Thorax 1993;48:287-289 287 Effect of oral on during sleep in patients with asthma Thorax: first published as 10.1136/thx.48.3.287 on 1 March 1993. Downloaded from A Hasani, J E Agnew, D Pavia, H Vora, S W Clarke

Abstract been shown to be enhanced by /32 adrenergic Background Lung mucociliary clear- drugs and methylxanthines.A-1 Oral slow ance rates are reduced during sleep in release bronchodilators are often prescribed patients with asthma. Methylxanthines to patients to treat nocturnal asthma. and /P2 agonists have been shown to We report a study in patients with asthma enhance rates of lung mucociliary clear- to compare the effects of controlled release ance. This study examined whether oral salbutamol (Volmax, a /32 agonist), theo- slow release bronchodilators may also phylline (Phyllocontin Forte Continus, a have an effect on this clearance mecha- methylxanthine), and placebo on overnight nism during sleep in patients with changes in lung mucociliary clearance. asthma. Methods Nine patients with asthma with a mean(SE) age of 65(5) years and Methods percentage predicted forced expiratory PATIENTS volume in one second (FEV1 of 61(9)% Twelve patients with asthma, six of whom participated in a double blind, placebo were male, volunteered for the study. Three controlled, within subject crossover (two female) were withdrawn, two because of study to assess the effect of two weeks of an exacerbation of their asthma (one during treatment with salbutamol (Volmax; the run in period and the other during the 8 mg twice daily) or theophylline (Phyilo- salbutamol period), and the third because he contin; 350 mg twice daily) on lung was unable to manage without an oral bron- mucociliary clearance during sleep. Lung chodilator during the run in period. http://thorax.bmj.com/ mucociliary clearance rates were mea- The patients who completed the study had sured by a radioaerosol technique. a mean(SE) age of 65(5) years, percentage Results The observation period for predicted FEV, of 61(9)% and a tobacco radioaerosol clearance was approxi- consumption of 12(5) pack years (seven ex- mately 0 3 hours before sleep, 6-0 hours smokers and two non-smokers). Seven during sleep and 0-6 hours after sleep. patients were receiving treatment with Mean mucociliary clearance rates for inhaled /32 agonists and corticosteroids, three

theophylline, placebo and salbutamol of whom were taking inhaled anticholinergic on October 2, 2021 by guest. Protected copyright. before sleep were: 39, 39, and 32%Ihour drugs. One other patient was receiving respectively; during sleep: 11, 10, and inhaled sodium cromoglycate only. The ninth 9%Ihour respectively; and after sleep: patient was on no medication. Five of the 39, 32, and 35%Ihour respectively. patients were also receiving treatment with Conclusion During sleep lung mucocil- oral bronchodilators (four methylxanthines iary clearance in stable asthma was and one a /32 agonist), which were discontin- reduced, which is in agreement with the ued for the one week run in period and for group's previous findings. Treatment the duration of the trial. All nine patients had Department of with shown a or Thoracic Medicine controlled/slow release oral bron- 15% greater reversibility of FEV, A Hasani chodilators had no effect on this reduced following the of 200 ,ug salbutamol D Pavia rate of clearance associated with sleep. (n = 5), or a 20% or greater difference H Vora between the maximum and minimum peak S W Clarke (Thorax 1993;48:287-289) expiratory flows (PEF) obtained for that day Department of Medical Physics on at least two days where the PEF had been J E Agnew measured on seven consecutive days (n = 6), Royal Free Hospital Lung mucociliary clearance, one of the lung's or both. and School of host defence clearance mechanisms, is Medicine, London impaired in patients with airways disease.1-4 STUDY DESIGN NW3 2QG Furthermore, lung mucociliary clearance has Salbutamol (8 mg twice daily), theophylline Reprint requests to: been shown to be reduced during sleep in (350 mg twice daily) and placebo tablets were Dr A Hasani healthy subjects5 and in patients with in a double blind, randomised, Received 15 May 1992 compared Retumed to authors asthma,6 and this may contribute to the crossover study of seven weeks' duration. 29 July 1992 mucus plugging which is known to be present Revised version received Patients underwent a one week run in period 12 October 1992 in the small airways of asthma sufferers.7 followed by three treatment periods, each of Accepted 16 October 1992 Tracheobronchial clearance rates have two weeks, which were not separated by wash 288 Hasani, Agnew, Pavia, Vora, Clarke

