1. Introduction and Background
1.1. Tobacco Cigarette
Recreational use of tobacco has centuries of history. The adverse effects of tobacco smoke have long been associated with damage and disease of nearly every organ in the body. The most common diseases associated with tobacco smoke are a variety of cancers, as well as cardiovascular and respiratory diseases [1] - [7] .
It is interesting to note that tobacco is the only legal drug that kills many of its users when used exactly as intended by its manufacturers. According to a World Health Organization (WHO) report, tobacco use is responsible for the death of nearly six million people across the world each year [7] . Recognizing this devastating smoking-related death rate, the western world has witnessed a drastic decline in cigarette use over the last few decades [8] . In this regard, in the US, one should not ignore the efforts made by the US Food and Drug administration (FDA). It should also be noted that the rate of smokers among the young population was in sharp increase at the time [9] [10] [11] . While the FDA and other advocacy groups were fairly successful in reducing tobacco smoking, another smoking alternative, the “electronic cigarette”, rapidly gained popularity at the global scale.
1.2. Electronic Cigarette
As an alternative to the traditional smoking, in 2006 the electronic cigarette has been introduced to the market [12] .
Electronic cigarettes are also known as “e-Cigarettes”, “e-cigs”, “vapes”, “e-hookahs”, “tank systems”, “mods”, “e-pipes”, “Cigalikes”, “APVs (Advanced Personal Vaporizers)”, “electronic nicotine delivery systems (ENDS)”, etc. They come in a variety of shapes, such as regular cigarettes, cigars, pipes, and some even look like USB flash drives, cigarette lighters, flashlights, pens, and other forms. Some include nicotine, but some don’t. Some even include marijuana. One of the latest versions of the e-Cigarettes is known as the “JUUL”. There are over 460 brands of e-Cigarettes available in the market [13] .
An electronic cigarette is a battery-operated device that dispenses nicotine aerosol without burning tobacco and is easily available everywhere despite lack of quality control of their manufacturing process, and their health effects [14] [15] [16] [17] . As soon as manufacturing started, they rapidly gained popularity in many countries.
Although this device was originally designed to reduce adult dependency on normal cigarettes and as a tobacco cessation tool, it has become the most popular among teenagers. According to the manufacturers of JUULs, they were meant for smokers and are not recommended for non-smokers. Despite this, many adolescent non-smokers picked up JUUL for recreational purposes [18] [19] [20] [21] .
Although use of combustible cigarettes among young population showed significant decline since the late 1990’s, the use of electronic cigarettes of all types is increasing globally. Even as soon as the introduction of the e-Cigarette to the market and despite lack of valid clinical data some scientists warned the public that the side effects of the e-Cigarettes may be even more devastating than from traditional cigarettes. Because of the lack of persuasive clinical data on potential negative health effects, authorities were not in a position to declare laws and regulations to this new smoking alternative. Until very recently, the FDA’s authority to regulate nicotine in tobacco products was limited to tobacco-derived nicotine. Then, in March 2022, Congress closed the loophole that manufacturers were exploiting. The new law allows the FDA to regulate nicotine regardless of the source, and further prohibits menthol in cigarettes and prohibiting flavors in cigars [22] .
Also because of its short history and novelty, only recently a few scientists and clinicians-initiated studies to investigate the possible harm that e-Cigarettes may cause to users. Here we briefly summarize the results of some of these investigations. Due to the short history of the e-Cigarettes, long term effects of e-Cigarette smoking have not yet been definitively established.
In an extensive study, Antoniewicz, et al. [23] looked at the acute effects of e-Cigarette aerosol inhalation with and without nicotine on the vasculature and the conducting airways of healthy subjects. The findings showed that the e-Cigarette aerosol with nicotine significantly increased blood pressure, heart rate, and arterial stiffness, It also caused obstruction of conducting airways which may cause acute impact on vascular and pulmonary functions. Chronic usage may lead to long term adverse health effects.
Vardavas, et al. [24] , in their short-term study showed that short term exposure to e-Cigarette aerosol exposure rapidly increased the FeNO (fractional exhaled nitric oxide), respiratory impedance, and respiratory resistance.
A recent longitudinal analysis investigated the association of chronic respiratory disease (chronic obstructive pulmonary disease, chronic bronchitis, emphysema or asthma) with e-Cigarette use. When compared for combustible tobacco smoking, current e-Cigarette use was associated with incidence of respiratory disease by a factor of 1.29 [25] .
In addition, a conclusive study by Cho and Paik [26] demonstrated that, among teenagers, more subjects with e-Cigarette use had asthma compared to those who did not use e-Cigarette, indicating that among the high school student group, e-Cigarette use can be a risk factor for asthma.
