Allergy & Asthma Disease Management Center: Ask the Expert: Asthma Treatment

- Asthma Treatment -

12/13/2005 RE: Use of short acting beta agonists

In adults with moderate asthma, intermittent, which are the effects of intermittent versus continues use of beta2-agonists of short duration of share inhalated?

Although the exact use of inhaled beta agonists may vary somewhat indifferent medical centers, almost all experts recommend againstcontinuous (daily) use of inhaled short acting beta agonists (SABA).
This is because of convincing epidemiologic evidence of an increased frequency of fatal and near fatal acute asthma attacks in patients who have used SABA daily as their only asthma treatment. There is good evidence that a decreased beneficial bronchodilating effect of SABA develops with chronic daily use. As a result, some patients use SABA repeatedly to get symptomatic relief, possibly contributing to the fatal/near fatal outcome.

Whether intermittent use of SABA should be the only treatment of intermittent asthma depends on the frequency of the need for SABA treatment and other issues such as the frequency of night-time awakenings because of asthma symptoms, etc. I suggest that you read the guidelines written by the expert panel in the National Asthma Education and Prevention Program (NAEPP) sponsored by the NIH. You can access those guidelines through a link from this AADMC website(www.aaaai.org/aadmc). Go to the Current Literature section of the AADMC website, click on "Updated asthma guidelines" and go to the section dealing with treatment. If the patient has moderate asthma, even if intermittent I suspect that daily controller therapy may be needed, using SABA only for rescue treatment.

11/14/05 re: comparative efficacy of blow-by and mask for nebulization

I am a registered respiratory therapist in Ohio. Just recently one of our pediatric pulmonologists required us to start giving aerosol treatments on all age groups with a mask only. In my personal experience I think that when you try to force an infant to wear an aerosol mask instead of just doing a blow by treatment, most infants, and children get scared and start crying. I think this just makes their breathing worse. Is there any evidence that an aerosol with mask is better therapy? Do infants and children inhale more medication this way?

Please pardon the delay in response. As an Internist/Allergist-Immunologist, I had no personal experience in the area of your question. Therefore, I consulted a Pediatrician colleague in the Children's Hospital of Philadelphia with considerable experience in such matters. He responded that he was having difficulty obtaining published data to support the common perception that delivery of nebulized solutions by mask was more effective than the blow-by technique. Part of this impression may be related to the finding that there are significant differences in the exact methodology and efficacy of blow-by techniques as utilized in different hospitals. His response is enclosed below.

I am still looking for those articles on differences between blowby vs mask techniques. Unfortunately, it has become one of those folklore aspects of medicine that just gets written in recent reviews that use of masks is better. There had been a few articles back in the 90's that I am having trouble finding that actually measured differences in delivery to the periphery of lung suggesting a greater efficacy of mask use. As a standard protocol for the asthma studies using nebs, treatments are always given with mask.

11/8/05 re: Lung transplant for severe asthma

We care for a 40 year old male with severe persistent asthma, who, in spite of our consistent efforts has gradually declined under our care for the last 10 years. He is maintained at this point on prednisone and inhaled therapy with O2 on reserve. Besides conventional therapy, he has been tried or we have considered methotrexate, cyclosporine and we were even able to get him on an anti-TNFalpha study. (He unfortunately had an adverse event.)

We have discussed the possibility of lung transplant in this otherwise healthy guy. Is this an option? If so what is the best way to start the process? In the interest of brevity, I won't give a complete history except to say that he is non atopic and seems to have a unique phenotype.

There is very little published evidence of lung transplantation for asthma (see enclosed abstract of a recent article referring to the paucity of such cases). Therefore, I consulted Dr. Robert Kotloff, Medical Director of the lung transplantation program in our institution. Dr. Kotloff's response is enclosed just below. If your patients has reached the point of truly irreversible airway obstruction, you could approach a lung transplant centers near you. Such information is generally available from the cardio-thoracic surgeons in the hospital with which your office is affiliated.

Dr, Kotloff's comments:

Due to the generally favorable prognosis of patients with asthma (even when severe) and the considerable risks of lung transplantation (with a median survival of only 5 years), very few transplants have been performed in asthmatics. We have performed transplantation for asthma on two occasions. In both cases, the patients had an initial classic history of reversible airways disease consistent with asthma, but both patients progressed to a far advanced degree of irreversible airflow obstruction (presumed due to airways remodeling). Both patients have had uneventful outcomes with long-term survival (greater than 5 years) achieved in both cases.

J Heart Lung Transplant. 2005 Oct;24(10):1700-3.
Bilateral lung transplantation for severe persistent and difficult asthma.
Wirtz HR, Kroegel C, Caffier P, Bittner H.
Department of Respiratory Medicine, University of Leipzig, Leipzig, Germany.

Although asthma is listed as an indication for lung transplantation, only 2 cases have been reported to date. Here, we describe a 42-year-old woman with progressive, severe, persistent bronchial asthma resistant to high-dose oral steroids and adjuvant immunosuppressive therapy. Because conventional and experimental therapeutic strategies failed, the patient was listed for bilateral lung transplantation and received a transplant shortly thereafter. At 12 months after transplantation, her lung function parameters are normal and an asthma attack has not occurred since.

10/11/05 re: Value of PEFR measurements in childhood asthma

I am a licensed respiratory therapist and a 3rd year physician assistant. I am conducting a research study. My proposal is: the use of home peak flow monitoring can reduce ER visits in asthmatic children. Does the use of peak flow reduces ER visits or doesn't make any difference without the use of the peak flow meter? I was wondering if you can provide me with past studies or the latest studies if possible regarding the use of peak flow meter in asthmatic children. I need some literature where I can use or compare for the studies. I would truly appreciate if you can help me with the study.

Your question about the value of monitoring the peak expiratory flow rate (PEFR) in the management of childhood asthma addresses a subject of considerable interest and some controversy. Space limitations do not allow discussion of the many reports in this area of investigation. I will pick just a few about which to comment. When the recommendations of the Expert Panel in the National Asthma Education and Prevention Program (NAEPP) were first promulgated in the early 1990's, the PEFR was included as a major component in asthma management in both adults and children, when technically feasible. However, my impression is that this recommendation was based in good part on a consensus decision based on personal experiences. This conclusion and recommendation about the value of the PEFR measurement is still voiced in some recent review articles (see enclosed abstracts).However, when the NAEPP Expert Panel met to update their guideline in the year 2002, they concluded that the findings in the limited number of relevant studies did not either convincingly support or refute any greater value of PEFR measurement when compared to careful monitoring of asthma symptoms in effective asthma management (particularly in the prevention of acute asthma exacerbations). Despite this, they recommended that PEFR monitoring should be carried out when feasible in patients with moderate to severe asthma, particularly in those patients who do not adequately recognize it when their symptoms worsen. I suggest that you read the relevant section (pg 85-92) of these NAEPP Updated Guidelines as of 2002 (www.nhlbi.nih.gov/guidelines/asthma/asthmafullrpt.pdf).

In the guidelines of the Global Initiative for Asthma (GINA) program, a highly respected international consortium of experts, most recently updated in 2004, the PEFR is considered a major component is asthma management. I suggest that you read the relevant section, starting on pg 13 of their document (www.ginasthma.com/download.asp?intId=95) to see their wording.

However, some recent reviews in 2005 have not found convincing evidence of the added value of PEFR monitoring (see enclosed abstract).

Why are there such differences in the conclusions stated? I think that the situation is complex. However, at least one factor may be the difficulty in getting technically consistent PEFR measurements by the patient at home, particularly in children. As you know, PEFR measurements are quite effort dependent, which presents problems at times.

Also, there are sometimes quality control issues with some PEFR devices. My personal view is that PEFR measurements are of particular value in those asthmatics: 1) who are readily trainable in the techniques and compulsive about doing the measurement in a technically consistent manner; and 2) are not readily aware when there is worsening asthma symptomatology.

Aust Fam Physician. 2005 Jul;34(7):535-9. Related Articles, Links
Spirometry: an essential clinical measurement.
Pierce R.
University of Melbourne and Institute for Breathing and Sleep, Austin
Health, Victoria, Australia.

BACKGROUND: Respiratory disease is common and amenable to early detection and management in the primary care setting. Spirometric evaluation of ventilatory function plays a critical role in the diagnosis, differentiation and management of respiratory illness such as asthma, chronic obstructive pulmonary disease and restrictive lung disorders, and is important in the assessment of lung health in smokers and those exposed to occupational and environmental hazards.
OBJECTIVE: This article covers the basic theory, fundamentals of test indications, performance and equipment, the interpretation of results and the nuances behind the spirogram and the flow-volume curve.
DISCUSSION: The use of spirometry by primary care physicians, practice nurses and physiotherapists is now practicable and supported by a comprehensive range of devices, training courses and reference materials. Systematic use of ventilatory assessment both in the clinic and with patient self monitoring of peak flow and FEV1 has the capacity to improve patient understanding, confidence in self management, and quality of life for those with lung disease. Spirometry may also provide a useful modality for following the progress of those with neuromuscular disease and incipient respiratory muscle weakness and for the promotion of respiratory health in the community setting, although further research in all these areas is required.

Clin Ther. 2005 Apr;27(4):393-406. Related Articles, Links The CONCEPT trial: a 1-year, multicenter, randomized, double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma.
FitzGerald JM, Boulet LP, Follows RM.
Respiratory Division, Vancouver General Hospital, Vancouver, BC,
Canada.

BACKGROUND: A patient-driven, adjustable maintenance dosing (AMD) approach to asthma therapy, in which the dose is adjusted by patients according to the severity of their symptoms, has recently been compared with fixed-dose therapy in open-label studies.
OBJECTIVE: This study used a double-blind, double-dummy design to compare the efficacy of 2 treatment approaches: stable dosing of salmeterol/fluticasone propionate (SAL/FP) and AMD of formoterol/budesonide (FOR/BUD).
METHODS: This was a 1-year, multicenter, randomized, double-blind, double-dummy study in adult patients with symptomatic asthma that was not controlled by therapy with 200 to 500 microg/d inhaled corticosteroid (ICS) plus a long-acting beta2 agonist, or with >500 to 1000 microg/d ICS alone. Patients were randomized to receive 1 inhalation of SAL/FP 50/250 microg BID or 2 inhalations of FOR/BUD 6/200 microg BID, both delivered via dry powder inhaler devices. After 4 weeks of stable dosing in both groups, eligible patients continued the study for an additional 48 weeks, receiving either a stable dose of SAL/FP or AMD of FOR/BUD. According to the AMD treatment plan, patients initially halved their dose and subsequently stepped up or down as indicated by the presence or absence of nocturnal awakenings due to asthma, frequency of rescue medication use, and changes in morning peak expiratory flow (PEF). The primary end point was the percentage of symptom-free days. Other parameters included daily asthma symptom scores, morning PEF, percentage of days free of rescue medication use, daily rescue medication use, percentage of nighttime awakenings due to asthma, percentage of weeks with well-controlled asthma, and number of exacerbations requiring oral corticosteroids or emergency department (ED) visits/hospitalizations. Tolerability was assessed in terms of adverse events spontaneously reported or elicited at clinic visits.
RESULTS: The intent-to-treat population comprised 688 patients (344 per treatment arm) with a mean age of 45 years and a mean baseline forced expiratory volume in 1 second 81% of the predicted normal value. After 4 weeks' stable dosing, 581 patients (295 SAL/FP, 286 FOR/BUD) continued beyond visit 3 into the remaining 48-week treatment period. Over weeks 1 through 52, patients receiving stable dosing of SAL/FP had a significantly greater percentage of symptom-free days compared with those receiving AMD of FOR/BUD (median, 58.8% vs 52.1%, respectively; P = 0.034). The incidence of asthma exacerbations requiring oral steroids or an ED visit/hospitalization was 47% lower with SAL/FP compared with FOR/BUD (adjusted annual mean rate, 0.18 vs 0.33; P = 0.008). During weeks 5 through 52, patients in the FOR/BUD AMD group used a mean of 1.8 inhalations/d (equivalent to BUD 360 microg/d), and 235 (82.2%) patients stepped down to 1 inhalation/d. Mean (SD) daily ICS exposure over 52 weeks was 463 (81) microg FP and 480 (238) microg BUD in the respective treatment arms.
CONCLUSIONS: In this adult population with persistent asthma, stable dosing of SAL/FP 50/250 microg BID resulted in significantly greater increases in symptom-free days, days free of rescue medication, and morning PEE, as well as almost halving the exacerbation rate, compared with AMD of FOR/BUD 6/200 microg. The results suggest that there is a minimum daily amount of maintenance therapy necessary to prevent exacerbations in adults with persistent asthma.

