Comparison of two forms of albuterol for treatment of acute bronchospasm in pediatric patients. (Original Article).

Background: The Circulaire nebulizer (C-Neb) is marketed as superior to low-dose albuterol for acute broachospasm.

Methods: This clinical trial design compared clinical and fiscal outcomes of patients treated with C-Neb and high-dose albuterol (HDA). Eligibility criteria included reactive airway disease, age >5 years, and asthma score (AS) of 2 to 10. Patients with odd medical record numbers received HDA, and those with even numbers received C-Neb. Treatment was concluded if AS was 0, peak flow was >70% predicted, or after three treatments.

Results: One hundred eight patients were enrolled: 48 received HDA, 52 received C-Neb, and 8 were excluded. The two groups were comparable by admission rates ([G.sup.2] = 0.90, P = 0.34), return visit rates ([G.sup.2] = 0.73, P = 0.39), and final AS (z = 0.59, P = 0.55). Side effects were similar: change in heart rate (t = 1.61, P = 0.11) and mean arterial pressure (t = 1.36, P = 0.17). Charges per treatment, per delivery, and total charges were greater for HDA.

Conclusion: The C-Neb is equally effective, has similar side effects, and requires less time and charges than HDA.

Key Words: albuterol, asthma, Circulaire nebulizer, peak flow

**********

Key Points

* Currently, devices used for delivery of aerosolized [beta]-agonists are able to deliver only 10% of the medication placed in the device to the lung.

* The Circulaire nebulizer has been shown to deliver high doses of [beta]-agonists in 2 to 4 minutes compared with the 45 minutes for a high-dose albuterol aerosol using current delivery methods.

* This study supports the use of the Circulaire nebulizer as a time-saving, cost-efficient, and effective therapy for mild to moderate asthma exacerbations in the emergency department setting.

Asthma affects 5% of the U.S. population and accounts for more than 5,000 deaths annually. (1-3) Acute bronchospasm requiring medical intervention is a common reason for Emergency Department (ED) visits. A recent survey estimated that there were over 1.5 million pediatric visits to EDs with this single diagnosis, accounting for nearly 17% of all pediatric visits to EDs in the United States. (4) In 1990, asthma costs were estimated at $6.2 billion. (5) Because pediatric hospital EDs are frequently the source of care for these patients, there is an increasing challenge to meet the demand with limited resources and manpower while maintaining quality of care.

Inhalation of aerosolized [beta]-agonists is the mainstay of therapy for acute bronchospasms. The most commonly used nebulizer treatment is a concentration of 0.03 ml/kg diluted in 3 ml of saline delivered over a 10- to 15-minute period. High-dose, continuous (0.09 ml/kg albuterol diluted to make 12 ml fluid), nebulized albuterol has been suggested as a more effective therapy in children and adults than low-dose regimens in acute exacerbation. (6,7) Compared with the low-dose regimen, the high-dose regimen resulted in significantly greater improvement in forced expiratory volume in 1 second, forced vital capacity, and wheezing score and a lower hospitalization rate. The changes in heart rate, respiratory rate, and blood pressure did not differ significantly between the groups. The incidence of side effects was not significantly different in the two populations. High-dose, frequently administered, nebulized albuterol was found to be both safe and effective in treating severe, acute asthma in children (6) and h as become the standard therapy for patients with asthma exacerbations in many EDs.

The devices currently available for delivery of aerosolized [beta]-agonists are able to deliver only 10% of the medication placed in the device to the lung. (8,9) Much of the medication is vented into the atmosphere or absorbed through the gastrointestinal tract of the patient, which can cause increased systemic side effects. (10) The Circulaire nebulizer (C-Neb) (WestMed, Inc., Englewood, Go) is currently being marketed as being superior to low-dose albuterol nebulizers because it produces smaller and more uniform particles; therefore, more medication is deposited in the lower airways and less is deposited in the pharynx, mouth, and stomach, (11,12) The Circulaire nebulizer is hooked to a circuit that includes a one-way valve to filter out the large particles and direct airflow. It also has a distensible reservoir to capture aerosol from the nebulizer during expiration (Fig. 1). This new method of nebulization has been shown in adults to result in a greater improvement in respiratory symptoms with no differ ences in clinical side effects (tremulousness, heart rate, nausea, and blood pressure) and to take less time, which may translate into cost savings. (10) Also, this device is designed to deliver the medication in 2 to 4 minutes, (13) compared with the 15 minutes for a standard aerosol and 45 minutes for a high-dose albuterol (HDA) aerosol. The C-Neb is currently being used in our ED and other pediatric EDs in the country at the discretion of the individual physicians. This study compares HDA aerosols with the C-Neb in terms of clinical effectiveness, charges, and side effects.

