Treatment of Acute Asthma*

Transcription

1 Treatment of Acute Asthma* Lack of Therapeutic Benefit and Increase of the Toxicity From Aminophylline Given in Addition to High Doses of Salbutamol Delivered by Metered-Dose Inhaler With a Spacer Carlos Rodrigo, M.D.; and Gustavo Rodrigo, M.D. We conducted a randomized, double-blind, placebocontrolled study to determine if intravenous aminophylline adds any benefit to high doses of inhaled salbutamol in patients ho presented for treatment of acute asthma. We studied 94 patients (mean age, 35.6 ± 11.2 years) ith moderate to severe acute asthma. All patients received therapy ith salbutamol delivered ith metered-dose inhaler (MDI) into a spacer device (Volumatic) in four puffs (400 ~ g at ) 10-min interval, and intravenous hydrocortisone (500 mg). Patients ere randomly assigned to receive either a loading dose of intravenous aminophylline folloed by a routine infusion (n=45) or an equal volume of placebo as a loading dose and infusion (n=49). The to groups shoed no differences in measurements of peak expiratory flo, FEV h and FVC at baseline and at the end of treatment. Hoever, the patients treated ith aminophylline had significantly more adverse effects (p<0.05). There ere no differences in the final mean dose of salbutamol (6.3 ± 44.5 mg for the placebo group and 5.8 ± 4.2 mg for the aminophylline group), hospital admission rate (10.2 percent for the placebo group and 9.0 percent for the aminophylline group), and mean duration of Emergency Department treatment (2.5 ± 1.83 h for the placebo group and 2.37 ± 1.75 h for the aminophylline group). The results ere similar hen the patients ere divided in accord ith the degree of respiratory obstruction (baseline FEV 1 <30 percent of predicted) and theophylline level at 30 min of treatment (placebo group patients ith theophylline level<10 mg/l vs aminophylline group patients ith theophylline level > 10 mg/l). We conclude that intravenous aminophylline adds to the toxicity but not the efficacy of inhaled salbutamol in the treatment of acute exacerbations of asthma. (Chest 1994; 106: ) ED=emergency department; FVC=forced vital capacity; MDI=metered-dose inhaler; PEF=peak expiratory flo; Key ords: inhaled salbutamol, intravenous aminophylline, treatment of acute asthma Intravenously administered aminophylline is idely used together ith inhaled {3-agonists in the treatment of patients ith acute exacerbation of asthma. Early studies have established the superiority of adequate doses of {3-agonists over aminophylline, and subsequently studies ere conducted to examine the question of the usefulness of adding aminophylline to optimal {3-agonist therapy in the setting of acute asthma. 1-7 Additionally, the declining use of aminophylline can be attributed to the lack of ell-designed trials that prove aminophylline's efficacy8 and to the narro therapeutic range, side effects, and toxicity The preponderance of evidence suggested that the addition of aminophylline played no useful role, and this thinking is reflected in the recommendations released by the National Heart, Lung, and Blood Institute, National Asthma Educational Program Expert Panel Report on the diagnosis and manage- *From the Centro de Terapia Intensiva, Asociaci6n Espanola 1a en Socorros Mutuos, and the Departamento de Emergencia, Hospital Central de las FF.AA. and Universidad Cat6lica del Uruguay, Montevideo. Manuscript received May 13, 1992; revision accepted March 11, ment of asthma. 13 They have excluded theophylline from the treatment recommendations for the Emergency Department (ED) management of acute asthma exacerbations in children and adults. Hoever, the question has been reopened by three ne studies that suggest that using aminophylline may lead to improved airflo and reduced duration of treatment among patients ith severe asthma.i 4-16 Therefore, e conducted a randomized, doubleblind, placebo-controlled study to determine if intravenous aminophylline adds any benefit to high doses of inhaled salbutamol and intravenous hydrocortisone therapy in patients ho presented for treatment of acute asthma to our ED. Patients METHODS We studied 94 patients ho presented to the ED of Military Hospital from Montevideo, Uruguay, for treatment of an acute exacerbation of asthma. All patients met the criteria of the American Thoracic Society (ATS). 17 The inclusion criteria for patients ere as follos: (1) age beteen 18 and 50 years; (2) peak expiratory flo (PEF) and FEV 1 belo 50 percent of predicted value; (3) excluded ere patients ith history of chronic cough, cardiac, hepatic, renal, or other medical disease, or pregnancy; CHEST /1 06 I 4 I OCTOBER,

