- Email: [email protected]
Circadian variations in chronic asthma and chronic obstructive pulmonary disease
Circadian Variations in Chronic Asthma and Chronic Obstructive Pulmonarv Disease J
THOMAS
L. PETTY, M.D. Denver, cobrado
Patients with airway obstruction of all types show circadian variation of airflow. This article reviews the results of studies that suggest both possible mechanisms for this phenomenon and strategies for its treatment. The strategies discussed include the use of sustained-release betaagonists and a once-a-day theophylline preparation, Uniphyl tablets, that is especially effective in asthmatic patients when administered in the evening. Also presented is a summary of future directions in the planning and implementation of individualized therapeutic strategies for patients with advanced chronic obstructive airways disease.
atients with airflow disorders usually have their P worst dyspnea, cough, and expectoration in the early morning. Careful serial measurements of peak expiratory airflow have shown that airflow obstruction in asthmatic patients peaks between 3:00 and 4:00 A.M. [l]. Diurnal changes in blood epinephrine, histamine, and cortisol levels have been offered as explanations for this phenomenon 121. It appears also that not only asthmatic patients but patients with all types of airway obstruction show regular patterns of variation of peak airflow over the day [3,4]. Whereas asthmatic patients show the so-called “morning dip” pattern [l], some patients with chronic bronchitis show a “double dip” pattern, some experience an evening reduction, and others exhibit no regular pattern at all 131. Furthermore, the regular use of bronchodilators can alter these patterns [3].
INFLUENCEOF BETA-AGONISTS Diurnal variation in forced expiratory volume in one second (FEVi) has been carefully studied in a small group of nonallergic patients with severe airflow obstruction [5]. The relationship between reduction in FEV, and urinary catecholamine and histamine metabolite concentrations was monitored both before and after the use of a long-acting oral beta-agonist (terbutaline) for one week. A 7:00 A.M. reduction in FEV, correlated with reduced plasma and urinary epinephrine levels, but a similar correlation with norepinephrine levels was not found. Histamine and histamine metabolite concentrations did not show a diurnal variation, suggesting no relationship with reduction in FEVi. Administration of slow-release terbutaline for one week prevented the early morning decrease in FEVi. This treatment significantly suppressed both plasma and urinary levels of epinephrine but had no effect on norepinephrine levels. These findings suggest that epinephrine is an important factor in the regulation of bronchial smooth muscle tone in patients with early morning dyspnea. The articles cited above suggest possible mechanisms for the diurnal variation in the severity of chronic airflow obstruction. Furthermore, it has been appropriately emphasized that the casual measurement of response to bronchodilators at midday cannot be used to predict the time or the magnitude of these variations [3]. Knowledge of the patients’ regular patterns of reduced airflow is more likely to be useful in planning preventive therapeutic strategy. So far, pharmacologic doses of corticosteroids have not proved useful [6], and anticholinergics have not been adequately examined. From the Webb-Waring Lung Institute, Diwion of Pulmonary Sciences, University of Colorado Health Sciences Center, Denver, Colorado. Requests for reprints should be addressed to Dr. Thomas L. Petty, Webb-Waring Lung institute, University of Colorado Health Sciences Center, Denver, Colorado 80262.
MORNINGVERSUSEVENINGDOSINGOF LONGACTINGTHEOPHYLLINE Preliminary studies [7,81 have suggested that longacting theophylline preparations can be used strategically at bedtime to improve control of nighttime July 29, 1988
The American Journal of Medicine
Volume 85 (suppl 1B)
21
reparation, in most cases twice a day, and an inhaled & eta-agonist used either regularly or on an as-needed basis throughout the year. No patients requiring in-
m AM
2
0 PM
1
T
T
G izi Ll
0 Week
1
Week
2
Week
3
Figure 1. Comparison of the FEV, values (mean + SEM) obtained in 20 asthmatic patients on Day 6 of Weeks 1, 2, and 3 of a morning or evening Uniphyl dosing regimen. The measurements were made 15 2 1 hours after administration.