J Gen Intern Med. 2004 Mar;19(3):237-42. Related Articles, Links
Erratum in:
*J Gen Intern Med. 2004 Aug;19(8):903.
Comment in:
*J Fam Pract. 2004 Aug;53(8):608.
Assessing symptoms and peak expiratory flow rate as predictors of asthma exacerbations.
Tierney WM, Roesner JF, Seshadri R, Lykens MG, Murray MD, Weinberger M.
Division of General Internal Medicine and Geriatrics, Department of Medicine, Indiana University School of Medicine, 1001 W. 10th Street, Room M200-OPW, Indianapolis, IN 46256, USA.

OBJECTIVE: To investigate peak expiratory flow rate (PEFR) and quality of life scores for their ability to predict exacerbations of asthma.
PARTICIPANTS AND METHODS: We identified adults who received oral or inhaled asthma medications from 36 community drugstores. We administered the McMaster Asthma Quality of Life Questionnaire (AQLQ) and measured PEFR, defining "red zone" (highest risk) as a PEFR < 50% of each patient's expected value based on gender, age, and height. We identified asthma exacerbations (breathing-related emergency department visits and hospitalizations) within 4 and 12 months after enrollment and used proportional hazards regression to assess the ability of PEFR and AQLQ scores to predict exacerbations, controlling for clinical and demographic factors.
RESULTS: A red zone PEFR was a significant univariable predictor of exacerbations within 12 months (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.1 to 3.0; P =.027). However, neither a red zone PEFR, the raw PEFR, or percent of predicted maximal PEFR were significantly predictive when controlling for AQLQ scores, clinical characteristics, or demographic data (P >.2). However, the 4 subscales of the AQLQ were each significant univariable and multivariable predictors of asthma exacerbations. For example, the overall AQLQ scale had a multivariable HR of 0.63 (95% CI, 0.46 to 0.87; P =.005) for exacerbations occurring within 4 months and 0.66 (95% CI, 0.54 to 0.82; P <.001) within 12 months.
CONCLUSIONS: PEFR added no predictive information to that contained in AQLQ scores and clinical and demographic data. These results support the National Institutes of Health asthma guidelines' recommendation.

6/16/05 re: Screening for inhalation therapy approach

We find a number of patients that have MDIs and DPIs prescribed in the hospital setting lack the coordination or effort to inhale the medication. Given the cost of these medication the impact of waste is financially significant. What objective criteria should be used to determine if a patient can or cannot make successfully use of the delivery systems. I am thinking specifically of inspiratory flow rate or negative inspiratory force values to guide respiratory therapist.

It is usually stated that a peak inspiratory flow rate of at least 60 Liters/minute is needed for individuals to adequately activate breath-activated inhaler devices. This flow rate requirement may be somewhat lower in small individuals/children. Use of a pressurized metered dose inhaler (MDI) with a holding chamber and attached face mask may meet the needs when individuals cannot adequately time activation of the MDI with inhalation (I have enclosed below my brief review of a lecture by Nathan where this point is made).

I suggest that you and/or the respiratory therapist read a recent report in the journal Chest by a committee that reviewed aerosol delivery devices in detail. I have enclosed an abstract of that article below.

Inhalational delivery systems in asthma treatment

SUMMARY
Although inhaled medications have been used increasingly in the management of childhood asthma, there is still a considerable difference of opinion as to the best way to deliver such medication in young children. Nathan of the Asthma and Allergy Associates in Colorado Springs , CO presented the results in several studies, including his own, at the Annual Meeting of the AAAAI in 2003. he concluded that fluticasone delivered by a MDI into a spacer (Aerochamber-Plus or Optihaler) fitted with a face mask was effectively inhaled after 6 inhalations by very young children. He felt that this approach was as effective as delivery by nebulization with a facemask with lower cost and more convenience for the patient's family (and inherently better compliance with therapy).

EDITOR'S COMMENTS
These findings confirm the impression in meta-analyses, published in recent years that the delivery of either inhaled beta agonists or inhaled corticosteroids can be as effective by MDI/spacer as by nebulization at considerably lower cost, assuming that an appropriately fitting mask is used in young children

Chest. 2005 Jan;127(1):335-71. Related Articles, Links
Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology.
Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL, Smaldone GC, Guyatt G;
American College of Chest Physicians; American College of Asthma, Allergy, and Immunology. Faculty of Health Sciences, McMaster University , Hamilton, ON, Canada.

BACKGROUND: The proliferation of inhaler devices has resulted in a confusing number of choices for clinicians who are selecting a delivery device for aerosol therapy. There are advantages and disadvantages associated with each device category. Evidence-based guidelines for the selection of the appropriate aerosol delivery device in specific clinical settings are needed. AIM: (1) To compare the efficacy and adverse effects of treatment using nebulizers vs pressurized metered-dose inhalers (MDIs) with or without a spacer/holding chamber vs dry powder inhalers (DPIs) as delivery systems for beta-agonists, anticholinergic agents, and corticosteroids for several commonly encountered clinical settings and patient populations, and (2) to provide recommendations to clinicians to aid them in selecting a particular aerosol delivery device for their patients. METHODS: A systematic review of pertinent randomized, controlled clinical trials (RCTs) was undertaken using MEDLINE, EmBase, and the Cochrane Library databases. A broad search strategy was chosen, combining terms related to aerosol devices or drugs with the diseases of interest in various patient groups and clinical settings. Only RCTs in which the same drug was administered with different devices were included. RCTs (394 trials) assessing inhaled corticosteroid, beta2-agonist, and anticholinergic agents delivered by an MDI, an MDI with a spacer/holding chamber, a nebulizer, or a DPI were identified for the years 1982 to 2001. A total of 254 outcomes were tabulated. Of the 131 studies that met the eligibility criteria, only 59 (primarily those that tested beta2-agonists) proved to have useable data.
RESULTS: None of the pooled metaanalyses showed a significant difference between devices in any efficacy outcome in any patient group for each of the clinical settings that was investigated. The adverse effects that were reported were minimal and were related to the increased drug dose that was delivered. Each of the delivery devices provided similar outcomes in patients using the correct technique for inhalation.
CONCLUSIONS: Devices used for the delivery of bronchodilators and steroids can be equally efficacious. When selecting an aerosol delivery device for patients with asthma and COPD, the following should be considered: device/drug availability; clinical setting; patient age and the ability to use the selected device correctly; device use with multiple medications; cost and reimbursement; drug administration time; convenience in both outpatient and inpatient settings; and physician and patient preference.

5/16/05 re: Asthma management in children

I am a Pulmonologist practicing in Syria and having some questions regarding Asthma managment.

1- I am having extreme difficulties to convince not only patients and parents of children with Asthma but also practicing physicians and especially Pediatrician in town to use inhaled steroid as a first line therapy in Asthma managment. Can you have any references to show them that it is safe to use this kind of therapy even in children less than 6 yera old for long term

2-I am having difficulties to prove to the patients and physicians that spacers and valve holding chambers are very important to use and every patient using inhaled steroid must use a spacedo you have any references to show them this recommendation

3-In seasonal Asthma should we treat asthma with inhaled steroids prior and during spring only or all the seasons

4-Some physicians in town using intramuscular injection of depot steroids such as Betamethasone dipropionat every 3 months to treat asthma instead of inhaled steroids? should they keep doing this method or it is not safe compared to ICS

5-Some physicians in town telling the parents of asthma patient that when the child reach puberty the asthma will go away? is this statment correct for all patients?

6-In the office can we use the same spacer to deliver short acting inhaled beta agonist as a part of post bronchodialator test with spirometry if we change the mask and the vavle and the mouth piece instead of using nebulizer. I am concern about contamination inside the Chamber. We have valved holding chamber similair to OptiChamber were we can detach the mask, the mouth piece and the valve

1) Inhaled corticosteroid (ICS) treatment in childhood asthma. I suggest that you read the updated (2002) Expert Panel report of the National Asthma Education and Prevention Program of the National Heart Lung Blood Institute (NIH), accessed online at www.nhlbi.nih.gov/guidelines/asthma/asthmafullrpt.pdf. This report by a group of asthma experts points out in the section starting on page 17 that low dose ICS treatment is the preferred pharmacotherapy in persistent asthma of all levels of severity children 5 years and older because the outcomes appear to be superior to alternative treatments (nedocromil, leukotriene antagonists, theophyllines). The recommendations were less definite in children less than 5 years old because of insufficient data comparing ICS with these alternative treatments. See the enclosed review of those NAEPP recommendations written by me for this AADMC website. Also see abstract (below) of a thoughtful article by Szefler, a leader in asthma treatment studies in the USA.However, the need for chronic ICS in mild persistent asthma has been questioned in a recently reported study by Boushey et al (see enclosed abstract). Therefore, "as needed" use of ICS may be sufficient in those with mild persistent asthma.

Because ICS have been used extensively in children only in the past decade, one cannot make definite statements about the long-term safety of these agents in children. However, at relatively low doses of 200 microg/day or less of ICS such as fluticasone and budesonide, there appears to be no serious adverse systemic effects in growing children. There may be a transient reduction in growth velocity but studies by Sorensen's group and others suggest that most children regain any loss in growth rates.

2) Use of spacer/holding chambers - A few meta-analyses and reviews have concluded that use of MDI with spacers/holding chambers are as effective in delivering either beta agonist of ICS as the same agent delivered by power nebulization in asthma treatment as long as the patient can time the actuation of the MDI with inhalation correctly (see enclosed below my review of one of these meta-analyses). Most studies have found that the such treatment by MDI without spacers is not as effective.

3) Treatment of seasonal asthma - Which season in which asthma treatment is given depends on the sensitivity of the individual patient. It turns out that aeroallergen sensitivities that correlate best with asthma symptom occurrence are the perennial allergens such as dust mites, pet animals, certain molds (alternaria) and cockroach (city dwellings with major cock roach infestation. If the asthma is truly only seasonal, a careful symptom diary correlating time of occurrence with allergen sensitivity should be a good guide for treatment.

4) Depo-steroid therapy - There is a lot of evidence that chronic systemic steroid therapy, particularly depo-steroid injections are not as safe as chronic ICS therapy. Recent studies have shown significant increase in bone demineralization with only 6-8 weeks of systemic steroid therapy. Such effects are of particular concern in growing children and post-menopausal females.
5) "Outgrowing asthma"- Several long-term studies including those by a group at the Univ of Arizona have shown that wheezing persists into adolescence in a sizable percentage of childhood asthmatics (see enclosed abstract). Apparently, the more sever the asthma in childhood, the more likely it is to persist. I have also observed many patients who had remission of childhood asthma around puberty only to recur in the 20-30 year age period. This pattern was documented in a report in the New England J of Medicine.

