High-
Versus
Low-Dose,
Frequently
Administered,
Nebulized
Albuterol
in Children
With Severe,
Acute
Asthma
Suzanne
Schuh,
MD,
FRCPC,
Patricia
Parkin,
MD,
FRCPC,
Aziza
Rajan,
MB, ChB,
Gerald
Canny,
MD,
FRCPC,
Rosalean
Healy,
MS
ChB,
Michael
Rieder,
MD, SRCPC,
Yok K. Tan,
BSc (Hon),
Henry
Levison,
MD, FRCPC,
and
Steven
J. Soldin,
PhD,
FACB
From the Divisions of Emergency, Chest, and Clinical Pharmacology (Department of Paediatrics) and the Department of Biochemistry, The Hospital for Sick Children, Toronto
ABSTRACT. Thirty-two 5- to 17-year-old children who had severe, acute asthma were randomly assigned to receive either high doses (0.15 mg/kg of body weight per
dose) or low doses (0.05 mg/kg of body weight per dose) of nebulized albuterol every 20 minutes for six doses.
Compared with the low-dose regimen, the high-dose
reg-imen resulted in significantly greater improvement in
forced expiratory volume in 1 second, forced vital
capac-ity, and wheeze score and a lower hospitalization rate.
The changes in heart rate, respiratory rate, blood
pres-sure, white blood cell count, and serum potassium con-centration did not differ significantly between the groups.
The incidence of side effects, which included tremor,
hyperactivity, and vomiting, was not significantly differ-ent in the two populations. Serum albuterol levels varied widely, but there was no correlation between the levels and the increase in heart rate or other side effects. High-dose, frequently administered, nebulized albuterol ap-pears both safe and effective in treating severe, acute asthma in children. Pediatrics 1989;83:513-518; asthma, albuterol, status asthmaticus.
ABBREVIATIONS. FEy1, forced expiratory volume in 1 second; FVC, forced vital capacity; PEFR, peak expiratory flow rate.
ever, relatively little is known about the optimal and safe dose of this drug. A recent study from our institution demonstrated the benefit of frequent inhalation of low doses of nebulized albuterol (0.05 mg/kg of body weight) in persons with severe asthma.’ For some time, we have had the impres-sion that using frequently administered high-dose (0.15 mg/kg of body weight) nebulized albuterol in the emergency department leads to dramatic im-provement within about two hours in most children
who have acute, severe asthma; in many instances, it obviates admission to the intensive care unit. Moreover, the use of high-dose frequently admin-istered albuterol for children requiring intensive care often eliminates the need for more aggressive therapy, such as IV albuterol or mechanical venti-lation (D. Bohn, personal communication, 1987).
The present study was designed to determine the efficacy and safety of high- v low-dose frequently administered albuterol therapy in children report-ing to the emergency department with acute, severe asthma. Biochemical effects of albuterol and albu-terol plasma levels were also examined.
The efficacy of nebulized albuterol in treating severe childhood asthma is well established.’
How-Received for publication March 18, 1988; accepted May 31, 1988.
Presented, in part, at the American Pediatric Society, Society for Pediatric Research Meeting, May 5, 1988, Washington, DC. Reprint requests to (5.5.) Division of Emergency, The Hospital for Sick Children, 555 University Aye, Toronto, Ontario M5G
1X8, Canada.
PEDIATRICS (ISSN 0031 4005). Copyright © 1989 by the American Academy of Pediatrics.
