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(Chest. 2005;128:1115-1120.)
© 2005 American College of Chest Physicians

Regular vs Ad-lib Albuterol for Patients Hospitalized With Acute Asthma*

Alpana Chandra, MD; Chang Shim, MD; Hillel W. Cohen, DrPH; Virginia Chung, MD; Diane Maggiore, MD; Kartik Mani, MBBS and Sunil Dhuper, MD

* From the Division of Pulmonary Medicine (Drs. Chandra, Shim, Chung, Maggiore, and Dhuper), Jacobi Medical Center; Department of Epidemiology and Population Health (Dr. Cohen); and Department of Medicine (Dr. Mani), Albert Einstein College of Medicine, Bronx, NY.

Correspondence to: Chang Shim, MD, Jacobi Medical Center, 1400 Pelham Parkway S, Suite 5N-50, Bronx, NY 10461; e-mail: cshim107{at}aol.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: Inhaled, short-acting ß-agonists and systemic corticosteroids form the mainstay of therapy in acute asthma exacerbation. Asthma, however, is an inflammatory disease of the airways, and its underlying pathology is not impacted by short-acting ß-agonists. While the efficacy of ad-lib ß-agonist administration in outpatient management of asthma symptoms is well established, little data exist to support this strategy in patients with acute, severe asthma. We postulate that as long as patients hospitalized with severe asthma exacerbation receive systemic corticosteroids, regular, scheduled administration of short-acting ß-agonists is unnecessary. Similar therapeutic outcomes can be achieved with the ad-lib administration of the short-acting ß-agonists.

Design: Prospective, randomized, double-blind, placebo-controlled trial.

Setting: Pulmonary floor of a 600-bed municipal hospital.

Patients or participants: Sixty-two patients hospitalized for acute asthma.

Interventions: Patients were randomized to receive either albuterol nebulizations (regular albuterol group) or saline solution nebulizations (ad-lib group) every 4 h with management of breakthrough symptoms with albuterol metered-dose inhaler or nebulizations for both groups. All patients received systemic corticosteroids. Peak expiratory flows, asthma symptoms, and need for rescue bronchodilator were followed up on each patient until discharge.

Results: There was no significant difference in the length of hospitalization (median length, 48 h for ad-lib group vs 57.5 h for regular albuterol group, p = 0.82), rate of improvement in peak flow, or symptoms between the two groups. Ad-lib ß-agonist use compared to regular albuterol scheduled use resulted in a significant reduction in the total number of albuterol treatments administered (median, 7 treatments vs 19 treatments, p = 0.001) during hospitalization.

Conclusions: In the management of asthma exacerbation, ad-lib administration of albuterol is therapeutically as effective as regular, scheduled administration. This method of drug administration also reduces the total dose of ß-agonists received by the hospitalized patient.

Key Words: adrenergic ß-agonists • asthma • bronchodilator • drug therapy • randomized control trial


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Asthma is an increasingly important cause of chronic morbidity among children and adults worldwide. High prevalence rates have been reported, particularly in many developed countries, as have increasing morbidity, hospital admission rates, use of medical services and, in some countries, increasing mortality rates.123 The standard of care for hospitalized asthma patients includes the administration of systemic corticosteroids and ß2-agonists at regular intervals.45678

However, there is no firm evidence to indicate the optimal schedule of treatment with short-acting ß agonists for patients with acute exacerbation of asthma. We performed a survey of the respiratory departments in the greater New York area teaching hospitals (unpublished data). It showed that patients admitted with acute asthma exacerbation are started on a regular, scheduled treatment regimen of nebulized short-acting ß2-agonists, such as albuterol, 2.5 mg q4h, with additional 2.5 to 10 mg every 1 to 4 h as needed for breakthrough symptoms. Our own practice with ß2-agonist administration in our institution is similar.

Airway obstruction in asthma exacerbation is a complex event with varying degrees of bronchospasm, inflammation, and mucus plugging. Inflammation is thought to be central to the pathogenesis of the disease, as it contributes not only to airflow obstruction but to bronchial hyperresponsiveness.910 Corticosteroids have been shown to reduce the airway cellular infiltrate in asthma, reduce airway smooth-muscle proliferation, inhibit procollagen synthesis, and cause vasoconstriction.11 ß-agonists are effective bronchodilators1213 but are largely devoid of antiinflammatory activity.14 Even though they offer temporary clinical improvement, the underlying inflammation persists.1516 In fact, excessive use of ß-agonists may be associated with increased bronchial hyperreactivity1617 and morbidity and mortality,18 especially in elderly patients and those with poorly controlled asthma.

