/j.amjmed.2015.01.033

      Abstract

      Electronic cigarettes (e-cigarettes) were introduced into the US market in 2007 and have quickly become a popular source of nicotine for many patients. They are designed to simulate smoking by heating a nicotine-containing solution producing an aerosol that the user inhales. The short- and long-term effects of e-cigarette use are still unclear, but their use is increasing. Some acute effects of e-cigarettes on heart rate, blood pressure, and airway resistance are reported. Although there are some reports of improved cessation in a subset of users, there are also studies reporting decreased cessation in dual users of regular and e-cigarettes. Additionally, there is no current regulation of these devices, and this allows virtually anyone with a form of online payment to obtain them.

      Keywords

      Clinical Significance
      • E-cigarettes have become a popular source of nicotine.
      • E-cigarettes have acute physiological effects, including increases in blood pressure, heart rate, and airway resistance.
      • The long-term effects of e-cigarettes are unknown.
      • There is insufficient evidence to recommend e-cigarettes for smoking cessation, although some reports of improved cessation exist. Dual use with regular cigarettes has been associated with decreased smoking cessation.
      • E-cigarettes should not be viewed as “safe” as they can cause acute lung disease, atrial fibrillation, and nicotine poisoning.
      Electronic cigarettes (e-cigarettes) are the most common type of a category of products called electronic nicotine delivery systems. E-cigarettes are relatively new products designed to simulate smoking by heating a solution that typically includes nicotine, flavorings, and a delivery system like propylene glycol or glycerin, or both. Other examples of these devices include cigars, pipes, and hookah-like products.
      • Grana R.
      • Benowitz N.
      • Glantz S.A.
      E-Cigarettes: a scientific review.
      • Chen I.-L.
      • Husten C.G.
      Introduction to tobacco control supplement.
      The first commercialized e-cigarette product was invented in 2003 and officially entered the US marketplace in 2007.

      Grana R, Benowitz N, Glantz SA. Background paper on E-cigarettes (Electronic Nicotine Delivery Systems). 2013. Available at: http://escholarship.org/uc/item/13p2b72n. Accessed August 27, 2014.

      • Brown C.J.
      • Cheng J.M.
      Electronic cigarettes: product characterisation and design considerations.
      These products have a particular nomenclature related to their use, and clinicians should know these terms to have productive conversations with patients (Table 1).
      • Chen I.-L.
      • Husten C.G.
      Introduction to tobacco control supplement.
      • Brown C.J.
      • Cheng J.M.
      Electronic cigarettes: product characterisation and design considerations.
      • Ingebrethsen B.J.
      • Cole S.K.
      • Alderman S.L.
      Electronic cigarette aerosol particle size distribution measurements.
      Table 1Electronic Cigarette Nomenclature
      NameDefinitionOther Names
      Electronic cigaretteThe device designed to produce aerosol by heating the solution in the cartridge.E-cig, smokeless cigarette, cig-a-like, vaporette, technofogger, personal vaporizer, vaping device, vapor pen, e-hookah.
      Electronic cigarette useThe act of inhaling the heated aerosolized solution and subsequently exhaling is similar to smoking a regular cigarette.Verbalized as “vaping.” An e-cigarette user may be described as a “vaper.” These terms are actually misnomers as the aerosol produced is technically not a vapor. The aerosol produced by e-cigarettes has a particulate phase, not just a gas phase like a vapor.
      • Ingebrethsen B.J.
      • Cole S.K.
      • Alderman S.L.
      Electronic cigarette aerosol particle size distribution measurements.
      Electronic cigarette solutionThe solution usually contains a mixture of propylene glycol or vegetable glycerin or both, with or without nicotine, and flavorings.E-juice, e-liquid, juice, vapor juice, smoke juice
      Hot cigaretteA regular tobacco cigarette
      ModsModifications made to an e-cigarette used to produce higher amounts of aerosolCloud chaser, cloud chasing

      Composition, Marketing, Sales Data, and Response From the Tobacco Industry

       Construction

      Electronic cigarettes have four parts: the battery, the heating element, the vaporizing chamber, and the solution cartridge (Figure).
      The battery is the power supply that provides the electrical current to the heating element needed to reach temperatures high enough to aerosolize the solution. This is usually a cylindrically shaped lithium ion rechargeable battery. The size and shape of the battery contributes significantly to the overall size and convenience of the e-cigarette; smaller devices allow easier transportability but usually need more frequent recharging. The lithium ion batteries provide higher voltages (>3 volts), necessary for producing the aerosol in the desired amounts, than traditional batteries (1.5 volts). There have been reports of these batteries overheating and exploding after being charged inappropriately or during an attempt to “light” the cigarette with a flame by mistake.

      BBC News. Man killed as e-cigarette explodes. Available at: http://www.bbc.com/news/uk-england-merseyside-28701515. Accessed August 27, 2014.

      The heating element provides the necessary heat for aerosolization of the nicotine solution. Many e-cigarette models include a voltage potentiometer that allows the user to select the amount of aerosol produced and nicotine concentration. A chamber houses the heating element and holds the aerosol until the user is ready to draw or inhale.
      The solution cartridge contains the flavored nicotine solution (see Table 1) for aerosolization. This liquid includes a vehicle solution (propylene glycol, low molecular propylene glycol, or vegetable glycerin), artificial flavorings, and variable concentrations of nicotine. This may be refillable by the user or exchanged for prefilled cartridges. The number of choices in the composition of e-cigarette solutions is increasing, and there is significant variability between the labeled content and the actual content and concentrations.
      • Brown C.J.
      • Cheng J.M.
      Electronic cigarettes: product characterisation and design considerations.

