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Emergency Department Treatment of Severe Asthma
clinical investigations Emergency Department Treatment of severe Asthma* Metered-Dose Inhaler Plus Holding Chamber Is Equivalent in Effectiveness to Nebulizer Ahamed H. ldris, M.D.;t Michael F. McDermott, M.D.;t John C. Raucci, M.P.H.N.; Angel Morrabel, M.D.; Susan McGorray, Ph.D.;§ and Leslie Hendeles, Pharm.D.1I Study objective: To compare the effectiveness of administration of albuterol by nebulizer or by a metered-dose inhaler having a holding chamber attachment (hereafter "inhaler") for treatment of acute asthma in an emergency department (ED). Design: A randomized, double-blind, placebo-controlled intervention study conducted at two sites. Setting: The EDs of a large municipal hospital and a university teaching hospital. lbtients: Thirty-five patients 10 to 45 years of age seeking treatment at an ED for acute asthma. Interventions: Patients were randomly assigned to receive either a1buterol by nebulizer plus placebo by inhaler (n 20) or albuterol by inhaler plus placebo by nebulizer (n 15). The dose was repeated every 30 min until the FEV, was at least 80 percent of predicted, the patient became asymptomatic, or 6 doses had been given. Measurements and results: All references in this article to spirometric measurements of forced expiratory volume in 1 s (FEV,), forced vital capacity (FVC), and peak expiratory Row rate (PEFR) represent percentages of the predicted normal value. No significant (p>O.58) differences occurred
in baseline mean FEV" FVC, or PEFR for the two groups. For both groups, significant improvement occurred in mean FEV, at 30 min (p<0.02) and at 60 min (p<0.02), and in maximum mean FEV, (p0.6) differences occurred between groups in mean FEV" FVC, or PEFR at 30 and 60 min, or in maximum improvement attained. The sample size was sufficiently large to detect a 12 percent difference in improvement with a power of 90 percent. Thirty-three of 35 patients were treated successfully with the study protocol, became asymptomatic, and were discharged home. One patient from each group required further treatment. Conclusions: There was no detectable difference in effectiveness of albuterol administered by nebulizer or the inhaler system for treatment of acute asthma. There was no detectable difference in effectiveness of albuterol administered by nebulizer or the inhaler system for the treatment of acute asthma when the dose was titrated to clinical response. When compared with nebulizer, the metered-dose inhaler with holding chamber delivers a full dose of a1buterol more quickly and at no higher cost. (Chest 1993; 103:665-72)
Necting as many as 10 million people in the United States, asthma is a major cause of emergency hospitalization. With over 1 million emergency department (ED) visits' and more than 450,000 hospital admissions" in the United States each year, acutely ill asthma patients are a common emergency.
Inhaled 13-adrenergic agonists such as albuterol, metaproterenol, and terbutaline are well-accepted treatments for acute asthma and bronchial obstruction. 2 -9 These drugs are usually diluted with normal saline solution and administered by gas-powered, hand-held nebulizer, the standard treatment in EOs. Alternatively, 13-adrenergic agonists may be administered by metered-dose inhaler. Although inhalation of
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*From the University of Florida College of Medicine, Gainesville; Departments of Surgery (Division of Emergency Medicine) and Medicine (Dr. Jdris): Statisties (Division of Biostatisties) (Dr. M<--Gorray); Phannacyand Pediatrics (Dr. Hendeles): Departments of Emergency Medicine (Dr. McDermott and Mr. Raueci) and Medicine (Dr. Morrabel), Cook County Hospital, Chieago; and the Chicago Medical School (Dr. MeDennott), North Chicago,
Ill. tAssistant Professor of Surgery and Medicine. :j:Assistant Professor of Emergency Medicine. §Assistant Professor of Statistics. IIProfessor of Pharmacy and Pediatries. Supported by a grant from Schering Laboratories, Presented in part at the National Association of EMS Physicians, Orlando, Fla, June 1991, and at the Ameriean College of Emergency Physicians Scientific Assembly, Boston, October 1991. Manuscript reeeived April 7; revision accepted July 9 Reprint requests: Dr. ldris, 9712 SW First Place, Cainesoille, Fl. 32607
For editorial comment see page 661 a metered dose is often prescribed for maintenance therapy for outpatients with asthma, this form of delivery has not been widely accepted by EOs as a way of treating severe asthma attacks, because nebuIization is believed to be more effective. However, several studies have evaluated the effectiveness of treating acute asthma using the conventional metereddose inhaler and a spacer attachment consisting of a tube or a reservoir holding chamber,":" In these CHEST I 103 I 3 I MARCH, 1993
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clinical trials, metered-dose inhalation with holding chamber compared favorably with nebulization for both hospitalized patients and those in EDs: measures of respiratory function showed equivalent improvement with both methods. Because ofIirnitations in methodology, these studies were unable to report the number and duration of treatments necessary to eliminate symptoms or the length of therapy before patients could be discharged home or required hospital admission. Such end points are important in judging whether a particular treatment method would be useful in an ED setting, where short treatment time would be an advantage. Our study compares the efficacy of treating acute asthma with albuterol given by nebulizer versus a metered-dose inhaler having a holding chamber attachment. We judged the success of each treatment by improvement in three variables, measured from the time of complete treatment until hospital discharge or hospital admission: forced expiratory volume in 1 s (FEV(), forced vital capacity (FVC), and peak expiratory flow rate (PEFR). METHODS AND MATERIALS
We prospectively studied 35 patients seeking treatment for acute asthma at one of two EDs: Cook County Hospital (n = 15), an 800bed acute care municipal teaching hospital in Chicago, and Shands Teaching Hospital (n = 20), a 568-bed acute and tertiary care hospital affiliated with the University of Florida College of Medicine in Gainesville. The review boards of both institutions approved the protocol, and all participants gave informed consent. Patients were excluded for the following reasons: if they were younger than 8 years or more than 45 years of age; had angina, respiratory failure, or chronic obstructive pulmonary disease; were unable to give informed consent or perform spirometric maneuvers; or had a history of smoking of ten pack-years or more. All patients who were asked to enroll in the study accepted, and no patient was dropped from the study for any reason. The following variables were measured before treatment: pulse rate, respiratory rate, oral temperature, blood pressure, serum theophylline level, plasma potassium and glucose levels, FEV" FVC, and PEFR. The last three variables were assessed with a spirometer (Respiradyne, Sherwood Medical Co, St. Louis, Mo), the patient making two forced exhalations. A third forced exhalation was requested if FEV, for the first two maneuvers differed by more than 10 percent. Seven patients were able to make only one satisfactory baseline forced exhalation, because severe coughing precluded a second effort. Patients were then randomly assigned to one of two treatments, both administered in a double-blind fashion. Twenty patients (the nebulizer group) received placebo by a metered-dose inhaler having a holding chamber attachment, immediately followed by administration of a1buterol by nebulizer. Placebo consisted of propellant gas only, one puff every minute for a total of four puffs. Albuterol (Proventil), 2.5 mg, was nebulized in 2 ml of normal saline solution. Fifteen other patients (the inhaler group) received a1buterol by metered-dose inhaler with holding chamber, one puff of 90 ILg of a1buterol every minute for a total of four puffs. Administration of placebo (2.5 ml normal saline solution) by nebulizer followed. Both groups used a holding chamber device (InspirEase, Key Pharmaceuticals, Inc, Miami, Fla) and a nebulizer (T Up-Draft II Nebu-U-Mist, Hudson Oxygen Therapy Sales Co, Temecula, Cali/). After the metered-dose inhaler was discharged into the 700-ml
