The Role of Nebulized Therapy in the Management of COPD: Evidence and Recommendations

Abstract

Current guidelines recommend inhalation therapy as the preferred route of drug administration for treating chronic obstructive pulmonary disease (COPD). Previous systematic reviews in COPD patients found similar clinical outcomes for drugs delivered by handheld inhalers - pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs) - and nebulizers, provided the devices were used correctly. However, in routine clinical practice critical errors in using handheld inhalers are highly prevalent and frequently result in inadequate symptom relief. In comparison with pMDIs and DPIs, effective drug delivery with conventional pneumatic nebulizers requires less intensive patient training. Moreover, by design, newer nebulizers are more portable and more efficient than traditional jet nebulizers. The current body of evidence regarding nebulizer use for maintenance therapy in patients with moderate-to-severe COPD, including use during exacerbations, suggests that the efficacy of long-term nebulizer therapy is similar, and in some respects superior, to that with pMDI/DPIs. Therefore, despite several known drawbacks associated with nebulized therapy, we recommend that maintenance therapy with nebulizers should be employed in elderly patients, those with severe disease and frequent exacerbations, and those with physical and/or cognitive limitations. Likewise, financial concerns and individual preferences that lead to better compliance may favor nebulized therapy over other inhalers. For some patients, using both nebulizers and pMDI/DPI may provide the best combination of efficacy and convenience. The impact of maintenance nebulizer treatment on other relevant clinical outcomes in patients with COPD, especially the progressive decline in lung function and frequency of exacerbations, needs further investigation.

Keywords :

• Chronic obstructive pulmonary disease (COPD)
• Nebulizer
• Pressurized metered dose inhaler (pMDI)
• Dry powder inhaler (DPI)
• Aerosols
• Inhaler
• Aerosol drug delivery device (ADDD)
• Exacerbations

Introduction

National and international guidelines recommend inhalation therapy as the preferred route of drug administration to treat asthma (1,2) and chronic obstructive pulmonary disease (COPD) (3–5) based on several advantages of this delivery route over oral or parenteral treatment (e.g., faster onset of action, lower dose requirement, reduced systemic side effects) (6). Several years ago, systematic reviews of the published literature concluded that drugs delivered by any of the 3 commonly prescribed inhalation devices – pressurized metered-dose inhalers (pMDIs) with or without spacers, dry powder inhalers (DPIs), and nebulizers—had similar efficacies in patients with asthma and COPD provided they were used appropriately (7–9).

However, in clinical practice, it is commonly observed that patients with a faulty inhalation technique get less symptom relief from handheld inhalers than patients who use the devices appropriately (10,11). Many patients, especially elderly patients with COPD, are unable to use their pMDIs and DPIs in an optimal manner (10–12). Furthermore, some drug formulations are not available for specific devices (e.g., there is no approved pMDI formulation of long-acting beta-agonists in the United States), thereby limiting the choice of particular drug/device combinations. In recent years, several new devices and drug formulations have entered the marketplace, and it is relevant to explore the merits of various drug/device combinations for specific patient populations. The recently published ERS/ISAM Task Force Report comprehensively reviews the characteristics of various aerosol delivery devices and discusses their appropriate use in clinical practice (13).

A growing body of evidence supports using nebulizers for maintenance therapy of respiratory disease in an outpatient setting, despite limitations that might negatively affect ambulatory use (e.g., reduced portability, increased time for drug administration, variability of drug output, and need for cleaning after each use) (14). The primary aim of this article is to explore the role of nebulizers for the treatment of patients with stable COPD and during exacerbations of the disease. Issues concerning the choice of aerosol delivery devices in patients receiving noninvasive or invasive mechanical ventilation are described elsewhere (15).

Selection of Articles for Review

The topic was divided into specific subsections, which were assigned to at least two authors each. Articles were selected for inclusion based on systematic reviews of the literature according to each subsection. Database searches (1996–current) of MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, limited to English language, used multiple primary topic headers combined with appropriate terms for each section of the paper (e.g., COPD + aerosols or COPD + inhaled therapy). The authors also identified relevant papers from reference lists of published articles and their own reference libraries. All relevant articles were included without any selection bias.

Aerosol Drug Delivery Systems

A variety of inhaled drugs are available for the treatment of COPD, including several long- and short-acting bronchodilators, anticholinergics, corticosteroids, and combination products. Although the choice of pharmacologic agent is unquestionably important, selecting an appropriate aerosol delivery device is also critical for successful therapy. Patients with COPD and their physicians need to consider the unique features of various inhalers that make the delivery of aerosol formulations more suitable to the ventilatory nuances imposed by the disease. For example, delivery systems that separate generation and inhalation of the aerosol (e.g., pMDI + spacer) might be more useful for elderly patients with COPD (6, 9).

Three categories of aerosol drug delivery systems (ADDSs) are currently used to deliver the above medications to patients with COPD: pMDIs, DPIs, and nebulizers. The number of different ADDS — each with different characteristics, requiring different inhalation techniques — can be confusing for both patient and clinician. Using multiple ADDDs – a common practice in patients with more severe disease – can add to the confusion, resulting in decreased adherence with therapy (16,17). Thus, for optimal clinical benefit, it is important to carefully and appropriately match the delivery system to the patient, and, whenever possible, to simplify the number and type of devices employed.

Pressurized Metered-dose Inhalers (pMDIs)

The pMDI remains the most commonly used handheld aerosol delivery device, despite the increasing use of DPIs and other handheld inhalers (6). Most of the newer pMDIs formulated with hydrofluoroalkane (HFA) propellants provide an aerosol with a lower forward jet velocity than older chlorofluorocarbon pMDIs (6,9,18,19). The decreased flow velocity makes it easier for patients who may have difficulty with the coordination required to inhale the medication. The issues of taking a slow rather than a rapid inhalation, whether to inhale from residual volume or functional residual capacity, and the length of breath-hold at end-inspiration are common to both solution and suspension HFA pMDIs (6,11). Priming and shaking the canister beforehand may be required for reproducible dosing, and patients should be reminded to review the package insert for specific instructions (6).

For patients who have difficulty with coordination, the use of a valved spacer with the pMDI should be encouraged. This allows a slower-moving and smaller-particle-sized aerosol to be formed, extending penetration into the lungs and potentially enhancing the response to therapy (6,9,18,19). Even with an HFA-pMDI, 50% or more of the aerosol may be deposited in the oropharyngeal region. This can be reduced, but not eliminated, with the use of a valved spacer. For some patients, a facemask may be easier to interface with the pMDI and spacer than a mouthpiece (6). Using a non-electrostatic spacer may increase the amount of drug available at the mouth compared to plastic spacers. The aerosol remains in suspension within non-electrostatic spacers for several seconds longer than within plastic spacers, allowing the patient to briefly delay inhaling the drug (6,20,21).