Patients and Methods

Patients

Patients were recruited during triage in the Children's Hospital Emergency Department over a 6-month period (May 1999-October 1999). Entry criteria included a history of asthma (reactive airway disease) as evidenced by a history of home albuterol use, past hospital admission or ED visit for bronchospasm, age >5 years, and a mild to moderate bronchospastic exacerbation (as determined by an asthma score [AS] between 2 and 10). Patients were excluded if they were currently taking systemic steroids or had already received a continuous nebulizer treatment at a physician's office or outlying hospital.

Measurements

On initial entry into the study, all patients had heart rate, respiratory rate, and oxygen saturations measured by oximetry using the Nelleor oximeter (Nellcor, Pleasanton, CA), on which the patients remained throughout the study. These clinical parameters were documented after each treatment. At the beginning and end of the study, an automatic blood pressure machine was used to measure blood pressure. The initial ASs were determined by one of the principal investigators by using the score shown in Table 1. Peak flow was measured using a hand-held instrument ([Tru.sub.PFM]Zone; Monaghan Medical Corp., Plattsburgh, NY), recording the best of three attempts. The parameters shown in Figure 1 were incorporated into the data flow sheet, and one of the investigators circled the finding best corresponding to the patients' condition after each treatment. Before data entry, one of the investigators assigned a number for all patients' asthma scores. Side effects were determined by observation (eg, whether patients wer e tremulous, vomiting) or by report from the patient initially and after each treatment.

Protocol

Informed consent was obtained at triage from the patient's parents (and the patient, if age > 14 years) according to institutional review board guidelines at triage if the patient met study criteria. Randomization was assigned according to medical record number. Patients who had a medical record number ending in an odd number were assigned to the control group receiving HDA aerosols (0.09 ml/kg albuterol diluted in saline to make 12 ml; maximum of 3 ml in 9 ml saline) and placed in the Hudson nebulizer (Hudson RCI, Temecula, CA) at a flow rate of 8 L/min. Patients whose medical record numbers ended in an even number were assigned to the study group receiving C-Neb (2 mg undiluted albuterol for the first dose and 1 mg for subsequent doses at a flow rate of 8 L/min). Asthma severity scores and the clinical parameters of heart rate, oxygen saturation, respiratory rate, and peak flows were measured initially and after each treatment. Blood pressures were determined at the start and at the end of the study. The st udy concluded when the patient was no longer having bronchospasm as determined by an AS of zero, a peak flow > 70% predicted, or after a total of three aerosol treatments. Because steroids have become a vital part of therapy for asthma exacerbations, 2 mg/kg prednisone orally (or Solu-Medrol 2 mg/kg intramuscularly if the patient was experiencing emesis) was given according to physician discretion. All patients were telephoned to determine return visit rates within the following 48 hours.

Statistical Analysis

A clinical trial design was used to compare clinical and fiscal outcomes and side effects of patients treated with C-Neb versus HDA. Sample size was determined to require a minimum of 45 patients in each group to achieve a power of 80% and a two-tailed [alpha] of 0.05 to allow detection of a 15% difference in admission rates. Return visit rates and charge differences were also compared. All data were analyzed using Epistat software (Epistat Services, Richardson, TX) after removal of identifiers. Student's t, Wilks' log likelihood, Mann-Whitney U, [chisquare] and D'Agostino's tests for normality were used for data analysis.

