Efficacy of Nebulised Ipratropium in Acute Bronchial Asthma

Transcription

1 ORIGINAL ARTICLE JIACM 2002; 3(4): Efficacy of Nebulised Ipratropium in Acute Bronchial Asthma Praveen Aggarwal*, Onkar Singh**, Jyoti P Wali***, Rohini Handa*, Sada N Dwivedi****, Ashutosh Biswas*****, Naveet Wig***** Abstract Introduction Acute bronchial asthma is a common medical emergency the world over. Nebulisation of β-agonists is the first line therapy in patients with acute asthma. Ipratropium bromide is also being used in patients with acute asthma, though its exact role remains to be defined. The present study is aimed at determining the efficacy of ipratropium in comparison to salbutamol in patients with acute bronchial asthma. Material and methods Sixty-nine patients with acute asthma were studied to determine the efficacy of ipratropium and salbutamol, given alone and in combination. Patients were randomised into 3 groups. Patients in group A and group B received 5 mg salbutamol and 500 µg ipratropium bromide respectively nebulised at 0 and 60 minutes, while group C received combination of 5 mg salbutamol and 500 µg ipratropium bromide at 0 minutes followed by saline at 60 minutes. The patients were monitored for 120 minutes with peak expiratory flow rate and vital signs. Blood gas analysis and electrolytes were obtained at entry and at 120 minutes. Observations The three groups did not differ significantly in age, and baseline vital signs, peak expiratory flow rate, and oxygen saturation. The peak expiratory flow rate increased gradually in all groups but there was no significant difference in the level of bronchodilatation among any group at any time during the study. There were no significant side effects experienced by patients in any of the groups. Furthermore, the requirement of additional medications also did not differ in the 3 groups. Conclusions Ipratropium appears to be an effective bronchodilator in patients with acute asthma. However, no significant benefit of combining ipratropium with salbutamol was found in the present study. Key words Salbutamol, Ipratropium, Nebulisation, Peak expiratory flow rate. Introduction Bronchial asthma is a frequently encountered clinical problem all over the world. In the United Kingdom, about 5% of the adults and 10% of children have asthma 1. Even in the absence of any reliable national data, it is conceivable that the situation in India may not be very different. Despite * Additional Professor ** Senior Resident *** Professor **** Additional Professor (Biostatistics) ***** Assistant Professor Department of Medicine, and Biostatistics All India Institute of Medical Sciences, New Delhi better understanding of the disease pathophysiology over the last two decades, there appears to be an increase in the morbidity and mortality due to asthma 2. Inhaled β-agonists are widely used in the treatment of acute asthma. Though anticholinergic agents have been used in the traditional medicinal cultures of many countries, their use in the past was limited by their multiple side effects. Interest in their use has returned with understanding of the role of cholinergic mechanism in the control of airway calibre, and the development of synthetic anticholinergic agents like ipratropium bromide, that are topically active but much less prone to produce side effects. Since different classes of

