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Bronchodilating effect of oxitropium bromide in heart disease patients with exacerbations of COPD: double-blind, randomized, controlled study
Vol. 96 (2002) 137^141
ORIGINAL ARTICLES
Bronchodilating e¡ect of oxitropium bromide in heart disease patients with exacerbations of COPD: double-blind, randomized, controlled study S.CENTANNI*w, P. SANTUS*w, F.CASANOVA*w, P.CARLUCCI*w, B. BOVERI*w, F.CASTAGNA*w, F. DI MARCO*, AND M.CAZZOLAw *Institute of Lung Disease, Respiratory Unit, San Paolo Hospital, University of Milan, Milan, and wDepartment of Respiratory Medicine, Unit of Pneumology and Allergology, A. Cardarelli Hospital, Naples, Itlay Abstract Anti-cholinergic agents are considered the bronchodilator therapy of ¢rst-choice in the treatment of patients with stable chronic obstructive pulmonary disease (COPD) associated with heart disease since they may be as e¡ective or more e¡ective than inhaled b2-agonists and, moreover, they do not interact with cardiac b-adrenoceptors. The aim of our study was to evaluate the bronchodilator activity of oxitropium bromide in outpatients su¡ering from exacerbations of COPD associated with heart diseases (ischaemic heart disease and/or arrhythmias).We recruited 50 consecutive outpatients (33 males and 17 females, mean age 686 years,15 current smokers and 35 ex-smokers). Each patient performed body plethismography in basal condition and 30 min after inhalation of 200 mg metered dose inhaler (MDI) oxitropium bromide administered by a device (Fluspacers). FEV1, FVC, MMEF25 -75, sRaw and tRaw were evaluated. Thirty minutes after 200 mg oxitropium bromide administration, we observed a signi¢cant improvement in FEV1 116%71 (mean 7SEM) (Po001);FVC,MMEF25 -75 sRaw variation was respectively: 92%706, 314729, 199711. Placebo did not signi¢cantly change pulmonary function.Our data suggestthat oxitropium bromide bronchodilator activity is e¡ective in exacerbations of COPD.r 2002 Elsevier Science Ltd doi:10.1053/rmed.2001.1219, available online at http://www.idealibrary.com on
Keywords acute exacerbation; COPD; oxitropium bromide.
INTRODUCTION The goals of treatment in acute exacerbation of chronic obstructive pulmonary disease (COPD) are the prompt resolution of symptoms and minimization of failure rate. In most patients with acute exacerbations of COPD, there appears to be a component of worsened air£ow obstruction that is particularly responsive to bronchodilators (1). Although the amount of reversibility achieved may be relatively small, any improvement in air£ow could be extremely important in the management of these patients (1). For this reason, bronchodilators are recommended in the management of this pathological condition that is de¢ned as a worsening of COPD symp-
Received 23 April 2001and accepted in revised form 25 September 2001. Correspondence should be addressed to: Mario Cazzola,Via del Parco Margherita 24, 80121Napoli, Italy. Fax: +39 0817473331; E-mail: [email protected]
toms caused by a rapid deterioration of the underlying respiratory function (2). In particular, as the airway obstruction becomes more severe, the therapeutic option is to add a short-acting inhaled b2 -agonist, such as salbutamol, as rescue medication to cause rapid relief of bronchospasm (3). Although substantial incremental increase in forced expiratory volume in 1 sec (FEV1) in response to increasing doses of b-agonists beyond those commonly used in clinical practice is restricted to a minority of patients (4), the optimal dosage might be greater than the conventional one (5). However, b-agonists have the potential to cause some systemic side-e¡ects that are more likely to occur with higher doses (6). Patients with COPD are of an age at which other chronic diseases, including cardiac disease, are common. Supraventricular and ventricular arrhythmias, as well as conduction disturbances of varying severity are frequently observed in COPD (7). The type of arrhythmia
138
that occurs in patients with COPD is in£uenced by their clinical state. Co-existing coronary heart disease, severe blood gas abnormalities and medication may precipitate the rhythm disturbances (8). Many clinicians are concerned about the potential e¡ect of bronchodilators, particularly b2 -agonists, on patients with cardiac disease. Also, the chronotropic and electrophysiological e¡ects of b2 -agonists are enhanced by conditions of hypoxaemia. Since inhaled ipratropium is bene¢cial as immediate therapy for asthma in the emergency department, some practitioners attempted to extrapolate these ¢ndings to treatment of COPD. In e¡ect, a few studies suggest the e⁄cacy of ipratropium alone is comparable with that of b2 -agonists in acute COPD (9^12). In the present study we have investigated the possible acute e¡ects of a normal dose of oxitropium bromide, which is another anti-cholinergic drug that has been shown to produce a similar degree of bronchodilation to that obtained with ipratropium bromide, but with a longer-lasting e¡ect (13), in cardiopathic patients with acute exacerbation of COPD.