[IIIIIIIIIAM 3-
2 22 l-
o Week
1
Week
2
Week
3
Figure 2 Comparison of the FVC values (mean * SEM) obtained in 20 asthmatic patients on Day 6 of Weeks 1, 2, and 3 of a morning or evening Uniphyl dosing regimen. The measurements were made 15 + 1 hours after administration.
TABLE I Serum Theophylline levels (mean -+ SEM)* AM. Dosing Week 2I Week 3
13.7 13.7?+ 1.2 1.5 12.6 ? 1.0
P.M. Dosing 15.5 2? 1.3 15.3 1.1 17.3 ? 1.0
Significance iz p 4.05
NS = not significant. *All values are in micrograms.
asthma. We also investigated such a preparation, once-a-day Uniphyl tablets (The Purdue Frederick Co., Norwalk, Connecticut), and found that it yields higher airflow (FEVJ and volume (forced vital capacity; FVC) values when given at bedtime than when given in the morning. Twenty stable year-round asthmatic patients (five men and 15 women) participated in the study. Their ages ranged from 23 to 68 years, with a mean age of 47 years. The FEVi values of all the patients were between 30 and 75 percent of predicted values, and all showed an improvement in FEV, of at least 15 percent after inhalation of a betaagonist aerosol (albuterol). The patients were already taking another oral sustained-release theophylline
22
July 29,
1988 The American Journal of Medicine
Volume 85 (suppl 1B)
haled or oral steroids participated in the trial. After baseline spirometry had been performed and blood had been drawn for the determination of serum theophylline levels, the patients were randomly assigned to receive Uniphyl at either 3:OOA.M. or 8:00 P.M. for three weeks. The patients switched to Uniphyl tablets from their previous twice-daily theophylline preparation on a milligram-for-milligram basis. Spirometry and serum theophylline level determinations were repeated 15 ? 1 hours after either the morning or evening dose on Day 6 of each of the three study weeks. At the end of three weeks, the patients switched from morning to evening or from evening to morning dosing and the protocol was repeated for the final three weeks of the study. Figures 1 and 2 show the mean FEVi and FVC values obtained on Day 6 of each of the three consecutive weeks. FEVi was slightly higher after evening dosing in all three study weeks, but the difference was statistically significant only in Weeks 1 and 3. The FVC values were significantly higher after evening dosing in all three weeks. Table I lists the mean serum theophylline levels obtained after three weeks of morning and evening dosing. Although the theophylline levels were somewhat higher after evening dosing in all three study weeks, the difference was statistically significant only in Week 3. This study did not examine the control of diurnal variations in detail, but the results do suggest that evening dosing with Uniphyl improves ventilatory function more than morning dosing. In a multi-investigator study [9], the clinical response of 171 asthmatic patients to once-a-day theophylline in the form of Uniphyl tablets was compared with their response to prestudy methylxanthines given at least twice a day. After a one-week baseline study of the patients’ previous therapies (in most cases theophylline with an inhaled beta-agonist), the patients switched to Uniphyl tablets. The transition to the research protocol was smooth. Both the patients’ and investigators’ global evaluations suggested a decline in the incidence of nocturnal awakenings and a corresponding reduction in nighttime inhaler use, as well as highly significant reductions in both nocturnal and early morning symptoms. Symptom scores for wheezing, dyspnea, chest tightness, and cough all improved significantly during the once-a-day evening regimen. Spirometric measurements in this multicenter trial also favored evening dosing, and side effects with evening dosing were similar to those with the patients’ previous twice-daily therapy. These data, together with our own, strongly suggest that evening dosing with Uniphyl can reduce nocturnal variation of chronic symptoms in patients with asthma. In contrast, the results of another study [lo] involving patients with advanced chronic obstructive pulmonary disease selected on the basis of heavy smoking, hyperinflation, and reduced gas transfer as judged by the single-breath diffusion test did not indicate that evening administration is better than morning in improving airflow and symptoms. It is likely that the factors responsible for the diurnal variations in airflow
are numerous and that therapeutic strategies will have to be individualized for maximal therapeutic benefit.
