Comparison of albuterol delivered by a metered dose

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1 Comparison of albuterol delivered by a metered dose inhaler with spacer versus a nebulizer in children with mild acute asthma Suzanne Schuh, MD, FRCP(C), David W. Johnson, MD, Derek Stephens, MSc, Sheilagh Callahan, RN, Patricia Winders, RN, and Gerald J. Canny, MD, FRCP(C) Objective: In children with mild acute asthma, to compare treatment with a single dose of albuterol delivered by a metered dose inhaler (MDI) with a spacer in either a weight-adjusted high dose or a standard low-dose regimen with delivery by a nebulizer. Study design: In this randomized double-blind trial set in an emergency department, 90 children between 5 and 17 years of age with a baseline forced expiratory volume in 1 second ( ) between 50% and 79% of predicted value were treated with a single dose of albuterol, either 6 to 10 puffs (n = 30) or 2 puffs (n = 30) with an MDI with spacer or 0.15 mg/kg with a nebulizer (n = 30). Results: No significant differences were seen between treatment groups in the degree of improvement in percent predicted (P =.12), clinical score, respiratory rate, or O 2 saturation. However, the nebulizer group had a significantly greater change in heart rate (P =.0001). Our study had 93% power to detect a mean difference in percent predicted of 8 between the treatment groups. Conclusion: In children with mild acute asthma, treatment with 2 puffs of albuterol by an MDI with spacer is just as clinically beneficial as treatment with higher doses delivered by an MDI or by a nebulizer. (J Pediatr 1999;135:22-7) Inhaled β2 agonists are first-line therapy for children with acute asthma exacerbations. Although these drugs are often delivered by wet nebulizers, this method has a number of disadvantages including high cost, need for an external power source, and inefficient drug delivery to the lung. 1-3 In contrast, me- From the Divisions of Emergency, Clinical Pharmacology, Chest, and Clinical Epidemiology, the Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Supported by grants from Physicians Services Incorporated, Trudell Medical, The Hospital for Sick Children Foundation and Department of Paediatrics, The Hospital for Sick Children. Submitted for publication Feb 2, 1998; revisions received Sept 29, 1998, and Jan 26, 1999; accepted Feb 5, Reprint requests: Suzanne Schuh, MD, FRCP(C), Emergency Department, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. Copyright 1999 by Mosby, Inc /99/$ /21/97894 tered dose inhalers are less expensive, less likely to be contaminated, extremely portable, and less time-consuming to use compared with nebulizers. 4 When a spacer is added to an MDI, drug deposition in the lower airways increases 2,5 with a corresponding tenfold decrease in oropharyngeal deposition. 2,3 The changes in deposition resulting from the use of a spacer mean that lower doses of β2 agonists are required when MDIs with spacers are used compared with nebulizers. Because of their advantages, MDIs with spacers are widely used, particularly in medical offices and home settings. The appropriate dose of albuterol to be used by MDIs with spacers in acute asthma has not been determined. Most previous research articles examining the issue of dosage have dealt with adults, 6-8 and most have various methodologic problems. The few existing pediatric studies also have inherent limitations. 9,10 ED See related articles, p. 5 and p. 28. Emergency department Forced expiratory volume in 1 second The standard recommended dose of albuterol with an MDI is 2 puffs (100 µg/puff) every 4 hours. 11 Although recent evidence suggests the need for a higher dosage (30 µg or 0.3 puffs/kg/ dose) in children with severe asthma both in the inpatient setting 12 and in the 22

