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Continuous Versus Intermittent Nebulizationof Salbutamol in Acute Severe Asthma: Lamia Besbes-Ouanes, MD*
See editorial, p. 236.
Semir Nouira, MD*
Souhail Elatrous, MD‡
Study objective: This study was conducted to compare the
Jalel Knani, MD*
clinical and spirometric effects of continuous and intermittent Mohamed Boussarsar, MD*
October 29, 1999. Revisions received nebulization of salbutamol in acute severe asthma.
Fekri Abroug, MD*
February 17, 2000, andApril 3, 2000. Accepted for Methods: Forty-two consecutive patients presenting to the
emergency department for acute severe asthma (peak expira- Address for reprints: Fekri Abroug,
tory flow [PEF] mean±SD, 24%±12% predicted) were prospec- tively randomly assigned to receive 27.5 mg of salbutamol by Bourguiba, Monastir 5000, Tunisia;216 3 460672, fax 216 3 460678; either continuous or intermittent nebulization over a 6-hour period. The continuous nebulization group received 15 mg of salbutamol during the first hour and 12.5 mg over the next 5 hours. The intermittent nebulization group received 5 mg of salbutamol every 20 minutes during the first hour and 2.5 mg 47/1/109169
doi:10.1067/mem.2000.109169
hourly over the next 5 hours. All participants received oxygenand intravenous hydrocortisone. Clinical and spirometricassessment was performed at baseline, 40 minutes, 60 min-utes, and at 3 and 6 hours after the start of the nebulization.
Secondary endpoints were the respective rates of hospitaliza-tion and treatment failure.
Results: A significant clinical and spirometric improvement
was observed in both groups over baseline as soon as the 40th
minute and was sustained thereafter (absolute PEF increase at
the sixth hour 30%±18% and 32%±22% in the continuous and
intermittent nebulization groups, respectively; P<.01 over base-
line). PEF and the clinical score evolved similarly in both groups.
There was no difference between the groups regarding the fail-
ure rate of the initial bronchodilator treatment to terminate the
asthma attack (3 [14%] in the continuous nebulization group
and 2 [9.5%] in the intermittent nebulization group, absolute
difference 4.5% [95% confidence interval –14% to 23%]). Eight
(38%) patients and 9 (43%) patients from the continuous and
intermittent nebulization groups, respectively, required hospital-
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ization according to predefined criteria (absolute difference we designed this prospective, randomized, double-blind 4.8% [95% confidence interval –24% to 34%]).
study to test the hypothesis that an equal total dose ofsalbutamol nebulized continuously induces a greater Conclusion: We did not observe an appreciable difference
bronchodilator effect and clinical improvement than between continuous and intermittent nebulization of salbutamol intermittent nebulization in acute severe asthma.
in acute severe asthma. The decision to use one of these nebu-lization methods should be based on logistical considerations.
[Besbes-Ouanes L, Nouira S, Elatrous S, Knani J, Boussarsar M, All consecutive patients who presented to the emergency Abroug F. Continuous versus intermittent nebulization of department of our hospital, a tertiary teaching hospital, salbutamol in acute severe asthma: a randomized, controlled with acute exacerbation of asthma between March 1996 trial. Ann Emerg Med. September 2000;36:198-203.] and June 1997 were screened. The following criteria wererequired for inclusion in the study: a measured peak expi- ratory flow (PEF) of less than 50% predicted in associationwith 2 of the following clinical criteria of severity: heart rate There is general agreement that nebulization of β -ago- 120 beats/min or greater, respiratory rate greater than or nists is the mainstay of therapy in patients with acute equal to 30 breaths/min, pulsus paradoxus greater than or asthma,1,2 and inhalation represents the route of choice.3-6 equal to 15 mm Hg, accessory muscles contraction, SaO2 Bronchodilator inhalation allows the deposition of high less than 92% on room air, and hypercapnia (>42 mm Hg).
doses of β -agonists directly to the bronchial receptors, Arterial blood gas values were determined in all patients.
