Nebulized Corticosteroids in Asthma and COPD. an Italian Appraisal

Nebulized Corticosteroids in Asthma and COPD. An Italian Appraisal

Andrea S Melani MD

Introduction In Vitro Studies Pharmacokinetic and Scintigraphic Studies Pharmacodynamics Discussion Summary

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- and COPD. Nebulized budesonide has been (14 ؍ term studies, mostly carried out in asthma (n 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 alter- natives 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 prop- erly. 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. Key words: beclomethasone dipropionate; budesonide inhalation suspension; fluticasone propionate; flunisolide; chronic persistent asthma; chronic obstructive pulmonary disease; inhaled corticosteroids; jet nebulizers; nebulization; nebulizer therapy; ultrasonic nebulizers. [Respir Care 2012;57(7):1161–1174. © 2012 Daedalus Enterprises]

Introduction tent asthma of infants, children, and adults, throughout the severity.1-3 ICSs are also administered to pre-schoolers Inhaled corticosteroids (ICSs) are commonly used for with intermittent wheezing, but with less evidence of clin- aerosolization. Long-term regular use of ICSs is the main- ical efficacy.4-8 Even if the therapeutic effect is more mod- stay of anti-inflammatory management in chronic persis- est than in asthma, regular use of an ICS in combination with an inhaled long-acting ␤ agonist is increasingly uti-

Dr Melani MD is affiliated with Fisiopatologia e Riabilitazione Respi- ratoria, Policlinico Le Scotte, Azienda Ospedaliera Universitaria Senese, Siena, Italy. Correspondence: Andrea S Melani MD, Fisiopatologia e Riabilitazione Respiratoria, Policlinico Le Scotte, Azienda Ospedaliera Universitaria Dr Melani has disclosed a relationship with Artsana. Senese, Viale Bracci I-53100 Siena Italy. E-mail: a.melani@ao-siena. toscana.it. Supplementary material related to this paper is available at http:// www.rcjournal.com. DOI: 10.4187/respcare.01414