NOCTURNALHYPOXEMIA
Today we have an immense armamentarium of therapeutic modalities that are of potential value to our patients. Inhaled and oral beta-agonists? long-acting theophyllines, and inhaled and oral steroids should all be employed in patients for whom they are appropriate. Home oxygen strategies and even periods of home mechanical ventilation (during sleep, for example) will continue to find application in selected patients. We are entering an era of specialized care strategies for patients with chronic obstructive pulmonary disease who have individual variations in the severity of their airflow obstruction and gas transfer.
The worsening of hypoxemia during the hours of sleep in patients with severe hypoxemia has been well documented [ 11,121. The availability of convenient recording pulse oximeters coupled with the clinical interest in sleep-disordered breathing and the consequences of hypoxemia have stimulated many studies of nighttime hypoxemia. Abundant evidence now exists that a significant number of persons whose oxygen levels are normal in the daytime may experience significant levels of sleep-related hypoxemia, with or REFERENCES without apnea or hypopnea [12,131. At least one con- 1. Turner-Watwlck M: On observing patterns of airflow obstruction in chrornc asthma. Br J Chest 19n, 71: 73-86. sequence of nocturnal hypoxemia is a high incidence of 2.DisClark TJH, Hetzel MR: Nocturnal asthma and circulating eptnephrine, histamine, and cardiac arrhythmias [ 141. Sleep-related hypoxemia cortisol fletter). N Enal J Med 1980: 303: 1300. could be a factor in the predominance of deaths in the 3. Connolly Ci% The elect of bronchodilators on diurnal rhythms in airway obstruction. Br early morning (mortality is the greatest between 5:OO J Dis Chest 1981; 75: 197-203. Dawkins KD, Muers MF: Diurnal variation in airflow obstruction in chronic bronchibs. and 6:00 A.M.) [151. Sleep hypoxemia may also be 4.Thorax 1981; 36: 618-621. partly responsible for the phenomenon of early morn- 5. Postma DS, Koeter GH. Keyser JJ, Meurs, H: Influence of slow-release terbutallne on the clrcadtan variation of catecholamines, histamine, and lung function in nonallergic ing death in patients with advanced chronic obstrucpatients with partly reversible airflow obstruction. J Allergy Clin lmmunol 1986; P 471tive pulmonary disease [16].
FUTUREDIRECTIONS Knowledge of the circadian variations that occur in patients with advanced chronic obstructive pulmonary disease can be useful in planning and implementing therapeutic strategies. In view of the simplicity and utility of the flowmeters now available for home use, home monitoring to establish patterns in changes in expiratory airflow during the day should become standard practice. Measurements of volume variation, i.e., daily changes in FVC, appear to be equally valuable, particularly since anticholinergic bronchodilators often improve vital capacity as well as forced expiratory flow [17]. In some patients, volume improves more than flow in response to inhaled bronchodilators [18], and in some the rise in FVC may parallel a reduction in residual volume, with no changes in flow [19]. Absolute changes in both FEVl and FVC may occur with no change in FEVJFVC percent [20]. A simple, inexpensive., disposable device that is now available for measurmg vital capacity could also be used in home-monitoring studies to improve our knowledge of changes in respiratory mechanics during the day [21]. This knowledge would augment data available from serial home peak flow measurements. The use of home oximetry with continuous recording of nighttime hypoxemia patterns seems certain to become widespread as a means of identifying patients at risk of developing reactive pulmonary hypertension as a prelude to fixed pulmonary vascular changes and COYpulmonale
[20].