Given their history, errors in inhalation technique for pMDIs have been well documented. Hand-breath coordination, a slow inspiratory flow rate (IFR), and breath-hold are critical steps for effective pMDI drug delivery (22,23). Patients with COPD have a higher incidence of errors in pMDI use (26%) than patients with asthma (13%) (10). However, in a more recent report differences in error rates for handling various inhalers between patients with asthma and COPD were not significant after adjustment for age, device, and level of instruction (11). Actuating a pMDI may be more difficult for patients with arthritis of the hands. Improper spacer technique also may lead to dosing errors (24). Both pausing before inhaling from a holding chamber/spacer and multiple actuations into a chamber/spacer – not uncommon patient practices – can significantly reduce drug availability (25).

Dry powder inhalers (DPIs)

As breath-actuated devices, DPIs eliminate the majority of problems associated with coordinating device actuation and inhalation that occur with pMDIs. However, these inhalers require the patient to generate a higher inspiratory flow rate to readily dispense the powder than pMDIs (1,19,26). Use of DPIs with increased airflow resistance may mean greater difficulty for some patients with severe COPD who cannot achieve an adequate IFR (19). The resistance of the DPI can vary 10-fold (0.02–0.20 cmH₂O^1/2/L/min), depending on design (6). Quinet and colleagues demonstrated in a geriatric population that lower than optimal inspiratory pressure and peak IFRs as well as decline in cognitive function limit the use of DPIs (27).

Inhalation at a less than optimal IFR for the specific DPI increases oropharyngeal deposition of the inhaled powder (6). Failure to hold the device correctly and improper dose and inhaler preparation also contribute to high error rates in some patients. Exhalation into the device prior to inhalation can be a serious problem with some DPIs, and even the exhalation-induced increase in humidity around the inhalation channel can affect product quality and dosing efficiency over time (6). These issues are complicated by the proliferation of DPIs with different designs and dose-loading engineering (10,28).

Nebulizers

Nebulizers are an alternate method to pMDIs and DPIs for providing aerosol therapy, provided the drug is available in liquid form. They are the most user-friendly of the inhaler devices for patients to use and are frequently prescribed de facto for patients with COPD (1). Developments over the past 10 years have made higher-efficiency nebulizers and computer-controlled delivery devices available for the management of patients with COPD (6).Conventional pneumatic nebulizers are inexpensive, but require a compressor or pressurized gas to operate. Additionally, lung deposition is variable and frequently less than that with the newer high-efficiency models due to drug wastage during the expiratory phase of the breathing cycle (6). Table 1 presents the features of the different types of nebulizers currently used.

Table 1  Features of different nebulizers⁶

Feature	Jet Nebulizer	Ultrasonic Nebulizer	Vibrating Mesh Nebulizer
Power source	Compressed gas or electric	Electric	Electric or battery
Portability	Limited	Limited	Portable
Treatment time (min)	15–20	4–10	<1–5
Output rate	Low	Higher	Highest
Performance variability	High	Intermediate	Low
Cleaning	Required after every use	Required after several uses	Required after every use
Environmental contamination	High with continuous use, low with breath activation	High with continuous use, low with breath activation	High with continuous use, low with breath activation
Cost	Very low	High	High
Formulation effects
Temperature	Decreases	Increases	Minimum change
Concentration	Increases	Variable	Minimum change
Suspensions, efficiency	Low	Poor	Variable
Denaturation	Possible	Probable	Possible

One of the primary advantages of nebulizers in COPD is the minimal coordination and effort required during inhalation compared to pMDIs and DPIs. The aerosol is continuously produced, and the patient can sit comfortably while taking medication, using tidal-volume breathing. If the patient requires a facemask, the design should provide a tight, but comfortable seal around the cheeks to avoid aerosol leakage into the environment and also to prevent/ reduce aerosol exposure to the eyes, an important consideration with anti-cholinergic therapy (6).

The most common complaints from patients reflect shortcomings of the device itself: conventional jet nebulizers are bulky and require an external power source (compressed gas, batteries or electricity). They require more preparation to set-up and take an average of 10–15 minutes to deliver the complete dose, and then must be cleaned. Other issues relate to the interaction of device and drug formulation. Formulation properties such as viscosity and surface tension can influence the production of the aerosol; for example, combining 2 medications from different vials may save time for the patient, but also may affect nebulizer performance, possibly delivering different quantities of the drugs used (6). Hygroscopic drugs can alter the final particle-size distribution of the aerosol, although this is less of a problem with nebulizers than pMDIs/DPIs. The efficiency of drug delivery with jet nebulizers can be improved by employing breath-enhanced or breath-actuated devices designed to minimize drug wastage during exhalation (29,30).

Newer designs of nebulizers, based on vibrating mesh or vibrating plate technologies or micro-pump engineering are highly efficient (Figure 1). Portable and handheld, some are small enough to fit in a pocket, and are usually battery-operated. Delivery efficiencies to the lung periphery are upwards of 60% of the nominal reservoir drug dose, with minimal loss of drug due to residual volume. These devices also deliver the required dose within a much shorter treatment time than conventional jet nebulizers – usually, over minutes (6). Vibrating mesh nebulizers can effectively nebulize solutions, suspensions, liposomal formulations, and proteins (6). The major drawback for the patient is the need to completely disassemble the devices for cleaning after each use, which is more challenging than cleaning the more commonly used jet nebulizers. Another nebulizer design (the Respimat® SoftMist™Inhaler Boehringer-Ingelheim, Ingelheim, Germany) provides a metered dose of liquid aerosol at a low velocity when a button on the device is pressed. Treatment, consisting of 1–2 actuations, translates into a markedly reduced treatment time for the patient. Currently, the Respimat is marketed in several countries for delivery of a combination of ipratropium bromide and fenoterol hydrobromide (Berodual®Respimat) or tiotropium solution (Spiriva®Respimat).

Figure 1.  Examples of marketed nebulizers that incorporate newer technologies. The eFlow (PARI, Midlothian, VA), MicroAir (Omron, Vernon Hills, IL,), I - Neb (Phillips Healthcare, Murrysville, PA) and Aeroneb (Aerogen, Galloway, IRE) incorporate VM/VAP aerosol generators. The I-neb and Akita Control System (Activaero,GER) employ Adaptive Aerosol Delivery technology as the patient/device interface for delivering and monitoring aerosol treatments. TheI-Neb and eFlow are formulation-specific for iloprost and cayston, respectively, and as such are not part of current COPD treatment paradigms. The Respimat (Boehringer-Ingelheim, Ingelheim GER) is a high efficiency soft-mist inhaler that employs a precise dosimetric system with multi-dose capability. All of these devices are approved for use in the United States. Photos courtesy of Myrna Dolovich, P.Eng.

