Metered Dose Inhaler Salbutamol Treatment of Asthma in the ED: Comparison of Two Doses With Plasma Levels GUSTAVO RODRIGO, MD,* CARLOS RODRIGO, MDI" Two cumulative doses of salbutamol delivered by metered dose inhaler (MDI) with a pear-shaped spacer were compared (400 I~g vs 600 I~g at 10-minute intervals). Twenty-two patients (mean age 35.1 -+ 11.1 years) with acute exacerbation of asthma were randomly assigned, in a doubleblind fashion, to receive salbutamol delivered with MDI into a spacer device in 4 puffs at 10-minute intervals (100 I~g or 150 Fg per actuation) during 3 hours (1200 t~g or 1800 I~g each 30 minutes). Mean peak expiratory flow rate (PEFR) and forced expiratory volume in the first
second (FEVl) improved significantly over baseline values for both groups (P < .001). Nevertheless, there were no significant differences between both groups for PEFR and FEVI at any time point studied. A significant net reduction of heart rate was observed in the 400 ~g group (P < .01). On the other hand, a significant increase in heart rate was observed in the 600 iLg group (P < .001).The QTc interval did not show a significant prolongation, and the two groups presented moderate decreases of serum potassium levels. There was a significant dose-related increase (P = .027) in Sao2. Additionally, the 600 ~g group generated a serum glucose level increase from 0.85 + 0.12 mg/100 mL to 1.04 + 0.25 mg/100 mL (P = .02). At the end of treatment, the salbutamol plasma levels were 10.0 -+ 1.67ng/mLfor the 400 I~ggroup, and 14.0 + 2.17for the 600 Izg group (P = .001). Finally,the overall symptom score in patients in the 600 ~g group was significantly greater than the score in the low dose group (P = ,02), with a higher incidence in 4 symptoms (tremor, headache, palpitations, and anxiety). These data support the notion that the treatment of acute asthma patients in the emergency department setting with salbutamol, 2.4 rag/h, delivered by MDI and spacer (4 puffs at 10-minute intervals) produces satisfactory bronchodilation, low serum concentration, and minimal extrapulmonary effects, However, an increase of 50% of the dose (600 p,g at 10-minute intervals) produced a nonsignificant, slightly better therapeutic response but with greater side effects, probably related to higher salbutamol levels. (Am J Emerg Med 1996;14:144-150, Copyright © 1996by W.B. SaundersCompany)
Inhaled beta-agonists are the first-choice bronchodilator drugs used to treat acute severe asthma) The evidence suggests that there is little difference between metered dose inhaler (MDI) with a spacer and nebulization in the treatment of acute severe asthma, and that comparable degrees of bronchodilatation can be observed for the two different delivery systems. 2-6 However, there is no agreement on the optimal dose. 7 Trials of treatment of acute asthma are
notoriously difficult to conduct and interpret. 8 Higher doses may be important because of the unpredictability of delivery systems, low tidal volumes, variable flow rates, increased frequency of breathing, peripheral dispersion of the inhaled medication, and narrowed airways. 9 Some authors suggest a dose of 4 to 15 puffs over time delivered with MDI, 1°,11 while the British Thoracic Society suggests that 20 to 50 puffs of beta-agonists may be required for maximum bronchodilation in patients with acute asthma. 12 The dose of beta-agonists, therefore, is empiric at best, and it should be based on response and side effects rather than on the weight or size of patients. The aim of treatment should be to induce maximal stimulation of [32-receptors without causing significant side effects. Additionally, there is evidence that patients respond to increasing doses of betaagonists. 13-~6 The cumulative technique produces greater bronchodilation than an equivalent single dose of aerosolized bronchodilator.17 The purpose of the present study was to define the optimal dose of salbutamol in the treatment of acute severe asthma patients in the emergency department (ED) setting. Thus, we compared two cumulative doses of salbutamol delivered by MDI with a pear-shaped spacer.
