Theophylline in chronic obstructive pulmonary disease

Theophylline in chronic obstructive pulmonary disease

Theophylline in chronic obstructive pulmonary disease John T. Sharp, M.D. Hines, 111. Although prolonged use of maintenance theophylline therapy in ch...

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Theophylline in chronic obstructive pulmonary disease John T. Sharp, M.D. Hines, 111. Although prolonged use of maintenance theophylline therapy in chronic obstructive lung disease remains controversial, evidence from well-designed studieJ indicates that it produces patient rmprovement as gauged by both objective and subjective measurements. An important reason to use sustained-release theophylline is to prevent episodes of’ bronchospasm by providing a .smooth around-the-clock bronchodilator qffect and thus reducing the need for periodic aerosolized beta agonists. Theophylline also increases diaphragmatic contractiliq and endurance, althouqh there is disagreement concerning the practical clinical .sign$cance of this effect. The drug improves cardiovascular function by increasing myocardial contractilir]v and by reducing pulmonary and systemic vascular resistances. The increased central respiratov drive produced by theophylline may be important in reducing the ventilatory depressant t$ects of oxygen therapy. The drug also acts to inhibit mediator release and improves several aspects of mucociliar?: ,functian, although, again, the clinical .sign$cance qf these actions has not been extablished. (J ALLERGYCLINIMMUNOL 1986:78:800-S.)

Prolonged use of maintenance theophylline therapy in reversible airway disease is accepted. Its similar use in chronic obstructive lung disease (chronic bronchitis and emphy:sema) remains controversial. The studies of Alexander et al.’ and Eaton et al.,‘. ’ although showing modest improvement (about 15%) in objective measurements of airway obstruction produced by theophylline, failed to show corresponding improvement of symptoms. Usually in evaluating evidence that a drug is effective we minimize the significance of subjective effects and tend to accept only objectively measurable evidence of improvement. It seems a bit paradoxical that in the case of theophylline use in COPD we have virtually done the opposite, discarding the objective evidence that the drug is dilating bronchi and insisting that to justify its use it must make patients feel better. I suggest that there may be some intrinsic benefit to reducing airway resistance, whether or not the patients feel better as a result. We know that the detection of changes in airway resistance and respiratory effort is less sensitive in patients with chronically elevated baseline levels of

From the Department of Medicine, Pulmonary Disease Section, and the Research Service, Hines Veterans Administration Hospital, Hines, III. Supported by the Veterans Administration Research Service and National Institutes of Health Grant HL-31558. Reprint requests. Dr. John Sharp, Pulmonary Division, P.O. Box 7. Hines VA Hospital, Hines, IL 60141.

800

Abbreviations used

COPD: FEV,: FRC: ‘?, : FVC: EMG: MSV: Pdi: Pdi,,,: T,: T,,,.

Chronic obstructive pulmonary disease Forcedexpiratory volume in 1 second Functional residual capacity Volume rate of expired gas Forcedvital capacity Electromyogram Maximal sustainableventilation Transdiaphragmaticpressure Maximal transdiaphragmaticpressure Duration of inspiration Duration of total respiratory cycle (breath)

resistance. In the study of Gottfried et al.” in which the ability of patients to detect increases in external resistance was tested, normal individuals could detect 18% increases and patients with asthma 15% increases. However, the resistance increment had to rise by an average of 49% before it could be detected by patients with COPD. This phenomenon, probably a form of sensory adaptation, may partially account for this discrepancy between improvement by objective criteria and lack of it by subjective indices. If it is accepted that an important goal of therapy in this disease is the prevention of clinical deterioration and of acute exacerbation of increased respiratory distress, there are published data that would support the use of orally administered maintenance theophylline particularly when used in combination with inhaled

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FIG. 1. Work of breathing. Effect of theophylline (- - - -1 on lung work per minute (W,) and minute volume (i/J compared with that of placebo (-1 in IO patients with COPD. Shown for comparison are data in four normal subjects who took no medications. Reduction in lung work with theophylline is significant (p < 0.005). Note that work decreased despite increase in minute volume. Measurements were made over 2-minute periods with subjects standing and walking on the level at 1.2 mph. Values are means i SEM.