Other improvements in nebulizer delivery systems include the use of control units that interface with the nebulizer, either a pneumatic design or one of the new technologies (e.g., the Akita® Jet Inhalation System, Activaero GmbH, Germany; the i-NEB AAD System, Philips Healthcare, Andover, MA, as shown in Figure 1) (6). These control units monitor the patient's breathing pattern and control the time at which the drug is introduced into the inspiratory phase of the breathing cycle. They also track when treatment is initiated and the amount of drug inhaled, thereby improving the efficiency of delivery and adherence to therapy (6).

For nebulizers with higher efficiencies and increased total (drug) output, the amount of drug loaded into the nebulizer may need to be adjusted to provide equivalent dosing to the lungs and avoid over-dosing. This information should be provided by the manufacturer based on sound bioequivalence studies. For example, a 2- to 4-fold decrease in ipratropium was needed for comparable bronchodilator response using an Aeroneb prototype compared to the Pari LC plus (31). Likewise, in bench models of noninvasive positive pressure ventilation, the fine particle dose delivered with a vibrating mesh nebulizer was 2- to 4-times higher compared to a jet nebulizer (32).

Considerations when choosing an aerosol drug delivery system for patients with COPD

How the patient uses the selected device and adheres to treatment may be influenced by personal preference, convenience, facility of use, economic factors, and the availability of competent caregiver assistance (11,33). Adherence, unlike compliance, represents an active choice on the part of the patient to follow prescribed therapy. Adherence failures may be “intentional” – also representing an active choice; however, for aerosol therapy, most failures are “unintentional” and related to incorrect device technique. Although all 3 types of devices require patient instruction and review to master technique, this is especially important for the handheld devices, for which regular monitoring of patient technique is needed to ensure optimal drug delivery.

Errors in using handheld inhalers are commonly observed in clinical practice. In one review, over 94% of 120 patients with asthma and COPD committed at least one error related to inappropriate technique, despite claiming to know how to use inhalation devices (33). In another review, 2,288 records of handheld inhaler technique among patients with asthma and COPD were examined (11).Critical mistakes were found among users of all the inhalers, with significant associations between inhaler misuse and older age (p = 0.008), less education (p = 0.001), and lack of instruction (p < 0.001). Misuse was associated with increased risk of urgent care and decreased disease control (11).

Information and instructions for use for a number of the aerosol devices and inhalers available for therapy are given on the educational websites of the American Association for Respiratory Care (34) and the American College of Chest Physicians (35) as well as in each product's package insert.

Proper breathing technique and repeated instruction can be problematic for older patients with COPD as well as for patients with recognized physical and/or cognitive limitations (36). Variable dosing may arise from poor technique that is not recognized by the patient (or caregiver) or, with recognition that the inhalation maneuver was suboptimal, from potential added puffs taken in compensation. Although many patients with COPD can use pMDIs (with or without a spacer) or DPIs for maintenance therapy, certain populations will benefit from administration by nebulizer (Table 2).

Table 2  Clinical scenarios where maintenance nebulizer therapy is preferred in patients with COPD*

1. Patients with cognitive impairment, e.g., Alzheimer's dementia, mental retardation or altered consciousness, that preclude effective use of handheld inhalers;

2. Patients with impaired manual dexterity due to arthritis, Parkinsonism, or stroke;

3. Patients who have severe pain or muscle weakness due to neuromuscular disease;

4. Patients who are unable to use pMDIs or DPIs in an optimal manner despite adequate instruction and training, such as those patients who are generally debilitated after hospitalization or by chronic illness and are unable to coordinate their breathing with a pMDI or they cannot generate adequate inspiratory flow for effective aerosol delivery from a DPI;

5. Patients with inadequate symptom relief with appropriate use of pMDIs/DPIs;

6. Patients who do not comply with the use of pMDIs and DPIs or who prefer to use nebulizers;

7. Patients who need respiratory medications that are not available in pMDI or DPI formulations, e.g., in the United States, SABAs are not available with DPIs, and LABAs are not available with pMDIs;

8. Patients who need higher bronchodilator or corticosteroid doses for optimal control of their disease; or when multiple agents need to be co-administered;

9. Patients who cannot afford therapy with pMDIs or DPIs.#

*Based on consensus of the authors’ expert opinion and clinical experiences.

#For Medicare eligible patients.

Abbreviations: LABAs, long-acting beta-agonists; SABAs, short-acting beta agonists.

In elderly patients and those with severe COPD and disabling dyspnea, delivering the total dose over several breaths by nebulizer may be more effective than delivery during a single breath by DPI or pMDI. In 2008, market analyses indicated that approximately 45% of patients with COPD had a nebulizer, and 69% of those patients used their nebulizer on a regular basis (37). Based on estimated prevalence of COPD in the United States, there are several million patients who use nebulizers on a regular basis (38).For these patients, using nebulized treatment may ensure adequate dosing and, possibly, slower progression of the disease as suggested in studies with handheld devices in patients who are monitored and capable of using the devices (39). Although it is typically expected that the outcomes are medication-related as opposed to device-related, there are no comparable data on disease progression in patients using nebulizers, and studies are warranted.

The Role of Nebulized Therapy in The Pharmacologic Management of COPD

Current guidelines for the management of COPD (3–5,40,41) present a comprehensive approach based on 1) assessing and monitoring disease, 2) reducing risk factors, 3) managing stable COPD, and 4) preventing and managing exacerbations. Guidance for therapy is based upon four stages of disease lung function abnormalities, classified by severity: mild, moderate, severe, and very severe (Figure 2). This section presents an overview of the use of nebulized therapy for the day-to-day management of COPD as well as for treatment of exacerbations (Table 3).

Figure 2.  Pharmacological therapy of COPD by severity classification (stages I – IV). Delivery by nebulizer may be appropriate at any stage according to patient needs and preferences. (Adapted from ATS/ERS41 and GOLD3).

Table 3  Commonly used nebulized medications for patients with COPD*

Medication	Nebulizer Solution (mg/mL)
Short-acting beta-agonists
Fenoterol‡	1
Levalbuterol	0.21, 0.42
Albuterol	0.21, 0.42
Long-acting beta-agonists
Formoterol	0.01**
Arformoterol	0.0075
Anti-cholinergics
Ipratropium bromide	0.2
Oxitropium bromide‡	1.5
Tiotropium	SMI***
Combination anticholinergic + short-acting beta-agonist in one inhaler
Ipratropium/fenoterol‡	0.5/1.25; SMI***
Ipratropium/albuterol	0.17/0.83; SMI***
Corticosteroids
Budesonide	0.125, .25

*Nebulizer solutions approved by the U.S. Food and Drug Administration. See individual prescribing information for details. For drugs that are not available in the United States, solution strengths are adapted from the GOLD guidelines (3).

