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The Effect of Theophylline on Sleep in Normal Subjects

1993; Elsevier BV; Volume: 103; Issue: 1 Linguagem: Inglês

10.1378/chest.103.1.5

1931-3543

Philip L. Smith, Alan R. Schwartz,

Circadian rhythm and melatonin

Until recently, the effect of bronchodilators on sleep architecture has been relatively unstudied. The assumption has been that medications that relieve airway obstruction during the daytime should do so during the night as long as plasma levels are maintained.1Zwillich CW Neagley SR Cicutto L White DP Martin RJ Nocturnal asthma therapy: inhaled bitolterol versus sustained-release theophylline.Am Rev Respir Dis. 1989; 139: 470-474Crossref PubMed Scopus (38) Google Scholar However, reestablishing airflow at night while remaining asleep is quite distinct from restoring normal airway function during wakefulness. It is well known that minor changes in various respiratory stimuli, such as hypercapnia, hypoxia, airway occlusion, and pulmonary irritation, produce arousals and disruption of the sleep pattern.2Bowes G Phillipson EA Arousal responses to respiratory stimuli during sleep (vol 21).in: Saunders NA Sullivan CE Sleep and breathing. Marcel Dekker, New York1984: 137-200Google Scholar Establishing, therefore, that a patient sleeps normally provides good indirect evidence that overall airway function is being adequately maintained.In general, sleep architecture can be viewed in terms of "quantity," as determined by the total sleep time and efficiency (actual recorded total sleep time divided by total time in bed), and "quality," as assessed by fragmentation due to small arousals lasting 10 to 20 s or shifts to fighter stages.3Carskadon MA Dement WC Normal human sleep: an overview.in: Kryger MH Roth T Dement WC Principles and practice of sleep medicine. WB Saunders, Philadelphia1989: 3-13Google Scholar Clinically significant disruption in either the quantity or quality of sleep results in the sensation of daytime fatigue and sleepiness. Since patients with underlying lung disease are known to already suffer from disrupted sleep,4Douglas NJ Flenley DC Breathing during sleep in patients with obstructive lung disease.Am Rev Respir Dis. 1990; 141: 1055-1070Crossref PubMed Google Scholar, 5Arand DL McGinty DJ Littner MR Respiratory patterns associated with hemoglobin desaturation during sleep in chronic obstructive pulmonary disease.Chest. 1981; 2: 183-190Crossref Scopus (31) Google Scholar, 6Calverley PMA Brezinova V Douglas NJ Catterall JR Flenley DC The effect of oxygenation on sleep quality in chronic bronchitis and emphysema.Am Rev Respir Dis. 1982; 126: 206-210PubMed Google Scholar, 7Fleetham J West P Mezon B Conway W Roth T Kryger M. Sleep, arousals, and oxygen desaturation in chronic obstructive pulmonary disease.Am Rev Respir Dis. 1982; 126: 429-433PubMed Google Scholar, 8Perez-Padilla R West P Lertzman M Kryger MH Breathing during sleep in patients with interstitial lung disease.Am Rev Respir Dis. 1985; 132: 224-229PubMed Google Scholar it is useful to distinguish any potential deleterious effect that a particular medication might have on overall sleep architecture apart from its beneficial effect on airway function.In this issue of Chest (see page 193), Kaplan and coworkers report the effects of theophylline on sleep architecture in ten healthy young men in a double-blind cross-over design. They found that theophylline decreased total sleep time by approximately a half hour (decreased quantity) as well as increased the number of arousals (decreased quality) by four episodes per hour. Otherwise, sleep efficiency, the distribution of stages of sleep, and sleep onset times were unaltered. These findings are in slight contradistinction to those of another recently published study of similar design, which showed no effect of theophylline on either sleep architecture or daytime cognitive performance.9Fitzpatrick MF Engleman HM Boellert F McHardy R Shapiro CM Deary IJ et al.Effect of therapeutic theophylline levels on the sleep quality and daytime cognitive performance of normal subjects.Am Rev Respir Dis. 1992; 145: 1355-1358Crossref PubMed Scopus (32) Google Scholar Since both studies were almost identical in design, it is hard to explain the differences in total sleep time other than to note that the study by Fitzpatrick et al9Fitzpatrick MF Engleman HM Boellert F McHardy R Shapiro CM Deary IJ et al.Effect of therapeutic theophylline levels on the sleep quality and daytime cognitive performance of normal subjects.Am Rev Respir Dis. 1992; 145: 1355-1358Crossref PubMed Scopus (32) Google Scholar contained a selection bias due to symptomatic dropout and a longer period of adaptation to theophylline.In fact, both studies are giving us similar clinical information. That is, theophylline probably does not clinically alter sleep architecture enough to cause clinical daytime dysfunction. This conclusion is based on recent sleep deprivation work demonstrating that less than 1 to 2 h of chronic reduction in total sleep time will not likely affect either symptomatic or objective measurements of daytime sleepiness.10Carskadon MA Dement WC Nocturnal determinants of daytime sleepiness.Sleep. 