477. 6. Soutar CA, Costello J, ljaduola V, et at Nocturnal and mornmg asthma: relationship to plasma corticosteroids and response to cortisol infuslon. Thorax 1975; 30: 436-440. 7. Busse WW, Bush RK: Comparison of morning and evening dosing with a 24.hour sustained-release theophylline, Uniphyl, for nocturnal asthma. Am J Med 1985; 79 (suppl 6A): 62-66. 8. ArkInstall WW, Atkrns ME, Harrison D, Stewalt JH: Once-daily sustained-release theophylline reduces diurnal variation in splrometry and symptomatology in adult asthmatics. Am Rev Respif Dis 1987; 135: 316-321. 9. Helm SG: Diurnal stabilization of asthma with once-daily evening administration of controlled-release theophylllne: a multi-investigator study. lmmunol Allergy Practice 1987; 9: 414-419. 10. Silvers GW, Petty TL, Conrad EA: Either AM or PM dosing with a sustained release theophylllne (Untphyl) in patients with COPD gives equal results (abstr). Am Rev Respir Dis 1988; 137: 34. 11. Track CH, tree EM: Oximeter studies in patients with chronic obstructive emphysema awake and during sleep. N Engl J Med 1962; 266 639-642. 12. Fletcher EC, Gray BA, Levin DC: Non-apneic mechanisms of arterial oxygen desaturation during rapid eye movement sleep. J Appl Physiol 1983; 54: 632-639. 13. Fletcher EC, Miller J, Divine GW, Fletcher JG, Miller T: Nocturnal oxyhemoglobin desaturabon In COPD pabents with arterial oxygen tensions above 60 mm Hg. Chest 1987; 92: 604-608. 14. Trllapur VG, Mir MA: Nocturnal hypoxemia and associated electrocardiographic changes In patients with chronic obstructive airways drsease. N Engl J Med 1982; 306: 125-130. 15. Smolensky M, Halberg F, Sargent F: Chemobiology of the life sequence. In: ltah S, Ogatuk YH, eds. Advances in climatic physiology. New York: Springer-Verlag, 1972: 281318. 16. Trilapur VG: Nocturnal deaths among patients with chronic bronchitis and emphysema (letter). Br Med J 1984; 289: 1540. 17. Lakshminarayan S: lpratroplum bromide in chronic bronchitis/emphysema. Am J Med 1986; 81 (suppl 5A): 76-80. 18. Girard WM, Light RW: Should the FVC be considered in evaluabng response to bronchodilator? Chest 1983; 84: 87-89. 19. Ramsdell JW, Tisi GM: Determination of bronchodilators in the clinical pulmonary function laboratory: role of changes in static lung volumes. Chest 1979; 76: 622-628. 20. Block AJ: Determination of bronchodilatation (letter). Chest 1980; 78: 496. 21. Anders Al, Baidwan B, Petty TL: An evaluation of the vitometer. a simple device for measuring vital capacity. Respiratory Care 1984; 29: 1144-1146.
July 29, 1988
The American Journal of Medicine
Volume 85 (wppl
1B)
23
THOMAS
L. PETTY, M.D. Denver, cobrado
Patients with airway obstruction of all types show circadian variation of airflow. This article reviews the results of studies that suggest both possible mechanisms for this phenomenon and strategies for its treatment. The strategies discussed include the use of sustained-release betaagonists and a once-a-day theophylline preparation, Uniphyl tablets, that is especially effective in asthmatic patients when administered in the evening. Also presented is a summary of future directions in the planning and implementation of individualized therapeutic strategies for patients with advanced chronic obstructive airways disease.
atients with airflow disorders usually have their P worst dyspnea, cough, and expectoration in the early morning. Careful serial measurements of peak expiratory airflow have shown that airflow obstruction in asthmatic patients peaks between 3:00 and 4:00 A.M. [l]. Diurnal changes in blood epinephrine, histamine, and cortisol levels have been offered as explanations for this phenomenon 121. It appears also that not only asthmatic patients but patients with all types of airway obstruction show regular patterns of variation of peak airflow over the day [3,4]. Whereas asthmatic patients show the so-called “morning dip” pattern [l], some patients with chronic bronchitis show a “double dip” pattern, some experience an evening reduction, and others exhibit no regular pattern at all 131. Furthermore, the regular use of bronchodilators can alter these patterns [3].
