Allergy & Asthma Disease Management Center: Ask the Expert: Inhaled Steroids

- Inhaled Steroids -

8/18/05 re: Use of nebulized fluticasone in infants

Can you kindly clarify whether inhaled fluticasone (Flixotide) can be used in infants (8 months) by nebulization. There is an article, Persistent wheezing in infants with an atopic tendency responds to inhaled fluticasone, by R J Chavasse, Y Bastian-Lee, H Richter, T Hilliard, P Seddon in Arch Dis Child 2001;85:143-148 (August). At the same time the guidelines in GINA is quite vague about the use of inhalational corticosteroid in this age group. There is concern that early use of Inhaled corticosteroid in infancy may impair lung growth or enhance the development of the TH2-type immune response, thus promoting, rather than suppressing, the development of asthma. Is this concern valid? Is there any study which supports this fear?

I cannot respond to your question specifically about nebulized fluticasone since fluticasone preparations for use in a nebulizer are not currently available for usual clinical practice in the USA. However, there is experience using nebulized budesonide in infants. This was recently reviewed by Berger and Shapiro, respected asthma investigators (see enclosed abstract). I suggest that you read the whole article. There is a potential concern about inhaled corticosteroids affecting lung growth in childhood. However, several groups have recently concluded that uncontrolled asthma in early childhood is itself a risk factor for decreased lung growth later in childhood. In the large, multi-institutional CAMP study, there was no significant difference in the "lung growth" as determined by the post-bronchodilator FEV-1 in children treated with inhaled budesonide vs placebo or nedocromil (Engl J Med. 2000;343:1054-63).

Ann Allergy Asthma Immunol. 2004 Apr;92(4):387-399; quiz 399-402, 463.
The use of inhaled corticosteroids for persistent asthma in infants and young children.
Berger WE, Shapiro GG.
Allergy and Asthma Associates of Southern California, Mission Viejo, California 92691, USA. weberger@gsm.uci.edu

OBJECTIVE: To review pediatric trials of inhaled corticosteroid (ICS) therapy and summarize data on the pediatric use of devices to facilitate delivery of ICSs.
DATA SOURCES: Relevant articles regarding ICS treatment of persistent asthma in children younger than 5 years were identified from MEDLINE and reference lists of review articles.
STUDY SELECTION: Key articles were selected by the authors.
RESULTS: Clinical trials from the United States and Europe consistently demonstrated that ICS therapy is the most favorable treatment option with regard to safety and efficacy for infants and young children with persistent asthma. This contention is supported by numerous trials of budesonide inhalation suspension in children ranging from 6 months through 8 years of age and data from older children treated with fluticasone propionate.
CONCLUSIONS: As the only corticosteroid available in the United States as a nebulized formulation and the only ICS product extensively studied in young children and infants, budesonideinhalation suspension is an appropriate first-line therapy for treatment of persistent asthma in this population.

1/30/05 re: Mouthwash for sore throat with Advair

I was recently talking with a patient who is suppose to take advair bid but does not take it consistently because it causes hoarseness and a scratchy throat. I discussed with her to rinse her mouth out with water and when she can to brush her teeth afterwards. She has again resumed taking her advair daily but the hoarseness and scratchy throat are also starting again. I've heard that mouthwash may help with this more than water, is this true and if so is there a particular mouthwash that works better?

I am not aware of a particular mouthwash that is especially effective in reducing the local adverse effects of Advair in the posterior pharynx/hypopharynx. I have consulted several colleagues with extensive experience using Advair and they are unaware of a particular benefit of mouthwash. Measures that reduce the rapid impact of the medication against the back of the throat tend to reduce this type of adverse effect.

I suggest that you contact your local Glaxo Smithkline detail rep, asking him/her to refer your question to the professional education department of their company. If something has been presented or written about a mouthwash effect in this situation those folks should know about it or can find out.

1/12/04 re: Azmacort spacer

It is my understanding that in general, addition of a spacer for delivery of an inhaled corticosteroid pMDI should result in an increase in the amount of drug inhaled (particularly for those patients who can not effectively coordinate the correct timing for actuation and inhalation). One currently marketed ICS product, Azmacort, includes a spacer/mouthpiece device. The product monograph indicates that an actuation delivers 200 mcg of product at the valve, but only 100 mcg from the spacer-mouthpiece. Is the remaining product deposited on the walls of the spacer?

There are a number of factors that affect the delivery of inhaled medications to the airways in spacer-containing devices. One of them, which I believe to be a factor in the Azmacort device, involves attraction of inhaled particles to the inside wall of the spacer.

This may be a greater problem with the triamcinolone droplets in the traditional CFC-propelled Azmacort because of their larger size and/or electrostatic attraction (see enclosed abstract). However, the delivery to the airways appears to be better now that HFA propellants are being substituted for the CFC propellants. Nevertheless, the overall efficacy of inhaled steroids is improved by use of an attached spacer because the oropharyngeal deposition is reduced, with an associated decrease in systemic absorption of the steroid. I am also enclosing my review (written for the current Literature section of this AADMC website) of a previous report comparing various spacers and nebulizers. That article is worth reading as are the publications of Dr. Myra Dolovich, an expert in inhalation therapy devices.

1: Drug Dev Ind Pharm. 2001 May;27(5):401-12.
Investigation of some commercially available spacer devices for the delivery of glucocorticoid steroids from a pMDI.
Williams RO 3rd, Patel AM, Barron MK, Rogers TL.
College of Pharmacy, University of Texas at Austin, 78712-1074, USA.

Five commercially available spacers were investigated to determine their influence on the percentage of drug retained in the spacer device, percentage fine particle fraction (FPF), percentage deposited in the induction port, mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD). Betamethasone valerate (BMV) and triamcinolone acetonide (TAA) were used as model drugs in the pressurized metered dose inhaler (pMDI) formulations containing the propellant HFA 134a. The BMV was dissolved in an ethanol/HFA 134a system, and the TAA was suspended in HFA 134a using ethanol as a dispersing agent. The metering chamber volume of the valve was either 50 microl or 150 microl. The spacer devices investigated included the ACE, Aerochamber, Azmacort, Easivent, and Ellipse spacers. Each spacer device was attached to an Andersen Cascade Impactor powered by a vacuum pump. Cascade impaction data were used to derive the percentage drug deposited in the induction port, MMAD, GSD, and FPF. The BMV particles emitted from the spacers were finer than the TAA particles because the dissolved drug precipitated as the cosolvent evaporated. The TAA particles had significantly larger MMADs because many undissolved drug particles were contained within each droplet following actuation. After evaporation of the liquid continuous phase, the suspended drug aggregated to form larger agglomerates than those particles precipitated from the BMV pMDI solution droplets. The addition of a spacer device lowered the MMAD to less than 4.7 microm for particles from both the BMV pMDI solution and the TAA pMDI suspension. The addition of a spacer device also lowered the percentage drug deposited in the induction port. The FPF was significantly increased when a spacer device was used. The MMAD significantly decreased when a spacer device was added for the two model drugs when using the 150-microl metering valves, but the difference was not statistically significant when the 50-microl valves were used (P < .05). The GSD was not influenced by the use of a spacer device. The use of a spacer device will enhance pMDI therapy by reducing the amount of drug deposited in the oropharyngeal region, which will lead to fewer instances of local and systemic side effects. In addition, the spacer devices investigated will allow a higher dose of drug to reach the deep lung, which may permit the use of lower dosage regimens with increased therapeutic efficacy.

Item for Current Literature Section
How to choose delivery systems for childhood asthma

Summary
Inhalational therapy has become the main therapeutic approach in asthma. However, the increasing number and variety of inhalation devices now available has lead to understandable confusion among clinicians. It is difficult to determine which of the competing commercial devices is truly best for their patients. O'Callaghan and Barry of the University of Leicester in the UK have reviewed this situation. They conclude that spacer devices and face masks attached to metered dose inhalers (MDI) are generally first choice for children < 5 years old. The choice of MDI type will depend on the nature of the medications used. By comparison, nebulizers are inefficient and expensive. The inhaled dose from a nebulizer increases with age of the patient until about 6 months, then decreases as the inspiratory flow rate exceeds the nebulizer delivery flow rate. Therefore, there is considerable variability in dosage delivered by most nebulizers with the possible exception of the Halo-lite which monitors the breathing patterns of the patient and delivers pulses of medication. Nevertheless, the authors feel that nebulizers have a decreasing role in asthma management, mainly in young children who cannot cooperate with use of MDI/spacers.

In children older than 5 years, the authors recommend MDI or dry powder inhalers (DPI) with spacers. Breath-activated inhalers have theoretical advantages but some children seem to stop inspiration when they first sense the propellant in their pharynx ("cold Freon effect").

Two types of spacers are generally used: 1) valve holding chambers allowing a patient to breathe tidally rather than timing activation with inspiration. Some evidence suggests that the larger the volume of such spacers the more drug is delivered to the lower airways (except possibly in small children). Also, the drug delivery characteristics and the best inhalational device may vary with the medication type delivered through the spacers; 2) extension devices between the MDI and the mouth reduces oropharyngeal deposition but still require timing the MDI activation with inspiration limiting their use in small children. These spacers cannot be used with breath- activated inhalers.

Reference - Arch Dis Child 2000;82:185-191

Editor's Comments
This review is more a set of authors' conclusions based on studies rather than describing the data from the studies themselves. Although some experts may take exception to some of these recommendations, I think that the recommendations are both reasonable and helpful. This brief article is worth reading to get more details. I have not included brand names mentioned by the authors because these are device names marketed in the UK and may be unavailable or called by other names elsewhere.

