Respiratory Medicine (1992) 86, 425-429
Chronic persistent cough: use of ipratropium bromide in undiagnosed cases following upper respiratory tract infection P. W. HOLMES*, C. E. BARTER AND R. J. PIERCE
Departments of Respiratory Medicine at Heidelberg Repatriation Hospital, Melbourne, and Monash Medical Centre, Clayton, Victoria, Australia
The clinical effects of inhaled ipratropium bromide were studied in 14 non-smoking patients with persistent post-viral infective cough employing a controlled double-blind, cross-over trial. Patients were selected if they demonstrated no apparent underlying cause for their persistent cough after appropriate radiological and respiratory function tests including methacholine reactivity and bronchoscopic examination. Inhaled ipratropium bromide (320 ltg day- J) produced significantly less day and night time cough (P < 0.05) with overall clinical improvement in 12 cases, five of whom had total resolution of their cough. We conclude that ipratropium bromide is an effective treatment in non-smoking adults with protracted cough following clinical upper respiratory tract infection. Introduction Protracted cough that persists for many months following a clinical upper respiratory tract infection (URTI) in previously normal subjects is a well described clinical problem. Using an anatomical diagnostic protocol as originally proposed by Irwin and co-workers (I), a cause of post-URTI cough can often be determined (2) and successful treatment achieved in the majority of cases (3). In some patients however, including those who undergo fiberoptic bronchoscopy (4), no specific cause for persistence of post-URTI cough can be identified and the cough continues for many months (5). Therapeutic trials of antibiotics, nasal decongestants, cough suppressants, inhaled bronchodilators and steroids (inhaled and oral) are frequently employed without benefit on the assumption that they may have a role as anti-tussive and anti-inflammatory agents in patients without airflow obstruction (3). During such therapeutic attempts in individual patients we had observed beneficial effects from inhaled atropine methonitrate in some cases of chronic persistent cough. Although a potent anti-cholinergic bronchodilator, this drug has some troublesome side effects when used in aerosol form so we elected to Received 13 May 1991 and accepted in revised form 25 November 1991. *To whomcorrespondenceand reprint requests should be addressed at: Department of Respiratory Medicine, Monash Medical Centre, Clayton Road, Clayton,Victoria3168,Australia. 0954-61I I/92]050425+ 05 $08.00/0
undertake a formal evaluation of the efficacy of the closely related compound ipratropium bromide which lacks these side effects when inhaled. A randomized double-blind, cross-over study design was thus employed to determine the clinical effects of inhaled ipratropium bromide on post-URTl cough and the mildly increased bronchial reactivity which often accompanies it (6). Methods PATIENTSELECTION Consenting non-smoking patients presenting with a persistent post-URTI cough of at least 8 weeks duration were studied. Entry criteria included absence of: (i) a past history of asthma; (ii) medications likely to induce cough; and (iii) symptoms suggesting gastrooesophageal reflux prior to or during coughing bouts. All patients had a normal physical examination, normal chest X-ray and sinus radiography, no evidence of any endobronchial mass at fiberoptic bronchoscopy, normal baseline forced vital capacity (FVC) and forced expiratory volume in 1 s (FEVI), and normal bronchial reactivity to methacholine challenge. Patients entering the study were also required to demonstrate a correct metered dose inhaler technique. The following therapies were not considered as exclusion criteria from the study, but all such therapy was ceased at least 2 weeks prior to the study. Ten patients had had previous therapy with inhaled flagonist bronchodilators; eight had previously taken © 1992Bailli~reTindall
426
P. IV. H o l m e s et al.
antibiotics; seven, inhaled steroids; six, nasal decongestants and anti-histamines; four, oral theophyllines; three, cough suppressants; three, soluble aspirin; two, inhaled nasal steroids; one, nasal cromoglycate; and one had been taking a short course oforal prednisolone. No patient had previously received ipratropium bromide.