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reservoir bag (InspirEase), the patient was instructed to inhale slowly from the mouthpiece so as not to cause the reed to emit a tone. A sound similar to that produced by a harmonica occurred if the inhalation rate exceeded 0.3 Us. We asked patients to hold their breath for 5 s after inhalation. The nebulizer was connected to a source of pressurized oxygen set to a flow rate of 5 Umin. Patients were instructed to inhale and exhale slowly through the mouthpiece only and were observed continuously for compliance. All patients were able to use the nebulizer and inhaler satisfactorily. We repeated treatments at 3O-min intervals and assessed pulse rate, respiratory rate, oral temperature, blood pressure, FEV" FVC, and PEFR immediately after each treatment. The study was terminated when the patient had six treatments, became symptom-free, or achieved an FEV, of at least 80 percent of predicted normal values. At the end of the study, we measured plasma potassium and glucose levels. The highest values for FEV" FVC, and PEFR for each treatment time were used for comparison. To eliminate biases of gender, age, and height, the values for FEV" FVC, and PEFR were expressed as percentages of predicted normal values. In addition, to eliminate bias introduced by differences in degree of airways obstruction," we used the following formula to express the actual improvement attained as a percentage of maximum improvement possible: Percent Response = Postalbuterol FEV, - initial FEV';predicted FEV,-initial FEV, X 100. Paired Student's t tests were used for comparisons between baseline values and first treatment, second treatment, and maximum values. Two-sample Student's t tests were used to test for differences between the inhaler and nebulizer groups; Wilcoxon rank-sum tests were used for these comparisons for ordinal data. Correlation and rank correlation coefficients were calculated to assess the relationships between pairs of variables. A p value of less than 0.05 was considered statistically significant. Published formulas and nomograms for women, '9.'" men, "'.21 and children" were used to calculate the predicted normal values for FEV" PEFR, and FVC. RESULTS
Table 1 shows that patients ranged in age from 10 to 45 years old, with no significant difference in median age for the two groups; 54 percent were Table 1- Baseline Choracteri8tics of lbtients* Group Characteristics No. of patients Median age (range), yr Male/female, No. History of asthma, yr:j: Serum theophylline No. of patients Median level (range), mgfL ~-agonist use before study (n=34) % of patients % of predicted normal valuer For FEV, For FVC For PEFR
Nebulizer Group
Inhaler Group
pt
20 23 (10-45) 9/11 14.2±9.8
15 25 (16-45) 7/8 12.4±7.6
0.55 0.69 0.57
14 7.1 (0-14.9)
8 4.35 (0.1-10)
0.32
73.7
66.7
0.46
37.5± 16.6 55.4± 18.8 36.9± 16.8
36.1 ± 15.2 54.2± 18.4 34.0± 14.0
0.80 0.86 0.58
*FEV, = forced expiratory volume in 1 s: FVC = forced vital capacity: PEFR = peak expiratory flow rate. tx2 for categorical variables; Student's t test for normally distributed continuous variables; Wilcoxon rank-sum test for variables with non-normal distributions, as determined by Fisher's exact test. :j:Mean±SD. Emergency Department Treabnent of severe Asthma (Idris lit 111)
FEY I as a percentage of predicted normal
NED LlZER
INIIA LER
60 50 40
30
20 10
o
Before treatment
234
5
6
No. of Treatments
FIGURE 1. Rate and degree of improvement in mean (± SO) forced expiratory volume in 1 s (FEV,), expressed as a percentage of predicted normal values. Data pertain to patients given albuterol by nebulizer or metered-dose inhaler with a holding chamber, for treatment of acute asthma attacks. There were no statistically significant differences when using a two-sample Student's t test to compare the two groups before treatment was given (p = 0.80) or for improvement after each treatment (p>0.55).
female, and only 9 percent of all patients smoked. Most patients in this study had chronic asthma: 66 percent had asthma for more than 8 years. None of the patients had a history of other chronic or complicating cardiac or respiratory illness. Patients reported the following chief complaints (listed in order of decreasing frequency): cough, shortness of breath, wheezing, congestion, and upper respiratory tract infection. Patients reported possible triggering factors regarding their current asthma attack, listed in order of decreasing frequency: upper repiratory tract infection, change in weather, allergens, and irritants. For the 25 patients reporting the length of their current asthma attack, the attack lasted the following number of hours before the patient sought ED care: less than 24 h for 46 percent of patients, 24 to 48 h for 37 percent of patients, and more than 48 h for 17 percent of patients. A detailed medication history obtained for 34 patients showed that 71 percent had used an inhaled (3adrenergic agonist before seeking ED care. For the 15 patients reporting a specific time of use, the length of time between use of the inhaler and presentation at the ED was less than 4 h for 53 percent of patients, 4 to 8 h for 33 percent of patients, and more than 8 h for 13 percent of patients. Additionally, of 34 patients, 32 percent had used prednisone within 21 days, and 11 percent had used an inhaled steroid. Serum theophylline levels measured immediately before treat-
ment for the 22 patients reporting previous use (Table 1) revealed that only 6 had a serum level of 10 J.Lmf¢L or more; 5 were in the nebulizer group, and 1 patient was in the inhaler group. All but one patient (97 percent) had wheezing on auscultation before treatment; 53 percent (n = 32) had nasal congestion, and 36 percent (n = 28) had sputum production. Spirometric testing performed before treatment showed no significant differences between the two groups regarding mean values for the percentage of predicted normal values for FEV\> FVC, or PEFR (Table 1). Both groups had significant improvement in mean values for the percentage of predicted normal values for FEV I and PEFR after the first treatment and continued to improve with each subsequent treatment. The nebulizer group had significant improvement in mean percent predicted FVC after the first treatment (Table 2). Comparison of the groups showed no significant (p>O.55) differences in improvement for the percentage of predicted normal values for FEV I (Fig 1), FVC, or PEFR after each treatment. The sample size was sufficiently large to allow detection of a 12 percent difference in improvement in these three variables with a power of 90 percent. The mean maximum percent predicted FEV I occurred at mean treatment times of92±47 min for the nebulizer group and at 92 ± 54 min for the inhaler group. Comparison of the two groups showed no CHEST I 103 I 3 I MAI'lCH, 1993
667
Table 2- Mean (± SD) Spirometric Values Expressed as a Percentage of Predicted Normal Values After Administration of Albuterol by Nebulizer or Metered-Dose Inhaler With Holding Chamber, for Treatment ofAcute Asthma· After Treatment Before Treatment
2
Maximum Improvement
% predicted FEV,
Nebulizer ~roup Inhaler ~roup % predicted PEFR Nebulizer ~roup Inhaler ~roup % predicted FVC Nebulizer group Inhaler ~roup Heart rate. heats/min Nebulizer ~roup Inhaler ~roup Respiratory rate, breaths/min Nebulizer ~roup Inhaler ~roup Blood pressure (systolic/diastolic), mm Nebulizer ~roup Inhaler ~roup
37.5± 16.5 36.1 ± 15.2
55.8±23.8t 52.4± 17.7t
54. I ± 24.6t:j: 55.3± 17.0t
63.9±20.4§ 63.2± 12.7§
36.9± 16.8 34.0± 14.0
50.4 ± 22.711 46.2± 17.711
49.7±20.4t:j: 53.1 ± 15. 7t~
6O.8±20.1§ 59.8± 15.4§
55.4± 18.8 54.2± 18.4
72.0±24.0t 67.7±20.4
70.2 ± 24.3t:j: 70.6± 18.3t~
81.0±21.0§ 79.0± 13.8§
104±20 93±1l
98±19 93±17
106± 18 95± 16
104± 18 94± 16
23±5 23±6
21±6 20±5
21±4 19±6
21±6 18±4
123±21 III ± 13 124± 16 79± 10
123±20 81 ± 14 124± 13 79± 12
126± 17 80± 14 123± 13 78± 12
125±21 77±13 122± 16 78± 12
H~
Response to treatment, ** % Nebulizer ~rouptt Inhaler ~rouptt
33.1 ±24.3 27.1±14.3
35.7±27.2:j: 32.6± 17.6~
45.9±24.8 42.1 ± 13.2
*FEV, = forced expiratory volume in 1 s; PEFR = peak expiratory flow rate; FVC = forced vital capacity. Paired Student's t test comparing values before and after treatment. tp<0.02. :j:n= 16. §p
significant difference at any of the measured intervals regarding mean values for respiratory rate, pulse rate, or systolic and diastolic blood pressures (Table 2). When heart rate before the first treatment was compared with rate after the last treatment, heart rate was lower for 51 percent of patients, higher for 40 percent, and unchanged for 9 percent; respiratory rate was lower for 69 percent, higher for 17 percent, and unchanged for 14 percent. When improvement in FEV 1 was expressed as a percentage of maximum improvement possible, comparison of the nebulizer and inhaler groups showed no significant differences after the first (p = 0.42) or second treatment (p = 0.72) or for mean maximum response (p = 0.57) (Table 2). The median number of treatments required to attain maximum response was three (one to six) for the nebulizer group and two (one to six) (p = 0.85) for the inhaler group. Further analysis, retrospectively, of the 14 patients who had the most severe asthma (an initial FEV 1 of less than 30 percent of the predicted normal value; range, 12 to 29 percent) showed that after the first 668