       Styles

      E-cigarettes are available in a number of models and styles. Many take the appearance of traditional cigarettes– a “filter” at the bottom with white tubing and a red or orange glow tip. The “filter” is usually the cartomizer exterior (cartomizer = fusion of the cartridge and atomizer) and the “tobacco” part is usually the battery exterior. Others do not mimic the look of cigarettes, because some customers want to easily demonstrate they are not truly smoking in a nonsmoking area. Some companies have created an identity through a distinctive design that promotes brand recognition, such as the Blu eCig electronic cigarettes (Lorillard, Walpole, MA). Companies are also introducing customizable devices that allow multiple looks by using exchangeable exteriors.

       Operation

      The type of battery–automatic or manual–has an important role in how the e-cigarette is used. With an automatic battery, the user simply draws on the device like a traditional cigarette. With a manual battery, a button must be pressed to activate the device and produce heating. The automatic type behaves more like traditional cigarettes.
      Many e-cigarette models include a voltage potentiometer that allows the user to select the amount of aerosol produced, thereby selecting the amount of nicotine to be inhaled.
      • Saitta D.
      • Ferro G.A.
      • Polosa R.
      Achieving appropriate regulations for electronic cigarettes.
      Other operational details depend on the e-cigarette’s intended use. There are disposable models intended for one-time use. Others are intended for multiple uses and must be refilled either manually or with prefilled cartridges, and regular cleaning is necessary.

       Marketing and Sales

      In April 2014, the US Food and Drug Administration (FDA) announced plans to nationally regulate e-cigarettes like tobacco products.

      US Food and Drug Administration (FDA). FDA news release. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm394667.htm. Accessed August 27, 2014.

      This includes restricted sales to minors and restricted advertising. Currently, the FDA’s Center for Tobacco Products is establishing a public docket in conjunction with a public workshop to gather information to advance the proposed regulation.

      Regulations.gov. Electronic cigarettes and public health workshop. Available at: http://www.regulations.gov/#!docketBrowser;rpp=25;po=0;D=FDA-2014-N-1936. Accessed December 5, 2014.

      Submission of comments ends in April 2015. Although some e-cigarette companies have announced their support of these proposed regulations, others are less enthusiastic. Until the regulations are finalized, the current state of the market is completely unregulated. The devices and the “e-juice” are available online to anyone with a means of online payment. Television and print ads are becoming more common, some particularly aimed at the youth market.
      • Duke J.C.
      • Lee Y.O.
      • Kim A.E.
      • et al.
      Exposure to electronic cigarette television advertisements among youth and young adults.
      Sales of e-cigarettes have been estimated at approximately $1.7 billion for 2013.

      Stanford DD. E-cig sales slide as regular smokers return to the real thing. Available at: http://www.bloomberg.com/news/2014-07-16/e-cig-sales-slide-as-regular-smokers-return-to-real-thing.html. Accessed August 27, 2014.

       Big Tobacco

      There are hundreds of e-cigarette companies in the US; most are small businesses that serve their local markets without a large online presence. Approximately 70% of the market belongs to 10 companies.

      McArdle M. E-cigarettes: a $1.5 billion industry braces FDA regulation. Available at: http://www.businessweek.com/articles/2014-02-06/e-cigarettes-fda-regulation-looms-for-1-dot-5-billion-industry#p1. Accessed August 27, 2014.

      The big tobacco companies have entered the market by either buying some of the more successful small business startups or by creating their own e-cigarette brands. Lorillard (Walpole, MA: Newport brand) owns the Blu eCigs brand, and Phillip Morris (Miami, FL; Marlboro brand) recently bought out the Green Smoke e-cigarette brand. Reynolds (Winston-Salem, NC; Camel brand) introduced its own e-cigarette brand called Vuse and had 55% market share in Colorado within 16 weeks. Philip-Morris USA/Altria Group market Mark 10 e-cigarettes.

      Use Patterns in the Public: Adults, Teenagers, Pregnancy

      The use of electronic cigarettes by children is increasing in the US, but remains much lower than use of traditional tobacco products. Recent data note that e-cigarette use by both high school and junior high students has increased, and reportedly over a quarter of a million never-smoking youths had tried e-cigarettes by 2013.

      Centers for Disease Control and Prevention (CDC). Notes from the field: electronic cigarette use among middle and high school students—United States, 2011-2012. MMWR Morb Mortal Wkly Rep. 2013;62(35);729-730. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6235a6.htm?s_cid=mm6235a6_w. Accessed August 27, 2014.