MATERIALS
AND
METHODS
Patients seeking treatment at our emergency de-partment were included in the study if they had clinical evidence of acute asthma, were at least 5 years of age, had an initial forced expiratory volume in 1 second (FEy,) less than 60% of the predicted value, and had no concurrent cardiopulmonary dis-ease. Informed parental consent was obtained, and the study was approved by the Human Ethics
Study Protocol
A history with respect to duration of asthma and of the present exacerbation, past and present med-ications, and previous hospitalizations was ob-tamed. Height, weight, heart rate, respiratory rate, blood pressure, and wheeze score were measured. Wheeze score was calculated as follows: 0, no wheezing; 1, wheezing audible only through a steth-oscope; 2, audible wheezing during quiet breathing;
3,
obvious wheezing and dyspnea; 4, respiratory distress and obvious use of accessory muscles. Heart rate was monitored throughout the study (Physio-logic Lifepack 8). Baseline FEy,, forced vital ca-pacity (FVC), and peak expiratory flow rate (PEFR) were measured using a small, hand-held, battery-operated turbine spirometer (P. K. Morgan, Kent, England). These measurements were re-peated after each dose of albuterol was adminis-tered (ie, every 20 minutes). The best of three attempts was recorded. Results were compared with published predicted values for height and sex.2Baseline laboratory investigations included WBC count and differential and serum potassium and serum albuterol levels (in all patients); in patients who had received theophylline within the previous 48 hours, serum theophylline levels were measured. The measurements were repeated 15 minutes after the last dose of albuterol. Albuterol levels were determined according to a modification of the method described by Tan and Soldin,’ using
ba-methane sulfate (Sigma, St Louis) as the internal standard.
The first dose of albuterol, 0.15 mg/kg of body weight (0.03 mL/kg of body weight of a 0.5%
res-piratory solution) to a maximum of 5 mg (1.0 mL), was administered by nebulizer (Whisper Jet
nebu-lizer, Intec, Marquest Medical Products, Engle-wood, CA) together with a 3-mL 0.9% saline solu-tion (flow rate 6 to 7 L/min) to all children. A face mask that fit tightly around the child’s nose and mouth was chosen so that
drug
delivery was not affected by either mouth or nose breathing and was as continuous as practicable. (A flow rate of 6 Li mm produced a particle size with a mass median diameter of 3.18 m, geometric SD 1.69.) This resulted in complete nebulization of the total vol-ume in 15 to 17 minutes.Patients were randomly assigned to either low-dose (0.05 mg/kg of body weight per dose) or high-dose (0.15 kg of body weight per dose) albuterol inhalation treatment, using a predetermined ran-domization scheme. Patients receiving the high-dose treatment received the standard solution. The pharmacist prepared the low-dose solution by add-ing a 0.9% saline solution to the standard solution.
Thus, equivalent volumes were prepared for both treatment groups, and parents, patients, and inves-tigators were unaware of the treatment assignment. Patients received six additional doses of albuterol by inhalation at 20-minute intervals, each inhala-tion lasting about 15 minutes. Doses were calcu-lated according to the patient’s weight, up to a
maximum of 5 mg per dose for the high-dose group and 1.7 mg per dose for the low-dose group of children weighing <40 kg. For those weighing 40 kg, 2.5 mg per dose was used to prevent undertreat-ment in the heavier children. Any side effects or cardiac rhythm abnormalities were noted.
The study was prematurely terminated in pa-tients who showed rapid improvement (FEy, >80% of the predicted value and wheeze score 0) and in those who required IV medication within 60 mm-utes of admission to the emergency department. To avoid bias, these patients were also included in the analysis. The decision to administer IV theophyl-line or steroids or to admit the child to the hospital was made by the attending pediatrician, who was not involved in the study.
Outcome was measured on the basis of clinical status (wheeze score and vital signs), pulmonary function tests, admission to the hospital, and side effects.
Statistical
Analysis
The results were analyzed statistically, using the Wilcoxon rank sum test to test the difference
be-tween the various pre- and posttreatment
measure-ments, the Student’s t test to evaluate the difference between the means in FEy, at each time point, and
x2
analysis to test the difference in admission rates. The mean percentage change in the parameters reported was calculated as follows: (last measure-ment - first [pretreatment] measurement)/first measurement. All patients received the same first dose; therefore, the mean percentage improvement in FEy1 between the second and the last measure-ments was also analyzed as follows: (last FEy, measurement - second measurement)/secondFEy, measurement.