RESPIRATORY CARE • JULY 2012 VOL 57 NO 7 1161 NEBULIZED CORTICOSTEROIDS IN ASTHMA AND COPD. AN ITALIAN APPRAISAL lized for the treatment of severe COPD with a history of In Vitro Studies repeated bronchitic exacerbations.9-11 The role of ICSs in acute asthma and COPD is promising,12 but not fully In vitro investigations allow for important observations evidence-based.13 on aerosol behavior and contribute to cover some uncer- The production of therapeutic aerosols requires specific tainties due to the lack of extensive in vivo studies. In the delivery devices such as inhalers and nebulizers. Current supplementary Appendices 2 and 3 I have displayed the guidelines for asthma.1,2 and COPD management,14,15 as in vitro experiments with the marketed formulations of well as for nebulized16,17 and aerosol therapy,13 do not nebulized ICSs.33,36–39,45-69 To the aim of giving more ho- provide sufficient, specific guidance on the selection of the mogeneous results, we have selected those studies report- most appropriate device in different clinical settings. So, ing the inhaled mass (IM) as the relevant parameter of according to local habits and availability, there is tremen- drug output, and the mass median aerodynamic diameter dous variability among countries in the diffusion of dif- (MMAD), the geometric standard deviation, and the re- ferent devices for administering an aerosol therapy.18,19 In spirable fraction by cascade impaction as indices of aero- more than 70 countries worldwide, ICSs are approved and sol granulometry. Once careful attention is paid to stan- utilized for nebulization in both children and adults, for dardizing the environmental conditions,70-73 cascade asthma and COPD. Sometimes, such as in Italy, the use of impaction methods are the most accurate means of study- nebulized ICSs is widespread20 and critically discussed.21 ing aerodynamic properties of suspensions such as ICSs. In many other countries ICSs are usually or exclusively Overall, jet nebulizers are the preferred system for neb- 35-36,47,74-76 delivered using hand-held inhalers; in the United States, ulizing ICSs. Several in vitro studies with BUD 77 budesonide is the only marketed nebulized ICS and ap- and FLU have shown a poor efficiency of conven- proved for children ages 1–8 years with asthma by the tional ultrasonic nebulizers for administering ICSs. FDA in August 2000. The availability of an effective neb- Likewise, although mesh nebulizers offer promising results,36,38-39,49,51,53-56,67,78 they have a higher purchase cost ulized ICS has been welcomed by U.S. clinicians22 and is than jet systems. Moreover, maintenance may be difficult, increasingly used.23 Previously, alternative types of ICSs, as repeated nebulizations with suspensions seem to pre- such as nasal or parenteral formulations, had been pro- dispose to clogging and blockage of mesh holes.79 Re- posed24,25 and used for the treatment of asthma.26,27 cently Berg and Picard68 evaluated 30 commonly used jet Four corticosteroids are currently marketed for nebuli- nebulizer/compressor systems to nebulize BUD. Mimick- zation: nebulized budesonide (BUD), beclomethasone di- ing the breathing pattern of a child, the IM of studied propionate (BDP), flunisolide (FLU), and fluticasone pro- aerosols ranged from 4% to 20% of initial drug charge pionate (FP). They are available as unit-dose vials of 2 mL; (and from 1% to 9%, simulating the infant’s breathing BUD, FP, and FLU are available as multiple strength for- pattern).68 These findings are also in substantial accor- mulations. All these drugs are well known for their high dance with most studies, shown in the supplementary affinity to the glucocorticoid receptor, good topical anti- Appendix 4,76,80-87 where the IM was evaluated using in- inflammatory activity, and low tendency for systemic ef- haling subjects and not a breathing simulator. The MMAD 28-31 fects. The composition and some properties of the proof studied aerosols ranged from 4.8 to 9.9 ␮m.68 It means prietary nebulized ICSs are reported in Appendix 1 in the that not all the studied systems seem to be suitable for supplementary materials at http://www.rcjournal.com. Poor nebulizing ICSs, because it is accepted that the probability water solubility is possibly the most relevant characteristic of being delivered to the lungs is relevant only when the of the currently marketed formulations, which are avail- drug is contained in nebulized particles smaller than 5 ␮m.16 able as suspensions, with some inherent drawbacks.32-34 Likewise, not only nebulizer systems producing aerosols Some novel varieties of nebulized ICS are being devel- with MMAD Ͼ 5 ␮m, but even those with MMAD of oped. They are obtained by adding solubilization enhanc- 2–3 ␮m are not suitable for efficient ICSs delivery.35,36,47,70 ers with the production of nano-suspensions and solutions, In fact, at least for the currently marketed nebulized ICSs or embodying the drug in micellar systems with the man- that are available as suspensions, the micronized drug is ufacturing of nano-emulsions and liposomal fluids.35 These distributed mainly in particles larger than 2–3 ␮mindi- newer formulations seem to be safe and stable, assure that ameter36 (as shown in supplementary Appendix 1), so that more drug is generated as aerosol by the nebulizer, and droplets with a smaller size would contain mainly water have improved particle size distribution,33,36-39 leading to and not drug. higher drug doses to the lungs40-42 and improved pharma- Interestingly, all components of the nebulizer system codynamics.43,44 are important in determining good lung delivery of ICSs The aim of this review is to evaluate whether nebuliza- (ie, the interface plays a very important role, largely mod- tion may be considered as a useful alternative to inhalers ifying the IM and also influencing the MMAD).58,64 This for administering ICSs in asthma and COPD. was confirmed by an ex vivo study where the mean IM of