      • Bunnell R.E.
      • Agaku I.T.
      • Arrazola R.A.
      • et al.
      Intentions to smoke cigarettes among never-smoking U.S. middle and high school electronic cigarette users, National Youth Tobacco Survey, 2011-2013.
      • Dutra L.M.
      • Glantz S.A.
      Electronic cigarettes and conventional cigarette use among US adolescents: a cross-sectional study.
      These data also show that during the same period, use of traditional cigarettes has decreased in these two groups. It appears that children and young adults are trying e-cigarettes on an experimental basis without intending to replace traditional cigarettes or to start a pattern of regular usage. College students often use e-cigarettes as replacements for traditional cigarettes either as a “safer alternative” or for experimentation.
      • Sutfin E.L.
      • McCoy T.P.
      • Morrell H.E.
      • Hoeppner B.B.
      • Wolfson M.
      Electronic cigarette use by college students.
      Use by adults is also increasing, and 21% of adults surveyed reported trying e-cigarettes in 2012, up from 10% in 2010. Adults also report using e-cigarettes as cessation tools and safer alternatives to traditional cigarettes.
      • Pokhrel P.
      • Fagan P.
      • Little M.A.
      • Kawamoto C.T.
      • Herzog T.A.
      Smokers who try e-cigarettes to quit smoking: findings from a multiethnic study in Hawaii.
      • Brown J.
      • Beard E.
      • Kotz D.
      • Michie S.
      • West R.
      Real-world effectiveness of e-cigarettes when used to aid smoking cessation: a cross-sectional population study.
      There are currently no data on either prevalence or biologic effects of e-cigarette use during pregnancy. It is important that clinicians recognize that any nicotine exposure is deleterious to maternal and fetal health.
      • Suter M.A.
      • Mastrobattista J.
      • Sachs M.
      • Aagaard K.
      Is there evidence for potential harm of electronic cigarette use in pregnancy?.

      Regulation by the FDA or Other National/International Entities

      The FDA has issued a proposed rule that would extend the regulation of e-cigarettes as tobacco products by the Food, Drug, and Cosmetic Act.

      US Food and Drug Administration (FDA). FDA news release. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm394667.htm. Accessed August 27, 2014.

      Currently, only e-cigarettes marketed for therapeutic purposes are regulated by the FDA Center for Drug Evaluation and Research. Regular cigarettes are regulated by the FDA Center for Tobacco Products.

      US Food and Drug Administration (FDA). Electronic cigarettes (E-cigarettes). Available at: http://www.fda.gov/NewsEvents/PublicHealthFocus/ucm172906.htm. Accessed December 5, 2014.

      The US will join other countries that have already initiated this process. In essence, the regulation of electronic cigarettes would mirror that of traditional tobacco products in terms of sales to minors and allowable marketing techniques. It does not include specific regulations on flavored or zero nicotine “e-juice.” States and individual municipalities will still be responsible for regulating the use of e-cigarettes in public places. Some countries, including Australia, Mexico, Brazil, Argentina, and Columbia, have completely banned e-cigarettes.
      In February 2014, the European Parliament issued a Memorandum of the EU Tobacco Products Directive regulating e-cigarettes (including solution composition, advertising, and marketing strategies), recognizing their increasing use and market and stating that as they are nicotine-containing products, safety and quality regulations are necessary. Products that do not contain nicotine will not be regulated by the Directive.

      European Commission. Public health: tobacco products directive memo. Available at: http://ec.europa.eu/health/tobacco/products/index_en.htm. Accessed August 27, 2014.

      Specific regulations, such as age limits, are to be set by individual members of the EU.