METHODS Fifty (33 men and17 women) consecutive outpatients patients su¡ering from acute exacerbation of COPD and with a history of ischaemic heart disease or arrhythmias supported by electrocardiogram (ECG) and/or Holter ECG, or echocardiogram were included in this study. The diagnosis of COPD was consistent with the diagnostic standards of the consensus statement of European Respiratory Society (ERS) (14) and established on the basis of clinical history, physical ¢ndings and spirometry. All patients were 440 years of age, current or previous smokers (410 pack-years) reporting chronic cough with sputum production on most days during at least 3 consecutive months in 2 consecutive years, had no change in symptom severity or treatment in the preceding 4 weeks, had shown no signs of a respiratory tract infection in the month preceding or during the trial, were not taking oral or inhaled corticosteroids for at least 3 months and had a FEV1 o 65% and a forced vital capacity (FVC) o 70% of predicted normal after bronchodilators had been withheld for 24 h and a best post-bronchodilator FEV1/FVC of less than 07. Patients with a history of asthma, allergic rhinitis, atopy, skin-test positivity or with a total blood eosinophil count over 400 mm 3 were excluded. Acute exacerbation was de¢ned as a sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD (15). All patients presented increased sputum purulence and/or volume, increased dyspnoea and/or wheeze, chest tight-
RESPIRATORY MEDICINE
ness and £uid retention, and had no indication for hospitalization, according to the BTS Guidelines (16). We excluded patients with co-morbidities (such as congestive heart failure or pulmonary embolus) or complications of COPD (e.g. pneumothorax) as the aetiology of exacerbation of their symptoms. No patient was su¡ering from febrile tracheobronchitis. Table 1 outlines the baseline characteristics of the population studied. No oral bronchodilators were permitted for 1 week before and during the study. Inhaled short-acting bronchodilator drugs and inhaled long-acting bronchodilator agents were not permitted for at least 6 h and 12 h prior to each test, respectively, but short-acting b2 -agonists were permitted soon after each test when required. Consumption of cola drinks, co¡ee, tea and smoking in the hours before and during the investigating were also avoided. All patients received a treatment with an oral antibiotic (co-amoxiclav or levo£oxacin) and an inhaled steroid (budesonide 400 mg or £uticasone 250 mg twice daily). The study, which was conducted according to the rules of the declaration of Helsinki and was approved by an independent scienti¢c ethics committee, was performed using a double-blind, cross-over, randomized design. All patients received two pu¡s of oxitropium bromide (100 mg pu¡ 1) or placebo which were inhaled via matched MDI with spacer (Fluspacers), on two consecutive days. Plethismographic testing was performed according to the procedures described in the American Thoracic Society (17) before and 30 min after inhalation of oxitropium or placebo. Three acceptable forced expiratory manoeuvres were performed in order to obtain two reproducible results for FVC and FEV1. The highest FVC, FEV1, maximal mid-expiratory £ow (MMEF25 75), and sRaw obtained from one or the other of the reproducible curves were kept for analysis. Between each plethismographic test was a 3 min pause, while patients remained in sitting position. Contemporaneously, we also measured oxygen saturation by pulse oximetry (SpO2) and heart rate. Symptoms (cough and dyspnoea) and vital signs (blood pressure and heart rate) were assessed at the same time intervals as the £ow rates. Just before each test, in basal
TABLE 1. Demographic characteristics of the randomized patients Sex (M/F) Age (years) Height (cm) Weight (kg) Smoking history (pack-years) Duration of disease (years) Values are mean (7SEM).
33/17 68(70?8) 170(70?8) 70(71?3) 31(72) 9(71)
OXITROPIUM BROMIDE IN HEART DISEASE PATIENTS WITH EXACERBATIONS OF COPD
condition and after inhalation of oxitropium or placebo, patients indicated the contemporary dyspnoea experienced on a bipolar visual analogue scale (VAS). The VAS consisted of a 20 cm horizontal line labelled ‘very much worse’ at the left end, ‘very much better’ at the right end and ‘no change’ in the middle.This VAS measurement has been shown to have an acceptable degree of withinsubject variability after inhalation of isotonic saline and to correlate su⁄ciently with DFEV1 shortly after inhalation of histamine or terbutaline (18). Every patient was asked a subjective evaluation about cough. All data analysis was using a computer software and all variables were reported as mean (7SEM) values. The statistical analysis was performed using the SPSS program (Statistical Package for the Social Sciences for Windows, version 70, Chicago IL, U.S.A.). Analysis of spirometric data for each treatment was performed using the Student’s t-test for paired variables. Mean responses were also compared by multi-factorial analysis of variance (ANOVA) to establish any signi¢cant overall e¡ect between the two treatments. In the presence of a signi¢cant overall ANOVA, Duncan’s multiple range testing with 95% con¢dence limits was used to identify where di¡erences were signi¢cant. A probability level of Po005 was considered signi¢cant for all tests (19).
