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The effect of nicotine and cigarette smoke on respiration

Institution: Scripps Research Institute
Investigator(s): Merrill Mitler, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7IT-0086 Award: $130,177
Subject Area: Epidemiology
Award Type: Inno Dev & Exp Awards (IDEAS)

Initial Award Abstract
There is a statistically significant increase in disease-related deaths during the hours between 1:00 and 9:00 A.M. This increase appears to be related, in part, to the physiological properties of sleep. Since the morning increase in mortality is world-wide, it is justified to examine the potential contributory roles of commonly used drugs. Cigarette smoking is widespread and delivers the drug, nicotine, as well as a variety of other substances found in cigarette smoke. The scientific literature on nicotine and cigarette smoke does not provide a clear understanding of the effects that these agents have on respiration. Some data suggest that nicotine is a respiratory stimulant and that it decreases upper airway resistance air-flow. Other data suggest that cigarette smoke tends to obstruct air-flow through the upper airway. However, there are no systematic studies on the effect these agents have on the control of breathing during wakefulness and sleep. Such studies would be important for understanding the impact of nicotine and cigarette smoke on cardiopulmonary disease and the degree to which cigarette smoking plays a role in the increased mortality observed in the early morning.

Our group is expert in studying the effects of drugs on respiration. For example, we have demonstrated that alcohol has a deleterious effect on breathing during sleep and may contribute to the morning peak in mortality. Our techniques are readily adaptable to the study of nicotine and cigarette smoke. It is not now known how nicotine or cigarette smoke affect respiration.

We will use special sleep laboratory techniques to test the following hypotheses: (a) That nicotine, through its respiratory stimulant effect, will increase the drive to breathe; (b) That the irritants contained in cigarette smoke will tend to increase upper airway resistance primarily through increased nasal resistance; (c) That the combination of increased inspiratory effort with increased upper airway resistance will cause instability of the upper airway and lead to more snoring and more airway obstruction during sleep in the smoking condition.

Our methodology will measure resistance to airflow through the airway and changes in breathing effort when oxygen and carbon dioxide levels in the air are experimentally altered. Subjects will be young adult, paid volunteer smokers (<40 years old and free of the long-term pulmonary effects of smoking). Measurements will be made when subjects are awake and when they are asleep under three conditions designed to alter systematically exposure to nicotine and to cigarette smoke: (1 ) After they have had their usual number of cigarettes during the day and also have been wearing for 2 days a 21 mg. transdermal nicotine patch so that blood levels of nicotine are continuously at or above their usual levels; (2) After 30 days of no smoking and the continued use of nicotine patches; (3) Seven days after continued abstinence from smoking and discontinuation of the nicotine patch.

Final Report
In this IDEA project, we assessed total upper airway resistance, nasal resistance, hypoxic drive and hypercapnic drive during wakefulness and sleep. Upper airway resistance is the resistance to airflow through the nose, mouth and throat during inspiration, and increased upper airway resistance causes snoring and sleep apnea. Nasal resistance is the resistance to airflow through the nose only. Hypoxic drive and hypercapnic drive are the increases in the effort to breath that occurs with lowering the oxygen content or raising the carbon dioxide in the air. We are studying young male smokers before and after smoking cessation to test the following hypotheses:

(3) that nicotine, through its respiratory stimulant effect, will increase hypercapnic and hypoxic respiratory responses.

(4) that the irritants contained in cigarette smoke will increase upper airway resistance.

(5) that the combination of increased inspiratory drive and increased upper airway resistance from tobacco smoke containing nicotine will cause instability of the upper airway and lead to more snoring and more obstructive respiratory events (sleep apnea) during sleep.

This study was funded for 18 months beginning in July 1998, but funding delays caused us to begin studying patients in October 1998. The study was estimated to last 18 months and involve 15 subjects, each of whom would sleep under monitoring for 3 nights over 5 weeks. At this time, we have completed evaluations and were able to study 15 patients, ending in July 2000. Four subjects failed screening criteria for reasons such as poor compliance with the screening procedures, positive drug screens, or positive oximetries. Three additional subjects dropped out after the first night of study. Two of these subjects were unable to comply with the smoking cessation. Complications of the studies were minor. One patient had marijuana metabolites in urine samples taken on the evening of his first 2 nights which is a problem for data analysis but did not raise safety concerns. One subject developed malaise, nausea, and vomitting the day that his 21 mg nicotine patch was placed, which resolved with removal of the patch. He finished the study with no complications wearing a 14 mg patch. Other subjects tolerated very well the nicotine patches, the discontinuation of smoking, and the discontinuation of the patch. Our study was not designed to measure changes in mood, appetite, or sleep in patients who quit smoking, but no spontaneous reports of problems have emerged.

We have begun a systematic analysis of the data. Preliminary inspection of each of the study nights shows several findings. First, our earlier observation that resistance rises during NREM sleep, especially SWS, and that it is relatively low in REM, gets additional support from these studies. Secondly, it appears there is a tendency for resistance to be greater in the presence of nicotine during NREM sleep but not during waking or REM. This is against our main hypothesis, and we will further analyze this finding with formal statistics. Nasal resistance appears to be higher in sleep than in wake, as well as higher when the subject was using tobacco compared to not. Our drive studies are difficult to interpret, and the data are poor because of many arousals and movements. A final analysis of all data and publication of the results is pending.