6) Contamination in spacer - I am not an expert in such matters. However, I have been told that there are effective means of disinfecting the spacers after each use. I suggest that you contact the supplier of the spacers used by you to find out which disinfection method works well for such spacers

J Allergy Clin Immunol. 2005 Apr;115(4):708-13.
Understanding mild persistent asthma in children: The next frontier.
Bisgaard H, Szefler SJ.

Limitations in asthma prevalence studies and difficulties in diagnosing pediatric asthma lead to uncertainty over the full extent of mild persistent asthma in children and adolescents. Although recent surveys have reported that the majority of pediatric patients with asthma in the United States and Europe have symptoms consistent with mild disease, these surveys have limitations in design. Thus, the true prevalence of mild asthma remains unknown. It is unclear whether children with mild persistent asthma progress to more severe asthma, but the risk of severe asthma exacerbations seems to be unrelated to the symptom severity. Clinical studies restricted to pediatric patients with mild asthma are limited, but available data do suggest substantial morbidity of mild persistent asthma in this population and support inhaled corticosteroid intervention. There is a need for further investigation into the true prevalence of mild persistent asthma in children and adolescents, and optimal treatment.

N Engl J Med. 2005 Apr 14;352(15):1519-28.
Comment in: N Engl J Med. 2005 Apr 14;352(15):1589-91.
Daily versus as-needed corticosteroids for mild persistent asthma.
Boushey HA, Sorkness CA, King TS, Sullivan SD, Fahy JV, Lazarus SC, Chinchilli VM, Craig TJ, Dimango EA, Deykin A, Fagan JK, Fish JE, Ford JG, Kraft M, Lemanske RF Jr, Leone FT, Martin RJ, Mauger EA, Pesola GR, Peters SP, Rollings NJ, Szefler SJ, Wechsler ME, Israel E; National Heart, Lung, and Blood Institute's Asthma Clinical Research Network.
University of California at San Francisco, San Francisco, USA.

BACKGROUND: Although guidelines recommend daily therapy for patients with mild persistent asthma, prescription patterns suggest that most such patients use these so-called controller therapies intermittently. In patients with mild persistent asthma, we evaluated the efficacy of intermittent short-course corticosteroid treatment guided by a symptom-based action plan alone or in addition to daily treatment with either inhaled budesonide or oral zafirlukast over a one-year period.
METHODS: In a double-blind trial, 225 adults underwent randomization. The primary outcome was morning peak expiratory flow (PEF). Other outcomes included the forced expiratory volume in one second (FEV1) before and after bronchodilator treatment, the frequency of exacerbations, the degree of asthma control, the number of symptom-free days, and the quality of life.
RESULTS: The three treatments produced similar increases in morning PEF (7.1 to 8.3 percent; approximately 32 liters per minute; P=0.90) and similar rates of asthma exacerbations (P=0.24), even though the intermittent-treatment group took budesonide, on average, for only 0.5 week of the year. As compared with intermittent therapy or daily zafirlukast therapy, daily budesonide therapy produced greater improvements in pre-bronchodilator FEV1 (P=0.005), bronchial reactivity (P<0.001), the percentage of eosinophils in sputum (P=0.007), exhaled nitric oxide levels (P=0.006), scores for asthma control (P<0.001), and the number of symptom-free days (P=0.03), but not in post-bronchodilator FEV1 (P=0.29) or in the quality of life (P=0.18). Daily zafirlukast therapy did not differ significantly from intermittent treatment in any outcome measured.
CONCLUSIONS: It may be possible to treat mild persistent asthma with short, intermittent courses of inhaled or oral corticosteroids taken when symptoms worsen. Further studies are required to determine whether this novel approach to treatment should be recommended

Current Lit Item
The revised asthma guidelines

SUMMARY
Background - In the year 2002, the National Asthma Education and Prevention Program (NAEPP) issued an update to its recommendations about the diagnosis and management of asthma based on reviews of more recent evidence and consensus decisions of the Expert Panel convened.

Findings - As reviewed recently by Stoloff, a member of the Expert Panel involved, the main addition/revisions to existent recommendations were: 1) inhaled corticosteroids (ICS) are the preferred initial therapy for persistent asthma (PA) of all degrees of severity; 2) for patients with moderate PA, addition of an inhaled long-acting beta agonist (LABA - such as salmeterol or formoterol) to low dose ICS therapy leads to better symptoms control, improved lung function and decreased need for rescue medication than the with ICS treatment alone. Indeed, adding an LABA is preferable to doubling the dose of ICS to improve asthma control; 3) addition of an LABA may permit reduction of the dose of ICS needed for asthma control. This is quite important since adverse systemic effects of ICS such as a decrease in growth velocity appear to be ICS dose-dependent. Such decreases in growth velocity appear to be non-progressive and may be reversible; 4) for severe asthma not adequately controlled on a combination of medium dose ICS plus LABA, increasing the daily ICS dose above 800-1000 mcg/day generally affords only a modest added benefit while definitely increasing the potential for adverse systemic effects.

REFERENCE - J Respir Dis 2004;25:210-19

EDITOR'S COMMENTS
This nice succinct review of the updated NAEPP treatment recommendations make some important points. One of the most important, in my opinion, was shown in a graph that illustrates the impressive dose-dependent increase in ICS efficacy in asthma (usually up to daily doses of 400-800 mcg/day in adults for most ICS agents, perhaps a lower daily dose for fluticasone). Above those daily doses, there is relatively little added benefit but a significant increase potential for adverse systemic effects. Severe asthmatics may require additional therapy such as the lowest dose of oral steroids needed for asthma control.

Of note, this review commented that ICS is the preferred controller medication for asthma in children < 5 years without an initial trial of inhaled cromolyn/nedocromil (as formerly recommended). Leukotriene antagonist (LA) agents may e considered an alternative but not preferred to ICS therapy in young children because of the lack of good controlled comparisons of LA and ICS treatments in young children.

Current Lit Item
Inhaled beta agonists administered by MDI/spacer vs nebulization for acute asthma exacerbations in young children

SUMMARY
Background - The delivery of inhaled beta agonist such as albuterol (Alb) of acute asthma exacerbations in young children has typically been by power nebulizers. However, some (but not all) studies in recent years have shown equal efficacy in acute asthma flare when albuterol is inhaled by the child using either a nebulizer or a meter dose inhaler (MDI) with a valved spacer (holding chamber). Are the two methods of delivering inhaled Alb in young children really equally effective?

Findings - Castro-Rodriguez and Rodrigo of the Univ. of Chile in Santiago carried out a meta-analysis of reports of randomized, prospective, controlled trials comparing nebulized Alb vs Alb delivered by MDI plus valved hold chamber (VHC) in the treatment of acute asthma exacerbations in children < 5 years old. In 6 trials involving 491 patients obtained from databases which met the authors criteria for inclusion, children who received Alb by MDI + VHC actually were admitted subsequently because of uncontrolled asthma less frequently than children of the same age treated with nebulized Alb (Odds Ratio (OR) = 0.42; p=0.002). This decreased admission rate following MDI + VHC treatment was even more striking in those children treated for moderate to severe asthma exacerbations (OR=0.27; p=0.003). The mean reduction in severity of asthma symptoms was also significantly greater in those treated with MDI + VHC than in those treated with nebulized Alb (p=0.0003).

Conclusions - The use of MDI + VHC was more effective than nebulization in delivery of inhaled beta-agonists to children <5 years old with moderate to severe acute asthma flares in terms of improving clinical scores and decreasing the need for hospitalization.

REFERENCE - J Pediatr 2004;45:172-7

EDITOR'S COMMENTS
As a non-pediatrician, I have been puzzled by the somewhat conflicting results of previous studies comparing nebulization with MDI + VHC in the delivery of inhaled beta agonists in acute childhood asthma. Following discussion with a highly experienced Pediatric Allergist/Immunologist I now realize that there are a number of variables, which differ among these studies than can affect the authors' conclusions. For example: 1) the type of VHC used (most children < 5 years of age cannot adequately time activation of MDI with inhalation); 2) the number of MDI puffs inhaled in a treatment. The "standard" 2 puff MDI treatment is not equivalent to the delivery of Alb, 5 mg/ml by nebulizer; 3) the use of a facial mask vs "blow by" in nebulization; 4) the outcome measure assessed (no mention of pulmonary function findings in the meta-analysis above. It would not be surprising if MDI + VHC (with adequate number of puffs inhaled) was as effective as nebulization. What was surprising is that children treated with MDI + VHC did that much better, at likely a considerably reduced cost

Am J Respir Crit Care Med. 2004 Jul 1;170(1):78-85. Epub 2004 Mar 17.
Comment in: Am J Respir Crit Care Med. 2004 Jul 1;170(1):8-9.
Persistence of asthma symptoms during adolescence: role of obesity and age at the onset of puberty.
Guerra S, Wright AL, Morgan WJ, Sherrill DL, Holberg CJ, Martinez FD.
Arizona Respiratory Center, University of Arizona, 1501 North Campbell Avenue,
P.O. Box 245030, Tucson, AZ 85724-5030, USA.

Little is known about rates and predictors of remission of childhood asthma after the onset of puberty. We used data collected at ages 6, 8, 11, 13, and 16 years from the Tucson Children's Respiratory Study, a population-based birth cohort. The onset of puberty was defined as the age of appearance of the first pubertal signs as reported by parents. Information on wheezing both before and after onset of puberty (mean +/- SD follow-up from onset of puberty, 4.2 +/- 1 year) was available for 781 children. Of these, 166 had asthma (either frequent wheezing or a physician-confirmed diagnosis plus any wheezing) in at least one survey before puberty. In this group, 58% of the children (97 of 166) reported the presence of wheezing after the onset of puberty (unremitting asthma). In contrast, only 30% (39 of 131) of the children with infrequent wheezing before puberty experienced wheezing episodes after the onset of puberty (unremitting wheezing). In addition to frequent wheezing before puberty, obesity, early onset of puberty, active sinusitis, and skin test sensitization were significant and independent predictors of unremitting asthma after the onset of puberty. Our findings from a population-based longitudinal cohort challenge the commonly held view that asthma usually remits during adolescence.

4/14/05 re: Asthma treatment guidelines

I am an Asthma Nurse Educator at a pediatric clinic. When teaching patients about managing their asthma, I use the standard green zone, yellow zone, and red zone plan. I have been instructing patients to do the following: use 2 puffs of albuterol with the MDI and spacer Q4 hours in the yellow zone. Repeat while in yellow zone Q4 hours, use 2-4 puffs of albuterol MDI with spacer Q2-4 hours (repeat every 20 minutes X 3) for red zone, call 911 if unable to get out of red zone.

I recently heard that the recommendation is now 4 puffs with the MDI and spacer in the yellow zone, and 4-8 puffs with the MDI and spacer in the red zone, repeat every 20 minutes X 3.

This was information from one of the pediatricians in the clinic. I am unable to find this in writing anywhere. Could you please help direct me in this area? Thank you so much for your time.