Results

One hundred eight patients were enrolled (48 patients in the HDA group and 52 patients in the C-Neb group, and 8 patients were excluded because of lack of complete data). There were 64 male patients and 36 female patients enrolled, with a mean age of 10.24 years and a median age of 10 years. The two groups were comparable by gender ([chisquare] = 0.02, P = 0.89), age (t = 0.60, P = 0.55), and severity by initial AS (z = 1.49, P = 0.13). No difference was found for admission rates ([G.sup.2] = 0.90, P = 0.34), return visit rates ([G.sup.2] = 0.73, P = 0.39), or final AS (z = 0.59, P = 0.55) (Table 2). Stratified results by peak flow (PE) (percentage predicted) revealed that, overall, 85% of HDA and 91% of C-Neb patients were discharged home with no complications or return visits (z = 0.53, P = 0.59). Eighty-three percent of the severe (PF <30% predicted) patients in the HDA group and 95% in the C-Neb group were discharged home and had no complications or return visits (z = 0.89, P = 0.38). There were no differ ences between the two groups in terms of severity by peak flow, with 95% of the HDA group and 90% of C-Neb group being moderate (PF <60% predicted) (Table 3).

Side effects were similar: vomiting in 4% (n = 2) of the HDA patients and 6% (n = 3) of the C-Neb patients; tremors in 6% (n = 3) of the HDA patients and 2% (n = 1) of the C-Neb patients; change in heart rate (t = 1.61, P = 0.11); and mean arterial blood pressure (t = 1.36, P = 0.17). Length of ED stay was longer in the HDA group (C-Neb, 82 minutes; HDA, 129 minutes; t = 3.8, P = 0.0002). There were six patients (three in each study group) who could not be contacted to determine return visit rates. The medical charts for these six patients were reviewed and it was determined that none of the six returned to our institution within the following 48 hours. Of the six patients who could not be contacted, five were female patients and one was a male patient, and four received steroids and two did not. Two patients required therapy in addition to the three aerosols given as part of the study. One patient received three Circulaire treatments and then was given one high-dose albuterol treatment before discharge from the ED. One patient was discharged after three Circulaire treatments and then returned 8 hours later to receive one HDA treatment.

Steroids were given to 64 patients (33 in the HDA group and 31 in the C-Neb group; [chisquare] = 0.56, P = 0.45). Sixtyseven patients had some form of therapy before the ED visit (29 in the HDA group and 37 in the C-neb group) (Table 4). There were six patients admitted (4 of 48 in the HDA group and 2 of 52 in the C-Neb group), and all six had received some prior therapy before their ED visits. For the patients with charge information available, the Circulaire treatment group had lower ED charges per treatment and per administration of treatment and lower total ED charges (Table 5).

Discussion

The 1985 National Health Interview survey estimated ED care for children with asthma at over $90 million. (5) As previously mentioned, pediatric hospital EDs are frequently the primary source of care for patients with acute exacerbations of asthma. In 1995, the Children's Hospital of Alabama Emergency Department treated 3,600 patients with acute exacerbations of asthma. The total charges amounted to approximately $2.1 million, with a compensation rate of about 50% (or an average of 9.8 patients per day at a cost of $586.10 per patient). With dwindling resources along with the demand for health maintenance organizations, preferred provider organizations, and the move toward capitation, it becomes imperative that cost-effectiveness be sought in all aspects of health care, especially in a costly area such as asthma care. Given two therapies that are equivalent regarding effectiveness and side effects experienced, preference would be given to the therapy that required the least amount of ED time and the least cos ts incurred.

The costs and charges in our institution are $4.55 for a C-Neb unit and $9.10 for the C-Neb administration, versus $3.79 for the Hudson nebulizer unit and $36.75 for the high-dose continuous albuterol administration. One of the advantages the C-Neb offers is the decreased time requirement for delivery of the medication (3--4 four minutes versus 45 minutes). In our study, the mean overall time spent in the ED was decreased from 129 minutes to 82 minutes by using the CNeb. This is a benefit to both the patient and the ED. This therapy would allow the patient to be treated more efficiently without increasing the number of side effects. EDs would benefit from the increased flow-through time for individual patients, allowing more patients to be seen.