RESULTS
TABLE 1. Initial Clinical Characteristics of the 32 Study Patients*
Characteristics High-Dose Group 9.4 ± 3.8
3 7 8 7 4 3 1 2 4 6 6 0 10 5 3 1 3 4 5 5 4 7
27.9 ± 5.5
42.4 ± 6.7
35.1 33.6 117.4 120.5 2.59 1.94 10.73 7.15
32.4 ± 5.9 42.6 ± 6.9
33.1 29.1 113.5 129.3 2.94 2.63 12.77 9.20 4.17 4.29
Age (mean yr ± SD)
Medication given within previous 24 h
Albuterol (nebulizer)
Albuterol (metered-dose inhaler)
Medications within 48 h
Theophylline
Orciprenaline (syrup) Cromolyn sodium
Beclomethasone dipropionate None
Duration of asthma (mean yr) Duration of present attack (h)
<24 24
>24
Forced expiratory volume in 1 s mean (mean
% of predicted value ± SD) Initial
After 1st dose
Forced vital capacity (mean % of predicted value ± SD)
Initial
After 1st dose
Peak expiratory flow rate (mean % of pre-dicted value ± SD)
Initial After 1st dose
Respiratory rate (mean No. breaths/mm) Initial
After 1st dose
Heart rate (mean No. beats/mm) Initial
After 1st dose
Mean wheeze score Initial
After 1st dose
WBC count (mean No. x 109/L)
Polymorphonuclear forms (mean No. x iO/ L)
Potassium (mean mmol/L) *Results are means ± SEM.
rate; and wheeze score (Table 1). Of the nine pa-tients who had been taking theophylline, only one had a therapeutic serum level at the time of arrival at the hospital.
After the first dose, the percentage improvement in FEy,, FVC, wheeze score, and change in vital signs was not statistically different in the two groups. However, between the beginning and the end of the study the FEy,, FVC, and wheeze score improved significantly in the high- v low-dose groups (Table 2, Figs 1 to 3 ). The difference be-tween the groups in the change in mean FEy, was significant (P < .05) beginning 60 minutes after the start of the study except at 120 minutes.
There was no difference between the two groups in the changes in the respiratory rate, heart rate,
WBC count, neutrophil count (30 patients only,
Low-Dose Group 8.6 ± 2.1
29.3 ± 10.9 32.4 ± 11.8 47.0 ± 12.7 46.6 ± 18.8
39.9 ± 16.0 42.2 ± 18.7 60.6 ± 11.1 53.4 ± 11.9
two specimens were lost), and serum potassium concentration (24 patients only, 12 in each group; eight specimens were hemolyzed). In most patients the heart rate increase occurred during the first 40 minutes. The mean maximum was 134
beats
per minute in the high-dose group (range, 90 to 160 beats per minute) and 133 beats per minute in thelow-dose group (range, 96 to 159 beats per minute). No difference in blood pressure changes was noted between the two groups.
200
-150
-.)1o0
8.
50
-400
300
200
100
0
Ui U. C
C 0
E
0 0 a E 0 0, C 0 U 0 a
HIGH DOSE LOW DOSE
Fig 2. Percentage change of forced expiratory volume in 1 second (FEy,) in two groups between first dose and end of study.
Fig 3. Percentage change of forced expiratory volume in 1 second in two groups between second dose and end of study.