We reasoned that this may also hold true for the hospitalized patients with exacerbation of asthma and that their clinical improvement is largely due to the administration of corticosteroids, which play a central role in controlling the inflammatory cascade. Regular, scheduled administration of albuterol treatments probably does little to alter the clinical course. We then hypothesized that the patients who received albuterol, only when required, for symptom relief (ad-lib albuterol group) would recover as quickly as the patients who are treated with regularly scheduled albuterol every 4 h in addition to the rescue treatments of albuterol for breakthrough symptoms (regular albuterol group). They would probably require less of the total dose of ß-agonist during hospitalization.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patient Selection
Patients who presented to the emergency department (ED) of Jacobi Medical Center with acute exacerbation of asthma as defined in the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report II5 were eligible to participate in the study if they met the following criteria: (1) a known history of asthma, (2) age 18 to 70 years, (3) ability to perform peak expiratory flow maneuver with good effort, and (4) ability to clearly communicate their symptoms. Patients were excluded if they met the following criteria: (1) required mechanical ventilation, (2) were pregnant, (3) had a smoking history > 20 pack-years, or (4) had a serious systemic disease, such as congestive heart failure, renal failure, or pulmonary disease other than asthma, such as pneumonia, tuberculosis, cancer, bronchiectasis, interstitial lung disease, sarcoidosis, pleural disease, kyphoscoliosis, and COPD.

Study Design
The study was conducted as a prospective, randomized, double-blind, placebo-controlled trial. The Committee of Clinical Investigations of Albert Einstein College of Medicine approved the study protocol. While being screened, the patients were routinely treated with inhaled ß-agonists by metered-dose inhaler (MDI) or nebulizer and anticholinergics by nebulizer every 20 min, with oxygen to achieve oxygen saturations of ≥ 92% and oral or IV corticosteroids if there was no immediate, complete reversal of obstruction. If the patient met the eligibility criteria, an informed, written consent was obtained, and he/she was started on the study protocol within 6 h of their arrival at the ED. Patients were randomly assigned to receive either nebulized albuterol (albuterol sulfate inhalation solution 0.5%, 0.5 mL to be mixed with 2.5 mL of normal saline solution q4h [Warrick Pharmaceuticals; Reno, NV]) or placebo nebulizations q4h (0.9% saline solution, 0.5 mL to be mixed with 2.5 mL of normal saline solution [Airlife Baxter Healthcare; Valencia, CA]).

In addition to the treatments of albuterol or saline nebulizations every 4 h, both groups of patients also received albuterol treatments (nebulizations or MDI) on an as-needed basis for breakthrough symptoms. Therefore, in terms of albuterol dosing, one group would receive albuterol every 4 h plus ad-lib treatments (regular albuterol group) and the other group would receive only ad-lib treatments (ad-lib albuterol group).

A pulmonary function technician not participating in the study generated a randomization sequence in blocks of six (three albuterol sulfate solution and three saline solution in each block) and assigned random sequential numbers. Codes for the numbers were kept in a sealed envelope to be opened at the completion of the study or in a medical emergency. The albuterol sulfate solution and the saline solution were dispensed from identical glass vials with code numbers to accomplish blinding. One physician enrolled all the patients in the study in sequence. To ensure double blinding, the physicians evaluating the patients and the patients themselves were unaware of the group to which they were assigned.

Baseline peak expiratory flow rate (PEFR),19 expressed as percentage of the predicted peak flow, and a "symptom severity score" were recorded for each patient on a flow sheet at the start of the study, then 4 h, 8 h, and 12 h after induction into the study and then twice daily (9 AM and 5 PM) thereafter until discharge. The PEFR was measured using a Wright peak flow meter (Armstrong Industries; Northbrook, IL). The symptom severity score was based on the patient’s subjective perception of the severity of his symptoms. A score of 0 to 3 was assigned each for shortness of breath, chest tightness, wheezing and cough (0 for none, 1 for mild, 2 for moderate, and 3 for severe), and a total score was calculated as the sum of each individual score, allowing a maximum of 12. A higher score reflected a greater severity of symptoms, and a decreasing score indicated improvement. Each patient received the nebulized study medication (albuterol or normal saline solution) every 4 h during the entire period of his stay in hospital except when asleep. An albuterol MDI (85 µg per actuation; Warrick Pharmaceuticals) was left at the patient’s bedside, and the patients were instructed to use it for breakthrough asthma symptoms.