INFLUENCEOF BETA-AGONISTS Diurnal variation in forced expiratory volume in one second (FEVi) has been carefully studied in a small group of nonallergic patients with severe airflow obstruction [5]. The relationship between reduction in FEV, and urinary catecholamine and histamine metabolite concentrations was monitored both before and after the use of a long-acting oral beta-agonist (terbutaline) for one week. A 7:00 A.M. reduction in FEV, correlated with reduced plasma and urinary epinephrine levels, but a similar correlation with norepinephrine levels was not found. Histamine and histamine metabolite concentrations did not show a diurnal variation, suggesting no relationship with reduction in FEVi. Administration of slow-release terbutaline for one week prevented the early morning decrease in FEVi. This treatment significantly suppressed both plasma and urinary levels of epinephrine but had no effect on norepinephrine levels. These findings suggest that epinephrine is an important factor in the regulation of bronchial smooth muscle tone in patients with early morning dyspnea. The articles cited above suggest possible mechanisms for the diurnal variation in the severity of chronic airflow obstruction. Furthermore, it has been appropriately emphasized that the casual measurement of response to bronchodilators at midday cannot be used to predict the time or the magnitude of these variations [3]. Knowledge of the patients’ regular patterns of reduced airflow is more likely to be useful in planning preventive therapeutic strategy. So far, pharmacologic doses of corticosteroids have not proved useful [6], and anticholinergics have not been adequately examined. From the Webb-Waring Lung Institute, Diwion of Pulmonary Sciences, University of Colorado Health Sciences Center, Denver, Colorado. Requests for reprints should be addressed to Dr. Thomas L. Petty, Webb-Waring Lung institute, University of Colorado Health Sciences Center, Denver, Colorado 80262.
MORNINGVERSUSEVENINGDOSINGOF LONGACTINGTHEOPHYLLINE Preliminary studies [7,81 have suggested that longacting theophylline preparations can be used strategically at bedtime to improve control of nighttime July 29, 1988
The American Journal of Medicine
Volume 85 (suppl 1B)
21
reparation, in most cases twice a day, and an inhaled & eta-agonist used either regularly or on an as-needed basis throughout the year. No patients requiring in-
m AM
2
0 PM
1
T
T
G izi Ll
0 Week
1
Week
2
Week
3
Figure 1. Comparison of the FEV, values (mean + SEM) obtained in 20 asthmatic patients on Day 6 of Weeks 1, 2, and 3 of a morning or evening Uniphyl dosing regimen. The measurements were made 15 2 1 hours after administration.
[IIIIIIIIIAM 3-
2 22 l-
o Week
1
Week
2
Week
3
Figure 2 Comparison of the FVC values (mean * SEM) obtained in 20 asthmatic patients on Day 6 of Weeks 1, 2, and 3 of a morning or evening Uniphyl dosing regimen. The measurements were made 15 + 1 hours after administration.
TABLE I Serum Theophylline levels (mean -+ SEM)* AM. Dosing Week 2I Week 3
13.7 13.7?+ 1.2 1.5 12.6 ? 1.0
P.M. Dosing 15.5 2? 1.3 15.3 1.1 17.3 ? 1.0
Significance iz p 4.05
NS = not significant. *All values are in micrograms.
asthma. We also investigated such a preparation, once-a-day Uniphyl tablets (The Purdue Frederick Co., Norwalk, Connecticut), and found that it yields higher airflow (FEVJ and volume (forced vital capacity; FVC) values when given at bedtime than when given in the morning. Twenty stable year-round asthmatic patients (five men and 15 women) participated in the study. Their ages ranged from 23 to 68 years, with a mean age of 47 years. The FEVi values of all the patients were between 30 and 75 percent of predicted values, and all showed an improvement in FEV, of at least 15 percent after inhalation of a betaagonist aerosol (albuterol). The patients were already taking another oral sustained-release theophylline
22
July 29,
1988 The American Journal of Medicine
Volume 85 (suppl 1B)
haled or oral steroids participated in the trial. After baseline spirometry had been performed and blood had been drawn for the determination of serum theophylline levels, the patients were randomly assigned to receive Uniphyl at either 3:OOA.M. or 8:00 P.M. for three weeks. The patients switched to Uniphyl tablets from their previous twice-daily theophylline preparation on a milligram-for-milligram basis. Spirometry and serum theophylline level determinations were repeated 15 ? 