2 THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 1 SCHUH ET AL emergency department, 13 the necessity for this aggressive approach in children arriving in the ED with a relatively mild episode remains to be determined. The objective of this study was to compare in children with mild acute asthma exacerbations clinical improvement after albuterol administration by an MDI with spacer, both the standard 2-puff dose and a higher, weight-adjusted dose, with the commonly used nebulizer dose of 0.15 mg/kg. METHODS The study design was a single-dose, double-blind, randomized, tripledummy trial with 3 treatment arms. One group (subsequently referred to as the higher dose MDI group ) received 6 to 10 puffs (100 µg/puff) of albuterol by an MDI (Glaxo Wellcome, Canada) with a clear plastic 140 ml spacer device with a mouthpiece (Aerochamber, Trudell Medical, London, Ontario, Canada). Children weighing <25 kg received 6 puffs, those between 25 and 34 kg received 8 puffs, and those weighing >34 kg received 10 puffs. 13 A second group (subsequently referred to as the low-dose MDI group ) received the standard dose of 2 puffs of albuterol with the previously described MDI with spacer irrespective of weight. A third group (subsequently referred to as the nebulizer group ) received 0.15 mg/kg albuterol (maximum 5 mg) (Glaxo-Wellcome, Canada) by a jet nebulizer (Whisper Jet, Intec Medical, Engelwood, Colo). To facilitate blinding, 2 MDIs were used for each patient. Subjects in the high- and low-dose MDI groups received 2 puffs of albuterol from MDI number 1, whereas those in the nebulizer group received 2 puffs of placebo from this MDI. Subjects in the highdose MDI group then received 4 to 8 puffs of albuterol from MDI number 2, whereas subjects in the other 2 groups received 4 to 8 puffs of placebo from MDI number 2. This treatment was immediately followed by wet nebulizer therapy with albuterol (nebulizer group) or a placebo (MDI groups). The MDIs containing the albuterol and the placebo were identical in appearance, and both their contents and the nebulizer solutions were indistinguishable by taste, color, or smell. The study took place in the ED of The Hospital for Sick Children, Toronto, between October 1994 and February Subjects included were children aged 5 to 17 years having an asthma exacerbation who arrived for care between 8 AM and 10 PM, who were able to reliably perform pulmonary function testing, and who had baseline forced expiratory volume in 1 second between 50% and 79% of the predicted value. We excluded children who had an of <50% because we thought it was unethical to treat patients this sick with only 2 puffs of albuterol. Also excluded were patients with their first wheezing episode, those who had used albuterol within 4 hours of the current visit, those with concurrent cardiopulmonary disease, and patients with known or suspected hypersensitivity to albuterol. Informed consent was obtained for all participants, and the study was approved by the ethics committee of the hospital. Two fully trained and experienced research nurses (S.C. and P.W.) enrolled all patients and performed all observations. The randomization code was generated by the hospital pharmacy from a standard table of random numbers in blocks. The code was used by the pharmacy to produce sequential patient packages containing the study drugs that were indistinguishable as to the assigned treatment group. The randomization code was not made available to anyone outside the pharmacy until after the study was complete. After each patient arrived in the ED and initial assessment was performed by the ED staff, the research nurses evaluated each child for study eligibility and, if eligible, obtained informed consent and completed a questionnaire regarding demographics, details of the present episode, and medications taken before arrival. After baseline measurements of pulmonary function, respiratory rate, heart rate (Physiologic Lifepack 8), and room air O 2 saturation by pulse oximetry (Nellcor Inc, Hayward, Calif) were taken and assessment of clinical severity by a modified clinical score was performed, 13 each child was instructed as to proper inhalation technique. The technique used was the deep-breathing technique, with a 5-second breath held after each actuation. This technique is known to result in optimal drug delivery. 3 The research nurses then administered 2 puffs from MDI number 1 and 4 to 8 puffs from MDI number 2. Care was taken to shake the MDIs between each puff, and the delivery of each puff was followed by 5 to 6 normal breaths through the mouthpiece to ensure adequate recovery between puffs. Albuterol or placebo mixed with 3 ml of normal saline solution was next given by the nebulizer with an oxygen flow of 6 to 8 L/min over a 15- to 20- minute period. A tight-fitting plastic face mask was used. To avoid any potential confounding effects, neither corticosteroids nor other bronchodilators were administered during the study. The primary outcome measure for the study was percent predicted. Pulmonary function was measured with a portable, battery-operated, handheld spirometer (PK Morgan Ltd, Kent, United Kingdom). After initial demonstration and teaching, was performed in sets of 6 and expressed as a percentage of that predicted for height and sex. 14 The highest value in each set was used for the analysis. Secondary outcomes included respiratory rate, heart rate, room air oxygen saturation, and accessory muscle, wheezing, and dyspnea scores. 