producing maximal bronchodilator effects with minimal Exclusion criteria included a history of chronic cough, car- systemic absorption and side effects. There is a consen- diac or hepatic disease, or pregnancy. Patients were not sus that frequent intermittent nebulizations (3 in the first excluded when they had used β -agonists drugs delivered hour) are appropriate,1,2,6-9 but continuous nebuliza- by metered-dose inhaler before ED arrival. Patients were tion is also proposed.1,2 Frequent administration of allocated by means of random table to receive salbutamol bronchodilators is thought to dilate the proximal either by continuous or intermittent nebulization. After bronchial tree, thereby allowing further distal deposition opening of the sealed allocation envelopes, mixtures for of subsequent bronchodilator treatments, which pro- nebulization were prepared by an uninvolved ED staff duces sustained bronchodilation and prevents bron- member. The study physician was blinded to the solution chospastic rebounds.10-13 All these benefits also might be used and to the nebulization modality.
obtained with continuous nebulization of bronchodila- All patients received a total dose of 27.5 mg of salbuta- tors.13-18 Recent studies comparing intermittent and mol (Ventolin for nebulization; GlaxoWellcome) over the continuous nebulization of β -agonists suggested that 6-hour study period. Aerosol was administered by a the latter might carry some advantages.14,15 However, pneumatic nebulizer (mini-nebulizer; Peters; 40-115510; these studies focused on pulmonary function change and Bobigny, France) with a face mask driven by an oxygen did not assess clinically relevant endpoints such as the flow rate of 6 L/min. A bench test showed that a 5-mL improvement of the clinical condition and the rate of solution was delivered within 12 to 13 minutes. Patients hospitalization or relapse. Moreover, beneficial effects received 15 mg of salbutamol during the first hour and were not found on an intention-to-treat basis and were 2.5 mg hourly thereafter. The reservoir of the pneumatic apparent only when a retrospective post hoc analysis was nebulizer was connected to a standard infusion pump by performed on the subset of the patients exhibiting the an 18-gauge needle. Syringes filled with 7.5 mL and 50 most severe bronchial obstruction.14,15 In addition, in mL of saline solution (intermittent nebulization group) or one study the regimen of intermittent nebulization did salbutamol solution (continuous nebulization group) not conform to that currently recommended for frequent were successively delivered to the reservoir over the first hour and over the next 5 hours, respectively. In addition, Finding a better way to administer β -agonists might the content of vials containing either saline solution (in be of utmost importance because severe bronchoconstric- the continuous nebulization group) or salbutamol (in the tion and acute severe asthma has been well identified as intermittent nebulization group) was added to the reser- the leading cause of mortality in asthma.19 Accordingly, voir every 20 minutes during the first hour, then hourly S E P T E M B E R 2 0 0 0
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for the remaining 5-hour study period. Hence, each patient Data are presented as mean±SD. Data were analyzed on received a nebulization of 5 mL every 20 minutes the first an intention-to-treat basis. Baseline data of the 2 groups were compared using Mann-Whitney U test for non-nor- In addition to nebulized salbutamol, all patients mally distributed continuous variables. Changes in PEF received oxygen delivered at a flow rate of 6 L/min and rates and clinical severity scores were evaluated using intravenous hydrocortisone hemisuccinate, 200 mg repeated-measures analysis of variance with the time by group as within-subject factor. Sample size calculations Clinical evaluations and PEF (best of 3 measurements) (β=.2 and 2-tailed α=.05) showed a study population of were performed at baseline and after 40 minutes, 1 hour, 19 in each group would have an 80% power to detect a 3 hours, and 6 hours from the start of nebulization.
13% difference in PEF (assuming SD of 14%)15,20 and a Clinical severity was measured by a scoring system that 2-point difference in clinical severity score (assuming SD assessed 5 components (dyspnea, wheezing, accessory muscles contraction, respiratory rate, and pulsus para- The study protocol was approved by the local ethics doxus), each rated on a score of 0 to 3 with a maximum committee of our hospital, and informed consent was score of 15 reflecting a severe attack.5 Patients had con- obtained from each participating patient.
tinuous cardiac monitoring throughout the study periodand ECGs were obtained at the sixth hour. Arterial blood gas values and serum potassium levels were measured atinclusion in the study and at the sixth hour.