      Biologic Effects

       Acute Physiological Effects

      Table 2
      • Vansickel A.R.
      • Cobb C.O.
      • Weaver M.F.
      • Eissenberg T.E.
      A clinical laboratory model for evaluating the acute effects of electronic “cigarettes”: nicotine delivery profile and cardiovascular and subjective effects.
      • Vakali S.
      • Tsikrika S.
      • Gennimata S.A.
      • et al.
      E-cigarette acute effect on symptoms and airway inflammation: comparison of nicotine with a non nicotine cigarette. 11th Annual Conference of the International Society for the Prevention of Tobacco Induced Diseases (ISPTID).
      • Farsalinos K.E.
      • Tsiapras D.
      • Kyrzopoulos S.
      • Savvopoulou M.
      • Voudris V.
      Acute effects of using an electronic nicotine-delivery device (electronic cigarette) on myocardial function: comparison with the effects of regular cigarettes.
      • Farsalinos K.E.
      • Romagna G.
      Chronic idiopathic neutrophilia in a smoker, relieved after smoking cessation with the use of electronic cigarette: a case report.
      • Flouris A.D.
      • Poulianiti K.P.
      • Chorti M.S.
      • et al.
      Acute effects of electronic and tobacco cigarette smoking on complete blood count.
      • Marini S.
      • Buonanno G.
      • Stabile L.
      • Ficco G.
      Short-term effects of electronic and tobacco cigarettes on exhaled nitric oxide.
      • Vardavas C.I.
      • Anagnostopoulos N.
      • Kougias M.
      • Evangelopoulou V.
      • Connolly G.N.
      • Behrakis P.K.
      Short-term pulmonary effects of using an electronic cigarette impact on respiratory flow resistance, impedance, and exhaled nitric oxide.
      • Gennimata S.
      • Palamidas A.
      • Kaltsakas G.
      • et al.
      Acute effect of e-cigarette on pulmonary function in healthy subjects and smokers.
      • Palamidas A.
      • Gennimata S.A.
      • Kaltsakas G.
      • et al.
      Acute effect on an e-cigarette with and without nicotine on lung function. 11th Annual Conference of the International Society for the Prevention of Tobacco Induced Diseases (ISPTID).
      outlines the reported physiological effects of e-cigarette use.
      Table 2Reported Physiologic Effects of E-cigarette Use
      ParameterEffectSource
      Serum carbon monoxide levelsNo definite effect with contradicting studies
      • Vansickel A.R.
      • Cobb C.O.
      • Weaver M.F.
      • Eissenberg T.E.
      A clinical laboratory model for evaluating the acute effects of electronic “cigarettes”: nicotine delivery profile and cardiovascular and subjective effects.
      • Vakali S.
      • Tsikrika S.
      • Gennimata S.A.
      • et al.
      E-cigarette acute effect on symptoms and airway inflammation: comparison of nicotine with a non nicotine cigarette. 11th Annual Conference of the International Society for the Prevention of Tobacco Induced Diseases (ISPTID).
      Diastolic blood pressureSignificant increase
      • Farsalinos K.E.
      • Tsiapras D.
      • Kyrzopoulos S.
      • Savvopoulou M.
      • Voudris V.
      Acute effects of using an electronic nicotine-delivery device (electronic cigarette) on myocardial function: comparison with the effects of regular cigarettes.
      Systolic blood pressureNo significant increase
      • Farsalinos K.E.
      • Tsiapras D.
      • Kyrzopoulos S.
      • Savvopoulou M.
      • Voudris V.
      Acute effects of using an electronic nicotine-delivery device (electronic cigarette) on myocardial function: comparison with the effects of regular cigarettes.
      Ventricular systolic and diastolic functionNo effect
      • Farsalinos K.E.
      • Tsiapras D.
      • Kyrzopoulos S.
      • Savvopoulou M.
      • Voudris V.
      Acute effects of using an electronic nicotine-delivery device (electronic cigarette) on myocardial function: comparison with the effects of regular cigarettes.
      Heart rateSignificant increase after 5 and 10 minutes of use
      • Vansickel A.R.
      • Cobb C.O.
      • Weaver M.F.
      • Eissenberg T.E.
      A clinical laboratory model for evaluating the acute effects of electronic “cigarettes”: nicotine delivery profile and cardiovascular and subjective effects.
      • Vakali S.
      • Tsikrika S.
      • Gennimata S.A.
      • et al.
      E-cigarette acute effect on symptoms and airway inflammation: comparison of nicotine with a non nicotine cigarette. 11th Annual Conference of the International Society for the Prevention of Tobacco Induced Diseases (ISPTID).
      Blood countsNo change in WBCs, lymphocytes and granulocytes
      • Farsalinos K.E.
      • Romagna G.
      Chronic idiopathic neutrophilia in a smoker, relieved after smoking cessation with the use of electronic cigarette: a case report.
      • Flouris A.D.
      • Poulianiti K.P.
      • Chorti M.S.
      • et al.
      Acute effects of electronic and tobacco cigarette smoking on complete blood count.
      Exhaled nitric oxide (FeNO)Significant decrease shortly after use
      • Marini S.
      • Buonanno G.
      • Stabile L.
      • Ficco G.
      Short-term effects of electronic and tobacco cigarettes on exhaled nitric oxide.
      • Vardavas C.I.
      • Anagnostopoulos N.
      • Kougias M.
      • Evangelopoulou V.
      • Connolly G.N.
      • Behrakis P.K.
      Short-term pulmonary effects of using an electronic cigarette impact on respiratory flow resistance, impedance, and exhaled nitric oxide.
      Respiratory impedances (a marker of peripheral airway flow resistance)Significant (18%) increase
      • Vardavas C.I.
      • Anagnostopoulos N.
      • Kougias M.
      • Evangelopoulou V.
      • Connolly G.N.
      • Behrakis P.K.
      Short-term pulmonary effects of using an electronic cigarette impact on respiratory flow resistance, impedance, and exhaled nitric oxide.
      Airway resistanceSignificant increase, including nicotine free solutions
      • Gennimata S.
      • Palamidas A.
      • Kaltsakas G.
      • et al.
      Acute effect of e-cigarette on pulmonary function in healthy subjects and smokers.
      • Palamidas A.
      • Gennimata S.A.
      • Kaltsakas G.
      • et al.
      Acute effect on an e-cigarette with and without nicotine on lung function. 11th Annual Conference of the International Society for the Prevention of Tobacco Induced Diseases (ISPTID).