15 These outcomes were measured before treatment and 30, 60, and 90 minutes after experimental therapy. Hospital disposition, additional treatment, and discharge medications were deter- 23

3 SCHUH ET AL THE JOURNAL OF PEDIATRICS JULY 1999 Fig 1. Mean absolute improvement (±SEM) of percent predicted from baseline in groups. Closed triangles, wet nebulizer. Closed circles, high-dose MDI group. Closed squares, low-dose MDI group. mined by ED pediatricians not involved in the study. Side effects reported by the patients or observed by the research nurses were recorded. The nurses also questioned each patient regarding the preferred method of drug administration for future home use. Each family was contacted by telephone 72 hours after discharge to see whether there had been any further unscheduled medical visits or hospitalizations for asthma at this or another institution since the experimental treatment was performed. Our primary analysis was based on the intent-to-treat principle. The primary outcome was analyzed by multivariate analysis of covariance, which allowed an examination of the changes in the percent predicted among the 3 groups over time with adjustments for weights and baseline values. The secondary analyses included ANOVA on the secondary variables. (Normal probability plots for each continuous variable were constructed to ensure each was normally distributed.) Chi-squared or Fisher s exact tests were used as appropriate to examine differences in proportions between treatment groups. All statistical tests were 2-tailed. We determined a priori that a clinically important difference among groups in the mean improvement in percent predicted was at least 8. Given this difference, an estimated SD in the control group of 10, an α of.05, and a β of.10, we calculated that we would need to enroll 30 subjects per group, or a total of 90 subjects. 16 Furthermore, each patient was defined as an excellent responder if the percent predicted improved by at least 15 from baseline to 90 minutes and as a poor responder if improved by <5. RESULTS During the study period from October 1, 1994, to February 28, 1997, approximately 6000 children were given the diagnosis of wheezing in our ED. Of these, 3853 were excluded because they were too young for the study. Further exclusions comprised 152 patients who were unable to perform spirometry, 240 patients with an 80% or more of the predicted, 200 children with a percent predicted <50, 58 children who had no history of wheezing or bronchodilator therapy, 68 patients excluded because of al- buterol use within 4 hours, 9 children with associated medical problems, 6 children whose families had a limited command of the English language, and 23 who refused to participate. A total of 394 subjects were excluded because of arrival outside of study hours and 11 children who were missed because the study nurses were not notified. Ninety patients were enrolled, and 30 were randomized to each of the 3 groups. Randomization produced groups that were equivalent with respect to demographics, baseline severity, history of present illness, history of hospitalizations, atopy, or medications taken before arrival (high dose group, mean age 9.1 years, baseline 63.1%; low dose group, mean age 8.9 years, 62.4%; nebulizer group, mean age 9.6 years, 63.0%). Sixteen patients had an unintended deviation from the study protocol in that they had received low-dose albuterol by MDI within 4 hours (mean dose 2.1 puffs within a mean of 2.7 hours; high dose group = 6, low dose group = 2, nebulizer group = 8). Subanalysis of the patients with and without this protocol deviation demonstrated no significant differences from the overall intent-to-treat analysis; hence, only the latter group is reported in the following text. Comparisons of