12/1/03 re: Use of inhaled corticosteroids (ICS) for acute asthma exacerbations

I am a pediatrician and am starting to see a great deal of respiratory illnesses. Many of my asthmatics (mild to severe) are starting to have acute exacerbations. In the past I have used ICS only as a controller medication. For those children with acute exacerbations I have either started or added an oral corticosteroid burst. Is there any clinical evidence to using ICS (specifically budesinide in the younger population) as the only burst medication in a child not currently on an ICS instead of adding oral steroids for children with acute exacerbations.

As you likely know, viral respiratory infections are one of the most common, if not the most common, triggers of acute asthma flares in children with chronic asthma. In some children, the wheezing occurs only with what appear to be viral URI. In a previous meta-analysis reviewed by me for this AADMC website (see Ref #1 below) it was concluded that institution of high dosage ICS at the onset of viral URI in children with past histories of repeated viral URI-triggered asthma could reduce the subsequent need for oral steroid treatment in that episode. However, chronic use of low dosage ICS did not apparently prevent such viral infection-triggered wheezing episodes.

In another report reviewed by me (see Ref #2 below), use of high dosage ICS at the onset of acute asthma flares did reduce the need for hospitalization but did not improve expiratory airflow rates significantly. In yet another study (see Ref#3), use of high doses of the ICS flunisolide was helpful in the management of acute asthma flares. The situation is complicated by the recent report which concluded that oral steroids were not significantly helpful in viral infection-triggered bronchiolitis.

Then what should one conclude? The apparent need for quite high doses of ICS in these acute situations raises the questions of how much of the ICS effect observed was due to some of these agents which were absorbed systemically (which would probably be be equivalent to 5-10 mg prednisone/day taken orally). I have not seen studies that directly address the question whether budesonide has such effects, but one would predict less systemic effects of budesonide than seen with use of flunisolide or beclomethasone. The high doses of ICS required to see these effects in acute asthma require multi-inhalation use of the ICS delivered by MDI or dry-powder inhaler. If one uses budesonide by nebulizer (Pulmocort Respules) it may be easier for the child to inhale the requisite doses. It should be mentioned that several studies have shown equal efficacy of a set dose of ICS delivered by MDI with spacer as by nebulizer delivery, assuming that the patient can operate an MDI adequately.

As an aside, I think that one must be sure that the child is not wheezing persistently aside from wheezing association with viral URI (e.g., on exertion, nocturnal, with repeated laughing or crying). If such persistent asthma is present, maintenance lower dose ICS may well be indicated, possibly with a resultant reduction in the frequency of viral URI-triggered asthma flares.

Reference #1
Item for Current Lit Section
Inhaled steroids for episodic wheezing associated with viral infections

Summary
Some children wheeze recurrently with certain viral respiratory infections but not at any other time and have no other manifestations suggestive of asthma. Some clinicians use inhaled corticosteroids (ICS) to treat individuals with viral infections-associated wheezing. However, it is unclear whether there is solid evidence to support this approach. McKean and Ducharme of the University of Leicester in the UK searched the Cochrane Airways Group database for evidence from randomized clinical trials of ICS used either: 1) just with the wheezing episodes, or 2) on a daily basis in an attempt to prevent wheezing episodes associated with viral infections. Three acceptable studies of episodic high-dose (1600-2250 microg/day) ICS started at the onset of apparent viral respiratory infections showed a definite reduction in the need for oral corticosteroid treatment of acute wheezing episodes and better symptomatic control, as compared to placebo inhaler therapy. However, in 2 acceptable studies, maintenance daily low dose (100 microg/day) ICS therapy was not followed by a significantly reduced proportion of wheezing episodes which required oral steroid therapy or hospital admission for treatment of the lower respiratory tract symptoms.

Reference - Cochrane Database Syst Rev 2000; CD001107

Editor's Comments
These findings suggest that an inflammatory reaction in the airways similar to that seen in asthma occurs in those with viral infection-associated wheezing. However, larger doses of ICS than usually needed for asthma control were used to prevent these wheezing episodes triggered by viral infections. It is unclear whether lower doses of ICS given at the time of viral infection were ineffective in preventing the occurrence of severe wheezing. The lack of prevention of wheezing episodes by daily maintenance ICS therapy (100 microg/day) in these cases would suggest that either a smoldering bronchial inflammation was not present between viral infections, or that such inflammation was not reduced sufficiently by the 100 microg/day ICS dose. It is worth keeping in mind that a significant percentage of those children who wheeze recurrently with common viral respiratory infections (but not at other times) in early childhood will later exhibit a pattern typical of chronic asthma.

Reference #2
Current Lit Item
Efficacy of inhaled steroids in the treatment of acute asthma

Summary
Treatment with inhaled corticosteroids (ICS) has become the major component in the chronic treatment of persistent asthma. The role of ICS in the treatment of acute asthma exacerbations is less clear. Edmonds et al of the University of Alberta in Canada and other institutions carried out a meta-analysis of randomized, controlled trials of ICS treatment in the therapy of acute asthma flares in the Emergency Department (ED). In 6 trials involving 352 adult and childhood asthmatics, it was found that ICS treatment was associated with a lower rate of subsequently required hospitalization for asthma uncontrolled in the ED (odds ratio=0.30). However, ICS therapy was followed by only a modestly greater increase in peak flow rates than seen with placebo treatment (weighted mean difference in PEFR=8%, range 3%-13%). In a separate analysis, the effects of ICS treatment were compared with that of systemic steroid treatment in the ED. In the 4 trials suitable for analysis there was such heterogeneity in findings to preclude any conclusions about the comparative effects of these 2 steroid approaches.

Reference - Ann Emerg Med 2002; 40:145-54

Editor's Comments
Controlled studies of ICS effects in the treatment of acute asthma in the ED are very difficult to carry out because of confounding variables which related to other treatment approaches used in the study and control patients. Nevertheless, it appears that ICS use at the onset of therapy in the ED has a very modest, if any, beneficial effect in the first hours of treatment but likely reduces the later progression of asthma exacerbation so that in-patient hospitalization is needed less frequently. These findings are not too surprising considering the previous observations that even high dosage intravenous steroids do not appear to induce impressive beneficial effects until perhaps 6-12 hours after initiation of such therapy. Although inflammatory changes in the airways likely play a major role in most acute asthma flares, reduction of such inflammation takes a while. In contrast, the bronchodilating effects of inhaled beta agonists in acute asthma start much earlier after such therapy is initiated.

Reference #3
Flunisolide aids in emergency asthma treatment

Summary
The value of inhaled steroid therapy in chronic moderate to severe asthma has been well-established. However, previous studies suggested that inhaled steroids were ineffective in severe acute asthma exacerbations. Drs. G Rodrigo and C. Rodrigo recently reported a controlled, blinded comparison of either flunisolide 1000 micrograms or inhaled placebo added to inhaled salbutamol (albuterol) given every 10 minutes for 3 hours. FEV1 levels were significantly greater in the flunisolide added group at 90, 120, 150 and 180 minutes after initiation of treatment. The authors concluded that such high dose inhaled steroid therapy is likely to be very useful in such acute exacerbation with prolonged symptoms prior to ER presentation.

Reference - Am J Respir Crit Care Med 1999; 157:698-703.

Editor's Comments - These findings are of interest and potential value. However, it should be stressed that the flunisolide doses administered were very large, - 1000 micrograms (a sizable daily dose for chronic asthma) given every 10 minutes for 3 hours. One can argue that the authors were just observing effects of systemically absorbed steroids. However, previous studies of systemic steroid treatment in status asthmaticus has shown little if any effects of the steroids themselves in the first 3 hours. Of interest, one of the earlier effects seen in such steroids was enhancement of beta agonist drug bronchodilatory effects. Further studies will be needed to determine whether steroids are deposited more effectively in the airways by inhalation than parental therapy in such patients. However, the common difficulty in taking deep inspiration in acute asthma.

5/20/03 re: Substitute for Flovent

There is a lot of talk here locally about the upcoming discontinuation of Flovent MDI because of regulations regarding CFCs. Assuming the child has mild-moderate persistent asthma that requires a daily controller medication, what one of the currently available ICS's would you recommend? Many of us have been using Flovent MDI with spacer as our number one choice for several years given the CAMP and other recent data (ICS as more efficacious than Nedocrimil and presumably Intal) and the ability to use such low doses with good clinical results. Young children are not able to use the discus preparation reliably. My initial thought is that I would prescribe Pulmicort respules for the very young, but using a nebulizer versus an inhaler with spacer +/- mask is so much more cumbersome and less portable. Any advice you have would be welcomed.

I understand your concern about not having available the fluticasone (Flovent/MDI) preparation which you have found very useful in treating childhood asthma. However, recall that the CAMP study to which you referred employed budesonide, not fluticasone, in the sizable population of childhood asthmatics (see enclosed abstract). As you may know, budesonide is available not only as Pulmocort Respules, used predominantly in very young children, but also as the Pulmocort inhalation powder in their Turbuhaler delivery system (licensed for use in children ages 6 years and older). The Turbulhaler delivery system was used in the CAMP study and also by Pederson's study of the effects of inhaled steroids on growth velocity of asthmatic children (see enclosed abstracts). Of course, Flovent is also available in their dry-powder inhalation approach (Diskus), licensed for use in children ages 4 years and older. A spacer can be used with the Diskus.

A careful meta-analysis has shown no difference in the efficacy of inhaled steroids delivered with such devices and an attached spacer versus the steroids delivered by a power nebulizer, provided that the patient can activate the inhalation device effectively. In the case of the Turbuhaler, this means having an inspiratory flow rate sufficient to activate the medication delivery system. My colleagues in the Pediatric Allergy field tell me that such inspiratory flow rates are sufficient in the large majority of childhood asthmatics. Therefore, I would recommend one of these approaches for a child of sufficient age and capacity to use them effectively.