**Formoterol nebulized solution is based on the unit dose vial containing 20 mcg in a volume of 2.0 ml.

***Available as the Soft Mist Inhaler (SMI), but not approved in the United States – The device delivers 5 mcg of tiotropium per actuation. The combination inhaler delivers 10 mcg of ipratropium and 25 mcg of fenoterol per actuation.

‡Not available in the United States.

Nebulized maintenance therapy for COPD

Most patients with early COPD – and even those with mild-to-moderate disease — use handheld inhalers for their regular maintenance therapy. Although the body of evidence clearly shows that all devices provide similar clinical benefit when used correctly, few studies have directly compared nebulizers and inhalers in the management of COPD. Table 4 summarizes some of the data available on the use of nebulized treatments for the maintenance therapy of COPD in ambulatory patients (42–59).

Table 4  Studies evaluating use of nebulized drugs for maintenance therapy in COPD.

Study publication	Study Design	Treatments (n)	Criteria	N (mean age)	Mean BL FEV1, L (%Predicted)	Outcomes
Nebulized bronchodilator (SABA, Anticholinergic)
Colice, 1996 (42)	85 day, R, DB, PC	TID SVN Tx: IB 0.5 mg (113) ALB 2.5 mg (110)	Moderate-to-severe COPD: FEV1<65% Pred FEV1/FVC < 70% Smoking > 10 pack-yr Hx	223 (64.2 yr)	1.01 (38.8%)	Day 85 Change in mean peak FEV1: IB, –0.013 L; ALB, –0.052 L (p < 0.05 v. day 1) Time to onset: IB, 30 min; ALB, 15 min Time to peak: IB, 1 hr; ALB, 1 hr Duration: IB, 4 hr; ALB, 3 hr
Friedman, 1996 (43)	85 day, R, DB, PC	TID SVN Tx: IB 0.5 mg (102) Metapro 15 mg (102)	Moderate-to-severe COPD: FEV1<65% Pred FEV1/FVC < 70% Smoking > 10 pack yr Hx	204 (61.5 yr)	1.07 (37.2%)	Day 85 Increase in mean peak FEV1: IB, 0.34 L; METAPRO, 0.31 L Time to onset: IB, 15 min; METAPRO, 5 min Time to peak: IB, 1 hr; METAPRO, 45 min (p = 0.009) Duration: IB, 4.5 hr; METAPRO, 3 hr (p = 0.039)
Combination: Nebulized SABA + Anticholinergic
Brophy et al, 2008 (44)	6 wk, 3-period, OL, R, CO	QID Tx with IB/ALB Low dose = 40/200 mcg by pMDI (during 2 wk run-in) Intermed dose = 120/600 mcg by pMDI (3 wk) High dose = 500 mcg/ 2.5 mg by Neb (3 wk)	Moderately severe COPD who were symptomatic despite using pMDI bdil, and: FEV1 ≤60% Pred FEV1:FVC <50% Reversibility after 200 mg ALB ≤15% and ≤200 mL	25 (68 yr)	0.88 (45%)	No statistically significant between Tx differences for pre- and post-bronchodilator lung function; 6-min walk distance; breathlessness score; or QOL scores FEV1, Low, 1.06; Intermed, 1.08, High (Neb), 1.08 15 patients preferred the High-dose Neb Tx, 10 preferred the Intermed dose pMDI
Combivent inhalation study group, 1997 (45)	85 day R, PG	TID Tx by SVN: ALB 3.0 mg (216) IB 0.5 mg (214) Combination (222)	Moderate to severe COPD, using ≥2 bdil for Sx control and: FEV1 ≤65% Pred FVC ≤70% Pred Smoking, ≥10 pack yr Hx	652 (64.9 yr)	0.91 (34.4%)	pm PEFR > with Combination than ALB or IB; am PEFR, QOL scores, Sx scores, physician global assessments were unchanged Increase in mean peak FEV1: Combination, 0.34; IB, 0.27; ALB, 0.29 (p < 0.001 Combination vs. both) AUC(0–8h): Combination, 1.06; IB, 0.97 (p = NS); ALB 0.77 (p = 0.009) Day 85 values not significantly different from Day 1 values for all Tx groups
Gross et al, 1998 (46)	6 wk, 3-period CO followed by 6 wk PG w/continued Tx from the last CO period	QID Tx: ALB 2.5 mg IB 0.5 mg Combination	COPD, using ≥ 1 bdil and: FEV1 25–65% Pred Smoking, ≥10 pack yr Hx	863 (66.3 yr)	1.145 (48.1%)	Increase in mean peak FEV1: Combination, 0.39; IB, 0.28; ALB, 0.31 (p < 0.001 Combination vs. both) AUC(0–8h): Combination, 1.50; IB, 1.14; ALB 1.15 (p < 0.001 Combination vs. both)
Levin et al, 1996 (47)	85 day, R, DB, PC	TID SVN Tx added to ALB solution (2.5 mg): IB 0.5 mg (100) PLA (95)	Moderate-to-severe COPD: FEV1 <65% Pred FEV1/FVC < 70% Smoking > 10 pack yr Hx	195 (64 yr)	1.02 (38.8%)	Day 1 increase in mean peak FEV1and in AUC(0–8h) was 26% and 64% greater with IB+ALB vs. PLA (p < 0.003, 0 < 0.0002), respectively; improvements were maintained through study Day 85 increase in mean peak FEV1: IB, 0.40; PLA 0.33 (p < 0.01)
Tashkin et al, 1996 (48)	85 day, R, DB, PC	TID SVN Tx added to METAPRO solution (15 mg): IB 0.5 mg (108) PLA (105)	Moderate-to-severe COPD: FEV1 <65% Pred FEV1/FVC < 70% Smoking > 10 pack yr Hx	213 (60.6 yr)	1.07 (37.4%)	Trends favoring IB observed, but no statistically significant between-Tx differences in FEV1 during study Greater acute effects on bronchodilation with IB
Tashkin et al, 2007 (49)	12 wk, PG (Primary outcome = health-related QOL using SGRQ)	ALB + IB given by Neb (37), pMDI (43), or concomitant Tx of Neb am and pm with pMDI in afternoon and evening (46)	COPD: FEV1 30-65% Pred FEV1/FVC <70% Smoking, ≥0 pack yr Hx	126 (62.3–65.9 yr)	1.2	Concomitant Tx > Neb > pMDIBUTimprovements were similar (pre- or post-bronchodilator FEV1; total Sx scores, QOL) Sx: greatest changes in Concomitant group (p < 0.05, wks 6, 12; wk 12 for Neb) Clinically significant improvement observed for Concomitant and Neb Tx groups for total QOL and Sx sub-scores and for Concomitant Tx for impacts sub-score