       Nicotine Levels

      One important aspect of e-cigarette use is that these devices are designed to deliver nicotine via the lungs. There are substantial differences in the amounts delivered by e-cigarettes compared with regular cigarettes and by different e-cigarette brands. Studies with automated smoking machines show that e-cigarettes deliver less nicotine per puff than regular cigarettes. However, the smoking “technique” does affect the actual nicotine delivered, as inexperienced e-cigarette smokers achieve lower serum nicotine concentrations than experienced e-cigarette smokers who achieve systemic concentrations similar to regular cigarettes.
      • Schroeder M.J.
      • Hoffman A.C.
      Electronic cigarettes and nicotine clinical pharmacology.
      In a study conducted with experienced e-cigarette users, the mean salivary cotinine (the principal metabolite of nicotine) levels were 322 ng/mL.
      • Etter J.F.
      • Bullen C.
      Saliva cotinine levels in users of electronic cigarettes.
      Mean salivary cotinine levels for regular cigarette smokers were 113 ng/mL, and 2.4 ng/mL for nonsmokers in one report.
      • Etter J.F.
      • Duc T.V.
      • Perneger T.V.
      Saliva cotinine levels in smokers and nonsmokers.
      E-cigarettes have a liquid reservoir of concentrated nicotine, and unintentional exposures from the ingestion of this liquid have been reported. Also, intentional intoxication by injection and ingestion, suicide attempts, and completed suicides associated with these concentrated nicotine vials have been reported. Nicotine is rapidly absorbed in lungs, skin, and mucous membranes, and the lethal dose ranges from 10 to 60 mg. As some e-cigarette liquids contain nicotine at a concentration of around 100 mg/mL, this presents the potential for lethal toxicity.
      • Cameron J.M.
      • Howell D.N.
      • White J.R.
      • Andrenyak D.M.
      • Layton M.E.
      • Roll J.M.
      Variable and potentially fatal amounts of nicotine in e-cigarette nicotine solutions.
      • Christensen L.B.
      • van't Veen T.
      • Bang J.
      Three cases of attempted suicide by ingestion of nicotine liquid used in e-cigarettes.
      • Cervellin G.
      • Luci M.
      • Bellini C.
      • Lippi G.
      Bad news about an old poison. A case of nicotine poisoning due to both ingestion and injection of the content of an electronic cigarette refill.
      Additionally, instances of “no nicotine” solutions actually containing nicotine have been reported.
      • Schroeder M.J.
      • Hoffman A.C.
      Electronic cigarettes and nicotine clinical pharmacology.

       Exposure to Chemical Substances Other Than Nicotine

      Many substances have been identified in e-cigarette solutions, including tobacco-specific nitrosamines, tobacco alkaloids, aldehydes, metals, volatile organic compounds, polycyclic aromatic hydrocarbons, flavors, solvent carriers, and drugs (tadalafil and rimonabant).
      • Hadwiger M.E.
      • Trehy M.L.
      • Ye W.
      • Moore T.
      • Allgire J.
      • Westenberger B.
      Identification of amino-tadalafil and rimonabant in electronic cigarette products using high pressure liquid chromatography with diode array and tandem mass spectrometric detection.
      The reported metals in aerosols and cartridges of e-cigarettes include cadmium, nickel, lead, chromium, and arsenic.
      • Cheng T.
      Chemical evaluation of electronic cigarettes.
      One report indicated that levels of nickel were 100 times higher than in regular cigarettes.
      • Williams M.
      • Villarreal A.
      • Bozhilov K.
      • Lin S.
      • Talbot P.
      Metal and silicate particles including nanoparticles are present in electronic cigarette cartomizer fluid and aerosol.
      Carbonyl compounds have also been reported present in e-cigarette aerosol.
      • Kosmider L.
      • Sobczak A.
      • Fik M.
      • et al.
      Carbonyl compounds in electronic cigarette vapors—effects of nicotine solvent and battery output voltage.
      The liquid composition of each brand of e-cigarette may differ, making it difficult to generalize about the potential toxic properties of these devices.

       “Second-hand Vapor”

      In contrast to regular cigarettes, which are in constant combustion when used, e-cigarettes release aerosols when the user exhales. Study of airborne particle production related to e-cigarette use is needed to determine any “second-hand” effects. It has been reported that consumption of e-cigarettes causes significant aerosol emissions and nicotine into indoor air.
      • Schripp T.
      • Markewitz D.
      • Uhde E.
      • Salthammer T.
      Does e-cigarette consumption cause passive vaping?.
      • Czogala J.
      • Goniewicz M.L.
      • Fidelus B.
      • Zielinska-Danch W.
      • Travers M.J.
      • Sobczak A.
      Secondhand Exposure to Vapors From Electronic Cigarettes.
      • Ballbe M.
      • Martinez-Sanchez J.M.
      • Sureda X.
      • et al.
      Cigarettes vs. e-cigarettes: passive exposure at home measured by means of airborne marker and biomarkers.
      Additionally, e-cigarettes chamber studies have proven that they are a source of “third-hand” exposure to nicotine from surfaces exposed to exhaled e-cigarette vapor.
      • Goniewicz M.L.
      • Lee L.
      Electronic cigarettes are a source of thirdhand exposure to nicotine.