139
FEV1 (mean di¡erences from baseline: 160 ml7113; 11 8% 71; Fig.1).On the contrary, after inhalation of placebo, the mean per cent increase in FEV1 was 25%702 (P4005). Analysis of the FVC, MMEF25 -75, and sRaw responses showed e¡ects similar to that of FEV1. In particular, oxitropium induced an percentage increase in FVC and MMEF25 -75 of 92% 706 (Po005) and 314% 72?9% (Po005), respectively, and a decrease in sRaw of 199% 711% (Po005) (Table 2). Only 27 out of 50 patients reported dyspnoea at rest. Twelve out of these 27 subjects, equal to 44% of them, noti¢ed a mild improvement of this symptom after inhalation of oxitropium bromide [these subjects were ‘low perceivers’ having a low level of perception of individual dyspnoea (DVAS 5^35%, mean 20%)], whereas 10, equal to 34%, reported a mild improvement after inhalation of placebo. Patients accepted theVAS and this made the assessment of dyspnoea easier. There were no signi¢cant modi¢cations of this symptom neither after the inhalation of the anti-cholinergic agent nor after that of place-
RESULTS All patients completed the 2-day study. There were no signi¢cant di¡erences (P4005) between the FEV1 values, blood pressure values, pulse rate, and SpO2 before the two treatments (Table 2). The improvements in FEV1 and FVC with oxitropium bromide versus placebo were both signi¢cant (Po005). Oxitropium bromide, but not placebo, induced a large and signi¢cant (Po005) dose-dependent increase in
FIG. 1. FEV1 value in basal condition and after inhalation of oxitropium bromide and placebo.
TABLE 2. Mean (7SEM) values of functional parameters attwo days baseline condition, after oxitropium or placebo treatment Oxitropium
FEV1(1) FEV1(%) FVC(1) FVC(%) MMEF25 -75(1) MMEF25 -75(%) sRaw BP (mmHg) HR (bpm) SpO2(%)
Placebo
Baseline
30 min after
Baseline
30 min after
1477008 586725 233701 714732 0897007 296723 318703 145721 85708 82717 9327031
1637008 651727 253701 808734 1127009 382727 261702 150718 87706 8572 9377033
1457008 578724 234701 718731 0897006 296722 319703 146723 83708 83716 9377032
157008 5947002 235701 736732 097007 30724 321703 148714 79707 84717 9357033
BP:Blood pressure; HR: heart rate; SpO2: pulse oximetry.
140
bo, although there was a trend for a mild improvement after oxitropium. No signi¢cant changes in pulse rate, SpO2, blood pressure, or cough were found after oxitropium as compared with placebo group (Table 2). No patient complained of adverse symptoms and did not notice any di¡erence in the taste of the inhaler.
DISCUSSION Exacerbations of COPD may cause speci¢c signs and symptoms, such as increased dyspnoea, productive cough with altered sputum and fever. Alternatively, the symptoms may be more non-speci¢c, such as malaise, fatigue, insomnia or sleepiness and depression. Such exacerbations are associated with impaired lung function (15). Unfortunately, it is often unknown at ¢rst approach to the critically ill patients with COPD how much of the airway obstruction may be reversible with bronchodilators. Nonetheless, current guidelines (2, 14, 17) recommend short-acting b2 -agonists as ¢rst-line treatment of acute exacerbation of COPD. There may be an advantage to more frequent dosing, particularly in patients with initially severe bronchospasm, although at the expense of more frequent side-e¡ects (20). The use of b-agonists may be potentially arrhythmogenic in patients with acute exacerbation of COPD (21). In fact, the chronotropic and electrophysiological e¡ects of these agents are enhanced by conditions of hypoxaemia; mild hypoxaemia (SpO2r90%) has been demonstrated to add something to prolongation of the QTc caused by fenoterol (22). On the other hand, b-agonists may decrease PaO2 by increasing blood £ow through poorly ventilated areas of the lung (23), thereby increasing ventilation/perfusion mismatch (24). When the initial PaO2 is below 60 mmHg, if a decrease in PaO2 is produced by a b2 -agonist, it may become clinically signi¢cant. Consequently, b2 -agonists therapy cannot be considered completely safe in patients with acute exacerbations of COPD. Furthermore, atrial and ventricular dysrhythmias are frequent in this pathological condition, occurring in as many as 80 ^90% of COPD patients with respiratory failure (25). Hypoxaemia, right ventricular enlargement associated left ventricular dysfunction, and iatrogenic factors are potential determinants of the density and complexity of these arrhythmias (7). In particular, patients with hypoxaemic COPD may have a subclinical autonomic neuropathy, which has been associated with a prolonged electrocardiograph QTc interval and risk of ventricular arrhythmias and death (26). Anti-cholinergics might, oppositely, be e¡ective agents in the critically ill patients with COPD (27), although the precise clinical role of anticholinergic compounds in acute exacerbations of COPD is still unclear.