Patients Twenty-two patients (mean age 35.1 +- 11.1 years) with acute exacerbation of asthma who were treated at the ED of Military Hospital, Montevideo, were enrolled in the trial. All patients met the criteria for the diagnosis of asthma of the American Thoracic Society38 The inclusion criteria for patients were: (1) age between 18 and 50 years; (2) a forced expiratory volume in the first second (FEV0 and a peak expiratory flow rate (PEFR) below 50% of predicted value; (3) no patients with history of chronic cough, cardiac, hepatic, renal, or other medical disease, or pregnancy; and (4) an expressed willingness to participate in the study, with written informed consent obtained. The study was approved by the Hospital Ethics Committee.
Treatment Regimen From the *Departamento de Emergencia, Hospital Central de las FF.AA, and l-Centro de Terapia Instensiva, Asociacion Espafiola la de Socorros Mutuos, Montevideo, Uruguay. Manuscript received February 27, 1995, returned March 25, 1995; revision received April 27, 1995, accepted May 9, 1995. Address reprint requests to Dr Rodrigo, Centro de Terapia Instensiva, Asociacion Espafiola Primera de Socorros Mutuos, Bulevar Artigas 1465, Montevideo 11300, Uruguay. Key Words: Treatment of acute severe asthma, inhaled salbutamol, comparison of two doses. Copyright © 1996 by W.B. Saunders Company 0735-6757/96/1402-000655.0(3/0 144
Patients who agreed to participate in the study were randomly assigned in a double-blind fashion to receive salbutamol delivered with MDI into a spacer device (Volumatic, Allen & Hanburys Ltd, Greenford, UK) in 4 puffs, at 10-minute intervals (salbutarnol 100 ~tg, or 150 ~tg per actuation). MDI canisters delivering 150 lag per actuation were specially prepared. Volumatic is a pear-shaped extension tube of 750 mL and 22-cm length with a one-way inhalation valve. Each puff was followed by two deep inhalations from the spacer. The protocol involved 3 hours of this treatment (1200 lag or 1800 lag each 30 minutes). After this time, all patients with poor response received 500 mg hydrocortisone intravenously,
RODRIGO AND RODRiGO • COMPARISON OF TWO DOSES OF SALBUTAMOL
in accord with our ED acute severe asthma current treatment protocol. Intravenous aminophylline and oxygen treatment were excluded in all patients. In accord with the Ethics Committee recommendations, our protocol included the administration of oxygen if Sao2 decreased to <90%; however, during the study, all patients had Sao2 values of >90%. Potassium was not administered.
Measurements The following variables were measured in each patient immediately before starting treatment and in 30-minute intervals until 3 hours after presentation: FEV1, PEFR, heart rate, QTc interval, and arterial oxygen saturation (Sao2). Additionally, serum potassium, glucose, and salbutamol levels were obtained at baseline and at the end of protocol treatment. Before treatment, serum theophylline concentration was determined in all subjects. PEFR was measured with a mini-Wright peak flow meter (Armstrong Industries, Inc, Northhrook, IL). The highest of three values was recorded. FEV1 was measured using a Vitalograph Compact spirometer (Vitalograph Ltd, Maids Moreton House, Buckingham, UK). Three successive maximal expiratory curves were recorded at each assessment, and the highest value was selected, according to the criteria of the American Thoracic Society.19 Heart rate was measured from continuous electrocardiogram (ECG). The QT interval was calculated as the mean of 5 consecutive beats from a rhythm strip recorded on standard lead II of an ECG at 50 mm/s. The QT interval was corrected for heart rate (QTc). 2° Sao 2 was measured with an ear oximeter (504 Pulse oximeter; Criticare Systems Inc, Waukesha, WI). Plasma potassium was assayed by flame photometry (IL 943 analyzer; Instrumentation Laboratories, Warrington, UK). Plasma glucose was analyzed by the glucose oxidase method (GM7 analyzer; Anaiox Instruments Ltd, London, UK). Finally, serum salbutamol levels were determined by highperformance liquid chromatography.2~At the end of the therapy, the patient was asked to indicate the presence or absence of each of 5 symptoms (nausea, palpitations, tremor, anxiety and headache). To compare side effects in each group, we compiled a composite symptom score for each subject by arbitrarily assigning each symptom a value of 1 if present and 0 if absent. Thus, for example, a subject who reported all 5 symptoms was assigned a score of 5, and a subject reporting no symptoms was assigned a score of 0.