To respond to your question, I obtained input from Dr. Stanley Szefler of the National Jewish Medical and Research Center in Denver CO. Dr. Szefler is an expert in asthma treatment who has served for some time on the Expert Panel that has drafted the asthma treatment guideline of the National Asthma Education and Prevention Program (NAEPP), sponsored by the NHLBI, NIH. As you likely know, the "green, yellow, red zone" approach to treatment was devised as part of the NAEPP program. Dr. Szefler's comments are enclosed below.

I am not aware of any guidelines statement that is similar to the modification in beta agonist use about which the questioner asked. My understanding is that the latest version of the NAEPP guidelines are on the web site http://www.nhlbi.nih.gov

3/9/05 re: Safety of Benadryl use in asthma

Should a patient with bilateral wheezing and in mild distress be prescribed Benadryl three times a day for a week along with his usual regime of albuterol spray and flovent. I would think that the drying effect of the antihistamine would pose more risk than benefit for the patient.

For many years there has been a concern among some clinicians that treatment with antihistamines such as diphenhydramine (Benadryl) will cause worsening of asthma because of the anticholinergic effects of these agents causing excessive drying of the thick bronchial secretions in this disorder. However, several recent careful studies have shown that treatment with such antihistamines do not significantly worsen active asthma. However, if an antihistamine were to be used, I suggest using one of the newer antihistamines such as fexofenadine (Allegra) which are much more selective antagonists of the histamine receptor than is Benadryl.. Therefore, these newer antihistamines have no anti-cholinergic effects which might cause drying of bronchial secretions.

A bigger question is whether antihistamine treatment has any beneficial effect in asthma. Several extensive studies have shown that such therapy has a very modest, if any, direct beneficial effect on the lower airways in asthma, particularly if the patient is being treated appropriately with agents such as inhaled corticosteroids. However, if the patient also has active allergic rhinitis (as many asthmatics do) such rhinitis may contribute to worsening of the asthma, as shown in a number of studies. Antihistamine treatment may help control the rhinitis with a secondary beneficial effect on the asthma.

11/18/04 re: Trials of omalizumab in young children

Dr. Zweiman's suggestion that omalizumab may be helpful is provocative. Since I am concerned about potential adverse effects of allergen immunotherapy in this four year old boy, omalizumab has great appeal. It would be very helpful to know if this treatment has ever been administered to young children. I would be willing to propose this to the family (who can well afford this treatment if insurance does not cover), but I would feel more comfortable if there was some data/prior experience that I could present.

To help respond to your question about the use of omalizumab in children less than 5 years old, I obtained input from Dr. Michael Kaliner who has written a recent thorough review of omalizumab treatment of allergic rhinitis ( see enclosed abstract; I have also enclosed abstracts of some other recent reviews of Anti-IgE therapy).The comments of Dr. Kaliner are enclosed below. You may wish to contact the professional relations department of Genentech, the contact info for which should be listed in the PDR, to see if there is some unpublished information about use of this agent in allergic rhinitis in young children.

I suspect that use of omalizumab in your patient would still be considered "off- label". Therefore, written informed consent should be obtained in advance. Recall that the serum IgE level as well as body size of the patient have to be considered in decisions about use of omalizumab and what dose to use.

Dr. Kaliner's comments

There have been very impressive studies of anti-IgE treatment in 6-12 yo with asthma but there have been no studies of anti-IgE for any respiratory indication below 6 yrs.

1: Curr Allergy Asthma Rep. 2004 May;4(3):237-44.
Omalizumab and the treatment of allergic rhinitis.
Kaliner MA.
Institute for Allergy and Asthma, 11160 Veirs Mill Road, Suite 414, Wheaton , MD 20902, USA. makaliner@aol.com

Anti-IgE therapy affects mechanisms in the allergic response that are IgE-dependent or IgE-mediated and common to both allergic asthma and allergic rhinitis. Clinical trials of omalizumab in the treatment of patients with allergic rhinitis or comorbid allergic rhinitis and moderate to severe allergic asthma have recorded significant reductions in symptom severity scores of both conditions. This novel therapy has increased the knowledge base concerning IgE-mediated allergic responses, and, in keeping with its actions established in the treatment of asthma, appears to be useful in the treatment of moderate to severe allergic rhinitis, as well.

Am J Health Syst Pharm. 2004 Jul 15;61(14):1449-59.
Omalizumab: a recombinant humanized anti-IgE antibody for allergic asthma.
Ruffin CG, Busch BE.
ACS State Healthcare, Atlanta, USA. charnelda.g.ruffin@kp.org

PURPOSE: The pharmacology, efficacy, dosage, adverse events, and economics of omalizumab are discussed. SUMMARY: Omalizumab, a recombinant DNA- derived humanized monoclonal antibody, binds to the C epsilon3 domain of immunoglobulin E (IgE) and forms complexes that inhibit the immune system's response to allergens by averting IgE-mediated inflammatory changes. Omalizumab exhibits a similar pharmacokinetic profile in adults, adolescents, and children. Omalizumab is indicated for adults and adolescents with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Because of the limited data regarding the safety and effectiveness of omalizumab in children, the drug is indicated for patients 12 years of age or older. The recommended starting dosage is 150-375 mg s.c. every two or four weeks. Dosages and frequency of dose administration are determined by total serum IgE level, measured before the start of treatment, and body weight. Omalizumab is generally well tolerated in adults and children with allergic asthma. Adverse events most commonly observed are injection-site reaction, viral infection, upper-respiratory-tract infection, sinusitis, headache, and pharyngitis. Three large phase III clinical trials demonstrated that omalizumab is more effective than placebo in controlling moderate to severe allergic asthma in patients who have poor disease control or exacerbations despite recommended therapy. Currently, there are no clinical comparisons of omalizumab with other standard treatments for asthma; therefore, it is difficult to determine its overall place in therapy. CONCLUSION: Omalizumab should be considered as a second- line therapy for patients with moderate to severe persistent allergic asthma.

Cochrane Database Syst Rev. 2004(3):CD003559.
Anti-IgE for chronic asthma in adults and children.
Walker S, Monteil M, Phelan K, Lasserson TJ, Walters EH.
National Respiratory Training Centre, The Athenaeum, 10 Church Street, Warwick, UK, CV34 4AB.

BACKGROUND: Omalizumab is a recombinant humanised monoclonal antibody directed against immunoglobulin E (IgE) to inhibit the immune system's response to allergen exposure. Omalizumab is directed against the binding site of IgE for its high affinity Fc receptor. It prevents free serum IgE from attaching to mast cells and other effector cells and prevents IgE mediated inflammatory changes.
OBJECTIVES: To determine the efficacy of anti-IgE in patients with allergic asthma
SEARCH STRATEGY: We searched the Cochrane Airways Group Asthma trials register (February 2003) for potentially relevant studies.
SELECTION CRITERIA: Randomised controlled trials examining anti-IgE administered in any manner for any duration.
DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study quality and extracted and entered data. Three modes of administration were identified from the published literature (inhaled, intravenous and subcutaneous injection). Subgroup analysis was performed by asthma severity. Data were extracted from published and unpublished sources.
MAIN RESULTS: Eight trials were included in the review, contributing a total of 2037 mild to severe allergic asthmatic participants with high levels of IgE. Treatment with intravenous and subcutaneous Omalizumab significantly reduced free IgE compared with placebo. Omalizumab led to a significant reduction in inhaled steroid consumption compared with placebo: -114 mcg/day (95% CI -150 to -78.13, two trials). There were significant increases in the number of participants who were able to reduce steroids by over 50%: odds ratio (OR) 2.50, 95% confidence interval (CI) 2.02 to 3.10 (four trials); or completely withdraw their daily steroid intake: OR 2.50, 95%CI 2.00 to 3.13 (four trials). Participants treated with Omalizumab were less likely to suffer an asthma exacerbation with treatment as an adjunct to steroids (OR 0.49, 95%CI 0.38 to 0.64, four trials), or as a steroid tapering agent (OR 0.47, 95% CI 0.37 to 0.60, four trials).
REVIEWERS' CONCLUSIONS: Omalizumab was significantly more effective than placebo at increasing the numbers of patients who were able to reduce or withdraw their inhaled steroids, but the mean difference in steroid consumption achieved with Omalizumab was of debatable clinical value. The impressive effects observed in control groups bring into question the true effect of Omalizumab. Omalizumab was effective in reducing asthma exacerbations as an adjunctive therapy to inhaled steroids. Omalizumab was well tolerated, although the safety profile requires longer term assessment. Patient and physician assessment of the drug was positive. Further assessment in paediatric and severe adult populations is necessary, as is double-dummy comparison with inhaled corticosteroids.

11/16/04 re: Evidence for corticosteroid use by patient

I am attempting to find evidence in the literature that supports prescribers entrusting asthma patients with an "emergency supply"or "crisis pack" of corticosteroids should they dip into their "redzones." I found one letter in BMJ, but for some reason and not finding any trials in their literature. Do you recall any citations to share?

I am unaware of any controlled study providing the evidence you seek about use of oral corticosteroids in patient (or parent) self-management of worsening asthma. Therefore, I obtained input from Dr. Gary Rachelefsky of the UCLA School of Medicine. Dr Rachelefsky is a highly experienced Pediatric Allergist-Immunologist who has participated in the writing of several asthma practice guidelines and written extensively about asthma management including his very good review in 2003 ((Pediatrics 2003; 112:382-97). Dr. Rachelefsky's comments are enclosed below.

Dr. Rachelefsky's comments:

There are no such reports in the literature I know of. However such treatment approaches are done by physicians who "practice� and teach self care to their patients and parents. When used appropriately, it is part of the process of self management and improved adherence to a treatment regimen.

10/14/04 re: Asthma treatment-beta agonists vs. inhaled steroids?

I am working as a general practitioner in U.K. This question of mine is about asthma management. Now recently the combination drugs are available in the market that is (salmeterol + Fluticasone), before we used to prescribe both of these separately. If you can tell me which one (combined or separate) of this method of prescription is good for the patient in both cost and efficacy. Also any study done on this topic to see which of this is good.

I have enclosed below my review of a recent meta-analysis of studies comparing the effects of various controller therapies in preventing acute asthma flares in chronic asthma. Almost all authorities state that inhaled corticosteroids (ICS) are the best controller therapy and should be used in all persistent asthma (daily or near-daily asthma symptoms when untreated) of any degree of severity. The advantage of using long-acting beta agonists (LABA) such as salmeterol or formoterol along with the ICS is that allows control of asthma with lower doses of ICS and therefore less chance of any systemic adverse effects of the ICS. Indeed, adding LABA can often improve asthma control better than doubling the dose of ICS. However, LABA should not be used as monotherapy for persistent asthma. There is less bronchodilating response when treating an acute asthma flare with inhaled salmbuterol (albuterol) in individuals receiving LABA as monotherapy. Within the past year warning has been sent out to physicians about a greater incidence of asthma fatalities in individuals with persistent asthma treated with salmeterol as monotherapy in the SMART study. Your question may also have been whether it is more effective to have the ICS and LABA in the same inhalational canister rather than used separately at the same time. Of course, such a combination inhaler is more convenient for the patient with possibly resultant better compliance with treatment. One study in Denver CO found somewhat better asthma control with use of a combination inhaler rather than 2 separate inhalers used at the same time. However, flexibility in dosing may be somewhat less with use of a combination inhaler. I cannot comment about cost factors in the UK. However, of note, Advair, the combination inhaler used in the USA is currently prescribed in about 28% of asthma-related office visits to primary care physicians. I should mention that the fluticasone/salmeterol inhaler is not the only combination inhaler available. Symbicort (now available in several European countries) is a combination of formoterol and budesonide. Formoterol has a possible advantage over salmeterol in a faster onset of bronchodilating action (as fast as salbutamol) while having a duration of bronchodilation at least as long as salmeterol.