Qasim, et al. [27] demonstrated that short term e-Cigarette exposure increases the risk of thrombogenesis and enhances platelet function in rats. Although their short-term exposure was defined as 2 exposures of 200 puffs per day for 5 days, they demonstrated that e-Cigarette exposures alter physiological hemostasis and increase the risk of thrombogenic events. They attributed this, at least in part, to the hyperactivation state of platelets. Taken together, the data demonstrate for the first time that e-Cigarettes alter physiological hemostasis and increase the risk of thrombogenic events. This is attributable, at least in part, to the hyperactive state of platelets. Thus, the negative health consequences of e-Cigarette exposure should not be underestimated and warrant further extensive investigation.
Rankin, et al. [28] assessed the toxic potential of e-Cigarettes and concluded that the e-Cigarette aerosol can alter the viability, inflammation, oxidative stress and genotoxicity of the human lung epithelial cell lines. In particular, they found that e-Cigarette aerosol containing nicotine, volatile organic compounds, aldehydes and polycyclic aromatic hydrocarbons decreased cell viability and increased DNA damage.
Hedman, et al. [29] , in their extensive study of over 30,000 subjects, found that respiratory symptoms were more common among e-Cigarette users compared to cigarette smokers.
In the most recent study, Adzrago, et al. [30] , looked at behavioral associations of e-Cigarette use. Their results indicate that moderate or severe anxiety or depression symptoms were more likely for current e-Cigarette users compared to former e-cigarette users.
In the last few years there has been growing evidence of the harmful effects of e-Cigarettes in pulmonary health including reports of “e-Cigarette or vaping use associated lung injury (EVALI)”, originally known as “vaping associated pulmonary illness (VAPI)”, gas exchange disturbance, reduced lung function, increased airway inflammation and oxidative stress, downregulation of immunity and increased risk of respiratory infection [31] .
The aim of this study is to investigate whether the use of e-Cigarette could have an immediate effect on respiratory mechanics.
2. Methods
Using a University of Maryland IRB approved protocol, respiratory resistance of 25 subjects was measured before and after using the e-Cigarette, so that in this case each subject was his/her own control. This included 24 male and one female subjects, 21 were Caucasian, three were Hispanic and one was Asian. The subjects were between 19 to 55 years of age (with only one 53 and one 55 years old). Subjects were selected regardless of their race, sex, and history of regular cigarette or e-Cigarette use.
For this work the respiratory resistance value of the subjects before and after the use of the e-Cigarette was used. The respiratory resistance was measured using the Airflow Perturbation Device (the APD). All subjects were tested with the same e-Cigarette device as well as the same APD unit. All e-Cigarettes had a similar nicotine pod with 59 mg/ml nicotine.
2.1. Brief Description of the APD
The Airflow Perturbation Device (APD) was initially developed as a simple, noninvasive, inexpensive, portable, and effortless respiratory diagnostic device for adults [32] - [38] .
The APD measures resistance of the respiratory system by periodically inserting a known added resistance in the flow path by means of a rotating wheel with open and screened segments. The added resistance causes a slight decrease in airflow and a change in mouth pressure. The magnitudes of the flow and pressure perturbations depend on the relative resistance inside the patient’s respiratory system and resistance of the APD itself. By measuring mouth pressure and airflow rate, with and without the APD resistance inserted into the path of the airflow, external resistance becomes known, and the internal respiratory resistance can then be easily determined noninvasively. The resistance (in cmH2O/l/s) is calculated by simply dividing the mouth pressure change, or perturbation, by the flow perturbation. In general, respiratory resistance in exhalation is slightly higher than respiratory resistance in inhalation.
APD measurements were favorably compared with spirometry, body plethysmograph, and IOS in adults [39] - [44] . It was used in exercising subjects [45] , and on subjects with paradoxical vocal fold motion [46] [47] [48] [49] [50] . The APD has also been used in a variety of other research projects, such as: Influence of nasal congestion on respiratory resistance [51] ; testing low doses of caffeine on respiratory resistance [52] ; comparison with esophageal balloon [53] ; diurnal effects of respiratory resistance [54] ; identification of patients with reactive airways [55] ; optimization of airway caliber [56] ; results using nasal strips [57] ; and induced anxiety [58] . Recently the APD was also used in assessment of bronchodilator response in children with asthma exacerbation [59] .