If you feel that it is necessary to use inhaled steroids delivered by an MDI approach, you may wish to consider Qvar, a beclomethasone preparation using an HFA (non-CFC) propellant. Although there is a potential disadvantage of using beclomethasone because there is a significant systemic absorption of this older inhaled steroid once swallowed, it has been shown the delivery of Qvar to the lower airways is much more effective than with beclomethasone in CFC-propelled MDI preps so that a lower daily dose is needed for asthma control. Fluticasone delivered with an HFA propellant in an MDI is also now under testing so this may represent another option (see enclosed abstract). In a recent comparison, beclomethasone/HFA and fluticasone/HFA had equal efficacy and systemic effects when used at 500 mcg/day (see enclosed abstract)

N Engl J Med. 2000;343:1054-63
Long-term effects of budesonide or nedocromil in children with asthma.
The Childhood Asthma Management Program Research Group.

BACKGROUND: Antiinflammatory therapies, such as inhaled corticosteroids or nedocromil, are recommended for children with asthma, although there is limited information on their long-term use. METHODS: We randomly assigned 1041 children from 5 through 12 years of age with mild-to-moderate asthma to receive 200 microg of budesonide (311 children), 8 mg of nedocromil (312 children), or placebo (418 children) twice daily. We treated the participants for four to six years. All children used albuterol for asthma symptoms. RESULTS: There was no significant difference between either treatment and placebo in the primary outcome, the degree of change in the forced expiratory volume in one second (FEV1, expressed as a percentage of the predicted value) after the administration of a bronchodilator. As compared with the children assigned to placebo, the children assigned to receive budesonide had a significantly smaller decline in the ratio of FEV1 to forced vital capacity (FVC, expressed as a percentage) before the administration of a bronchodilator (decline in FEV1:FVC, 0.2 percent vs. 1.8 percent). The children given budesonide also had lower airway responsiveness to methacholine, fewer hospitalizations (2.5 vs. 4.4 per 100 person-years), fewer urgent visits to a caregiver (12 vs. 22 per 100 person-years), greater reduction in the need for albuterol for symptoms, fewer courses of prednisone, and a smaller percentage of days on which additional asthma medications were needed. As compared with placebo, nedocromil significantly reduced urgent care visits (16 vs. 22 per 100 person-years) and courses of prednisone. The mean increase in height in the budesonide group was 1.1 cm less than in the placebo group (22.7 vs. 23.8 cm, P=0.005); this difference was evident mostly within the first year. The height increase was similar in the nedocromil and placebo groups. CONCLUSIONS: In children with mild-to-moderate asthma, neither budesonide nor nedocromil is better than placebo in terms of lung function, but inhaled budesonide improves airway responsiveness and provides better control of asthma than placebo or nedocromil. The side effects of budesonide are limited to a small, transient reduction in growth velocity

N Engl J Med 2000 Oct 12;343(15):1064-9
Effect of long-term treatment with inhaled budesonide on adult height in children with asthma.
Agertoft L, Pedersen S.
Department of Pediatrics, University of Southern Denmark and Kolding Hospital, Kolding.

BACKGROUND: Short-term studies have shown that inhaled corticosteroids may reduce the growth of children with asthma. However, the effect of long-term treatment on adult height is uncertain. METHODS: We conducted a prospective study in children with asthma to examine the effect of long-term treatment with inhaled budesonide on adult height. We report on 211 children who have attained adult height: 142 budesonide-treated children with asthma, 18 control patients with asthma who have never received inhaled corticosteroids, and 51 healthy siblings of patients in the budesonide group, who also served as controls. RESULTS: The children in the budesonide group attained adult height after a mean of 9.2 years of budesonide treatment (range, 3 to 13) at a mean daily dose of 412 microg (range, 110 to 877). The mean cumulative dose of budesonide was 1.35 g (range, 0.41 to 3.99). The mean differences between the measured and target adult heights were +0.3 cm (95 percent confidence interval, -0.6 to + 1.2) for the budesonide-treated children, -0.2 cm (95 percent confidence interval, -2.4 to +2.1) for the control children with asthma, and +0.9 cm (95 percent confidence interval, -0.4 to +2.2) for the healthy siblings. The adult height depended significantly (P<0.001) on the child's height before budesonide treatment. Although growth rates were significantly reduced during the first years of budesonide treatment, these changes in growth rate were not significantly associated with adult height. CONCLUSIONS: Children with asthma who have received long-term treatment with budesonide attain normal adult height.

Can Respir J 2003 Mar;10(2):103-9
Fluticasone propionate 100 microg bid using a non-CFC propellant, HFA 134a, in asthmatic children.
Lyttle B, Gilles J, Panov M, Emeryk A, Wixon C.
Department of Paediatrics, Children's Hospital of Western Ontario, London,
Canada.

BACKGROUND: Secondary to phasing out chlorofluorocarbons (CFCs), the Fluticasone propionate (FP) pressurized metered-dose inhaler has been formulated in a nonozone-depleting propellant, hydrofluoralkane (HFA) 134a. OBJECTIVES: To demonstrate equivalent efficacy and safety of FP 200 microg daily propelled by HFA 134a to FP 200 microg daily propelled by CFCs 11 and 12 over a four-week treatment period in pediatric asthmatic patients. METHODS: The study was multinational, randomized, double blind and of parallel group design. Eligible patients aged 16 years and younger were steroid naive or receiving 500 microg/day or less of beclomethasone dipropionate, budesonide or flunisolide, or 250 microg/day or less of inhaled FP. The primary efficacy variable was mean morning peak expiratory flow with equivalence determined if the 90% CIs for the treatment differences between groups were within +/- 15 L/min. RESULTS: Three hundred fifteen patients (mean age 9.3 +/- 2.8 years) were randomly assigned; 158 patients received FP HFA 134a and 157 patients received FP CFC. Over the four-week treatment period, mean morning peak expiratory flow increased from baseline in both groups (14 L/min and 17 L/min, respectively), with a mean treatment difference of -2 L/min. Equivalence was demonstrated between the groups (90% CI -6 to +3 L/min; P=0.589). Both formulations were well tolerated with no serious drug-related events. CONCLUSIONS: FP propelled by HFA 134a has equivalent efficacy and comparable safety to FP propelled by CFC propellants at a microgram equivalent dose in pediatric asthmatic patients.

Thorax 2002 Oct;57(10):865-8
Airway and systemic effects of hydrofluoroalkane fluticasone and beclomethasone in patients with asthma.
Currie GP, Fowler SJ, Wilson AM, Sims EJ, Orr LC, Lipworth BJ.
Asthma & Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, UK.

BACKGROUND: With the transition to hydrofluoroalkane-134a propellants
in metered dose inhalers, it is important to consider the efficacy and safety profiles of formulations containing inhaled corticosteroids. We examined the airway and systemic effects of hydrofluoroalkane-134a fluticasone propionate (FLU-HFA) and beclomethasone dipropionate (BEC-HFA) at recommended labelled doses. METHODS: Twenty mild to moderate asthmatics were randomised in crossover fashion to receive 6 weeks of 500 micro g/day followed by 1000 micro g/day FLU-HFA and BEC-HFA. Measurements were made at baseline after placebo run in and washout, and after each randomised treatment. The primary airway outcome for benefit was the dose of methacholine provoking a fall in forced expiratory volume in 1 second (FEV(1)) of 20% or more (methacholine PD(20)) and for systemic adverse effects was overnight urinary cortisol/creatinine (OUCC). RESULTS: For mean responses, both doses of BEC-HFA and FLU-HFA produced significant improvements in PD(20) compared with baseline. The improvement was not significantly greater with 1000 micro g/day FLU-HFA versus BEC-HFA, a 1.69 fold difference (95% CI 0.94 to 3.04). Both doses of BEC-HFA but not FLU-HFA caused significant suppression of OUCC compared with baseline, with significantly (p<0.05) lower values at 1000 micro g/day for BEC-HFA versus FLU-HFA (1.97 fold difference (95% CI 1.28 to 3.02)). CONCLUSION: There was no difference in the airway and systemic effects in patients with mild to moderate asthma between FLU-HFA and BEC-HFA at a dose of 500 micro g/day. At 1000 micro g/day there was increased systemic bioactivity with BEC-HFA compared with FLU-HFA, without any gain in airway efficacy.

5/5/03 re: Inhaled dexamethasone treatment for croup

I am a pediatrics resident in Portugal and have become familiar with numerous protocols for treating stridor/laringitis/croup, which in many ways seem scientifically and logically conflicting. My question is based on the fact that many hospitals here use the IM formulation of dexamethasone for inhalatory treatment of stridor/laringitis/croup whether in association or not with epinephrine. Is it your opinion that:

1. Inhaled dexamethasone is useful?
2. That it is useful in this formulation and in what dosage?
3. That it is comparable with Budesonide?
4. How would you treat stridor/laringitis/croup with inhalatory means?

As a member of the Allergy and Immunology Section in an academic Dept. of Medicine, I have not participated in the care of young children for many years. Therefore, I consulted Dr. Joel Fiedler, a very experienced Pediatric Allergist/Immunologist in the Childrens' Hospital of Philadelphia. His response is enclosed below. My personal impression from a Medline review is that dexamethasone 0.6 mg/kg given IM or in a few divided oral doses is recommended as initial treatment for any child with croup of severity that hospitalization is being considered. Most controlled studies have shown that inhalation of budesonide 2 mg is an effective as oral dexamethasone although one study reported less delayed croup symptoms in those treated with the systemic dexamethasone. One review reports that lower doses of oral dexamethasone (0.16 mg/kg) as are effective in croup as higher doses. However, my impression is that most authorities recommend the 0.6 mg/kg dose. I have enclosed abstracts of several pertinent reports after Dr. Fiedler's comments.