percent predicted among the 3 groups revealed no significant differences (Fig 1). Inclusion of the subjects weights and their baseline did not qualitatively change the comparison among treatment groups. The comparisons among treatment groups for the secondary outcomes are listed in the Table. No significant differences were seen among treatment groups for these outcomes except for heart rate. The nebulizer group had a significantly higher heart rate at each assessment time (Fig 2). There were 19 excellent responders in the trial: 9 (30%) of 30 in the high dose MDI group, 4 (13%) of 30 in the low dose MDI group, and 6 (20%) of 30 in the nebulizer group. A 24

4 THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 1 SCHUH ET AL total of 31 children responded poorly : 11 (37%) of 30 in the high dose group, 13 (43%) of 30 in the low dose group, and 7 (23%) of 30 in the nebulizer group (P =.23). At the conclusion of the study, 53 children received more than 1 further nebulization of albuterol in the ED (17 [57%] of 30 in the high dose group; 22 [73%] of 30 in the low dose group, and 14 [47%] of 30 in the nebulizer group; P =.11). Forty-seven children were given oral steroids while in the ED: 16 (53%) in the high dose group, 18 (60%) in the low dose group, and 13 (43%) in the nebulizer group (P =.4). Discharge medications included oral corticosteroids in 56 patients (18 [60%] in the high dose group, 19 [63%] in the low dose group, and 19 [63%] in the nebulizer group) and inhaled corticosteroids in 49 children (19 [63%] in the high dose group, 15 [50%] in the low dose group, and 15 [50%] in the nebulizer group). Of the 84 patients discharged, 55 went home receiving 2 puffs of albuterol 4 times daily, whereas 29 were prescribed the higher albuterol dose (0.2 to 0.3 puffs/kg per dose) by an MDI with spacer, depending on the attending physicians clinical judgment (9 in the high dose group, 13 in the low dose group, 7 in the nebulizer group; P =.17). Six children were hospitalized: 1 in the high dose group, 3 in the low dose group, and 2 in the nebulizer group. Telephone follow-up revealed that 5 patients had unscheduled medical visits because of relapse (2 in the high dose group, 1 in the low dose group, 2 in the nebulizer group), of whom 2 were hospitalized. Virtually all families preferred the MDI with spacer for future use (81 of 90). Side effects occurred in only 4 children: 1 patient with a mild tremor (nebulizer group), 1 child with headache (high dose group), 1 subject with vomiting (nebulizer group), and 1 child with tremor, vomiting, and headache (low dose group). None of the side effects caused termination of Fig 2. Mean increase in heart rate (beats per minute ± SEM) from baseline in groups. Closed triangles, wet nebulizer. Closed circles, high-dose MDI group. Closed squares, low-dose MDI group. Table. Secondary outcome measures: mean changes (±SD) from baseline to 90 minutes Measure High dose Low dose Nebulizer P value Respiratory rate (breaths/min) 0.7 ± ± ± Heart rate (beats/min)* +3.4 ± ± ± Oxygen saturation % (room air) +0.6 ± ± ± 1.6 Accessory muscle score 0.5 ± ± ± Wheeze score 0.5 ± ± ± Dyspnea score 0.3 ± ± ± or a significant delay in the experimental therapy, and all side effects had resolved by the end of the trial. DISCUSSION In this pediatric trial outpatients with mild acute asthma treated with a low dose of albuterol (200 µg) by MDI with spacer had a similar improvement in percent predicted to those children prescribed doses 3 to 5 times higher by an MDI and those treated by nebulizer. Furthermore, with the exception of changes in heart rate, no significant differences were seen among the 3 groups in outcome measures at 90 minutes. Several adult studies have attempted to determine the albuterol dose needed by MDI to achieve effectiveness comparable to the standard nebulizer doses, with disparate results. The equivalent dose response ratio of MDI to nebulizer ranges from 1:1 to 1: ,17,18 A number of pediatric studies have also examined this issue in both outpatients and inpatients, with the equivalent dose MDI to nebulizer response ratios ranging between 1:1 and 1: ,19-21 Many of these studies have methodologic limitations such as small sample size, 11,19 lack of blinding 10 or single blinding, 12 use of subjective outcomes, 10 or a brief observation period. 13,20 Most of these trials suggest that MDI therapy is equivalent to de- 25