Comparison of the reduction of acute asthma exacerbations by different anti-asthma therapies

A reduction in the frequency of acute asthma exacerbations (AAE) is considered an important outcome measurement in persistent asthma. This report described a systematic review of randomized double-blind controlled studies in 1980-2004 of the effects of various pharmacologic treatments on clinically relevant AAE in adult patients with chronic asthma. They found that, compared to placebo therapy, the use of inhaled corticosteroids was most effective in reducing the frequency of AAE (a mean decrease of 55%). Monotherapy with long-acting beta agonists was associated with a 25% reduction in the frequency of AAE. Treatment with a combination of inhaled steroids and long-acting beta agonists led to an additional 26% reduction in AAE frequency when compared to inhaled steroid monotherapy. Such a combination treatment was more effective in reducing the AAE frequency than was increasing the dose of inhaled steroids as monotherapy. Treatment with leukotriene modifiers/receptor antagonists reduced AAE by 41%, but was significantly less effective than inhaled steroids in this regard. Use of monoclonal anti-IgE antibodies with concomitant inhaled corticosteroid therapy was associated with 45% fewer AAE. The authors concluded that inhaled corticosteroids are the single most effective therapy for reducing AAE frequency in adults with persistent asthma. However, for those unable or unwilling to take corticosteroids, the use of leukotriene modifiers/receptor agonists may be reasonable. Anti-IgE treatment may be considered as adjunctive therapy for young adults with asthma who have clear evidence of allergies and elevated serum IgE levels.

Sin et al JAMA. 2004;292:367-76

10/11/04 re: Treatment for albuterol-intolerant asthmatic

I am a respiratory therapist and have contacted you to seek recommendations for the next step in the management of a patient that has come under my care. The patient is a 15 year old girl with long-standing poorly controlled asthma despite excellent compliance with adjunctive therapy (Advair, Singulair). The patient currently uses nebulized levalbuterol (Xopenex) for control of acute attacks, and has a documented and verified, per the treating physician, idiosyncratic reaction (worsening of bronchospasm) to racemic albuterol (Proventil). Due to financial constraints the patient's family is unable to afford continued use of Xopenex and the physician has turned to me to ask my guidance as an RT. The patient is also seeking something with better portability (preferably in the form of an MDI) for treatment of attacks that occur while at school or elsewhere. A battery powered ultrasonic nebulizer was suggested by the physician but is not covered by the patient's insurance and the family lacks the funding to pay for it themselves. I am at a loss when it comes to being able to think of a medication that would be suitable for such a case. Can you please provide me with some guidance or point me in the direction of a source for the information I seek?

I suggest a trial of inhaled formoterol, if use of that beta agonist is covered by the patient's insurance. Formoterol is a beta agonist with onset of bronchodilation as rapid as that of albuterol (starting within a few minutes) but a duration of this effect at least as long as salmeterol (8-12 hours). It is currently available in the USA in a dry powder inhaler (Foradil with Aerolizer, see enclosed abstract) but may also become available in a Turbuhaler as it is in Europe (see enclosed abstracts). I suggest that you contact the Novartis representative to get a supply of free samples of Foradil for use in a trial therapy of the patient. Although there are no guarantees, I think that there is less likelihood of inducing a paradoxical bronchospasm with formoterol than with racemic albuterol inhalation.

Curr Med Res Opin. 2002;18(8):445-55.
Formoterol delivered via a dry powder inhaler (Aerolizer): results from long-term clinical trials in children.
Pearlman DS, Kottakis J, Till D, Della Cioppa G.
University of Colorado Health Sciences Center, Denver, Colorado, USA .

Over 500 children with asthma, aged 5-12 years, have been treated with formoterol fumarate (Foradil) delivered via the Aerolizer dry powder inhaler in clinical trials, with treatment periods of up to 15 months. In pivotal double-blind trials, two dose levels, 12 and 24 microg taken twice daily, provided significant benefit in terms of lung function measurements and symptom control (a lower dose of 6 microg twice daily appeared insufficient with this formulation). The higher, 24 microg dose appeared to provide an additional margin of benefit in a subgroup of children with more unstable/severe disease when the results from long-term follow-up (12-15 months) were analyzed. Formoterol was shown to have a good safety profile when taken as regular maintenance treatment and when used as rescue medication by patients already receiving formoterol as regular maintenance treatment. In this flexible regimen, with formoterol used for rescue and maintenance, the overall daily intake of formoterol was low, with 96.1% of all treatment days (n = 2452) covered by a total daily dose (regular + rescue) of 48 microg (four doses) or less. There was no increase in the average daily intake of rescue formoterol over time. The clinical efficacy associated with this regimen was maintained over time and, in the case of morning peak expiratory flow rate, steadily improved over time. The Foradil Aerolizer inhalation system is simple to use and has a low resistance to inspiratory airflow that maximises the patient's control over dosing, while minimising the risk of under- and overdosing. These features may be especially valuable in a young patient population.

Paediatr Drugs. 2003;5(1):63-8; discussion 69.
Formoterol delivered by Turbuhaler: in pediatric asthma.
Cheer SM, Warner GT, Easthope SE.
Adis International Inc., Langhorne, Pennsylvania 19047, USA.

Formoterol is an inhaled long-acting beta (2)-adrenoceptor agonist, with a rapid onset of action and a bronchodilator effect that lasts for at least 12 hours. As add-on therapy to anti-inflammatory medication (e.g. corticosteroids), formoterol 4.5 and 9 microg twice daily delivered by Turbuhaler for 3 months significantly improved lung function (change from baseline in forced expiratory volume in 1 second and/or peak expiratory flow) compared with placebo in randomized, double-blind trials in pediatric patients (aged 6-17 years). In addition, formoterol 9 microg twice daily for 12 weeks reduced the use of rescue medication compared with salmeterol 50 microg twice daily in a non-blind trial in pediatric patients (aged 7-16 years). Single-dose formoterol 4.5 or 9 microg delivered by Turbuhaler provided significant prophylaxis against exercise-induced bronchoconstriction compared with placebo, and demonstrated a longer duration of effect than terbutaline, in a randomized, double-blind, crossover trial in pediatric patients (aged 8-17 years). Formoterol delivered by Turbuhaler was well tolerated in pediatric patients, with respiratory infection being the most commonly reported adverse event.

Pulm Pharmacol Ther. 2002;15(2):175-83.
Formoterol Turbuhaler 4.5 microg (delivered dose) has a rapid onset and 12-h duration of bronchodilation.
Selroos O, Ekstrom T.
AstraZeneca R&D, S-221 87, Lund, Sweden.

Clinical trials show that formoterol (Oxis) Turbuhaler 4.5 microg delivered dose (6 microg metered dose) has a rapid onset of bronchodilation similar to that of salbutamol and a 12-h duration of action. Maximum increase in FEV(1) and duration of bronchodilation are dose-dependent, the 4.5 microg dose being the lowest dose tested giving both effects. Clinical studies investigating onset of bronchodilation show a significant increase in specific airway conductance occurring within 1 min after inhalation of formoterol Turbuhaler 4.5 microg. When measured from 3-20 min after inhalation, formoterol Turbuhaler 4.5 microg showed similar increases in FEV(1) to salbutamol administered via pMDI. No difference in onset of bronchodilation was observed between the formoterol Turbuhaler 4.5 and 9 microg doses. Single-dose studies and studies of 1-12 weeks' duration show that formoterol Turbuhaler 4.5 microg produces a significant and clinically important mean bronchodilating effect for > or =12 h after inhalation. In the cited studies no significant differences in duration of bronchodilation were observed between the formoterol Turbuhaler 4.5 and 9 microg doses. Conclusion: clinical data show that formoterol Turbuhaler 4.5 microg is an effective dose in patients with asthma, with a rapid onset of bronchodilation and a duration of at least 12 h. Copyright 2002 Elsevier Science Ltd.

7/23/04 re: Proper use of inhaled beta agonists; cough

I am new at the asthma disease management game and at the risk of sounding completely ignorant, I have two questions. My first question is, a patient told me today that she is using Advair daily but hasn't had to use the albuterol for a few weeks. If the patient is on an inhaled steroid, should they be using the rescue inhaler first, even if they are not currently in an episode, for improved efficacy of the steroid? My second question is this. For about the last 14 years, 1 in HI, and 13 in Las Vegas, I have had a problem with a chronic cough only in the months of April/May, Aug/Sept. Allergies to mold and grasses only. I have been unable to use any quick relief inhalers because of hypersensitivity resulting in tachycardia. I was only able to get maybe one hour relief anyway. Inhaled steroids seemed to make no difference. There is no wheezing or any acute attacks, just chronic, nonproductive coughing and only at those times of the year. Now that I am in Portland, OR, I have no idea what's going to happen but hope for the best. How would you classify this?

Question #1: For years, many of us recommended to our patients that they use an inhaled beta agonist (IBA) such as albuterol before using their inhaled corticosteroid (ICS) preparation because of the theory that the bronchodilation induced by albuterol would permit better penetration of the ICS into the more distal lower airways. However, to my knowledge, there was never any study showing that such deeper penetration of the ICS did occur when albuterol was used first (which generally requires use of radiolabeled ICS for investigation). Also, there was no convincing evidence that overall asthma outcomes were better with this combined approach. When evidence started emerging about the potential deleterious effects of chronic standing dose use of albuterol (tachyphylaxis during rescue use of albuterol for acute asthma flares, epidemiological evidence suggesting increased asthma mortality) most asthma specialists stopped recommending using albuterol in standing doses this way. However, the situation appears to be quite different when long- acting IBA are used in standing doses chronically. When such agents are used along with an ICS, asthma can generally be controlled with about half the dose of the ICS required when the ICS is used alone. There may be a subtle decrease in responsiveness to the rescue use of albuterol in such treated individuals but over all asthma outcomes are better with this combination therapy. Advair is such a combination of an ICS (fluticasone) and a long-acting IBA (salmeterol). It is true that the onset of the bronchodilation effect of salmeterol is not until 15-30 minutes after inhalation. Therefore, one may not get the potential benefit of very rapid onset bronchodilation that could enhance ICS penetration into the lower airways. However, such penetration of ICS may also depend on the type of delivery system employed and the type of propellant in preparations contained in meter dose inhalers. If you wish to use a combination approach with a faster onset of bronchodilation, you may wish to consider Symbicort, a combination of formoterol, a long-acting IBA and budesonide (ICS with potency close to that of fluticasone). The onset of bronchodilation induced by formoterol is as rapid as with use of albuterol (generally within 1-2 minutes) while the duration of this effect is at least as long as with salmeterol (8-12 hours).

Question #2: Your description of your problem sounds as if you may have what has been called �cough-equivalent asthma,� presenting as a dry cough without obvious wheezing or dyspnea. The way to investigate this is to first have spirometry studies during a time when you are symptomatic. If the FEV-1 is significantly decreased and/or FEV-1/FVC ratio is low, that diagnosis is strongly suggested. However, cough-equivalent asthma can occur with normal spirometry. But in such cases, there is evidence of bronchial hyper-responsiveness (�twitchy airways�) which can be detected in a methacholine inhalation challenge test. Insofar as treatment is concerned, it may take several weeks of the use of adequate doses of ICS before the tendency to coughing is suppressed. You may wish to try one of the long-acting IBA mentioned above, either alone or in combination with an ICS. Such IBA sometimes induce less tachycardia than does albuterol. If these are not tolerated, you can try a leukotriene antagonist such as Singulair, 10 mg taken once daily for a week to see if your cough is reduced. If there is good evidence that exposure to the aeroallergens you mentioned with trigger/aggravate your coughing episodes, avoidance measures should be undertaken. It is possible that the situation may change with your move to Oregon. If you continue to have problems in Oregon, I recommend consultation with a certified allergist there. You can find the names of such allergists through the allergist referral service of the AAAAI (check the AAAAI website at www.aaaai.org )

7/7/04 re: Stability of combined albuterol, ipratropium and budesonide

Besides the manufacturer's package insert, where can I look for more information regarding the stability when combining albuterol, ipratropium, and budesonide for a nebulizing asthma therapy? Any suggestions would be appreciated.