2 and (4) an expressed illingness to participate in the study, ith ritten informed consent obtained. The study as approved by the Hospital Ethics Committee. Treatment Regimens Patients ho agreed to participate in. the study received salbutamol delivered ith metered-dose inhaler (MDI) into a spacer device (Volumatic, Allen & Hanburys Ltd, England) in four puffs actuated one at a time, at 10-min intervals (100 JJ.g per actuation). Volumatic is a pear-shaped extension tube of 750 ml and 22 em length ith a one-ay inhalation valve. Each puff as folloed by to deep inhalations from the spacer. They also received hydrocortisone, 500 mg intravenously. At once, patients ere randomly assigned in a double-blind fashion to receive a loading dose of either aminophylline, 5.6 mg/ kg of body eight over 20 min (n=45), or an equivalent volume of placebo (0.9 sodium chloride) (n=49), folloed by a constant infusion of aminophylline, 0.9 mg/ kg/ h, or an equivalent volume of placebo. Each patient as given Oz by nasal prongs at a rate of 4 L /rnin. Measurements The folloing variables ere measured in each patient immediately before starting treatment and, in 30-min intervals until hospital discharge or hospital admission, ithin the first 6 h after presentation: heart rate, respiratory rate, systolic and diastolic blood pressure, PEF, FEY J, FVC, accessory-muscle use, dyspnea, and heezing. Heart rate as measured from continuous electrocardiogram. The PEF as measured ith a flometer (Mini Wright Peak Flometer, Armstrong Industries Inc, Northbrook, Ill). The highest of three values as recorded. The FEY 1 and FVC ere measured using a spirometer (Vitalograph Compact Spirometer, Vitalograph Ltd, Maids Moreton House, Buckingham, UK) that as calibrated daily using a test syringe. Three successive maximal expiratory curves ere recorded at each assessment, and the highest value as selected, according to the criteria of the ATS 18 Accessory-muscle use as defined as visible retraction of the sternocleidomastoid muscles. Dyspnea as defined as the patient's on assessment of breathlessness. Wheezing as defined as musical or histling breath sounds heard ith a stethoscope during expiration. Serum theophylline concentrations ere determined from all subjects pretreatment and at 30 min of treatment after the completion of the loading infusion. Patients ere admitted to the hospital according to standard and accepted guidelines for admission: previous ED treatment ithin 24 h, the self-reported (patient) inability to attain preexacerbation status, if accessory-muscle use as abated, if heezing as judged minimal to complete resolved, if they ere free of dyspnea, and the inability of the patient to alk 20 m ithout exacerbation of symptoms and signs, despite 6 h of ED treatment. The decision to discharge or admit a patient as made by senior ED staff ithout knoledge of previous patient group allocation. At the end of the therapy (either to hospital admission or to home), the patient as asked to indicate the presence or absence of each five symptoms (nausea, palpitations, tremor, anxiety, and headache). To compare side effects in each group, e compiled a composite symptom score for each subject by arbitrarily assigning each symptom a value of l if present and 0 if absent. Thus, for example, a subject ho reported all five symptoms as assigned a score of 5, and a subject reporting no symptoms as assigned a score of 0. Statistical Analysis Standard sample-size calculations for a FEY 1 increase of 18 percent ith a=0.05 and /3=0.20 yielded a necessary sample size of approximately The Mann-Whitney U test, the x 2 test ith Yates' correction, and unpaired Student's t test ere used to compare baseline and discharge data for both patient groups. Changes in PEF, FVC, and FEY 1 ere evaluated using a to-ay analysis of variance ith one beteen-subject factor (placebo- Table!