RESPIRATORY MEDICINE
Since inhaled anti-cholinergics are bene¢cial as immediate therapy for asthma in the emergency department, some practitioners attempted to extrapolate these ¢ndings to treatment of COPD (28). Inhaled ipratropium is commonly accepted as the drug of choice for long-term management of chronic bronchitis and emphysema, but little evidence is available to promote its administration alone or in conjunction with a b2 -agonist as part of initial management of COPD exacerbations. Unfortunately, studies that have compared ipratropium in combination with b-agonists for acute exacerbations COPD have found no particular added bene¢t to the addition of ipratropium to inhaled b-agonists (29^32). Perhaps there was no advantage in adding an anti-cholinergic agent because the patients were already receiving maximum doses of other bronchodilators (33). Anyway, anti-cholinergics may have selective advantages for managing patients who respond poorly to b2 -agonist therapy alone (34). The results of the present study suggest that anti-cholinergic agents may also have a role in ¢rst-line treatment of acute exacerbation in COPD patients with pre-existing heart disease. Even though the reversibility tests do not predict the degree of symptomatic bene¢t an individual will obtain, we can presumed that the bronchodilatation with the reduction of airway resistance may improve exercise tolerance and reduce respiratory fatigue. Our data have clearly demonstrated that oxitropium not only induced a substantial bronchodilation, but was also safe. In fact, it did not induce signi¢cant modi¢cations in heart rate or in SpO2, although four patients presented at baseline a decrease in SpO2 under 90%. This ¢nding is a true advantage of an anti-cholinergic agent, which may be particularly important in the critically ill patient with multiple organ failure in whom excessive tachycardia may reduce oxygen delivery (28).
REFERENCES 1. Ikeda A, Nishimura K, Izumi T. Pharmacological treatment in acute exacerbations of chronic obstructive pulmonary disease. Drugs Aging 1998; 12: 129^137. 2. ATS Statement. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease: inpatient management of COPD. Am J Respir Crit Care Med 1995; 152(Suppl): S97^S106, S78 ^S83. 3. Fromm RE Jr, Varon J. Acute exacerbations of obstructive lung disease. What to do when immediate care is crucial. Postgrad Med 1994; 95: 101^106. 4. Jaeschke R,Guyatt GH,Cook D, et al.The e¡ect of increasing doses of b-agonists on air£ow in patients with chronic air£ow limitation. Respir Med 1993; 87: 433^ 438. 5. Newhouse M, Dolovich M. Aerosol therapy: nebulized vs metered dose inhaler.Chest 1987; 91: 799^ 800. 6. Clark DJ, Lipworth BJ. Dose-response of inhaled drugs in asthma. An update.Clin Pharmacokinet 1997; 32: 58 ^74. 7. Brashear RE. Arrhythmias in patients with chronic obstructive pulmonary disease. Med Clin North Am 1984; 68: 969^981.
OXITROPIUM BROMIDE IN HEART DISEASE PATIENTS WITH EXACERBATIONS OF COPD
8. Gorecka D. Cardiac arrhythmias in chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 1997; 52: 278 ^281. 9. Backman R, Hellstr˛m P. Fenoterol and ipratropium bromide in respirator treatment of patients with chronic bronchitis. CurrTher Res 1985; 38: 135^140. 10. Rebuck AS, Chapman KR, Abboud R, et al. Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airway disease in the emergency room. Am J Med 1987; 82: 59^ 64. 11. Lloberes P, Ramis L, Montserrat JM, et al. E¡ect of three di¡erent bronchodilators during an exacerbation of chronic obstructive pulmonary disease. Eur Respir J 1988; 1: 536 ^539. 12. Karpel JP, Pesin J, Greenberg D, Gentry E. A comparison of the effects of ipratropium bromide and metaproterenol sulfate in acute exacerbations of COPD.Chest 1990; 98: 835^ 839. 13. Minette A, Marcq M. Oxitropium bromide (Ba 253), an advance in the ¢eld of anticholinergic bronchodilating treatments. Rev Inst Hyg Mines 1979; 34: 115^123. 14. Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). Eur Respir J 1995; 8: 1398 ^1420. 15. Rodriguez-Roisin R. Toward a consensus de¢nition for COPD exacerbations.Chest 2000; 117: 398S ^ 401S. 16. The COPD Guidelines Group of the Standards of Care Committee of the BTS. BTS guidelines for the management of chronic obstructive pulmonary disease.Thorax 1997; 52(Suppl 5): S1^S28. 17. AmericanThoracic Society. Standardization of spirometry; 1994 update. Am J Respir Crit Care Med 1995; 152: 1107^1136. 18. Noseda A, Schmerber J, PrigogineT,Yernault JC. Perceived e¡ect on shortness of breath of an acute inhalation of saline or terbutaline: variability and sensitivity of a visual analogue scale in patients with asthma or COPD. Eur Respir J 1992; 5: 1043^1053. 19. Snedecor GV, Cochran WG. Statistical Methods. 8th ed. Ames: lowa State University Press,1989. 20. Emerman CL, Cydulka RK. E¡ect of di¡erent albuterol dosing regimens in the treatment of acute exacerbation of chronic obstructive pulmonary disease. Ann Emerg Med 1997; 29: 474 ^ 478. 21. Demirkan K, Kuhl D, Headley AS, Self T. Can we justify ipratropium therapy as initial management of acute exacerbations of COPD? Pharmacotherapy 1999; 19: 838 ^ 843.