Although I have not seen ant controlled comparison of inhaled dexamethasone with inhaled budesonide, it would seem to me that budesonide should be preferred. Inhalation of a parenteral dexamethasone preparation should exhibit more systemic adverse effects than budesonide for several reasons. Although this may not be a big problem with use of only one or two doses of inhaled dexamethasone, why use this agent if budesonide suspension designed for inhalation is available?

I have no experience with or knowledge of post-extubation treatment. I suggest that you contact specialists in Pediatric Intensive Care units.
_________________________________________

Dr. Fiedler's comments:

The usual recommendation for IM dexamethasone is 0.6 mg/kg/ IM once. A lot of times oral dexamethasone can be used over the course of 2-3 days which is what the outpatient pediatricians do. I do remember seeing some studies that came out of Toronto Children's whereby budesonide was used via nebulization with variable success in mild to moderate success in the ER- the dosage used was 2mg/4ml saline (higher dose than we have available as pulmicort respules). If you need a source on the use of steroids to treat croup- i would recommend the Harriet Lane Handbook.
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Drugs 2000 Nov;60(5):1141-78
Budesonide inhalation suspension: a review of its use in infants, children and adults with inflammatory respiratory disorders.
Hvizdos KM, Jarvis B.
Adis International Limited, Auckland, New Zealand.

Budesonide, a topically active corticosteroid, has a broad spectrum of clinically significant local anti-inflammatory effects in patients with inflammatory lung diseases including persistent asthma. In infants and young children with persistent asthma, day- and night-time symptom scores, and the number of days in which beta2-agonist bronchodilators were required, were significantly lower during randomised, double-blind treatment with budesonide inhalation suspension 0.5 to 2 mg/day than placebo in 3 multicentre trials. Significantly fewer children discontinued therapy with budesonide inhalation suspension than with placebo because of worsening asthma symptoms in a study that included children who were receiving inhaled corticosteroids at baseline. Recent evidence indicates that budesonide inhalation suspension is significantly more effective than nebulised sodium cromoglycate in improving control of asthma in young children with persistent asthma. At a dosage of 2 mg/day, budesonide inhalation suspension significantly reduced the number of asthma exacerbations and requirements for systemic corticosteroids in preschool children with severe persistent asthma. In children with acute asthma or wheezing, the preparation was as effective as, or more effective than oral prednisolone in improving symptoms. In children with croup, single 2 or 4mg dosages of budesonide inhalation suspension were significantly more effective than placebo and as effective as oral dexamethasone 0.6 mg/kg or nebulised L-epinephrine (adrenaline) 4mg in alleviating croup symptoms and preventing or reducing the duration of hospitalisation. Early initiation of therapy with budesonide inhalation suspension 1 mg/day appears to reduce the need for mechanical ventilation and decrease overall corticosteroid usage in preterm very low birthweight infants at risk for chronic lung disease. In adults with persistent asthma, budesonide inhalation suspension < or =8 mg/day has been compared with inhaled budesonide 1.6 mg/day and fluticasone propionate 2 mg/day administered by metered dose inhaler. Greater improvements in asthma control occurred in patients during treatment with budesonide inhalation suspension than with budesonide via metered dose inhaler, whereas fluticasone propionate produced greater increases in morning peak expiratory flow rates than nebulised budesonide. Several small studies suggest that the preparation has an oral corticosteroid-sparing effect in adults with persistent asthma and that it may be as effective as oral corticosteroids during acute exacerbations of asthma or chronic obstructive pulmonary disease. The frequency of adverse events was similar in children receiving budesonide inhalation suspension 0.25 to 2 mg/day or placebo in 12-week studies. During treatment with budesonide inhalation suspension 0.5 to 1 mg/day in 3 nonblind 52-week studies, growth velocity in children was generally unaffected; however, a small but statistically significant decrease in growth velocity was detected in children who were not using inhaled corticosteroids prior to the introduction of budesonide Inhalation suspension. Hypothalamic-pituitary-adrenal axis function was not affected by short (12 weeks) or long (52 weeks) term treatment with nebulised budesonide. In conclusion, budesonide inhalation suspension is the most widely available nebulised corticosteroid, and in the US is the only inhaled corticosteroid indicated in children aged > or =1 year with persistent asthma. The preparation is suitable for use in infants, children and adults with persistent asthma and in infants and children with croup.
__________________________________________

Ugeskr Laeger 1998 Apr 6;160(15):2253-6
[Inhaled budesonide versus intramuscular dexamethasone in the treatment of pseudo-croup]
[Article in Danish]
Pedersen LV, Dahl M, Falk-Petersen HE, Larsen SE.
Esbjerg Centralsygehus, paediatrisk afdeling.

We randomised 59 children hospitalized for croup to treatment with either inhaled budesonide or injected dexamethasone. Group A were treated with two inhalations of 1000 micrograms budesonide and group B received dexamethasone 0.6 mg/kg intramuscularly. We used a modified Westley-score, based on chest-wall retractions, barking cough, respiratory frequency and stridor. The children was aged three months to six years (mean 20 months). Three hours after the first treatment there was significant improvement in score amongst all children (p < 0.001), but no difference between the two groups (p < 0.20). Six and 12 hours after the first treatment there were significantly better clinical scores in group B (p = 0.001, p = 0.0004). Based on this study we recommend dexamethasone 0.6 mg/kg intramuscularly for children to be treated for croup.
_________________________________________________

Pediatr Pulmonol 1995 Dec;20(6):355-61
Oral and inhaled steroids in croup: a randomized, placebo-controlled trial.
Geelhoed GC, Macdonald WB.
Emergency Department, Princess Margaret Hospital for Children, Perth, Western Australia.

It was the objective of this study to compare the efficacy of oral dexamethasone and inhaled budesonide in children hospitalized with croup, using a three-way, double blind, randomized, placebo-controlled clinical trial design. The trial was carried out in the Emergency Department Observation Ward of a tertiary pediatric hospital. The subjects for the study were 80 children (age range 5 to 158 months) who were hospitalized with croup. Children received either 2 mg of nebulised budesonide, dexamethasone syrup (0.6 mg/kg) or a placebo. Median duration of hospitalization was shorter for children treated with dexamethasone (12 hr) and budesonide (13 hr) compared to placebo (20 hr) (P < 0.03). There was no significant difference in hospitalization time between children treated with dexamethasone and budesonide. Median time to a croup score of < or = 1 was shorter for children treated with dexamethasone (2 hr) or budesonide (3 hr) compared to those who received placebo (8 hr) (P < 0.01). Croup scores for both steroid groups were significantly lower than the placebo group by 1 hr and remained so subsequently. The croup scores did not differ significantly in the 2 steroid treated groups. Six of the 30 children (20%) in the placebo group required adrenaline after the first hour compared to none of the 50 children in the steroid treated groups (P < 0.02). We conclude that oral dexamethasone and inhaled budesonide are both effective in reducing symptoms and duration of hospitalization in children with croup.
_______________________________________________

Pediatr Pulmonol 1997 May;23(5):370-4
Croup.
Geelhoed GC.
Emergency Department, Princess Margaret Hospital for Children, Perth, Australia.

The management of mild to severe croup has undergone dramatic changes in the last 5 years, primarily due to the increased understanding of the benefits of treating it with steroids. Steroids have been used in the treatment of croup for many years, but, until recently, their use has remained controversial. Earlier studies were often not blinded or used inappropriate outcome measures, such as respiratory rate, which have not proven appropriate. Two attempts to review the literature in 1980 and 1989 cautiously supported the use of steroids. Despite these recommendations many practitioners continued to view croup in most cases as a benign self-limited condition, and since steroids have potential side-effects, their use was not considered justified. More recently, however, a number of developments such as the successful use of the inhaled steroid budesonide and oral dexamethasone have reinforced the argument for using steroids. Recent work has also shown that both inhaled and systemic steroids work by 1 hour and dramatically reduce morbidity and hospitalization time. The demonstration that an oral dose of 0.15 mg/kg dexamethasone is as effective as larger doses has made the use of systemic steroids more acceptable to many practitioners. All children with croup severe enough to be admitted to hospital should receive steroids. Two recent studies have shown that steroids also benefitted children who presented to emergency departments for treatment, but whose croup was not considered severe enough for admission. The type of steroid, the dose, and the mode of administration will need to be decided by the attending clinician.

2/17/03 re: Control of chronic asthma in 3 year old child

I am a pediatric nurse with a 3 year old asthmatic son who flares with URIs and weather changes. Our pediatricians had him on numerous medications: nebulized Budesonide (0.5 mg, BID), Salmeteral MDI (2 puffs, bid), Singulair (4mg, daily), Zyrtec, and Xopenex (1.75 mg, q 4hrs/prn) for over a year.

Under all those medications, his wheezing did not seem controlled and he had dificulty sleeping. And many times with a URI, he ended up with pneumonia.
Recently we started seeing an Allergist who tested him for 21 common allergens and performed a food RAST. He only tested positive to dust and mold and is currently undergoing immunotherapy for them.

This allergist had us d/c all meds except Zyrtec, daily and Xopenex as needed. My son seems to be doing much better and has only had a few acute exacerbations where Xopenex was indicated.

Our pediatricians feel that he should still be on some sort of inhaled corticosteroid. I'm wondering if there is any others who are against ritual use of the inhaled corticosteroids for patients that respond well without.