The MDI technique was reviewed and corrected, if necessary, at the start of the protocol. The patients were instructed to make a record of the number of albuterol MDI doses (each dose comprised of two MDI puffs) used for the breakthrough asthma symptoms in a diary left at their bedside. The entries were reviewed daily to ascertain their accuracy. Patients were asked to call the respiratory therapist or nurse for rescue nebulized albuterol, in addition to the use of their bedside albuterol MDI, when symptoms warranted. The physician conducting the study closely monitored the rescue MDI dosing, frequency of respiratory therapist/nurse intervention, and the need for any additional therapy (eg, subcutaneous epinephrine, magnesium sulfate, noninvasive or invasive ventilation), and kept a detailed log of all such events.

Besides the study drug and rescue bronchodilator treatments, each patient was treated with systemic corticosteroids, oral prednisone 40 to 60 mg/d. Administration of other medications such as antibiotics and antacids was left to the discretion of the treating physician on the medical ward, but the patient’s own list of home medications for asthma such as montelukast sodium, inhaled corticosteroids, and theophylline was continued.

Patients were discharged from the hospital based on the criteria outlined in the NAEPP Expert Panel Report II.5 At the time of discharge, the patient had to be free of nocturnal symptoms of asthma, free of asthma symptoms on waking in the morning, and their PEFR in the morning before bronchodilator had to be ≥ 80% of their predicted or best value. However, a small number of patients (three in the regular albuterol group and two in the ad-lib group) were discharged even before they met the discharge criteria when they strongly wished to be discharged for personal reasons and they seemed to be reliable.

Primary outcome measures evaluated were the length of hospitalization, the rate of improvement in symptoms, and the rate of increase in PEFR. Secondary outcome measures evaluated were the number of total bronchodilator treatments, and the number of rescue bronchodilator treatments.

Length of stay was calculated from the time of enrollment into the study until 9 AM on the day of discharge. For the patient whose length of stay was prolonged for reasons other than medical, the day of discharge was designated to be the day asthma discharge criteria were met and data collection was stopped. The time of entry into the study was chosen to be the time when the decision to admit the patient was made by the ED staff. That is the time when the study team took control of the care of patient. We did not include the hours of stay in the ED prior to study enrollment in the calculation of length of stay. That is because we wanted to study the effect of regularly scheduled vs ad-lib albuterol treatments on the length of stay as the primary outcome and this treatment strategy had not been implemented yet. We chose 9 AM as the discharge time for calculating the length of stay because it was the time of the day when the discharge decisions were actually made by the clinicians based on the overnight and early morning symptoms and the morning PEFR as recommended by NAEPP guidelines.5 The time that the patients actually left the floor was variable and dependent largely on clinically unrelated personal factors.

Statistical Methods
Demographic data were analyzed with respect to age, gender, history of smoking, history of mechanical ventilation, baseline severity, history of corticosteroids use, duration of asthma, and PEFR on arrival at the ED. Categorical data were analyzed with comparison of proportions and a {chi}2 test. Number of albuterol treatments, PEFR and symptom scores were measured on a continuous scale, but as they were not normally distributed they were analyzed using the nonparametric Mann Whitney U test. All p values < 0.05 were considered statistically significant, and all tests were two tailed. Statistical analysis was performed electronically (Prism; Graphpad Software; San Diego, CA; and SPSS for Windows; SPSS; Chicago, IL). Statistical power was also calculated (Power and Precision; Dataxiom Software; Los Angeles, CA).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Of the 80 patients screened for participation by the research staff, 64 patients (80% of those screened) were recruited and randomized (Fig 1 ). Randomization resulted in 30 patients in the regular albuterol group (the group receiving albuterol as the study nebulization every 4 h) and 34 patients in the ad-lib group (the group receiving 0.9% saline solution as the study nebulization every 4 h). All patients were treated with systemic corticosteroids and nebulized albuterol in the ED over a 4- to 6-h period prior to enrollment in the study. In the ad-lib group, one patient withdrew consent on the second day of hospitalization and another patient required mechanical ventilation 12 h after induction into the study and after receiving four rescue nebulized albuterol treatments. The data for the 62 remaining patients who completed the study were analyzed.