2 bronchodilators promote smooth muscle relaxation via different intracellular pathways, it is reasonable to compare their effects in the initial management of acute bronchial asthma and to see whether combination of two or more bronchodilators might be more effective than the individual agents. While some studies have found inhaled ipratropium to be an effective bronchodilator in acute asthma, others have reported it to have no additional benefit when combined with beta-adrenergic agents. The present study was conducted in acute asthmatic patients (1) to study the bronchodilator effect of nebulised ipratropium bromide, and (2) to compare the efficacy of combined nebulisation of salbutamol and ipratropium bromide with either of these agents given alone. Material and methods Eligibility criteria : Adult patients with acute bronchial asthma presenting to the emergency room of the All India Institute of Medical Sciences, a tertiary care hospital, were included in the present study. Patients of acute asthma presenting during working hours were considered for inclusion in the study. A patient was considered to be asthmatic if he/she had been previously diagnosed or treated for bronchial asthma, or had history and findings suggestive of bronchial asthma as defined by the American Thoracic Society Criteria 3. Case definition for acute asthma was dyspnoea and wheeze in a known asthmatic patient with deterioration of his usual symptoms. Patients between the ages of 13 to 50 years who were able to perform repeated peak flow tests were included in the study. Patients with one or more of the following were excluded: associated other respiratory conditions like pneumothorax or pneumonia, cardiac or any other major illness detected historically or on clinical and/or radiological examination; glaucoma defined as a patient with gradually diminishing vision, raised intra-ocular tension as judged by digital tonometry, or a diagnosed case of glaucoma; features suggestive of prostatic hyperplasia; and pregnant patients. Assessment of the patients : On arrival at the emergency room, a detailed history was taken and clinical examination performed to rule out any associated illness. Medications received by the patient within 24 hours prior to their visit were recorded. The degree of spasm was determined both subjectively and objectively. Dyspnoea was graded on Borg s scale (0-10), 0 being no breathing difficulty and 10 being the maximum difficulty 4. For objective assessment, peak expiratory flow rate (PEFR) was measured as the best of three readings using a mini Wright s peak flow metre. The same instrument was used in the entire study. Pulse, blood pressure, and presence of pulsus paradoxus above 10 mmhg were recorded. Accessory-muscle use was graded in a scale from 0 to 3 in which 0 denotes absent, 1 mild, 2 moderate, and 3 severe use 5. The severity of asthma was ranked according to the Hedstrand s scale 6,7. Blood gases, acid-base status, and electrolytes were analysed in all patients using AVL autoanalyser. Randomisation, medication, and assessment of response : After fulfilling the inclusion criteria, patients were randomly allocated to three groups. For randomisation of the patients into three groups, random numbers were drawn from the random number table to decide allocation group of patients well in advance. The drugs were administered by ultrasonic nebuliser over a period of 5 minutes in the following dosages: Group A - 5 mg salbutamol at 0 and 60 minutes; Group B µg ipratropium bromide at 0 and 60 minutes; Group C - 5 mg salbutamol and 500 µg ipratropium bromide at 0 minute followed by saline nebulisation at 60 minutes. Each nebulisation solution was prepared in 4 ml normal saline. All the clinical parameters and PEFR were recorded at 0, 15, 60, 75, and 120 minutes. Blood gases and electrolytes were determined at 120 minutes. At the end of the study, all the patients were treated as per the 354 Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December 2002

3 instructions of emergency physicians. Additional medications administered during the present visit till discharge from the emergency room or admission to the hospital were recorded. All the patients received oxygen at 4 L/minute throughout the study. If considered necessary, patients were administered hydrocortisone intravenously by the treating physician. If any patient deteriorated any time during the study, he was withdrawn from the study. Side effects developed by patients during the study were recorded. Statistical methods : The data was analysed using appropriate statistical methodology. Descriptive statistics (range, mean, and standard deviation) were calculated for each quantitative variable. Comparisons between groups related to qualitative data (number of ex-smokers, number of patients not receiving any treatment) were done by chi square (with Yates correction) or Fisher s Exact test. In case of more than two groups, if assumptions fulfilled, qualitative data were compared using chi-square test. Since normality assumption was fulfilled in relation to quantitative variables, their comparison between three groups was carried out through one-way analysis of variance (ANOVA). Since comparison of baseline results between three groups did not show significant difference (p > 0.05), the results at a given point of time between groups were compared to assess changes in them. To assess the normality, as a rule of thumb, equality of mean, median, and mode was assessed (results not reported). In case of even moderate deviation from normality, this test is robust to provide reliable results. Similarly, to compare quantitative data over time within a group, two-way ANOVA was carried out to compare results over a period of time. In case of significant results under analysis of variance, Tukey s multiple range test was carried out to identify the pairs of observations having significantly different results. The results were considered significant at 5% level, i.e., p < Results Seventy patients were enrolled for the study and were randomised into three groups. There were 25 patients in group A, 22 in group B, and 23 in group C. One patient from group B was withdrawn from the study due to worsening of dyspnoea. The groups did not differ significantly as regards their present age, age at onset of asthma, history of smoking in the past, duration of the present episode of acute asthma, dyspnoea score as graded by modified Borg s scale (0-10), and taking some treatment at home before presentation. None of the patients received aminophylline or nebulisation before presenting to our hospital. These observations are shown in table I. The effect of treatment on pulse, blood pressure, and PEFR is shown in table II. The changes in the pulse rate within the group were not significant. However, when the groups were compared with each other, group B patients showed a greater reduction in the pulse rate compared to group A and C at all periods of time after initiation of treatment (p < 0.05). The changes in blood pressure and respiratory rate were not significant when various groups were compared to each other. Asthma severity as measured by the Hedstrand s scale, also did not show any significant difference among the various groups. There was a significant rise (p < 0.05) in PEFR at the end of 120 minutes in all the three groups (Fig. 1). Increase in PEFR between the groups was tested by analysis of variance at different time intervals and this was not found to be significant (p > 0.05). Even at 60 minutes, there was no significant difference in increase in PEFR between group A and group C. Data was also analysed by comparing patients with severe asthma (as defined by initial PEFR below 140 L/min). There were 16 patients in group A, 13 in group B, and 14 in group C who had PEFR < 140 L/min at the time of presentation; however, no significant difference was found among various groups as regards their response to the medications. Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December