Table I
Active Placebo
Periodicclinical reviews Improved
Worse
N o change
10 I
1 3
2 9
Z 2 (Yates correction), n = 13, P < 0.001. STUDY DESIGN
The study consisted of a randomized, double-blind, cross-over trial with two 3-week treatment periods separated by a 1-week washout period. Patients were randomly allocated to either ipratropium bromide (four 20-~g puffs, four times daily) or placebo (four puffs four times daily) in the first treatment period and then crossed over to the alternate regimen for the second treatment period. PERIODIC CLINICAL REVIEW
The patients were evaluated clinically and symptoms were assessed at the beginning and end of each treatment period by the same physician in each case who rated symptoms as improved, unrhanged, or worse. DALLY SYMPTOM SCORES
Each patient also kept a daily symptom score card on which was recorded day-time cough, night-time cough and any associated sputum production, postnasal drip, sneezing, dyspnoea associated with coughing bouts, and wheeze. Each symptom was assessed by the patient on a scale of 0-3 where; 0 = no symptom; 1 = mild; 2 = moderate; and 3 = severe symptoms. Mean daily scores were estimated for each of the 3-week treatment periods. LUNG FUNCTION ASSESSMENT
Pre- and post-bronchodilator (200/zg salbutamol by metered dose inhaler) spirometry was obtained at the beginning and end of each treatment period, in the morning, at least 4 h after trial medication. Measurements of FVC and FEV~ were the best of at least three matched traces provided there was a matching measurement within 5% of this value obtained using either a Godard or a Sensomedics 2400 series watersealed spirometer. Methacholine responsiveness was measured on recruitment and at the completion of the study. If it had become apparent that methacholine responsiveness was changing during the course of the study, later patients were to have received a methacholine dose response curve at the change-over period. We used a modified dosimetric technique with ten-fold serial concentrations ofmethacholine chloride in saline starting with 0.01% and ending with 10%
solution. This was preceded by a saline control inhalation and all concentrations were delivered with a calibrated Bennett's twin nebulizer. The maximal dose delivered in all cases was 1.6mg of methacholine chloride. With this technique, small changes in very low PD20 values would be detected, though small changes in high PD20 values may well not be identified. The PD20 to methacholine obtained by this method in subjects with asthma closely matches the PD20 described by Yan et al. to histamine with up to eight increments delivered by a DeVilbiss (Somerset, Pasadena, U.S.A.) Nebuliser No. 40 (7). In a separate series of seven asthmatic subjects we have found a good correlation between the PD20 using methacholine as in this study and that of Yan et al. using histamine (r 0.89, P
Chronic persistent cough: use of ipratropium bromide in undiagnosed cases following upper respiratory tract infection P. W. HOLMES*, C. E. BARTER AND R. J. PIERCE
Departments of Respiratory Medicine at Heidelberg Repatriation Hospital, Melbourne, and Monash Medical Centre, Clayton, Victoria, Australia
The clinical effects of inhaled ipratropium bromide were studied in 14 non-smoking patients with persistent post-viral infective cough employing a controlled double-blind, cross-over trial. Patients were selected if they demonstrated no apparent underlying cause for their persistent cough after appropriate radiological and respiratory function tests including methacholine reactivity and bronchoscopic examination. Inhaled ipratropium bromide (320 ltg day- J) produced significantly less day and night time cough (P < 0.05) with overall clinical improvement in 12 cases, five of whom had total resolution of their cough. We conclude that ipratropium bromide is an effective treatment in non-smoking adults with protracted cough following clinical upper respiratory tract infection. Introduction Protracted cough that persists for many months following a clinical upper respiratory tract infection (URTI) in previously normal subjects is a well described clinical problem. Using an anatomical diagnostic protocol as originally proposed by Irwin and co-workers (I), a cause of post-URTI cough can often be determined (2) and successful treatment achieved in the majority of cases (3). In some patients however, including those who undergo fiberoptic bronchoscopy (4), no specific cause for persistence of post-URTI cough can be identified and the cough continues for many months (5). Therapeutic trials of antibiotics, nasal decongestants, cough suppressants, inhaled bronchodilators and steroids (inhaled and oral) are frequently employed without benefit on the assumption that they may have a role as anti-tussive and anti-inflammatory agents in patients without airflow obstruction (3). During such therapeutic attempts in individual patients we had observed beneficial effects from inhaled atropine methonitrate in some cases of chronic persistent cough. Although a potent anti-cholinergic bronchodilator, this drug has some troublesome side effects when used in aerosol form so we elected to Received 13 May 1991 and accepted in revised form 25 November 1991. *To whomcorrespondenceand reprint requests should be addressed at: Department of Respiratory Medicine, Monash Medical Centre, Clayton Road, Clayton,Victoria3168,Australia. 0954-61I I/92]050425+ 05 $08.00/0