treatment, when compared with pretreatment FEV.. mean percent predicted FEV 1 had increased from 22 ± 7 percent to 33 ± 15 percent (NS) for the nebulizer group (n = 8), and from 22 ± 4 percent to 39 ± 16 percent (p<0.05) for the inhaler group (n = 6). After the second treatment, when compared with baseline values, both groups had significant increases in mean percent predicted FEV 1: to 36± 18 percent (p<0.05) for the nebulizer group, and to 48 ± 20 percent (p<0.02) for the inhaler group. However, when the groups were compared with each other, there were no significant differences in improvement after the first (p = 0.42) or second treatment (p = 0.18). Serum theophylline level did not correlate significantly with rate (p = 0.68) or degree (p = 0.22) of improvement (Spearman rank correlation coefficient analysis). The lower the pretreatment percent predicted FEV I, the more treatments were required (p
Table 3-Number of Treatments Required by the Nebulizer Group and the Inhaler Group No. of Treatments 2
3
4
5
6
No. of patients, % Nebulizer group 4 (20) 4 (20) 3 (15) 3 (15) 2 (10) 4 (20) 2 (13) 5 (33) 1 (7) 4 (27) 2 (13) 1 (7) Inhaler ~roup
prior use of ~-adrenergic agonists and the percent predicted FEV. before treatment (p=0.99), the response to the first treatment (p = 0.53), or the number of treatments given (p = 0.55). During the study period, no patient was given theophylline, 5 of20 patients in the nebulizer group were given intravenous methylprednisolone, and 1 was given oral prednisone. One of 15 patients in the inhaler group was given intravenous methylprednisolone. When steroids were given, it was usually within 1 h of discharge from the ED. The time required for assembly of the metereddose inhaler with holding chamber, and for instruction in its use, was consistently less than 3 min; the time to dispense a full dose was another 3 min. Total treatment time was less than 6 min for the first treatment and 3 min for each subsequent treatment, as further assembly and training were unnecessary. Assembly and administration time for the first nebulizer treatment was 11 to 15 min; subsequent treatments took 10 to 14 min. Length of stay in the ED did not differ significantly for the two groups. The mean number of treatments administered was 3.4 ± 1.8 for the nebulizer group and 3.1 ± 1.6 for the inhaler group (p = 0.72) (Table 3). Ninety-four percent of patients were treated successfully within the study protocol and were discharged home; 94 percent of patients were asymptomatic at the time of hospital discharge and had a mean percent predicted FEV, of 65 percent. Only 17 percent ofpatients achieved a percent predicted FEV. of 80 percent or more. One patient from each treatment group required further treatment. Although seven patients (20 percent) complained of increased shakiness or tremor after treatment, these effects could not be demonstrated objectively. DISCUSSION
Albuterol delivered by metered-dose inhaler with holding chamber was as effective as albuterol delivered by nebulizer for treating patients with acute asthma. In that regard, our study agrees with other clinical trials investigating patients who presented to an ED with acute asthma. However, our study differs substantially in method.IO·'3.15 We did not give a fixed number ofdoses to all subjects but, instead, continued treatment until preestablished criteria were met: the elimination of symptoms, the achievement of an FEV,
of at least 80 percent of predicted normal values, or the administration of six treatments. Thus, we were able to assess length of stay in the ED and discharge outcome for the two treatment groups. Seventy percent of the nebulizer group and 80 percent of the inhaler group were treated, became asymptomatic, and were discharged home within 2 h, 94 percent of patients were treated successfully and discharged within 3 h. Most patients had moderate-to-severe asthma; almost 63 percent had a pretreatment FEV, ofless than 40 percent of predicted normal values. Results from those patients with the most severe obstruction (FEV I <30 percent of predicted normal value) showed a trend toward greater improvement with the inhaler system. Response to both the first and second treatment in this group were greater than that for the nebulizer group when compared to initial values. Given the small sample size in this subset and the likely variation, it is not surprising that even a moderate difference would not exhibit statistical significance. Nevertheless, this trend toward greater improvement in the inhaler group among the most obstructed patients deserves comment and further investigation. Additionally, the results reinforce the observation that more severely obstructed patients require a greater number of treatments to attain maximal benefit. For the busy ED requiring rapid, effective treatment, there appears to be no advantage in using nebulizers rather than metered-dose inhalers with holding chambers. The mean dose of albuterol required to achieve maximum response was 7.63 ± 3.9 mg for the nebulizer group and 1.11 ± 0.64 mg for the inhaler group. The drug potency ratio was 6.9:1 (nebulizer:inhaler) favoring the inhaler, a ratio similar to that found by others.F' One nebulizer treatment (2.5 mg of albuterol) is equivalent to four puffs (0.36 mg of albuterol) given by the inhaler system. The possibility exists that the response to albuterol was overestimated in the nebulizer group. When compared with the inhaler group, more patients in the nebulizer group had been using theophylline before entry to the study, and their mean serum theophylline level was 63 percent higher. Nevertheless, we found that serum theophylline level did not have an independent effect on the rate or magnitude of improvement of airways obstruction. Pretreatment FEV I was significantly inversely related to the number of treatments required. Thus, patients with the most severe asthma required a longer stay in the ED and more treatment before becoming asymptomatic. Nevertheless, the mean number of treatments administered was similar for both groups. The decreased deposition of inhaled drug in the small airways of asthmatic patients with bronchial obstruction may account for the increased number of treatments required by the CHEST I 103 I 3 I MARCH. 1993
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patients in our study who had a poor baseline percent predicted FEV I' 24 In addition, the airways obstruction of severe asthma may have had an increased inflammatory component less responsive to ~-adrenergic agonist drugs. Patients with acute asthma often seek ED care only after hours of unsuccessfully treating themselves with a ~-adrenergic agonist via metered-dose inhaler. When they then respond to nebulized inhalation treatments in the ED, the nebulizer appears to be more effective. In our study, 71 percent of patients had administered a ~-adrenergic agonist by metered-dose inhaler at home shortly before entry into the study but remained sufficiently symptomatic to seek ED care. Of those patients, 93 percent and 90 percent were treated successfully with nebulizer or metered-dose inhaler with holding chamber, respectively. This suggests that patients in the present study failed to use the conventional metered-dose inhaler effectively at home or that conventional doses by metered-dose inhaler were ineffective despite appropriate technique. As many as 90 percent of asthmatic patients do not use a conventional metered-dose inhaler effectively.25-28 To maximize delivery of drug particles to the peripheral airways, the user should hold the inhaler 4 cm from the mouth, inhale slowly (ie, <1 Us), and should hold the breath for 5 to 10 S.29 If inhalation is too rapid, inertial forces cause more drug particles to be deposited on the pharynx and upper respiratory tract, and less drug reaches the small airways. Because particles that do reach the lower airways require 5 to 10 s for deposition onto the mucosa, holding the breath for less than 5 s causes much of the drug to be exhaled. Most patients find it difficult to coordinate all of the maneuvers that produce effective drug delivery to the lungs, especially during acute exacerbations. Holding chamber attachments were designed to overcome technical problems inherent in using the metered-dose iinhaler. The attachment (InspirEase) used in this study consists of a 700-ml reservoir bag and a mouthpiece that holds the pressurized drug canister. The drug is discharged into the fully inflated reservoir, and the patient slowly inhales the drug from the bag. A whistle in the mouthpiece sounds if the patient inhales at an inspiratory flow rate greater than 0.3 Us.JO Some patients in the present study activated the whistle very briefly during the first treatment, but by the second and subsequent treatments, they had learned to inhale slowly enough so that the whistle did not sound. None of the patients inhaled too rapidly. For patients with severe asthma, flow-through devices that allow inhalation of volumes larger than that allowed by our device (InspirEase) might be better tolerated. None of the patients in our study had difficulty using our device (InspirEase), although some patients, after inhaling the full 700-ml volume from 670