I have no personal experience with the combination of albuterol, ipratropium, and budesonide administered in the same nebulizer treatment. Since albuterol and ipratropium have been mixed together successfully in the same MDI for some time (Combivent), I would check with the Professional Services dept of the manufacturers of Combivent (Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT 06877-0368. Tel # likely listed in the Physician's Desk Reference.) I would then ask them about the compatibility of adding budesonide to the combination of the other two medications.

6/16/04 re: Comparison of IV theophylline and IV salbutamol (albuterol) in acute asthma

I am a Nurse Consultant working in Accident and Emergency Care in a teaching hospital north of England. I am currently working on a systematic review of the above subject and have completed an extensive search of databases looking for randomized control trials (RCT's). I have located some RCT's dating back to the 1970's and 1980's. I wondered if you were aware of any more recent RCT's or unpublished RCT's that may not have made it on to the databases?

I am not aware of any recent randomized controller comparisons of IV theophyllines vs. salbutamol. Therefore, I consulted Dr. Miles Weinberger of the Univ. of Iowa, one of the leading investigators of theophylline therapy in asthma. His response is enclosed below. As you can see, the 2 references he provided are quite old. I suspect that the dearth of recent reports reflects the considerable decrease in most academic centers in the use of both IV aminophylline and IV beta agonists in the management of severe acute asthma exacerbations.

Dr. Weinberger's response:

I didn't find any randomized controlled trials. The following is what I did find on the comparison:

British Journal of Diseases of the Chest
(Reference 1 of 2)

81160518
Evans WV Monie RD Crimmins J Seaton A
Aminophylline, salbutamol and combined intravenous infusions in acute severe asthma.
In: Br J Dis Chest (1980 Oct) 74(4):385-9 ISSN: 0007-0971

<Albuterol/AD/TU> <Aminophylline/AD/TU> <Asthma/DT> <Acute Disease> <Adolescence> <Adult> <Clinical Trials> <Drug Administration Schedule> <Drug Therapy, Combination> <Female> <Human> <Infusions, Parenteral> <Male> <Middle Age> <Peak Expiratory Flow Rate> <Clinical Trial> <Randomized Controlled Trial> <Medline File>

Twenty-one patients admitted to the hospital with acute severe asthma were allocated in a random, single-blind manner to receive intravenous infusions for 24 hours of either aminophylline or salbutamol or a combination of the two drugs. Infusions were administered by a slow infusion pump with an initial loading dose given over 15 minutes, followed by a continuous lower dose of the drug 24 hours as follows:
1. Aminophylline 0.285 mg/kg/min for 15 min followed by 0.014 mg/kg/min (20 mg/min. followed by 1 mg/min for a 70 kg subject).
2. Salbutamol 0.285 microgram/kg/min for 15 min followed by 0.057 microgram/kg/min (20 microgram/min followed by 4 microgram/min for a 70 kg subject).
3. Combined regimen of the above infusions.

In addition each patient received intravenous hydrocortisone (4 g) and potassium chloride (4 g) in 2 litres of 5% dextrose infused over 24 hours and 35% oxygen given via a Ventimask. Peak expiratory flow rates showed a significant improvement after 15 minutes treatment with aminophylline and the combined infusion, but this was not seen until 60 minutes with the salbutamol infusion. No synergistic bronchodilator effect was seen with the combined infusion. The results show that intravenous aminophylline is superior to intravenous salbutamol in the doses given in the initial treatment of acute asthma and that the combination when given intravenously is not better than aminophylline alone.

Registry Numbers: 18559-94-9 (Albuterol)
317-34-0 (Aminophylline)

British Medical Journal
(Reference 2 of 2)

78145631
Johnson AJ Spiro SG Pidgeon J Bateman S Clarke SW
Intravenous infusion of salbutamol in severe acute asthma.
In: Br Med J (1978 Apr 22) 1(6119):1013-5 ISSN: 0007-1447

<Albuterol/AD/TU> <Asthma/DT/PP> <Acute Disease> <Adult> <Aminophylline/TU> <Female> <Forced Expiratory Volume> <Human> <Infusions, Parenteral> <Male> <Middle Age> <Peak Expiratory Flow Rate> <Vital Capacity> <Clinical Trial> <Randomized Controlled Trial> <Medline File>

Out of 62 asthmatic patients admitted to hospital with an acute exacerbation of their disease, those whose symptoms had not sufficiently improved 15 minutes after an initial intensive regimen were randomly allocated to receive an intravenous infusion of either salbutamol 10 microgram/min (20 patients) or aminophylline 1 mg/min (19 patients). During the infusions, which lasted 36 hours, peak expiratory flow rates and spirometric values improved in both groups, but differences between the groups did not achieve statistical significance. Although salbutamol may be infused safely for a prolonged period to patients with acute asthma, it has no particular advantage over aminophylline. Furthermore, in patients who respond poorly to initial intensive treatment, the subsequent infusion of a bronchodilator may not increase the rate of recovery from the rate that would occur naturally.

Update (6/16/2004)
I did not include the two references enclosed below when I responded recently to your question. They may be of interest to you in case you had not seen them.

Eur J Emerg Med. 2003 Sep;10(3):219-24.
The administration of beta2-agonists for paediatric asthma and its adverse reaction in Australian and New Zealand emergency departments: a cross-sectional survey.
Habashy D, Lam LT, Browne GJ.
Department of Emergency Medicine, The Children's Hospital at Westmead, Royal Alexandra Hospital for Children, Locked Bag 4001, Westmead NSW 2145, Australia.

Aim: To determine the current use of beta2-agonists, in particular salbutamol, for the management of acute asthma in children in emergency departments throughout Australia and New Zealand.

Methods: A cross-sectional survey using a questionnaire that sought to determine the current use of salbutamol and any adverse drug reactions in paediatric emergency departments.

Results: Out of 37 hospitals eligible as paediatric emergency departments, 33 (89.1%) responded to the survey, 54.5% having guidelines for the management of acute asthma. Of the paediatric emergency departments surveyed, 45.5% used metered-dose inhaler spacer combination in the treatment of mild to moderate asthma. All paediatric emergency departments used nebulized salbutamol for acute severe asthma. In addition, 85% of paediatric emergency departments used continuous-infusion intravenous salbutamol in unresponsive patients, 63.6% administering a single-dose intravenous salbutamol bolus before commencing the infusion. District paediatric emergency departments were more likely to treat with continuous-infusion intravenous salbutamol outside of the intensive care unit. Clinical unresponsiveness to inhaled salbutamol and clinical improvement were the reported criteria in all paediatric emergency departments for the use and cessation of intravenous salbutamol. Adverse drug reactions were common: tremor (90%), hypokalaemia (45.5%) and supraventricular tachycardia (21%), particularly if continuous-infusion intravenous salbutamol administered. Eight deaths from asthma were reported, none being related to adverse drug reactions.

Conclusion: We report a wide variation of salbutamol use in paediatric emergency departments and a high prevalence of type A adverse drug reactions when continuous-infusion intravenous salbutamol therapy was administered. More evidence is needed on the clinical significance of the adverse effects reported in this study and optimal doses for the safe use of continuous-infusion intravenous salbutamol therapy in paediatric emergency departments.

Chest. 2001 May;119(5):1480-8.
Efficacy of IV theophylline in children with severe status asthmaticus.
Ream RS, Loftis LL, Albers GM, Becker BA, Lynch RE, Mink RB.
Division of Critical Care, Saint Louis University and the Cardinal Glennon Pediatric Research Institute, St. Louis, MO, USA.

Study Objective: To determine whether adding IV theophylline to an aggressive regimen of inhaled and IV beta-agonists, inhaled ipratropium, and IV methylprednisolone would enhance the recovery of children with severe status asthmaticus admitted to the pediatric ICU (PICU).

Design: A prospective, randomized, controlled trial. Asthma scoring was performed by investigators not involved in treatment decisions and blinded to group assignment.

Setting: The PICU of an urban, university-affiliated, tertiary-care children's hospital.

Patients: Children with a diagnosis of status asthmaticus who were admitted to the PICU for < or = 2 h and who were in severe distress, as indicated by a modified Wood-Downes clinical asthma score (CAS) of > or = 5.

Interventions: All subjects initially received continuous albuterol nebulizations; intermittent, inhaled ipratropium; and IV methylprednisolone. The theophylline group was also administered infusions of IV theophylline to achieve serum concentrations of 12 to 17 microg/mL. A CAS was tabulated twice daily.

Measurements and Results: Forty-seven children (median age, 8.3 years; range, 13 months to 17 years) completed the study. Twenty-three children received theophylline. The baseline CASs of both groups were similar and included three subjects receiving mechanical ventilation in each group. All subjects receiving mechanical ventilation and theophylline were intubated before drug infusion. Among the 41 subjects who were not receiving mechanical ventilation, those receiving theophylline achieved a CAS of < or = 3 sooner than control subjects (18.6 +/- 2.7 h vs. 31.1 +/- 4.5 h; p < 0.05). Theophylline had no effect on the length of PICU stay or the total incidence of side effects. Subjects receiving theophylline had more emesis (p < 0.05), and control patients had more tremor (p < 0.05).

Conclusions: Theophylline safely hastened the recovery of children in severe status asthmaticus who were also receiving albuterol, ipratropium, and methylprednisolone. The role of theophylline in the management of asthmatic children in impending respiratory failure should be reexamined.

4/12/04 re: Higher doses of Xopenex in asthma treatment

I am a wondering if there is any supporting literature or current strategies in the treatment of asthma exacerbation with the use of xopenex beyond the reccomended dosages.

As you likely know, Xopenex (levalbuterol), abbreviated Lev here, was marketed with the purported advantage over racemic albuterol (RacAlb) that there would be less beta agonist adverse effects in treatment with a similar molar concentration. There was never any convincing evidence that there would significantly different bronchodilating effects of equivalent molar concentrations of Lev and RacAlb.

The question could be raised whether patients might be treated with higher than recommended molar concentrations of Lev (with potential for greater bronchodilating activity) since this may not be limited by adverse side effects. However, more recent studies by several groups have shown no differences in the incidence of tremor or differences in the increase in heart rate induced by treatment with equivalent molar concentrations of Lev and RacAlb (see material enclosed below). Therefore, increasing the amount of Lev used in asthma treatment would likely present the same potential risks for adverse effects as would be present with use of increasing doses of RacAlb. This risk may be a particular problem in those with underlying cardiac problems, particularly coronary artery disease and arrythmias. Also, it is conceivable that the tachyphylaxis observed during chronic therapy with inhaled beta agonists might be more pronounced when larger than recommended doses of Lev are used.
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Am J Ther. 2003 Sep-Oct;10(5):341-7.
Retrospective comparison of nebulized levalbuterol and albuterol for adverse events in patients with acute airflow obstruction.
Scott VL, Frazee LA.
Department of Pharmacy, Akron General Medical Center Akron, OH 44307, USA.