1 hours after either the morning or evening dose on Day 6 of each of the three study weeks. At the end of three weeks, the patients switched from morning to evening or from evening to morning dosing and the protocol was repeated for the final three weeks of the study. Figures 1 and 2 show the mean FEVi and FVC values obtained on Day 6 of each of the three consecutive weeks. FEVi was slightly higher after evening dosing in all three study weeks, but the difference was statistically significant only in Weeks 1 and 3. The FVC values were significantly higher after evening dosing in all three weeks. Table I lists the mean serum theophylline levels obtained after three weeks of morning and evening dosing. Although the theophylline levels were somewhat higher after evening dosing in all three study weeks, the difference was statistically significant only in Week 3. This study did not examine the control of diurnal variations in detail, but the results do suggest that evening dosing with Uniphyl improves ventilatory function more than morning dosing. In a multi-investigator study [9], the clinical response of 171 asthmatic patients to once-a-day theophylline in the form of Uniphyl tablets was compared with their response to prestudy methylxanthines given at least twice a day. After a one-week baseline study of the patients’ previous therapies (in most cases theophylline with an inhaled beta-agonist), the patients switched to Uniphyl tablets. The transition to the research protocol was smooth. Both the patients’ and investigators’ global evaluations suggested a decline in the incidence of nocturnal awakenings and a corresponding reduction in nighttime inhaler use, as well as highly significant reductions in both nocturnal and early morning symptoms. Symptom scores for wheezing, dyspnea, chest tightness, and cough all improved significantly during the once-a-day evening regimen. Spirometric measurements in this multicenter trial also favored evening dosing, and side effects with evening dosing were similar to those with the patients’ previous twice-daily therapy. These data, together with our own, strongly suggest that evening dosing with Uniphyl can reduce nocturnal variation of chronic symptoms in patients with asthma. In contrast, the results of another study [lo] involving patients with advanced chronic obstructive pulmonary disease selected on the basis of heavy smoking, hyperinflation, and reduced gas transfer as judged by the single-breath diffusion test did not indicate that evening administration is better than morning in improving airflow and symptoms. It is likely that the factors responsible for the diurnal variations in airflow
are numerous and that therapeutic strategies will have to be individualized for maximal therapeutic benefit.
NOCTURNALHYPOXEMIA
Today we have an immense armamentarium of therapeutic modalities that are of potential value to our patients. Inhaled and oral beta-agonists? long-acting theophyllines, and inhaled and oral steroids should all be employed in patients for whom they are appropriate. Home oxygen strategies and even periods of home mechanical ventilation (during sleep, for example) will continue to find application in selected patients. We are entering an era of specialized care strategies for patients with chronic obstructive pulmonary disease who have individual variations in the severity of their airflow obstruction and gas transfer.
The worsening of hypoxemia during the hours of sleep in patients with severe hypoxemia has been well documented [ 11,121. The availability of convenient recording pulse oximeters coupled with the clinical interest in sleep-disordered breathing and the consequences of hypoxemia have stimulated many studies of nighttime hypoxemia. Abundant evidence now exists that a significant number of persons whose oxygen levels are normal in the daytime may experience significant levels of sleep-related hypoxemia, with or REFERENCES without apnea or hypopnea [12,131. At least one con- 1. Turner-Watwlck M: On observing patterns of airflow obstruction in chrornc asthma. Br J Chest 19n, 71: 73-86. sequence of nocturnal hypoxemia is a high incidence of 2.DisClark TJH, Hetzel MR: Nocturnal asthma and circulating eptnephrine, histamine, and cardiac arrhythmias [ 141. Sleep-related hypoxemia cortisol fletter). N Enal J Med 1980: 303: 1300. could be a factor in the predominance of deaths in the 3. Connolly Ci% The elect of bronchodilators on diurnal rhythms in airway obstruction. Br early morning (mortality is the greatest between 5:OO J Dis Chest 1981; 75: 197-203. Dawkins KD, Muers MF: Diurnal variation in airflow obstruction in chronic bronchibs. and 6:00 A.M.) [151. Sleep hypoxemia may also be 4.Thorax 1981; 36: 618-621. partly responsible for the phenomenon of early morn- 5. Postma DS, Koeter GH. Keyser JJ, Meurs, H: Influence of slow-release terbutallne on the clrcadtan variation of catecholamines, histamine, and lung function in nonallergic ing death in patients with advanced chronic obstrucpatients with partly reversible airflow obstruction. J Allergy Clin lmmunol 1986; P 471tive pulmonary disease [16].