the reservoir, inhaled additional volume from around the mouthpiece. In a comparison of aerosol deposition, patients using their usual technique and a metered-dose inhaler having a conventional actuator had only 6 percent of the dose deposited into the lungs; patients using our device (InspirEase) had 15 percent of the dose deposited in the lungs." Oropharyngeal deposition was 86 percent with the conventional metered-dose inhaler and 10 percent with our modification (InspirEase); 59 percent of the dose remained in the reservoir (InspirEase). Holding chamber attachments appear to deliver more drug to the peripheral airways. Outpatient therapy should be aided by hospital use of the metered-dose inhaler with holding chamber. The patient receives instruction in the proper use of the holding chamber device during treatment in the ED and immediately sees improvement in asthma symptoms. These incentives should encourage continued use of this superior technique at home. If the patient requires several rounds of treatment, even more opportunity for instruction in technique would be provided. Although the inhaler system required 1 min more than the nebulizer for assembly and patient instruction, this time was well spent instructing patients in proper inhalation technique - knowledge that can be applied at home for more effective preventive management of asthma. Many patients with acute exacerbations of asthma would benefit from the home use of holding chambers because of the more consistent delivery of aerosol to the pulmonary airways. By enhancing techniques of administration of beta-adrenergic agonists during early stages of asthma exacerbations, holding chambers increase the reliability of treatment during this critical period. With these devices, patients can administer rescue doses of inhaled beta-adrenergic agonists before departing for or on the way to the hospital; or, if they have received appropriate training, they can better implement recommendations for home management. In our study, the metered-dose inhaler with holding chamber required less than 6 min for assembly, instruction, and delivery of the first full dose of drug, whereas the nebulizer required 12 to 15 min for delivery of the first full dose. This advantage may make the metered-dose inhaler with holding chamber ideal for prehospital care of acute asthma, because ambulance transport time is frequently under 10 min. Also, the metered-dose inhaler with holding chamber is compact and requires little storage space; unlike the nebulizer, it does not require a source of compressed gas or other elaborate equipment for its operation. Although the metered-dose inhaler with holding chamber was found to be feasible in prehospital treatment, further study in this setting would be necessary for a definitive assessment." Emergency Department Treatment of SevereAsthma(Idris al al)
The metered-dose inhaler with holding chamber has other advantages. We notice that some patients breathe through the nose when the mouthpiece of the nebulizer is in the mouth, thus losing drug to the air. This loss of drug is difficult to recognize because the nebulized vapor is almost invisible against most backgrounds. In contrast, our device (InspirEase) has a drug reservoir bag that collapses when the patient inhales, thus confirming drug inhalation. Because a recent report described large variation in the rate of nebulization for nebulizers;" we studied this variable for the units used in our study. Twelve nebulizers were randomly selected from those used in the study and were tested for variation in rate by nebulizing 2.5 ml of saline solution with a gas flow rate of 5 Umin. We then measured the volume of solution that remained after nebulization ceased. The median rate of nebulization was 0.188 mllmin (range, 0.162 to 0.222 mllmin). The variation in rate was 37 percent (100 X [highest rate - lowest rate ]Ilowest rate), and the mean residual volume was 0.47 ± 0.08 m!' It is possible that the greater variation in response found in the nebulizer group was caused by variation in the rate of nebulization. Metered-dose inhalers are usually more consistent in the amount of drug dispensed with each discharge than are nebulizers, which vary in rate by more than 128 percent." The metered-dose inhaler with holding chamber has been shown to reduce costs in treating hospitalized patients.">' In ED settings, if the holding chamber and adrenergic drug are to be prescribed to patients after hospital discharge, then the costs within the ED are competitive with those incurred by use of nebulizers. The cost of time for instruction by nurses in the use of the holding chamber is $1.50 to $4.50. The patient charge is $16.85 for the holding chamber attachment and $19.70 for the drug canister (total, $36.55). The patient can use the holding chamber attachment for more than 1 month; and the drug canister, which contains 200 metered inhalations, can provide further treatment at home. We estimated the cost of the nebulizer unit to be $2.30; medication, $0.30 per dose; and respiratory technician time, $2.50 (total, $5.10). Of course, following discharge from the ED, an inhaler and optimally a holding chamber would be prescribed for outpatient use, a cost that would already be covered if it had been used in the ED. During the study, an investigator stayed at the bedside during all training and treatments. Where the inhaler system is being used in routine clinical practice (Cook County Hospital), a physician or nurse stays at the patient's side during the initial training and during subsequent administrations if the patient is experiencing any difficulty with technique. Since the patient is often markedly symptomatic during the first round of
therapy, the physician is present until symptoms improve. The purpose of this study was to compare two methods of administering an inhaled J3-adrenergic agonist for the treatment of acute asthma. The study was not designed to evaluate steroid use either in the ED management of acute asthma or in the hospital discharge regimen following an acute exacerbation. It is worth noting that only 14 percent of study patients had received steroid medication shortly before seeking ED care. Regular use of inhaled steroids or selfadministered burst therapy may have prevented some of the exacerbations. Present recommendations include at least consideration of steroids for all patients discharged from the ED.34 After ED discharge, 20 of 35 study patients were given a prescription for steroids. Many patients were given follow-up appointments, and all were given an investigator's phone number to call if they had problems. No patient called the investigator. CONCLUSIONS
Albuterol administered by metered-dose inhaler with holding chamber is an effective, rapid alternative to nebulizer therapy for moderate and severe acute asthma. This method helps patients master correct inhalation technique in the course of treatment in the ED. Further study is necessary to establish its role in the prehospital setting and in treatment of patients with the most severe asthma tie, those who have an FEV t <30 percent of the predicted normal value). ACKNOWLEDGMENTS: The authors thank Pauline Snider for editorial assistance, Susan Lorash for help with manuscript preparation, and Richard J. Melker, M.D., Ph.D., for thoughtful critique of the manuscript. REFERENCES
1 McDonald AJ. Asthma. Emerg Med Clin North Am 1989; 7:21935 2 Self TH, Abou-Shala N, Burns R, Stewart CF, Ellis RF, Tsiu SJ, et al. Inhaled albuterol and oral prednisone therapy in hospitalized adult asthmatics: does aminophylline add any benefit? Chest 1990; 98:1317-21 3 Shim C, Williams MH Jr. Bronchial response to oral versus aerosol metaproterenol in asthma. Ann Intern Med 1980; 93:42831 4 Siegel D, Sheppard D, Gelb A, Weinberg PF. Aminophylline increases the toxicity but not the efficacy of an inhaled betaadrenergic agonist in the treatment of acute exacerbations of asthma. Am Rev Respir Dis 1985; 132:283-86 5 Newhouse M, Dolovich M. Aerosol therapy: nebulizer vs metered dose inhaler [editorial]. Chest 1987; 91:799-800 6 Parker SR, Mellins RB, Sogn DD. Asthma education: a national strategy. Am Rev Respir Dis 1989; 140:848-53 7 Newhouse MT, Dolovich MB. Control of asthma by aerosols. N Engl J Med 1986; 315:870-74 8 Nelson HS. Adrenergic therapy of bronchial asthma. J Allergy Clin Immunol 1986; 77:771-85 9 Barnes PJ. A new approach to the treatment of asthma. N Engl J Med 1989; 321:1517-27 10 Turner JR, Corkery KJ, Eckman D, Gel I> AM, Lipavsky MA, Sheppard D. Equivalence of continuous flow nebulizer and CHEST 1103 I 3 I MARCH. 1993