The objective of this study was to retrospectively compare the mean change in heart rate (HR) of patients with acute airflow obstruction treated with nebulized levalbuterol vs. albuterol. The study was conducted at the Akron General Medical Center, a 537-bed adult tertiary care teaching and research medical center. The participants were patients (> or = 18 years old) presenting to the emergency department with acute airflow obstruction. This was a retrospective chart review. Treatment groups received either levalbuterol (0.63 mg) or albuterol (2.5 mg). Respiratory care notes record HRs before and after nebulization of levalbuterol or albuterol. Primary analysis was conducted on days 1 and 3 of therapy to determine whether there is a difference between levalbuterol and albuterol with regard to mean change in HR with each treatment. In the primary analysis data, 35 subjects in each treatment group were compared. The mean age (+/- SD) was 65 +/- 16.4 and 68 +/- 16.5 for levalbuterol and albuterol, respectively. On day 1 of therapy, the difference in the mean change in HR with albuterol compared with levalbuterol was 1.0 bpm (95% CI, -1.6 to 3.7). On day 3, a statistically significant difference occurred in mean change in HR between treatment groups at 2.7 bpm (95% CI, 0.02 to 5.4). An increase in HR of 2.7 bpm by albuterol compared with levalbuterol on day 3 of therapy was the only significant finding among the analyses. However, this finding did not demonstrate dangerous elevations in HR following treatment with albuterol. Even the upper end of the confidence interval range at 5.4 bpm does not support a clinically significant difference in tachycardia with the pure isomer compared with the racemic mixture during acute airway obstruction.
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(Pediatrics in Review. 2004;25:108-109.)

2004 American Academy of Pediatrics

Point-Counterpoint: A Comparison of Levalbuterol and Racemic Albuterol in the Treatment of Pediatric Asthma

Myles B. Abbott, MD
Clinical Professor of Pediatrics
University of California School of Medicine
San Francisco, CA
(Dr. Abbott is a consultant for Express Scripts)

Robert H. Levin, PharmD
Professor Emeritus of Clinical Pharmacy
University of California School of Medicine
San Francisco, CA

Jennifer A. Miller, MD
Children's Hospital & Research Center
Oakland, CA

A reader writes: In regard to their article "Levalbuterol in Managing Pediatric Asthma" ( Pediatr Rev. 2002;23:401[Free Full Text]), the authors concluded that levalbuterol does not decrease adverse effects (tachycardia, tremors, nervousness) and, thus, has no clinical advantages over the use of racemic albuterol. From my research and clinical experience, I strongly disagree.

The issue of determining which medications cause the fewest adverse effects and are most effective in managing this disease has become a priority, especially for short-acting beta2 agonists. The introduction of levalbuterol to the market has prompted a debate about its efficacy and safety. With the use of albuterol, patients and parents commonly complain of beta2-initiated adverse effects. Concerns revolve around increased heart rate, hyperactivity of the child, and nervousness. Parents worry about increased behavioral problems in their children. The multicenter, randomized, double-blind studies consistently provided data that levalbuterol is associated with a lower incidence of jumpiness and nervousness than albuterol. (1)(2)(3)(4)

Research can only provide part of the information. My anecdotal experience has shown that patients and their families verbally report a decrease in the beta2-mediated adverse effects and improvement in behavioral problems when patients were switched to levalbuterol. Cost, as with any medication, is always a factor. As the authors mentioned, levalbuterol is more expensive than albuterol. The minimal extra expense of levalbuterol may be warranted when patients experience a decrease in beta2-mediated adverse effects and families see improvements in behavior. The authors reply: The writer maintains that levalbuterol has fewer adverse effects (eg, hyperactivity) than albuterol in pediatric patients. She relies on anecdotal experience and cites four sources to support her assertion. However, the studies cited do not substantiate this assertion. The first citation (1) is not a peer-reviewed study, but rather an abstract of a study "supported by a grant" from the manufacturer of levalbuterol. The study documented fewer admissions to the hospital in the levalbuterol group compared with the albuterol group. The authors of the abstract stated that there were no significant adverse effects reported in either group. The Gawchik and associates (2) and Milgrom and colleagues (3) articles, which we cited in our original article, do not mention hyperactivity, nervousness, behavioral problems, or jumpiness. Gawchik and associates stated that tremor did not occur in any patient in either arm of the study; Milgrom and colleagues did not study tremor. As shown in the Table, both articles found no statistically significant difference in heart rate change between albuterol and levalbuterol at equipotent doses (levalbuterol is one-half the dose of albuterol-0.625 mg versus 1.25 mg).

Levalbuterol Albuterol

Gawchik and colleagues

Dose 0.63 mg 1.25 mg

Heart rate change 10.8 beats/min 10.6 beats/min

Dose 1.25 mg 2.5 mg

Heart rate change 15.9 beats/min 10.2 beats/min

Milgrom and colleagues

Dose 0.63 mg 1.25 mg

Heart rate change

Day 0 7 beats/min 7 beats/min

Day 21 4 beats/min 6 beats/min

The article from The Medical Letter (also referenced in our article), concludes, "Levalbuterol appears to have no clinically significant advantage over racemicalbuterol."

The writer also states that using levalbuterol entails only "minimal extra expense," but the data are clear that the cost difference between levalbuterol and albuterol is far from "minimal." The data we cited show that levalbuterol is nearly 10 times more expensive than albuterol (acquisition cost of $1.87 vs. $0.19). The Medical Letter shows levalbuterol to be six times more expensive ($198.00 versus $33.08 for 100 doses).

In summary, the current pediatric medical literature supports our conclusion that albuterol remains the first-line rescue treatment of choice for acute symptomatic asthma. Furthermore, in equipotent doses, levalbuterol has not been shown to be more efficacious or cause fewer adverse effects than albuterol. Nonetheless, if the clinician and family feel that albuterol therapy is causing undesirable adverse effects, a change to levalbuterol may be worthwhile and does not appear to be harmful.

References

1. Carl J, Myers T, Kercsmar C. Comparison of levalbuterol and albuterol for treatment of acute asthma in pediatric patients. Chest.2001; 120 :137S

2. Gawchik SM, Saccar CL, Noonan M, et al. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allerg Clin Immunol.1999; 103 :615 -621[Medline]

3. Milgrom H, Skoner DP, Bensch G, et al. Low-dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol. J Allerg Clin Immunol.2001; 108 :938 -945[Medline]

4. Levalbuterol for asthma. The Medical Letter.1999; 1054

4/1/04 re: Alternative to HFA-propped albuterol

What is the latest proposal on HFA inhalers? Will they allow CFC inhalers for patients with documented reactions to HFA inhalers?

In 2000, a patient had a very severe reaction to HFA albuterol inhaler. What options will be available to these patients?

If your patient definitely had a severe reaction to inhalation of the HFA propellant, I do not think that use of CFC -propelled medications is a realistic long-term approach. Even if one obtained some of the decreasing supply of CFC-propelled albuterol on a "compassionate use" basis, there will soon be little if any CFC-based preps available as manufacturers stop production to meet the regulations in the Montreal agreement of several years ago (re ozone depletion by CFC).

A better alternative would be a dry powder inhaler (DPI) containing a beta agonist. Comparison studies in Europe have shown that salbutamol (another name for albuterol) delivered by DPI is as effective as the same agent delivered by a HFA-containing MDI (see enclosed abstract). You may wish to consider use of formoterol, a newer beta agonist available in a DPI formulation (Foradil). This agent is unique in having onset of bronchodilating action as early as albuterol but persisting much longer (at least as long as salmeterol)- see enclosed abstracts.
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: Respir Med. 2002 Nov;96(11):957-9.
Clinical equivalence between salbutamol hydrofluoroalkane pMDI and salbutamol Turbuhaler at the same cumulative microgram doses in paediatric patients.
Gustafsson P, Kallman S, Whitehead PJ.
Department of Paediatrics, Central Hospital, Skovde, Sweden.

This study aimed to demonstrate equivalent efficacy and safety between salbutamol delivered via the HFA134a pMDI (Hydrofluoroalkane 134a pressurized Metered Dose Inhaler) and the Turbuhaler dry powder inhaler in asthmatic children. This was a randomised, double-blind, double-dummy, placebo-controlled, crossover study in 10 asthmatic children aged 6-15 years who demonstrated at least 10% reversibility of FEV1 after inhaling 400 microg of salbutamol. On 5 single study days subjects received either placebo or cumulative doses of 100, 200, 400 and 800 microg of salbutamol at 30 minute intervals. Both devices were placebo on one study day while each device was active on two study days. FEV1 was measured before and 20 minutes after each dose. Heart rate was measured before spirometry. Mean FEV1 and heart rate at each time point and the area under the dose response time curve (AUC) were analysed using ANOVA. FEV1 increased similarly after cumulative doses of salbutamol on each of the study days, irrespective of device. Mean treatment difference in AUC was 0.01 L. min (95%CI -0.05 to 0.08 L). Heart did not differ at any dose. It is concluded that salbutamol delivery from a HFA pMDI and Turbuhaler is equivalenton a microgram basis in asthmatic children for efficacy and safe.
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Clin Ther. 2003 Nov;25(11):2635-46.
Tolerability of short-term, high-dose formoterol in healthy volunteers and patients with asthma.
Ostrom NK.
Allergy and Asthma Medical Group and Research Center, San Diego, California

BACKGROUND: Formoterol is a long-acting (>or=12 hours) beta(2)-receptor agonist with a rapid onset of action (1-3 minutes). It is approved in the United States, delivered via a single-dose dry-powder inhaler (DPI), for use in combination with anti-inflammatory therapy for the maintenance treatment of asthma and for the prevention of exercise-induced bronchospasm. Potential exposure of patients to higher doses than are currently approved is an important consideration in assessing the safety profile of formoterol. OBJECTIVE: This article reviews data from clinical trials investigating the effects of short-term use (4-48 hours) of high doses of formoterol (maximum, 228 microg). METHODS: Comparative and noncomparative studies of the effects of short-term, high-dose formoterol, inhaled via metered-dose inhaler (MDI) or single-dose DPI, were identified through searches of the literature indexed on MEDLINE, EMBASE, Current Contents, and Science Citation Index from their inception through August 15, 2003. RESULTS: This review included 1 open-label noncomparative study of high-dose formoterol in 12 healthy volunteers (mean age, 29 years), 1 placebo-controlled dose-escalation study of formoterol in 20 patients with asthma (mean age, 30 years), and 3 comparative studies of formoterol and short-acting beta(2)-agonists. The latter included a dose-escalation study in 13 patients with asthma (mean age, 47.2 years), a high-dose study in 12 healthy volunteers (mean age, 27 years), and a dose-escalation study in 9 children with asthma (mean age, 10 years). In the study in healthy volunteers, the metabolic and cardiovascular effects of high single doses of formoterol (maximum, 120 microg) were small and had no clinical consequences. In the placebo-controlled dose-escalation study in patients with asthma, however, the metabolic effects of formoterol at doses from 24 to 96 microg and the cardiovascular effects of formoterol at doses from 48 to 96 microg differed significantly from those of placebo (P < 0.05 to P <0.001) but were unlikely to result in clinically significant adverse effects. In the studies comparing formoterol with short-acting beta(2)-agonists in patients with stable asthma, the Cardiovascular and metabolic effects of short-term, high-dose formoterol (cumulative dose, up to 228 microg) were comparable to those of high-dose albuterol (salbutamol) (cumulative dose, up to 3800 microg). Studies of high-dose formoterol delivered via multidose DPI (not available in the United States) have reported a safety profile similar to those of high-dose terbutaline and albuterol. CONCLUSION: In studies of the short-term use of high-dose formoterol delivered via an MDI or single-dose DPI, this agent had a safety profile comparable to that of short-acting beta(2)-agonists.
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J Asthma. 2003;40(5):505-14.
Formoterol delivered via the dry powder Aerolizer inhaler versus albuterol MDI and placebo in mild-to-moderate asthma: a randomized, double-blind, double-dummy trial.
Pleskow W, LaForce CF, Yegen U, Matos D, Della Cioppa G.
Radiant Research, Encinitas, California, USA.