Data Analysis All data were analyzed with an SPSS PC Plus software package (Version 5.0; SPSS Inc, Chicago, IL). Estimations from power calculations2z showed that the use of 22 subjects was sufficiently sensitive to detect a 21% difference in PEFR, a 26% difference in FEV1, an 8% difference in plasma potassium, a 14% difference in plasma glucose, an 18% in heart rate, a 9% in QTc, and 1.6% points in Sao2, with oL = 0.05 and t3 = 0.20 (ie, with 80% power). Two-way repeated measures analysis of variance (ANOVA) was performed to assess dose and time effects. One-way repeated measures ANOVA was used to compare baseline values for each variable. After a significant ANOVA, the Newman Keuls test was used to test equality of means. Baseline data of the two treatments were compared by t test for independent samples, Mann-Whitney U test or Wilcoxon matched pairs test. Chi-square was used for categorical variables. A P < .05 using a two-tailed test was considered significant for all statistical tests. Means are reported with standard deviations in the text.
RESULTS Mean baseline values of the two groups did not differ significantly (Table 1).
TABLE 1. Baseline Characteristics of Patients (mean _+ SD)
Age (yr) Male/Female Weight (kg) Heart Rate (beats/min) Predicted PEFR (L/rain) PEFR (% of predicted) PEFR (L/min) Predicted FEV1 (L) FEV~ (% of predicted) FEV, (L) QTc (ms) Sao2 (%) K÷ (mmol/L) Glucose (mg/100) Salbutamol (tJg/mL) Theophylline (mg/L)
400 pg/10 min (n = 11)
600 tJg/10 min (n = 11)
33.7 (13.7) 4/6 65.0 (14.2) 107.7 (21.6) 520.6 (66.1) 29.2 (8.57) 156.8 (55.3) 3.33 (0.7) 25.6 (9.2) 0.84 (0.27) 398.4 (18.7) 96.0 (1.82) 4.22 (0.56) 91.2 (8) 0.36 (0.77) 2.8 (3.0)
36.6 (6.81) 4/7 66.9 (0.8) 99.7 (21.1) 521.8 (68.3) 32.5 (6.91) 170.4 (42.8) 3.16 (0.65) 29.7 (9.3) 0.92 (0.28) 399.0 (23.0) 95.7 (1.76) 4.16 (0.32) 85.0 (12) 0.81 (1.11) 2.12 (3.7)
.5 .8 .8 .8 .9 .2 .2 .7 .1 .1 .5 .7 .8 .1 .4 .4
Three patients (27.3%) used corticosteroids within the past 7 days in the 400 lag group and 4 (36.3%) in the 600 lag group (P > .2). Six patients (54.5%) used methylxantines 24 hours before treatment in the ED in the 400 lag group, and 4 (36.3%) in the 600 lag group (P > .2). Finally, ten patients (90.9%) had received beta-agonist pretreatment in the 400 lag group and 8 (72.7%) in the 600 lag group (P > .2). All patients had theophylline levels below 10 mg/L.
Airway Responses The spirometric values at 30, 60, 90, 120, 150, and 180 minutes are shown in Figure 1. The relationships between the cumulative doses of salbutamol and the change in FEV1 and PEFR were analyzed. The magnitude of improvements in PEFR over baseline values in both the 400 lag and the 600 lag groups were significant at all times of treatment (P < .01). Mean PEFR improved significantly over baseline values for both groups (P < .001). In spite of the 600 lag group showing slight differences (especially in PEFR) over the 400 lag group, these differences did not reach statistical significance between both groups for PEFR and FEV1 at any time point studied. At final disposition the mean percentage of predicted P E F R was 50.1 _+ 13.7% (258.1 _+ 88.7 L/rain) in the 400 lag group and 55.5 + 15.2% (284.0 + 73.1 L/rain)in the 600 lag group. The same pattern held for changes in FEV1. The plateau was not attained within our dose range. After 3 hours o f protocol, the mean percentage predicted FEV1 was 48.4 _+ 15.9 (l.52 + 0.48 L) in the 400 lag group and 53.4 + 19.2 (1.59 + 0.52 L) in the 600 lag group.
