Review ArticleReviews

Nebulized Corticosteroids in Asthma and COPD. An Italian Appraisal

Andrea S Melani
Respiratory Care July 2012, 57 (7) 1161-1174; DOI: https://doi.org/10.4187/respcare.01414

Abstract

Inhaled corticosteroids (ICSs) are the mainstay of anti-inflammatory treatment in subjects with asthma and COPD. This review evaluates the role of nebulizers as an alternative to inhalers for delivering ICSs in asthma and COPD. I selected 16 randomized, placebo-controlled, blinded, long-term studies, mostly carried out in asthma (n = 14) and COPD. Nebulized budesonide has been demonstrated to be effective and safe in children ages 1–8 years, and, with less evidence, in infants and adults with asthma. Other investigations, with the addition of in vitro and in vivo comparison studies, have shown that nebulized beclomethasone, fluticasone, and flunisolide are effective alternatives to nebulized budesonide in asthma and COPD. Efficient delivery of nebulized ICSs requires that the nebulizer system, the nebulized drug formulation, and the inhaling subject interact properly. The practices of mixing nebulized ICSs with bronchodilators and using nebulized ICSs in acute settings are promising, but require further confirmations, and at present cannot be recommended. I conclude that nebulizers may be considered as an effective alternative to inhalers for delivering ICSs and can be recommended to asthmatic and COPD subjects who are unwilling or unable to use inhalers. Newer formulations could possibly offer a relevant advance for a more efficient nebulization of ICSs.

Introduction

Inhaled corticosteroids (ICSs) are commonly used for aerosolization. Long-term regular use of ICSs is the mainstay of anti-inflammatory management in chronic persistent asthma of infants, children, and adults, throughout the severity.1–3 ICSs are also administered to pre-schoolers with intermittent wheezing, but with less evidence of clinical efficacy.4–8 Even if the therapeutic effect is more modest than in asthma, regular use of an ICS in combination with an inhaled long-acting β agonist is increasingly utilized for the treatment of severe COPD with a history of repeated bronchitic exacerbations.9–11 The role of ICSs in acute asthma and COPD is promising,12 but not fully evidence-based.13

The production of therapeutic aerosols requires specific delivery devices such as inhalers and nebulizers. Current guidelines for asthma.1,2 and COPD management,14,15 as well as for nebulized16,17 and aerosol therapy,13 do not provide sufficient, specific guidance on the selection of the most appropriate device in different clinical settings. So, according to local habits and availability, there is tremendous variability among countries in the diffusion of different devices for administering an aerosol therapy.18,19 In more than 70 countries worldwide, ICSs are approved and utilized for nebulization in both children and adults, for asthma and COPD. Sometimes, such as in Italy, the use of nebulized ICSs is widespread20 and critically discussed.21 In many other countries ICSs are usually or exclusively delivered using hand-held inhalers; in the United States, budesonide is the only marketed nebulized ICS and approved for children ages 1–8 years with asthma by the FDA in August 2000. The availability of an effective nebulized ICS has been welcomed by U.S. clinicians22 and is increasingly used.23 Previously, alternative types of ICSs, such as nasal or parenteral formulations, had been proposed24,25 and used for the treatment of asthma.26,27

Four corticosteroids are currently marketed for nebulization: nebulized budesonide (BUD), beclomethasone dipropionate (BDP), flunisolide (FLU), and fluticasone propionate (FP). They are available as unit-dose vials of 2 mL; BUD, FP, and FLU are available as multiple strength formulations. All these drugs are well known for their high affinity to the glucocorticoid receptor, good topical anti-inflammatory activity, and low tendency for systemic effects.28–31 The composition and some properties of the proprietary nebulized ICSs are reported in Appendix 1 in the supplementary materials at http://www.rcjournal.com. Poor water solubility is possibly the most relevant characteristic of the currently marketed formulations, which are available as suspensions, with some inherent drawbacks.32–34

Some novel varieties of nebulized ICS are being developed. They are obtained by adding solubilization enhancers with the production of nano-suspensions and solutions, or embodying the drug in micellar systems with the manufacturing of nano-emulsions and liposomal fluids.35 These newer formulations seem to be safe and stable, assure that more drug is generated as aerosol by the nebulizer, and have improved particle size distribution,33,36–39 leading to higher drug doses to the lungs40–42 and improved pharmacodynamics.43,44

The aim of this review is to evaluate whether nebulization may be considered as a useful alternative to inhalers for administering ICSs in asthma and COPD.

In Vitro Studies

In vitro investigations allow for important observations on aerosol behavior and contribute to cover some uncertainties due to the lack of extensive in vivo studies. In the supplementary Appendices 2 and 3 I have displayed the in vitro experiments with the marketed formulations of nebulized ICSs.33,36–39,45–69 To the aim of giving more homogeneous results, we have selected those studies reporting the inhaled mass (IM) as the relevant parameter of drug output, and the mass median aerodynamic diameter (MMAD), the geometric standard deviation, and the respirable fraction by cascade impaction as indices of aerosol granulometry. Once careful attention is paid to standardizing the environmental conditions,70–73 cascade impaction methods are the most accurate means of studying aerodynamic properties of suspensions such as ICSs.

Overall, jet nebulizers are the preferred system for nebulizing ICSs. Several in vitro studies with BUD35–36,47,74–76 and FLU77 have shown a poor efficiency of conventional ultrasonic nebulizers for administering ICSs. Likewise, although mesh nebulizers offer promising results,36,38–39,49,51,53–56,67,78 they have a higher purchase cost than jet systems. Moreover, maintenance may be difficult, as repeated nebulizations with suspensions seem to predispose to clogging and blockage of mesh holes.79 Recently Berg and Picard68 evaluated 30 commonly used jet nebulizer/compressor systems to nebulize BUD. Mimicking the breathing pattern of a child, the IM of studied aerosols ranged from 4% to 20% of initial drug charge (and from 1% to 9%, simulating the infant's breathing pattern).68 These findings are also in substantial accordance with most studies, shown in the supplementary Appendix 4,76,80–87 where the IM was evaluated using inhaling subjects and not a breathing simulator. The MMAD of studied aerosols ranged from 4.8 to 9.9 μm.68 It means that not all the studied systems seem to be suitable for nebulizing ICSs, because it is accepted that the probability of being delivered to the lungs is relevant only when the drug is contained in nebulized particles smaller than 5 μm.16 Likewise, not only nebulizer systems producing aerosols with MMAD > 5 μm, but even those with MMAD of 2–3 μm are not suitable for efficient ICSs delivery.35,36,47,70 In fact, at least for the currently marketed nebulized ICSs that are available as suspensions, the micronized drug is distributed mainly in particles larger than 2–3 μm in diameter36 (as shown in supplementary Appendix 1), so that droplets with a smaller size would contain mainly water and not drug.

Interestingly, all components of the nebulizer system are important in determining good lung delivery of ICSs (ie, the interface plays a very important role, largely modifying the IM and also influencing the MMAD).58,64 This was confirmed by an ex vivo study where the mean IM of nebulized BUD was 5–7% of the nominal dose inhaled through a face mask, while this percentage increased up to 9–12% through a mouthpiece.87 The same study showed that a good seal between the face and the mask approximately doubled the IM.87 Another study with BUD has shown that the blow-by method of administration largely compromised the IM.88 Thus, not only the nebulizer system, but even the modalities of inhalation widely influence the aerosol properties of nebulized ICSs. Barry and O'Callaghan46 have demonstrated the role of the inhaling patient in an in vitro study, where they modified the inspiratory flow to resemble different breathing patterns and saw major differences in IM of nebulized BUD. In another ex vivo study, when 163 children ages 6 months to 7.9 years inhaled BUD through a Spira nebulizer, the IM ranged from 1.9% to 40.6% of the nebulizer load, according to the breathing modalities.85 Manufacturers have tried to reduce the variability of performance related to the different breathing patterns of inhaling patients, leading, with advances in nebulizer technology, to the delivery of breath-enhanced and synchronized nebulizers.

As shown in the supplementary Appendix 3, some studies have found that BDP and FLU do not substantially differ from BUD regarding IM and droplet size distribution.59,66,69 Less information is available for FP. Without any explanation of the method used, Westbroek et al89 reported a respirable fraction of 12–16% of the initial FP charge for 3 commonly used nebulizer systems such as the SideStream/PortaNeb, the Pari LC Plus/Proneb Ultra and the Cirrus/PulmoAide. Importantly, not only the drug, but all other components of the liquid formulation have a relevant role for efficient drug delivery: increasing the fill volume from 2 mL to 7 mL improves the nebulizer efficiency up to 3-fold, but also increases the treatment time, while aerodynamic properties did not change.90,91 Mixing is another common practice when more medications are prescribed simultaneously.20,92–94 Some in vitro studies have investigated the consequences of mixing different drugs for nebulization. When bronchodilators and ICSs are mixed, no physico-chemical incompatibility was found.61,95–99 Moreover, as shown in supplementary Appendices 2 and 3, at least for BDP, BUD, and FLU, mixing of ICSs and bronchodilators does not necessarily compromise the IM and the droplet size distribution of aerosols,61,66,69,100 as initially thought.101

Pharmacokinetic and Scintigraphic Studies

It is agreed that a relevant amount of drug has to be delivered to the lung for effective aerosol treatment. Pharmacokinetics evaluates pulmonary bioavailability for a given drug. The pharmacokinetics of ICSs have been extensively reviewed.102–106 Scintigraphic studies investigate lung drug delivery for a given aerosol. Because the dose released to the lower airways is nearly completely absorbed into the broncho-pulmonary circulation, the lung drug delivery roughly equals pulmonary bioavailability.

Regarding the nebulized ICSs, in healthy adults when 3 different nebulizers (Pari Inhalier Boy, Pari LC Plus, and Maxin MA-2) were used in a breath-synchronized manner, the systemic bioavailability of BUD was 13% of label claim and approximately 50–70% of the IM.107 In 10 asthmatic children ages 3–6 years who inhaled quietly through the mouthpiece of the Pari LC Plus/Master system, the systemic availability of BUD was 6.1% of label charge, corresponding to a quarter of the IM.84 This result is in keeping with a scintigraphic study where the lung deposition of BUD in 2 children inhaling quietly with good seal of face mask via the Pari LC Plus/Proneb Ultra nebulizer was 5–8% of label claim.108 The same study confirmed the key role of the inhaling subject for efficient drug lung delivery: 2 children, one whose mask was not sealed to the face, the other who was crying, showed a lung deposition of, respectively, 0.1% and 1% of initial charge.108

Some pharmacokinetics studies have shown a substantial dose proportionality in both mean plasma and area under the curve levels when increasing doses of ICSs were nebulized. This result has been observed in 10 adult asthmatics who inhaled a daily dose of, respectively, 2 mg and 8 mg BUD, in a cross-over manner, with the Inhalier Boy.109 Murphy et al110 also obtained a similar finding when different doses of BUD (0.5 mg and 1 mg once daily, 1 mg and 2 mg twice a day) were administered to 120 moderate-to-severe adult asthmatics with the Pari LC Plus/Master system through a mouthpiece. In the same study, in an attempt to compare a nebulizer with an inhaler, a 3-fold difference in potency was estimated, favoring the Turbuhaler dry powder inhaler. Using the Pari LC Plus/Master system with a mouthpiece, another single-dose study in 12 healthy adults observed a dose proportionality by nebulizing BDP 1.6 mg and 3.2 mg; in the same study the comparison with chlorofluorocarbon-propelled BDP via metered-dose inhaler (MDI) added to a valved holding chamber (VHC) suggested a 2-fold potency ratio between MDI and nebulizer, favoring the first device.111 These results with marketed ICS formulations do not consider some recent advances in nebulizer technology: in 10 asthmatics (mean age 20 months) ages 6–41 months, the mean lung deposition for a novel formulation of nebulized budesonide via an eFlow was 34% of nominal dose: a percentage similar to that of the most efficient inhalers.42