1162 RESPIRATORY CARE • JULY 2012 VOL 57 NO 7 NEBULIZED CORTICOSTEROIDS IN ASTHMA AND COPD. AN ITALIAN APPRAISAL nebulized BUD was 5–7% of the nominal dose inhaled released to the lower airways is nearly completely ab- through a face mask, while this percentage increased up to sorbed into the broncho-pulmonary circulation, the lung 9–12% through a mouthpiece.87 The same study showed drug delivery roughly equals pulmonary bioavailability. that a good seal between the face and the mask approxi- Regarding the nebulized ICSs, in healthy adults when 3 mately doubled the IM.87 Another study with BUD has different nebulizers (Pari Inhalier Boy, Pari LC Plus, and shown that the blow-by method of administration largely Maxin MA-2) were used in a breath-synchronized manner, compromised the IM.88 Thus, not only the nebulizer sys- the systemic bioavailability of BUD was 13% of label tem, but even the modalities of inhalation widely influ- claim and approximately 50–70% of the IM.107 In 10 asth- ence the aerosol properties of nebulized ICSs. Barry and matic children ages 3–6 years who inhaled quietly through O’Callaghan46 have demonstrated the role of the inhaling the mouthpiece of the Pari LC Plus/Master system, the patient in an in vitro study, where they modified the in- systemic availability of BUD was 6.1% of label charge, spiratory flow to resemble different breathing patterns and corresponding to a quarter of the IM.84 This result is in saw major differences in IM of nebulized BUD. In another keeping with a scintigraphic study where the lung depo- ex vivo study, when 163 children ages 6 months to 7.9 years sition of BUD in 2 children inhaling quietly with good seal inhaled BUD through a Spira nebulizer, the IM ranged of face mask via the Pari LC Plus/Proneb Ultra nebulizer from 1.9% to 40.6% of the nebulizer load, according to the was 5–8% of label claim.108 The same study confirmed the breathing modalities.85 Manufacturers have tried to reduce key role of the inhaling subject for efficient drug lung the variability of performance related to the different breath- delivery: 2 children, one whose mask was not sealed to the ing patterns of inhaling patients, leading, with advances in face, the other who was crying, showed a lung deposition nebulizer technology, to the delivery of breath-enhanced of, respectively, 0.1% and 1% of initial charge.108 and synchronized nebulizers. Some pharmacokinetics studies have shown a substan- As shown in the supplementary Appendix 3, some stud- tial dose proportionality in both mean plasma and area ies have found that BDP and FLU do not substantially under the curve levels when increasing doses of ICSs were differ from BUD regarding IM and droplet size distribu- nebulized. This result has been observed in 10 adult asth- tion.59,66,69 Less information is available for FP. Without matics who inhaled a daily dose of, respectively, 2 mg and any explanation of the method used, Westbroek et al89 8 mg BUD, in a cross-over manner, with the Inhalier Boy.109 reported a respirable fraction of 12–16% of the initial FP Murphy et al110 also obtained a similar finding when dif- charge for 3 commonly used nebulizer systems such as the ferent doses of BUD (0.5 mg and 1 mg once daily, 1 mg SideStream/PortaNeb, the Pari LC Plus/Proneb Ultra and and 2 mg twice a day) were administered to 120 moderate- the Cirrus/PulmoAide. Importantly, not only the drug, but to-severe adult asthmatics with the Pari LC Plus/Master all other components of the liquid formulation have system through a mouthpiece. In the same study, in an a relevant role for efficient drug delivery: increasing the attempt to compare a nebulizer with an inhaler, a 3-fold fill volume from 2 mL to 7 mL improves the nebulizer difference in potency was estimated, favoring the Turbu- efficiency up to 3-fold, but also increases the treatment haler dry powder inhaler. Using the Pari LC Plus/Master time, while aerodynamic properties did not change.90,91 system with a mouthpiece, another single-dose study in Mixing is another common practice when more medica- 12 healthy adults observed a dose proportionality by neb- tions are prescribed simultaneously.20,92-94 Some in vitro ulizing BDP 1.6 mg and 3.2 mg; in the same study the studies have investigated the consequences of mixing comparison with chlorofluorocarbon-propelled BDP via different drugs for nebulization. When bronchodilators metered-dose inhaler (MDI) added to a valved holding and ICSs are mixed, no physico-chemical incompatibility chamber (VHC) suggested a 2-fold potency ratio between was found.61,95-99 Moreover, as shown in supplementary MDI and nebulizer, favoring the first device.111 These re- Appendices 2 and 3, at least for BDP, BUD, and FLU, sults with marketed ICS formulations do not consider some mixing of ICSs and bronchodilators does not necessarily recent advances in nebulizer technology: in 10 asthmatics compromise the IM and the droplet size distribution of (mean age 20 months) ages 6–41 months, the mean lung aerosols,61,66,69,100 as initially thought.101 deposition for a novel formulation of nebulized budesonide via an eFlow was 34% of nominal dose: a percent- Pharmacokinetic and Scintigraphic Studies age similar to that of the most efficient inhalers.42

It is agreed that a relevant amount of drug has to be Pharmacodynamics delivered to the lung for effective aerosol treatment. Phar- macokinetics evaluates pulmonary bioavailability for a Pharmacodynamics evaluates the clinical value of a cer- given drug. The pharmacokinetics of ICSs have been ex- tain drug, using both efficacy and safety measures. Unfor- tensively reviewed.102-106 Scintigraphic studies investigate tunately, a full pharmacodynamic evaluation of nebulized lung drug delivery for a given aerosol. Because the dose ICSs is not available for several reasons. First, ICSs have