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22. O’Driscoll BR, Taylor RJ, Horsley MG, et al. Nebulized salbutamol with and without ipratropium bromide in acute air£ow obstruction. Lancet 1989; 1: 1418 ^1420. 23. Rebuck AS, Chapman KR, Abboud R, et al. Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am J Med 1987; 82: 59^ 64. 24. Kuhl DA, Agiri OA, Mauro LS. Beta-agonists in the treatment of acute exacerbation of chronic obstructive pulmonary disease. Ann Pharmacother 1994; 28: 1379^1388. 25. Moayyedi P, Congleton J, Page RL, et al. Comparison of nebulised salbutamol and ipratropium bromide with salbutamol alone in the treatment of chronic obstructive pulmonary disease. Thorax 1995; 50: 834 ^ 837. 26. Cazzola M, Centanni S, Donner CF. Anticholinergic drugs. Pulm Pharmacol Ther 1998; 11: 381^392. 27. Hudson LD, Kurt TL, Petty TL, et al. Arrhythmias associated with acute respiratory failure in patients with chronic obstruction. Chest 1973; 63: 661. 28. Siefkin AD.Optimal pharmacologic treatment of the critically ill patient with obstructive airways disease. Am J Med 1996; 100(Suppl A): 54S ^ 61S. 29. Stewart AG, Waterhouse JC, Howard T. The QTc interval, autonomic neuropathy and mortality in hypoxaemic COPD. Respir Med 1995; 89: 79^ 84. 30. ConradsonTB, Eklundh G, Olofsson B, et al.Cardiac arrhythmias in patients with mild-to-moderate obstructive pulmonary disease. Comparison of b-agonist therapy alone and in combination with a xanthine derivative, enprophylline or theophylline. Chest 1985; 88: 537^542. 31. Bremner P, Burgess CD, Crane J, et al. Cardiovascular e¡ects of fenoterol under conditions of hypoxaemia.Thorax 1992; 47: 814 ^ 817. 32. Jenne JW. Physiologic actions of beta-adrenergic agonists. In: Le¡ AR, ed. Pulmonary and Critical Care Pharmacology and Therapeutics. New York, McGraw-Hill,1996; 473^ 487. 33. Karpel JP.The use of anticholinergic drugs in acute exacerbations of chronic obstructive pulmonary disease. In: Gross NJ, ed. AnticholinergicTherapyin Obstructive Airways Disease.Franklin Scienti¢c Publications, London,1993; 145^154. 34. Viegas CA, Ferrer A, Montserrat JM, et al. Ventilation ^perfusion response after fenoterol in hypoxemic patients with stable COPD. Chest 1996; 110: 71^77.
ORIGINAL ARTICLES
Bronchodilating e¡ect of oxitropium bromide in heart disease patients with exacerbations of COPD: double-blind, randomized, controlled study S.CENTANNI*w, P. SANTUS*w, F.CASANOVA*w, P.CARLUCCI*w, B. BOVERI*w, F.CASTAGNA*w, F. DI MARCO*, AND M.CAZZOLAw *Institute of Lung Disease, Respiratory Unit, San Paolo Hospital, University of Milan, Milan, and wDepartment of Respiratory Medicine, Unit of Pneumology and Allergology, A. Cardarelli Hospital, Naples, Itlay Abstract Anti-cholinergic agents are considered the bronchodilator therapy of ¢rst-choice in the treatment of patients with stable chronic obstructive pulmonary disease (COPD) associated with heart disease since they may be as e¡ective or more e¡ective than inhaled b2-agonists and, moreover, they do not interact with cardiac b-adrenoceptors. The aim of our study was to evaluate the bronchodilator activity of oxitropium bromide in outpatients su¡ering from exacerbations of COPD associated with heart diseases (ischaemic heart disease and/or arrhythmias).We recruited 50 consecutive outpatients (33 males and 17 females, mean age 686 years,15 current smokers and 35 ex-smokers). Each patient performed body plethismography in basal condition and 30 min after inhalation of 200 mg metered dose inhaler (MDI) oxitropium bromide administered by a device (Fluspacers). FEV1, FVC, MMEF25 -75, sRaw and tRaw were evaluated. Thirty minutes after 200 mg oxitropium bromide administration, we observed a signi¢cant improvement in FEV1 116%71 (mean 7SEM) (Po001);FVC,MMEF25 -75 sRaw variation was respectively: 92%706, 314729, 199711. Placebo did not signi¢cantly change pulmonary function.Our data suggestthat oxitropium bromide bronchodilator activity is e¡ective in exacerbations of COPD.r 2002 Elsevier Science Ltd doi:10.1053/rmed.2001.1219, available online at http://www.idealibrary.com on
Keywords acute exacerbation; COPD; oxitropium bromide.