out periods. Although the study design was and expressed in terms of a penetration such that the three treatment periods fol- index.'5 lowed one another immediately, in practice During the observation period any this was not always possible because of previ- samples produced were collected and

ous commitments by the patients, or exacer- weighed and their radioactive content Thorax: first published as 10.1136/thx.48.3.287 on 1 March 1993. Downloaded from bation of their asthma, or both. Those who measured. had an exacerbation did not proceed into the next leg of the study until one month after the PULMONARY ]FUNCTION end of symptoms, or cessation of any oral The FEVy for each patient was measured with corticosteroid treatment, or both. The a Vitalograph spirometer at the start of the patients were allowed to take their regular study and during the half hour which preced- treatment throughout the study. The compli- ed the inhalation of the radioaerosol on each ance with test medication was assessed by study night. Predicted values were obtained issuing a known number of tablets and count- on the basis of the patient's sex, age and ing those returned at the end of each treat- height. 16 ment period. The last tablet was taken after the inhalation of radioaerosol, before sleep, STATISTICAL ANALYSIS and under supervision. The data were analysed with the Wilcoxon Informed written consent was obtained signed rank sum test for matched pairs.'7 The from each patient and the study was level of significance was taken at p < 0 05. approved by the hospital's ethical subcom- mittee. Results TRACHEOBRONCHIAL CLEARANCE The mean(SE) rates of compliance with trial Tracheobronchial clearance was measured by medication were 99 (2)%, 98 (1)%, and an objective, non-invasive radioaerosol tech- 98 (3)% for placebo, theophylline, and salbu- nique which has been described in detail else- tamol, respectively. Usage of other medica- where.'2 The initial deposition of the tracer tion remained unchanged during the three radioaerosol was measured with two scintilla- periods. The mean (SE) alveolar deposition tion detectors placed midway along the rates (18 (4)%, 26 (6)%, and 27 (6)%, sternum anteroposteriorly to the seated respectively for placebo, theophylline, and patients.'3 A count was made immediately salbutamol) and the mean (SE) penetration after inhalation and at approximately 0 3, 6 indices (0X29 (006), 0 38 (0X10), and and 36 hours thereafter. Sequential counts of 0X42 (0 12) respectively for placebo, theo- lung activity were recorded over a period of phylline and salbutamol) for the patients fol- 20-25 minutes before sleep, and for approxi- lowing the three treatments were similar. The mately 40 minutes after the sleep period. For percentage predicted FEVy values measured http://thorax.bmj.com/ the periods before and after sleep a least at the laboratory for each treatment were squares fit to the count versus time data was 53 (7)%, 55 (8)%, and 60 (9)% respectively used to estimate the clearance rate. For the for placebo, theophylline, and salbutamol (p sleep period the rate of clearance was calcu- < 0.05 for salbutamol v placebo). lated from the difference between mean read- The mean (SE) durations of the observa- ings at the beginning and end of that period. tion periods before, during, and after sleep In each instance clearance was expressed in following radioaerosol inhalation were 23(5),

relation to the lung radioactive content at the 350 (9), 38 (6); 18 (3), 342 (8), 36 (7); and on October 2, 2021 by guest. Protected copyright. start of the period in question. 22 (3), 357 (8), 38 (8) minutes respectively The amount of radioaerosol present in the for placebo, theophylline and salbutamol. at 36 hours was taken to be an estimate The rates of clearance for the periods before, of alveolar deposition.'4 The initial topo- during and after sleep following the three graphical distribution of the radioaerosol treatments are shown in the figure. There within the lungs was measured by a large field were no significant differences in the rates of of view gamma camera linked to a computer radioaerosol clearance from the lungs between the three treatments for the three periods. Within each of the three treatments the rate of clearance during sleep was signifi- Mean (SE) a tracheobronchial clearance cantly lower than the rates before and after rates for nine asthma sleep (p < 0-01). patients before, during and after sleep following Only one patient produced sputum during treatment with the observation period (placebo: 3-6 g con- theophylline, placebo, and taining 15% of the initial tracheobronchial salbutamol. deposition; theophylline: 2-0 g containing 31% of the initial tracheobronchial deposi- tion).