Study Limitations

Patients in severe respiratory distress were not included in this study because these patients would most likely require additional therapy that would complicate comparisons (eg, Atrovent, magnesium sulfate, intubation). We can make no conclusions regarding severe exacerbations and the use of albuterol versus C-Neb.

Symptoms after treatment were subjectively recorded by patient report or by observation. Many patients (n = 26) reported experiencing nausea and/or emesis before any ED treatment. The symptoms reported after treatment may not have been attributable to the treatment, but rather may have been caused by the illness.

Because of the inherent time difference in the two treatment groups, we were unable to perform a blinded comparison. The asthma scoring system was used along with clinical examination to determine need for additional therapy and adequate response for discharge in an attempt to limit investigator bias. The AS has been shown to be a reasonable predictor of severity, with good interrater reliability. (14) The judgment of clinical findings is subjective, but to reduce variability, one investigator assigned the actual AS to all patients on the basis of clinical criteria circled on a form at the time of visit. It is still possible, however, that there was some variability in scoring. D'Agostino's test for normality was applied to the ASs in this study, and a normal distribution with no outliers was demonstrated.

Conclusion

The C-Neb was found to be equally effective (no difference in admission or return visit rates) without an increase in the incidence of side effects. C-Nebs had a significantly lower mean length of ED stay. This study supports the C-Neb as a time-saving, cost-efficient, and effective therapy for mild to moderate asthma exacerbations in the ED setting.

Table 1

Asthma Severity Scale scores (a)

                                        Score

Parameter                    0         1         2

Oxygen saturation (%)      >95%      90-95%    <90%
Cyanosis                   Negative  Negative  Positive
Altered consciousness      No        No        Yes
Wheeze on auscultation     None to   Moderate  Severe to
                             mild                none
Use of accessory muscles   Absent    Moderate  Marked
Respiratory breath sounds  Equal     Unequal   Decreased/
                                                 absent
Initial peak flow or       >60%      40-60%    <40%
  [FEV.sub.1] (predicted
  or child's best)

(a)FEV, forced expiratory volume.

Table 2

Results (a)

                     High-does
Parameter          albuterol (%)  C-Neb (%)       t test

Admission rate      4/48 (8 %)    2/52 (4%)  [G.sup.2] = 0.90
                                                     P = 0.34
Return Visit rate   6/44 (14%)    4/50 (8%)  [G.sup.2] = 0.73
                                                     P = 0.39

(a)C-Neb, Circulaire nebulizer.

Table 3

Severity (a)

Peak flow      High-dose
predicted (%)  albuterol  C-Neb

<40%              33       23
40-60%            10       22
>60%               2        5

(a)C-Neb, Circulaire nebulizer.

Table 4

Prior therapy (a)

                                  High-Dose
Therapy                           Albuterol  C-Neb

MDI                                  18       27
Home or clinic nebulizer              9        9
Fluticasone propionate (Flonase)      2        1

(a)MDI, metered-dose inhaler.

Table 5

Charge information (a)

                    High-dose               Comparison
Billed item         albuterol   C-Neb        (95% CI)

Aerosol treatment    $110.60    $72.80  t = 3.38, P = 0.001
                                            (5.4-60.2)
Administration and   $444.80   $338.00  t = 2.42, P = 0.02
 aerosol                                   (19.3-195.5)
Total ED charge      $664.70   $552.80  t = 1.98, P = 0.05
                                           (-0.6-224.6)

(a)C-Neb, Circulaire nebulizer.

CI, confidence interval

ED, Emergency Department.

Accepted March 22, 2002.

Acknowledgment

We thank the staff of the Children's Hospital Emergency Department for their patience and support.

References

(1.) Jagoda A, Shepherd SM, Spevitz A, Joseph MM. Refractory asthma: Part 1--Epidemiology, pathophysiology, pharmacologic interventions. Ann Emerg Med 1997;29:262-274.