Chronotropic Responses The changes in heart rate for the two groups are shown in Figure 2. A significant (P < .01) net reduction of heart rate was observed in the 400 jag group. The final mean heart rate was 97.9 -+ 19.7. No patient presented an increase in heart rate, and two patients did not show changes. The remaining nine subjects had reductions at the end of the protocol ranging
AMERICAN JOURNAL OF EMERGENCY MEDICINE • Volume 14, Number 2 • March 1996
35 180 30 25
20 .-.140 .~_ E '-t 120 n'I.L ILl n 100
"-" 112 I r-
m -5 t-r- - 1 0 O -15
T i m e (mln)
FIGURE 2. Change in heart rate (HR) in response to cumulative doses of inhaled salbutamol (@, 400 pg/10 min; [X--i,600 pg/10 min). Values are shown as mean and SD. *P < .05 v s baseline; **P < .05 v s 600 lag/10 rain.
1.2 from 7 beats/min to 35 beats/rain. Significant decrease in heart rate over baseline value were seen at 180 minutes of treatment (P < .05). On the other hand, a significant increase in heart rate was observed in the 600 ~tg group (P < .001). The final mean heart rate was 107.4 _ 13.5. There was a significant increase in heart rate at 150 and 180 minutes over baseline value (P < .05). The repeated measures A N O V A showed a significant dose effect (P = .002); the 600 lag group presented significant differences at 120, 150, and 180 minutes (P < .05). Despite the continuous E C G recording, there were no signs of arrhythmia.
~0.6 O 0.4
I 90 Time (min)
There was no significant prolongation in the QTc interval of both groups (P = .6) (Figure 3). QTc intervals at baseline, 90, and 180 minutes were 398.4 + 19.6 ms, 394.5 + 22.1 ms, 391 -+ 29 ms, and 404.0 + 27.2, respectively, in the 400 pg group, and 399.0 + 4--
FIGURE 1. (A) Change in PEFR and (B) change in FEVI in response to cumulative doses of inhaled salbutamol (@, 400 gg/10 min; [~, 600 lag/10 rain). Values are shown as mean and standard deviation (SD). *P < .01 v s baseline.
RODRIGO AND RODRIGO • COMPARISON OF TWO DOSES OF SALBUTAMOL
baseline value. The mean baseline and final Sao2 levels were 96.0 + 1.96% and 96.8 + 1.64% in the 400 lag group, and 95.7 + 1.84% and 95.8 _+ 2.24% in the 600 lag group. There were significant differences between both groups at 60, 90, 120, and 150 minutes (Figure 5).
The mean pretreatment and final serum glucose levels were 91.2 + 7 mg/100 mL and 87.9 _+ 8 mg/100 mL (P = .7) in the low-dose group. On the other hand, in the 600 lag group, the serum glucose level increased significantly from 85 + 12 rag/100 mL to 104 _+ 25 mg/100 mL (P = .02) (Figure 6).
The mean baseline and end-treatment serum salbutamol levels were 0.36 + 0.77 ng/mL (range 0 to 2 ng/mL) and 10.4 _+ 1.57 ng/mL (range 3 to 14 ng/mL) (P = .003) for the low-dose group, and 0.81 _+ 1.1 ng/mL (range 0 to 3 ng/mL) and 14.0 -+ 2.17 (range 3 to 17 ng/mL) (P = .003) for the high-dose group, respectively. At the end of treatment, there was a significant difference between the groups (P = .001).