4 Table I : Baseline characteristics of the patients in various groups. Parameter Group A (n=25) Group B (n=21) Group C (n=23) Age in years (mean ± SD) 31.5 ± ± ± 8.9 Male : female (numbers) 12:13 10:11 8:15 Age (in years) at onset of 19.3 ± ± ± 8.7 asthma (mean ± SD) Number of ex-smokers Duration (in hours) of present attack 14.3 ± ± ± 7.6 (mean ± SD) No. of patients who took some treatment at home for the present attack Dyspnoea score (Borg s scale) Moderate (score : 3-5) Severe (score : 6-7) Very severe (score : 8-10) Asthma severity (Hedstrand s scale) 2.5 ± ± ± 0.81 Table II : Changes in pulse rate, blood pressure, and peak expiratory flow rate (PEFR) during treatment. Groups Time (minutes) Pulse rate (per minute) Group A 103.6± ± ± ± ±14.3 Group B 101.1± ± ± ± ±9.4 Group C 110.7± ± ± ± ±15.3 A vs. B (p value) n.s < 0.05 < 0.05 < 0.05 < 0.05 B vs. C (p value) n.s. < 0.05 < 0.05 < 0.05 < 0.05 A vs. C (p value) n.s. n.s. n.s. n.s. n.s. Blood Pressure (systolic/diastolic) in mmhg Group A 124.2/ / / / /80.4 Group B 119.8/ / / / /80.0 Group C 112.9/ / / / /79.6 A vs. B (p value) n.s. n.s. n.s. n.s. n.s. B vs. C (p value) n.s. n.s. n.s. n.s. n.s. A vs. C (p value) n.s. n.s. n.s. n.s. n.s. PEFR (L/minute) Group A 131.4± ± ± ± ±120.5 Group B 156.4± ± ± ± ±106.3 Group C 143.5± ± ± ± ±118.2 A vs. B (p value) n.s. n.s. n.s. n.s. n.s. B vs. C (p value) n.s. n.s. n.s. n.s. n.s. A vs. C (p value) n.s. n.s. n.s. n.s. n.s. n.s. = not significant. 356 Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December 2002

5 The arterial oxygen tension was found to be reduced at the time of presentation in each of the three groups (mean of 77.8 mmhg, 76.5 mmhg, and 77.4 mmhg in group A, B, and C respectively). At the end of two hours of the study, there was significant (p < 0.05) improvement in PaO 2 in each of the three groups. However, there was no significant difference (p > 0.05) among the groups. Potassium levels fell significantly in group A patients (from 3.93 ± 0.33 meq/l to 3.63 ± 0.38 meq/l). The changes in potassium concentration in other two groups were not significant. No significant side effects were noted in any of the patients during the study. Prior to discharge, further treatment was required in 14, 13, and 11 patients in group A, B, and C respectively. Parenteral steroids were administered during the study in 14, 10, and 11 patients respectively. All the three groups were comparable in regard to their requirement of additional drugs during their stay in the emergency department (p > 0.05). The mean duration of their stay in the emergency room was 3.5 hours in group A, 3.02 hours in group B, and 3.9 hours in group C. This difference was not significant statistically. Only one patient (group B) required admission to the hospital. Discussion In recent years, there has been renewed interest in the use of anticholinergic bronchodilator agents, particularly since ipratropium became Fig. 1 : Percent changes in PEFR from baseline at different times. available. This agent has a favourable ratio of bronchodilator action to extra-bronchial side effects. It has been well established that inhaled anticholinergics are effective medications for the patients with chronic obstructive airway disease. In comparison, the precise role of anticholinergics in the management of acute asthma remains controversial. We conducted the present study in order to clarify the role of ipratropium nebulisation in patients with acute asthma. The study showed that nebulisation of ipratropium is as effective as salbutamol, a β- agonist. Combination of these two agents does not appear to add to the efficacy of the individual agents. Some of the studies conducted in 1980s showed ipratropium and a β-agonist to be equally effective in patients with acute asthma On the other hand, Karpel et al 11 and Watson et al 12 found a β-agonist to be more effective than an anticholinergic agent. On the whole, a metaanalysis published in 1993 concluded that anticholinergics should not be used alone to treat acute asthmatic exacerbations 13. The present study however, has indicated that nebulised ipratropium is as effective as salbutamol in patients with acute asthma. Studies comparing the combination therapy (ipratropium and a β-agonist) with a β-agonist alone have also provided conflicting results. Higgins et al 14 reported no difference in peak expiratory flow rate after treatment with either nebulised salbutamol alone or salbutamol and ipratropium. Three large double-blind randomised trials reported recently from USA 15, Canada 16, and New Zealand 17 have not provided uniform results. Lanes et al 18 analysed the data of these three studies and reported that addition of ipratropium bromide to salbutamol in the treatment of acute asthmatic patients produced small but insignificant improvement in lung functions, but then reduced the need for additional treatment, as also subsequent asthma exacerbations, and hospitalisation. As these major studies have been published from different continents with different population groups, we performed the study on Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December