During the study period, 102 consecutive patients pre- In case of clinical deterioration during the study and sented to the ED with acute asthma, and 42 fulfilled the when the initial treatment protocol failed to terminate the inclusion criteria and were randomly assigned to study asthma attack, patients were admitted to the ICU andadditional treatment was given. Treatment usually con-sisted of nebulized ipratropium bromide and intravenous aminophylline. At the end of the sixth hour, patients were Baseline characteristics of study patients. discharged from the ED when the following criteria werepresent: SaO greater than 92% on room air, no persistent Continuous
Intermittent
use of accessory respiratory muscles, pulsus paradoxus Nebulization
Nebulization
less than 12 mm Hg, PaCO less than 45 mm Hg, and pH Characteristic
greater than 7.35 with a PEF value more than 60% pre-dicted.7 Patients who did not meet these criteria were Primary outcome measures were changes in spiromet- ric values and clinical scores. Spirometric improvement Previous medication, No. (%)*
was assessed according to the magnitude and time course of PEF change. Clinical improvement was assessed by a change in the clinical severity score. In developing this score, a reduction by 3 points reflected significant im- provement in the asthma severity. Therefore, we consid- ered the time needed to achieve a reduction by 3 points in the clinical severity score, as well as the proportions of Interval between attack onset and ED arrival (h) patients in each group whose score was reduced by 3 points at the first evaluation time, to be clinically rele- vant. Patients whose PEF or clinical severity score did not improve during the first hour of the study were compared.
Secondary outcome measures were failure to improve rate (with ICU admissions) and hospitalization rate.
The frequency of untoward β -agonist effects (heart rate change, hypokalemia, and ECG changes) were also *Some patients were receiving more than one medication.
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treatment. Demographic and clinical characteristics of needed to reduce the clinical severity score by at least 3 the study patients are shown in the Table. Mean PEF was points was not statistically different between both groups 24%±12% predicted. Hypoxemia was present in all (114±9.3 minutes versus 102±9.4 minutes, respectively).
patients with a mean PaO /FIO ratio of 198±55 mm Hg, All but 5 patients were successfully treated in the ED.
whereas hypercapnia was present in 35% of patients.
Three (14%) patients in the continuous nebulization Twenty-one patients in each group were randomly group and 2 (9.5%) patients in the intermittent nebuliza- assigned to receive either continuous nebulization or tion group did not improve and required supplemental intermittent nebulization. Each group had identical treatment (absolute difference 4.5%; 95% CI –14% to demographic and clinical characteristics (Table).
23%). All these patients were hospitalized in the ICU and Both nebulization modalities improved PEF and clini- received additional medications as needed. Mechanical cal severity score compared with the baseline value. The ventilation was required in only one patient from the absolute PEF increase at the 6-hour evaluation time was intermittent nebulization group. There were no deaths in 30%±18% and 32±%22% in the continuous and inter- the study population. There was no statistical difference mittent nebulization groups, respectively (P<.01 over in the hospitalization rate between the study groups; 8 baseline) (Figure 1). The decrease in clinical severity (38%) patients and 9 (43%) patients in the continuous scores at the 6-hour evaluation time was 6.3±3.1 and nebulization and intermittent nebulization groups, 6.1±2.9 in the continuous and intermittent nebulization respectively, were hospitalized according to the prestated groups, respectively (P<.01 over baseline) (Figure 2).
criteria (absolute difference 4.8%; 95% CI –24% to 34%).
Neither the magnitude nor the time course of PEF and No major untoward effects related to salbutamol nebu- clinical severity score improvement were statistically dif- lization were recorded in the present study. In particular, ferent between the study groups. Similar proportions of the serum potassium concentration decreased by the patients achieved a reduction by 3 points in the clinical same magnitude in both groups (–0.44 and –0.40 mmol/L, severity score by the 40th minute: 38% and 33% in the respectively) and was slightly reduced at the end of the continuous nebulization and the intermittent nebuliza- study period (3.4±0.4 mmol/L and 3.6±0.4 mmol/L in the tion groups, respectively (absolute difference 5%; 95% continuous and intermittent nebulization groups, respec- confidence interval [CI] –22% to 32%). The time interval tively). The heart rate was also decreased by 20 and 18beats/min, respectively. No other ECG changes wereobserved in any of the study patients.
Figure 1.
Percent predicted PEF for continuous (solid line) and intermit-tent (dashed line) nebulization groups. Bars represent 1 SD. Figure 2.