RESPIRATORY CARE • JULY 2012 VOL 57 NO 7 1163 NEBULIZED CORTICOSTEROIDS IN ASTHMA AND COPD. AN ITALIAN APPRAISAL anti-inflammatory activity, but the value of direct bio- the hypothalamic-pituitary-adrenal axis was studied in 293 markers of airway inflammation, such as exhaled nitric pediatric asthmatics, ages 6 months to 8 years, for up to oxide or eosinophil cell count, needs to be fully estab- 52 weeks, without any clinically important difference, as lished. So the most commonly used parameters to assess compared to the conventional treatment group (where 35% the efficacy of ICSs, such as the improvement in baseline were using ICSs via inhalers).138 On the whole, adrenal lung function and symptom scores, the reduction of bron- suppression seems to occur occasionally at the highest chitic exacerbations, and rescue ␤ agonists use, are indi- doses after long-term regular treatment periods, perhaps in rect and relatively insensitive indices. It means that the susceptible individuals.131,139 Another major concern in dose-response effect is relatively flat, making it possible to pediatric age is the possibility of a negative effect of ICSs detect differences only when the ICS is at least quadrupled on body height. Again, the most information is available over the baseline dose.112-118 Second, the improvement (or for BUD: a total of 670 pediatric asthmatics were random- worsening) in the control of asthma occurs within some ized in a 2:1 ratio to receive BUD (titrated to the lowest days from starting (or stopping) treatment, but treatment is clinically effective dose, with median total daily dose rang- required for up to 4–8 weeks119,120 or more121 to reach the ing from 0.5 to 1 mg) or conventional asthma therapy for maximum effect. This complicates the interpretation of 52 weeks, in a real life setting,138 with no difference of results from cross-over, step-down, or step-up titration stud- growth between groups, even when stratified by sex and ies.122,123 On the other hand, a full estimation of ICS po- age.140 A small but statistically significant difference in tency requires parallel studies of long-term duration (at growth velocity (Ϫ0.8 cm/y, P ϭ .002) was observed only least 1 month of regular treatment) with a large sample between the BUD group and that of conventional treat- size of subjects for a range of drug dosages and disease ment where ICSs were not allowed.131 Likewise, as more severity, studies not easily performed.124 extensively shown for ICSs administered via MDIs, this In Table 1 I have reported 16 randomized, blind, pla- result did not affect the final height to be achieved.141-144 cebo-controlled studies with nebulized ICSs in patients Post-marketing surveillance data have confirmed the safety with chronic persistent asthma and COPD.6,89,113,125-137 of nebulized ICSs across all ages.145,146 BUD and BDP Three studies had a cross-over design; the remaining were have also been used safely in pregnant women.147-150 Im- parallel. Five studies,125,128,133,135,136 including 187 sub- portantly, despite the fact that substantial facial and eye jects, used FLU at different daily doses up to 2 mg. Two deposition may occur using nebulizer with face mask,151 studies, enrolling 192 subjects, used BDP at daily doses of local adverse events are not commonly reported. Skin re- 0.8–4 mg. A study with FP at daily doses of 1–4 mg, lated side effects have been observed only in 2% of chil- included 301 adults with severe asthma. The clinical ex- dren, with no reports of cataract.152,153 perience with BUD is the most extensive, for a total of 8 In Table 2 I have reported 18 comparative studies that studies enrolling 1,258 asthmatic subjects, mostly pediat- included nebulized ICSs.6,82,109-110,117,139,154-165 Five stud- ric (0.5–8 years of age). Compared to placebo, BUD sig- ies used inhalers as the benchmark against which the com- nificantly improved disease control for both subjects not parison has been set up. Three of these studies explored previously receiving ICSs nor well controlled by broncho- the clinical value of nebulized BDP. BDP administered via dilators, and for those on prior ICSs use. Efficacy was the Pari LC Plus/ProNeb Turbo demonstrated to be not already demonstrated at a daily dose of 0.5 mg with once less effective than the same drug delivered via inhalers at daily administration of BUD, although evidence support- half dose in 301 asthmatics of different ages and disease ing the efficacy of the twice daily and higher dosing is severity.158-160 The results of earlier studies with nebulized stronger. BDP were contrasting,166-168 probably as a result of the Although ICSs have a better therapeutic ratio than sys- low strength of the used preparation, impeding a sufficient temic corticosteroids, when higher doses are administered, lung drug delivery.169 Another study showed that an 8 mg relevant absorption occurs, with the potential to give sys- daily dose of BUD given to 10 adult asthmatics via an temic adverse effects. Measurements of adrenal suppres- Inhalier Boy for 4 weeks was more effective than a 1.6 mg sion are usually considered as the most sensitive marker daily dose of budesonide delivered via MDI with VHC.109 for ICSs’ systemic activity. In fact, exogenous corticoste- On the contrary, Murphy et al did not find any difference roids can attenuate natural production of cortisol by a neg- in efficacy and safety between different doses of BUD and ative feedback on the hypothalamic-pituitary-adrenal axis. budesonide given via the dry powder inhaler Turbuhaler at Safety data are available mainly for BUD. Ten adult asth- a daily dose of 0.4 mg twice a day.110 Investigating the matics who inhaled an 8 mg daily dose of BUD via the systemic activity of ICSs, Wales et al170 did not observe Inhalier Boy system had morning cortisol levels lower any consequence after inhalation of a single 4 mg dose of than when they receiveda2mgdaily dose.109 However, BUD, while serum cortisol levels significantly decreased these high dosages of BUD are seldom used in clinical when the same volunteers inhaled either budesonide 4 mg practice. The effect of BUD at daily doses up to 2 mg on using a Turbuhaler or 4 mg fluticasone propionate using