aerosolized beta agents. Taylor et al. ,’ in a randomized double-blind crossover study in patients with chronic bronchitis and reversible airflow obstruction, compared sustained-release theophylline and aerosolized albuterol, singly and in combination, with placebo. They defined treatment failure as the necessity for therapy in addition to the experimental regimen. Treatment failure occurred in nine patients receiving placebo, eight receiving albuterol alone, six receiving theophylline alone, and only one receiving combined therapy. By a ranking system based on both treatment failures and mean daily peak flow rates, first preference was given to combined therapy in 13 patients, theophylline alone in six patients, albuterol alone in four patients. and placebo in two patients. Thus the combination of theophylline with a beta agent was most effective in preventing episodes of clinical deterioration. We all recognize that patients with COPD commonly develop transient acute exacerbations of respiratory distress consistent with episodic bronchoconstriction. A recent study by Ramsdell et a1.6provides data relating to such episodes that may further justify the maintenance use of theophylline, alone or combined with beta agents. These investigators selected patients with COPD (mean baseline FEV, 0.96 L) who showed no spirometric improvement after inhaled isoproterenol. They used methacholine bronchial provocation to test for bronchial hyperreactivity. Patients

with asthma were rigidly excluded. All their 22 patients had very abnormal results in methacholine bronchial challenge tests, despite their lack of response to aerosolized bronchodilator. The authors suggested that this bronchial hyperreactivity was the basis for acute transient episodes of bronchoconstriction that characterized exacerbations. They further suggested that a major benefit from maintenance bronchodilator therapy may be to prevent these acute exacerbations. By this line of reasoning, a reduction in the number of times a patient uses an inhaler for relief of dyspnea becomes a valid measurement of the symptom relief afforded by his or her maintenance theophylline. There m,ay be important goals in therapy in addition to making the patient feel better, and attention to these goals is important in making therapeutic decisions. If we insisted that patients with hypertension feel better with therapy before embarking on long-term maintenance .:reatment of that disease, we would hardly ever treat hypertension. Although the FEV, is the usual measurement to assessimprovement in airway obstruction in response to medication, Bellamy and Hutchison7 in a study of albuterol in severe emphysema found that preference for the active drug correlated better with improvement in vital capacity and reduction in residual volume than it did wth improvement in FEV,. In other words, relief of dyspnea correlated best with reduction in lung hyperinflation and less well with improvement in max-

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imal expiratory flow rates. This all makes sense when considered in terms of the relationship of inspiratory muscle function to lung volume. We know that lung hyperinflation shortens diaphragmatic muscle fiber lengths and reduces that muscle’s effectiveness as a force and pressure generator.8,9 Our work on postural relief of dyspnea in COPD demonstrated that sudden posturally induced increases in lung volume and accompanying decreases in diaphragmatic fiber length abruptly produce dyspnea. ‘“. ” It is reasonable to postulate that drug-induced reductions in lung volume via bronchodilation would also promptly reduce dyspnea. Such drug-induced reductions in lung volume (FRC) have the beneficial effect of allowing the inspiratory muscles to function more efficiently, and in certain critical clinical circumstances this would postpone or prevent inspiratory muscle fatigue, the prelude to hypercapnic respiratory failure. Our recent study” in 10 patients with severe emphysema touches on the same points. We looked at the effects of theophylline on mechanical work done on the lung, with patients at rest and walking on a treadmill. A double-blind randomized crossover design was used, and serum theophylline levels during drug runs averaged 12.3 mg/L. Fig. 1 shows the effects of theophylline on pulmonary work with patients walking and standing. Data in four normal subjects receiving no medications are shown for comparison. Theophylline produces a 16% decrease in pulmonary work during walking despite a modest increase in ventilation ( V,). Pulmonary resistance was reduced by a similar percentage. The patients uniformly preferred theophylline over placebo, and their preference was correlated with the improvement in FVC but not with the improvernent in FEV,. This result is very reminiscent of the above results of Bellamy and Hutchinson with albuterol.’ Another important reason to use theophylline in the management of COPD is to achieve smoothness in the control of bronchodilation, which is difficult to attain with oral or inhaled beta agents alone. In a study by Lee and Evans,” combining theophylline with inhaled beta agents reduced fluctuation in the FEV, and in particular raised the trough FEV, values although affecting the peak levels rather little. It is probably more important to raise the trough levels than to achieve higher peak levels as far as symptom relief is concerned. Although the study referred to was performed in children with asthma, experience with elderly patients with COPD would indicate that the principle applies to them as well. Several studies have shown patient preference for theophylline over placebo, among them the studies of Mahler et al., I4 Murciano et al. ,I5 and Jenne et al.‘* The first and third of these used randomized double-