FUTUREDIRECTIONS Knowledge of the circadian variations that occur in patients with advanced chronic obstructive pulmonary disease can be useful in planning and implementing therapeutic strategies. In view of the simplicity and utility of the flowmeters now available for home use, home monitoring to establish patterns in changes in expiratory airflow during the day should become standard practice. Measurements of volume variation, i.e., daily changes in FVC, appear to be equally valuable, particularly since anticholinergic bronchodilators often improve vital capacity as well as forced expiratory flow [17]. In some patients, volume improves more than flow in response to inhaled bronchodilators [18], and in some the rise in FVC may parallel a reduction in residual volume, with no changes in flow [19]. Absolute changes in both FEVl and FVC may occur with no change in FEVJFVC percent [20]. A simple, inexpensive., disposable device that is now available for measurmg vital capacity could also be used in home-monitoring studies to improve our knowledge of changes in respiratory mechanics during the day [21]. This knowledge would augment data available from serial home peak flow measurements. The use of home oximetry with continuous recording of nighttime hypoxemia patterns seems certain to become widespread as a means of identifying patients at risk of developing reactive pulmonary hypertension as a prelude to fixed pulmonary vascular changes and COYpulmonale
[20].
477. 6. Soutar CA, Costello J, ljaduola V, et at Nocturnal and mornmg asthma: relationship to plasma corticosteroids and response to cortisol infuslon. Thorax 1975; 30: 436-440. 7. Busse WW, Bush RK: Comparison of morning and evening dosing with a 24.hour sustained-release theophylline, Uniphyl, for nocturnal asthma. Am J Med 1985; 79 (suppl 6A): 62-66. 8. ArkInstall WW, Atkrns ME, Harrison D, Stewalt JH: Once-daily sustained-release theophylline reduces diurnal variation in splrometry and symptomatology in adult asthmatics. Am Rev Respif Dis 1987; 135: 316-321. 9. Helm SG: Diurnal stabilization of asthma with once-daily evening administration of controlled-release theophylllne: a multi-investigator study. lmmunol Allergy Practice 1987; 9: 414-419. 10. Silvers GW, Petty TL, Conrad EA: Either AM or PM dosing with a sustained release theophylllne (Untphyl) in patients with COPD gives equal results (abstr). Am Rev Respir Dis 1988; 137: 34. 11. Track CH, tree EM: Oximeter studies in patients with chronic obstructive emphysema awake and during sleep. N Engl J Med 1962; 266 639-642. 12. Fletcher EC, Gray BA, Levin DC: Non-apneic mechanisms of arterial oxygen desaturation during rapid eye movement sleep. J Appl Physiol 1983; 54: 632-639. 13. Fletcher EC, Miller J, Divine GW, Fletcher JG, Miller T: Nocturnal oxyhemoglobin desaturabon In COPD pabents with arterial oxygen tensions above 60 mm Hg. Chest 1987; 92: 604-608. 14. Trllapur VG, Mir MA: Nocturnal hypoxemia and associated electrocardiographic changes In patients with chronic obstructive airways drsease. N Engl J Med 1982; 306: 125-130. 15. Smolensky M, Halberg F, Sargent F: Chemobiology of the life sequence. In: ltah S, Ogatuk YH, eds. Advances in climatic physiology. New York: Springer-Verlag, 1972: 281318. 16. Trilapur VG: Nocturnal deaths among patients with chronic bronchitis and emphysema (letter). Br Med J 1984; 289: 1540. 17. Lakshminarayan S: lpratroplum bromide in chronic bronchitis/emphysema. Am J Med 1986; 81 (suppl 5A): 76-80. 18. Girard WM, Light RW: Should the FVC be considered in evaluabng response to bronchodilator? Chest 1983; 84: 87-89. 19. Ramsdell JW, Tisi GM: Determination of bronchodilators in the clinical pulmonary function laboratory: role of changes in static lung volumes. Chest 1979; 76: 622-628. 20. Block AJ: Determination of bronchodilatation (letter). Chest 1980; 78: 496. 21. Anders Al, Baidwan B, Petty TL: An evaluation of the vitometer. a simple device for measuring vital capacity. Respiratory Care 1984; 29: 1144-1146.
July 29, 1988
The American Journal of Medicine
Volume 85 (wppl
1B)
23