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  		Figure 1. Patient recruitment.

 
Demographic data for the patients are shown in (Table 1 ). The two groups were similar with respect to age, race, baseline asthma severity, history of corticosteroid use, and smoking history. The group randomized to receive regularly scheduled albuterol treatments had 33% men (10 of 30 patients) and the ad-lib group had 19% men (6 of 32 patients). However, the difference in this gender distribution was not significant (p = 0.18). In the regular albuterol group (group A), 53% patients had a peak flow rate < 30% of their predicted at the time of arrival to the ED, while 41% of the ad-lib group patients were in this category. The mean PEFR on arrival at the ED for the regular albuterol group was 27 ± 11% predicted, and that for the ad-lib group was 28 ± 12% predicted (p = 0.31).


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  		Table 1. Demographic Data*

 
Median length of hospitalization for the regular albuterol group was 57.5 h (interquartile range [IQR], 24.00 to 71.25 h) vs 48 h for the ad-lib albuterol group (IQR, 38.6 to 72.0 h) [p = 0.83]. There was a trend toward a longer hospital stay in the regular albuterol group that did not achieve significance and could not be explained from the data in this relatively small cohort.

At the start of the study protocol, the median symptom severity score was comparable in the two groups: 6.25 for the regular albuterol group, and 6.7 for the ad-lib albuterol group (Fig 2 ). Both groups rapidly attained relief of symptoms with a similar trend of improvement. The median change in the symptom severity score from the time of induction into the study to discharge was – 4.0 in both groups (p = 0.35) [IQR, – 6.0 to – 2.0 for the regular albuterol group, and – 6.0 to – 3.0 for the ad-lib group].



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  		Figure 2. At the start of the study protocol, the median symptom severity scores were 6.25 of 12 for the regular albuterol group and 6.7 of 12 for the ad-lib group. Both groups attained relief of symptoms rapidly with a similar trend of improvement.

 
The median change in the percentage of predicted peak flow from the day of admission to discharge from hospital (Fig 3 ) was also similar in the two groups: 28.4% for the regular albuterol group (IQR, 15.9 to 40.8%) and 25.0% for the ad-lib albuterol group (IQR, 15.8 to 43.2%) [p = 0.93].



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  		Figure 3. The percentage of predicted PEFR for each participant at the initiation of the study was 41 ± 13% in the regular albuterol group vs 46 ± 15% in the ad-lib group (p = 0.16; 95% confidence interval, – 2.06 to 12.06). Similar trends of increase noted for both groups during the hospital stay.

 
The regular albuterol group received a significantly higher median number of total treatments (19.5 treatments, regular plus rescue) compared to the ad-lib group median total of only 7.0 treatments (p = 0.001), all of which were rescue treatments. The median number of rescue treatments for the two groups were similar: 10.5 (IQR, 2.0 to 17.5) for the regular albuterol group and 7.00 (IQR, 3.3 to 16.3) for the ad-lib albuterol group (p = 0.75).

Post hoc power analysis revealed 99% power to detect a difference of at least 50% in the length of hospitalization; 95% power to detect a 50% difference in the PEFR increase, and a 76% power to detect a 50% difference in the symptom improvement between the two groups. Few side effects were reported in either group. Respiratory therapy/nursing intervention for breakthrough symptoms in either group was rare. Neither the patients nor the treating physicians could guess the group assignment, and there were no observed differences in the patients’ expressed satisfaction with treatment and the hospital course between the two groups.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
It has been repeatedly suggested that regular use of ß-agonists might be associated with deterioration of asthma control in patients with stable asthma.161718 Guidelines recommend that short-acting ß-agonists be used only on an as-needed basis for outpatient management of asthma.5 However, there is no evidence to support a similar recommendation for the hospitalized asthma patients. We attempted to address this issue in a patient population admitted to a large municipal hospital. Our results showed that the treatment with ß-agonists on an as-needed basis (ad-lib) for the hospitalized asthma patients led to fewer ß-agonist treatments and was as efficacious as the regular administration with respect to improvement in symptoms, increase in PEFR and length of hospital stay.