      Role in Smoking Cessation

      The published data on e-cigarettes for smoking reduction or cessation are conflicting. To date, smaller trials, not necessarily designed to measure smoking cessation, have not shown a benefit of e-cigarette use in cessation outcomes.
      • Bullen C.
      • McRobbie H.
      • Thornley S.
      • Glover M.
      • Lin R.
      • Laugesen M.
      Effect of an electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user preferences and nicotine delivery: randomised cross-over trial.
      • Dawkins L.
      • Turner J.
      • Hasna S.
      • Soar K.
      The electronic-cigarette: effects on desire to smoke, withdrawal symptoms and cognition.
      • Polosa R.
      • Caponnetto P.
      • Morjaria J.B.
      • Papale G.
      • Campagna D.
      • Russo C.
      Effect of an electronic nicotine delivery device (e-Cigarette) on smoking reduction and cessation: a prospective 6-month pilot study.
      Although manufacturers have promoted these devices for cessation since their introduction into the market, this has not been FDA approved, and no current applications have been submitted for approval of this indication.
      Survey and observational data have reported conflicting results. One particularly large survey reported 81% complete smoking substitution with a median time of e-cigarette use of 10 months.
      • Farsalinos K.E.
      • Romagna G.
      • Tsiapras D.
      • Kyrzopoulos S.
      • Voudris V.
      Characteristics, perceived side effects and benefits of electronic cigarette use: a worldwide survey of more than 19,000 consumers.
      Another “real-world” survey reported higher abstinence at 12 months with e-cigarettes use than with other nicotine replacements and no aid.
      • Brown J.
      • Beard E.
      • Kotz D.
      • Michie S.
      • West R.
      Real-world effectiveness of e-cigarettes when used to aid smoking cessation: a cross-sectional population study.
      Recently, a longitudinal study of smokers and e-cigarette use reported that daily users of e-cigarettes were 6 times as likely as nonusers/triers to report quitting.
      • Biener L.
      • Hargraves J.L.
      A longitudinal study of electronic cigarette use in a population-based sample of adult smokers: association with smoking cessation and motivation to quit.
      In contrast, a study of smoking cancer patients referred to a tobacco cessation program reported e-cigarette users were twice as likely to be smoking at follow-up as compared with nonusers, after adjusting for nicotine dependence, quit attempts, and cancer diagnosis. In this study, e-cigarette users were more nicotine dependent.
      • Borderud S.P.
      • Li Y.
      • Burkhalter J.E.
      • Sheffer C.E.
      • Ostroff J.S.
      Electronic cigarette use among patients with cancer: characteristics of electronic cigarette users and their smoking cessation outcomes.
      Also, a large Korean Web-based survey showed that current cigarette smokers were much more likely to use e-cigarettes than were nonsmokers.
      • Lee S.
      • Grana R.A.
      • Glantz S.A.
      Electronic cigarette use among Korean adolescents: a cross-sectional study of market penetration, dual use, and relationship to quit attempts and former smoking.
      In the longitudinal study cited above, intermittent e-cigarette use was negatively associated with the motivation to quit.
      • Biener L.
      • Hargraves J.L.
      A longitudinal study of electronic cigarette use in a population-based sample of adult smokers: association with smoking cessation and motivation to quit.
      These studies suggest that e-cigarette use and particularly, dual use, could reduce the likelihood of quitting.
      Two clinical trials have been completed,
      • Bullen C.
      • Howe C.
      • Laugesen M.
      • et al.
      Electronic cigarettes for smoking cessation: a randomised controlled trial.
      • Caponnetto P.
      • Campagna D.
      • Cibella F.
      • et al.
      EffiCiency and safety of an eLectronic cigAreTte (ECLAT) as tobacco cigarettes substitute: a prospective 12-month randomized control design study.
      and 2 are ongoing [NCT01979796, NCT01785537]
      • Caponnetto P.
      • Polosa R.
      • Auditore R.
      • et al.
      Smoking Cessation and Reduction in Schizophrenia (SCARIS) with e-cigarette: study protocol for a randomized control trial.
      • Manzoli L.
      • La Vecchia C.
      • Flacco M.E.
      • et al.
      Multicentric cohort study on the long-term efficacy and safety of electronic cigarettes: study design and methodology.
      on the use of e-cigarettes specifically for smoking reduction or cessation. The first trial
      • Bullen C.
      • Howe C.
      • Laugesen M.
      • et al.
      Electronic cigarettes for smoking cessation: a randomised controlled trial.
      • Bullen C.
      • Williman J.
      • Howe C.
      • et al.
      Study protocol for a randomised controlled trial of electronic cigarettes versus nicotine patch for smoking cessation.
      included 657 subjects and found that at 6 months the verified abstinence rates were 7.3%, 5.8%, and 4.1% with nicotine-containing e-cigarettes, nicotine patches, and placebo e-cigarettes, respectively. This study did not demonstrate any superiority of nicotine e-cigarettes compared with the other treatments. The ECLAT
      • Caponnetto P.
      • Campagna D.
      • Cibella F.
      • et al.
      EffiCiency and safety of an eLectronic cigAreTte (ECLAT) as tobacco cigarettes substitute: a prospective 12-month randomized control design study.
      • Caponnetto P.
      • Auditore R.
      • Russo C.
      • Cappello G.C.
      • Polosa R.
      Impact of an electronic cigarette on smoking reduction and cessation in schizophrenic smokers: a prospective 12-month pilot study.
      trial included 300 smokers who did not intend to quit. They were divided into 3 groups: 2 were offered different nicotine concentrations in e-cigarettes, compared with a third placebo group. The authors concluded that the use of e-cigarettes, with or without nicotine, decreased cigarette consumption and facilitated sustained tobacco abstinence without causing significant side effects.

       Dual Use

      Dual use of e-cigarettes and regular cigarettes has been reported as the main pattern of use, and there is some evidence that this might be associated with increased nicotine dependence.
      • Borderud S.P.
      • Li Y.
      • Burkhalter J.E.
      • Sheffer C.E.
      • Ostroff J.S.
      Electronic cigarette use among patients with cancer: characteristics of electronic cigarette users and their smoking cessation outcomes.
      Among middle school and high school students, dual use was found in 61%-81% of users.
      • Grana R.
      • Benowitz N.
      • Glantz S.A.
      E-Cigarettes: a scientific review.
      In one large Internet survey, continued dual use was reported at 19%, with only 3.5% of participants using zero nicotine solutions.
      • Farsalinos K.E.
      • Romagna G.
      • Tsiapras D.
      • Kyrzopoulos S.
      • Voudris V.
      Characteristics, perceived side effects and benefits of electronic cigarette use: a worldwide survey of more than 19,000 consumers.
      It is important that the clinician identify this dual use pattern and the clinical implications of e-cigarettes being an additional (rather than substituting) source of nicotine.