INTRODUCTION The goals of treatment in acute exacerbation of chronic obstructive pulmonary disease (COPD) are the prompt resolution of symptoms and minimization of failure rate. In most patients with acute exacerbations of COPD, there appears to be a component of worsened air£ow obstruction that is particularly responsive to bronchodilators (1). Although the amount of reversibility achieved may be relatively small, any improvement in air£ow could be extremely important in the management of these patients (1). For this reason, bronchodilators are recommended in the management of this pathological condition that is de¢ned as a worsening of COPD symp-
Received 23 April 2001and accepted in revised form 25 September 2001. Correspondence should be addressed to: Mario Cazzola,Via del Parco Margherita 24, 80121Napoli, Italy. Fax: +39 0817473331; E-mail: [email protected]
toms caused by a rapid deterioration of the underlying respiratory function (2). In particular, as the airway obstruction becomes more severe, the therapeutic option is to add a short-acting inhaled b2 -agonist, such as salbutamol, as rescue medication to cause rapid relief of bronchospasm (3). Although substantial incremental increase in forced expiratory volume in 1 sec (FEV1) in response to increasing doses of b-agonists beyond those commonly used in clinical practice is restricted to a minority of patients (4), the optimal dosage might be greater than the conventional one (5). However, b-agonists have the potential to cause some systemic side-e¡ects that are more likely to occur with higher doses (6). Patients with COPD are of an age at which other chronic diseases, including cardiac disease, are common. Supraventricular and ventricular arrhythmias, as well as conduction disturbances of varying severity are frequently observed in COPD (7). The type of arrhythmia
138
that occurs in patients with COPD is in£uenced by their clinical state. Co-existing coronary heart disease, severe blood gas abnormalities and medication may precipitate the rhythm disturbances (8). Many clinicians are concerned about the potential e¡ect of bronchodilators, particularly b2 -agonists, on patients with cardiac disease. Also, the chronotropic and electrophysiological e¡ects of b2 -agonists are enhanced by conditions of hypoxaemia. Since inhaled ipratropium is bene¢cial as immediate therapy for asthma in the emergency department, some practitioners attempted to extrapolate these ¢ndings to treatment of COPD. In e¡ect, a few studies suggest the e⁄cacy of ipratropium alone is comparable with that of b2 -agonists in acute COPD (9^12). In the present study we have investigated the possible acute e¡ects of a normal dose of oxitropium bromide, which is another anti-cholinergic drug that has been shown to produce a similar degree of bronchodilation to that obtained with ipratropium bromide, but with a longer-lasting e¡ect (13), in cardiopathic patients with acute exacerbation of COPD.
METHODS Fifty (33 men and17 women) consecutive outpatients patients su¡ering from acute exacerbation of COPD and with a history of ischaemic heart disease or arrhythmias supported by electrocardiogram (ECG) and/or Holter ECG, or echocardiogram were included in this study. The diagnosis of COPD was consistent with the diagnostic standards of the consensus statement of European Respiratory Society (ERS) (14) and established on the basis of clinical history, physical ¢ndings and spirometry. All patients were 440 years of age, current or previous smokers (410 pack-years) reporting chronic cough with sputum production on most days during at least 3 consecutive months in 2 consecutive years, had no change in symptom severity or treatment in the preceding 4 weeks, had shown no signs of a respiratory tract infection in the month preceding or during the trial, were not taking oral or inhaled corticosteroids for at least 3 months and had a FEV1 o 65% and a forced vital capacity (FVC) o 70% of predicted normal after bronchodilators had been withheld for 24 h and a best post-bronchodilator FEV1/FVC of less than 07. Patients with a history of asthma, allergic rhinitis, atopy, skin-test positivity or with a total blood eosinophil count over 400 mm 3 were excluded. Acute exacerbation was de¢ned as a sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD (15). All patients presented increased sputum purulence and/or volume, increased dyspnoea and/or wheeze, chest tight-
RESPIRATORY MEDICINE