2.2. Details of the Measurements
To use the APD, a disposable antimicrobial filter was attached to the pneumotachometer of the APD. This antimicrobial filter is a standard antimicrobial filter used at many Pulmonary Function Test clinics. A nose clip was also used to assure mouth only breathing. The users were instructed to seal the antimicrobial filter with their lips to avoid any air leak. Each subject was asked to sit in an upright position against the back of a chair and normally breathe in-and-out of the APD. They were also asked to make sure to keep their tongue flat on the base of the mouth in order not to block or reduce the air flow while breathing. Because this was a research project, each respiratory resistance measurement was repeated in triplicates. The APD is set to measure the respiratory resistance for one minute, after which the device automatically stops, and 3 separate values of the respiratory resistance (in inhalation, exhalation, and the mathematical average) were displayed on the screen of the APD. The measurements were consistently repeated after one minute wait time.
Exactly the same measurements were performed before the use of the e-Cigarette (baseline control), and a minute later after using the e-Cigarette (experimental). For the experimental condition subjects were asked to use the e-Cigarette vapor (inhale) for one poke (3 seconds) only. This was monitored by the person who was conducting the experiment, and at the 3-second timeline the subject was asked to stop using the e-Cigarette. After each measurement the data from the APD screen were copied into an Excel spreadsheet for further analysis. A total of 6 measurements (one minute apart) were recorded.
3. Analysis and Results
The database was a simple one. Figure 1 shows average Respiratory Resistance values in inhalation and exhalation for the 25 subjects. Respiratory resistance in exhalation is, as expected, slightly higher than Inhalation respiratory resistance for all subjects except two that were reversed. Resistance changes after vaping for six subjects were negligible (perhaps within the sensitivity of the APD measurement). For the two subjects for whom the respiratory resistance reduced, this can be due to the existence of a disorder called “Paradoxical Vocal Fold Motion (PVCM)” [46] [47] [48] [49] [50] . This, however, may not be true here because our sample size is fairly small and also other tests such as laryngoscopy is needed to definitively identify the existence of PVCM [46] .
Figure 2 shows the average Respiratory Resistance vales for all 25 subjects before the use of e-Cigarette (Avg), and after exposure to the e-Cigarette (JAvg). As can be seen, in general the Respiratory resistance values increased significantly for all subjects after e-Cigarette use (only for 3 seconds), except for 2 that slightly decreased; 4 also showed no change.
We have also looked at the inhalation and exhalation resistance values before and after e-Cigarette exposure to see which resistance (inhalation or exhalation) was responsible for the changes seen in Figure 2. Comparing Figure 3 and Figure 4 may indicate that e-Cigarette exposure affects inhalation somewhat more than exhalation.
4. Statistical Analysis
Table 1 shows the averages of the Respiratory Resistance Values (with Standard Error of the Mean, SEM) for both cases, before and after e-Cigarette smoking. Although this study was based on a small number of subjects, a student t-test was conducted and indicated that the 3 seconds exposure to e-Cigarette vapor significantly increased the Respiratory Resistance value (at p = 0.0001 level).
![]()
Figure 1. Respiratory resistance values in inhalation and exhalation.
![]()
Figure 2. Average respiratory resistance values before and after e-Cigarette use.
![]()
Figure 3. Inhalation respiratory resistance values before and after e-Cigarette use.
![]()
Figure 4. Exhalation respiratory resistance values before and after e-Cigarette use.
![]()
Table 1. Respiratory Resistance values before and after e-Cigarette smoking.
5. Discussion
To our knowledge, this is the first study to investigate an immediate physiologic response after inhalation from an e-Cigarette. Based on the findings of this small sample study, the use of even one poke e-Cigarette inhalation for 3 seconds demonstrated a statistically significant increase in respiratory resistance. Increased resistance has been shown to precede changes in pulmonary function of patients with obstructive airway diseases such as COPD and asthma. It is possible that this measurable effect on respiratory system may indicate a similar health effect. Given that e-Cigarette users typically use the device longer than 3 seconds several times a day may have a greater respiratory health impact. Future studies with a large number of subjects and longer e-Cigarette exposure time will be needed to determine short and long term effects of e-Cigarette in pulmonary mechanics and respiratory health.
In smoking the inhaled nicotine entered the body is rapidly distributed through the bloodstream and crosses the blood-brain barrier and reaches the brain within 10 - 20 seconds after inhalation [60] . In this work we have shown that the inhaled nicotine starts adversely affecting the pulmonary system in only 3 seconds.
6. Conclusion
Very short exposure time to e-Cigarette vapor (3 seconds only), caused an immediate adverse physiologic effect in respiratory resistance. Further research on the effects of short and long term usage of e-Cigarette in respiratory physiology and pulmonary health will be worthy of investigation.
Acknowledgements and Disclosures
This work was partially supported by the NIH Grant HL078055 (JV). The authors declare that there is no conflict of interests.
Authors’ Contributions
All authors contributed to the study conception and design; Jake Morales and Jafar Vossoughi contributed to the subject data collection; Jafar Vossoughi and Arthur Johnson conducted the data analysis; all four authors contributed to the manuscript preparation and editing.