      E-Cigarette Toxicity

      Reported adverse events related to e-cigarettes are usually mild to moderate and transient. However, e-cigarette exposure calls to poison control centers are increasing; for example, a 2014 study including Texas poison control centers found 2, 6, 11, and 43 reports in 2009, 2010, 2011, and 2012, respectively.
      • Ordonez J.E.
      • Kleinschmidt K.C.
      • Forrester M.B.
      Electronic cigarette exposures reported to Texas poison centers.
      The reported events include nausea, vomiting, mouth and airway irritation, chest pain, and palpitations.
      • Cantrell F.L.
      Adverse effects of e-cigarette exposures.

       Lung

      Limited controlled studies are available on the safety of e-cigarettes or long-term health effects. There is little knowledge or regulation of the composition of each device or vaping liquid, and health officials do not know the effects on the lungs and heart or the risk for cancer. Nicotine, volatile organic compounds, heavy metals, and particle irritants are risks highlighted in recent studies.
      Documented acute adverse effects on the lungs have been limited to case reports and existing knowledge of material contained within the e-liquid. Significant exposure to the primary ingredient of the e-liquid, propylene glycol, while generally considered by the FDA to be safe, can cause irritation to the upper and lower respiratory track mucosa. A case of eosinophilic pneumonia 1 hour after smoking an e-cigarette has been reported.
      • Thota D.
      • Latham E.
      Case report of electronic cigarettes possibly associated with eosinophilic pneumonitis in a previously healthy active-duty sailor.
      This patient was treated with antibiotics and steroids and improved. There is also a reported case of lipoid pneumonia attributed to the glycerin-containing solution used in e-cigarettes. This patient’s symptoms and chest radiograph returned to normal after quitting e-cigarette use.
      • McCauley L.
      • Markin C.
      • Hosmer D.
      An unexpected consequence of electronic cigarette use.
      Another case report described the temporal association between sub-acute bronchiolitis and the use of e-cigarettes. Symptoms and pulmonary function tests returned to baseline after e-cigarette cessation without other treatment.
      • Hureaux J.
      • Drouet M.
      • Urban T.
      A case report of subacute bronchial toxicity induced by an electronic cigarette.
      Although uncommon, these cases point to the unpredictable and potentially serious side effects of e-cigarettes.

       Cardiovascular

      E-cigarette use can increase the heart rate and blood pressure and has the potential to cause cardiac events and arrhythmias in individuals with or at risk for cardiac disease.
      • Lippi G.
      • Favaloro E.J.
      • Meschi T.
      • Mattiuzzi C.
      • Borghi L.
      • Cervellin G.
      E-cigarettes and cardiovascular risk: beyond science and mysticism.
      However, studies using echocardiographic assessment of cardiac function did not show any effects after e-cigarette use.
      • Farsalinos K.E.
      • Tsiapras D.
      • Kyrzopoulos S.
      • Savvopoulou M.
      • Voudris V.
      Acute effects of using an electronic nicotine-delivery device (electronic cigarette) on myocardial function: comparison with the effects of regular cigarettes.
      There has been one case report of a temporal association between e-cigarette use and paroxysmal atrial fibrillation in a 70-year-old woman.
      • Monroy A.
      • Hommel E.
      • Smith S.
      • Raji M.
      Paroxysmal atrial fibrillation following electronic cigarette use in an elderly woman.
      Most of the presumed cardiac effects are thought to be secondary to the nicotine delivered by e-cigarettes. Although smokeless tobacco-associated cardiac events have been studied in the past, it is difficult to extrapolate data to e-cigarettes, considering their different mechanism of nicotine delivery.
      • Willis D.
      • Popovech M.
      • Gany F.
      • Zelikoff J.
      Toxicology of smokeless tobacco: implications for immune, reproductive, and cardiovascular systems.
      There are currently no published studies on e-cigarette use and thrombosis, platelet reactivity, atherosclerosis, or blood vessel function.

       Cancer Risk

      The long-term effect of e-cigarette use on cancer risk is unknown. However, e-cigarette users can be exposed to known carcinogens. One study compared the aerosol generated from 12 brands of e-cigarettes with regular cigarette smoke.
      • Goniewicz M.L.
      • Knysak J.
      • Gawron M.
      • et al.
      Levels of selected carcinogens and toxicants in vapour from electronic cigarettes.
      The e-cigarette aerosol contained lower levels of toxicants compared with cigarettes. Carcinogen levels were 9 to 450 times lower than those in conventional tobacco products. However, a more recent study utilizing the newer “tank-style” systems with higher voltage batteries reported that these e-cigarettes might expose users to equal or even greater levels of carcinogenic formaldehyde than in tobacco smoke.
      • Kosmider L.
      • Sobczak A.
      • Fik M.
      • et al.
      Carbonyl compounds in electronic cigarette vapors—effects of nicotine solvent and battery output voltage.
      The heating element in the e-cigarette causes the incidental generation of carbonyl compounds in e-cigarette smoke mist.
      • Kosmider L.
      • Sobczak A.
      • Fik M.
      • et al.
      Carbonyl compounds in electronic cigarette vapors—effects of nicotine solvent and battery output voltage.
      • Uchiyama S.
      • Ohta K.
      • Inaba Y.
      • Kunugita N.
      Determination of carbonyl compounds generated from the E-cigarette using coupled silica cartridges impregnated with hydroquinone and 2,4-dinitrophenylhydrazine, followed by high-performance liquid chromatography.
      The vaping liquid products (glycerol and propylene glycol) are oxidized into formaldehyde, acetaldehyde, acrolein, glyoxal, and methylglyoxal. A 2009 study commissioned by the FDA found known carcinogens diethylene glycol and nitrosamines in trace amounts.