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metered-dose inhaler with reservoir ba~ for treatment of acute airflow obstruction. Chest 1988; 93:476-81 Berenberg MJ, Baigelman \V, Cupples LA, Pearce L. Comparison of metered-dose inhaler attached to an Aerochamber with an updraft nebulizer for the administration of metaproterenol in hospitalized patients. J Asthma 1985; 22:87-92 Summer \V, Elston R, Tharpe L, Nelson S, Haponik EF. Aerosol bronchodilator delivery methods: relative impact on pulmonary function and cost of respiratory care. Arch Intern Med 1989; 149:618-23 Beasley CR\V, O'Donnell Tv. Pear shaped spacer nebuhaler compared with nebulised solution for terbutaline administration in acute severe asthma. NZ Med J 1985; 98:854-55 Benton G, Thomas RC, Nickerson BG, M<:Quitty JC, Okikawa J. Experience with a metered-dose inhaler with a spacer in the pediatric emergency department. Am J Dis Child 1989; 143:67881 Morgan MDL, Singh BY, Frame MH, Williams SJ. Terbutaline aerosol given through pear spacer in acute severe asthma. BMJ 1982; 285:849-50 Gervais A, Begin P. Bronchodilatation with a metered-dose inhaler plus an extension, using tidal breathing vs jet nebulization. Chest 1987; 92:822-24 Jasper AC, Mohsenifar Z, Kahan S, Goldberg HS, Koerner SK. Cost-benefit comparison of aerosol bronchodilator delivery methods in hospitalized patients. Chest 1987; 91:614-18 Mitchell CA, Armstrong JG, Bartholomew MA, Scicchitano R. Nebulized fenoterol in severe asthma: determinants of the dose response. Eur J Respir Dis 1983; 64:340-46 Smith JR, Kory RC. Laboratory aids in investigating pulmonary disease. In: Baum GL, ed. Textbook of pulmonary diseases. Boston: Little Brown & Co, 1965; 11-50 Gregg 1, Nunn AJ. Peak expiratory flow in normal subjects. BMJ 1973; 3:282-84 Kory RC, Callahan R, Boren HG, Syner JC. The Veterans Administration-Army Cooperative Study of Pulmonary Function: I. clinical spirometry in normal men. Am J Med 1961; 30:243-58 Godfrey S, Kamburoff PL, Nairn JR. Spirometry, lung volumes and airway resistance in normal children aged 5 to 18 years. Br
J Dis Chest 1970; 64:15-24 23 Colaeone A, Afilalo M, Wolkove N, Kreisman H. Dose response to inhaled salbutamol (S) administered by metered dose inhaler (MDI) or wet nebulizer (WN) in the treatment of acute asthma [abstract]. Am Rev Respir Dis 1991; 143:A650 24 Laube BL, Swift DL, Wagner HN Jr, Norman PS, Adams GK III. The effect of bronchial obstruction on central airway deposition of a saline aerosol in patients with asthma. Am Rev Respir Dis 1986; 133:740-43 25 Shim C, Williams MH Jr. The adequacy of inhalation of aerosol from canister nebulizers. Am J Med 1980; 69:891-94 26 Konig P. Spacer devices used with metered-dose inhalers: breakthrough or gimmick? Chest 1985; 88:276-84 27 Crompton GK. Problems patients have using pressurized aerosol inhalers. Eur J Respir Dis 1982; 63(suppI119):IOI-04 28 Newman Sp' Woodman G, Clarke SW, Sackner MA. Effect of InspirEase on the deposition of metered-dose aerosols in the human respiratory tract. Chest 1986; 89:551-56 29 Dolovich M, Ruffin RE, Roberts R, Newhouse MT. Optimal delivery of aerosols from metered dose inhalers. Chest 1981; 8O(suppl):911-15 30 Tobin MT, Jenouri G, Danta I, Kim C, Watson H, Sackner MA. Response to bronchodilator drug administration by a new reservoir aerosol delivery system and a review of other auxiliary delivery systems. Am Rev Respir Dis 1982; 126:670-75 31 Hawkins J, Hakala K, Heller MB, Kaplan RM, Schneider S, Stewart RD. Metered-dose aerosolized bronchodilators in prehospital care: a feasibility study. J Emerg Med 1986; 4:273-77 32 AlvineGF, Rodgers P, Fitzsimmons KM, Ahrens RC. Disposable jet nebulizers: how reliable are they? Chest 1992; 101:316-19 33 Orens DK, Kester L, Fergus LC, Stoller JK. Cost impact of metered dose inhalers vs small volume nebulizers in hospitalized patients: the Cleveland Clinic experience. Respir Care 1991; 36:1099-1104 34 National Asthma Education Program, Expert Panel Report. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute of the National Institutes of Health, US Dept of Health and Human Services; publication No. 91-3042, August 1991, Bethesda, Md
EmergencyDepartment Treatment 015e119re Asthma (/dris et aI)
in baseline mean FEV" FVC, or PEFR for the two groups. For both groups, significant improvement occurred in mean FEV, at 30 min (p<0.02) and at 60 min (p<0.02), and in maximum mean FEV, (p
Necting as many as 10 million people in the United States, asthma is a major cause of emergency hospitalization. With over 1 million emergency department (ED) visits' and more than 450,000 hospital admissions" in the United States each year, acutely ill asthma patients are a common emergency.
Inhaled 13-adrenergic agonists such as albuterol, metaproterenol, and terbutaline are well-accepted treatments for acute asthma and bronchial obstruction. 2 -9 These drugs are usually diluted with normal saline solution and administered by gas-powered, hand-held nebulizer, the standard treatment in EOs. Alternatively, 13-adrenergic agonists may be administered by metered-dose inhaler. Although inhalation of
=
=
*From the University of Florida College of Medicine, Gainesville; Departments of Surgery (Division of Emergency Medicine) and Medicine (Dr. Jdris): Statisties (Division of Biostatisties) (Dr. M<--Gorray); Phannacyand Pediatrics (Dr. Hendeles): Departments of Emergency Medicine (Dr. McDermott and Mr. Raueci) and Medicine (Dr. Morrabel), Cook County Hospital, Chieago; and the Chicago Medical School (Dr. MeDennott), North Chicago,
Ill. tAssistant Professor of Surgery and Medicine. :j:Assistant Professor of Emergency Medicine. §Assistant Professor of Statistics. IIProfessor of Pharmacy and Pediatries. Supported by a grant from Schering Laboratories, Presented in part at the National Association of EMS Physicians, Orlando, Fla, June 1991, and at the Ameriean College of Emergency Physicians Scientific Assembly, Boston, October 1991. Manuscript reeeived April 7; revision accepted July 9 Reprint requests: Dr. ldris, 9712 SW First Place, Cainesoille, Fl. 32607
For editorial comment see page 661 a metered dose is often prescribed for maintenance therapy for outpatients with asthma, this form of delivery has not been widely accepted by EOs as a way of treating severe asthma attacks, because nebuIization is believed to be more effective. However, several studies have evaluated the effectiveness of treating acute asthma using the conventional metereddose inhaler and a spacer attachment consisting of a tube or a reservoir holding chamber,":" In these CHEST I 103 I 3 I MARCH, 1993
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clinical trials, metered-dose inhalation with holding chamber compared favorably with nebulization for both hospitalized patients and those in EDs: measures of respiratory function showed equivalent improvement with both methods. Because ofIirnitations in methodology, these studies were unable to report the number and duration of treatments necessary to eliminate symptoms or the length of therapy before patients could be discharged home or required hospital admission. Such end points are important in judging whether a particular treatment method would be useful in an ED setting, where short treatment time would be an advantage. Our study compares the efficacy of treating acute asthma with albuterol given by nebulizer versus a metered-dose inhaler having a holding chamber attachment. We judged the success of each treatment by improvement in three variables, measured from the time of complete treatment until hospital discharge or hospital admission: forced expiratory volume in 1 s (FEV(), forced vital capacity (FVC), and peak expiratory flow rate (PEFR). METHODS AND MATERIALS
We prospectively studied 35 patients seeking treatment for acute asthma at one of two EDs: Cook County Hospital (n = 15), an 800bed acute care municipal teaching hospital in Chicago, and Shands Teaching Hospital (n = 20), a 568-bed acute and tertiary care hospital affiliated with the University of Florida College of Medicine in Gainesville. The review boards of both institutions approved the protocol, and all participants gave informed consent. Patients were excluded for the following reasons: if they were younger than 8 years or more than 45 years of age; had angina, respiratory failure, or chronic obstructive pulmonary disease; were unable to give informed consent or perform spirometric maneuvers; or had a history of smoking of ten pack-years or more. All patients who were asked to enroll in the study accepted, and no patient was dropped from the study for any reason. The following variables were measured before treatment: pulse rate, respiratory rate, oral temperature, blood pressure, serum theophylline level, plasma potassium and glucose levels, FEV" FVC, and PEFR. The last three variables were assessed with a spirometer (Respiradyne, Sherwood Medical Co, St. Louis, Mo), the patient making two forced exhalations. A third forced exhalation was requested if FEV, for the first two maneuvers differed by more than 10 percent. Seven patients were able to make only one satisfactory baseline forced exhalation, because severe coughing precluded a second effort. Patients were then randomly assigned to one of two treatments, both administered in a double-blind fashion. Twenty patients (the nebulizer group) received placebo by a metered-dose inhaler having a holding chamber attachment, immediately followed by administration of a1buterol by nebulizer. Placebo consisted of propellant gas only, one puff every minute for a total of four puffs. Albuterol (Proventil), 2.5 mg, was nebulized in 2 ml of normal saline solution. Fifteen other patients (the inhaler group) received a1buterol by metered-dose inhaler with holding chamber, one puff of 90 ILg of a1buterol every minute for a total of four puffs. Administration of placebo (2.5 ml normal saline solution) by nebulizer followed. Both groups used a holding chamber device (InspirEase, Key Pharmaceuticals, Inc, Miami, Fla) and a nebulizer (T Up-Draft II Nebu-U-Mist, Hudson Oxygen Therapy Sales Co, Temecula, Cali/). After the metered-dose inhaler was discharged into the 700-ml