Pharmacodynamics

Pharmacodynamics evaluates the clinical value of a certain drug, using both efficacy and safety measures. Unfortunately, a full pharmacodynamic evaluation of nebulized ICSs is not available for several reasons. First, ICSs have anti-inflammatory activity, but the value of direct biomarkers of airway inflammation, such as exhaled nitric oxide or eosinophil cell count, needs to be fully established. So the most commonly used parameters to assess the efficacy of ICSs, such as the improvement in baseline lung function and symptom scores, the reduction of bronchitic exacerbations, and rescue β agonists use, are indirect and relatively insensitive indices. It means that the dose-response effect is relatively flat, making it possible to detect differences only when the ICS is at least quadrupled over the baseline dose.112–118 Second, the improvement (or worsening) in the control of asthma occurs within some days from starting (or stopping) treatment, but treatment is required for up to 4–8 weeks119,120 or more121 to reach the maximum effect. This complicates the interpretation of results from cross-over, step-down, or step-up titration studies.122,123 On the other hand, a full estimation of ICS potency requires parallel studies of long-term duration (at least 1 month of regular treatment) with a large sample size of subjects for a range of drug dosages and disease severity, studies not easily performed.124

In Table 1 I have reported 16 randomized, blind, placebo-controlled studies with nebulized ICSs in patients with chronic persistent asthma and COPD.6,89,113,125–137 Three studies had a cross-over design; the remaining were parallel. Five studies,125,128,133,135,136 including 187 subjects, used FLU at different daily doses up to 2 mg. Two studies, enrolling 192 subjects, used BDP at daily doses of 0.8–4 mg. A study with FP at daily doses of 1–4 mg, included 301 adults with severe asthma. The clinical experience with BUD is the most extensive, for a total of 8 studies enrolling 1,258 asthmatic subjects, mostly pediatric (0.5–8 years of age). Compared to placebo, BUD significantly improved disease control for both subjects not previously receiving ICSs nor well controlled by bronchodilators, and for those on prior ICSs use. Efficacy was already demonstrated at a daily dose of 0.5 mg with once daily administration of BUD, although evidence supporting the efficacy of the twice daily and higher dosing is stronger.

View this table:
Table 1.

Characteristics of Randomized, Placebo-Controlled, Blind Studies With Nebulized ICSs in Asthma and COPD

Although ICSs have a better therapeutic ratio than systemic corticosteroids, when higher doses are administered, relevant absorption occurs, with the potential to give systemic adverse effects. Measurements of adrenal suppression are usually considered as the most sensitive marker for ICSs' systemic activity. In fact, exogenous corticosteroids can attenuate natural production of cortisol by a negative feedback on the hypothalamic-pituitary-adrenal axis. Safety data are available mainly for BUD. Ten adult asthmatics who inhaled an 8 mg daily dose of BUD via the Inhalier Boy system had morning cortisol levels lower than when they received a 2 mg daily dose.109 However, these high dosages of BUD are seldom used in clinical practice. The effect of BUD at daily doses up to 2 mg on the hypothalamic-pituitary-adrenal axis was studied in 293 pediatric asthmatics, ages 6 months to 8 years, for up to 52 weeks, without any clinically important difference, as compared to the conventional treatment group (where 35% were using ICSs via inhalers).138 On the whole, adrenal suppression seems to occur occasionally at the highest doses after long-term regular treatment periods, perhaps in susceptible individuals.131,139 Another major concern in pediatric age is the possibility of a negative effect of ICSs on body height. Again, the most information is available for BUD: a total of 670 pediatric asthmatics were randomized in a 2:1 ratio to receive BUD (titrated to the lowest clinically effective dose, with median total daily dose ranging from 0.5 to 1 mg) or conventional asthma therapy for 52 weeks, in a real life setting,138 with no difference of growth between groups, even when stratified by sex and age.140 A small but statistically significant difference in growth velocity (−0.8 cm/y, P = .002) was observed only between the BUD group and that of conventional treatment where ICSs were not allowed.131 Likewise, as more extensively shown for ICSs administered via MDIs, this result did not affect the final height to be achieved.141–144 Post-marketing surveillance data have confirmed the safety of nebulized ICSs across all ages.145,146 BUD and BDP have also been used safely in pregnant women.147–150 Importantly, despite the fact that substantial facial and eye deposition may occur using nebulizer with face mask,151 local adverse events are not commonly reported. Skin related side effects have been observed only in 2% of children, with no reports of cataract.152,153

In Table 2 I have reported 18 comparative studies that included nebulized ICSs.6,82,109–110,117,139,154–165 Five studies used inhalers as the benchmark against which the comparison has been set up. Three of these studies explored the clinical value of nebulized BDP. BDP administered via the Pari LC Plus/ProNeb Turbo demonstrated to be not less effective than the same drug delivered via inhalers at half dose in 301 asthmatics of different ages and disease severity.158–160 The results of earlier studies with nebulized BDP were contrasting,166–168 probably as a result of the low strength of the used preparation, impeding a sufficient lung drug delivery.169 Another study showed that an 8 mg daily dose of BUD given to 10 adult asthmatics via an Inhalier Boy for 4 weeks was more effective than a 1.6 mg daily dose of budesonide delivered via MDI with VHC.109 On the contrary, Murphy et al did not find any difference in efficacy and safety between different doses of BUD and budesonide given via the dry powder inhaler Turbuhaler at a daily dose of 0.4 mg twice a day.110 Investigating the systemic activity of ICSs, Wales et al170 did not observe any consequence after inhalation of a single 4 mg dose of BUD, while serum cortisol levels significantly decreased when the same volunteers inhaled either budesonide 4 mg using a Turbuhaler or 4 mg fluticasone propionate using an MDI with a VHC. Finally, in another study on 14 healthy adults in which the effect of a single 2 mg dose of FP on hypothalamic-pituitary-adrenal axis was compared to MDI added to VHC, the latter showed approximately a 7-fold higher suppressant effect, as compared to the nebulizer Pari LC Plus.171 Overall, the problem of equivalence among different devices remains undefined. Other comparative studies have addressed the problem of individualizing (or adjusting) the lowest effective dose of nebulized ICS (mostly with BUD) to obtain asthma control, without any ultimate conclusion. The dose-response effect is not well defined with nebulized ICSs: only when the ICS dosage was increased 4-fold was a difference sometimes observed in terms of efficacy117,154 and safety.109 Likewise, the dose-response trend was observed for some efficacy variables only in one113 of the 3 seminal pediatric randomized double-blind placebo-controlled studies with BUD,113,130,131 and not at all after patient stratification by age.172

View this table:
Table 2.

Characteristics of Randomized Blinded Comparison Studies Lasting for at Least 1 Week in Asthmatics Using Nebulized ICSs*

The results of placebo-controlled blinded studies evaluating the role of nebulized ICSs in acute settings are displayed in the supplementary Appendix 5.173–182 These studies have been performed in either emergency rooms or in hospital. Although the active treatment group often shows some advantage in terms of efficacy with respect to the placebo arm, no firm conclusion can be drawn. Overall, the clinical importance of ICSs in acute settings is not well defined. At present, the use of an ICS at 4 times the maintenance dose is considered an alternative to systemic corticosteroids only for mild-to-moderate acute asthmatic episodes.1 In more severe attacks, current guidelines recommend the early use of systemic corticosteroids, but do not include ICSs.183 Unfortunately, systemic corticosteroids induce relevant adverse effects, even with short-term treatments.184,185 The results of blinded comparison studies evaluating the role of nebulized ICSs in acute settings are displayed in the supplementary Appendix 6.173,177–178,180,186–193 Ten of these 12 studies compared nebulized ICSs to systemic corticosteroids, which are the mainstay of anti-inflammatory treatment in exacerbations. Due to differences in methods and enrolled population, the results of different studies cannot be pooled, and firm conclusions cannot be obtained. The problem of equivalence between nebulized ICSs and systemic corticosteroids also remains undefined. A significant dose-related suppression was observed in adult asthmatics with oral prednisolone at daily doses ranging from 5 to 20 mg, but not with BUD given via a Ventstream/PortaNeb nebulizer system at daily dosages ranging from 1 to 4 mg for 4 days.194 Moreover, ICSs could be not only safer than systemic corticosteroids, but also assure earlier results via non-genomic effects.195–197 Possibly, the critical parameter for clinical efficacy, at least in asthmatics, might not be the total dose of ICSs, but rather the timings of delivery, with earlier repeated administrations (every 15–20 min for up to 2–4 h) giving greater benefits.198 Finally, the value of ICSs for the treatment of asthmatic and COPD exacerbations is promising,12,198–201 but not fully evidence-based and cannot be recommended. The confirmation of an important role for ICSs in acute settings would enlarge the use of nebulized ICSs, as many health caregivers prefer to administer aerosol therapy via nebulizers in the hospital202 and in emergency departments.203

Although most randomized placebo-controlled blinded studies have administered nebulized ICSs alone, 8 trials used co-admixtures of ICSs and bronchodilators.136,137,173,174,176,179,181,182 A study where FLU was mixed with bronchodilators and administered via the Nebula system was carried out in at least moderate COPD, with a trend of improved symptom score and reduced severe exacerbation rate.136 The remaining studies were performed in asthmatics: 6 studies were performed in acute settings, mixing either BUD173,174,176,181,192 or FP179 with bronchodilators, via a variety of nebulizer systems. Four173,174,176,192 of these studies showed a significant result in terms of clinical efficacy when the co-admixture including the nebulized ICSs was compared to the placebo arm. The last study observed a significant improvement in symptom score and symptom free days in children with intermittent wheezing who received a co-admixture of BDP and albuterol via the Comp Air Elite system.137 Although promising, the clinical effects of mixing nebulized ICSs with other nebulizable drugs needs confirmation to be recommended.

Discussion

Several large randomized controlled studies in subjects with chronic persistent asthma have demonstrated the efficacy and safety of BUD at daily doses from 0.5 mg to 1 mg, with a range of jet nebulizers (Aiolos, DeVilbiss 646, Hudson Up-draft, Pari Inhalier Boy, Pari LC Plus, and VentStream). In vitro and some in vivo comparative and placebo controlled studies suggest that nebulized BDP, FLU, and FP, with some differences among them, are also clinically effective and safe. Clear-cut indications about the recommended drug dosages are difficult, because a dose-response trend is inconsistently observed for nebulized ICSs. From a practical point of view, it means that, when the desired clinical effect is achieved, the total daily dose of the nebulized ICS must be individualized for each patient, with the goal of tapering to the lowest effective dose to maintain disease control and to avoid the risk of relevant systemic side effects.