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blind crossover design, and the study of Mahler et al. I4 used a rather elaborate three-component rating system for evaluating symptom relief. Thus far I have dealt only with the bronchodilator effects of theophylline in COPD. This quite properly has rece.ved the most attention because airway obstruction is of prime importance in COPD, theophylline clearly relieves it, and this therapeutic effect can be assessedby a relatively simple test, spirometry. Other effects of theophylline are not as obvious or as easy to measure, but they may be of importance in certain clinical situations encountered in patients with COPD. ‘These effects are (1) increased respiratory muscle contractility and endurance, (2) increased myocardial contractility, (3) reduction in pulmonary vascular resistance, (4) increase in central respiratory drive, (5) inhibition of mediator release, (6) mucociliary clearance effect, and (7) a diuretic effect. RESPIRATORY MUSCLE EFFECTS OF THEOPHYLLINE There is no question that theophylline increases contractility and endurance of animal diaphragms both in vitro and in vivo16. ” and of the human diaphragm.18 Particularly impressive are the experiments of Viires et al., I9 which convincingly showed that theophylline not only prevented but cured fatigue of the dog diaphragm in animals made hypoxic, hypercapnic. and acidotic by resistive loaded breathing. Equally important are the studies of Supinski et al.,” which showed that the response to theophylline of the canine diaphragm was greater in the presence of hypoxic depression of the muscle than during normoxia. However, these experiments were done in previously normal animals in which a severe mechanical stress produced sudden acute respiratory failure. The clinical situation in humans with COPD of many years’ duration is probably rather different. The chronic stress to the inspiratory muscles of breathing through an elevated resistance at shorter than optimal muscle fiber lengths on the one hand may improve muscle function through a training effect or on the other hand may injure the muscle through relentless application of excessive stress. Varying degrees of chronic stress on the respiratory muscles may make their response to acute stress very different from that of muscle not chronically stressed. This difference may be a major reason why data on the effectiveness of theophylline in patients with COPD are less clear-cut and therefore less convincing. Consequently disagreement has arisen as tc whether the respiratory muscle actions of the drug are significant in humans with COPD. Murciano et al.lS have shown in patients with COPD who had both hypoxia and hypercapnia that theophylline wil.hin the accepted therapeutic range increases

