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

Figures & data

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

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.

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.

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.

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)

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).

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