As you may know, the current recommendations of the National Asthma Education and Prevention Program (NAEPP), formulated by a group of asthma experts convened by the NHLBI (NIH) are quite firm that chronic asthma is best treated by standing does of "controller" anti-inflammatory therapy and not just prn use of inhaled beta agonists such as Xoponex. I suggest that you read these recently updated recommendations through a link from this AADMC website to the Journal of Allergy and Clinical Immunology (JACI). You can access this by clicking "other links" and then click Journal of Allergy and Clinical Immunology in the AADMC Home page or read the hard copy in a supplement to the 11/02 issue of the JACI. Most experts feel that adequate doses of inhaled corticosteroids are the currently most effective controller therapy.

Therefore, the situation in your child does seem atypical. Several thoughts about it have arisen in my mind.

1) Does your child have uncomplicated asthma or are there other disorders that may mimic or aggravate asthma (e.g., cystic fibrosis, hypogammaglobulinemia with secondary infection, etc.)? Unfortunately, the usual pulmonary function tests to help diagnose asthma are usually not reliably feasible in 3 year olds.

2) Is it possible that difficult sleeping in your child was not due so much to the asthma but stimulatory effects of the salmeterol (Serevent) if this long-acting beta agonist was used in the early evening (particularly if he was also given Xopenex during the same evening)?

3) It is possible that your child was not getting sufficient inhaled corticosteroid into the lower airways? Your description did not make clear the exact type and dose of inhaled steroid previously used in your child�s treatment. Some physicians have used MDI-delivered inhaled steroids connected to an in-line inhalation device. However, the corticosteroids contained in such MDI are micronized particle suspensions. Such particles may adhere to the in-line tubing, etc. with reduction in the dosage reaching the mouth. It is preferable to use the preparation of budesonide (a corticosteroid) designed specifically for nebulizer (in-line) use.

4) Is it possible that the improvement in your child�s asthma status you describe is related to a reduction in exposure to offending allergens due to avoidance measures carried out by you? If the immunotherapy you mentioned was started within just the past few months it is probably too early to ascribe any impressive benefit from this treatment approach.

My bottom line impression is -- If true asthma is the major problem, your child would likely do better if treated with standing doses of inhaled corticosteroids. I agree that Singulair and Zyrtec can be rhinitis often makes asthma control more effective.

2/1/03 re: Use of Flovent in-line for treatment

I am the director of a department in a teaching hospital. Recently the interns have been utilizing Flovent MDI in line. The ordering doctors are using the same dosing as a patient using the MDI to his mouth. The staff is wondering if this is sufficient. Have there been any studies that determined fall out? What are your recommendations?

I assume that your description refers to the use of Flovent, an inhaled steroid, added to a line from a nebulizer or other reservoir for inhalation administration in the treatment of acute asthma. I had never heard of this approach for the use of Flovent but it sounded very atypical, and possibly not very effective. Therefore, I referred your question to Dr. Stanley Szefler of the National Jewish Medical and Research Center in Denver, CO, a leading expert in the use of inhaled steroids in asthma treatment. His thoughtful response is enclosed below.

I am not sure what they mean by in-line. I suspect it means with a nebulizer or perhaps with an oxygen line. I would be concerned about just putting it in a nebulizer. Fluticasone is the most insoluble of the inhaled corticosteroids and there is a good chance that it would not mix well and get caught on tubing or other pieces. If nebulization is the intended use then I would say go with products that have been formulated and prepared for this route,i.e. Budesonide nebulizing suspension (Pulmicort Respules).

To clarify my question. We have used other MDIs in line on a ventilator circuit. There are adaptors designed for this. Usually we have increased the number of puffs when we do this. We were wondering if we should increase the number of puffs. I will be using pulmocort instead. Thank you.

Thank you for responding with additional clarification about your original question. I realize that the contents of a MDI may be inserted into on-line inhalation set-ups. However, my understanding is that the corticosteroid preparations in such MDI are not in solution but are a suspension of micronized particles. As pointed out in the comments of Dr. Szefler (sent to you previously) there is real potential for such particles to adhere to in-line tubing, etc. This is particularly true for preparations of fluticasone, a compound which is relatively insoluble. Thus, it is unpredictable how much of the MDI-delivered preparations inserted into the in-line setup actually reaches the mouth.

That is why Dr. Szefler recommended use of the budesonide solution preparation designated for nebulizer use. This budesonide preparation differs from the Pulmocort MDI-delivered preparation of budesonide. If the physicians still wish to insert MDI-delivered corticosteroids into the line, I would recommend using at least twice the dose intended for MDI delivery directly into the mouth, - at least 1000 micrograms/day. Such dosage is appropriate for treatment of moderately severe asthma.

12/18/02 re: Inhaled steroid usage

I am an asthma nurse (a new position for this HMO) working in various clinics belonging to the same HMO. We do not have any Allergists on staff and asthma care has typically been done by the family practice/internal med. physicians on staff. In helping assist with the care of asthmatics, and doing evaluations, I have come across a few situations where I am unable to find reliable answers.
First, I am finding a fair number of asthmatics who are on serevent only for control of their symptoms. I am aware that for those with persistent asthma, this will mask their inflammation, and they are put on appropriate ICS along with LABA if needed (we have put guidelines in place based upon the NIH's 1998/revised 2002 recommendations). My question is about those who have normal spirometry, occasional symptoms (<2 times per week), rare night time sx, but are largely aggravated by exercise. Is it appropriate that this population is treated with serevent BID only (with rescue available)? They do not seem to have symptoms or spirometry that would suggest putting them on an ICS controller. But after having it pounded into my head for so many years that serevent is not an appropriate controller med, I'm leery of patients being on LABA only, but can not find sufficient information saying whether or not it is appropriate.

My second question is about those with positive TB skin tests, but no signs of active TB. Should they be taking ICS? Again, reviewing on-line literature, I'm not finding much except that immunosuppressives can worsen existing, or cause new infections. Nothing that relates specifically to ICS use in asthmatics who test positive for TB, but have no active infection. If they should not be on ICS, what might be an appropriate alternative?

You raised two important questions about therapy of asthma with inhaled corticosteroids (ICS). The issues related to chronic therapy with salmeterol are these, as I see it. When it was originally reported by investigators in Canada and New Zealand that chronic therapy of asthma with inhaled albuterol was associated with a worse prognosis (even increased fatalities) in asthma, it was felt that this outcome might be related to an increase in bronchial reactivity. Some reports describe this outcome even if chronic therapy with ICS (generally eclomethasone) was also prescribed, although this was less clear-cut.

When salmeterol became available, the question arose whether chronic monotherapy with this longer-acting beta agonist would also lead to eventual worsening of asthma. As far as I can tell, that has never been shown definitively. Certainly, some asthmatic patients appear asymptomatic with good spirometric values on salmeterol as monotherapy. However, there does appear to be two valid concerns about the chronic use of salmeterol as monotherapy.

1) Some studies have shown a decreased acute bronchodilating response to inhaled albuterol used as rescue medication for acute asthma flares in individuals on chronic salmeterol therapy.

2) Even when symptoms are controlled and baseline spirometry is normalized during chronic salmeterol monotherapy, bronchial hyper-reactivity is not reduced significantly. This puts the patient at increased risk for triggering of asthma flares by certain viral infections and inhaled irritants.

Therefore, most experts in the field would recommend controller medication in chronically symptomatic asthmatics. The dose of ICS required may be reduced by concomitant use of inhaled salmeterol or formoterol. Such combination therapy is recommended for certain asthmatic patients in the recently updated NAEPP guidelines. I suggest that you read these updated guidelines, which can be accessed at the AAAAI website (open www.aaaai.org, then click on Professional section, then click on Updated NAEPP Guidelines). I also suggest that you read the very recent editorial by Dr. Robert Strunk in the J. of Allergy and Clinical Immunology, 12/02 issue. As you may know, there is a combination fluticasonel/salmeterol inhaler with several dosage formulations. Use of this combination agent may enhance patient compliance with therapy since it has been shown that patient compliance decreases with an increased complexity of inhaler therapy.

With regard to your second question, I am aware of only occasional reports of activation of TB in individuals using ICS chronically (see enclosed abstract). If this occurs, the frequency appears to be quite low. It would be prudent to obtain baseline chest X-rays and follow-up X-ray annually while the patient with a positive PPD skin test is on ICS therapy. However, your question raises the issue whether a relatively short course of ant-TB therapy should be given to an individual with a positive PPD skin test. The answer is currently thought to depend on the size of the positive PPD skin test, any risk factors for TB and the age of the patient.

Diagnostic standards and classification of tuberculosis in adults and children
Am. J. Resp. Crit Care Med 161:1376, 2000
_____________________________________________________

Allergy 1992;47327-30
Pulmonary tuberculosis in patients treated with inhaled beclomethasone.
Shaikh WA.
Allergy Clinic, Bombay Hospital Institute of Medical Sciences, India.

Inhaled beclomethasone dipropionate (BDP) has been used with few side-effects in the treatment of bronchial asthma for 2 decades. Until now the manifestation of tuberculosis (TB) in patients on inhaled BDP has not been reported. Eight patients with allergic asthma, of a total of 548 asthmatics (1.46%) seen over a 2-year period, developed active TB following the use of inhaled BDP. All were sputum-positive for acid-fast bacilli (AFB) on smear and/or culture, all responded well to a combination of anti-TB drugs, and none showed evidence of immunological or pituitary-adrenal suppression. Two patients agreed to a repeat administration of BDP; both developed TB again within 2 weeks and are again on anti-TB treatment.

10/29/02 re: Asthma triggered by exercise/cold air

28 year old male with exercise and cold induce asthma being bothered with cold weather in the Midwest after living in tropics for two years. He is using albuterol
MDI frequently. Is there a MDI or singulare to use for maintenance to reduce use of albuterol ?