Nebulized LABA
Baumgartner et al, 2007 (50)	12 wk R, DB, DD	By Neb: ARFOR 15 mcg BID (141) ARFOR 25 mcg BID (143) ARFOR 50 mcg QD (146) By pMDI: SAL 42 mcg BID (144) PLA (143)	COPD: FEV1 ≤ 65% Pred and > 0.7L FEV1/FVC ≤70% Smoking ≥15 pack yr Hx	717 (62.9 yr)	1.22 (40.6%)	After 12 wk: %change in peak FEV1 from pre-dose: ARFOR 15/25/50 mcg, 21.2/20.5/28.6%; SAL, 15.1%; PLA 13.6% (p < 0.01 vs. PLA and <0.05 vs. SAL for all doses ARFOR) %change in AUC(1–12h): ARFOR 15/25/50 mcg, 7.2/7.4/16.0%; SAL, 4.8%; PLA, 2.7% (p < 0.01 vs. PLA for all doses ARFOR; p < 0.05 vs. SAL for ARFOR 50 mcg) Wk 12, median time to response: ARFOR 15/25/50 mcg, 10.3/14.3/3.5 min; SAL, 132 min; PLA, 326.6 min At 12 wk, statistically significant improvements in TDI v. PLA with ARFOR but not SAL; improvement in trough FEV1, rescue IB and ALB, and SGRQ scores were comparable for ARFOR and SAL (both > PLA)
Donohue et al, 2008a (51)	52 wk OL extension after 12 wk DB, DD [see Gross et al, 2008 (53)]	BID Tx: FFIS 20 mcg (463) FFDP 12 mcg (106)	Moderate to severe COPD: FEV1 30-70% Pred FEV1/FVC <70% Smoking, ≥10 pack yr Hx	569 (64.3 yr)	1.34	Safety data comparable between groups, both were well tolerated COPD exacerbations (%subjects): FFIS, 15.8%; FFDP, 17.9%
Donohue et al, 2008b (52)	12 mo, prospective OL MC, R, AC, PG extension after 12 wk R DB, DD [see Baumgartner et al, 2007 (50); Hanrahan et al, 2008 (56)]	By Neb: ARFOR 50 mcg QD (528) By pMDI: SAL 42 mcg BID (265)	COPD: FEV1 ≤ 65% Pred and > 0.7L FEV1/FVC ≤70% Smoking, ≥15 pack yr Hx	793 (62.9 yr)	1.13 (38.0%)	AEs similar but tremor more frequent w/ ARFOR COPD exacerbations (%subjects): ARFOR, 32%; SAL 27.5% Similar improvements in PFTs, reductions in supplemental IB and rescue ALB, maintained, throughout the 12 mo
Gross et al, 2008 (53)	12 wk R, DB, DD	BID Tx: FFIS 20 mcg (123) FFDP 12 mcg (114) PLA (114)	Moderate to severe COPD: FEV1 30-70% Pred FEV1/FVC <70% Smoking ≥10 pack yr Hx	351 (62.8 yr)	1.34 (44.5%)	FEV1-AUC(1-12h): FFIS and FFDP > PLA (p < 0.0001, both); also peak FEV1, trough FEV1, FVC-AUC(0–12h) FFIS subjects had significant and clinically relevant improvements in QOL and Sx scores vs. PLA; FFDP had significant changes in Sx scores vs. PLA No significant differences between active Tx
Hanania et al, 2009 (54)	6 wk R,DB, PC	BID Tx added to OL TB (18 mcg): FFIS 20 mcg (78) PLA (77)	Moderate to severe COPD: FEV1 25–65% Pred FEV1/FVC <70% Smoking ≥10 pack yr Hx	155 (65.4 yr)	1.22 (46.1%)	Significant improvements with FFIS v PLA in FEV1-AUC(0–3h,) FEV1, FVC, post-dose IC – starting at day 1 and maintained through the 6 wk Peak FEV1, wk 6: FFIS, 1.64 L; PLA, 1.48 L (p < 0.0001) AUC(0–3h), wk 6: FFIS, 1.57 L; PLA, 1.38 L (p < 0.0001) FFIS patients had fewer AEs including COPD exacerbations. TDI, SGRQ, and Sx scores did not differ between Tx
Hanania et al, 2010 (55)	6 mo R, DB, DD	BID Tx: By Neb: ARFOR 15 mcg (149) ARFOR 25 mcg (147) By DPI FORMOT 12 mcg (147)	COPD: FEV1 ≤ 65% Pred and > 0.7L FEV1/FVC ≤70% Smoking ≥15 pack yr Hx	443 (63.8 – 65.4 y)	≈1.2 (41.0%)	Similar improvements all Tx for FEV1, IC, TDI, rescue SABA, supplemental IB, SGRQ Mean peak change in FEV1 at wk 26: ARFOR 15/25, 0.30/0.34 L; FORMOT, 0.26 L
Hanrahan et al, 2008 (56)	Data pooled from 2 12 wk R, PC studies	By Neb: ARFOR 15 mcg BID (288) ARFOR 25 mcg BID (292) ARFOR 50 mcg QD (293) By pMDI: SAL 42 mcg BID (290) PLA (293)	COPD: FEV1 ≤ 65% Pred and > 0.7L FEV1/FVC ≤70% Smoking ≥15 pack yr Hx	1,456 (62.9 yr)	1.23 (40.6%)	% Change at Wk 12: Peak FEV1: ARFOR 15/25/50, 22/20.7/27.9%; SAL 14%; PLA 13.7% AUC(0–12h): ARFOR 15/25/50, 8.4/7.5/15.2%; SAL 4.3%; PLA 2.5% Wk 12, median time to response: ARFOR 15/25/50, 10.1/12.8/3.1 min; SAL 142.4 min; PLA 353.4 min
Sutherland et al, 2009 (57)	R, OL, CO	2 wk Tx: FFIS 20 mcg by Neb BID IB+ALB 18/103 mcg by pMDI QID	COPD: FEV1 25–80% Pred FEV1/FVC <70% Smoking > 10 pack yr Hx	109 (62 yr)	1.37 (52.8%)	2 wk am Pre-dose FEV1: FFIS, 1.42 L; IB+ALB 1.32 L (p = 0.0015) Patient satisfaction and perception of disease control, including medication getting into the lungs: significantly greater with FFIS in older (>65 yr), male, and severe/very severe subgroups
Tashkin et al, 2008 (58)	6 wk R, DB, P	BID Tx added to OL TB (18 mcg): 20 mcg FFIS (78) PLA (77)	COPD: FEV1 25–65% Pred FEV1/FVC <70% Smoking > 10 pack yr Hx	185 (65.6 yr)	1.19 (38.4%)	At Wk 6: Peak FEV1: FFIS, 1.61 L; PLA, 1.42 L (p < 0.0001) AUC(0–3h): FFIS, 1.52 L; PLA, 1.34 L (p < 0.0001) Significant improvements with FFIS vs. PLA also for FVC, TDI, Sx scores FFIS patients had fewer AEs including COPD exacerbations SGRQ scores did not differ between Tx
Nebulized corticosteroid
Paggiaro et al, 2006 (59)	6 mo MC, R, DB, PG,	BID Tx added to ALB/IB (1,875/375 mcg) by Neb and: FLU I,000 mcg (n = 58) PLA (n = 56)	COPD: FEV1 35-70% Pred FEV1/FVC <89% Smoking >10 pack yr Hx	121 (66 yr)	1.4 (53.2%)	Primary outcome, frequency of severe exacerbations: FLU, 19; PLA, 34 (p = 0.054) Patients experiencing ≥ 1 exacerbation: FLU, 16; PLA, 26 (p = 0.059) Type 3 Anthoniesen's exacerbations were significantly reduced w/FLU (p = 0.044) Significant improvements in both groups for FEV1