T i m e (min)
The overall symptom score in patients in the 600 tag group (1.36 _+ 0.97) was significantly greater than the score in the low dose group (0.45 ___0.49, P = .02), and there was a
FIGURE 3. Change in QTc interval in response to cumulative doses of inhaled salbutamol (O, 400 tag/10 min; [~, 600 pg/10 min). Values are shown as mean and SD. 23.3 ms, 423.0 _+ 49.5 ms, and 414.4 + 45.1 ms, respectively, in the 600 lag group. There was no difference between both groups at any time. Nonetheless, the 600 lag group showed a different pattern characterized by a nonsignificant, increased QTc. At the end of treatment, QTc enlargements were seen in 7 patients in the 400 lag group (range 10 to 44 ms) and 8 patients in the 600 lag group (range 2 to 81 ms). Plasma Potassium
The mean baseline and final serum potassium levels were 4.22 _+ 0.58 mmol/L and 3.99 _+ 0.62 mmol/L (P = .8) in the 400 tag group and 4.16 _+ 0.32 mmol/L and 3.74 + 0.79 mmol/L (P = .3) in the 600 lag group. Four and six patients showed net decreases in plasma potassium in the low- and high-dose groups, respectively (Figure 4). There were no differences between the final serum potassium level in both groups (P = .4). The lowest individual serum potassium values after treatment were 3.0 and 2.9 mmol/L. The normal values are considered to range from 3.5 to 5.0 mmol/L. Oxygen Saturation
The two-way repeated measures ANOVA showed a significant dose effect (P = .027). Whereas the 400 lag group produced a nonsignificant increase in mean change in Sao2 (P = . 12), the 600 lag group presented minimal changes over
E to i
~3 o to
o + 2
3.74____0.79 I rls
Pre and Post Samples FIGURE 4. patient.
Baseline and posttreatment potassium levels of each
AMERICAN JOURNAL OF EMERGENCY MEDICINE • Volume 14, Number 2 • March 1996
higher incidence in 4 symptoms (tremor, headache, palpitations, and anxiety) (Table 2).
In this trial, we found that the treatment of acute severe asthma patients in the ED setting with two different doses of salbutamol delivered by MDI with spacer produces a comparable bronchodilator response but different side effect rates related to the dose administered. One of the characteristics of this study was that we employed MDI and spacer rather than nebulized administration of beta-agonists in ED treatment. In general, the MDI plus spacer or holding chamber is the most convenient, versatile, and cost-effective way to deliver aerosols. =3,24These devices should be the first choice for delivery in adults and cooperative children, z5 However, few studies have evaluated this form of drug delivery in patients with acute severe asthma. We demonstrated dose-related responses in both FEV1 and PEFR to cumulative doses of salbutamol (400 lag or 600 pg at 10-minute intervals) delivered with MDI into a spacer device (Volumatic). No significant improvements were seen in spirometric response because both treatment protocols produced similar bronchodilatation. The 600 lag dose caused a higher incidence of side effects and a significantly higher overall adverse symptom score
140 E c) c)
o o c o
0~ 80 ¢0
o 91.2__7 I
87.9±8 I ns
85.2_+12 104.6_+25 I 1 p
Pre and Post Samples 2.4
FIGURE 6. Baseline and posttreatment glucose levels of each patient.
than did the 400 lag dose. The higher incidence of tremor, palpitations, anxiety, and headache likely reflected a larger systemic absorption of salbutamol. Accordingly, there was a significant difference between both groups in plasma salbutamol levels, related to the cumulative dose administered. Other studies have shown different results. Thus, inhalations of 0.2 to 3 mg of aerosolized salbutamol result in plasma levels of < 4 ng/mL. 26,27On the other hand, Lin et a128treated seven adult acute asthmatics in the ED using 0.4 mg/kg/h salbutamol delivered by continuous nebulization over 4 hours, obtaining a mean end-treatment serum salbutamol level of 37.7 _ 15.1 ng/mL (range between 11.0 ng/mL and 48.2 ng/mL). These data suggest that continuously aerosolized salbutamol at this dose/rate can result in very high serum salbutamol levels. In contrast, we obtained a mean end-treatment serum salbutamol level of 10.0 ng/mL and 14
1.2 O c O
ct~ - 0 . 6 r"
FIGURE 5. Change in oxygen saturation in response to cumulative doses of inhaled salbutamol (0, 400 Hg/10 rain; [k-q,600 pg/10 rain). Values are shown as mean and SD. **P < .05 v s 600 pg/10 min.