-Baseline Characteristics of Patients* Placebo Aminophylline (n=49) (n=45) p Value Age, yr 35.0 (13.2) 36.2 (9.4) >0.2 Male,% >0.2 Weight, kg 58.6 (11.3) 64.3 (13.2) >0.2 Height, m 1.6 (0.15) 1.6 (0.10) >0.2 Heart rate, beats/ min (15.4) (17.6) >0.2 Blood pressure, mm Hg Systolic (17.4) (16.8) >0.2 Diastolic 78.3 (13.6) 77.4 (14.6) >0.2 Respiratory rate, / min 23.1 (5.7) 22.8 (5.0) >0.2 Predicted PEF, L/ min (61.6) (68.7) >0.2 PEF, mean % of predicted 33.3 (10.6) 30.4 (16.0) 0.1 PEF, L/ min (51.0) (63.8) 0.1 Predicted FVC, L 3.8 (0.86) 3.5 (0.83) >0.2 FVC, mean % of predicted 43.4 (13.6) 38.8 (16.5) >0.2 FVC, L 1.7 (0.56) 1.5 (0.81) >0.2 Predicted FEY 1, L 3.3 (0.82) 3.0 (0.70) >0.2 FEY 1, mean % of predicted 27.7 (9.27) 26.5 (13.7) >0.2 FEV1, L 0.9 (032) 0.7 (0.36) >0.2 Accessory-muscle usef 1.4 (0.58) 1.4 (0.70) >0.2 Dyspneaf 1.7 (0.48) 1.7 (0.68) >0.2 Wheezingf 1.5 (050) 1.6 (0.58) >0.2 Theophylline, mg/ L 3.3 (4.53) 3.5 (4.65) >0.2 Duration of attack, h 30.6 (21.2) 29.4 (30.4) >0.2 *Results are mean values ( ±SD). x 2 categorical variables; Student's t test for normally distributed continuous variables; Mann-Whitney U test for variables ith nonnormal distributions. fwhere 0 denotes absent, 1 mild, 2 moderate, and 3 severe Lack of Benefit, Increased Toxicity from Aminophylline and Salbutamol (Rodrigo, Rodrigo)

3 t)50 c u.. 0 ' / ~- - ' ' 0 ~ " ~; ] l:j AIIII-TWioll [_,,,' ] *' *' 0 "r c :::40 u..30 ~ 3 0 ~ r 11. u r [:.;;: : ::] 80 70,' 11.40,''! ~,' <f. l u30 20 ' ' ' j j j j 0 _, _, J, 0 j L _l l MINUTES MINUTES MINUTES FIGURE 1. Spirometric values (PEF, FEV 1, and FVC) at 0, 30, 60, and 120 min after administration of placebo or aminophylline. The data points are mean values and the brackets represent 1 SD. aminophylline), and one ithin-subject factor (time, baseline, 30 min, 60 min, and end of treatment), ith the Neman-Keul's multiple range test. All probabilities reported are to tailed. All data are reported as mean ± 1 SD. A p value of less than 0.05 as considered statistically significant. RESULTS The to groups ere comparable ith respect for any measured variable (Table 1). The number of patients ho used corticosteroids ithin the past 7 days as 18 (36.7 percent) in the placebo group and 15 (33.3 percent) in the aminophylline group (p>0.2). Tenty-six patients (53.0 percent) used methylxanthines 24 h before presenting in the placebo group, and 21 (47.7 percent) in the aminophylline group (p>0.2). Finally, 31 patients (63.2 percent) had received!3-agonists pretreatment in the placebo group and 29 (65.9 percent) in the aminophylline group (p>0.2). The spirometric values at 30, 60, and 120 min are shon in Figure 1. Mean PEF improved significantly over baseline values for the placebo and aminophylline groups (p<0.001 by analysis of variance). The magnitude of placebo and aminophylline PEF improvements ere significant at 30 min (75.7 ± 46.0 L/ min and 73.1 ±49.2 L/ min, p<0.01), and at the end of treatment (112.4 ± 52.4 L/ min and ± 62.8 L/ min, p<0.01). Mean FVC improved significantly over pretreatment values for both groups (p<0.001). The placebo and aminophylline improvements ere significant at 30 min (0.68 ± 0.44 L and 0.62 ± 0.47 L, respectively, p<0.01) and at the end of treatment (0.94±0.58 Land 0.87±0.54 L, p<0.01). Finally, the same pattern held for changes in FEV 1 : at 30 min, FEV 1 increased 0.51 ± 0.30 L in the placebo group and 0.48 ± 0.38 L in the aminophylline group (p<0.01), and at the end of treatment, FEV 1 rose ± 0.41 Lin the placebo group and 0.68 ± 0.45 Lin the aminophylline group. Hoever, there as no significant difference beteen both groups for any variable at any time point studied. At final disposition, both groups did not present significant differences. The mean duration of ED treatment as 2.50 ± 1.83 h in the placebo group and 2.37 ± 1.75 h in the aminophylline group (p>0.2). The hospital admission rate did not differ beteen both groups; of nine admitted patients, five (10.2 percent) ere from the placebo group and four (9 percent) ere from the aminophylline group (p>0.2 by x 2 