Clinical severity score changes for continuous (solid line) andintermittent (dashed line) nebulization groups. Bars represent 1 SD. *P<.05 over baseline. S E P T E M B E R 2 0 0 0
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populations. Two studies by Moler et al27 and Portnoyand Aggarwal28 used an open-label design and were In the present study, no appreciable difference was uncontrolled. Both studies showed the efficacy and safety observed between continuous and intermittent nebuliza- of this nebulization modality. More recently, studies tion of salbutamol in patients presenting to the ED with including adult patients were performed to compare both acute severe asthma in regard to spirometry (PEF), clini- β -agonist nebulization modalities.13-18 Most of these cal symptoms (clinical score), or disposition (hospitaliza- studies were hampered by the wide variation in asthma tion rate). However, this was a small study with limited severity of the included patients, the limited duration of power to detect differences in failure and hospitalization the study, and evaluation of only spirometric improve- rate. Accordingly, the decision to use intermittent or con- ment. Overall, most of these studies did not document an tinuous nebulization should be made on the basis of additional benefit from continuous nebulization. When logistical considerations (expense and nurse workload).
performing post hoc analysis on subsets of patients with The dosage regimen of salbutamol used in this study the most severe bronchial obstruction, Rudnitsky et al14 might appear quite high, especially in the light of findings and Lin et al15 reported a superior effect of continuous that two thirds of asthma attacks are terminated with nebulization compared with intermittent nebulization. doses as low as 2.4 to 3.6 mg of salbutamol from a metered- The controlled study by Papo et al13 enrolled patients dose inhaler20 and 5 to 7.5 mg from a nebulizer.8 How- already hospitalized in a pediatric ICU with severe status ever, it should be emphasized that the dosage regimen of asthmaticus and found greater efficacy with continuous the first hour (3 doses, 5 mg each) was in agreement with β -agonist nebulization. Seventeen children with acute the current international recommendations.1,2,5,7,8,21-23 severe asthma (Wood asthma score >5) were randomly It should also be noted that no major side effects were assigned to receive continuous or intermittent nebuliza- observed in the present study and that with such a dosage tion of salbutamol (0.3 mg/kg per hour). Efficacy criteria regimen, serum levels of salbutamol are not elevated.5 consisted of the elapsed time to achieve a steady clinical We elected to use a pneumatic nebulizer with a small situation free from signs of impending acute respiratory reservoir to avoid large amounts of residual volume, which failure (Wood score <5 for at least 4 hours) and the need can amount to as much as 20 mL when large nebulizers for respiratory therapy. Continuous nebulization allowed (60-mL) are used.15 An additional advantage of nebulizers children to achieve more rapidly the assigned clinical with small reservoirs is that they permit a double-blind objective, shortened the duration of hospitalization, and study by allowing the use of the same type of reservoir for reduced the respiratory therapy time. However, the study both continuous and intermittent nebulization.
by Papo et al was not blinded, had a too small sample size, Most clinical trials dealing with acute asthma used and the randomization process yielded a continuously spirometric improvement as the main outcome measure.
treated group whose weight was 10 kg more than the However, the change in pulmonary function is not intermittent group, suggesting that the first group directly related to clinical improvement and other rele- received greater dosage of salbutamol.
vant outcome measures such as the rate of hospitalization Continuous nebulization of β -agonists might be or discharge from the ED.24 In the current study, we com- expected to enhance the pulmonary function of patients pared both nebulization modalities with spirometry, as with acute asthma and ameliorate their clinical status more well as change in clinical status and the rate of hospital- rapidly than intermittent nebulization.13-15 These effects ization. In addition, because the early physiologic and should result in a reduced rate of hospitalization and the clinical response to nebulized β -agonists has been need for invasive procedures such as mechanical ventila- recently shown to be an important factor in the prediction tion or intravenous β -agonists. It has been speculated that of the need of hospitalization and the potential for relapse, these beneficial effects occur through an early deposition of both nebulization modalities were compared with regard β -agonists in the distal bronchi as bronchoconstriction is to their rapidity of action, as expressed by the proportions alleviated proximally and a sustained stimulation of pul- of patients whose condition did not improve and required monary β -adrenergic receptors, thereby preventing the ICU admission by the first 40 minutes of the nebulization rebound bronchospasm that might occur with intermittent and the time interval needed to gain 3 points in the clini- delivery.13 These effects might also be related to the high blood levels of bronchodilators produced by continuous The first publications on continuous nebulization of nebulization of β -agonists, leading to synergistic effects of β -agonists in acute asthma were conducted in pediatric localized and systemic actions of β -agonists.29 However, A N N A L S O F E M E R G E N C Y M E D I C I N E S E P T E M B E R 2 0 0 0
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Moler et al30 designed a controlled trial to address this 13. Papo MC, Frank J, Thompson AE. A prospective randomized study of continuous versus issue and recorded similar levels of plasma terbutaline con- intermittent nebulized albuterol for severe status asthmaticus in children. Crit Care Med.
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Bourguiba Hospital, without whom this study would not have been possible.
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