Side Effects of Treatment
Symptoms Tremor Headache Palpitations Anxiety Nausea Total mean _+ SD
400 IJg/lO min (n = 11)
600 tJg/lO min (n = 11)
2 1 1 0 1
5 2 3 3 1
0.45 _+ 0.49
1.36 -+ 0.97
RODRIGO AND RODRIGO • COMPARISON OF TWO DOSES OF SALBUTAMOL
ng/mL after treating acute severe asthma patients using salbutamol doses of 37 lag/kg/h and 55 lag/kg/h delivered by MDI and spacer. On the other hand, we obtained a net increase in FEV1 of approximately 90%, compared with the 36.8% reported by Lin et al. We conclude that the two cumulative doses of salbutamol administered with MDI plus spacer in this study produced low plasma levels of this drug. Spacers decrease particle velocity and reduce the number of large particles. Both of these features reduce oropharyngeal and large-airway deposition with a consequent reduction in systemic absorption. Both groups showed opposite heart rate patterns. The 400 lag group presented a net decrease, but the 600 lag group showed a significant increase. Lin et al28 showed a significant increase in heart rate with time. Schuh et a129 demonstrated heart rate increases with serum salbutamol levels of 12.4 and 19.8 ng/mL. Jointly, these studies suggest that there may be a dose or serum level threshold in which salbutamol produces tachycardia. Initial tachycardia in acute asthma may be related to disease severity, which may be relieved with bronchodilator therapy. 3° However, salbutamol treatment may increase or decrease heart rate associated with the dose administered and particularly with the serum level obtained. In this study, heart rate presented two opposite patterns, probably related to the serum salbutamol levels resulting from the two treatment protocols. Prolongation of QTc has been observed by a number of investigators after high doses of beta-agonists. 31,32 For example, Wong et al, 32 after a cumulative dose of 26 puffs of salbutamol (2.6 mg) administered by MDI in ten patients with mild asthma, obtained a mean maximum change in QTc of 35 ms. In the present study, even though there was no significant difference between groups, the 600 lag group exhibited a moderate QTc enlargement. It has been previously found that beta-agonists cause hypokalemia owing to a direct cellular uptake of potassium through increased Na-K ATPase activity. 33 In our study, a moderate reduction in the serum potassium level was seen with the two doses, although the difference between the two drug regimens was not statistically significant. Furthermore, the mean serum potassium values during both regimens remained within the normal range. However, a reduction to <3.2 mmol/L, which may be considered a critical value, was seen one time after the low salbutamol dose, and four times in the 600 lag group. Beta-agonist treatment during acute asthma has been shown to cause a decrease in Pao2 in asthmatic subjects. 34 In contrast, this study showed a significant dose effect increase of Sao2. Whereas the 400 lag group caused a moderate increase, the 600 lag group presented minimal changes over baseline value. Finally, beta-agonists are known to increase blood glucose levels, probably through an effect on gluconeogenesis. In our study, there was a significant increase in the glucose level in the 600 lag group, in contrast to the 400 lag group, whose glucose level did not change after 3 hours of treatment. In summary, our data support the notion that the treatment of acute asthma patients in the ED with salbutamol, 2.4 mg/h, delivered by MDI and spacer (4 puffs at 10-minute intervals) produces satisfactory bronchodilation, low serum
concentration, and minimal extrapulmonary effects. This dose seems to be very effective and safe. On the other hand, increasing the dose by 50% (600 ~tg at 10-minutes intervals) produced an equivalent therapeutic response with greater side effects likely related to the increase in salbutamol absorption. The 600 pg dose level showed higher side effects. Our data suggest that 4 puffs of salbutamol at 10-minute intervals (100 lag per actuation) delivered with MDI into a spacer device (Volumatic) make an effective yet apparently safe dose in the treatment of acute severe asthma in the ED setting. Given the small sample size of each group, caution should be taken in the interpretation of these results. Further studies are needed with larger sample sizes to better delineate the dose that should be administered to patients who present to the ED with acute asthma exacerbations.
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