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diaphragmatic contractility as measured by Pdi,,, and increases the endurance of the diaphragm during inspiratory resistive breathing. Increased endurance was measured as the absence of a decrease in the diaphragmatic EMG high/low ratio after theophylline administration, a decrease that had clearly occurred before theophylline administration. Decline in the diaphragm’s high/low ratio is an index of fatigue, at least of high-frequency fatigue, and theophylline had prevented it. The mechanism of enhanced endurance was believed by the investigators to be the increase in Pdi,,,, which in turn caused the Pdi actually used to overcome the resistance to be a smaller fraction of the maximal possible Pdi. Because the time-tension index that determines fatigue is the product of Pdi/Pdi,,, times the duty cycle, T,/T,,,,” increasing Pdi,,, has the effect of reducing the time-tension index, which in turn increases endurance time and postpones fatigue. It should be added, however, that this study, excellent though it was, used only an electromyographic criterion to detect fatigue and did not measure the fall in Pdi as fatigue developed. This mechanical (pressure or tension) change is of greater importance than the EMG change for two reasons.*’ First, the EMG change often indicates only high-frequency fatigue, which is not as important as low-frequency fatigue because it may not be accompanied by a drop in tension generation and because recovery is rapid. Second, there is evidence that the important type of fatigue in relation to respiratory failure is low-frequency fatigue, which was not clearly demonstrated to be present in the work by Murciano et aLI5 It is, however, very significant that Murciano et al. demonstrated substantial increases in Pdi,,, and endurance and that they used a most suitable patient group, that is, patients with significant arterial hypoxia and hypercapnia. Recently Belman et a1.22published studies that challenge the inference that contractility changes induced by theophylline are important clinically in COPD. They studied the effect of aminophylline given intravenously on the MSV, a valid measure of respiratory muscle endurance. In both normal individuals and patients with COPD they recorded mean increases in MSV of ~:3 Llmin, which was a 2Y0 increase in normal subjects and a 7% increase in patients. A complicating factor in comparing the data of Belman et al. with those of Murciano et al.lS is that different tests were used to assessthe effects of the drug, tests that measure different aspects of respiratory muscle function. Furthermore, the patients were different. Those of Belman et al. had normal CO, tension and only mild hopoxia, whereas those of Murciano et al. had both more severe hypoxia and hypercapnia. Finally, in the study by Belman et al. no evidence was

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provided that either normal subjects or patients developed mspiratory muscle fatigue. Actually, 1 know of no evidence demonstrating that the fall in maximal ventilation that occurs initially during the performance of the MSV test is necessarily related to respiratory muscle fatigue. Consequently, the practical clinical usefulness of theophylline as a preventive or therapy for respiratory muscle failure is unsettled in my opinion. I believe that we need studies in which more variables are measured and in which a variety of carefully characterized patients are observed in larger numbers We need to know in what type of patient and in what clinical circumstances the drug is most useful (and least useful) with regard to its effect on the respiratory muscles. Finally, questions arise concerning theophylline’s respiratory muscle effects in relation to dyspnea. Is dyspnea necessarily related to respiratory muscle fatigue? If so, under what circumstances? How close to inspiratory muscle fatigue are patients during day-today activities that produce dyspnea? 1s any of the symptom relief afforded by theophylline and beta agonists related to improved resistance to fatigue induced by the drug? To my knowledge, there are no clear-cut answers to these questions. However, on the basis of scattered observations 1 have formed some opinions. First, I believe that dyspnea usually occurs in the absence of respiratory muscle fatigue and that most of the time it has little to do with fatigue. It does certainly have a lot to do with respiratory effort and its perception, however.2’ In a series of severely disabled patients with COPD in whom we induced stress to the limits of their tolerance by leg exercise combined with inspiratory resistance breathing, most had no mechanical or electromyographic evidence of diaphragmatic fatigue at a point when they were intensely dyspneic and had to terminate the procedure (Kondragunta VR and Sharp JT, unpublished observations). As to whether theophylline may relieve dyspnea in part because of its effect on the inspiratory muscles, theoretical considerations suggest that it might, because it is capable of increasing the maximal pressures that the inspiratory muscles can generate. As a result of this drug-induced change, a given respiratory task requires a smaller percentage of the maximal available pressure. This could produce a decrease in perceived inspiratory effort with consequent reduction in the symptom of dyspnea. CARDIOVASCULAR

EFFECTS

The studies of Parker et a1.‘4.*’ and of Matthay al,::h. 27 show clearly that theophylline, whether given intravenously as aminophylline or in long-term oral sustained-release form, improves cardiovascular et