ness and £uid retention, and had no indication for hospitalization, according to the BTS Guidelines (16). We excluded patients with co-morbidities (such as congestive heart failure or pulmonary embolus) or complications of COPD (e.g. pneumothorax) as the aetiology of exacerbation of their symptoms. No patient was su¡ering from febrile tracheobronchitis. Table 1 outlines the baseline characteristics of the population studied. No oral bronchodilators were permitted for 1 week before and during the study. Inhaled short-acting bronchodilator drugs and inhaled long-acting bronchodilator agents were not permitted for at least 6 h and 12 h prior to each test, respectively, but short-acting b2 -agonists were permitted soon after each test when required. Consumption of cola drinks, co¡ee, tea and smoking in the hours before and during the investigating were also avoided. All patients received a treatment with an oral antibiotic (co-amoxiclav or levo£oxacin) and an inhaled steroid (budesonide 400 mg or £uticasone 250 mg twice daily). The study, which was conducted according to the rules of the declaration of Helsinki and was approved by an independent scienti¢c ethics committee, was performed using a double-blind, cross-over, randomized design. All patients received two pu¡s of oxitropium bromide (100 mg pu¡ 1) or placebo which were inhaled via matched MDI with spacer (Fluspacers), on two consecutive days. Plethismographic testing was performed according to the procedures described in the American Thoracic Society (17) before and 30 min after inhalation of oxitropium or placebo. Three acceptable forced expiratory manoeuvres were performed in order to obtain two reproducible results for FVC and FEV1. The highest FVC, FEV1, maximal mid-expiratory £ow (MMEF25 75), and sRaw obtained from one or the other of the reproducible curves were kept for analysis. Between each plethismographic test was a 3 min pause, while patients remained in sitting position. Contemporaneously, we also measured oxygen saturation by pulse oximetry (SpO2) and heart rate. Symptoms (cough and dyspnoea) and vital signs (blood pressure and heart rate) were assessed at the same time intervals as the £ow rates. Just before each test, in basal
TABLE 1. Demographic characteristics of the randomized patients Sex (M/F) Age (years) Height (cm) Weight (kg) Smoking history (pack-years) Duration of disease (years) Values are mean (7SEM).
33/17 68(70?8) 170(70?8) 70(71?3) 31(72) 9(71)
OXITROPIUM BROMIDE IN HEART DISEASE PATIENTS WITH EXACERBATIONS OF COPD
condition and after inhalation of oxitropium or placebo, patients indicated the contemporary dyspnoea experienced on a bipolar visual analogue scale (VAS). The VAS consisted of a 20 cm horizontal line labelled ‘very much worse’ at the left end, ‘very much better’ at the right end and ‘no change’ in the middle.This VAS measurement has been shown to have an acceptable degree of withinsubject variability after inhalation of isotonic saline and to correlate su⁄ciently with DFEV1 shortly after inhalation of histamine or terbutaline (18). Every patient was asked a subjective evaluation about cough. All data analysis was using a computer software and all variables were reported as mean (7SEM) values. The statistical analysis was performed using the SPSS program (Statistical Package for the Social Sciences for Windows, version 70, Chicago IL, U.S.A.). Analysis of spirometric data for each treatment was performed using the Student’s t-test for paired variables. Mean responses were also compared by multi-factorial analysis of variance (ANOVA) to establish any signi¢cant overall e¡ect between the two treatments. In the presence of a signi¢cant overall ANOVA, Duncan’s multiple range testing with 95% con¢dence limits was used to identify where di¡erences were signi¢cant. A probability level of Po005 was considered signi¢cant for all tests (19).
139
FEV1 (mean di¡erences from baseline: 160 ml7113; 11 8% 71; Fig.1).On the contrary, after inhalation of placebo, the mean per cent increase in FEV1 was 25%702 (P4005). Analysis of the FVC, MMEF25 -75, and sRaw responses showed e¡ects similar to that of FEV1. In particular, oxitropium induced an percentage increase in FVC and MMEF25 -75 of 92% 706 (Po005) and 314% 72?9% (Po005), respectively, and a decrease in sRaw of 199% 711% (Po005) (Table 2). Only 27 out of 50 patients reported dyspnoea at rest. Twelve out of these 27 subjects, equal to 44% of them, noti¢ed a mild improvement of this symptom after inhalation of oxitropium bromide [these subjects were ‘low perceivers’ having a low level of perception of individual dyspnoea (DVAS 5^35%, mean 20%)], whereas 10, equal to 34%, reported a mild improvement after inhalation of placebo. Patients accepted theVAS and this made the assessment of dyspnoea easier. There were no signi¢cant modi¢cations of this symptom neither after the inhalation of the anti-cholinergic agent nor after that of place-
RESULTS All patients completed the 2-day study. There were no signi¢cant di¡erences (P4005) between the FEV1 values, blood pressure values, pulse rate, and SpO2 before the two treatments (Table 2). The improvements in FEV1 and FVC with oxitropium bromide versus placebo were both signi¢cant (Po005). Oxitropium bromide, but not placebo, induced a large and signi¢cant (Po005) dose-dependent increase in
FIG. 1. FEV1 value in basal condition and after inhalation of oxitropium bromide and placebo.