Three main drawbacks have limited a larger use of nebulized ICSs. First, most trials on ICSs have used inhalers, so that they have stronger evidence in efficacy than nebulizers. Second, some nebulizer systems are not suitable for efficient lung delivery of ICSs. This observation is relevant, as nebulized drugs and nebulizers are sold separately and a lot of physicians are not familiar with the practice of nebulized ICSs. This raises concerns that the nebulization of ICSs is not always optimally performed. Effectively, in real life, a variety of nebulizer systems and operating modalities have been described for nebulizing ICSs, and many of these practices are not evidence-based.20,94,204 Third, all currently marketed nebulized ICSs have a relatively poor lung delivery. Most inhalers have greater efficiency than nebulizers for delivering ICSs. Although bioequivalence in clinical outcome among different devices might be overcome by increasing the dosage of the nebulized ICS, it implies longer times of administration, a major determinant for poor adherence to treatment,110 and higher costs. By estimating a 1:2 potency ratio between BUD and budesonide Turbuhaler205 and equivalence between nebulized BUD, BDP, FLU, and FP, the cost (by Italian standards) for a 10-day course of treatment is approximately €5 for budesonide Turbuhaler at a daily dosage of 0.4 mg, versus €28 for BUD, €20 for FLU and FP, and €12 for BDP. However, the cost of nebulized ICSs is variable among countries. The United States price for a 10-day course of BUD at daily doses of 0.25, 0.5, and 1 mg is, respectively, $27, $42, and $68.206

Thus, at present, nebulizers are a second choice, compared to hand-held inhalers, for delivering ICSs. Nebulized ICSs can be prescribed to patients who are unwilling or unable to use inhalers. However, this occurrence is common not only in infants, but even in the elderly, where, despite improvement in technology, inhaler misuse remains common in real life and is associated with poor disease control.207 Accordingly, most adult patients who receive home nebulizer therapy are advanced in age and have many associated comorbid diseases, severe respiratory conditions, and common failure with other therapies.20,204,208–210 Interestingly, in asthmatic children with a history of either hospitalization or emergency department visits for asthma, only the use of nebulized BUD has been associated with reduce risk of relapse.211,212 In addition, a decrease in systemic corticosteroid use and a trend of reduced emergency department visits and hospitalizations have been reported in elderly patients with chronic lung diseases regularly using nebulized ICSs.210 Newer formulations of ICSs could probably improve the efficiency of nebulizers, possibly becoming equivalent to that of inhalers with the best lung drug deposition.38,39,41–44 Interestingly, newer ICSs with customized nebulizers can effectively deliver aerosols with MMADs smaller than 2–3 μm, with the potential of improved lung delivery211 and better clinical outcomes212 to infants, a traditionally complicated group to treat with therapeutic aerosols.213,214

Summary

I conclude that nebulized ICSs are currently a valid alternative to inhalers in asthma and COPD. Meaningful recommendations for good practice with nebulized ICSs should be implemented in clinical practice. Additional research is required to confirm the promising role of ICSs in acute settings and the possibility of mixing nebulized ICSs and bronchodilators. Other studies should clarify whether ongoing ICS formulations may offer clinically important advantages over the currently available nebulized ICSs.

Footnotes

  • Correspondence: Andrea S Melani MD, Fisiopatologia e Riabilitazione Respiratoria, Policlinico Le Scotte, Azienda Ospedaliera Universitaria Senese, Viale Bracci I-53100 Siena Italy. E-mail: a.melani{at}ao-siena.toscana.it.

  • Dr Melani has disclosed a relationship with Artsana.

  • Supplementary material related to this paper is available at http://www.rcjournal.com.