666
reservoir bag (InspirEase), the patient was instructed to inhale slowly from the mouthpiece so as not to cause the reed to emit a tone. A sound similar to that produced by a harmonica occurred if the inhalation rate exceeded 0.3 Us. We asked patients to hold their breath for 5 s after inhalation. The nebulizer was connected to a source of pressurized oxygen set to a flow rate of 5 Umin. Patients were instructed to inhale and exhale slowly through the mouthpiece only and were observed continuously for compliance. All patients were able to use the nebulizer and inhaler satisfactorily. We repeated treatments at 3O-min intervals and assessed pulse rate, respiratory rate, oral temperature, blood pressure, FEV" FVC, and PEFR immediately after each treatment. The study was terminated when the patient had six treatments, became symptom-free, or achieved an FEV, of at least 80 percent of predicted normal values. At the end of the study, we measured plasma potassium and glucose levels. The highest values for FEV" FVC, and PEFR for each treatment time were used for comparison. To eliminate biases of gender, age, and height, the values for FEV" FVC, and PEFR were expressed as percentages of predicted normal values. In addition, to eliminate bias introduced by differences in degree of airways obstruction," we used the following formula to express the actual improvement attained as a percentage of maximum improvement possible: Percent Response = Postalbuterol FEV, - initial FEV';predicted FEV,-initial FEV, X 100. Paired Student's t tests were used for comparisons between baseline values and first treatment, second treatment, and maximum values. Two-sample Student's t tests were used to test for differences between the inhaler and nebulizer groups; Wilcoxon rank-sum tests were used for these comparisons for ordinal data. Correlation and rank correlation coefficients were calculated to assess the relationships between pairs of variables. A p value of less than 0.05 was considered statistically significant. Published formulas and nomograms for women, '9.'" men, "'.21 and children" were used to calculate the predicted normal values for FEV" PEFR, and FVC. RESULTS
Table 1 shows that patients ranged in age from 10 to 45 years old, with no significant difference in median age for the two groups; 54 percent were Table 1- Baseline Choracteri8tics of lbtients* Group Characteristics No. of patients Median age (range), yr Male/female, No. History of asthma, yr:j: Serum theophylline No. of patients Median level (range), mgfL ~-agonist use before study (n=34) % of patients % of predicted normal valuer For FEV, For FVC For PEFR
Nebulizer Group
Inhaler Group
pt
20 23 (10-45) 9/11 14.2±9.8
15 25 (16-45) 7/8 12.4±7.6
0.55 0.69 0.57
14 7.1 (0-14.9)
8 4.35 (0.1-10)
0.32
73.7
66.7
0.46
37.5± 16.6 55.4± 18.8 36.9± 16.8
36.1 ± 15.2 54.2± 18.4 34.0± 14.0
0.80 0.86 0.58
*FEV, = forced expiratory volume in 1 s: FVC = forced vital capacity: PEFR = peak expiratory flow rate. tx2 for categorical variables; Student's t test for normally distributed continuous variables; Wilcoxon rank-sum test for variables with non-normal distributions, as determined by Fisher's exact test. :j:Mean±SD. Emergency Department Treabnent of severe Asthma (Idris lit 111)
FEY I as a percentage of predicted normal
NED LlZER
INIIA LER
60 50 40
30
20 10
o
Before treatment
234
5
6
No. of Treatments
FIGURE 1. Rate and degree of improvement in mean (± SO) forced expiratory volume in 1 s (FEV,), expressed as a percentage of predicted normal values. Data pertain to patients given albuterol by nebulizer or metered-dose inhaler with a holding chamber, for treatment of acute asthma attacks. There were no statistically significant differences when using a two-sample Student's t test to compare the two groups before treatment was given (p = 0.80) or for improvement after each treatment (p>0.55).
female, and only 9 percent of all patients smoked. Most patients in this study had chronic asthma: 66 percent had asthma for more than 8 years. None of the patients had a history of other chronic or complicating cardiac or respiratory illness. Patients reported the following chief complaints (listed in order of decreasing frequency): cough, shortness of breath, wheezing, congestion, and upper respiratory tract infection. Patients reported possible triggering factors regarding their current asthma attack, listed in order of decreasing frequency: upper repiratory tract infection, change in weather, allergens, and irritants. For the 25 patients reporting the length of their current asthma attack, the attack lasted the following number of hours before the patient sought ED care: less than 24 h for 46 percent of patients, 24 to 48 h for 37 percent of patients, and more than 48 h for 17 percent of patients. A detailed medication history obtained for 34 patients showed that 71 percent had used an inhaled (3adrenergic agonist before seeking ED care. For the 15 patients reporting a specific time of use, the length of time between use of the inhaler and presentation at the ED was less than 4 h for 53 percent of patients, 4 to 8 h for 33 percent of patients, and more than 8 h for 13 percent of patients. Additionally, of 34 patients, 32 percent had used prednisone within 21 days, and 11 percent had used an inhaled steroid. Serum theophylline levels measured immediately before treat-
ment for the 22 patients reporting previous use (Table 1) revealed that only 6 had a serum level of 10 J.Lmf¢L or more; 5 were in the nebulizer group, and 1 patient was in the inhaler group. All but one patient (97 percent) had wheezing on auscultation before treatment; 53 percent (n = 32) had nasal congestion, and 36 percent (n = 28) had sputum production. Spirometric testing performed before treatment showed no significant differences between the two groups regarding mean values for the percentage of predicted normal values for FEV\> FVC, or PEFR (Table 1). Both groups had significant improvement in mean values for the percentage of predicted normal values for FEV I and PEFR after the first treatment and continued to improve with each subsequent treatment. The nebulizer group had significant improvement in mean percent predicted FVC after the first treatment (Table 2). Comparison of the groups showed no significant (p>O.55) differences in improvement for the percentage of predicted normal values for FEV I (Fig 1), FVC, or PEFR after each treatment. The sample size was sufficiently large to allow detection of a 12 percent difference in improvement in these three variables with a power of 90 percent. The mean maximum percent predicted FEV I occurred at mean treatment times of92±47 min for the nebulizer group and at 92 ± 54 min for the inhaler group. Comparison of the two groups showed no CHEST I 103 I 3 I MAI'lCH, 1993
667
Table 2- Mean (± SD) Spirometric Values Expressed as a Percentage of Predicted Normal Values After Administration of Albuterol by Nebulizer or Metered-Dose Inhaler With Holding Chamber, for Treatment ofAcute Asthma· After Treatment Before Treatment
2
Maximum Improvement
% predicted FEV,
Nebulizer ~roup Inhaler ~roup % predicted PEFR Nebulizer ~roup Inhaler ~roup % predicted FVC Nebulizer group Inhaler ~roup Heart rate. heats/min Nebulizer ~roup Inhaler ~roup Respiratory rate, breaths/min Nebulizer ~roup Inhaler ~roup Blood pressure (systolic/diastolic), mm Nebulizer ~roup Inhaler ~roup
37.5± 16.5 36.1 ± 15.2
55.8±23.8t 52.4± 17.7t
54. I ± 24.6t:j: 55.3± 17.0t
63.9±20.4§ 63.2± 12.7§
36.9± 16.8 34.0± 14.0
50.4 ± 22.711 46.2± 17.711
49.7±20.4t:j: 53.1 ± 15. 7t~
6O.8±20.1§ 59.8± 15.4§
55.4± 18.8 54.2± 18.4
72.0±24.0t 67.7±20.4
70.2 ± 24.3t:j: 70.6± 18.3t~
81.0±21.0§ 79.0± 13.8§
104±20 93±1l
98±19 93±17
106± 18 95± 16
104± 18 94± 16
23±5 23±6
21±6 20±5
21±4 19±6
21±6 18±4
123±21 III ± 13 124± 16 79± 10
123±20 81 ± 14 124± 13 79± 12
126± 17 80± 14 123± 13 78± 12
125±21 77±13 122± 16 78± 12
H~
Response to treatment, ** % Nebulizer ~rouptt Inhaler ~rouptt
33.1 ±24.3 27.1±14.3
35.7±27.2:j: 32.6± 17.6~
45.9±24.8 42.1 ± 13.2