Abbreviations: AC, active controlled; AE, adverse events; ALB, albuterol; ARFOR, arformoterol; AUC, area under the curve; Bdil, bronchodilator; BID, bis in die, twice-a-day; BL, baseline; CO, crossover; COPD, chronic obstructive pulmonary disease; DB, double-blind; DD, double-dummy; FEV₁, forced expiratory volume in 1 second; FVC, forced (expiratory) vital capacity; FFDP, formoterol fumarate dry powder; FFIS, formoterol fumarate inhalation solution; FLU, flunisolide; Hx, history; IB, ipratropium bromide; IC, inspiratory capacity; Intermed, intermediate; LABA, long-acting beta-agonists; MC, multicenter; METAPRO, metaproterenol; Neb, nebulizer; OL, open-label; pMDI, pressurized metered dose inhaler; PC, placebo-controlled; PEFR, Peak Expiratory Flow Rate; PG, parallel group; PLA, placebo; Pred, predicted; QID, quarter in die, 4 times-a-day; QOL, quality of life; R, randomized; SABA, short acting beta-agonists; SAL, salmeterol; SGRQ, St. George's Respiratory Questionnaire; SVN, small volume nebulizer; Sx, symptoms; TB, tiotropium bromide; TDI, transition dyspnea index; TID, ter in die, 3 times-a-day; Tx, treatment; vs., versus; Wk, week(s); Yr, year(s)

Short-acting bronchodilators

Use of a short-acting bronchodilator agent by nebulization is recommended at all stages of COPD management for relief of acute bronchospasm. Improvement in lung function with a nebulized albuterol-ipratropium (2500/500 mcg) combination product compared to the individual treatments of albuterol or ipratropium was evident in a 6-week, 3-period, crossover study of 863 patients (46). The nebulized combination product resulted in a 24% greater improvement in FEV₁compared to albuterol alone and a 37% greater improvement than with ipratropium alone. Similarly, the area under the curve for FEV₁ was 30% and 32% greater with the combination than albuterol or ipratropium, respectively (46).

In patients with COPD combination therapy (albuterol + ipratropium) given by nebulizer, morning and night, with midday use of a pMDI, provided adequate control and improvement in quality of life (49). In this 12-week study by Tashkin and coworkers (49), 126 patients received treatment by nebulization (albuterol 2,500 mcg + ipratropium 500 mcg) 4 times-a-day, pMDI (albuterol 90 mcg + ipratropium 18 mcg) 2 puffs 4 times-a-day, or nebulization in the morning and evening with midday use of pMDI. Symptoms were significantly improved (p ≤ 0.05) in both nebulizer groups, but health-related quality of life, measured with the St. George Respiratory Questionnaire Quality of Life Instrument (SGRQ), was better in the nebulizer + pMDI group, possibly reflecting enhanced symptom relief provided by the nebulizer and the convenience of pMDI treatment when away from home during the day (49).

Long-acting bronchodilators

As disease severity increases, a long-acting bronchodilator agent (LABD) is recommended as routine, maintenance therapy (3,41). The only LABD currently available in nebulized form is formoterol, as the racemic mixture, formoterol fumarate inhalation solution (FFIS) at a strength of 20 mcg/2 ml, or as the enantiomeric formulation, arformoterol at a strength of 15 mcg/2 ml (60,61).Studies have demonstrated the effectiveness of both products in the regular treatment of patients with COPD with or without adding tiotropium bromide DPI (50–58). Tiotropium, a long-acting anti-cholinergic, is not available in a nebulized formulation in the United States but is available by micronebulizer (Respimat®) in Europe (6,26).

The FFIS 20 mcg/2 ml administered twice daily over a period of 12 weeks demonstrated a rapid onset of action associated with increased FEV₁ and improvements in symptoms and quality-of-life scores (53). The persistence of improvement over time showed no loss of efficacy or tachyphylaxis and was comparable to formoterol (12 mcg) given by DPI twice daily. In this study, there were no significant differences in the efficacy of either treatment with regard to lung function or symptoms; however, only the patients using FFIS showed statistically significant improvements in quality of life (QOL) (53). A 12-month, open-label trial comparing the two preparations found comparable retention and adherence rates, with no between-group differences in adverse events, laboratory values or cardiovascular events (51).

Nebulized arformoterol 15-mcg twice-a-day has been studied in several trials, although head-to-head comparisons with FFIS have not been conducted. In a placebo-controlled, 12-week, double-blind, randomized study of 717 patients with COPD 3 doses of arformoterol (15 mcg bid, 25 mcg bid, 50 mcg qd) were compared to salmeterol pMDI, 42 mcg twice-a-day (50). The FDA-approved dose of 15 mcg arformoterol twice-a-day provided sustained and significant improvement in FEV₁ over the 12-week study, with a mean change in peak FEV₁ at study end of 252 mL (21.2%) compared to 190 mL (15.1%) for salmeterol (p < 0.05 vs. arformoterol) and 170 mL (13.6%) for placebo (p < 0.01 vs. arformoterol).

When compared to placebo, improvements in other parameters – SQRQ, rescue albuterol, supplemental ipratropium – were similar between the treatments; although changes in the transition dyspnea index (TDI) only reached statistical significance with arformoterol. Perhaps the greatest difference between the treatments was the median time to response: between 3 and 14 minutes for arformoterol compared to 132 minutes for salmeterol at 12 weeks, and the placebo response at 327 minutes (50).

In a study of 155 COPD patients, Hanania and colleagues evaluated FFIS (20 mcg) twice-a-day as add-on therapy to once daily tiotropium bromide (18 mcg) (54). The group receiving FFIS + tiotropium showed greater improvements in FEV₁, FVC, and inspiratory capacity, with efficacy maintained over the entire 6 weeks of the study. The combination group also experienced fewer adverse events: 37% versus 51% for those receiving tiotropium alone. The additional improvement in FEV₁ with the combined product was approximately 130 ml compared to tiotropium alone and 410 ml compared to no treatment (54).