References

  1. 1.↵
    Global Initiative for Asthma. Global strategy for asthma management and prevention. Updated 2007. http://www.ginasthma.com. Accessed April 25, 2012
  2. 2.↵
    National Heart, Lung and Blood Institute. Expert panel Report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI; 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed April 25, 2012
  3. 3.↵
    1. Bacharier LB,
    2. Boner A,
    3. Carlsen KH,
    4. Eigenmann PA,
    5. Frischer T,
    6. Goetz M,
    7. et al
    . Diagnosis and treatment of asthma in childhood: the PRACTALL consensus report. Allergy 2008;63(1):5-34.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. McKean M,
    2. Ducharme F
    . Inhaled steroids for episodic viral wheeze of childhood. Cochrane Database Syst Rev 2000;(2):CD001107.
  5. 5.
    1. Bisgaard H,
    2. Hermansen MN,
    3. Loland L,
    4. Halkjaer LB,
    5. Buchvald F
    . Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006;354(19):1998-2005.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Bacharier LB,
    2. Phillips BR,
    3. Zeiger RS,
    4. Szefler SJ,
    5. Martinez FD,
    6. Lemanske RF Jr.,
    7. et al
    ; for the Childhood Asthma Research and Education Network of the National Heart, Lung and Blood Institute. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing J Allergy Clin Immunol 2008;122(6):1127-1135.
    OpenUrlCrossRefPubMed
  7. 7.
    1. Brand PL,
    2. Baraldi E,
    3. Bisgaard H
    ; on behalf of the ERS Task Force. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence based approach. Eur Respir J 2008;32(4):1096-1110.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Castro-Rodriguez JA,
    2. Rodrigo GJ
    . Efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis. Pediatrics 2009;123(2):e519-e525.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Suissa S,
    2. Barnes PJ
    . Inhaled corticosteroids in COPD: the case against. Eur Respir J 2009;34(1):13-16.
    OpenUrlFREE Full Text
  10. 10.
    1. Postma DS,
    2. Calverley P
    . Inhaled corticosteroids in COPD: a case in favour. Eur Respir J 2009;34(1):10-12.
    OpenUrlFREE Full Text
  11. 11.↵
    1. Puhan MA,
    2. Bachmann LM,
    3. Kelijnen J,
    4. ter Riet G,
    5. Kessels AG
    . Inhaled drugs to reduce exacerbations in patients with chronic obstructive pulmonary disease: a network meta-analysis. BMC Med 2009;7:2.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Rodrigo GJ
    . Inhaled corticosteroids as rescue medication in acute severe asthma. Expert Rev Clin Immunol 2008;4(6):723-729.
    OpenUrlPubMed
  13. 13.↵
    1. Dolovich MB,
    2. Ahrens RC,
    3. Hess DR,
    4. Anderson P,
    5. Dhand R,
    6. Rau JL,
    7. et al
    . Device selection and outcomes of aerosol therapy: evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest 2005;127(1):335-371.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Celli BR,
    2. MacNee W
    , committee members of ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23(6):932-946.
    OpenUrlFREE Full Text
  15. 15.↵
    Global Initiative for Chronic Obstructive Lung disease. Global strategy for the diagnosis, management and prevention of COPD. Updated 2006. http://www.goldcopd.com Accessed April 25, 2012
  16. 16.↵
    British Thoracic Society Nebuliser Project Group. Current best practice for nebuliser treatment. Thorax 1997;52(Suppl 2):S1-S24.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Boe J,
    2. Dennis JH,
    3. O'Driscoll BR,
    4. Bauer TT,
    5. Carone M,
    6. Dautzenberg B,
    7. et al
    . on behalf of a European Respiratory Society Task Force on the use of nebulizers. European Respiratory Society guidelines on the use of nebulizers. Eur Respir J 2001;18(2):228-242.
    OpenUrlFREE Full Text
  18. 18.↵
    1. Vermeire P
    . European trends in inhalation therapy. Eur Respir Rev 1994;4(18):89-91.
    OpenUrl
  19. 19.↵
    1. Lavorini F,
    2. Corrigan CJ,
    3. Barnes PJ,
    4. Dekhuijzen PR,
    5. Levy ML,
    6. Pedersen S,
    7. et al
    . on behalf of Aerosol Drug Management Improvement Team. Retail sales of inhalation devices in European countries: so much for a global policy. Respir Med 2011;105(7):1099-1103.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Melani AS,
    2. Pirrelli M,
    3. Sestini P,
    4. DelDonno M,
    5. Bonavia M,
    6. Canessa P,
    7. et al
    ; on behalf of the Associazione Italiana Pneumologi Ospedalieri Educational Group. GENebu Project. Equipment and drugs used for home nebulizer therapy in Italy. Monaldi Arch Chest Dis 2002;57(5-6):231-236.
    OpenUrlPubMed
  21. 21.↵
    1. Clavenna A,
    2. Rossi E,
    3. Berti A,
    4. Pedrazzi G,
    5. DeRosa M,
    6. Bonati M
    ; ARNO Working Group. Inappropriate use of antiasthmatic drugs in the Italian paediatric population. Eur J Clin Pharmacol 2003;59(7):565-569.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Szefler SJ
    . Clinical need for a nebulized corticosteroid. J Allergy Clin Immunol 1999;104(Suppl 4):162S-168S
    OpenUrlCrossRef
  23. 23.↵
    1. Marcus P
    . The role of nebulized inhaled corticosteroid therapy in adult patients with asthma and chronic obstructive pulmonary disease. Adv Ther 2005;22(4):407-418.
    OpenUrlPubMed
  24. 24.↵
    1. Leflein J,
    2. Brown E,
    3. Hill M,
    4. Kelly HW,
    5. Loffert TD,
    6. Nelson HS,
    7. Szefler SJ
    . Delivery of glucocorticoids by jet nebulization: aerosol characteristics and output. J Allergy Clin Immunol 1995;95(5 Pt 1):944-949.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Berlinski A,
    2. Waldrep JC
    . Aerosol characterization of nebulized intranasal glucocorticoid formulations. J Aerosol Med 2001;14(2):237-244.
    OpenUrlPubMed
  26. 26.↵
    1. Konig P,
    2. Shatley M,
    3. Levine C,
    4. Mawhinney TP
    . Clinical observations of nebulized flunisolide in infants and young children with asthma and bronchopulmonary dysplasia. Pediatr Pulmonol 1992;13(4):209-214.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Allen ED,
    2. Whitaker ER,
    3. Ryu G
    . Six-week trial of nebulized flunisolide nasal spray: efficacy in young children with moderately severe asthma. Pediatr Pulmonol 1997;24(6):397-405.
    OpenUrlPubMed
  28. 28.↵
    1. Pakes GE,
    2. Brogden RN,
    3. Heel RC,
    4. Speight TM,
    5. Avery GS
    . Flunisolide: a review of its pharmacological properties and therapeutic efficacy in rhinitis. Drugs 1980;19(6):397-441.
    OpenUrlCrossRefPubMed
  29. 29.
    1. Jarvis B,
    2. Faulds D
    . Inhaled fluticasone propionate: a review of its therapeutic efficacy at dosages ≤ 500 μcg/day in adults and adolescents with mild to moderate asthma. Drugs 1999;57(5):769-803.
    OpenUrlCrossRefPubMed
  30. 30.
    1. Berger WE
    . Budesonide inhalation suspension for the treatment of asthma in infants and children. Drugs 2005;65(14):1973-1989.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Nicolini G,
    2. Cremonesi G,
    3. Melani AS
    . Inhaled corticosteroid therapy with nebulized beclomethasone dipropionate. Pulm Pharmacol Ther 2010;23(3):145-155.
    OpenUrlPubMed
  32. 32.↵
    1. Edman P
    . Pharmaceutical formulations- suspensions and solutions. J Aerosol Med 1994;7(Suppl 1):3S-6S
    OpenUrlPubMed
  33. 33.↵
    1. Keller M,
    2. Jauernig J,
    3. Lintz FC,
    4. Knoch M
    . Nebulizer nanosuspensions: important device and formulation interactions. Respir Drug Deliver 2002;8:197-206.
    OpenUrl
  34. 34.↵
    1. Schuschnig U,
    2. Urbishek M,
    3. Luber M,
    4. Selzer T,
    5. Tiffin N,
    6. Friedrich I,
    7. Keller M
    . Comparison of delivery efficiency in a nasal cast model of fluticasone propionate suspensions and a novel solution aerosolized via the PARI Vibrent. Respir Drug 2006;11:741-743.
    OpenUrl
  35. 35.↵
    1. Knoch M,
    2. Keller M
    . The customised electronic nebuliser: a new category of liquid aerosol drug delivery systems. Expert Opin Drug Deliver 2005;2(2):377-390.
    OpenUrl
  36. 36.↵
    1. Berlinski A,
    2. Waldrep JC
    . Effect of aerosol delivery system and formulation on nebulized budesonide output. J Aerosol Med 1997;10(1):307-318.
    OpenUrl
  37. 37.
    1. Bouwman AM,
    2. Heijstra MP,
    3. Schaefer NC,
    4. Duiverman EJ,
    5. LeSouef PN,
    6. Devadeson SG
    . Improved efficiency of budesonide nebulization using surface-active agents. Drug Deliv 2006;13(5):357-363.
    OpenUrlPubMed
  38. 38.↵
    1. Amami A,
    2. Chrystyn H,
    3. Clark BJ,
    4. Abdelrahim ME,
    5. York P
    . Evaluation of supercritical fluid engineered budesonide powder for respiratory delivery using nebulisers. J Pharm Pharmacol 2009;61(12):1625-1630.
    OpenUrlPubMed
  39. 39.↵
    1. Amami A,
    2. York P,
    3. Chrystyn H,
    4. Clark BJ
    . Evaluation of a nanoemulsion-based formulation for respiratory delivery of budesonide by nebulizers. AAPS Pharm Sci Tech 2010;11:1147-1151.
    OpenUrl
  40. 40.↵
    1. Kraft WK,
    2. Steiger B,
    3. Beussink D,
    4. Quiring JN,
    5. Fitzgerald N,
    6. Greenberg HE,
    7. et al
    . The parmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers. J Clin Pharmacol 2004;44(1):67-72.
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Shrewsbury SB,
    2. Bosco AP,
    3. Uster PS
    . Pharmacokinetics of a novel submicron budesonide dispersion for nebulized delivery in asthma. Int J Pharm 2009;365(1-2):12-17.
    OpenUrlPubMed
  42. 42.↵
    1. Schuepp KG,
    2. Devadeson S,
    3. Roller C,
    4. Minocchieri S,
    5. Moeller A,
    6. Hamacher J,
    7. Wildhaber J
    . Aerosol delivery of nebulised budesonide in young children with asthma. Respir Med 2009;103(11):1738-1745.
    OpenUrlCrossRefPubMed
  43. 43.↵
    1. Basu K,
    2. Nair A,
    3. Williamson PA,
    4. Mukhopadhyay S,
    5. Lipworth B
    . Airway and systemic effects of soluble and suspension formulations of nebulized budesonide in asthmatic children. Ann Allergy Asthma Immunol 2009;103(5):436-441.
    OpenUrlPubMed
  44. 44.↵
    1. Williamson PA,
    2. Menzies D,
    3. Nair A,
    4. Tutuncu A,
    5. Lipworth BJ
    . A proof-of-concept study to evaluate the anti-inflammatory effects of a novel soluble cyclodextrin formulation of nebulised budesonide in patients with mild to moderate asthma. Ann Allergy Asthma Immunol 2009;102(2):161-167.
    OpenUrlCrossRefPubMed
  45. 45.↵
    1. Nikander K,
    2. Wunderlich E
    . Output of budesonide suspension for nebulisation using different Pari jet nebulizer-compressor situations. J Aerosol Med 1997;10(1):100S
    OpenUrl
  46. 46.↵
    1. Barry PW,
    2. O'Callaghan C
    . Drug output from nebulizers is dependent on the method of measurement. Eur Respir J 1998;12(2):463-466.
    OpenUrlAbstract
  47. 47.↵
    1. Smaldone GC,
    2. Cruz-Rivera M,
    3. Nikander K
    . In vitro determination of inhaled mass and particle distribution for budesonide nebulizing suspension. J Aerosol Med 1998;11(2):113-125.