*FEV, = forced expiratory volume in 1 s; PEFR = peak expiratory flow rate; FVC = forced vital capacity. Paired Student's t test comparing values before and after treatment. tp<0.02. :j:n= 16. §p
significant difference at any of the measured intervals regarding mean values for respiratory rate, pulse rate, or systolic and diastolic blood pressures (Table 2). When heart rate before the first treatment was compared with rate after the last treatment, heart rate was lower for 51 percent of patients, higher for 40 percent, and unchanged for 9 percent; respiratory rate was lower for 69 percent, higher for 17 percent, and unchanged for 14 percent. When improvement in FEV 1 was expressed as a percentage of maximum improvement possible, comparison of the nebulizer and inhaler groups showed no significant differences after the first (p = 0.42) or second treatment (p = 0.72) or for mean maximum response (p = 0.57) (Table 2). The median number of treatments required to attain maximum response was three (one to six) for the nebulizer group and two (one to six) (p = 0.85) for the inhaler group. Further analysis, retrospectively, of the 14 patients who had the most severe asthma (an initial FEV 1 of less than 30 percent of the predicted normal value; range, 12 to 29 percent) showed that after the first 668
treatment, when compared with pretreatment FEV.. mean percent predicted FEV 1 had increased from 22 ± 7 percent to 33 ± 15 percent (NS) for the nebulizer group (n = 8), and from 22 ± 4 percent to 39 ± 16 percent (p<0.05) for the inhaler group (n = 6). After the second treatment, when compared with baseline values, both groups had significant increases in mean percent predicted FEV 1: to 36± 18 percent (p<0.05) for the nebulizer group, and to 48 ± 20 percent (p<0.02) for the inhaler group. However, when the groups were compared with each other, there were no significant differences in improvement after the first (p = 0.42) or second treatment (p = 0.18). Serum theophylline level did not correlate significantly with rate (p = 0.68) or degree (p = 0.22) of improvement (Spearman rank correlation coefficient analysis). The lower the pretreatment percent predicted FEV I, the more treatments were required (p
Table 3-Number of Treatments Required by the Nebulizer Group and the Inhaler Group No. of Treatments 2
3
4
5
6
No. of patients, % Nebulizer group 4 (20) 4 (20) 3 (15) 3 (15) 2 (10) 4 (20) 2 (13) 5 (33) 1 (7) 4 (27) 2 (13) 1 (7) Inhaler ~roup
prior use of ~-adrenergic agonists and the percent predicted FEV. before treatment (p=0.99), the response to the first treatment (p = 0.53), or the number of treatments given (p = 0.55). During the study period, no patient was given theophylline, 5 of20 patients in the nebulizer group were given intravenous methylprednisolone, and 1 was given oral prednisone. One of 15 patients in the inhaler group was given intravenous methylprednisolone. When steroids were given, it was usually within 1 h of discharge from the ED. The time required for assembly of the metereddose inhaler with holding chamber, and for instruction in its use, was consistently less than 3 min; the time to dispense a full dose was another 3 min. Total treatment time was less than 6 min for the first treatment and 3 min for each subsequent treatment, as further assembly and training were unnecessary. Assembly and administration time for the first nebulizer treatment was 11 to 15 min; subsequent treatments took 10 to 14 min. Length of stay in the ED did not differ significantly for the two groups. The mean number of treatments administered was 3.4 ± 1.8 for the nebulizer group and 3.1 ± 1.6 for the inhaler group (p = 0.72) (Table 3). Ninety-four percent of patients were treated successfully within the study protocol and were discharged home; 94 percent of patients were asymptomatic at the time of hospital discharge and had a mean percent predicted FEV, of 65 percent. Only 17 percent ofpatients achieved a percent predicted FEV. of 80 percent or more. One patient from each treatment group required further treatment. Although seven patients (20 percent) complained of increased shakiness or tremor after treatment, these effects could not be demonstrated objectively. DISCUSSION
Albuterol delivered by metered-dose inhaler with holding chamber was as effective as albuterol delivered by nebulizer for treating patients with acute asthma. In that regard, our study agrees with other clinical trials investigating patients who presented to an ED with acute asthma. However, our study differs substantially in method.IO·'3.15 We did not give a fixed number ofdoses to all subjects but, instead, continued treatment until preestablished criteria were met: the elimination of symptoms, the achievement of an FEV,
of at least 80 percent of predicted normal values, or the administration of six treatments. Thus, we were able to assess length of stay in the ED and discharge outcome for the two treatment groups. Seventy percent of the nebulizer group and 80 percent of the inhaler group were treated, became asymptomatic, and were discharged home within 2 h, 94 percent of patients were treated successfully and discharged within 3 h. Most patients had moderate-to-severe asthma; almost 63 percent had a pretreatment FEV, ofless than 40 percent of predicted normal values. Results from those patients with the most severe obstruction (FEV I <30 percent of predicted normal value) showed a trend toward greater improvement with the inhaler system. Response to both the first and second treatment in this group were greater than that for the nebulizer group when compared to initial values. Given the small sample size in this subset and the likely variation, it is not surprising that even a moderate difference would not exhibit statistical significance. Nevertheless, this trend toward greater improvement in the inhaler group among the most obstructed patients deserves comment and further investigation. Additionally, the results reinforce the observation that more severely obstructed patients require a greater number of treatments to attain maximal benefit. For the busy ED requiring rapid, effective treatment, there appears to be no advantage in using nebulizers rather than metered-dose inhalers with holding chambers. The mean dose of albuterol required to achieve maximum response was 7.63 ± 3.9 mg for the nebulizer group and 1.11 ± 0.64 mg for the inhaler group. The drug potency ratio was 6.9:1 (nebulizer:inhaler) favoring the inhaler, a ratio similar to that found by others.F' One nebulizer treatment (2.5 mg of albuterol) is equivalent to four puffs (0.36 mg of albuterol) given by the inhaler system. The possibility exists that the response to albuterol was overestimated in the nebulizer group. When compared with the inhaler group, more patients in the nebulizer group had been using theophylline before entry to the study, and their mean serum theophylline level was 63 percent higher. Nevertheless, we found that serum theophylline level did not have an independent effect on the rate or magnitude of improvement of airways obstruction. Pretreatment FEV I was significantly inversely related to the number of treatments required. Thus, patients with the most severe asthma required a longer stay in the ED and more treatment before becoming asymptomatic. Nevertheless, the mean number of treatments administered was similar for both groups. The decreased deposition of inhaled drug in the small airways of asthmatic patients with bronchial obstruction may account for the increased number of treatments required by the CHEST I 103 I 3 I MARCH. 1993
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patients in our study who had a poor baseline percent predicted FEV I' 24 In addition, the airways obstruction of severe asthma may have had an increased inflammatory component less responsive to ~-adrenergic agonist drugs. Patients with acute asthma often seek ED care only after hours of unsuccessfully treating themselves with a ~-adrenergic agonist via metered-dose inhaler. When they then respond to nebulized inhalation treatments in the ED, the nebulizer appears to be more effective. In our study, 71 percent of patients had administered a ~-adrenergic agonist by metered-dose inhaler at home shortly before entry into the study but remained sufficiently symptomatic to seek ED care. Of those patients, 93 percent and 90 percent were treated successfully with nebulizer or metered-dose inhaler with holding chamber, respectively. This suggests that patients in the present study failed to use the conventional metered-dose inhaler effectively at home or that conventional doses by metered-dose inhaler were ineffective despite appropriate technique. As many as 90 percent of asthmatic patients do not use a conventional metered-dose inhaler effectively.25-28 To maximize delivery of drug particles to the peripheral airways, the user should hold the inhaler 4 cm from the mouth, inhale slowly (ie, <1 Us), and should hold the breath for 5 to 10 S.29 If inhalation is too rapid, inertial