(2.) Henderson SO, Acharya P, Kilaghbian T, Perez J, Korn CS, Chan LS. Use of heliox-driven nebulizer therapy in the treatment of acute asthma. Ann Emerg Med 1999;33:141-146.

(3.) Grant EN, Wagner R, Weiss KB. Observations on emerging patterns of asthma in our society. J Allergy Clin Immunol 1999;104:S1-S9.

(4.) Crain EF, Weiss KB, Fagan MJ. Pediatric asthma care in US emergency departments: Current practice in the context of the National Institutes of Health guidelines. Arch Pediatr Adolesc Med 1995;149:893-901.

(5.) Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. N Engl J Med 1992;326:862-866.

(6.) Schuh S, Parkin P, Rajan A, Canny G, Healy R, Rieder M, et al. High-versus low-dose, frequently administered, nebulized albuterol in children with severe, acute asthma. Pediatrics 1989;83:513-518.

(7.) Papo MC, Frank J, Thompson AE. A prospective, randomized study of continuous versus intermittent nebulized albuterol for severe status asthmaticus in children. Crit Care Med 1993;21:1479-1486.

(8.) American Association for Respiratory Care. Aerosol consensus statement: 1991. Respir Care 1991;36:916-921.

(9.) Lewis RA, Fleming JS. Fractional deposition from a jet nebulizer: How it differs from a metered dose inhaler. Br J Dis Chest 1985;79:361-367.

(10.) Hoffman L, Smithline H. Comparison of Circulaire to conventional small volume nebulizer for the treatment of bronchospasm in the emergency department. Respir Care 1997;42:1170-1174.

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On March 19, 2003, the Alliance for Lupus Research (ALR), a leading source of private funding for lupus research, awarded $1 million to Robert H. Carter, MD, of the University of Alabama at Birmingham to further his research aimed at the development of targeted antibodies as a potential treatment for patients with lupus.

White blood cells, known as B cells, play a central role in the development of lupus, yet they are also critical for the healthy functioning of the immune system. Dr. Carter's study focuses on developing and testing antibodies that selectively target only aberrant B cells that contribute to lupus while sparing normal B cells that defend against bacterial and viral infection. The study, titled "Novel Treatments of Lupus Targeting Necrosis Factor-Superfamily Receptors on B Cells," could lead to more refined therapies that target only disease-causing B cells in people with lupus and provide a significant advantage over the less specific drugs currently used for lupus, which can have serious side effects.

Dr. Carter's is one often 2003 ALR grants, totaling $5,905,790, intended to advance the understanding and treatment of lupus. The ALR funds innovative lupus research in 2-year intervals.

Systemic lupus erythematosus, commonly called lupus, is an autoimmune disease in which antibodies attack the kidneys and other organs. Potentially fatal, lupus strikes young women primarily.

"It is the Alliance's greatest hope that this new generation of work will have a significant and rapid impact on the lives of lupus patients," said John H. Klippel, MD, scientific director of the ALR.

Robert Wood Johnson IV of the Johnson & Johnson health care family, who is also the owner of the New York Jets, founded The Alliance for Lupus Research with the Arthritis Foundation to enhance the profile and scope of lupus research. Since its inception in 1999, the ALR has committed more than $24 million to lupus research, which has led to remarkable gains toward unlocking the mysteries of this disease. The ALR directs 100% of funds raised to peer-reviewed research and scientific programs. For more information on lupus and the Alliance for Lupus Research, a Section 501(c)(3) organization, visit http://www.lupusresearch.org/ or call [phone].

From the Department of Pediatrics, Division of Emergency Medicine, University of Alabama at Birmingham, and the Emergency Department, Children's Hospital of Alabama, Birmingham, AL.

Presented in part at the Southern Society for Pediatric Research. Winner of the Young Investigator Award, February 2000.

Reprint requests to Kathy Monroe, MD, Division of Emergency Medicine, Department of Pediatrics, University of Alabama at Birmingham, Midtown Center, 1600 7th Avenue S., Birmingham, AL 35233. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9605-0440