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function in patients with COPD. In the studies of Parker et al. with cardiac catheterization, patients with COPD with and without car pulmonale were observed. In response to a rather large intravenous dose of aminophylline all1 patients showed reductions in pulmonary artery pressure, pulmonary vascular resistance, and both right and left ventricular filling pressures and stroke work. Differences were noted between patients with car pulmonale and those without. Patients without car pulmonale showed increases in cardiac output, oxygen consumption, and oxygen saturation. whereas those with car pulmonale did not. The data indicated that benefits were produced by a combination of decreasing the afterload on the ventricles (i.e., pulmon,ary and systemic vasodilation) and an improvement in intrinsic myocardial contractility. The more recent studies of Matthay et al. used noninvasive radionuclide angiocardiography and demonstrate improvement in the ejection fraction of both ventricles and in the left ventricular ejection rate. In four patients with car pulmonale who had the lowest right ventricular eje’ction fractions, ejection fractions also increased, in two instances to values within the normal range Improvements in right ventricular ejection fraction are sustained for at least 4 months when oral sustained-release theophylline is used. 27Recent work by Colucci et al.18 has shown that in contrast to the long-lasting theophylline effect, improvement in ejection fraction during the use of the Pz-agonist pirbuterol is transient because of tachyphylaxis. Thus theophylline may have an advantage over beta agonists in that its beneficial cardiovascular effects are not transient but persist over months. CENTRAL RESPIRATORY

STIMULATION

There is no question that theophylline increases ventilation via an increase in central respiratory drive. Whereas conflicting data exist concerning theophylline’s effect on the CO, response curve, the drug clearly augments the response to hypoxia.*’ This is a particularly useful property of the drug in treatment of patients with severe chronic airway disease, as pointed out by Galdston and Myles in 1962.‘” These workers demonstrated that aminophylline countered the respiratory depression seen with oxygen administration in patients with COPD and hypercapnia. They also showed that simultaneous use of acetazolamide augmented this action of theophylline, although acetazolamide alone did not alter respiratory depression during oxygen breathing. I have a hunch that one of the reasons we get away with using low-flow oxygen with so little severe respiratory depression is that most of our patients have a good load of theophylline aboard. Another aspect of theophylline’s stimulatory effect

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on respiratory drive concerns the problem of symptomatic relief. Those who are knowledgeable about respirator,y sensation tell us that the sense of respiratory effort, which is very closely related to the sensation of dyspnea, is increased when central respiratory drive or central respiratory motor output is increas’zd.“’ An implication of this is that a drug like theophylline. which increases central respiratory drive, may for this reason increase the sensation of respiratory effort or dyspnea despite the fact that it is otherwise benefiting the patient. This action of theophylline may afford yet another explanation as to why there is often lack of correspondence between objective physiologic benefit and symptomatic response. EFFECTS ON MEDIATOR

RELEASE

There is evidence that theophylline acts through inhibition of mediator release to suppress inflammation. Ishizaka” has shown that theophylline levels of 10d4 mol/L significantly inhibit membrane phospholipid methylation and calcium ion influx in rat mast cells. It is not known whether this action is of any importance in COPD, but the theophylline concentrations at which it occurs are close to the accepted therapeutic range. MUCOCIILIARY

CLEARANCE

In vitro testing has shown that theophylline increases ciliary beat frequency, increases the flux of water into the tracheobronchial tree, and promotes mucous secretion by the bronchial glands.” Modest improvement in tracheobronchial clearance of radiolabeled particles has been described in chronic bronchitis during maintenance theophylline therapy.” The clinical impact of these effects in patients, however, is not clear. I will say nothing about the diuretic effects of theophylline, because they are of little importance when compared with the powerful loop diuretics now in common use. However, in my house staff days the joint use of theophylline and mercurials was a most powerful and effective diuretic combination. It was the best we had at that time. COMBINEiD USE OF THEOPHYLLINE P,-AGONIISTS

WITH

I will conclude by mentioning the ability of theophylline to augment reponses to beta agonists. Smith et a1.“4have shown that maintenance slow-release theophylline given the previous evening substantially increased early morning peak flow rates in patients with asthma using aerosol terbutaline four times daily. Experience indicates that such combined use is similarly effective in COPD.