The patients randomized to receive scheduled albuterol nebulizations, as in conventional practice, required as many rescue treatments as the ad-lib group, thereby suggesting that the scheduled administration of short-acting ß-agonists may not be necessary. Both groups of patients stayed in the hospital for a similar length of time, with no meaningful difference either in the trend of improvement in asthma symptoms or the absolute increase in the percentage of predicted PEFR. While our study was not designed to compare other clinical outcomes, decreased use of ß-agonist can be expected to reduce the risk of known side effects associated with ß-agonists such as palpitations, tremor, headache, metabolic effects, and tachycardia.

Similar results have been reported in an open study by Bradding et al,20 who evaluated the efficacy of nebulized albuterol delivered on a regular vs as-required schedule to patients admitted with asthma exacerbation. They enrolled the patients in the study 24 h after admission to the hospital. They did not report any data on symptoms.

Our study is limited by the relatively small sample size. Another potential criticism is that the study was carried out in an inner-city hospital with preponderance of minority patients. Although our study population mainly comprised of Hispanics (58%) and African Americans (31%), we do not think that it should affect its applicability in general. The minority populations in United States appear to have an increased risk of asthma morbidity and mortality.1921 Genotype-stratified studies222324 have also suggested that polymorphism at the sixteenth amino acid residue of the ß2-adrenergic receptor is associated with adverse effects of regular ß2-agonist use in asthmatic patients. A sixth of US asthmatic patients have the Arg/Arg genotype, and the allele frequency is even greater in individuals of African descent.25 However there is also a suggestion that even as-needed use of albuterol may not be the best strategy for these patients.24 Since patients were equally distributed by ethnicity in our two comparison groups, we do not expect this to have a significant bearing on our results.

Another potential criticism of our study is that the 0.9% normal saline solution used as placebo may in itself have a therapeutic effect by hydrating and loosening sticky secretions. However, studies26 using saline solution nebulizations for sputum induction in acute asthma patients have noted a potential for significant bronchoconstriction. While we would have preferred a placebo that was devoid of a potential bronchoconstrictive effect, any bias that such an effect would introduce to our study would be to increase the number of rescue treatments in the ad-lib group or to worsen the symptom severity in that group. Since neither was observed, we believe that the impact of any bronchoconstrictive bias from saline solution strengthens rather than weakens the confidence in our results.

By using the "symptom severity score" in our study, we were able to quantitatively compare the improvement in symptoms in the two groups. We found an excellent correspondence between the PEFR and symptom severity score.

While we did not do a cost analysis in this study, it is likely that reduction in the number of albuterol administrations, the cost of labor saved (time spent by the respiratory therapist in delivering albuterol via a nebulizer) and even a possible reduction in risk of infection via nebulizer27 would result in considerable savings in the cost of managing asthma patients in the hospital. In health-care environment of today, where the cost of managing hospitalized asthma patients is high,2829 other similar studies specifically addressing the cost factor are needed.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Our findings provide evidence to support the administration of short-acting ß-agonists only on an as-needed basis to patients hospitalized with acute asthma exacerbation without compromising their clinical recovery or length of hospital stay. In the absence of data to support the existing practice of administering regularly scheduled bronchodilator treatments with additional doses for breakthrough symptoms, we see no need to incur the likely increased costs and increased risk of side effects that this practice might entail.


   Footnotes
 
Abbreviations: ED = emergency department; IQR = interquartile range; MDI = metered-dose inhaler; NAEPP = National Asthma Education and Prevention Program; PEFR = peak expiratory flow rate