The objectives of this study were to compare the efficacy and tolerability of twice-daily formoterol dry powder 12 microg and 24 microg (Foradil) delivered via Aerolizer inhaler with four times daily albuterol (salbutamol) 180 microg delivered via metered dose inhaler (MDI) and placebo. A total of 554 adolescents and adults (ages 12-75 years) with mild-to-moderate asthma were randomized to this 12-week, multicenter, double-blind, double-dummy, placebo-controlled, parallel-group study. Twelve-hour spirometry measurements were taken at weeks 0, 4, 8, and 12. A total of 484 patients completed the study (122, 116, 127, and 119 given formoterol 12 microg, formoterol 24 microg, albuterol, and placebo, respectively). For the primary efficacy variable, the forced expiratory volume in 1 second (FEV1), both formoterol 12 microg and 24 microg were statistically superior to placebo at all time points on all test days (p < or = 0.017) and to albuterol at most time points on all test days (p < or = 0.001). The onset of improvement in FEV1 was rapid, with 15% increase within 5 min in 57%, 71%, and 65% of formoterol 12 microg, formoterol 24 microg, and albuterol patients, respectively. Formoterol was also superior to placebo and albuterol in terms of secondary efficacy variables: FEV1 area under the curve, percentage of predicted FEV1, forced vital capacity and forced expiratory flow, asthma symptom scores, and peak expiratory flows. In conclusion, both formoterol doses were superior to placebo in all lung function measurements. Overall, compared with albuterol, both formoterol doses produced superior bronchodilation. Formoterol and albuterol were safe and well-tolerated.

3/1/04 re: Inhaled therapy in infants

I am a pediatrician here in a small town America and I put great importance and emphasis on asthma and allergy control. I have a question here that needs your expertise. What is your opinion on using a holding chamber with MDI (i.e. babyhaler) for an infant? I am not quite sold on this because I am not sure that the passive breathing of an infant is effective for medication delivery. For these age groups I still recommend the nebulizer via mask (not blow-by, although I have a tough time convincing the respiratory therapist in the hospital that this is practice is not efficient either). I do recommend using the holding chamber for kids old enough to understand how to use it. Are there any studies on this? Or are there merits with the babayhaler worth considering? If you can comment about the blow-by technique through the nebulizer, I will truly appreciate it too (and maybe show this to the respiratory therapists).

Because I have not personally been involved in the treatment of infants for many years, I consulted Dr. Susan Schuval of the North Shore/L.I.J Medical Center in New York . Dr. Schuval is a highly experienced Pediatric Allergist/Immunologist who is a member the Advisory Committee for our AADMC website. Her response is enclosed below.

Use of Spacers with Face Masks in Infants

In older children and adults, the addition of spacers, or valved holding chambers, to pressurized metered dose inhalers (MDI's) has been shown to result in effective drug delivery. Delivery of medications is quicker, more convenient, and generally less expensive than aerosol delivery via nebulization. There is less oropharyngeal deposition of medication and enhanced drug delivery to the lower airways. Infants, however, are generally nosebreathers, and require the use of a facemask rather than a mouthpiece for effective drug delivery via nebulizer or via MDI with holding chamber. Use of the facemask with the valved holding chamber has been shown to be as effective as the nebulizer. In order for maximal efficacy, the mask must be held firmly against the infant's face, resulting in a tight seal. Airleaks around the seal may result in less effective drug delivery as does infant crying. Studies have shown the importance of parental instruction in proper technique to ensure proper dosing, but even with adequate technique, the amount of drug delivered may be variable. Comparison of various holding chambers with facemasks have shown that the Aerochamber with Mask is superior to the Babyhaler, both of which are superior to the Nebuchamber.

Generally, facemasks or mouthpieces are recommended for use with the nebulizer. However, a recent AAAAI abstract reported that blowby using a corrugated extension tube resulted in acceptable drug delivery to infants and toddlers. Blowby with mask was not effective. Another recent study described the use of a nebulizer hood for sleeping infants rather than a mask with the nebulizer. Total lung distribution of medications was effective and the hood was well-tolerated by the infants and well-accepted by the parents.

References:

Amirav I, Balanov I, Gorenberg M, et al. Nebulizer hood compared to mask in wheezy infants: aerosol therapy without tears. Archives of Diseases in Childhood 2003;88:719-723.

Amirav I, Newhourse MT. Aerosol therapy with valved holding chambers in young children: Importance of facemask seal. Pediatrics 2001;108(2):389-94.

Geller DE, Kesser B. Blowby vs. Face Mask for nebulized drugs in young children. Journal of Allergy and Clinical Immunology 2004;113(2):S32.

2/23/04 re: Use of formoterol in a power nebulizer

I am a respiratory therapist employed at a major medical teaching institution in California. Recently, I received a directive through my supervisor, from a doctor that is treating a 10 year old child for severe asthma. Because the child is unable to effectively take foradil DPI, the doctor has requested that we add the foradil into a small volume nebulizer, mixed with another brochodialtor solution. How effective is foradil in this manner of treatment. And is it appropriate to do so.

I think that you are asking whether formoterol (Form) can be added to a nebulizer for asthma treatment. The term Foradil refers to a commercial DPI preparation of Form which would not be suitable for addition to a nebulizer for treatment. I know of no Form suspension suitable for nebulizer therapy and could not find reference to such in a Medline search. However, I did find reference to the use of Foradil DPI mechanically activated into a Turbohaler with a spacer (see enclosed abstract). Since this approach was reportedly used successfully in pre-school children, I would imagine that this approach might work in the patient you mentioned.

As an aside, I would be cautious about using Foradil and another bronchodilator (presumably short-acting such as albuterol) concomitantly in a child. As you likely know, the onset of beta agonist effect of formoterol is a rapid as that of albuterol. As well as having a longer duration of action. Therefore, one may get adverse effects (e.g.-cardiac) shortly after inhalation of both formoterol and albuterol doses at the same time.

Am J Respir Crit Care Med. 2001 Jul 15;164(2):256-9.
Bronchodilation and bronchoprotection in asthmatic preschool children from formoterol administered by mechanically actuated dry-powder inhaler and spacer.
Nielsen KG, Bisgaard H.
Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

We evaluated the bronchodilatory and the bronchoprotective effect of the long-acting beta(2)-agonist formoterol administered as dry powder from a mechanically actuated dry-powder inhaler (DPI) using spacer in 12 asthmatic children 2 to 5 yr of age. Lung function was measured as the specific airway resistance (sRaw) in a whole body plethysmograph. Hyperventilation of cold, dry air was used as bronchial challenge, and the responsiveness was estimated as change in sRaw. The bronchoprotective effect of formoterol Turbohaler 9 microg was compared with salbutamol 200 microg and placebo at 15 min, 4 and 8 h postdose in a randomized, double-blind, placebo-controlled, crossover study. All treatments were administered from DPI (Turbohaler) actuated mechanically into a spacer. Formoterol and salbutamol caused similar and significant Bronchodilation at the first measurement 3 min postdose. Formoterol offered a sustained and stable bronchodilation for at least 8 h. Salbutamol provided significant bronchodilation for less than 4 h. Formoterol caused significant bronchoprotection of 80% for at least 8 h compared with placebo, and from 4 h onward compared with salbutamol. Bronchoprotection from salbutamol lasted less than 4 h. In conclusion, formoterol administered as dry powder in a single dose provided rapid and sustained bronchodilation and clinically significant bronchoprotection for at least 8 h in 2- to 5-yr-old asthmatic children. Furthermore, this study suggests that mechanical actuation of DPI using a spacer is effective for aerosol treatment of young asthmatic children.

2/2/04 re: Value of CAM in allergies and asthma

I am a Doctorate student (in the field of Asthma), from INDIA, Could you please provide me information about the CAM practice in Asthma? Is there any proven efficacy of CAM drugs in acute asthmatic episodes in ED or long term administration of CAM drugs is reducing the frequency of attacks by increasing the PEFR and FEV1 significantly?

A number of investigators such as Bielory, Ziment and other groups have written recent reviews and metanalyses of the effects of complementary and alternative medicine (CAM) approaches in asthma and allergies (see enclosed abstracts for examples). The general impression from a limited number of controlled studies is that such CAM approaches are not consistently better than placebo treatment in asthma. However, some of these authors have stressed that definitive conclusions cannot be drawn yet because most of the reported 'benefits' of CAM treatment are based on protocols which are not scientifically rigorous. Also, one cannot extrapolate from findings in a particular study of an herbal or other CAM supplement to community practice because of the considerable variation in the amount of truly active ingredient in products sold over the counter with reportedly similar contents listed on the label. For example, a recent chemical analysis of a number of samples of Echinacea obtained from several: 'health food stores' showed no relationship between the levels of Echinacea claimed on the label and what was actually found in the contents of that bottle.

When considering CAM approaches one also has to be aware that some herbal preparations may interact with prescribed medications, including some used in the treatment of cardiac disorders. Therefore, there is a potential for either decreasing or increasing blood levels of the prescribed medication. When such herbal preparations are taken concomitantly.
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Curr Opin Allergy Clin Immunol. 2003 Oct;3(5):395-9.
Review of complementary and alternative medicine in treatment of ocular allergies.
Bielory L, Heimall J.
Department of Medicine, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA.

PURPOSE OF REVIEW: Ocular allergy is a common complaint of allergy sufferers, many of whom may choose to use complementary and alternative medicine in the treatment of these symptoms. In this review major complementary and alternative medicine modalities including herbal therapies, acupuncture, homeopathy, alternative immunotherapy and behavior modification are assessed for evidence of their effectiveness in the treatment of ocular allergy symptoms. RECENT FINDINGS: Certain herbs including Euphrasia officinalis, Petasites hybridus and Argemone mexicana have been evaluated in control studies in the treatment of ocular allergy. Honey is no more effective than placebo in the treatment of ocular allergy. Acupuncture used regularly has demonstrated some positive trends in ocular allergy sufferers. Homeopathy has shown conflicting results in the treatment of ocular allergy, while alternative forms of immunotherapy have been shown to develop immunologic tolerogenic effects in the control of the condition. SUMMARY: Several forms of complementary and alternative medicine have been studied for their effectiveness in treatment of ocular allergy symptoms. Further research is needed to assess mechanisms of action and to establish practice guidelines for the use of these modalities.
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J Asthma. 2003;40 Suppl:47-53.
Alternative treatment for allergy and asthma.
Bielory L, Chiaramonte L, Ehrlich P, Field J.
Division of Allergy/Immunology, UMDNY-New Jersey Medical School, USA.

Treatment of asthma remains complex. Patients who are considering alternative and complementary treatments for asthma should have a good understanding of what the treatment entails, and whether it has proven ability to make an impact in the disease. One should remember, however, these treatments are made to complement most traditional therapies and not to replace them Allergy Asthma Proc. 2001 Jan-Feb;22(1):33-7.
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