TABLE 2. Percentage Change Between First and Last Measurements*
High-Dose Group
Low-Dose Group
P Value
Forced expiratory volume in 1 s (% increase)
From baseline 131.8 ± 20.5 58.2 ± 14.9 .011
From 1st treatment 34.5 ± 6.0 9.6 ± 7.0 .0039 Forced vital capacity
From baseline 79.4 ± 11.9 39.5 ± 15.4 .0098
From 1st treatment 15.5 ± 10.1 2.3 ± 7.9 NS
Wheeze score (% decrease)
From baseline 75.4 ± 10.1 39.7 ± 10.8 .022
From 1st treatment 61.3 ± 15.0 30.0 ± 16.6 .020
Heart rate (% increase)
From baseline 15.8 ± 4.1 20.2 ± 5.8 NS
From 1st treatment 11.2 ± 6.9 2.7 ± 4.7 NS
Respiratory rate (% decrease)
From baseline 14.8 ± 5.7 1.2 ± 7.7 NS
From 1st treatment 13.4 ± 10.1 12.1 ± 7.7 NS
WBC (% increase) 7.6 ± 7.8 3.2 ± 6.2 NS
Neutrophil count (% increase) 35.3 ± 21.0 21.8 ± 10.0 NS
Serum potassium (% decrease) 19.9 ± 3.2 19.2 ± 2.6 NS
* Results are means ± SEM.
___
highdoseT
[dose_
T
i/oO
P
.-...
I
,r-#{149}-
1--i
I
44
, I I I t I
-1---20 40 60 80 100 120 140 160 180
time (minutes)
Fig 1. Mean percentage of improvement of forced ex-piratory volume in 1 second from baseline in high- com-pared with low-dose groups.
patients in the high-dose group improved rapidly and one failed to respond to therapy, whereas three patients in the low-dose group improved rapidly and three got worse or failed to respond to treat-ment.
The mean pretreatment albuterol levels were low and not statistically different in the two groups (1.01 ± 2.4 ng/mL in the high-dose group and 2.50 ± 4.6 ng/mL in the low-dose group). The mean
posttreatment levels were 19.8 ± 10.7 ng/mL (range, 0.9 to 46.3 ng/mL) in the high-dose group and 12.4 ± 6.5 ng/mL (range, 6.0 to 30.4 ng/mL) in
100
k!i!14
% Change-20806040200
-40 HIGHDOSE LOWDOSE
(patients with tremor had a mean level of 16.9 ng/ mL; those with no tremor had a mean level of 13.0 ng/mL), or vomiting (patients with vomiting had a mean level of 17.2 ng/mL; those without vomiting had a mean level of 14.0 ng/mL). All ofthe patients who received albuterol only by a metered dose in-haler at home had baseline levels of 0.
The side effects were mild in both groups, and the differences between the groups were not statis-tically significant. There were 12 patients (eight in the high-dose group and four in the low-dose group)
who experienced tremor and hyperactivity, which was usually mild and subsided quickly after the therapy. One child complained of a mild headache that required no treatment. Four patients (three in the high-dose group) vomited during the study. Two of them had been nauseated when they arrived for treatment and one had vomited at home before coming to the hospital. No children complained of palpitations, and no arrhythmias were noted on the EEG.
Ten patients in the low-dose group and four patients in the high-dose group required admission to the hospital, all for medical reasons
(x2,
P < .033). During the next 48 hours, none of the other children required hospitalization and only one pa-tient required additional albuterol inhalations in the emergency department.DISCUSSION
Inhaled albuterol is the preferred treatment for acute asthma in children. The main benefit of in-halation therapy is that high levels of the drug are concentrated at the site of action, giving the desired therapeutic result with minimal side effects.4
A recent study at our institution showed the superiority of frequent low doses of this drug (0.05 mg/kg of body weight per 20 minutes) rather than the more customary hourly administration (0.15 mg/kg of body weight per hour) in achieving earlier maximal response and preventing deterioration be-tween doses.’ In most studies attempting to estab-lish the “optimal” dose of the drug adult subjects with stable asthma, a small sample, or a low dose of the drug were used. Our high-dose group, in which much higher doses were used than previously reported, had a significantly better result than the low-dose group, as measured by improvement in FEy,, FVC, wheeze score, and hospitalization rate.