5 SCHUH ET AL THE JOURNAL OF PEDIATRICS JULY 1999 livery by nebulizer, with 2 showing that an MDI may be superior. 19,20 No studies have compared the efficacy of nebulizer treatment with that of low- and high-dose MDI therapy. In our study larger patients improved as much after 2 puffs of albuterol as smaller children. Our results are consistent with those of Tal et al, 22 who showed that adults deposited a higher proportion of the inhaled drug in the lung than small children, resulting in a comparable weight-adjusted dose. This result implies that at least for our study population, the dose delivered by MDI does not require adjustment for weight. Neither the low dose nor the high dose MDI groups had any side effects. The sustained increase in the heart rate in the nebulizer group had also been reported by other authors 13,21 and is likely the result of greater deposition, pooling, and delayed absorption of albuterol from the upper airway. Although no significant differences were seen among any of the treatment groups, the low dose MDI group had a smaller improvement in percent predicted and consequently fewer excellent and more poor responders. Did our study have adequate power to detect a clinically important difference? Our study had 93% power to detect a difference among treatment groups of percent predicted of 8, and we think that smaller differences among treatment groups are not likely to be clinically significant. One limitation of our study is that we used a nebulizer that generates a comparatively low proportion of particles in the respirable range of 1 to 5 mm as opposed to other nebulizers currently on the market, 23 and we used a mask instead of a mouthpiece, which results in less deposition in the lung. 24 A second limitation of our study was the inclusion of 16 children who were treated with bronchodilators within 4 hours of study treatment. However, it is unlikely that their inclusion biased our results. First, a subanalysis without these patients demonstrated no significant differences from the intent-totreat analysis. Second, because only 2 of these 16 children were randomized to the low dose MDI group, whereas 14 were randomized to the other 2 groups, this should have biased our results, if anything, toward finding a treatment difference. The main limitation of our study, however, is the restricted generalizability to children with relatively mild asthma exacerbations. The mild baseline severity of disease in our population is the most likely explanation for our not finding significant differences among the treatment groups. A higher dose of albuterol by MDI with a spacer is probably required when treating children with severe acute asthma. 13 Although it would have been ideal to include sicker subjects, we thought it was not ethical to do this. Our findings, however, can probably be generalized to the treatment of children with mild symptoms of asthma in the home. In children with mild acute asthma, treatment with 2 puffs of albuterol by an MDI with a spacer is just as clinically beneficial as treatment with higher doses of albuterol delivered by an MDI with a spacer or by a nebulizer. We thank Dr Allan Coates for his helpful comments, our medical and nursing colleagues for their cooperation, and Michelle McKenna and Andrea Giggey for typing this article. REFERENCES 1. Newman SP, Clarke SW. Therapeutic aerosols-physical and practical considerations. Thorax 1983;38: Newman SP, Millar AB, Lennard- Jones TR, Moren F, Clarke SW. Improvement of pressurized aerosol deposition-with nebuhaler spacer device. Thorax 1984;39: Newhouse MT, Dolovich MB. Control of asthma by aerosols N Engl J Med 1986;315: Canny GJ, Levison H. Aerosols: therapeutic use and delivery in childhood asthma. Ann Allergy 1988;60: Newman SP, Pavia D, Moren F, Sheahan NF, Clarke S. Deposition of pressurized aerosols in the human respiratory tract. 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In: Hardman JG, Limbard LE, editors. Goodman and Gilman s the pharmacologic basis of therapeutics. 9th ed. New York: Mc- Graw-Hill; p Parkin P, Saunders NR, Diamond A, Winders PM, MacArthur C. Randomized trial spacer vs nebulizer for acute asthma. Arch Dis Child 1995;72: Kerem E, Levison H, Schuh S, O Brodovich H, Reisman J, Bentur L, Canny G. Comparison of nebulizer vs nebuhaler for the delivery of albuterol in acute childhood asthma. J Pediatr 1993;123: Weng T, Levison H. Standards of pulmonary function in children. Am Rev Respir Dis 1969;99: Kerem E, Canny G, Tibshirani R, Reisman J, Bentur L, Schuh S, Levison H. Clinical-physiological correlations in acute asthma. Pediatrics 1991;87: Fleiss J. The design and analysis of clinical experiments. Appendix A-2. New York: John Wiley & Sons; Calacone A, Afilalo M, Wolkove N, Kreisman H. A comparison of albuterol administered by metered dose 26