Discussion The rate of tracheobronchial clearance of deposited radioaerosol depends on its site of deposition within the lungs.'" In this study alveolar deposition and the penetration index Effect of oral bronchodilators on tracheobronchial clearance 289

for both bronchodilators and placebo were are very unlikely to clear those airways during similar, so direct comparison of rates of the night. tracheobronchial clearance between treat- We thank the volunteer patients for participating in the study ments is appropriate. and Glaxo Laboratories Ltd for supplying the drugs and for Tracheobronchial clearance comprises financial support. Thorax: first published as 10.1136/thx.48.3.287 on 1 March 1993. Downloaded from lung mucociliary clearance and . The Agnew JE, Little F, Pavia D, Clarke SW. Mucus clearance from the airways in chronic : smokers and ex- contribution of productive cough in this study smokers. Bull Eur Physiopathol Respir 1982;18:473-84. is small,'9 so tracheobronchial clearance is 2 Puchelle E, Zahm JM, Girard F, Bertrand A, Polu JM, Ung F, et al. Mucociliary transport in vivo and in vitro. likely to reflect lung mucociliary clearance Relations to sputum properties in chronic bronchitis. itself. Enhancement of a depressed rate of EurJ Respir Dis 1980;61254-64. 3 Agnew JE, Bateman JRM, Sheahan NF, Lennard-Jones lung mucociliary clearance, which is encoun- AM, Pavia D, Clarke SW. Efect of oral corticosteroids tered in various lung diseases,' 420 can be on mucus clearance by cough and mucociliary transport in stable asthma. Bull Eur Physiopathol Respir 1983;19: beneficial since a reduced residence time of 37-41. bronchial secretions should lessen the risk of 4 Bateman JRM, Pavia D, Sheahan NF, Agnew JE, Clarke SW. Impaired tracheobronchial clearance in patients chest infections.2' If a is also with mild stable asthma. Thorax 1983;38:463-7. shown to enhance clearance of secretions, this 5 Bateman JRM, Pavia D, Clarke SW. The retention of lung secretions during the night in normal subjects. Clin is an additional benefit of the drug. Sci Mol Med 1978;55:523-7. Salbutamol9 has been shown to enhance lung 6 Pavia D. Mucociliary clearance at night. Effect of physical activity, posture and circadian rhthm. In: Bames PJ, mucociliary clearance rates in chronic bron- Levy J, eds. Nocturnal asthma. International Congress chitis when given topically from a metered Symposium Series, No. 73. London: Royal Society of Medicine, 1984. dose inhaler, albeit at 2-5 times the normal 7 Dunnill MS. In adentification of asthma. In: Porter R, recommended dose. Methylxanthines have Birch J, eds. CIBA Foundation Study Group, No. 38, Edinburgh and London: Churchill Livingstone, 1971. been shown to enhance lung mucociliary 8 Cotromanes E, Gerrity TR, Garrard CS, Harshbarger clearance,2223 and administration of 450 mg RD, Yeates DB, Kendzierski DL, et al. Aerosol penetra- tion and mucociliary transport in the healthy human aminophylline twice daily for one week result- lung. Effect of low serum theophylline levels. Chest ed in enhancement of mucus clearance in 1985;88: 194-200. 9 Fazio F, Lafortuna C. Effect of inhaled salbutamol on 75% of the study population." Both /32 ago- mucociliary clearance in patients with chronic bronchi- nists and methylxanthines have been reported tis. Chest 1981;80:827-30. 10 Matthys H, Kohler D. Effect of theophylline on mucocil- to enhance ciliary beat frequency2425 and iary clearance in man. EurJ Respir Dis 1980;61:98-102. mucus secretion,2627 and this could influence 11 Sutton PP, Pavia D, Bateman JRM, Clarke SW. The effect of oral aminophylline on lung mucociliary clear- lung mucociliary clearance. ance in man. Chest 1981;80:889-91. During sleep lung mucociliary clearance 12 Pavia D, Sutton PP, Agnew JE, Lopez-Vidriero MT, Newman SP, Clarke SW. Measurement of bronchial rates have been shown to be reduced, both in mucociliary clearance. EurJY Respir Dis 1983;64:41-56. healthy subjects5 and in patients with 13 Thomson ML, Pavia D. Long-term tobacco smoking and mucociliary clearance from the human lung in health asthma.6 A pilot double blind crossover study and respiratory impairment. Arch Environ Health 1973; on four asthma patients treated for one week 26:86-9. 