High doses of inhaled albuterol are needed in acute asthma because only about 10% of the dose actually reaches the lung,9”#{176}the decreased airway caliber further decreases the aerosol penetrance,’#{176}” and the quantity of drug reaching the lung decreases as the patient’s pattern of respiration is altered.’2
Although the initial, high, dose may open the air-ways and allow greater penetration and bronchod-ilator effect from subsequent smaller doses, it was insufficient for many of our patients in the low-dose group. The albuterol doses in our study were suspended in 3 mL of saline and nebulized with an oxygen flow of 6 to 7 L/min. A combination of 4-mL volume and 6-L/min flow rate is recommended to ensure high aerosol output, small particle size, and short treatment time.’3
Whereas the dangers of toxic side effects of al-buterol may be real for adult subjects, our study suggests that there is little reason to suspect
detri-mental side effects in healthy children or young adults who do not have preexisting heart disease or biochemical abnormalities. Albuterol-induced
tachycardia may be dose related,6’9 but results of our study indicated a slightly greater increase of heart rate in the low-dose than the high-dose group. These results reflect the fact that the heart rate is influenced by other factors, such as severity of the disease and subsequent distress to the patient. In most subjects, the increase occurred within the first 40 minutes of treatment; thereafter, the rate re-mained steady or declined. This finding is similar to that of Bohn et al’4 using IV albuterol. The fi-receptor desensitization effect may play a role in this phenomenon.’4
Not surprisingly, the incidence of tremor in our study was greater in the high-dose group, but the tremor was mild and subsided quickly. As expected from our past experience, vomiting was infrequent and often attributable to the disease itself rather than the drug.
The children in both groups demonstrated an equal decrease in serum potassium levels (20%). Adrenaline alone (and therefore stress) can cause
hypokalemia.’5 This might partially explain the equal decrease in both groups. The patients in the low-dose group did not improve as much and, there-fore, could have had higher circulating catechol-amine levels than their high-dose counterparts. Al-though the degree of hypokalemia that occurred is acceptable and safe in healthy children undergoing this intense therapy for only a short time (the majority of emergency department patients), potas-sium concentrations should be monitored and pos-sibly supplemented in children who need this regi-men for many hours, such as those in an intensive care unit.
home than in the high-dose group, the two groups
were similar with respect to duration of asthma, duration of present attack, baseline pulmonary
function test results, and vital signs (Table 1). It is unlikely, therefore, that home therapy with j32-ag-onists influenced the outcome of the study.
To our knowledge, serum albuterol levels have not been previously reported after repeated doses
of nebulized albuterol in asthmatic patients, al-though reports of measurements after oral or IV administration exist.’7 Because we have used large doses, some of our serum levels far exceed those reported before.’7 Because the nebulized drug effect
is largely local, it is difficult to use the term “ther-apeutic blood level.” Rather, the drug serum level may be regarded as an indicator of toxicity. The wide range of levels achieved in our study appears to be safe.
In conclusion, frequent high doses of nebulized
albuterol appear to be effective and safe in treating
otherwise healthy children who have severe, acute asthma. The mild, temporary side effects are neg-ligible compared with the risk of prolonging patient distress and the potential necessity of resorting to more aggressive forms of therapy that have greater risks. We do not, however, advocate this regimen for home use.
ACKNOWLEDGMENTS
This research was supported by the Paediatric Con-sultants of The Hospital for Sick Children and the
Med-ical Council of Canada (Centennial Fellowship for Dr Rieder).
The authors thank the pharmacy staff, particularly Lee Dupuls, Cheryl Leeson, and Linda Morris, for their
help in organizing this study; the emergency medical and
nursing staffs and Dr D. Bohn of the intensive care unit,
for their support; and Donna Karry and Anna Moretti for typing the manuscript. The statistical analysis was carried out in cooperation with the Department of
Pre-ventive Medicine and Biostatistics, University of
To-ronto. The paper was prepared with the assistance of the
Medical Publications Department, The Hospital for Sick Children.
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