test). Similar results ere obtained hen patients admitted to the hospital ere examined separately (Table 2). The final mean dose of salbutamol as 63 puffs, equivalent to 6.3 mg (range beteen 12 puffs or 1.2 mg and 148 puffs or 14.8 mg) for the placebo group and 58 puffs, equivalent to 5.8 mg (range beteen 12 puffs or 1.2 mg and 148 puffs or 14.8 mg) for the aminophylline group (p>0.2). At discharge from the ED, the mean theophylline level in the patients receiving aminophylline as 14.7 ± 7.4 mg/ L (median, 12.0 mg/ L ith an interquartile range of 10 to 17.5 mg/ L), hereas the mean level in the placebo group as 3.3 ± 4.53 mg/ L (median, 2.6 mg/ L ith an interquartile range of 0 to 4.5 mg/ L) (p<0.001). Further, among subjects receiving aminophylline, at 30 min of treatment, 62 percent of discharged patients had theophylline levels of more than 10 mg/ L, and all the admitted patients had theophylline levels of more than 10 mg/ L. Linear regression analysis did not reveal any signif- CHEST /106/4/ OCTOBER

4 Table 2-Characteristics of All Subjects at Final Disposition and of Patients Who Were Admitted* Placebo (n=49) All Subjects Aminophylline (n=45) Admitted p Placebo Aminophylline p Value (n=5) (n=4) Value Age, yr Baseline PEF, mean % of predicted Final PEF, mean % of predicted 56.4 (18.6) 51.3 (16.7) Baseline FVC, mean % o f predicted Final FVC, mean % of predicted 70.4 (19.6) 66.8 (21.8) Baseline FEV1, mean % of predicted Final FEV 1, mean % of predicted 51.2 (17.9) 50.5 (19.5) Emergency department treatment 2.5 (1.83) 2.3 (1.73) duration, h Accessory-muscle use Dyspnea Wheezing 38.6 (11.9) (10.5) > (6.8) 19.0 (11.4) > (14.5) 24.2 (14.3) > (17.7) 38.8 (18.5) >0.2 > (10.3) 42.8 (14.4) > (4.47) 16.5 (7.76) >0.2 > (14.1) 22.5 (12.9) >0.2 > (0.89) 1.5 (0.57) > (0.20) 1.2 (0.95) > (0.54) 1.7 (0.50) >0.2 *Results are mean values ( ± SD ). icant correlation beteen initial and final plasma theophylline concentrations over the course of the study and improvement in FEV 1 in either placebo group or aminophylline group. The patients ere divided in accord ith the theophylline level at 30 min of treatment (placebo group patients ith serum theophylline level <10 mg/ L, n=40, vs aminophylline group patients ith serum theophylline level >10 mg/ L, n=38). There ere no differences in ED treatment duration (2.43± 1.88 hand 2.36± 1.79 h respectively, p>0.2), baseline PEF as mean percent of predicted (34.0 ± 10.9 percent and 29.7 ± 12.8 percent, respectively, p=0.13), final PEF as mean percent of predicted (56.7 ± 19.4 percent and 51.0 ± 17.6 percent, respectively, p=0.17), baseline FEV 1 as mean percent of predicted (28.2±9.55 percent and 27.9±14.4 percent, respectively, p>0.2), and final FEV 1 as mean percent of predicted (53.6 ± 17.0 percent and 51.9±20.9 percent, respectively, p>0.2). When e considered the severity of respiratory obstruction and the theophylline level at 30 min of treatment, there ere no differences beteen groups (placebo group patients ith FEV 1 <30 percent predicted on admission to the ED, and serum theophylline level <10 mg/ L vs aminophylline group patients ith FEV 1 <30 percent predicted on admission to the ED, and serum theophylline level> 10 mg/ L) (Table 3). The overall symptom score in patients treated ith aminophylline (1.2±1.25, mean±sd) as significantly greater than the score in the placebo group (0.65 ± 0.86, p<0.05, Mann-Whitney U test), and there as a higher incidence in four (nausea, palpitation, anxiety, and headache) of five symptoms monitored (Fig 2). Tremor as the most common side effect in the placebo group (30 percent) and nausea as more frequent in the aminophylline group (37.5 percent). Finally, the to groups produced a nonsignificant decrease in the heart rate. At the end of treatment, the placebo group shoed a decrease of ± 11.9 percent (median, 0 percent ith an interquartile range of to 7.00 percent) and the aminophyl- Table 3-Comparison Beteen Placebo Group Patients With FEV 1 <30 Percent Predicted on Admission to the Emergency Department and Serum Theophylline Level <10 mg/ L to Aminophylline Group Patients With FEV1 <30 Percent Predicted and Serum Theophylline Level ~ 1mg/ 0 L* Placebo Aminophylline (n=13) (n=16) p Value Age, yr Emergency d epartment treatment duration, h Final mean dose of salbutamol, mg Baseline PEF, mean % of predicted Final PEF, mean % of predicted Baseline FEVt, mean % of predicted Final FEV 1. mean % of predicted 39.5 (12.5) 36.1 (10.5) > (1.31) 2.5 (1.66) > (31.1) 62.2 (41.4) > (7.5) 18.2 (6. 6) (16.7) 45.9 (13.7) > (5.9) 18.5 (8.0) > (9.9) 49.2 (13.0) >0.2 *Results are mean values ( ± SD) Lack of Benefit, Increased Toxicity from Aminophylline and Salbutamol (Rodrigo, Rodrigo)