If your patient has daily or almost daily asthmatic symptoms because of the cold weather now present in the Midwest, I would recommend that he be treated with an inhaled corticosteroid (ICS) agent. He may require only a relatively low dose (e.g., 400 microgr of budesonide or 250 mcg of fluticasone) inhaled by MDI or dry powder inhaler once a day. Use of an inhaled long acting beta agonist such as salmeterol (Serevent) or formoterol (Foradil) 2 puffs along with the ICS treatment will frequently allow control of symptoms at lower doses of ICS than when the ICS is used alone (see enclosed abstract). Advair is now marketed as a combination of fluticasone and salmeterol in one inhaler. I would stress to the patient that albuterol inhalation should be reserved only for acute asthma flares or possibly prior to exercise (see below).

The doses of ICS noted above have very little likelihood of inducing adverse systemic side-effects in an average-sized adult. However, if the patient is very reluctant to use any ICS, one can consider use of a leukotriene antagonist such as Singulaire 10 mg once daily, if the asthma is mild-moderate (FEV-1 more than 70% 0f predicted). However, several studies have shown that Singulaire is not as effective as ICS agents, even in the low doses mentioned above.

With regard to exercise-induced asthma (EIA), the patient should be advised to avoid running sports, particularly in cold weather. Swimming is much less likely to trigger asthma than running in cold weather. If the patient insists on running, it should be done in a relatively warm environment with adequate humidity. Use of salmeterol or formoterol inhaled 15-30 minutes prior to the start of exercise and a "warming up" exercise before full exercise will prevent or reduce the severity of EIA. Singulair has been shown to prevent or reduce EIA for up to about 20 hours after dosing. I have enclosed below my review in the Current Literature section of this AADMC website of a good recent review of the treatment of EIA by Randolph.

I suggest that you look at the recently updated guidelines of the National Asthma Education and Prevention Program of the NHLBI. This can be accessed through a link in the Current Literature section of this AADMC website. You may also find very helpful the very good review of asthma by Busse and Lemanske (N Engl J Med. 2001 Feb 1;344(5):350-62).

JAMA 2001 May 23-30;285(20):2594-603
Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial.
Lemanske RF Jr, Sorkness CA, Mauger EA, Lazarus SC, Boushey HA, Fahy JV, Drazen JM, Chinchilli VM, Craig T, Fish JE, Ford JG, Israel E, Kraft M, Martin RJ, Nachman SA, Peters SP, Spahn JD, Szefler SJ; Asthma Clinical Research Network for the National Heart, Lung, and Blood Institute.
University of Wisconsin Children's Hospital, 600 Highland Ave, K4/916-9988, Madison, WI 53792, USA. rfl@medicine.wisc.edu

CONTEXT: Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid (ICS) therapy. OBJECTIVE: To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen. DESIGN AND SETTING: A 24-week randomized, controlled, blinded, double-dummy, parallel-group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 through January 1999. PARTICIPANTS: One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide (400 microg twice per day). INTERVENTION: Patients continued triamcinolone therapy and were randomly assigned to receive add-on therapy with either placebo (placebo-minus group, n = 21) or salmeterol xinafoate, 42 microg twice per day (n = 154) for 2 weeks. The entire placebo-minus group was assigned and half of the salmeterol group (salmeterol-minus group) was randomly assigned to reduce by 50% (for 8 weeks) then eliminate (for 8 weeks) triamcinolone treatment. The other half of the salmeterol group (salmeterol-plus group) was randomly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks (active control group). MAIN OUTCOME MEASURE: Time to asthma treatment failure in patients receiving salmeterol. RESULTS: Treatment failure occurred in 8.3% (95% confidence interval [CI], 2%-15%) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8% (95% CI, 0%-7%) of the salmeterol-plus group during the same period. Treatment failure occurred in 46.3% (95% CI, 34%-59%) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7% (95% CI, 5%-22%) of the salmeterol-plus group. The relative risk (95% CI) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 (2.0-9.2) compared with the salmeterol-plus group (P<.001). CONCLUSIONS: Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol, a substantial reduction (50%) in triamcinolone dose can occur without a significant loss of asthma control. However, total elimination of triamcinolone therapy results in a significant deterioration in asthma control and, therefore, cannot be recommended.

Current Literature Item
Treatment of exercise-induced asthma

Summary
Exercise, particularly running and cold weather exercises, induces asthmatic reactions in about 17 million Americans. In some cases, the asthma occurs only with exercise (EIA) but not at other times. Avoidance of exercise frequently limits the quality of life in some individuals. Therefore, treatment prevention approaches to EIA are important. This subject was reviewed by Randolph, associated with
the Department of Pediatrics in Yale University, New Haven, CT. "Warming up exercises" to about 50% of maximal heart rate before full exercise may help tolerance of that full exercise. Also use of "cold weather" type masks to help warming and humidification of inspired care can also be helpful. However, most individuals with EIA need pharmacologic pre-treatment before vigorous exercise. Short acting beta agonist (2 puffs of albuterol) inhaled 15 minutes prior to exercise will reduce the incidence/severity of EIA for up to 4 hours increasing the number of inhaled puffs may be more protective but may lead to more systemic adrenergic effects causing side effects and limiting performance. Long acting beta agonists (salmeterol, formoterol) will protect against EIA for 9-12 hours, particularly helpful in individuals who exercise repeatedly (e.g., school children, competitive athletes). However, because of its slower onset of action, salmeterol must be inhaled 30-60 minutes prior to exercise. Salmeterol is generally delivered by an MDI for children 4 years or older while delivery by a dry powder inhaled is feasible in those 12 years or older. However, some children are not helped by
inhaled long acting beta agonists, for reasons not well understood. Also a degree of tolerance to the protective effects of inhaled salmeterol or formoterol may develop with daily use of theses agents for more than a month, even when inhaled corticosteroid therapy is used concomitantly.

Because of the potential for tolerance developing with frequent repeated use of inhaled beta agonists, some experts recommend the use of inhaled nedocromil or cromolyn ( non-beta agonists) 10-20 minutes prior to exercise. In some cases, both nedocromil and beta agonists are needed to give complete protection in EIA. If inhaled medication is not desired or contraindicated, one can consider use of a leukotriene antagonist (zafirlukast, montelukast) taken orally one hour prior to exercise. In the case of montelukast, some protective effects against EIA persist for at least 12 hours, and sometimes almost 24 hours.

Reference
J Resp Dis 2002;23:423-432

Editor�s Comments
I have been impressed with the use of formoterol as pre-treatment before exercise in reducing EIA. Its onset of action is as fast as albuterol but the protective effect is much longer (9-12 hours) without prolonged adrenergic systemic effects. The use of formoterol is currently prohibited in Olympic competition because of concerns about potential anabolic (performance enhancing) effects. However, a study reviewed in this Current Literature section, showed no such performance enhancing effects of formoterol. Use of inhaled shorter-acting beta agonists such as albuterol, are permitted in most competitive athletics provided that the athlete can provided documentation from his/her physician that EIA has occurred.

4/11/02 re: Nebulizers more effective than MDI?

I have patients responding to ads to get nebulizers vs. MDI. I have read studies saying it is no more effective; but I can't find them to show the patients that I and the insurance company in this case are not bad guys.

I have enclosed a review I wrote some time ago of an analysis of the published studies comparing the efficacy of nebulizers vs. that of MDI or DPI for inhaled steroid treatment. As you can see, the author of this analysis concluded that nebulized steroids were no more effective than steroids in a properly used MDI.
Also enclosed is my review of another report showing that use of an MDI/spacer was actually more effective than a jet nebulizer in the delivery of salbutamol (albuterol) in the treatment of acute asthma in children.

To my knowledge, there has been no more recent data to contradict these conclusions of the lack of superiority of nebulizers in the treatment of individuals who can use an MDI/spacer properly.

Nebulized corticosteroids in the treatment of asthmatic patients

Summary
Some clinicians who believe that machine-powered nebulization is a more effective means of delivering anti-asthma medications have been pleased to see the current availability of the steroids, budesonide and fluticasone, in nebulizer solutions in some parts of the world.But is their use really advantageous?

This subject was reviewed by Hill of the Northern General Hospital in Sheffield, UK. On the basis of a literature review, she has concluded that the most likely group to be prescribed nebulized corticosteroids (NCS) are the minority of asthmatics who require very high doses of inhaled corticosteroids by MDI (ICS) and/or frequently used oral steroids. There is little evidence from controlled studies that NCS is more effective than high dose ICS in this group. There may be less side effects from either NCS or high dose ICS than from oral steroids used in doses yielding the same beneficial anti-asthma effects. A few, small studies have shown that NCS are as effective as oral steroids in acute severe exacerbations of asthma. Larger, randomized controlled studies are needed for all these comparisons. Meanwhile, one cannot ignore the much higher cost and time involved in nebulized treatment than in oral steroid therapy.

Reference
Thorax 1999;54:661-63

Editor�s Comments
There is strong belief by some clinicians that power nebulization should deliver steroids more effectively to the lower airways than do MDI or dry powder inhalers (DPI). The evidence summarized by Hill does not make a strong case for major advantages of NCS therapy with the exception of use in those (e.g., small children) in whom effective MDI or DPI use is not feasible.