6 Indian patients. In the present study, no significant difference was found over a 120-minute period among three groups with acute asthma treated with salbutamol, ipratropium, or their combination. However, the benefits of combination therapy persisted till 120 seconds despite administering only one dose at the beginning of the study. It is possible that nebulising a second dose of combination therapy at 60 minutes (as was done in other two groups) would have produced results in favour of the combination therapy. This has been shown in a study published recently 5. Stoodley et al 19 analysed data from 10 recent studies, reporting on a total of 1,377 patients with asthma. Compared with placebo, the use of ipratropium was associated with a pooled 7.3% improvement in FEV 1, corresponding to an absolute improvement in FEV 1 in the ipratropium/ β-agonist group, which was 100 ml above that seen for the group that received β-agonist only. Similarly, the pooled estimate of treatment effect in trials that reported data as PEFR was 22.1%, corresponding to an absolute PEFR improvement of 32 L/min in favour of the ipratropium/β-agonist combination group. Further, it was found that studies enrolling patients with more severe airflow obstruction showed greater absolute benefits of combination bronchodilator therapy. For the 3 trials reporting hospital admission data (n = 1,031), patients receiving ipratropium also had a relative risk of hospitalisation of 0.73 compared to β-agonist group. The use of ipratropium was not associated with any severe adverse effects when used in conjunction with β 2 -agonist. The authors concluded that though the significance of modest additional bronchodilatation with ipratropium is unclear, it would seem reasonable to recommend the use of combination ipratropium/beta-agonist therapy in acute adult asthmatic exacerbations. This is supported by a recent study in which repeated inhalations of salbutamol and ipratropium were administered and compared with repeated inhalations of salbutamol and placebo 5. The study showed that the combination therapy using frequent inhalations of drugs produced a substantial benefit compared to the placebo group, particularly in patients with FEV 1 less than 30% and with long duration of symptoms before presentation. In the present study, we could not find any significant difference in the response to treatment when patients with severe asthma (PEFR < 140 L/min) were compared. Since only one patient required hospitalisation, we were unable to make any comment on the role of ipratropium in reducing the rate of hospitalisation. In another systematic review of 10 randomised controlled trials conducted in children and adolescents with acute asthma 20, it was concluded that adding multiple doses of anticholinergics to beta agonists was safe, improved lung function, and reduced hospital admission, particularly in patients with severe asthma. Conclusion The present study indicated no significant difference between the efficacy of nebulised ipratropium and salbutamol in patients with acute asthma. There appears to be no benefit of adding ipratropium to salbutamol in the treatment of these patients. However, conducting a similar study on larger number of patients particularly with repeated doses of the combination therapy is required to draw difinitve conclusions. References 1. Pearson MG. Asthma guidelines. Who is guiding whom and where to? Thorax 1993; 48: Gergen PJ, Weiss KB. The increasing problem of asthma in the United States. Am Rev Respir Dis 1992; 146: American Thoracic Society: Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease and asthma. Am Rev Respir Dis 1987; 136: Borg G, Linderholm H. Exercise performances and perceived exertion in patients with coronary insufficiency, arterial hypertension and vasoregulatory asthenia. Acta Med Scand 1970; 187: Rodrigo GJ, Rodrigo C. First-line therapy for adult patients with acute asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the emergency department. Am J Respir Crit Care Med 358 Journal, Indian Academy of Clinical Medicine Vol. 3, No. 4 October-December 2002

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