5 40 I 0AMINOPHYLLINE I DPLACEBO I en 1- z ~ 30 l:) z (.) a.. 10 NAUSEA PALPITATIONS TREMOR HEADACHE ANXIETY line group shoed a decrease of ± 16.0 (median, percent ith an interquartile range of -13 to 5.0 percent) (p>0.2). DISCUSSION As in previous studies, 2-5 e found that the addition of intravenous aminophylline in standard doses to a regimen of intensive inhaled salbutamol, for moderate to severe acute exacerbations of asthma, does not improve short-term outcome. At final disposition, placebo and aminophylline groups did not differ in airflo, hospital admission rate, and time in the ED. Moreover, combined therapy ith aminophylline and salbutamol did cause a higher incidence of side effects and a significantly higher overall adverse symptom score than did therapy ith salbutamol alone. With respect to the possibility of drug interaction beteen previous therapy and the study treatments as an explanation of these results, e can reject this possibility. Thus, there ere no significant differences hen e considered the severity of respiratory obstruction and the theophylline level at 30 min of treatment. Additionally, e did not find any positive correlation beteen the initial and final plasma theophylline concentrations over the course of the study and the changes in FEV 1. In the same ay, previous treatments ith corticosteroids and /3-agonists did not differ beteen groups. Recently, in a randomized, double-blind, placebocontrolled study, Wrenn et al 16 reported that the administration of aminophylline to acutely symptomatic patients ith asthma or chronic obstructive pulmonary disease markedly decreased hospital admissions. Surprising, the authors also found that adding aminophylline to /3-agonists had no effect on FIGURE 2. Percent of patients ho reported side effects at the end of treatment. pulmonary function, physician assessment of the response of treatment, or time in the ED. It is difficult to understand ho aminophylline could influence hospital admission rates differentially ithout producing identifiable clinical or physiologic differences (or both) beteen groups. One possibility suggested by the protocol is that factors other than, or in addition to, objective measures of severity ere used in deciding hom to admit. Although the authors did not participate in the disposition of the patients, one must onder about the uniformity of the application of the hospital admission criteria by those ho did. 20 Finally, e did not confirm results from Lalla et al, 14 ho found significant differences beteen placebo and aminophylline groups in FEY 1 at 1 h and 4 h of treatment. Nevertheless, this article presents important methodologic problems, the most significant being an inadequate sample size (n=i8). Similarly, the mean theophylline concentration of the aminophylline group obtained after 4 h of treatment as 8.31 ± 2.71, suggesting that many patients of this group ere undertreated. In summary, our study suggests that intravenous aminophylline adds little or nothing to the short-term bronchodilator effect of an inhaled /3-adrenergic agonist in patients ith acute exacerbated asthma. On the basis of this, e conclude that aminophylline is eak and potentially toxic bronchodilator ith a narro therapeutic indo and numerous drug interactions that make its use complicated. It suggests that repeated inhalation of high doses of a /3-adrenergic alone delivery by MDI ith a spacer device (Volumatic) may be the optimal bronchodilator therapy for ED treatment of acute exacerbations of asthma. When the combination of systemically administered corticosteroid and inhaled salbutamol is CHEST I 106 I 4 I OCTOBER,

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