1982; 5: S73-81PubMed Google Scholar Likewise, the minimal increase in hourly arousals in the study by Kaplan et al will probably not significantly alter daytime function since we know that older normal individuals, who have demonstrated much higher arousal rates, did not show clinically significant alterations in daytime sleepiness.11Knight H Millman RP Gur RC Saykin AJ Doherty JU Pack AI Clinical significance of sleep apnea in the elderly.Am Rev Respir Dis. 1987; 136: 845-850Crossref PubMed Scopus (60) Google Scholar, 12Phillips BA Berry DTR Schmitt FA Magan LK Gerhardstein DC Cook YR Sleep-disordered breathing in the healthy elderly: clinically significant? Chest. 1992; 101: 345-349Google Scholar Finally, after adjusting for the age differences between the subjects in the studies by Kaplan et al and Fitzpatrick et al,9Fitzpatrick MF Engleman HM Boellert F McHardy R Shapiro CM Deary IJ et al.Effect of therapeutic theophylline levels on the sleep quality and daytime cognitive performance of normal subjects.Am Rev Respir Dis. 1992; 145: 1355-1358Crossref PubMed Scopus (32) Google Scholar it can be seen that the distribution of sleep architecture, the sleep onset latency, the sleep efficiency, and wake after sleep onset were almost identical, suggesting that theophylline did not directly alter the fundamental mechanisms that determine the specific stages of sleep.These two studies provide useful new information in evaluating the effectiveness of treatment of obstructive airway disease during sleep. For example, 10 years ago Montplaisir et al13Montplaisir J Walsh J Malo JL Nocturnal asthma: features of attacks, sleep and breathing patterns.Am Rev Respir Dis. 1982; 125: 18-22PubMed Google Scholar noted a marked increase in total sleep time of almost 2 h when a group of asthmatic patients were treated. Although the precise regimen was not specified, the improvement most likely was due to better management of nocturnal airway function. Moreover, from the few studies that have examined sleep in patients with chronic obstructive and restrictive disease, it is clear that there are typically striking reductions in the quantity of sleep, with total sleep times often averaging 200 to 250 min. Thus, rather than worrying too much about the minimal effects of theophylline on sleep architecture in normal individuals, it would now seem more useful to know whether patients whose sleep is so severely disrupted can be helped by pharmacologic or other means. Until recently, the effect of bronchodilators on sleep architecture has been relatively unstudied. The assumption has been that medications that relieve airway obstruction during the daytime should do so during the night as long as plasma levels are maintained.1Zwillich CW Neagley SR Cicutto L White DP Martin RJ Nocturnal asthma therapy: inhaled bitolterol versus sustained-release theophylline.Am Rev Respir Dis. 1989; 139: 470-474Crossref PubMed Scopus (38) Google Scholar However, reestablishing airflow at night while remaining asleep is quite distinct from restoring normal airway function during wakefulness. It is well known that minor changes in various respiratory stimuli, such as hypercapnia, hypoxia, airway occlusion, and pulmonary irritation, produce arousals and disruption of the sleep pattern.2Bowes G Phillipson EA Arousal responses to respiratory stimuli during sleep (vol 21).in: Saunders NA Sullivan CE Sleep and breathing. Marcel Dekker, New York1984: 137-200Google Scholar Establishing, therefore, that a patient sleeps normally provides good indirect evidence that overall airway function is being adequately maintained. In general, sleep architecture can be viewed in terms of "quantity," as determined by the total sleep time and efficiency (actual recorded total sleep time divided by total time in bed), and "quality," as assessed by fragmentation due to small arousals lasting 10 to 20 s or shifts to fighter stages.3Carskadon MA Dement WC Normal human sleep: an overview.in: Kryger MH Roth T Dement WC Principles and practice of sleep medicine. WB Saunders, Philadelphia1989: 3-13Google Scholar Clinically significant disruption in either the quantity or quality of sleep results in the sensation of daytime fatigue and sleepiness. Since patients with underlying lung disease are known to already suffer from disrupted sleep,4Douglas NJ Flenley DC Breathing during sleep in patients with obstructive lung disease.Am Rev Respir Dis. 1990; 141: 1055-1070Crossref PubMed Google Scholar, 5Arand DL McGinty DJ Littner MR Respiratory patterns associated with hemoglobin desaturation during sleep in chronic obstructive pulmonary disease.Chest. 