    OpenUrlCrossRef
  48. 48.
    1. Barry PW,
    2. O'Callaghan C
    . An in vitro analysis of the output of budesonide from different nebulizers. J Allergy Clin Immunol 1999;104(6):1168-1173.
    OpenUrlCrossRefPubMed
  49. 49.↵
    1. Luangkhot J,
    2. Jauernig J,
    3. Balcke A,
    4. Lintz FC,
    5. Liening-Ewert R,
    6. Stangl R,
    7. et al
    . Characterisation of salbutamol solution compared to budesonide suspensions consisting of submicron and micrometer particles in the PARI LC STAR and a new PARI electronic nebuliser (e-Flow). Drug Deliv Lungs XI 2000:14-17.
  50. 50.
    1. O'Callaghan C,
    2. Barry JW,
    3. Kantar A
    . Analysis of the output of beclomethasone dipropionate from different nebulisers. Riv Ital Pediatr 2000;26:821-824.
    OpenUrl
  51. 51.↵
    1. Fink JB,
    2. Uster P,
    3. Simon M
    . In vitro evaluation of budesonide nebulizing suspension with a novel aerosol generator. J Aerosol Med 2001;14:387.
    OpenUrl
  52. 52.
    1. O'Callaghan C,
    2. White J,
    3. Jackson J,
    4. Barry PW,
    5. Kantar A
    . The output of flunisolide from different nebulisers. J Pharm Pharmacol 2002;54(4):565-569.
    OpenUrlCrossRefPubMed
  53. 53.↵
    1. Tservistas M,
    2. Sommer E,
    3. Knoch M,
    4. Hunziker G
    . Ultrasonic and perforated-mesh nebulizers: fundamental differences in function and performance. XIV Congress ISAM, Baltimore June 2003;P016.
  54. 54.
    1. Bosco AP,
    2. Dolovich MB
    . Improved aerosolization of suspensions using electronic micropump technology compared to conventional pneumatic nebulization. Chest 2004;126(Suppl):816S.
    OpenUrl
  55. 55.
    1. Fink JB,
    2. Simmons R
    . Nebulization of steroid suspension: an in vitro evaluation of the Aeroneb Go Nebulizer and the Pari LC Plus nebulizers. Chest 2004;126(Suppl):816S-817S.
    OpenUrl
  56. 56.↵
    1. Lintz F-C,
    2. von Opolski S,
    3. Hug M,
    4. Bucholski A,
    5. Keller M
    . Development of aqueous solubilized corticoid formulations for nebulization with a vibrating membrane nebulizer. AAPS Annual Meeting, Baltimore November 2004;1128M.
  57. 57.
    1. O'Callaghan C,
    2. White J,
    3. Jackson J,
    4. Barry PW,
    5. Kantar A
    . Delivery of nebulised budesonide is affected by nebuliser type and breathing pattern. J Pharm Pharmacol 2005;57(6):787-790.
    OpenUrlCrossRefPubMed
  58. 58.↵
    1. Smaldone GC,
    2. Berg E,
    3. Nikander K
    . Variation in pediatric aerosol delivery: importance of facemask. J Aerosol Med 2005;18(3):354-363.
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Vaghi A,
    2. Berg E,
    3. Liljedahl S,
    4. Svensson JO
    . In vitro comparison of nebulised budesonide (Pulmicort Respules) and beclomethasone dipropionate (Clenil per aerosol). Pulm Pharmacol Ther 2005;18(2):151-153.
    OpenUrlPubMed
  60. 60.
    1. Zhou Y,
    2. Ahuja A,
    3. Irvin CM,
    4. Kracko D,
    5. McDonald JD,
    6. Cheng YS
    . Medical nebulizer performance; effects of cascade impactor temperature. Respir Care 2005;50(8):1077-1108.
    OpenUrlPubMed
  61. 61.↵
    1. Akapo S,
    2. Gupta J,
    3. Martinez E,
    4. McCrea C,
    5. Ye L,
    6. Roach M
    . Compatibility and aerosol characteristics of formoterol fumarate mixed with other nebulizing solutions. Ann Pharmacother 2008;42(10):1416-1424.
    OpenUrlCrossRefPubMed
  62. 62.
    1. Bosco AP,
    2. Castillo MC,
    3. Luangvala MM
    . An in vitro evaluation of the aerosol equivalence of a generic budesonide inhalation suspension: a preliminary critique on equivalence compared to a proprietary budesonide inhalation suspension. Respir Drug Deliver 2008;2:619-622.
    OpenUrl
  63. 63.
    1. Bosco AP,
    2. Castillo MC,
    3. Luangvala
    . A novel submicron formulation of nebulized budesonide significantly improves the fine particle fraction of drug available for inhalation from various jet nebulizers compared to a marketed budesonide suspension. J Allergy Clin Immunol 2009;123(Suppl 1):S594.
    OpenUrl
  64. 64.↵
    1. Harris KW,
    2. Smaldone GC
    . Facial and ocular deposition of nebulized budesonide. Effects of face mask design. Chest 2008;133(2):482-488.
    OpenUrlCrossRefPubMed
  65. 65.
    1. Lieberman E,
    2. Bai T,
    3. Hatley R
    . Characterization of the performance of a new portable jet nebulizer system for the delivery of budesonide suspension for nebulization. Eur Respir J 2008;32:702S
    OpenUrl
  66. 66.↵
    1. O'Callaghan C,
    2. White JA,
    3. Jackson JM,
    4. Barry PW,
    5. Kantar A
    . Nebulisation of corticosteroids suspensions and solutions with a β2-agonist. J Pharm Pharmacol 2008;60(5):601-605.
    OpenUrlPubMed
  67. 67.↵
    1. Luangvala MM,
    2. Castillo MC,
    3. Bosco AP
    . A novel submicron aqueous colloid of budesonide significantly improves the aerodynamic particle sizing distribution of budesonide from various jet nebulizers compared to a marketed suspension (abstract). Am J Respir Crit Care Med 2009;179:A2769.
    OpenUrl
  68. 68.↵
    1. Berg E,
    2. Picard RJ
    . In vitro delivery of budesonide from 30 jet nebulizer/compressor combinations using infants and child breathing patterns. Respir Care 2009;54(12):1671-1678.
    OpenUrlPubMed
  69. 69.↵
    1. Melani AS
    . Effects on aerosol performances of mixing of either budesonide or beclomethasone dipropionate with albuterol and ipratropium bromide. Respir Care 2011;56(3):319-326.
    OpenUrlAbstract/FREE Full Text
  70. 70.↵
    1. Finlay WH,
    2. Stapleton KW,
    3. Zuberbuhler P
    . Predicting regional lung dosages of a nebulized suspension: Pulmicort (budesonide). Particulate Sci Technol 1997;15:243-251.
    OpenUrl
  71. 71.
    1. Finlay WH,
    2. Stapleton KW
    . Undersizing of droplets from a vented nebulizer caused by aerosol heating during transit through an Andersen impactor. J Aerosol Sci 1999;30:105-109.
    OpenUrlCrossRef
  72. 72.
    1. Jauernig J,
    2. Schuschnig U,
    3. Hug M,
    4. Keller M
    . Validation of a test set-up utilizing the 28.3 L/min Andersen Cascade Impactor (ACI) for the aerodynamic assessment of nebulized aqueous formulations. Respir Drug Delivery 2002;8:537-539.
    OpenUrl
  73. 73.↵
    1. Zhou Y,
    2. Ahuja A,
    3. Irvin CM,
    4. Kracko D,
    5. McDonald JD,
    6. Cheng YS
    . Evaluation of nebulizer performance under various humidity conditions. J Aerosol Med 2005;18(3):283-293.
    OpenUrlPubMed
  74. 74.↵
    1. Berg E,
    2. Bockstrom K,
    3. Dahlback M,
    4. Nerbrink O
    . Output and particle size distribution of Pulmicort suspension generated from MAD2 and Pariboy jet nebulisers. J Aerosol Sci 1988;19(7):1093-1096.
    OpenUrl
  75. 75.
    1. Dahlback M
    . Behavior of nebulizing solutions and suspensions. J Aerosol Med 1994;1(7 Suppl):S13-S18.
    OpenUrl
  76. 76.↵
    1. Nikander K,
    2. Turpeinen M,
    3. Wollmer P
    . The conventional ultrasonic nebulizer proved inefficient in nebulizing a suspension. J Aerosol Med 1999;12(2):47-53.
    OpenUrlPubMed
  77. 77.↵
    1. Nicolini G,
    2. Panza I
    . Nebulization of inhaled corticosteroid viscous solutions by ultrasonic nebulizer. Allergy 2002;57(Suppl 73):339S.
    OpenUrl
  78. 78.↵
    1. Dalby RN,
    2. Byron PR,
    3. Peart J,
    4. Farr SF
    1. Yoshiyama Y,
    2. Yazaki T,
    3. Arai M,
    4. Asai K,
    5. Kanke M
    . The nebulization of budesonide suspensions by a newly designed mesh nebulizer. In: Dalby RN, Byron PR, Peart J, Farr SF , editors. Respiratory drug delivery, 8th edition. Raleigh: Davis Horvood: 2002;487-489.
  79. 79.↵
    1. Vecellio L
    . The mesh nebulized: a recent technical innovation for aerosol delivery. Breathe 2006;2:253-260.
    OpenUrl
  80. 80.↵
    1. Lødrup Carlsen KC,
    2. Nikander K,
    3. Carlsen K-H
    . How much nebulised budesonide reaches infants and toddlers? Arch Dis Child 1992;67(9):1077-1079.
    OpenUrlAbstract/FREE Full Text
  81. 81.
    1. Nikander K
    . Drug delivery systems. J Aerosol Med 1994;1(7 Suppl):S19-S23.
    OpenUrl
  82. 82.↵
    1. Wennergren G,
    2. Nordvall SL,
    3. Hedlin G,
    4. Möller C,
    5. Wille S,
    6. Åsbrink-Nilsson E
    . Nebulized budesonide for the treatment of moderate to severe asthma in infants and toddlers. Acta Paediatr 1996;85(2):183-189.
    OpenUrlCrossRefPubMed
  83. 83.
    1. Vikre-Jorgensen J,
    2. Agertoft L,
    3. Pedersen S
    . Dose titration of nebulized budesonide in young children. Pediatr Pulmonol 1997;23(4):270-277.
    OpenUrlCrossRefPubMed
  84. 84.↵
    1. Agertoft L,
    2. Andersen A,
    3. Weibull E,
    4. Pedersen S
    . Systemic availability and pharmacokinetics of nebulised budesonide in preschool children. Arch Dis Child 1999;80(3):241-247.
    OpenUrlAbstract/FREE Full Text
  85. 85.↵
    1. Nikander K,
    2. Bisgaard H
    . Impact of constant and breath-synchronized nebulization on inhaled mass of nebulized budesonide in infants and children. Pediatr Pulmonol 1999;28(3):187-93.
    OpenUrlCrossRefPubMed
  86. 86.
    1. Nikander K,
    2. Turpeinen M,
    3. Wollmer P
    . Evaluation of pulsed and breath-synchronized nebulization of budesonide as a means of reducing nebulizer wastage of drug. Pediatr Pulmonol 2000;29(2):120-126.
    OpenUrlCrossRefPubMed
  87. 87.↵
    1. Nikander K,
    2. Agertoft L,
    3. Pedersen S
    . Breath-synchronized nebulization diminishes the impact of patient-device interfaces (face mask and mouthpiece) on the inhaled mass of nebulized budesonide. J Asthma 200037(5):451-459.
  88. 88.↵
    1. Geller DE,
    2. Kesser KC,
    3. Janssens HM,
    4. Tiddens HA
    . Delivery of budesonide inhalation suspension (BIS) through an infant upper airway model (abstract). Am J Respir Crit Care Med 2003;167:A508.
    OpenUrl
  89. 89.↵
    1. Westbroek J,
    2. Saarlainen A,
    3. Laher M,
    4. O'Brien J,
    5. Barnacle H,
    6. Efthimiou J
    . Oral steroid-sparing effect of two doses of nebulized fluticasone propionate and placebo in patients with severe chronic asthma. Respir Med 1999;93(9):689-699.
    OpenUrlCrossRefPubMed
  90. 90.↵
    1. Smaldone GC,
    2. McKenzie J,
    3. Cruz-Rivera M
    . Effects of nebulized volume on drug delivery: budesonide inhalation suspension (abstract). Am J Respir Crit Care Med 2000;161;(Suppl 3):A36.
    OpenUrl
  91. 91.↵
    1. Malpass J,
    2. Nagel M,
    3. Doyle C,
    4. Ali R,
    5. Avvakoumova V,
    6. Mitchell Y
    . A breath actuated jet nebulizer has dosimetric capability for a suspension formulation based on differing volume fill of medication as well as run time. Eur Respir J 2010;36(Suppl):54.
    OpenUrl
  92. 92.↵
    1. Rosenfeld M,
    2. Emerson J,
    3. Astley S,
    4. Joy P,
    5. Williams-Warren J,
    6. Standaert TA,
    7. et al
    . Home nebulizer use among patients with cystic fibrosis J Pediatr 1998;132(1):125-131.