TABLE 2. Mean (7SEM) values of functional parameters attwo days baseline condition, after oxitropium or placebo treatment Oxitropium
FEV1(1) FEV1(%) FVC(1) FVC(%) MMEF25 -75(1) MMEF25 -75(%) sRaw BP (mmHg) HR (bpm) SpO2(%)
Placebo
Baseline
30 min after
Baseline
30 min after
1477008 586725 233701 714732 0897007 296723 318703 145721 85708 82717 9327031
1637008 651727 253701 808734 1127009 382727 261702 150718 87706 8572 9377033
1457008 578724 234701 718731 0897006 296722 319703 146723 83708 83716 9377032
157008 5947002 235701 736732 097007 30724 321703 148714 79707 84717 9357033
BP:Blood pressure; HR: heart rate; SpO2: pulse oximetry.
140
bo, although there was a trend for a mild improvement after oxitropium. No signi¢cant changes in pulse rate, SpO2, blood pressure, or cough were found after oxitropium as compared with placebo group (Table 2). No patient complained of adverse symptoms and did not notice any di¡erence in the taste of the inhaler.
DISCUSSION Exacerbations of COPD may cause speci¢c signs and symptoms, such as increased dyspnoea, productive cough with altered sputum and fever. Alternatively, the symptoms may be more non-speci¢c, such as malaise, fatigue, insomnia or sleepiness and depression. Such exacerbations are associated with impaired lung function (15). Unfortunately, it is often unknown at ¢rst approach to the critically ill patients with COPD how much of the airway obstruction may be reversible with bronchodilators. Nonetheless, current guidelines (2, 14, 17) recommend short-acting b2 -agonists as ¢rst-line treatment of acute exacerbation of COPD. There may be an advantage to more frequent dosing, particularly in patients with initially severe bronchospasm, although at the expense of more frequent side-e¡ects (20). The use of b-agonists may be potentially arrhythmogenic in patients with acute exacerbation of COPD (21). In fact, the chronotropic and electrophysiological e¡ects of these agents are enhanced by conditions of hypoxaemia; mild hypoxaemia (SpO2r90%) has been demonstrated to add something to prolongation of the QTc caused by fenoterol (22). On the other hand, b-agonists may decrease PaO2 by increasing blood £ow through poorly ventilated areas of the lung (23), thereby increasing ventilation/perfusion mismatch (24). When the initial PaO2 is below 60 mmHg, if a decrease in PaO2 is produced by a b2 -agonist, it may become clinically signi¢cant. Consequently, b2 -agonists therapy cannot be considered completely safe in patients with acute exacerbations of COPD. Furthermore, atrial and ventricular dysrhythmias are frequent in this pathological condition, occurring in as many as 80 ^90% of COPD patients with respiratory failure (25). Hypoxaemia, right ventricular enlargement associated left ventricular dysfunction, and iatrogenic factors are potential determinants of the density and complexity of these arrhythmias (7). In particular, patients with hypoxaemic COPD may have a subclinical autonomic neuropathy, which has been associated with a prolonged electrocardiograph QTc interval and risk of ventricular arrhythmias and death (26). Anti-cholinergics might, oppositely, be e¡ective agents in the critically ill patients with COPD (27), although the precise clinical role of anticholinergic compounds in acute exacerbations of COPD is still unclear.
RESPIRATORY MEDICINE
Since inhaled anti-cholinergics are bene¢cial as immediate therapy for asthma in the emergency department, some practitioners attempted to extrapolate these ¢ndings to treatment of COPD (28). Inhaled ipratropium is commonly accepted as the drug of choice for long-term management of chronic bronchitis and emphysema, but little evidence is available to promote its administration alone or in conjunction with a b2 -agonist as part of initial management of COPD exacerbations. Unfortunately, studies that have compared ipratropium in combination with b-agonists for acute exacerbations COPD have found no particular added bene¢t to the addition of ipratropium to inhaled b-agonists (29^32). Perhaps there was no advantage in adding an anti-cholinergic agent because the patients were already receiving maximum doses of other bronchodilators (33). Anyway, anti-cholinergics may have selective advantages for managing patients who respond poorly to b2 -agonist therapy alone (34). The results of the present study suggest that anti-cholinergic agents may also have a role in ¢rst-line treatment of acute exacerbation in COPD patients with pre-existing heart disease. Even though the reversibility tests do not predict the degree of symptomatic bene¢t an individual will obtain, we can presumed that the bronchodilatation with the reduction of airway resistance may improve exercise tolerance and reduce respiratory fatigue. Our data have clearly demonstrated that oxitropium not only induced a substantial bronchodilation, but was also safe. In fact, it did not induce signi¢cant modi¢cations in heart rate or in SpO2, although four patients presented at baseline a decrease in SpO2 under 90%. This ¢nding is a true advantage of an anti-cholinergic agent, which may be particularly important in the critically ill patient with multiple organ failure in whom excessive tachycardia may reduce oxygen delivery (28).
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