1981; 2: 183-190Crossref Scopus (31) Google Scholar, 6Calverley PMA Brezinova V Douglas NJ Catterall JR Flenley DC The effect of oxygenation on sleep quality in chronic bronchitis and emphysema.Am Rev Respir Dis. 1982; 126: 206-210PubMed Google Scholar, 7Fleetham J West P Mezon B Conway W Roth T Kryger M. Sleep, arousals, and oxygen desaturation in chronic obstructive pulmonary disease.Am Rev Respir Dis. 1982; 126: 429-433PubMed Google Scholar, 8Perez-Padilla R West P Lertzman M Kryger MH Breathing during sleep in patients with interstitial lung disease.Am Rev Respir Dis. 1985; 132: 224-229PubMed Google Scholar it is useful to distinguish any potential deleterious effect that a particular medication might have on overall sleep architecture apart from its beneficial effect on airway function. In this issue of Chest (see page 193), Kaplan and coworkers report the effects of theophylline on sleep architecture in ten healthy young men in a double-blind cross-over design. They found that theophylline decreased total sleep time by approximately a half hour (decreased quantity) as well as increased the number of arousals (decreased quality) by four episodes per hour. Otherwise, sleep efficiency, the distribution of stages of sleep, and sleep onset times were unaltered. These findings are in slight contradistinction to those of another recently published study of similar design, which showed no effect of theophylline on either sleep architecture or daytime cognitive performance.9Fitzpatrick MF Engleman HM Boellert F McHardy R Shapiro CM Deary IJ et al.Effect of therapeutic theophylline levels on the sleep quality and daytime cognitive performance of normal subjects.Am Rev Respir Dis. 1992; 145: 1355-1358Crossref PubMed Scopus (32) Google Scholar Since both studies were almost identical in design, it is hard to explain the differences in total sleep time other than to note that the study by Fitzpatrick et al9Fitzpatrick MF Engleman HM Boellert F McHardy R Shapiro CM Deary IJ et al.Effect of therapeutic theophylline levels on the sleep quality and daytime cognitive performance of normal subjects.Am Rev Respir Dis. 1992; 145: 1355-1358Crossref PubMed Scopus (32) Google Scholar contained a selection bias due to symptomatic dropout and a longer period of adaptation to theophylline. In fact, both studies are giving us similar clinical information. That is, theophylline probably does not clinically alter sleep architecture enough to cause clinical daytime dysfunction. This conclusion is based on recent sleep deprivation work demonstrating that less than 1 to 2 h of chronic reduction in total sleep time will not likely affect either symptomatic or objective measurements of daytime sleepiness.10Carskadon MA Dement WC Nocturnal determinants of daytime sleepiness.Sleep. 1982; 5: S73-81PubMed Google Scholar Likewise, the minimal increase in hourly arousals in the study by Kaplan et al will probably not significantly alter daytime function since we know that older normal individuals, who have demonstrated much higher arousal rates, did not show clinically significant alterations in daytime sleepiness.11Knight H Millman RP Gur RC Saykin AJ Doherty JU Pack AI Clinical significance of sleep apnea in the elderly.Am Rev Respir Dis. 1987; 136: 845-850Crossref PubMed Scopus (60) Google Scholar, 12Phillips BA Berry DTR Schmitt FA Magan LK Gerhardstein DC Cook YR Sleep-disordered breathing in the healthy elderly: clinically significant? Chest. 1992; 101: 345-349Google Scholar Finally, after adjusting for the age differences between the subjects in the studies by Kaplan et al and Fitzpatrick et al,9Fitzpatrick MF Engleman HM Boellert F McHardy R Shapiro CM Deary IJ et al.Effect of therapeutic theophylline levels on the sleep quality and daytime cognitive performance of normal subjects.Am Rev Respir Dis. 1992; 145: 1355-1358Crossref PubMed Scopus (32) Google Scholar it can be seen that the distribution of sleep architecture, the sleep onset latency, the sleep efficiency, and wake after sleep onset were almost identical, suggesting that theophylline did not directly alter the fundamental mechanisms that determine the specific stages of sleep. These two studies provide useful new information in evaluating the effectiveness of treatment of obstructive airway disease during sleep. For example, 10 years ago Montplaisir et al13Montplaisir J Walsh J Malo JL Nocturnal asthma: features of attacks, sleep and breathing patterns.Am Rev Respir Dis. 1982; 125: 18-22PubMed Google Scholar noted a marked increase in total sleep time of almost 2 h when a group of asthmatic patients were treated. Although the precise regimen was not specified, the improvement most likely was due to better management of nocturnal airway function. Moreover, from the few studies that have examined sleep in patients with chronic obstructive and restrictive disease, it is clear that there are typically striking reductions in the quantity of sleep, with total sleep times often averaging 200 to 250 min. Thus, rather than worrying too much about the minimal effects of theophylline on sleep architecture in normal individuals, it would now seem more useful to know whether patients whose sleep is so severely disrupted can be helped by pharmacologic or other means.