    OpenUrlCrossRefPubMed
  93. 93.
    1. Pujol MS,
    2. Menat C,
    3. Henon T,
    4. Jacquet M,
    5. Woronoff Lemsi MC
    . [Prescriptions of aerosol therapy. A survey of practices at the Besançon University Hospital]. Presse Med 2000;29:824-828. Article in French.
    OpenUrlPubMed
  94. 94.↵
    1. Salles M,
    2. deMonte M,
    3. Dubus JC,
    4. Diot P
    . [Nebulized corticosteroids and pediatricians: results of the NUAGES survey]. Arch Pediatr 2008;15:1520-1524. Article in French.
    OpenUrlPubMed
  95. 95.↵
    1. Gronberg S,
    2. Magnusson P,
    3. Bladh N
    . Chemical compatibility of budesonide inhalation suspension (Pulmicort) with other nebulization products (abstract). Am J Respir Crit Care Med 2001;163:A588.
    OpenUrl
  96. 96.
    1. McKenzie JE,
    2. Cruz-Rivera M
    . Compatibility of budesonide inhalation suspension with four nebulizing solutions. Ann Pharmacother 2004;38(6):967-972.
    OpenUrlCrossRefPubMed
  97. 97.
    1. Kamin W,
    2. Schwabe A,
    3. Kramer I
    . Physicochemical compatibility of fluticasone-17-propionate nebulizer suspension with ipratropium and albuterol nebulizer solutions. Int J COPD 2007;2(4):599-607.
    OpenUrl
  98. 98.
    1. Bonasia PJ,
    2. McVicar WK,
    3. Williams B,
    4. Ong S
    . Chemical and physical compatibility of levoalbuterol inhalation solution concentrate mixed with budesonide, ipratropium bromide, cromolyn sodium, or acetylcysteine sodium. Respir Care 2008;53(12):1716-1722.
    OpenUrlAbstract/FREE Full Text
  99. 99.↵
    1. Bonasia P,
    2. Cook C,
    3. Cheng Y,
    4. Ong S
    . Compatibility of arformoterol tartrate inhalation solution with three nebulized drugs. Curr Med Res Opin 2007;23(10):2477-2483.
    OpenUrlCrossRefPubMed
  100. 100.↵
    1. Berlinski A,
    2. Waldred JC
    . Nebulized drug admixtures: effect on aerosol characteristics and albuterol output. J Aerosol Med 2006;19(4):484-490.
    OpenUrlCrossRefPubMed
  101. 101.↵
    1. DiBerardino,
    2. Scaglione F
    . Mixing albuterol and corticosteroid is not additive. Allergy 1999;54(9):1012-1013.
    OpenUrlPubMed
  102. 102.↵
    1. Brattsand R
    . Development of inhaled steroids: past, present and prospects. Respir Drug Deliver 2002;8:1-14.
    OpenUrl
  103. 103.
    1. Derendorf H,
    2. Nave R,
    3. Drollmann A,
    4. Cerasoli F,
    5. Wurst W
    . Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eur Respir J 2006;28(5):1042-50.
    OpenUrlAbstract/FREE Full Text
  104. 104.
    1. Winkler J,
    2. Hochhaus G,
    3. Derenderf H
    . How the lung handles drugs. Pharmacokinetics and pharmacodynamics of inhaled corticosteroids. Proc Am Thorac Soc 2004;1:356-363.
    OpenUrlCrossRefPubMed
  105. 105.
    1. Gulliver T,
    2. Morton R,
    3. Eid N
    . Inhaled corticosteroids in children with asthma: pharmacological determinants of safety and efficacy and other clinical considerations. Paediatr Drugs 2007;9(3):185-194.
    OpenUrlCrossRefPubMed
  106. 106.↵
    1. Kantar A,
    2. Mroueh S,
    3. Fiocchi A
    . A reappraisal of the clinical efficacy of nebulized flunisolide in pediatric asthma: the Italian experience. Allergy Asthma Proc 2007;28(6):571-587.
    OpenUrlCrossRefPubMed
  107. 107.↵
    1. Dahlstrom K,
    2. Thorsson L,
    3. Larsson P,
    4. Nikander K
    . Systemic availability and lung deposition of budesonide via three different nebulizers in adults. Ann Allergy Asthma Immunol 2003;90(2):226-232.
    OpenUrlPubMed
  108. 108.↵
    1. Schuepp KG,
    2. Devadeson S,
    3. Roller C,
    4. Wildhaber JH
    . A complementary combination of delivery device and drug formulation for inhalation therapy in preschool children. Swiss Med Wkly 2004;134(13-14):198-200.
    OpenUrlPubMed
  109. 109.↵
    1. Bisgaard H,
    2. Nikander K,
    3. Munch E
    . Comparative study of budesonide as a nebulized suspension vs pressurized meter-dose inhaler in adult asthmatics. Respir Med 1998;92(1):44-49.
    OpenUrlCrossRefPubMed
  110. 110.↵
    1. Murphy K,
    2. Noonan M,
    3. Silkoff PE,
    4. Uryniak T
    . A 12-week multicenter, randomized, partially blinded, parallel-group study of budesonide inhalation suspension in adolescents and adults with moderate to severe persistent asthma previously receiving inhaler corticosteroids with metered-dose or dry powder inhaler. Clin Ther 2007;29(6):1013-1026.
    OpenUrlPubMed
  111. 111.↵
    1. Poli G.,
    2. Acerbi D
    . Comparison of the bioavailability and systemic effects of beclomethasone dipropionate suspension for nebulization and beclomethsone dipropionate via a metered-dose inhaler after single-dose administration in healthy male volunteers. Respir Med 2003;97(Suppl B):S5-S9.
    OpenUrlPubMed
  112. 112.↵
    1. Haathela T,
    2. Jarvinen M,
    3. Kava T,
    4. Kiviranta K,
    5. Koskinen S,
    6. Lehtonen K,
    7. et al
    . Comparison of a beta2-agonist, terbutaline, with an inhaled corticosteroid, Budesonide in newly detected asthma N Engl J Med 1991;325(6):388-392.
    OpenUrlCrossRefPubMed
  113. 113.↵
    1. Baker J,
    2. Mellon M,
    3. Wald J,
    4. Welch M,
    5. Cruz-Rivera M,
    6. Walton-Bowen K
    . A multiple-dosing, placebo-controlled study of budesonide nebulizing suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999;103(2):414-421.
    OpenUrlAbstract/FREE Full Text
  114. 114.
    1. Juniper EF,
    2. Kline PA,
    3. Vanzielghem MA,
    4. Ramsdale EH,
    5. O'Byrne PM,
    6. Hargreave FE
    . Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990;142(4):832-836.
    OpenUrlCrossRefPubMed
  115. 115.
    1. Waalkens HJ,
    2. van Essen-Zandvliet EE,
    3. Hughes MD,
    4. Gerritsen J,
    5. Duiverman EJ,
    6. Knol K,
    7. et al
    . Cessation of long-term treatment with inhaled corticosteroid (budesonde) in children with asthma results in deterioration. Am Rev Respir Dis 1993;148(5):1252-1257.
    OpenUrlPubMed
  116. 116.
    1. Haathela T,
    2. Jarvinen M,
    3. Kava T,
    4. Kiviranta K,
    5. Koskinen S,
    6. Lehtonen K,
    7. et al
    . Effects of reducing or discontinuiing inhaled budesonide in patients with mild asthma. N Engl J Med 1994;331(10):700-705.
    OpenUrlCrossRefPubMed
  117. 117.↵
    1. Grimfeld A,
    2. Lesbros D,
    3. Ostinelli J,
    4. Caswell C
    . Long term study of nebulized budesonide in young children with moderate to severe asthma. Eur Respir J 1994;7(Suppl 18):27S
    OpenUrl
  118. 118.↵
    1. Pauwels RA,
    2. Lofdahl C-G,
    3. Postma DS,
    4. Tattersfield,
    5. O'Byrne P,
    6. Barnes P,
    7. Ullman A
    , for the Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. Effect of Inhaled Formoterol and Budesonide on Exacerbations of Asthma. N Engl J Med 1997;337(20):1405-1411.
    OpenUrlCrossRefPubMed
  119. 119.↵
    1. Szefler SJ,
    2. Martin RJ,
    3. King TS,
    4. Boushey HA,
    5. Cherniack RM,
    6. Chinchilli VM,
    7. et al
    . Significant variability in response to inhaled corticosteroid for persistent asthma. J Allergy Clin Immunol 2002;109(3):410-418.
    OpenUrlCrossRefPubMed
  120. 120.↵
    1. Bateman ED,
    2. Boushey HA,
    3. Bousquet J,
    4. Busse WW,
    5. Clark TJH,
    6. Pauwels RA,
    7. Pedersen SE
    , for the GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL Study. Am J Respir Crit Care Med 2004;170(8):836-844.
    OpenUrlCrossRefPubMed
  121. 121.↵
    1. Masoli M,
    2. Holt S,
    3. Weatherall M,
    4. Beasley R
    . Dose-response relationship of inhaled budesonide in adult asthma: a meta-analysis. Eur Respir J 2004;23(4):552-558.
    OpenUrlAbstract/FREE Full Text
  122. 122.↵
    1. Masoli M,
    2. Weatherall M,
    3. Holt S,
    4. Beasley R
    . Systematic review of the dose–response relation of inhaled fluticasone propionate. Arch Dis Child 2004;89(10):902-907.
    OpenUrlAbstract/FREE Full Text
  123. 123.↵
    1. O'Byrne PM,
    2. Bisgaard H,
    3. Godard PP,
    4. Pistolesi M,
    5. Palmqvist M,
    6. Zhu Y,
    7. et al
    . Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005;171(2):129-136.
    OpenUrlCrossRefPubMed
  124. 124.↵
    1. Beasley R,
    2. Sterk PJ,
    3. Kerstjens HA,
    4. Decramer M
    . Comparative studies of inhaled corticosteroids in asthma. Eur Respir J 2001;17(4):579-580.
    OpenUrlFREE Full Text
  125. 125.↵
    1. Piacentini GL,
    2. Sette L,
    3. Peroni DG,
    4. Bonizzato C,
    5. Bonetti S,
    6. Boner AL
    . Double-blind evaluation of effectiveness and safety of flunisolide aerosol for treatment of bronchial asthma in children. Allergy 1990;45(8):612-616.
    OpenUrlCrossRefPubMed
  126. 126.
    1. van Bever HP,
    2. Schuddinck L,
    3. Wojciechowski M,
    4. Stevens JW
    . Aerosolised budesonide in asthmatic infants: a double blind study. Pediatr Pulmonol 1990;9(3):177-180.
    OpenUrlPubMed
  127. 127.
    1. Ilangovan P,
    2. Pedersen P,
    3. Godfrey S,
    4. Nikander K,
    5. Noviski N,
    6. Warner JO
    . Treatment of severe steroid dependent preschool asthma with nebulised budesonide suspension. Arch Dis Child 1993(3):68:356-359.
    OpenUrlAbstract/FREE Full Text
  128. 128.↵
    1. DeBenedictis FM,
    2. Martinati LC,
    3. Solinas LF,
    4. Tuteri G,
    5. Boner AL
    . Nebulized flunisolide in infants and young children with asthma: a pilot study. Pediatr Pulmonol 1996;21(5):310-315.
    OpenUrlPubMed
  129. 129.
    1. DeBlic J,
    2. Delacourt C,
    3. LeBourgeois M,
    4. Mahut B,
    5. Ostinelli J,
    6. Caswell C,
    7. Scheinmann P
    . Efficacy of nebulized budesonide in treatment of severe infantile asthma: a double-blind study. J Allergy Clin Immunol 1996;98(1):14-20.
    OpenUrlCrossRefPubMed
  130. 130.↵
    1. Shapiro G,
    2. Bronsky EA,
    3. LaForce CF,
    4. Mendelson L,
    5. Pearlman D,
    6. Schwartz RH,
    7. Szefler SJ
    . Dose-related efficacy of budesonide administered via dry powder inhaler in the treatment of children with moderate to severe persistent asthma. J Pediatr 1998;132(6):976-982.
    OpenUrlCrossRefPubMed
  131. 131.↵
    1. Kemp JP,
    2. Skoner DP,
    3. Szefler SJ,
    4. Walton-Bowen K,
    5. Cruz-Rivera M,
    6. Smith JA
    . Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999;83(3):231-239.
    OpenUrlPubMed
  132. 132.
    1. Melani AS,
    2. DiGregorio A
    . Four-week nebulized beclomethasone dipropionate in stable COPD patients with exertional dyspnoea. Monaldi Arch Chest Dis 1999;54(3):224-227.
    OpenUrlPubMed
  133. 133.↵
    1. Piacentini GL,
    2. Bodini A,
    3. Costella S,
    4. Vicentini L,
    5. Mazzi P,
    6. Suzuki Y,
    7. et al
    . Exhaled nitric oxide in asthmatic children exposed to relevant allergens: effect of flunisolide. Eur Respir J 2000;15(4):730-734.
    OpenUrlAbstract
  134. 134.
    1. Berger WE,
    2. Qaqundah PY,
    3. Blake K,
    4. Rodriguez-Santana J,
    5. Irani AM,
    6. Xu J,
    7. Goldman M