1164 RESPIRATORY CARE • JULY 2012 VOL 57 NO 7 R

ESPIRATORY Table 1. Characteristics of Randomized, Placebo-Controlled, Blind Studies With Nebulized ICSs in Asthma and COPD

Study Daily Population, Mean Age, y Nebulizer Setting Drug Duration, Diagnosis Results* Reference Dosage, mg no. (range) weeks

C 1 Unspecified jet FLU 0.5 BID 8 20 10 (8–13) Asthma SS; PC20 , FEV1, PEF, AE: NS 125 ARE Econeb powered at 6 L/min, FM BUD 0.5 BID 4 23 0.8 (0.3–1.4) Asthma SS, WAE, BD: NS 126‡ Hudson Updraft II/CR60, open FM BUD 1 BID 8 36 2 (1–5) Severe asthma 1SS; 2SCU†; BD: NS 127§ N EBULIZED • 1 J Nebula, FM FLU 0.002/kg BID 12 23 1 (0.3–2.6) Asthma SS; BD, DO, AE: NS 128 ULY DeVilbiss 646/CR60, open FM BUD 1 BID 12 38 1.4 (0.5–2.5) Severe asthma 1SS; 2SCU; AE, BD, WAE†: NS 129‡ 1 2 2 1 ࿣ Pari LC Plus/Master, MP BUD 0.25 BID 12 178 6.7 (4–9) Moderate to severe asthma SS†; BD; DO; PEF; FEV1, AE: NS 130 02V 2012 0.5 BID 1SS†; 2BD; 2DO; 1PEF; 1FEV ; AE: NS 1 C

1 2 2 1 IN ORTICOSTEROIDS 1 BID SS†; BD; DO; PEF; FEV1, AE: NS 1 2 Pari LC Plus/Master, MP or FM BUD 0.25 OD 12 480 4.7 (0.5–8) Mild to moderate asthma PEF†; BD†; SS†, FEV1, DO†, AE: NS 113¶ OL 1 1 2 1 OD, SS†; PEF†; BD†; FEV1, DO†, AE: NS 1 1 2 2 7N 57 0.25 BID SS†; PEF†; BD†; DO†; FEV1, AE: NS 1 1 2 2 0.5 BID SS†; PEF†; BD†; FEV1; DO†; AE: NS 1 2

O Pari LC Plus/Master, MP BUD 0.25 OD 12 359 4.7 (0.4–8) Mild asthma SS†; BD; FEV1, AE, PEF, DO: NS 131** 1 2 1 1165 7 0.5 OD SS†; BD; FEV1; AE, PEF, DO: NS 1 2 2 1 1OD SS†; BD; DO; FEV1; AE, PEF: NS

SideStream/CR60 BDP 2 BID 4 26 70 (67–75) Severe COPD SS, FEV1, BD, 6MWT: NS 132‡ A

2 2 AND STHMA SideStream/Portaneb (36–37% of FP 0.5 BID 12 301 (19–83) Severe asthma SCU†; DO; SS, FEV1, PEF, AE: NS 89§ 1 2 2 total), LC Plus/Boy (54–57%), 2 BID SS; SCU†; DO; FEV1, PEF, AE: NS Cirrus/PulmoAide (6–9%), FM (Ͻ 65%) or MP 2 Bimboneb FLU 0.5 BID 2 32 (6–15) Asthma ENO†; FEV1, SS: NS 133

LC Plus/Master, FM or MP BUD 0.5 OD 12 141 0.7 (0.5–1) Mild to moderate asthma 1SS; AF†, DO: NS 134†† A COPD. 1OD 1SS; AF†, DO: NS Bimboneb FLU 0.8 8 10 (6–13) Asthma 2ENO†; 2EN 135

Nebula FLU 1 BID 24 114 66 (54–75) Moderate to severe COPD SS, SAE†, QOL, 6MWT, FEV1:NS 136

Pari LC Plus BUD 1 BID‡‡ 52 128 3 (1–4.9) Intermittent asthma 1SS; SFD†, DO, QOL, AE: NS 6‡‡ N

1 1 I Comp Air Elite BDP 0.4 BID 12 166 2.3 (1–4) Intermittent wheezing SFD†; SS; BD, AE: NS 137 TALIAN

* The studies have a parallel design unless otherwise specified. FM ϭ face mask † The primary outcome(s) of the study. BUD ϭ budesonide

2 Indicates a significant decrease for a given outcome when the active group is compared to the placebo arm. WAE ϭ wheezing/asthma exacerbations rate A