forces cause more drug particles to be deposited on the pharynx and upper respiratory tract, and less drug reaches the small airways. Because particles that do reach the lower airways require 5 to 10 s for deposition onto the mucosa, holding the breath for less than 5 s causes much of the drug to be exhaled. Most patients find it difficult to coordinate all of the maneuvers that produce effective drug delivery to the lungs, especially during acute exacerbations. Holding chamber attachments were designed to overcome technical problems inherent in using the metered-dose iinhaler. The attachment (InspirEase) used in this study consists of a 700-ml reservoir bag and a mouthpiece that holds the pressurized drug canister. The drug is discharged into the fully inflated reservoir, and the patient slowly inhales the drug from the bag. A whistle in the mouthpiece sounds if the patient inhales at an inspiratory flow rate greater than 0.3 Us.JO Some patients in the present study activated the whistle very briefly during the first treatment, but by the second and subsequent treatments, they had learned to inhale slowly enough so that the whistle did not sound. None of the patients inhaled too rapidly. For patients with severe asthma, flow-through devices that allow inhalation of volumes larger than that allowed by our device (InspirEase) might be better tolerated. None of the patients in our study had difficulty using our device (InspirEase), although some patients, after inhaling the full 700-ml volume from 670
the reservoir, inhaled additional volume from around the mouthpiece. In a comparison of aerosol deposition, patients using their usual technique and a metered-dose inhaler having a conventional actuator had only 6 percent of the dose deposited into the lungs; patients using our device (InspirEase) had 15 percent of the dose deposited in the lungs." Oropharyngeal deposition was 86 percent with the conventional metered-dose inhaler and 10 percent with our modification (InspirEase); 59 percent of the dose remained in the reservoir (InspirEase). Holding chamber attachments appear to deliver more drug to the peripheral airways. Outpatient therapy should be aided by hospital use of the metered-dose inhaler with holding chamber. The patient receives instruction in the proper use of the holding chamber device during treatment in the ED and immediately sees improvement in asthma symptoms. These incentives should encourage continued use of this superior technique at home. If the patient requires several rounds of treatment, even more opportunity for instruction in technique would be provided. Although the inhaler system required 1 min more than the nebulizer for assembly and patient instruction, this time was well spent instructing patients in proper inhalation technique - knowledge that can be applied at home for more effective preventive management of asthma. Many patients with acute exacerbations of asthma would benefit from the home use of holding chambers because of the more consistent delivery of aerosol to the pulmonary airways. By enhancing techniques of administration of beta-adrenergic agonists during early stages of asthma exacerbations, holding chambers increase the reliability of treatment during this critical period. With these devices, patients can administer rescue doses of inhaled beta-adrenergic agonists before departing for or on the way to the hospital; or, if they have received appropriate training, they can better implement recommendations for home management. In our study, the metered-dose inhaler with holding chamber required less than 6 min for assembly, instruction, and delivery of the first full dose of drug, whereas the nebulizer required 12 to 15 min for delivery of the first full dose. This advantage may make the metered-dose inhaler with holding chamber ideal for prehospital care of acute asthma, because ambulance transport time is frequently under 10 min. Also, the metered-dose inhaler with holding chamber is compact and requires little storage space; unlike the nebulizer, it does not require a source of compressed gas or other elaborate equipment for its operation. Although the metered-dose inhaler with holding chamber was found to be feasible in prehospital treatment, further study in this setting would be necessary for a definitive assessment." Emergency Department Treatment of SevereAsthma(Idris al al)
The metered-dose inhaler with holding chamber has other advantages. We notice that some patients breathe through the nose when the mouthpiece of the nebulizer is in the mouth, thus losing drug to the air. This loss of drug is difficult to recognize because the nebulized vapor is almost invisible against most backgrounds. In contrast, our device (InspirEase) has a drug reservoir bag that collapses when the patient inhales, thus confirming drug inhalation. Because a recent report described large variation in the rate of nebulization for nebulizers;" we studied this variable for the units used in our study. Twelve nebulizers were randomly selected from those used in the study and were tested for variation in rate by nebulizing 2.5 ml of saline solution with a gas flow rate of 5 Umin. We then measured the volume of solution that remained after nebulization ceased. The median rate of nebulization was 0.188 mllmin (range, 0.162 to 0.222 mllmin). The variation in rate was 37 percent (100 X [highest rate - lowest rate ]Ilowest rate), and the mean residual volume was 0.47 ± 0.08 m!' It is possible that the greater variation in response found in the nebulizer group was caused by variation in the rate of nebulization. Metered-dose inhalers are usually more consistent in the amount of drug dispensed with each discharge than are nebulizers, which vary in rate by more than 128 percent." The metered-dose inhaler with holding chamber has been shown to reduce costs in treating hospitalized patients.">' In ED settings, if the holding chamber and adrenergic drug are to be prescribed to patients after hospital discharge, then the costs within the ED are competitive with those incurred by use of nebulizers. The cost of time for instruction by nurses in the use of the holding chamber is $1.50 to $4.50. The patient charge is $16.85 for the holding chamber attachment and $19.70 for the drug canister (total, $36.55). The patient can use the holding chamber attachment for more than 1 month; and the drug canister, which contains 200 metered inhalations, can provide further treatment at home. We estimated the cost of the nebulizer unit to be $2.30; medication, $0.30 per dose; and respiratory technician time, $2.50 (total, $5.10). Of course, following discharge from the ED, an inhaler and optimally a holding chamber would be prescribed for outpatient use, a cost that would already be covered if it had been used in the ED. During the study, an investigator stayed at the bedside during all training and treatments. Where the inhaler system is being used in routine clinical practice (Cook County Hospital), a physician or nurse stays at the patient's side during the initial training and during subsequent administrations if the patient is experiencing any difficulty with technique. Since the patient is often markedly symptomatic during the first round of
therapy, the physician is present until symptoms improve. The purpose of this study was to compare two methods of administering an inhaled J3-adrenergic agonist for the treatment of acute asthma. The study was not designed to evaluate steroid use either in the ED management of acute asthma or in the hospital discharge regimen following an acute exacerbation. It is worth noting that only 14 percent of study patients had received steroid medication shortly before seeking ED care. Regular use of inhaled steroids or selfadministered burst therapy may have prevented some of the exacerbations. Present recommendations include at least consideration of steroids for all patients discharged from the ED.34 After ED discharge, 20 of 35 study patients were given a prescription for steroids. Many patients were given follow-up appointments, and all were given an investigator's phone number to call if they had problems. No patient called the investigator. CONCLUSIONS
Albuterol administered by metered-dose inhaler with holding chamber is an effective, rapid alternative to nebulizer therapy for moderate and severe acute asthma. This method helps patients master correct inhalation technique in the course of treatment in the ED. Further study is necessary to establish its role in the prehospital setting and in treatment of patients with the most severe asthma tie, those who have an FEV t <30 percent of the predicted normal value). ACKNOWLEDGMENTS: The authors thank Pauline Snider for editorial assistance, Susan Lorash for help with manuscript preparation, and Richard J. Melker, M.D., Ph.D., for thoughtful critique of the manuscript. REFERENCES
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EmergencyDepartment Treatment 015e119re Asthma (/dris et aI)