    . Safety of budesonide inhalation suspension in infants aged six to twelve months with mild to moderate persistent asthma or recurrent wheeze. J Pediatr 2005;146(1):91-95.
    OpenUrlCrossRefPubMed
  135. 135.↵
    1. Bodini A,
    2. Peroni DG,
    3. Zardini F,
    4. Corradi M,
    5. Alinovi R,
    6. Boner AL,
    7. Piacentini GL
    . Flunisolide decreases exhaled nitric oxide and nitrotyrosine levels in asthmatic children. Mediators Inflamm 2006;2006(4):31919.
    OpenUrlPubMed
  136. 136.↵
    1. Paggiaro PL,
    2. Vagaggini B,
    3. DiFranco A,
    4. Zingoni M,
    5. Fano M,
    6. Biraghi M
    , on behalf of the COGNE Study group. Efficacy of nebulized flunisolide combined with salbutamol and ipratropium bromide in stable patients with moderate-to-severe chronic obstructive pulmonary disease. Respiration 2006;73(5):603-606.
    OpenUrlPubMed
  137. 137.↵
    1. Papi A,
    2. Nicolini G,
    3. Baraldi E,
    4. Boner AL,
    5. Cutrera R,
    6. Rossi GA,
    7. Fabbri LM
    , on behalf of the Beclomethasone and Salbutamol Treatment (BEST) for Children Study group. Regular vs prn nebulized treatment in wheeze preschool children. Allergy 2009;64(10):1463-1471.
    OpenUrlCrossRefPubMed
  138. 138.↵
    1. Scott MB,
    2. Skoner DP
    . Short-term and long-term safety of budesonide inhalation suspension in infants and young children with persistent asthma. J Allergy Clin Immunol 1999;104(4 Pt 2):200S-209S
    OpenUrlCrossRef
  139. 139.↵
    1. Cetinkaya F,
    2. Kayiran P,
    3. Memioglu N,
    4. Tarim OF,
    5. Eren N,
    6. Erdem E
    . Effects of nebulized corticosteroids on hypothalamic-pituitary-adrenal axis in young children with recurrent or persistent wheeze. Pediatr Allergy Immunol 2008;19:773-776.
    OpenUrlPubMed
  140. 140.↵
    1. Skoner DP,
    2. Szefler SJ,
    3. Welch M,
    4. Walten-Bowen K,
    5. Cruz-Rivera M,
    6. Smith JA
    . Longitudinal growth in infants and young children treated with budesonide inhalation suspension for persistent asthma. J Allergy Clin Immunol 2000;105(2):259-268.
    OpenUrlCrossRefPubMed
  141. 141.↵
    1. Agertoft L,
    2. Pedersen S
    . Effect of long term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;343(15):1064-1069.
    OpenUrlCrossRefPubMed
  142. 142.
    Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343(15):1054-1063.
    OpenUrlCrossRefPubMed
  143. 143.
    1. Guilbert TW,
    2. Morgan WJ,
    3. Zeiger RS,
    4. Mauger DT,
    5. Boehmer SJ,
    6. Szefler SJ,
    7. et al.
    , Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354(19):1985-1997.
    OpenUrlCrossRefPubMed
  144. 144.↵
    1. Murray CS,
    2. Woodcock A.,
    3. Langley SJ,
    4. Morris J,
    5. Custovic A
    . Secondary prevention of asthma by the use of inhaled fluticasone proprionate in wheezy infants: double-blind randomized, controlled study. Lancet 2006;368(9537):754-762.
    OpenUrlCrossRefPubMed
  145. 145.↵
    1. Cruz-Rivera M,
    2. Lyzell E,
    3. Fitzpatrick S
    . Low frequency of adverse events reported through postmarketing surveillance for Pulmicort Respules (budesonide inhalation suspension) in the US adult population. J All Clin Immunol 2002;109(Suppl 292):abstract 895.
  146. 146.↵
    1. Lyzell E,
    2. Cruz-Rivera M,
    3. Fitzpatrick S
    . Safety of Pulmicort Respules (budesonide inhalation suspension) in geriatric patients: postmarketing surveillance and clinical study data. J All Clin Immunol 2002;109(Suppl 292):abstract 894.
  147. 147.↵
    1. Greenberger PA,
    2. Patterson R
    . Beclomethasone dipropionate for severe asthma during pregnancy. Ann Intern Med 1983;98(4):478-480.
    OpenUrlPubMed
  148. 148.
    1. Ericson A,
    2. Kallen B
    . Use of drugs during pregnancy-unique Swedish registration method that can be improved. Information from the Swedish Medical Products Agency 1999;1:8-11.
    OpenUrl
  149. 149.
    1. Kallen B,
    2. Rydhstroem H,
    3. Aberg A
    . Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999;93:392-395.
    OpenUrlCrossRefPubMed
  150. 150.↵
    1. Norjavaara E,
    2. Gerhardsson de Verdier M
    . Normal pregnancy outcomes in a population based study including 2968 pregnant women exposed to budesonide. J Allergy Clin Immunol 2003;111(1):736-742.
    OpenUrlCrossRefPubMed
  151. 151.↵
    1. Sangwan S,
    2. Gurses BK,
    3. Smaldone GC
    . Facemasks and facial deposition of aerosols. Pediatr Pulmonol 2004;37(5):447-452.
    OpenUrlCrossRefPubMed
  152. 152.↵
    1. Szefler SJ,
    2. Fitzpatrick S,
    3. Cruz-Rivera M,
    4. Lyzell E
    . Lack of cataracts and other localized adverse events in children treated with nebulized Pulmicort Respules [Budesonide inhalation suspension] (abstract). Am J Respir Crit Care Med 2001;163:A589.
    OpenUrl
  153. 153.↵
    1. Peters SP
    . Safety of inhaled corticosteroids in the treatment of persistent asthma. J Nat Med Assoc 2006;98(6):851-861.
    OpenUrlPubMed
  154. 154.↵
    1. Pedersen S,
    2. Hansen OR
    . Dose-response relationships to nebulized budesonide in children with asthma (abstract). Am J Respir Crit Care Med 1997;155(2 part 2):A268.
    OpenUrl
  155. 155.
    1. Volovitz B,
    2. Soferman R,
    3. Blau H,
    4. Nussinovitch M,
    5. Varsano I
    . Rapid induction of clinical response with a short-term high-dose starting schedule of budesonide nebulizing suspension in young children with recurrent wheezing episodes. J Allergy Clin Immunol 1998;101(4):464-469.
    OpenUrlCrossRefPubMed
  156. 156.
    1. Lødrup Carlsen KC,
    2. Carlsen K-H,
    3. Nikander K,
    4. Leegaard J,
    5. Havnen J,
    6. Steen-Johnsen J,
    7. Winsness A
    . Nebulized budesonide after hospitalization for recurrent bronchial obstruction in children younger than 18 months. Pediatr Allergy Immunol 2001;12(3):159-165.
    OpenUrlCrossRefPubMed
  157. 157.
    1. Price J,
    2. Lenney W,
    3. Duncan C,
    4. Green L,
    5. Flood Y,
    6. Daley-Yates P,
    7. et al
    . HPA-axis effects of nebulised fluticasone propionate compared with oral prednisolone in childhood asthma. Respir Med 2002;96(8):625-631.
    OpenUrlPubMed
  158. 158.↵
    1. Bisca N,
    2. Cernatescu I,
    3. Dragomir D,
    4. Iacomi A,
    5. Mirceau M,
    6. Orascanu D
    . Comparison of the efficacy and safety of beclometasone dipropionate suspension for nebulization and beclometasone dipropionate via a metered-dose inhaler in paediatric patients with moderate to severe exacerbation of asthma. Respir Med 2003;97(Suppl. B):S15-S20.
    OpenUrl
  159. 159.
    1. Bousquet J,
    2. Meziane H,
    3. Chanez P,
    4. Mueser M,
    5. Umile A
    . The response of two different dosages of beclometasone dipropionate suspension for nebulization versus a standard dose of beclometasone dipropionate via a metered-dose inhaler on bronchoprovocation testing in adults with asthma. Respir Med 2003;97(Suppl B):S11-S14.
    OpenUrlPubMed
  160. 160.↵
    1. Grzelewska-Rzymowska I,
    2. Kroczynska-Bednarek J,
    3. Zarkovic J
    . Comparison of the efficacy and safety of high doses of beclometasone dipropionate suspension for nebulization and beclometasone dipropionate via a metered-dose inhaler in steroid-dependent adults with moderate to severe asthma. Respir Med 2003;97(Suppl B):S21-S26.
    OpenUrlPubMed
  161. 161.
    1. Volovitz B,
    2. Nussinovitch M
    . Effect of high starting dose of budesonide inhalation suspension on serum cortisol concentration in young children with recurrent wheezing episodes. J Asthma 2003;40(6):625-629.
    OpenUrlPubMed
  162. 162.
    1. DeBenedictis FM,
    2. Del Giudice MM,
    3. Vetrella M,
    4. Tressanti F,
    5. Tronci A,
    6. Testi R,
    7. Dasic G
    , FLIC12 Study Group. Nebulized fluticasone proprionate vs budesonide as adjunctive treatment in children with asthma exacerbation. J Asthma 2005;42(5):331-336.
    OpenUrlPubMed
  163. 163.
    1. Zielen S,
    2. Rose MA,
    3. Bez C,
    4. Jarisch A,
    5. Reichenbach J,
    6. Hofmann D
    . Effectiveness of budesonide nebulising suspension compared to disodium cromoglycate in early childhood asthma. Curr Med Res Opin 2006;22(2):367-373.
    OpenUrlPubMed
  164. 164.
    1. La Grutta S,
    2. Nicolini G,
    3. Capristo C,
    4. Bellodi SC,
    5. Rossi GA
    . Once daily nebulized beclomethasone is effective in maintaining pulmonary function and improving symptoms in asthmatic children. Monaldi Arch Chest Dis 2007;67(1):30-38.
    OpenUrlPubMed
  165. 165.↵
    1. Decimo F,
    2. Maiello N,
    3. Miraglia Del Giudice M,
    4. Amelio R,
    5. Capristo C,
    6. Capristo AF
    . High-dose inhaled flunisolide versus budesonide in the treatment of acute asthma exacerbations in preschool-age children. Int J Immunopathol Pharmacol 2009;22(2):363-370.
    OpenUrlAbstract/FREE Full Text
  166. 166.↵
    1. Storr J,
    2. Lenney CA,
    3. Lenney W
    . Nebulised beclomethasone dipropionate in preschool asthma. Arch Dis Child 1986;61(3):270-273.
    OpenUrlAbstract/FREE Full Text
  167. 167.
    1. Webb MCS,
    2. Milner AD,
    3. Hiller EJ,
    4. Henry RL
    . Nebulised beclomethasone dipropionate suspension. Arch Dis Child 1986;61(11):1108-1110.
    OpenUrlAbstract/FREE Full Text
  168. 168.↵
    1. Pedersen W,
    2. Prahl P
    . Jet-nebulized beclomethasone dipropionate in the management of bronchial asthma. Topical steroids for asthmatic children younger than 4 years. Allergy 1987;42(2):272-275.
    OpenUrlCrossRefPubMed
  169. 169.↵
    1. O'Callaghan C
    . Particle size of beclomethasone dipropionate produced by two nebulisers and two spacing devices. Thorax 1990;45(2):109-111.
    OpenUrlAbstract/FREE Full Text
  170. 170.↵
    1. Wales D,
    2. Makker H,
    3. Kane J,
    4. McDowell P,
    5. O'Driscoll BR
    . Systemic bioavailability and potency of high-dose inhaled corticosteroids. A comparison of four inhaler devices and three drugs in healthy adult volunteers. Chest 1999;115(5):1278-1284.
    OpenUrlCrossRefPubMed
  171. 171.↵
    1. Dempsey OJ,
    2. Humphreys M,
    3. Coutie WJ,
    4. Lipworth BJ
    . Relative lung delivery of fluticasone propionate via large volume spacer or nebuliser in healthy volunteers. Eur J Clin Pharmacol 2001;57(9):637-641.
    OpenUrlPubMed
  172. 172.↵
    1. Mendelson L,
    2. Cook D,
    3. Cruz-Rivera M,
    4. Fitzpatrick S,
    5. Smith JA
    . Twice-daily budesonide inhalation suspension in infants and children <4 and > or = 4 years of age with persistent asthma. J Asthma 2002;39(3):227-237.
    OpenUrlPubMed
  173. 173.↵
    1. Daugbjerg P,
    2. Brenoe E,
    3. Forchhammer H,
    4. Frederiksen B,
    5. Glazowski MJ,
    6. Ibsen Kaas K,
    7. et al
    . A comparison between nebulized terbutaline, nebulized corticosteroid and systemic corticosteroid for acute wheezing in children up to 18 months of age. Acta Paediatr 1993;82(6-7):547-551.
    OpenUrlPubMed
  174. 174.↵
    1. Bautista MS,
    2. Balderas J