1 Indicates significant improvement for a given outcome when the active group is compared to the placebo arm. BD ϭ use of rescue bronchodilator PPRAISAL ‡ Crossover study design with no wash-out period. SCU ϭ systemic corticosteroid use § All subjects were inhaled corticosteroid (ICS) dependent (at least 5 mg total daily dose of prednisolone or equivalent). DO ϭ drop-out rate ࿣ All on prior stable ICS use. OD ϭ once daily ¶ 31% of subjects on prior stable ICS use. BDP ϭ beclomethasone dipropionate ** No prior ICS use. 6MWT ϭ 6-min walking distance †† 15–22% on prior oral corticosteroid use. MP ϭ mouthpiece ‡‡ Subjects of active group received a 7-day course of nebulized ICS for each exacerbation. FP ϭ fluticasone propionate FLU ϭ flunisolide ENO ϭ exhaled nitric oxide BID ϭ twice daily EN ϭ exhaled nitrotyrosine SS ϭ symptom score AF ϭ adrenal function by morning post-cosyntropin plasma cortisol value PC20 ϭ provocational concentration of methacholine that produces a 20% decrease in FEV1 SAE ϭ severe exacerbation rate PEF ϭ peak expiratory flow QOL ϭ quality of life measurement AE ϭ adverse events SFD ϭ symptom free days NS ϭ no significant difference between groups 16R 1166 Table 2. Characteristics of Randomized Blinded Comparison Studies Lasting for at Least 1 Week in Asthmatics Using Nebulized ICSs*

Study Population Mean Age, y Nebulizer Setting Drug Daily Dosage, mg Duration, Results† Reference no. (range) weeks

DeVilbiss 646/CR60/FM‡ BUD 0.25 BID vs 1 BID 64 (0.5–3.3) 12 High dose Ͼ low dose for SS; SCU: NS 117 Aiolos/FM§ BUD 0.25 BID vs 1 BID࿣ 102 2 (0.4–3.9) 18 SS, MED: NS 82

Ͼ N Unspecified nebulizer¶ BUD 0.5 BID vs 2 BID 46 (6–15) 4 High dose low dose for PEF and FEV1; SS: NS 154 Pari Inhalier Boy/CR60** BUD 1 BID vs 4 BID vs budesonide 26 45 (27–62) 4 High dose (but not low dose) Ͼ MDI for SS, BD, 109 EBULIZED MDI 0.8 BID PEF, AE VentStream/FM‡ BUD 0.25 BID vs 1 BID 42 1.5 (0.5–3) 1 High dose Ͼ low dose for SS; BD, DO, AE: NS 155 Acorn22 Mizer/CR60/FM‡ BUD 0.1 BID vs 0.5 BID࿣ 49 0.75 (0.1–1.4) 12 SS, WAE, BD, AE: NS 156

SideStream†† FP 1 BID vs PRE 31 8.2 1 FP Ͼ PRE for AE 157 C RIOTRISIN ORTICOSTEROIDS Pari LC Plus/ProNeb Turbo‡¶ BDP 1.6 BID vs BDP MDI 151 11 (6–16) 4 SS, PEF‡‡, FEV1, BD: NS 158 0.8 BID Pari LC Plus/ProNeb Turbo‡ BDP 1.6–3.2 BID vs BDP MDI 30 26 (18–60) 3 PC20 ‡‡, PEF, AE: NS 159 0.8 BID Pari LC Plus/ProNeb Turbo§§ BDP 3–4 BID vs BDP MDI 124 45 (18–70) 12 SS, PEF‡‡, FEV1, BD: NS 160 1.5–2 BID VentStream/FM BUD 0.25 BID vs 1 BID࿣ 22 (0.5–3) 1 AE: NS 161 Artsana SP100‡ BUD, FP BUD 0.5 BID vs FP 168 (4–15) 1.5 SS, AE, PEF: NS 162

0.25 BID A Pari LC Plus‡¶ BUD 1 BID vs montelukast 4 OD 173 3 (1–4.9) 52 SFD‡‡, DO, QOL, AE, SS: NS 6 AND STHMA Pari LC Plus/FM BUD 0.5 BID vs DSCG 20 TID 82 1.5 (1–2.6) 12 BUD Ͼ DSCG for SS, WAE; BD, AE: NS 163 Comp Air Elite‡ BDP 0.8 OD vs 0.4 BID 65 (5–12) 12 SS, BD, PEF, FEV1: NS 164 Pari LC Plus/Master‡ BUD 0.5 OD vs 1 OD vs 1 BID vs 758 40 (12–77) 12 SS, FEV1‡‡, PEF, BD, AE: NS 110 2 BID vs budesonide