Inhaled corticosteroids

Inhaled corticosteroids are recommended with LABD for patients at GOLD (Global Initiative for Chronic Lung Disease) stages III and IV (Figure 2) (3). Recent studies have shown that GOLD stage II patients might also benefit, with specific regard to improvements in quality of life, decreased exacerbations, better lung function, and lower risk of mortality (3). Budesonide is the only corticosteroid currently available in the United States for treatment of COPD in a combination inhaler with formoterol (Symbicort® 160/4.5, AstraZeneca) (62). Data are not available for nebulized budesonide, but based on the authors’ unpublished experiences, FFIS and budesonide can be used twice-a-day with a jet nebulizer. A small 6-month study of regular therapy with nebulized flunisolide (1,000 mcg) in 114 COPD patients showed numerical, but not statistically significant, reductions in exacerbation rates (the primary variable) in addition to improvement in FEV₁ (59).

All recommended drug categories for the chronic treatment of COPD are available in nebulized form, though inhaled corticosteroids are not approved as monotherapy for COPD in the United States. Nebulized drugs have been found to be efficacious in patients with COPD for a chronic use strategy and may be most cost-effective with the current Medicare reimbursement system in patients who qualify under Part B coverage.

In summary, the limited data available suggest that when patients use their aerosol devices correctly, maintenance therapies provide similar clinical benefits. Nebulized LABDs alone and in combination with tiotropium may yield slightly better outcomes in some patients (50–58). Based on very limited data, it seems that older, male patients with more severe COPD do better (and prefer) nebulized therapy (44,57). However, as discussed previously, it is likely that other subgroups might also benefit. Whether nebulized delivery in such patients could slow disease progression has not yet been determined.

Inhaled pharmacotherapy during exacerbations of COPD (ECOPD)

The GOLD guidelines define an exacerbation of chronic obstructive pulmonary disease (ECOPD) as an event in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD (3). An average of 22% of patients with stage II disease, 33% with stage III and 47% with stage IV have two or more ECOPD events in the first year of follow-up. The single best predictor of exacerbations across all GOLD stages appears to be a previous history of exacerbations (63).

Hospitalizations due to ECOPD are significant events in the natural history of COPD as they are associated with a more rapid decline in lung function, worsening quality of life, and increased morbidity and mortality (50,51).Complete recovery from ECOPD may take up to 3 months after hospital discharge (52). Therefore, an optimal therapeutic approach to reducing the incidence and severity of ECOPD can improve long-term health status and may conserve health care resources and costs (53,54).

The symptomatic deterioration associated with ECOPD routinely requires treatment with antibiotics and/or corticosteroids in addition to bronchodilators, and may require hospitalization (3,41,64).For acutely dyspneic patients being treated for an episode of ECOPD, the potential for variability in drug delivery with handheld inhalers may have a negative impact on clinical outcomes (65). Therefore, nebulization may be the preferred method for administering inhaled medications in the acute setting of ECOPD as little effort and coordination are needed on the part of the patient (18,66,67). With the development of newer generations of high-efficiency nebulizers, a more effective delivery of bronchodilators and corticosteroids may potentially change ECOPD outcomes (68).

Short-acting bronchodilators

Substantial evidence shows that both short-acting beta agonists (SABAs) and short-acting anticholinergic agents (SAACs) can increase the FEV₁ and FVC by 15 to 30% over a period of 60 to 120 minutes when given during an ECOPD(69), and both induce similar bronchodilation (70). Inhaled SABAs such as albuterol and levalbuterol administered via a nebulizer or a pMDI are the cornerstone of therapy for ECOPD due to their rapid onset of action (71,72). In the absence of a prompt response to SABAs, the addition of a SAAC is recommended. Ipratropium is routinely administered in addition to SABA agents in most patients with ECOPD, and several studies have reported that the combination produces greater bronchodilation than either agent alone (73,74).However, other trials have not found the same positive outcomes after administration of SABA/SAAC combination in patients with ECOPD (75).

Regarding the potential deterioration of gas exchange in patients with ECOPD following administration of SABAs, Khoukaz and Gross (76) and Polverino et al. (77) found that in hospitalized patients with ECOPD, administration of albuterol did not aggravate the already compromised pulmonary gas exchange, and the declines observed were small, transient, and clinically insignificant. Although administration of a single dose of a SABA may increase heart rate by almost 10 beats per minute and reduce serum potassium by 0.36 mEq/L, these findings are relatively rare and do not appear to increase the risk of fatal or nonfatal acute myocardial infarction (78).

Long-acting bronchodilators

As the cornerstone of the pharmacotherapy of patients with stable COPD, use of long-acting beta agonists (LABAs) and long-acting anticholinergic agents (LAACs) is associated with significant reduction in the rate of ECOPD (79–83). Although formoterol is not approved for use as a rescue medication in the United States, its fast onset of action has drawn attention to a potential role as stand-alone medication or in combination with other bronchodilators in the management of ECOPD (84,85). Incorporating BID formoterol into a bronchodilator protocol for hospitalized patients with asthma or COPD reduced the need for respiratory therapist-administered treatments with SABAs (86). Adding once-daily tiotropium to the protocol further reduced utilization of health-care resources including bronchodilator costs and hospital length of stay (87).

Corticosteroids

The administration of systemic corticosteroids is strongly recommended in the treatment of ECOPD in published guidelines (4,40,41). In addition to improving symptoms and lung function, adding a corticosteroid to bronchodilator therapy significantly reduces treatment failure rates and length of hospital stays (88–91). Short courses of oral corticosteroids have been shown to be as efficacious as intravenous corticosteroids for treating most episodes of ECOPD (92), except in severe refractory cases or patients with impaired gastrointestinal absorption. However, the risk of serious adverse effects can outweigh clinical benefits, particularly as the rate of ECOPD increases in parallel with deteriorating lung function. A growing body of evidence favors using a moderate, rather than high dose of systemic corticosteroid (91,93,94).

The risk:benefit issue has led clinicians to explore using inhaled corticosteroids (ICS), which have high anti-inflammatory activity but a substantially lower systemic side-effect profile than oral or parenteral corticosteroids (95–97). Most trials of ICS in patients with COPD have shown some systemic absorption at high doses, but the clinical significance is unclear. Two meta-analyses evaluated the effects of ICS on bone mineral density (BMD) in adult patients with asthma and COPD and found that even after 2–3 years of administration, there was no significant decrease in the BMD (98,99).