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In conclusion, I have outlined the several actions of theophylline particularly with respect to its use in chronic obstructive lung disease. I have further pointed out some of the features of the drug and of the patients in whom it is being used that make evaluation of its benefits somewhat difficult at times. We continue to use the drug with some enthusiasm in our COPD clinic, generally together with aerosol or oral /3,-agonists. With reasonable caution and common sense combined with attention to modem dosing guidelines,” the drug can be used safely and effectively.

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theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Enpl J Med 1984;31 1:349. Aubier M, Murciano D. Viirea N, Lecocguic Y, Pariente R. Diaphragm contractility enhanced by aminophylline: role of extracellular calcium. J Appl Physiol 1983;54:460. Supinski GS, Deal EC, Norcia M, Kelsen SG. Effect of hypoxemia and hyperinflation on the diaphragmatic muscle response to aminophylline [Abstract]. Am Rev Respir Dis 1984;129(4 Pt 2):270. Aubis:r M. De Troyer A, Sampson M, Macklem PT. Roussos C. Aminophylline improves diaphragmatic contractility. N Engl J Med 1981;305:249. Viire:; N, Aubier M, Murciano D, Fleury B. Talamo C. Pariente R. Effects of aminophylline on diaphragmatic fatigue during acute respiratory failure. Am Rev Respir Dia 1984; 129:396. Bellemare F, Grassino A. Effect of pressure and timing of contrtction on human diaphragmatic fatigue. J Appl Physiol 198253: I 190. Jones DA. Howell S, Roussos C. Edwards RTH. Low frequency fatigue in isolated skeletal muscles and the effects of methylxanthines. Clin Sci 1982;63: 161. Belman MJ. Sieck GC. Mazar A. Aminophylline and its infuencc on ventilatory endurance in humans. Am Rev Respir Dis lS85;131:226. Killiar KJ. The objective measurement of breathlessness. Chest 1985;88(suppl):84S. Parker JO, Kelkar K. West RO. Hemodynamic effects of aminophylline in car pulmonale. Circulation 1966;33:17. Parker JO. Askekian PB. Di Giorgi S, West RO. Hemodynamic effects of aminophylline in chronic obstructive pulmonary disease. Circulation 1967;35:365. Matthay RA, Berger HJ. Loke J, Gottschalk A. Zaret BL. Effects of aminophylline upon right and left ventricular performan:e in chronic obstructive pulmonary disease: noninvasive assessment by radionuclide angiocardiography. Am J Med 1978:65:903. Mattha;! RA, Berger HJ, Davies R, Loke J. Gottschalk A. Zaret BL. Improvement in cardiac performance by oral long acting theophylline in chronic obstructive pulmonary disease. Am He.lrt J 1982;104:1022. Colucci WS, Alexander RW, Williams GH, et al. Decreased lymphocyte beta-adrenerglc-receptor density in patients with heart faNlure and tolerance to the beta-adrenegic agonist pirbuterol. N Engl J Med 1981;305: 185. Lakshmmarayan S, Sahn SA, Weil JV. Effect ofaminophylline on ventilatory responses in normal man. Am Rev Respir Dis 1978; I I7:33 Galdston M, Myles MC. The use of aminophylline in respiratory depression and carbon dioxide retention induced by oxygen inhalation in patients with pulmonary emphysema. Am .I Med 1962;33:852. Ishizaka T. IgE and mechanisms of IgE-mediated hypersensitivity. .\nn Allergy 1982;48:313. Pavia D, Sutton PP, Lopez-Vidriero MD, Agnew JE. Clark5 SW. Drug effects on mucociliary function. Eur .I Respir Dis 1983;64(juppI 28):304. Sutton PI? Pavia D, Bateman JRM, Clark SW. The effect of oral aminophylline on lung mucociliary clearance in man. Chest 198I;80(suppI):889. Smith JA. Weher RW. Nelson HS. Theophylline and aerosolized terbutaline in the treatment of bronchial asthma. Chest 1980;78:816. Hendeles L. Weinberger MM. Theophylline. A “state of the art” review. Pharmacotherapy 1983:3:2.