14 Camner P, Philipson K. Human alveolar deposition of with slow release aminophylline (450 mg 4 pm particles. Arch Environ Health 1978;36:181-5. http://thorax.bmj.com/ twice daily) showed that three of the four 15 Agnew JE, Pavia D, Clarke SW. Airways penetration of inhaled radioaerosol. An index to small airways func- patients had a faster clearance rate during tion? EurJ Respir Dis 198 1;62:239-55. sleep while on aminophylline than on place- 16 Cotes JE. Lung function. Assessment and application in medi- cine. 4th edn. Oxford: Blackwell, 1979. bo.28 This study provides strong evidence that 17 Siegel S. Non-parametric statistics for the behavioral sciences. during sleep the rate of lung mucociliary Tokyo: McGraw-Hill, 1956. 18 Agnew JE, Bateman JRM, Watts M, Paramananda V, clearance in asthma patients is slower than Pavia D, Clarke SW. The importance of aerosol pene- when the patients are awake, in agreement tration for lung mucociliary clearance studies. Chest 1981 with previous observations.628 This retarda- ;80:843-6. 19 Hasani A, Pavia D, Agnew JE, Clarke SW. Regional on October 2, 2021 by guest. Protected copyright. tion has been shown in normal subjects to be mucus clearance within the human lung during produc- tive cough andFET. EurJrRespir Dis 1990;3:153s. associated with sleep itself, and is not related 20 Currie DC, Pavia D, Agnew JE, Lopez-Vidriero MT, to posture or circadian rhythm.5 Reduction of Diamond PD, ColePJ, et al. Impaired tracheobronchial clearance in . Thorax 1987;42: 126-30. clearance of lung secretions during sleep, in 21 Pavia D. Acute respiratory infections and mucociliary addition to the already impaired lung clearance. Eury Respir Dis 1987;71 :219-26. 22 Matthys H, Vastag E, Daikeler G, Kohler D. The influ- mucociliary clearance in asthma patients,3 ence of aminophylline and pindolol on the mucociliary may well contribute to the early morning clearance in patients with chronic bronchitis. Br J Clin Pract 1983;23:82-6. wheeze, cough, and dip in pulmonary func- 23 Schmidt G, Rauke C, Creutzig H,Oellerich M, Sybercht tion reported by such patients. GW. Influence of theophylline on mucociliary clearance and maximum inspiratorv mouth occlusion pressure. Br has shown, however, that two Our study JfClinPract 1983;23:15-21. weeks of treatment with an oral controlled 24 Melville GN, Horstmann G, Iravani J. Adrenergic com- pounds and the . 1976;33: release /2 agonist or slow release methylxan- 261-9. thine does not enhance lung mucociliary 25 Iravani J, Melville GN. Effect of drugs and environmental factors on ciliary movement. Respiration 1975;32: clearance during sleep in patients with 157-64. asthma. This finding contrasts with the obser- 26 PhippsRJ, Williams IP, Richardson PS, Pell J, PackRJ, Wright N. Sympathomimetic drugs stimulate the output vations reported with both these types of of secretory from the human bronchi in drugs in healthy subjects and in patients vitro. Clin Sci 1982;63:23-8. 27 WhimsterWF, Reid L. The influence of dibutyryl when awake,"92322 and must therefore be cvclic adenosine monophosphate and other substances on regarded as disappointing. Mucus secretion human bronchial mucus discharge. Exp Mol Pathol 1973;18:234-40. rates may decrease during sleep, thus lessen- 28 Pavia D, Agnew JE, Clarke SW. Physiological, pathologi- ing the load applied to the mucociliary escala- cal and drug-induced alteration in tracheobronchial mucociliary clearance. In: Isles AF, Von Wichert P, tor. Our data suggest that the asthma patients eds. Sustained release theophylline and nocturnal asthma. who fall asleep with partly blocked airways Switzerland: Excerpta Medica, 1985:44-59.