Systemic corticosteroids have onset of action within a few hours of administration, reaching a peak effect after approximately 24 hours. ICS may exert their first anti-inflammatory effects within the first hour, and most attain peak effects within a few hours (100). Three studies comparing the efficacy of systemic corticosteroids and high-dose ICS delivered by pMDI in acute asthma exacerbations (100–102) reported similar improvements in symptoms, peak expiratory flow (PEF), FEV₁, treatment failure rates, and anti-inflammatory effects. To date, only 4 published studies have evaluated the efficacy of high-dose nebulized corticosteroids in ECOPD (Table 5) (103–106).

Table 5  Studies on the use of nebulized budesonide (BUD) vs. prednisolone (PRED) for exacerbations of chronic obstructive pulmonary disease

Study	N	Nebulized BUD dose	Prednisolone dose (comparator)	Study period (days)	Conclusions
Morice et al. (1996)103	20	2 mg BID	Oral, 30 mg daily	5	BUD safer; no between-tx difference in response
Maltais et al. (2002)104	171	2 mg QID	Oral 30 mg BID	3	BUD = alternative for systemic CCS
Mirici and Akgun (2003)105	40	4 mg BID	IV, 40 mg daily	10	BUD = alternative for systemic CCS
Gunen et al. (2007)106	121	1.5 mg QID	IV, 40 mg daily	10	BUD safer; an alternative for systemic CCS

Abbreviations: BID, “bis in die” (two times-a-day); BUD, budesonide; CCS, corticosteroid; IV, intravenous; PRED, prednisolone; QID, “quarter in die” (4 times-a-day).

Earlier studies reported nebulized budesonide to be as efficacious as systemic corticosteroid with no adverse events (103,105). Maltais et al. compared the efficacy of nebulized budesonide and systemic corticosteroid for the first 72 hr of hospitalization in 171 patients with nonacidotic ECOPD and found no differences for improved FEV₁, hospital duration, and occurrence of adverse events (104). Systemic treatment was associated with a more substantial decrease in PaCO₂ and a larger increase in post-bronchodilator FEV₁, suggesting that it may be a better option for patients with imminent acute respiratory failure who require ventilatory support or admission to an intensive care unit.

However, a higher dose and/or more frequent administration of ICS may provide the same efficacy as systemic corticosteroid as demonstrated for asthma exacerbations (107). Gunen et al. conducted the first comprehensive study comparing both short- and long-term effects of high-dose nebulized budesonide (1.5 mg qid) and systemic prednisolone (40 mg) (106). They confirmed that high-dose nebulized budesonide was as effective as systemic corticosteroid for the short- and long-term treatment of 159 patients hospitalized with ECOPD, except in very severe cases. Particularly important is the fact that nebulized budesonide has been shown to be chemically stable and physically compatible when mixed for simultaneous administration with other common nebulized medications used to treat patients with ECOPD, including albuterol, levalbuterol, and ipratropium bromide inhalation solutions (108).

Recommendations and Summary

Inhalation therapy is the cornerstone of treatment for patients with asthma and COPD, and pMDIs and DPIs remain the first line choice for maintenance treatment of these disorders. However, elderly patients, patients with severe disease, and those with other physical and/or cognitive limitations frequently cannot optimally use the handheld inhalers; for such patients nebulizers should be employed on a domiciliary basis.

Nebulizers are more forgiving to poor inhalation technique, especially poor coordination, than pMDIs because the aerosol is delivered over several breaths and no special breathing maneuvers are needed. Likewise, the requirement to generate adequate peak inspiratory flows that limits effective DPI use in elderly patients with severe COPD is not a barrier for nebulizer therapy. Some patients may prefer nebulizers because the costs of the equipment and medications are covered by Medicare, unlike pMDIs and DPIs for which separate coverage under Medicare part D is needed. Although there are no convincing data to show superiority of nebulizers for maintenance therapy in patients with COPD, better clinical outcomes could be expected for patients who prefer to use nebulizers over other handheld inhalers as well as those who have difficulty using pMDIs or DPIs. As such, we recommend nebulized delivery of drugs for COPD in the following situations:

• Elderly patients, particularly male patients over 65 years of age

• Patients with severe disease and frequent exacerbations

• Patients who have physical and/or cognitive limitations

• For inhalation drug delivery during exacerbations of COPD, especially when higher than routine drug doses are needed

• When monetary concerns favor nebulized therapy over other inhalers

• Patients who prefer nebulized therapy over other inhalers.

For some patients with COPD, the dual use of nebulizers and pMDI/DPI may achieve the best combination of efficacy and convenience. However, to minimize confusion, clinicians should make efforts to employ a single platform for delivery of all inhaled medications. Nebulizers could fulfill this requirement for many patients with COPD.

In summary, for optimal treatment of COPD, consideration of patient characteristics when recommending and prescribing an aerosol delivery device can help to minimize device use errors. The patient's age, cognitive status, visual acuity, manual dexterity and manual strength, ability to coordinate actuation of the inhaler with inhalation of the aerosol released may be as important as disease severity in determining the appropriate approach to delivery of medication. For many patients, using a nebulizer alone or in addition to a pMDI or DPI provides an easy-to-use and cost-effective therapy. Further studies are needed to determine whether this approach will also reduce episodes of exacerbations requiring an Emergency Department visit or hospital admission or diminish the rate of progressive decline in lung function associated with COPD.

Declaration of Interest Statements

Disclosure of potential conflict of interest: Bradley Chipps, MD, has received grants for clinical research from Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Sunovion, and Merck (Schering). He has also received grants for educational activities from Alcon, Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Sunovion, and Merck (Schering). Dr. Chipps serves as an Advisor for consultation to Alcon, Genentech, AstraZeneca, GlaxoSmithKline, Meda, Novartis, Sunovion, Merck (Schering), ISTA, Quintiles, and Dey Pharmaceuticals; and he is on the Speakers’ Bureau of Alcon, Genentech, AstraZeneca, GlaxoSmithKline, Meda, Novartis, Sunovion, Merck (Schering), ISTA, and Dey Pharmaceuticals.

Rajiv Dhand, MD, has received grants for clinical research from GlaxoSmithKline and Novartis; has served as a consultant for Mylan Pharma and Astra-Zeneca and is on the Speakers’ Bureau of GlaxoSmithKline.

Myrna Dolovich, P.Eng., has nothing to disclose.

Judith Farrar, PhD, has nothing to disclose.

Timothy Myers, RRT-NPS, serves on the TiNA Advisory Board and is a consultant for Boehringer Ingelheim.

Ruben Restrepo, MD, RRT has nothing to disclose.

Disclosure of sponsor involvement:

This manuscript was supported in part by an unrestricted educational grant from Dey Pharmaceuticals. The company had no involvement in the development, writing, or review of the manuscript other than providing access to market data analyses on the number of patients with COPD who use nebulizers in the United States. That data would not otherwise have been available to the authors.