6 THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 1 SCHUH ET AL inhaler or wet nebulizer in acute asthma. Chest 1993;104: Salzman GA, Steele MT, Pribble JP, Elenbaas RM, Pyszczynski DR. Aerosolized metaproterenol in the treatment of asthmatics with severe airflow obstruction: comparison of two delivery methods. Chest 1989;95: Fuglsang G, Pederson S. Comparison of nebuhaler and nebulizer treatment of acute severe asthma in children. Eur J Respir Dis 1986;69: Lin YZ, Hsieh KH. Metered dose inhaler and nebulizer in acute asthma. Arch Dis Child 1995;72: Chow K, Cunningham SJ, Crain EF. Metered-dose inhalers with spacers vs nebulizers for pediatric asthma. Arch Pediatr Adolesc Med 1995;149: Tal A, Golan H, Graver N, Aviram H, Albin D, Quastel MR. Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction. J Pediatr 1996;128: Hess D, Fisher D, Williams P, Pooler S, Kacmarek R. Medication nebulizer performance. Chest 1996;110: Chua HL, Collis GC, Newbury AM, Chan K,Bower GD, Sly PD, Le Souef PN. The influence of age on aerosol deposition in children with cystic fibrosis. Eur Resp J 1994;7: Years Ago in The Journal of Pediatrics SEROTHERAPY IN PERTUSSIS Place EW, Keller MJ, Shaw EW. J Pediatr 1949;34: Place et al report a prospective comparative study of hyperimmune serum therapy versus no therapy in 150 children hospitalized because of pertussis at Boston City Hospital in 1946 to Roughly equal numbers of children were assigned to 4 intervention groups to receive serum from hyperimmunized horses or rabbits, human serum, or no therapy. An attempt was made to match across intervention groups for age and severity of illness. The intervention assignment was not blinded, and no placebo was used. Surprisingly few and only mild reactions occurred in children given horse or rabbit serum. Although pertussis agglutinating antibody titers rose immediately after doses of antiserum, no clinical benefit was noted in any intervention group compared with the control group. Investigators were more impressed with the beneficial effects of sulfonamides and the newly available penicillin on the course of secondary pneumonia and otitis media. Interest in antiserum (especially rabbit-derived) therapy against pertussis had been building over the decade before publication of this more scientific study. Results of this study, as well as a dramatic reduction in pertussis after introduction of whole-cell pertussis vaccine, were probably responsible for waning interest in antiserum therapy. As with many other partially controlled infectious diseases, waning interest outstripped waning disease. Pertussis has not been eliminated. Pertussis has, in fact, increased in the United States since 1976, when a low number of cases (1010) were reported. Changing epidemiology has made infants under 6 months of age most susceptible to infection and vulnerable to excessive morbidity and mortality. Re-enter hyperimmune globulin therapy stage left. With substantive evidence of pertussis as a bacterial toxin-mediated disease, the 50-year-old question is being asked again. A Phase III efficacy trial is ongoing at several sites in Canada and the United States under the Orphan Drug Program of the US Food and Drug Administration. The trial is designed to evaluate, in hospitalized children with pertussis, the clinical effectiveness of intravenously administered, purified immune globulin derived from adult volunteers immunized with a pertussis toxoid vaccine. This time around, double-blind, saline placebo controlled methodology is being used, and paroxysmal coughing episodes are being defined by a smart Physiac Monitor (Physio Analytics, Newton, Mass) programmed to be tripped by audio or respiratory changes compatible with a paroxysm of coughing. Stay tuned. Sarah S. Long, MD Section of Infectious Diseases St. Christopher s Hospital for Children Philadelphia, PA