Turbuhaler 0.4 BID A COPD. Omron CX3‡ BUD, FP 0.25 BID࿣ 37 0.8 (0.5–2) 12 AE: NS 139 ESPIRATORY Nebula/MB5/spacer MP‡ FLU, BUD FLU 0.04 mg/kg BID vs BUD 46 4 (3–5) 3 AR, SS, AE, BD: NS 165 0.5 BID࿣ N * The studies have a parallel design unless otherwise specified. PEF ϭ peak expiratory flow I

Ͼ indicates a significant difference between treatments. MDI ϭ chlorofluorocarbon metered-dose inhaler added to a valved holding chamber TALIAN † When more dosages are applied, the result is intended as the same for all dosages unless otherwise specified. BD ϭ use of rescue bronchodilator C ‡ Not on prior inhaled corticosteroid (ICS) use. AE ϭ adverse events ARE § Unstable moderate to severe asthma. DO ϭ drop-out rate ࿣ ϭ With down titration. WAE wheezing/asthma exacerbations rate A •

¶ Moderate persistent asthma. FP ϭ fluticasone propionate PPRAISAL

J ϭ

ULY ** Unstable moderate asthma despite prior stable ICSs use (0.4–1 mg daily of BDP or equivalent); crossover design, PRE oral prednisolone no wash-out period. No details for MDI use. BDP ϭ beclomethasone dipropionate †† 71% on prior stable ICS use of no more than 0.4 mg BDP or equivalent; oral prednisolone was given at a daily PC ϭ provocational concentration that produces a % decrease in FEV 02V 2012 dosage of 2 mg/kg (maximum 40 mg) for 4 days, followed by 1 mg/kg (maximum 20 mg) for 3 days; crossover study OD ϭ once daily design with a 2–4 week wash-out period. SFD ϭ symptom free days ‡‡ Indicates the primary outcome of the study. QOL ϭ quality of life measurement §§ Moderate to severe persistent unstable asthma despite prior stable ICSs use at mean daily dosage of 0.6 mg of BDP or equivalent. DSCG ϭ disodium cromoglycate