Received for publication September 28, 2004. Accepted for publication January 11, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Neri, M, Spanevello, A (2000) Chronic bronchial asthma from challenge to treatment: epidemiology and social impact. Thorax 55(Suppl2),S57-S58[CrossRef]
  2. FitzGerald, JM, Macklem, P Fatal asthma. Annu Rev Med 1996;47,161-168[CrossRef][ISI][Medline]
  3. Weiss, KB, Gergen, PJ, Wagener, DK Breathing better or wheezing worse? The changing epidemiology of asthma morbidity and mortality. Annu Rev Public Health 1993;14,491-513[ISI][Medline]
  4. The British guidelines on asthma management 1995 review and position statement. Thorax 1997;52,1S-120S[Free Full Text]
  5. National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma. 1997,46-47 National Institutes of Health. Bethesda, MD:
  6. Nebulizer therapy: guidelines. British Thoracic Society Nebulizer Project Group. Thorax 1997;52(Suppl 2),S4-S24
  7. Lin, RY, Sauter, D, Newman, T, et al Continuous versus intermittent albuterol nebulization in the treatment of acute asthma. Ann Emerg Med 1993;22,1847-1853[CrossRef][ISI][Medline]
  8. Rudnitsky, GS, Eberlein, RS, Schoffstall, JM, et al Comparison of intermittent and continuously nebulized albuterol for treatment of asthma in an urban emergency department. Ann Emerg Med 1993;22,1842-1846[CrossRef][ISI][Medline]
  9. Bjornsdottir, US, Cypcar, DM Asthma: an inflammatory mediator soup. Allergy 1999;54(Suppl 49),55-61
  10. Horwitz, RJ, Busse, WW Inflammation and asthma. Clin Chest Med 1995;16,583-602[Medline]
  11. Wilson, JW What causes airway remodeling in asthma? Clin Exp Allergy 1998;28,534-536[CrossRef][ISI][Medline]
  12. Lipworth, BJ, Clark, RA, Dhillon, DP, et al ß-Adrenoceptor responses to high doses of inhaled salbutamol in patients with bronchial asthma. Br J Clin Pharmacol 1988;26,527-533[ISI][Medline]
  13. Choo-Kang, YF, Simpson, WT, Grant, IW Controlled comparison of the bronchodilator effects of three ß-adrenergic stimulant drugs administered by inhalation to patients with asthma. BMJ 1969;2,287-289[Medline]
  14. Bissonnette, EY, Befus, AD Anti-inflammatory effect of ß2-agonists: inhibition of TNF-{alpha} release from human mast cells. J Allergy Clin Immunol 1997;100,825-831[CrossRef][ISI][Medline]
  15. Strube, G, Rudolf, M For and against: should steroids be the first line treatment for asthma? BMJ 2000;320,47-49[Free Full Text]
  16. Sears, MR, Taylor, DR, Print, CG, et al Regular inhaled ß-agonist treatment in bronchial asthma. Lancet 1990;336,1391-1396[CrossRef][ISI][Medline]
  17. Hancox, RJ, Cowan, JO, Flannery, EM, et al Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled ß-agonist treatment. Respir Med 2000;94,767-771[Medline]
  18. Spitzer, WO, Suissa, S, Ernst, P, et al The use of ß-agonists and the risk of death and near death from asthma. N Engl J Med 1992;326,501-506[Abstract]
  19. Castro, M, Schechtman, KB, Halstead, J, et al Risk factors for asthma morbidity and mortality in a large metropolitan city. J Asthma 2001;38,625-635[CrossRef][ISI][Medline]
  20. Bradding, P, Rushby, I, Scullion, J, et al As-required versus regular nebulized salbutamol for the treatment of acute severe asthma. Eur Respir J 1999;13,290-294[Abstract]
  21. Claudio, L, Tulton, L, Doucette, J, et al Socioeconomic factors and asthma hospitalization rates in New York City. J Asthma 1999;36,343-350[ISI][Medline]
  22. Israel, E, Drazen, JM, Liggett, SB, et al The effect of polymorphisms of the ß(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000;162,75-80[Abstract/Free Full Text]
  23. Taylor, DR, Drazen, JM, Herbison, GP, et al Asthma exacerbations during long term ß-agonist use: influence of ß(2)-adrenoceptor polymorphism. Thorax 2000;55,762-767[Abstract/Free Full Text]
  24. Israel, E, Chinchilli, VM, Ford, JG, et al Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;364,1505-1512[CrossRef][ISI][Medline]
  25. Weir, TD, Mallek, N, Sandford, AJ, et al ß2-Adrenergic receptor haplotypes in mild, moderate and fatal/near fatal asthma. Am J Respir Crit Care Med 1998;158,787-791[Abstract/Free Full Text]
  26. Wark, PA, Simpson, JL, Hensley, MJ, et al Safety of sputum induction with isotonic saline in adults with acute severe asthma. Clin Exp Allergy 2001;31,1745-1753[CrossRef][ISI][Medline]
  27. Dautzenberg, B Prevention of nosocomial infection during nebulization and spirometry [in French]. Rev Pneumol Clin 2001;57,91-98[Medline]
  28. Stanford, R, McLaughlin, T, Okamoto, LJ The cost of asthma in the emergency department and hospital. Am J Respir Crit Care Med 1999;160,211-215[Abstract/Free Full Text]
  29. Weiss, KB, Gergen, PJ, Hodgson, TA An economic evaluation of asthma in the United States. N Engl J Med 1992;326,862-866[Abstract]




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