      US Food and Drug Administration (FDA). Evaluation of e-cigarettes. 2009(DPATR-FY-09-23). Available at: http://www.fda.gov/downloads/Drugs/SCienceResearch/UCM173250.pdf. Accessed August 27, 2014.

      Diethylene glycol is an organic compound used as a solvent and is currently banned from food and drugs. Nitrosamine is a known carcinogen found in cosmetics, pesticides, and most rubber products.

      Statements Made by National Medical Societies

      The Tobacco Control Committee of the American Thoracic Society, in conjunction with the Forum of International Medical Societies, issued this statement in July 2014: “As a precaution, electronic nicotine delivery devices should be restricted or banned until more information about their safety is available.” The American Thoracic Society does not endorse e-cigarettes as a smoking cessation aid, noting the lack of FDA approval.
      • Schraufnagel D.E.
      • Blasi F.
      • Drummond M.B.
      • et al.
      Electronic cigarettes: a position statement of the Forum of International Respiratory Societies.
      The American Heart Association (AHA) has recently issued a Policy Statement recognizing the increase in e-cigarette use and the need to develop a clear policy on their use. The statement acknowledges that e-cigarette use has the potential to renormalize smoking behavior, sustain dual use, and initiate or maintain nicotine addiction. The statement also recognizes the potential of e-cigarettes for harm reduction if current smokers use them as substitutes for regular cigarettes. The AHA considers e-cigarettes that contain nicotine to be tobacco products and therefore supports their regulation under existing laws relating to the use and marketing of tobacco products. As yet, the AHA finds the available evidence insufficient to promote e-cigarettes as a smoking cessation aid.
      • Bhatnagar A.
      • Whitsel L.P.
      • Ribisl K.M.
      • et al.
      Electronic cigarettes: a policy statement from the American Heart Association.

      Statements Made by International Medical Societies

      The World Health Organization published an extensive review on the topic of e-cigarettes: “Background Paper on E-cigarettes (Electronic Nicotine Delivery Systems)” in 2013.

      Grana R, Benowitz N, Glantz SA. Background paper on E-cigarettes (Electronic Nicotine Delivery Systems). 2013. Available at: http://escholarship.org/uc/item/13p2b72n. Accessed August 27, 2014.

      The Spanish Society for Pulmonary Medicine and Thoracic Surgery has issued an official communication advocating for the regulation of e-cigarettes as a medicinal product, and stating that there is insufficient evidence to use e-cigarettes for smoking cessation.
      • Jimenez Ruiz C.A.
      • Solano Reina S.
      • de Granda Orive J.I.
      • et al.
      El cigarrillo electrónico. Declaración oficial de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) sobre la eficacia, seguridad y regulación de los cigarrillos electrónicos [Spanish].

      Conclusions

      Current studies report increased use of e-cigarettes by teens and adults. Based on a few studies, e-cigarettes appear to have some immediate adverse health effects, but studies reporting long-term effects on pure e-cigarette users as well as dual users are needed. E-cigarette use as a tobacco cessation product is not currently FDA approved, and a recent FDA-proposed regulation signals a possible change in FDA position toward the e-cigarette industry. Regarding e-cigarette use as a smoking cessation aid, some survey data do show improved cessation, particularly with “intensive” e-cigarette use. However, dual use has been associated with failed smoking cessation in several studies. The health effects of “intensive” e-cigarette use are unknown. As e-cigarette manufacturing changes, the newer and “hotter” products may expose patients to higher levels of known carcinogens. Physicians have a responsibility to understand these devices and to know about possible adverse effects. As e-cigarette use increases, patients and physicians will need to communicate effectively about this inhaled nicotine product. Useful Patient Education pages have been published in English and Spanish and may be used by physicians and smoking cessation programs.
      • Sugerman D.T.
      JAMA patient page. e-Cigarettes.
      • Grana R.A.
      • Ling P.M.
      • Benowitz N.
      • Glantz S.
      Electronic cigarettes. Cardiology patient page.

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      Linked Article

      • Nicotine Lethal Dose: Ignorance or Counterfeit?
        The American Journal of MedicineVol. 128Issue 10
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          Orellana-Barrios et al1 must be commended for the clear information they provide us on e-cigarettes to educate our patients. However, they stated “Nicotine…lethal dose ranges from 10-60 mg”1 without reference. Indeed, none exists, and searches can only retrieve circular and misleading references from dubious textbooks.2 More than 500 mg of oral nicotine is required to kill an adult.2 Moreover, ingestion cannot be massive because of incoercible vomiting.
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