OL FM ϭ face mask TID ϭ thrice daily BUD ϭ budesonide inhalation suspension MP ϭ mouthpiece 7N 57 BID ϭ twice daily FLU ϭ flunisolide SS ϭ symptom score AR ϭ airways resistance by forced oscillation technique SCU ϭ systemic corticosteroid use O NS ϭ no significant difference between groups 7 MED ϭ minimum final effective dose which assured asthma control NEBULIZED CORTICOSTEROIDS IN ASTHMA AND COPD. AN ITALIAN APPRAISAL an MDI with a VHC. Finally, in another study on 14 earlier repeated administrations (every 15–20 min for up healthy adults in which the effect of a single 2 mg dose of to 2–4 h) giving greater benefits.198 Finally, the value of FP on hypothalamic-pituitary-adrenal axis was compared ICSs for the treatment of asthmatic and COPD exacerba- to MDI added to VHC, the latter showed approximately a tions is promising,12,198-201 but not fully evidence-based 7-fold higher suppressant effect, as compared to the neb- and cannot be recommended. The confirmation of an im- ulizer Pari LC Plus.171 Overall, the problem of equivalence portant role for ICSs in acute settings would enlarge the among different devices remains undefined. Other com- use of nebulized ICSs, as many health caregivers prefer to parative studies have addressed the problem of individu- administer aerosol therapy via nebulizers in the hospital202 alizing (or adjusting) the lowest effective dose of nebu- and in emergency departments.203 lized ICS (mostly with BUD) to obtain asthma control, Although most randomized placebo-controlled without any ultimate conclusion. The dose-response effect blinded studies have administered nebulized ICSs alone, is not well defined with nebulized ICSs: only when the 8 trials used co-admixtures of ICSs and bronchodila- ICS dosage was increased 4-fold was a difference some- tors.136,137,173,174,176,179,181,182 A study where FLU was times observed in terms of efficacy117,154 and safety.109 mixed with bronchodilators and administered via the Likewise, the dose-response trend was observed for some Nebula system was carried out in at least moderate COPD, efficacy variables only in one113 of the 3 seminal pediatric with a trend of improved symptom score and reduced se- randomized double-blind placebo-controlled studies with vere exacerbation rate.136 The remaining studies were per- BUD,113,130,131 and not at all after patient stratification by formed in asthmatics: 6 studies were performed in acute age.172 settings, mixing either BUD173,174,176,181,192 or FP179 The results of placebo-controlled blinded studies eval- with bronchodilators, via a variety of nebulizer systems. uating the role of nebulized ICSs in acute settings are Four173,174,176,192 of these studies showed a significant re- displayed in the supplementary Appendix 5.173-182 These sult in terms of clinical efficacy when the co-admixture studies have been performed in either emergency rooms including the nebulized ICSs was compared to the placebo or in hospital. Although the active treatment group often arm. The last study observed a significant improvement in shows some advantage in terms of efficacy with respect symptom score and symptom free days in children with to the placebo arm, no firm conclusion can be drawn. intermittent wheezing who received a co-admixture of BDP Overall, the clinical importance of ICSs in acute settings and albuterol via the Comp Air Elite system.137 Although is not well defined. At present, the use of an ICS at 4 times promising, the clinical effects of mixing nebulized ICSs the maintenance dose is considered an alternative to sys- with other nebulizable drugs needs confirmation to be temic corticosteroids only for mild-to-moderate acute recommended. asthmatic episodes.1 In more severe attacks, current guidelines recommend the early use of systemic corticosteroids, Discussion but do not include ICSs.183 Unfortunately, systemic corticosteroids induce relevant adverse effects, even with Several large randomized controlled studies in subjects short-term treatments.184,185 The results of blinded com- with chronic persistent asthma have demonstrated the ef- parison studies evaluating the role of nebulized ICSs in ficacy and safety of BUD at daily doses from 0.5 mg to acute settings are displayed in the supplementary Appen- 1 mg, with a range of jet nebulizers (Aiolos, DeVilbiss dix 6.173,177-178,180,186-193 Ten of these 12 studies compared 646, Hudson Up-draft, Pari Inhalier Boy, Pari LC Plus, nebulized ICSs to systemic corticosteroids, which are the and VentStream). In vitro and some in vivo comparative mainstay of anti-inflammatory treatment in exacerbations. and placebo controlled studies suggest that nebulized BDP, Due to differences in methods and enrolled population, FLU, and FP, with some differences among them, are also the results of different studies cannot be pooled, and firm clinically effective and safe. Clear-cut indications about conclusions cannot be obtained. The problem of equiva- the recommended drug dosages are difficult, because a lence between nebulized ICSs and systemic corticoste- dose-response trend is inconsistently observed for nebu- roids also remains undefined. A significant dose-related lized ICSs. From a practical point of view, it means that, suppression was observed in adult asthmatics with oral when the desired clinical effect is achieved, the total daily prednisolone at daily doses ranging from 5 to 20 mg, but dose of the nebulized ICS must be individualized for each not with BUD given via a Ventstream/PortaNeb nebulizer patient, with the goal of tapering to the lowest effective system at daily dosages ranging from 1 to 4 mg for 4 days.194 dose to maintain disease control and to avoid the risk of Moreover, ICSs could be not only safer than systemic relevant systemic side effects. corticosteroids, but also assure earlier results via non- Three main drawbacks have limited a larger use of neb- genomic effects.195-197 Possibly, the critical parameter for ulized ICSs. First, most trials on ICSs have used inhalers, clinical efficacy, at least in asthmatics, might not be the so that they have stronger evidence in efficacy than neb- total dose of ICSs, but rather the timings of delivery, with ulizers. Second, some nebulizer systems are not suitable

RESPIRATORY CARE • JULY 2012 VOL 57 NO 7 1167 NEBULIZED CORTICOSTEROIDS IN ASTHMA AND COPD. AN ITALIAN APPRAISAL for efficient lung delivery of ICSs. This observation is Summary relevant, as nebulized drugs and nebulizers are sold sep- arately and a lot of physicians are not familiar with the I conclude that nebulized ICSs are currently a valid practice of nebulized ICSs. This raises concerns that the alternative to inhalers in asthma and COPD. Meaningful nebulization of ICSs is not always optimally performed. recommendations for good practice with nebulized ICSs Effectively, in real life, a variety of nebulizer systems and should be implemented in clinical practice. Additional re- operating modalities have been described for nebulizing search is required to confirm the promising role of ICSs in ICSs, and many of these practices are not evidence- acute settings and the possibility of mixing nebulized ICSs based.20,94,204 Third, all currently marketed nebulized ICSs and bronchodilators. Other studies should clarify whether have a relatively poor lung delivery. Most inhalers have ongoing ICS formulations may offer clinically important greater efficiency than nebulizers for delivering ICSs. Al- advantages over the currently available nebulized ICSs. though bioequivalence in clinical outcome among different devices might be overcome by increasing the dosage of REFERENCES the nebulized ICS, it implies longer times of administra- 1. Global Initiative for Asthma. Global strategy for asthma manage- tion, a major determinant for poor adherence to treatment,110 ment and prevention. Updated 2007. http://www.ginasthma.com. and higher costs. 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