Use of MDI with spacers vs jet nebulizer in acute childhood asthma

Summary
Administration of inhaled beta-agonist bronchodilators through a jet nebulizer has been a traditional mainstay in the in-patient management of acute asthmatic episodes in small children. Dewar et al from the Southampton General Hospital in the UK recently reported a study of treatment of acute asthma in children older than 3 years who did not require intravenous therapy. Children (n=61) were randomized to receive either: a) up to 5 mg salbutamol (albuterol) per hour via jet nebulizer; or b) up to 10 puffs salbutamol (100 mcq/puff)/hour by MDI with an attached large volume spacer. The median hospital stays were 36.5 hours for the MDI/spacer group, and 40 hours for the jet nebulizer. More significantly, children in the MDI/spacer group were doing consistently better than those in the jet nebulizer group 2 weeks after discharge, possibly because of the training in MDI/spacer usage received previously as in-patients. Costs were somewhat lower for the MDI/spacer treatment.

Reference
Arch Dis Child. 1999;80:421-23

Editor�s Comments
These findings of "superiority" or at least equivalence of MDI/spacer usage compared to jet nebulizer use are dependent on: 1) use of a sufficiently large volume spacer; 2) ability of the child to inhale and exhale adequately; 3) cooperation by both patient/family and hospital staff. The authors pointed out that it may take some time to overcome the "jet nebulizer" culture for treating acute childhood asthma present in the medical staff of many institutions.

2/2/02 re: Discontinue inhaled steroids during systemic steroid therapy?

In acute asthmatic exacerbation, while giving systemic corticosteroids paraenterally, should we add at this point corticosteroids by inhalation or should they be started only after stopping the I.V. rout?

My practice has been to withhold inhaled corticosteroids (ICS) during the initial treatment of an acute asthma flare with systemic steroids for 2 reasons:
1) The doses of intravenous steroid generally used for acute asthma flares lead too much higher steroid levels in the airway mucosa than would be achieved with even sizable doses of ICS. Therefore, ICS use would add little to the effects of the large I.V. doses of steroids.

2) When patients present with an acute asthma flare, they frequently do not tolerate the rapid inhalation of medications such as ICS because of triggering of coughing. Therefore, I try to avoid use of ICS at that point when the patient is already using inhaled beta-agonists (which are needed)

However, I generally do recommend starting ICS therapy before the patient is discharged from the hospital (even though the patient is usually discharged on a tapered course of oral steroids) to emphasize to the patients the importance of maintenance ICS therapy for their asthma.

2/1/02 re: Gynecomastia following withdrawal of inhaled steroid therapy

Yesterday a colleague asked me if I knew of any relationship to withdrawal of inhaled CS (budesonide) and the development of gynecomastia. This regards an 8-year-old boy with moderate persistent asthma. He is not on cimetidine or any medications that I know that cause this condition. Dong quai is now on the list. He has a normal gonadal exam and is too young in my experience for the typical adolescent male with this problem. Any comments?

I am not aware of such an association nor were two pediatric allergists with considerable experience with inhaled corticosteroid therapy of childhood asthma whom I consulted. Also, I could not find reference to such an association in a Medline search.

9/12/01 re: Symptom controller in green inhaler

I am a student, and I need a piece of information for a coursework assignment, and I cannot find it on your website. I am looking for the name of the symptom controller that is normally contained in a green inhaler.

You did not specify whether the inhaler medication about which you were inquiring was for the nose or bronchial administration. The term "controller" is generally applied to agents which suppress the allergic inflammatory reaction in the nose or lower airways. This contrasts with the "reliever" medications, such as albuterol, which decreases asthma symptoms without significant anti-inflammatory effects.
The only controller meds in inhalers which are at least partially green, of which I am aware, are Nasonex and Flonase. Both are nasal steroid preparations.

Serevent, in a green dispenser, is a long-acting beta agonist, which relieves bronchial airway obstruction but is not an anti-inflammatory agent.

You can get a better idea of the appearance of these, and other, inhalers by looking in the blue page section at the beginning of the current Physicians Desk Reference (PDR).

5/10/01 re: Inhaled steroids and Addison's Disease

I recently saw a 30 yr. old lady with moderate asthma. She was on inhaled steroids for 6 months and became tired and lethargic. The medication was Flovent 220 at 2 puffs bid for a 6 month period. A local physician diagnosed Addison's Dz and I do find low A. M. cortisols in the chart. She has refrained from use of steroids and is afraid of a recurrence if they are again prescribed. Are there any reports of sensitive receptors or recurrences of Addison's if one were to need/use them again for asthma or allergic rhinitis?

Systemic effects, including HPA suppression, are not unusual with chronic use of high dosage inhaled corticosteroids (ICS). However, frank Addison's disease is unusual unless there is another factor present. Therefore, my first question is whether the patient has independent Addison's disease. The endocrine study profile differs in primary Addison's disease (no decreased pituitary function) from the suppression of pituitary function by ICS. This can be readily investigated. If the patient has independent Addison's disease and there is concern about additive problems with use of ICS, the dosage employed is very important. Fluticasone, while more potent than most other ICS, has to be used at lower inhaled doses to avoid HPA suppression (less than 500 microg/day). See enclosed abstract. For ICS such as budesonide, one can go somewhat higher although HPA suppression occurs in some individuals inhaling as little as 600-800 microg/day. Systemic absorption is increased about twofold if a large volume spacer is used. Beclomethasone in usual MDI formulations should be avoided since there is not extensive first-pass catabolism in the liver of swallowed beclomethasone. Another alternative to consider is Qvar in which the HFA propellant system leads to more efficient lower airways distribution of beclomethasone and a resultant need for a lower daily inhaled dose (see enclosed abstract).

J Asthma 1999 Sep;36(6):477-86
Measures of hypothalamic-pituitary-adrenal function in patients with asthma treated with inhaled glucocorticoids: clinical and research implications.
Wolthers OD, Honour JW.
Department of Paediatrics, Randers Hospital, Denmark.

In asthmatic patients treated with inhaled glucocorticoids there may be a risk of suppression of hypothalamic-pituitary-adrenal (HPA) function. The aim of the present study was to review peer-refereed data on HPA function in asthmatic patients taking inhaled glucocorticoids, and to discuss the value of HPA function measures in clinical practice and research. There is no evidence that inhaled glucocorticoids in recommended doses cause clinically significant HPA insufficiency. If sensitive measures of basal adrenal activity are used, however, dose-related suppressive effects with specific drugs and application systems can be detected. In adults, fluticasone propionate appears to be more potent than budesonide or triamcinolone acetonide in suppressing measures of basal adrenal activity. Measures of basal adrenal activity are useful in clinical trials that assess and compare systemic activity of specific drugs, application devices, and administration regimens, but have no place in the management of asthmatics..

Int J Clin Pract Suppl 1998 Sep;96:33-8
Steroid safety: the endocrinologist's view.
Grossman A.
Department of Endocrinology, St Bartholomew's Hospital, London, UK.

Asthma guidelines recommend the use of inhaled glucocorticoids (GCS). However, high doses increase the risk of systemic effects including suppression of the hypothalamic-pituitary-adrenal (HPA) axis by negative feedback, reduction of bone mass, inhibition of growth in children and skin thinning. Plasma concentration depends on the dose delivered from the inhaler, the distribution of delivery (ratio of lung to gut), and the degree of first-pass metabolism. Improving lung delivery increases lung absorption and reduces gut absorption and, depending on the extent of first-pass metabolism, may have significant effects on the systemic drug load. Qvar (3M Pharmaceuticals' hydrofluoroalkane beclomethasone dipropionate (HFA-BDP)), which produces an extra fine aerosol, improves lung delivery without producing clinically significant HPA suppression within the recommended dose range. Within this range Qvar produces no more HPA suppression than an equal dose of CFC-BDP and, in addition, lower doses of Qvar are effective in asthma control.

Drugs 1999 May;57(5):769-803
Inhaled fluticasone propionate: a review of its therapeutic efficacy at dosages < or = 500 microg/day in adults and adolescents with mild to moderate asthma.
Jarvis B, Faulds D.
Adis International Limited, Mairangi Bay, Auckland, New Zealand.

Fluticasone propionate is a corticosteroid with comparatively high receptor affinity and topical activity. Inhaled fluticasone propionate < or =500 microg/day provided effective corticosteroid maintenance treatment in patients with mild to moderate asthma in randomised, controlled clinical studies of 4 to 24 weeks in duration. Dosages of 50 to 250 microg twice daily produced consistent improvement in spirometric measures of lung function, reduced the frequency of as-needed beta2-agonist bronchodilator use, asthma symptom scores and night-time wakenings, and prevented asthma exacerbations compared with placebo. Fluticasone propionate < or =250 microg twice daily provided significantly greater improvements in lung function than nedocromil 4 mg 4 times daily, theophylline (5 to 15 mg/L) or zafirlukast 20 mg twice daily. Health-related quality of life improved significantly with fluticasone propionate 88 microg twice daily, but not zafirlukast 20 mg twice daily or placebo. In comparative trials in which fluticasone propionate was given at half the dosage of beclomethasone dipropionate, budesonide or flunisolide, fluticasone propionate < or =250 microg twice daily produced equivalent or greater improvement in spirometric parameters and equivalent reductions in the use of as-needed beta2-agonists than beclomethasone dipropionate, budesonide or flunisolide. Fluticasone propionate 250 microg twice daily was generally more effective than triamcinolone acetonide 200 microg 4 times daily in two 24-week trials. The combination of inhaled fluticasone propionate < or =250 plus salmeterol < or =50 microg twice daily allowed for the use of lower dosages of the inhaled corticosteroid. The incidence of adverse events in patients receiving inhaled fluticasone propionate 50 to 250 microg twice daily was similar to that in beclomethasone dipropionate 168 to 500 microg twice daily and budesonide 100 to 600 microg twice daily recipients and greater than that in recipients of triamcinolone acetonide 200 microg 4 times daily in comparative trials. The incidence of oral candidiasis was < or =8% in patients treated with fluticasone propionate < or =250 microg twice daily or other agents. There was no evidence of clinically significant hypothalamo-pituitary-adrenal (HPA) axis suppression with fluticasone propionate < or =250 microg twice daily in comparative trials.
Conclusions: Inhaled fluticasone propionate < or =500 microg/day is an effective antiinflammatory therapy for mild to moderate asthma in adolescents and adults. The drug is more effective than nedocromil, theophylline or zafirlukast and is at least as effective as other inhaled corticosteroids administered at twice the fluticasone propionate dosage. The addition of inhaled salmeterol allows the use of lower maintenance dosages of fluticasone propionate. The drug is well tolerated and there is no evidence of a clinically significant effect of this dosage on HPA axis function. Hence, fluticasone propionate < or =500 microg/day is a particularly suitable agent for patients with mild to moderate asthma.