    . The efficacy of combined inhaled steroids and β2 agonist in the treatment of acute asthma in children 6-18 years of age versus inhaled β2 agonist alone. Eur Respir J 1994;7(Suppl 18):93S.
    OpenUrl
  175. 175.
    1. Sung L,
    2. Osmond MH,
    3. Klassen TP
    . Randomized, controlled trial of inhaled budesonide as an adjunct to oral prednisone in acute asthma. Acad Emerg Med 1998;5(3):209-213.
    OpenUrlPubMed
  176. 176.↵
    1. Tsai YG,
    2. Lee MY,
    3. Yang KD,
    4. Chu DM,
    5. Yuh YS,
    6. Hung CH
    . A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma. J Pediatr 2001;139(3):433-437.
    OpenUrlCrossRefPubMed
  177. 177.↵
    1. Maltais F,
    2. Ostinelli J,
    3. Bourbeau J,
    4. Tonnel AB,
    5. Jacquemet N,
    6. Haddon J,
    7. et al
    . Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med 2002;165(5):698-703.
    OpenUrlCrossRefPubMed
  178. 178.↵
    1. Milani GKM,
    2. Rosario Filho NA,
    3. Riedi CA,
    4. Figueiredo BC
    . Nebulized budesonide to treat acute asthma in children. Jornal de Pediatria 2004;80(2):106-112.
    OpenUrlPubMed
  179. 179.↵
    1. Estrada-Reyes E,
    2. Del Rio Navarro BE,
    3. Rosas-Vargas MA,
    4. Nava-Ocampo AA
    . Co-administration of salbutamol and fluticasone for emergency treatment of children with moderate acute asthma. Paediatr Allergy Immunol 2005;16(7):609-614.
    OpenUrlCrossRefPubMed
  180. 180.↵
    1. Nuhoglu Y,
    2. Atas E,
    3. Nuhoglu C,
    4. Iscan M,
    5. Ozcay S
    . Acute effect of nebulized budesonide in asthmatic children. J Invest Allerg Clin Immunol 2005;15(3):197-200.
    OpenUrlPubMed
  181. 181.↵
    1. Sekerel BE,
    2. Sackesen C,
    3. Tuncer A,
    4. Adalioglu G
    . The effect of nebulized budesonide treatment in children with mild to moderate exacerbations of asthma. Acta Paediatr 2005;94(10):1372-1377.
    OpenUrlCrossRefPubMed
  182. 182.↵
    1. Gunen H,
    2. Hacievliyagil SS,
    3. Yetkin O,
    4. Golbas G,
    5. Cem L,
    6. In E
    . The role of nebulized budesonide in the treatment of exacerbations of COPD. Eur Respir J 2007;29(4):660-667.
    OpenUrlAbstract/FREE Full Text
  183. 183.↵
    1. Camargo CA Jr..,
    2. Rachelefsky G,
    3. Schatz M
    . Managing asthma exacerbations in the emergency department: Summary of the National Asthma Education and Prevention Program Export Panel Report 3 guidelines for the management of asthma exacerbations. J Allergy Clin Immunol 2009;124(Suppl 2):S5-S14.
    OpenUrlPubMed
  184. 184.↵
    1. Henzen C,
    2. Suter A,
    3. Lerch E,
    4. Urbinelli R,
    5. Schorno XH,
    6. Briner VA
    . Suppression and recovery of adrenal response after short-term high-dose glucocrticoid treatment. Lancet 2000;355(9203):542-545.
    OpenUrlCrossRefPubMed
  185. 185.↵
    1. Ducharme FM,
    2. Ochs HD,
    3. Resendes S,
    4. Zhang X,
    5. Mazer DB
    . A short burst of oral corticosteroid for children with acute asthma: is there an impact on immunity? Pediatric Allergy Immunology Pulmonogy 2010;23(4):243-252.
    OpenUrl
  186. 186.↵
    1. Mitchell CA,
    2. Alpers JH,
    3. Morton SM,
    4. Baggoley CJ,
    5. Croker WD,
    6. Walsh AJ,
    7. et al
    . Comparison of nebulized budesonide with oral prednisolone in the treatment of severe acute asthma. Eur Respir J 1995;8(Suppl):490S.
    OpenUrl
  187. 187.
    1. Francis P,
    2. Geelhoed G,
    3. Harris MA,
    4. Morton J,
    5. Efthimiou J,
    6. Barnacle H
    . Effect of nebulised fluticasone propionate 1 mg twice daily compared with oral prednisolone in pre-school chidren aged 48 months or less with an acute exacerbation of asthma. Eur Respir J 1997;10(Suppl 25):275S.
    OpenUrl
  188. 188.
    1. Winter JH,
    2. Dhillon DP,
    3. Winter JE,
    4. Feeney Y,
    5. Allen D,
    6. Maslen T
    . Effect of the early substitution of nebulised fluticasone propionate 2 mg bd for oral prednisolone 50 mg od in adults during the early recovery period of an acute exacerbation of asthma. Eur Respir J 1997;10:174S.
    OpenUrl
  189. 189.
    1. Devidayal,
    2. Singhi S,
    3. Kumar L,
    4. Jayshree M
    . Efficacy of nebulized budesonide compared to oral prednisolone in acute bronchial asthma. Acta Paediatr 1999;88(8):835-840.
    OpenUrlCrossRefPubMed
  190. 190.
    1. Matthews EE,
    2. Curtis PD,
    3. McLain BI,
    4. Morris LS,
    5. Turbitt ML
    . Nebulized budesonide verus oral steroid in severe exacerbations of childhood asthma. Acta Paediatr 1999;88(8):841-843.
    OpenUrlCrossRefPubMed
  191. 191.
    1. Manjra AI,
    2. Price J,
    3. Lenney W,
    4. Hughes S,
    5. Barnacle H
    . Efficacy of nebulized fluticasone propionate compared with oral prednisolone in children with an acute exacerbation of asthma. Respir Med 2000;94(12):1206-1214.
    OpenUrlCrossRefPubMed
  192. 192.↵
    1. Sano F,
    2. Cortez GK,
    3. Sole D,
    4. Naspitz CK
    . Inhaled budesonide for the treatment of acute wheezing and dyspnea in children up to 24 months old receiving intravenous hydrocortisone. J Allergy Clin Immunol 2000;105(4):699-703.
    OpenUrlCrossRefPubMed
  193. 193.↵
    1. Razi CH,
    2. Turktas I,
    3. Bakirtas A
    . Comparison of single 2000-μg dose treatment vs sequential repeated-dose 500-μg treatments with nebulized budesonide in acute asthma exacerbations. Ann Allergy Asthma Immunol 2008;100(4):370-376.
    OpenUrlPubMed
  194. 194.↵
    1. Wilson AM,
    2. McFarlane LC,
    3. Lipworth BJ
    . Systemic bioactivity profiles of oral prednisolone and nebulized budesonide in adult asthmatics. Chest 1998;114(4):1022-1027.
    OpenUrlCrossRefPubMed
  195. 195.↵
    1. Rhen T,
    2. Cidlowski JA
    . Antiinflammatory action of glucocorticoids: new mechanisms for old drugs. N Engl J Med 2005;353(16):1711-1723.
    OpenUrlCrossRefPubMed
  196. 196.
    1. Horvath G,
    2. Wanner A
    . Inhaled corticosteroids: effects of the airways vasculature in bronchial asthma. Eur Respir J 2006;27(1):182-187.
    OpenUrl
  197. 197.↵
    1. Belda J,
    2. Margarit G,
    3. Martinez C,
    4. Bellido-Casado J,
    5. Casan P,
    6. Torrejón M,
    7. et al
    . Anti-inflammatory effects of high-dose inhaled fluticasone versus oral prednisolone in asthma exacerbations. Eur Respir J 2007;30(6):1143-1149.
    OpenUrlAbstract/FREE Full Text
  198. 198.↵
    1. Rodrigo GJ
    . Rapid effects of inhaled corticosteroids in acute asthma. An evidence-based evaluation. Chest 2006;130(5):1301-1311.
    OpenUrlCrossRefPubMed
  199. 199.
    1. Edmonds ML,
    2. Camargo CA Jr.,
    3. Brenner B,
    4. Rowe BH
    . Inhaled steroids in acute asthma following emergency department discharge. Cochrane Database Syst Rev 2000;3:CD002316.
    OpenUrlPubMed
  200. 200.
    1. Edmonds ML,
    2. Camargo CA Jr.,
    3. Pollack CV Jr.,
    4. Rowe BH
    . Early use of inhaled corticosteroids in the emergency department treatment of acute asthma. Cochrane Database Syst Rev 2003;(3):CD002308.
  201. 201.↵
    1. Volovitz B
    . Inhaled budesonide in the management of acute worsenings and exacerbations of asthma: a review of the evidence. Respir Med 2007;101(4):685-695.
    OpenUrlCrossRefPubMed
  202. 202.↵
    1. Parkin PC,
    2. Saunders NR,
    3. Diamond SA,
    4. Winders PM,
    5. Macarthur C
    . Randomised trial spacer v. nebuliser for acute asthma. Arch Dis Child 1995;72(3):239-240.
    OpenUrlAbstract/FREE Full Text
  203. 203.↵
    1. Mason N,
    2. Roberts N,
    3. Yard N,
    4. Partridge MR
    . Nebulisers or spacers for the administration of bronchodilators to those with asthma attending emergency departments? Respir Med 2008;102(7):993-998.
    OpenUrlCrossRefPubMed
  204. 204.↵
    1. Melani AS,
    2. Sestini P,
    3. Aiolfi S,
    4. Barbato N,
    5. Canessa P,
    6. DeAngelis G,
    7. et al
    ; on behalf of the Associazione Italiana Pneumologi Ospedalieri (AIPO) Educational Group. GENebu Project: home nebulizer use and maintenance in Italy. Eur Respir J 2001;18(4):758-763.
    OpenUrlAbstract/FREE Full Text
  205. 205.↵
    1. Rachelefsky G
    . Inhaled corticosteroids and asthma control in children: assessing impairment and risk. Pediatrics 2009;123:353-366.
    OpenUrlAbstract/FREE Full Text
  206. 206.↵
    PharmacyChecker.com. In the news: Pulmicort Respules price comparison: select product. http://www.pharmacychecker.com/Strength.asp?drugId=57112 Accessed April 25, 2012.
  207. 207.↵
    1. Melani AS,
    2. Bonavia M,
    3. Cilenti V,
    4. Cinti C,
    5. Lodi M,
    6. Martucci P,
    7. et al
    ; on behalf of the Gruppo Educazionale Associazione Italiana Pneumologi Ospedalieri (AIPO). Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med 2011;105(6):930-938.
    OpenUrlCrossRefPubMed
  208. 208.↵
    1. Roberts CM,
    2. Lowe D,
    3. Bucknall CE,
    4. Ryland I,
    5. Kelly Y,
    6. Pearson MG
    ; on behalf of the British Thoracic Society Audit Subcommittee of the Standards of Care Committee and the Royal College of Physicians of London. Clinical audit indicators of outcome following admission to hospital with acute exacerbation of chronic obstructive pulmonary disease. Thorax 2002;57(2):137-141.
    OpenUrlAbstract/FREE Full Text
  209. 209.
    1. Krishnan JA,
    2. Demott M,
    3. McCoy JV,
    4. Chanmugam A,
    5. Rand CS
    . Nebulized beta2-agonist use in high-risk inner-city adults with asthma. J Asthma 2003;40(4):367-373.
    OpenUrlPubMed
  210. 210.↵
    1. Marcus P,
    2. Oppenheimer EA,
    3. Patel PA,
    4. Katz LM,
    5. Doyle JJ
    . Use of nebulized inhaled corticosteroids among older adult patients: an assessment of outcome. Ann Allergy Asthma Immunol 2006;96(5):736-743.
    OpenUrlPubMed
  211. 211.↵
    1. Camargo CA Jr.,
    2. Ramachandran S,
    3. Ryskina KL,
    4. Lewis BE.,
    5. Legorreta AP
    . Association between common asthma therapies and recurrent asthma exacerbations in children enrolled in a state Medicaid plan. Am J Health Syst Pharm 2007;64(10):1054-1061.
    OpenUrlAbstract/FREE Full Text
  212. 212.↵
    1. McLaughlin T,
    2. Leibman C,
    3. Patel P,
    4. Camargo CA Jr.
    . Risk of recurrent emergency department visits or hospitalizations in children with asthma receiving nebulized budesonide inhalation suspension compared with other asthma medications. Curr Med Res Opin 2007;23(6):1319-1328.
    OpenUrlPubMed
  213. 213.↵
    1. Schuepp KG,
    2. Jauernig J,
    3. Janssens HM,
    4. Tiddens HA,
    5. Straub DA,
    6. Stangl R,
    7. et al
    . In vitro determination of the optimal particle size for nebulized aerosol delivery to infants. J Aerosol Med 2005;18(2):225-235.
    OpenUrlPubMed
  214. 214.↵
    1. Amirav I,
    2. Newhouse MT,
    3. Minocchieri S,
    4. Castro-Rodriguez JA,
    5. Schuepp KG
    . Factors that affect the efficacy of inhaled corticosteroids for infants and young children. J Allergy Clin Immunol 2010;125(6):1206-1211.
    OpenUrlPubMed
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