undertake a formal evaluation of the efficacy of the closely related compound ipratropium bromide which lacks these side effects when inhaled. A randomized double-blind, cross-over study design was thus employed to determine the clinical effects of inhaled ipratropium bromide on post-URTl cough and the mildly increased bronchial reactivity which often accompanies it (6). Methods PATIENTSELECTION Consenting non-smoking patients presenting with a persistent post-URTI cough of at least 8 weeks duration were studied. Entry criteria included absence of: (i) a past history of asthma; (ii) medications likely to induce cough; and (iii) symptoms suggesting gastrooesophageal reflux prior to or during coughing bouts. All patients had a normal physical examination, normal chest X-ray and sinus radiography, no evidence of any endobronchial mass at fiberoptic bronchoscopy, normal baseline forced vital capacity (FVC) and forced expiratory volume in 1 s (FEVI), and normal bronchial reactivity to methacholine challenge. Patients entering the study were also required to demonstrate a correct metered dose inhaler technique. The following therapies were not considered as exclusion criteria from the study, but all such therapy was ceased at least 2 weeks prior to the study. Ten patients had had previous therapy with inhaled flagonist bronchodilators; eight had previously taken © 1992Bailli~reTindall
426
P. IV. H o l m e s et al.
antibiotics; seven, inhaled steroids; six, nasal decongestants and anti-histamines; four, oral theophyllines; three, cough suppressants; three, soluble aspirin; two, inhaled nasal steroids; one, nasal cromoglycate; and one had been taking a short course oforal prednisolone. No patient had previously received ipratropium bromide.
Table I
Active Placebo
Periodicclinical reviews Improved
Worse
N o change
10 I
1 3
2 9
Z 2 (Yates correction), n = 13, P < 0.001. STUDY DESIGN
The study consisted of a randomized, double-blind, cross-over trial with two 3-week treatment periods separated by a 1-week washout period. Patients were randomly allocated to either ipratropium bromide (four 20-~g puffs, four times daily) or placebo (four puffs four times daily) in the first treatment period and then crossed over to the alternate regimen for the second treatment period. PERIODIC CLINICAL REVIEW
The patients were evaluated clinically and symptoms were assessed at the beginning and end of each treatment period by the same physician in each case who rated symptoms as improved, unrhanged, or worse. DALLY SYMPTOM SCORES
Each patient also kept a daily symptom score card on which was recorded day-time cough, night-time cough and any associated sputum production, postnasal drip, sneezing, dyspnoea associated with coughing bouts, and wheeze. Each symptom was assessed by the patient on a scale of 0-3 where; 0 = no symptom; 1 = mild; 2 = moderate; and 3 = severe symptoms. Mean daily scores were estimated for each of the 3-week treatment periods. LUNG FUNCTION ASSESSMENT
Pre- and post-bronchodilator (200/zg salbutamol by metered dose inhaler) spirometry was obtained at the beginning and end of each treatment period, in the morning, at least 4 h after trial medication. Measurements of FVC and FEV~ were the best of at least three matched traces provided there was a matching measurement within 5% of this value obtained using either a Godard or a Sensomedics 2400 series watersealed spirometer. Methacholine responsiveness was measured on recruitment and at the completion of the study. If it had become apparent that methacholine responsiveness was changing during the course of the study, later patients were to have received a methacholine dose response curve at the change-over period. We used a modified dosimetric technique with ten-fold serial concentrations ofmethacholine chloride in saline starting with 0.01% and ending with 10%
solution. This was preceded by a saline control inhalation and all concentrations were delivered with a calibrated Bennett's twin nebulizer. The maximal dose delivered in all cases was 1.6mg of methacholine chloride. With this technique, small changes in very low PD20 values would be detected, though small changes in high PD20 values may well not be identified. The PD20 to methacholine obtained by this method in subjects with asthma closely matches the PD20 described by Yan et al. to histamine with up to eight increments delivered by a DeVilbiss (Somerset, Pasadena, U.S.A.) Nebuliser No. 40 (7). In a separate series of seven asthmatic subjects we have found a good correlation between the PD20 using methacholine as in this study and that of Yan et al. using histamine (r 0.89, P