11/6/00 re: Are systemic steroids needed during an operation on a child receiving inhaled steroids?

Is there any evidence to support the use of Flovent over other inhaled corticosteroids in pediatric patients? The physicians at our institution want to add it to the hospital formulary claiming that it works better in pediatric patients but with no supporting evidence. They cite that you can administer it twice a day but I don't really consider that an argument since you can administer other steroid preparations twice daily also. Because it cost twice as much as Azmacort, we are recommending a compromise to our medical staff. To use Azmacort in the children who are aged 12 and older and reserve Flovent for the children who need the assistance of the pediatric spacer device.

You have addressed a complex subject of considerable current interest and debate.
Fluticasone (Flut) has achieved considerable popularity in certain quarters because of :

Very little systemic bioavailability of any swallowed Flut.

Considerably higher affinity of Flut than other inhaled corticosteroids (ICS) for the functional glucocorticoid receptor. Proponents of Flut feel that this increased affinity leads to greater and more prolonged binding of Flut to steroid receptors in the airways, leading to more potent clinical efficacy. Indeed, early studies showed the Flut was about twice as effective as beclomethasone in asthma treatment (1,2). Therefore, reduced doses of Flut would be required for asthma control Indeed, the greater potency of Flut. Has prompted trials of inhaled Flut for acute severe asthma flares, where it was found to be not as effective as oral steroids (3) Studies reviewed by Lipworth ( 4 ) suggest that the relative potency of triamcinolone (Azmacort), among other ICS, was somewhere between Flut. And beclomethasone.

However, the question has arisen whether any Flut which is absorbed into the systemic circulation from the respiratory tract tissues would have more systemic side-effects than seen with use of other ICS because Flut would bind more avidly to tissues in the HPA axis, skeleton, etc. As a result, the volume of systemic Flut distribution is greater, leading to more prolonged retention in the systemic compartment. The type of delivery system and nature of the propellant are also important factors (4) For example, it may be feasible to get similar therapeutic and systemic effects using half the dosage of ICS incorporating the newer propellant HFA than the older CFC propellant now being phased out. Earlier studies suggested less side-effects from Flut than "equivalent" doses of beclomethasone (1,5) However, more recent studies have suggested that systemic effects of Flut may occur with inhaled doses about half that seen with other ICS. This observation is re-enforced by the impression of my experienced colleagues in Pediatric Allergy that systemic side-effects are more commonly seen since small children have been treated with Flut.

Therefore, my bottom line impression at this time is that, overall. Flut is likely a significantly more potent ICS than the older agents, allowing reduction in the daily dose needed for asthma control in many (but not all) patients. However, at the same time, one has to keep the daily dosage of Flut lower to avoid systemic side-effects. In small children, the "safe" daily dosage of Flut may not be more than 400 mcg/day. If the manufacturers of Flut can price this ICS appropriately low, there may be some cost saving as a result since daily Flut doses may be lower. Obviously, efforts should be made to allow reduction of lower daily doses of any ICS, while maintaining asthma control through, trials of addition of non-steroid agents to the treatment program(6)

References:

1. Respir Med 1993; 87:609-20
2. Eur. Resp. J. 1993;6: 877-85
3. New Eng. J. Med 2000; 343:689-94
4. Drug Saf 2000 Jul;23(1):11-33
5 Am J Respir Care Med 1996; 153:924-30
6 Drugs2000;59 Suppl 1 15-22
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6/13/00 re: Are systemic steroids needed during an operation on a child receiving inhaled steroids?

Have there been any reports or the need for parenteral steroids prior to or during surgery for children on any form or combinations of inhaled steroids?

The answer to your question depends on the cumulative daily dose of inhaled steroids used in the child. For most inhaled steroids, doses of 400mcg/day or less are not associated with systemic effects on the HPA axis. Therefore, there should be a normal physiologic response to any stress. In contrast, cumulative inhaled steroid doses of over 800 mcg/day commonly lead to modest HPA suppression; systemic steroids administration during major surgery or other stress may be advisable. Don't forget to include nasal steroid doses when calculating the cumulative daily dose in patients using both nasal and bronchial steroids.

5/24/99 re: provide information about Flixotide

Please provide all information related to the following asthmatic drug which is I understand new on the market: Flixotide +Fluticasone Propionate +spray inhaler.

As I understand it, flixotide is a recently released version of the inhaled steroid fluticasone. I have contacted a representative of Glaxo-Wellcome, the manufacturer of the product. The term flixotide has been used for fluticasone in a discus dry powder inhaler delivery system
thought to be at least as effective as the MDI preparation but not requiring a propellant (such as the CFC scheduled for discontinuation in the near future).
A combination of inhaled fluticasone and salmeterol is currently marketed by Glaxo in Europe as Seretide. This combination is not yet released in the USA, but when it is, will be marketed as Advair.

4/27/99 re: Optimal timing of inhaled corticosteroid administration

What dosing intervals do you suggest for inhaled corticosteroids in asthma? Some of my colleagues believe that the 2nd of a bid dose should be given in the late afternoon rather than the evening. Remembering that our own cortisol secretion ebbs in the evening and early morning, others suggest that a q12h dosing is more appropriate and would improve early morning symptoms more effectively.

Various timing regimens for inhaled corticosteroids (ICS) have been recommended in different reports. I believe that the answer to your question depends on the severity of the asthma being treated. For example, for relatively mild-moderate persistent asthma, Pincus et al from the National Jewish Medical and Research Center in Denver found that triamcinolone inhaled once a day at 3-4 PM was as effective as the same total dose divided into two treatments given in the AM and evening. Perhaps, this is the basis of the recommendation of your colleague for late afternoon rather than evening dosing.
My personal preference is to use ICS q12h in the early AM and evening with the understanding that much of the beneficial effects of ICS are cumulative over a period of days/weeks rather than just an immediate effect over hours. Also, data reviewed in a symposium held at the American Academy of Allergy, Asthma and Immunology meeting in March 1999 suggest that daily total inhaled doses of <400 mcg of budesonide or triamcinolone (and likely <200 mcg of fluticasone) are not associated with any suppression of the HPA axis, regardless of the dosing schedule. (See review of this symposium in In the News Section of this AADMC web site).

2/25/99 re: Inhaled dexamethasone dosage

We are looking for dosage guidelines for dexamethasone given in an aerosalized form. Our primary focus is with children, however we are interested if it is also effective in adults who present with asthma symptoms.

There is little information about current administration of nebulized dexamethasone for asthma because the use of this agent decreased markedly when newer inhaled steroids became available. These newer inhaled steroids have much less systemic effects that equimolar concentrations of inhaled dexamethasone. It is true that a number of newer preparations are not available in formulation for power nebulizers. However, with appropriate techniques and spacers, all these inhaled steroids can be given by meter-dose inhalers to children. There have been some concerns raised about effects on growth velocity (and possibly on the eye) in subjects receiving high doses of inhaled steroids for a prolonged duration (see "Breaking News" at the top of the Home Page of this AADMC web site).

9/25/98 re: doses of inhaled steroids

EPR II recomends low, medium and high dose for children based on beclomethasone 42 mcg/puff and fluticasone 44 mcg/puff. I know this is the actuater dose. I wonder if the label on the inhaler you have says 42 mcg or 50 mcg. We have both drugs in Venezuela but the label says 50 mcg (it does no specify if is the actuater or the valve dose). Would 8 puffs of beclomethasone be a medium dose or low dose based on this?
I wonder why there is not a dose written for budesonide MDI (only turbohaler that is 200 mcg/dose). Is it assumed as the same dose of beclrmethasone. What about the label and the actuater dose in this case?

There is considerable confusion about the use of various inhaled steroid preparations because of variations in concentrations/puff, different delivery systems (with/without spacers) and possibly differences in potency/microgram of the drugs. In regard to your specific questions:
1) beclomethasone propionate (BP) is in 2 concentrations - regular, 42 micrograms/puff and Vanceril-DS 84 micrograms/puff at the activator in MDI marketed in the USA. I am not personally familiar with BP preparations used outside the USA; 2) budesonide is currently marketed in the USA only in the Turbuhaler formulation, in the concentration 200 micrograms/puff. However, it is important to remember that only 5-10% of the dose delivered by the usual MDI reaches the lower airways where it is needed. The Turbuhaler reportedly delivers twice as much of its inhaled steroid as does the typical MDI. Of course, the delivery characteristics of these MDI may change with the required future substitution of different
propellants when the current CFC propellants must be withdrawn.
Once delivered to the lower airways, fluticasone may be up to twice as potent/microgram as other inhaled steroids with attendant increase in systemic absorption. (See review of "Is fluticasone superior to other inhaled steroids" in the Current Literature Section of this AADMC web site.)

Having said all that, my impression is that most experts in the field feel that up to 400 �gm/day of most inhaled steroid preparations constitutes a moderate dosage. Doses of � 1000 micrograms/day are considered high dosage, associated with a greater frequency of HPA suppression and possibly other systemic side-effects.

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