Nebulizer inhalation therapy | The role of inhalation therapy in the management of COPD patients will become more important

Chronic obstructive pulmonary disease ( COPD ) is a common, treatable, preventable disease that is a significant cause of morbidity and mortality among chronic diseases. COPD is currently ranked as the fourth leading cause of death in the United States and is projected to become the third leading cause of death worldwide by 2030. More than 16 million people in the United States have been diagnosed with COPD, but it is estimated that millions more remain undiagnosed. The global burden of COPD is expected to increase due to continued exposure to COPD risk factors, such as tobacco smoke and air pollution.

Inhalation delivery is the preferred route of administration for COPD treatment because it can achieve high drug concentrations locally in the lungs, thereby improving efficacy and reducing systemic adverse events ( AEs ) compared to other routes of administration (such as oral or intravenous injection). Bronchodilators and muscarinic antagonists, beta - agonists, and inhaled corticosteroids ( ICS ) are the basis of drug therapy for COPD patients. These agents are usually delivered via nebulizers and handheld inhalation devices , including dry powder inhalers ( DPIs ) , pressurized metered dose inhalers ( pMDIs ) , and soft mist inhalers ( SMIs ) .

Although Tashkin has discussed innovations in nebulized medication therapy and its role in COPD patients, there have been important new developments since his review was published . With the approval of the nebulized long-acting muscarinic antagonists ( LAMAs ) glycopyrrolate and revenacin, and now the development of the first nebulized dual phosphodiesterase 3/4 inhibitor , RPL554 , nebulized therapy is an increasingly promising alternative to handheld inhaler devices .

Therefore, the purpose of this narrative review is to highlight the recent advances and treatment prospects of nebulizer therapy and COPD . We first discuss the pathophysiology of COPD and considerations for inhaler devices. Second, we review the latest status of recently approved and newly marketed nebulizer therapies, nebulizer therapies currently in development, and technological advances in nebulizer devices. Finally, we discuss the current status of nebulizer therapy use in patients with COPD .

Pathophysiology of COPD and inhaler device considerations

Small airway disease is one of the cardinal features of COPD . Narrowing and destruction of small airways (diameter <2 mm ) are characteristic of early COPD and precede the development of emphysema. Anatomical changes in these airways include structural abnormalities of the conducting airways (e.g., peribronchiolar fibrosis, mucus plugging) and loss of alveolar attachments due to emphysema, resulting in instability of these airways associated with reduced elastic recoil. Abnormal small airways are the primary site of airflow resistance in COPD , and drug targeting of the small airways remains one of the main goals of COPD treatment.

Direct drug delivery via inhalation is an attractive approach in the treatment of pulmonary diseases because it promotes high bioavailability of therapeutic drugs ( 10–200- fold higher than gastrointestinal delivery) and is independent of dietary variability, extracellular enzymes, and interpatient metabolic differences that may affect gastrointestinal absorption. However, the deposition of drug molecules in the lungs can be affected by particle- and patient-related factors, such as airway geometry, airway humidity, particle size, pathological processes that affect airway luminal patency, breathing patterns, and lung clearance mechanisms. Therefore, these factors can affect the therapeutic efficacy of inhaled therapies.

Aerosol particle size is one of the most important determinants of drug deposition in the lung. Each inhaler device has specificities in how it prepares the dose and delivers the drug to the airways, which determines the density and size of the particles produced (Figure 1 ). Aerosol particle size is typically based on mass median aerodynamic diameter ( MMAD ) and the optimal MMAD range is 1–5 μm . Some studies have shown that medium-sized particles (≈3 μm ) are more effective at bronchodilating compared with smaller particles. Inhalers with aerosol particle sizes greater than 5 μm deliver lower doses and are associated with greater oropharyngeal deposition and reduced lung delivery compared with inhalers with smaller aerosol particle sizes and higher delivery efficiency . The patient's peak inspiratory flow rate ( PIFR ) generally determines the velocity of particles in the air, which in turn affects their probability of impact in the oropharynx and larynx. Therefore, optimizing drug delivery requires the use of fine aerosol particles inhaled at appropriate flow rates, and a " one-size-fits-all " approach may not be appropriate for the treatment of COPD .

Current inhalation delivery systems

Although pMDIs , DPIs , and SMIs may be appropriate for some COPD patients, certain patient populations may have challenges with using these devices . Patients with cognitive impairment, neuromuscular impairment, or ventilatory impairment (and limited assistance from caregivers) and those with suboptimal peak inspiratory flow rates may not receive the full benefit of handheld inhaler devices . With respect to pMDIs , these patient populations may have difficulty coordinating inhaler device triggering with inspiration, have difficulty producing a deep enough inspiration, inhale too quickly, and / or be unable to hold their breath long enough to effectively deliver medication. To overcome some of the limitations associated with underuse of pMDIs , inhalation devices such as spacers and valved applicators can be used with pMDIs to improve the efficiency of aerosol delivery . In addition, breath-actuated pMDIs are useful for patients who have difficulty properly timing inspiration. However, breath-actuated pMDIs do not help patients who stop inhaling during inspiration, and they still require a minimum PIFR of 20–30 L/min . Similar to breath-actuated pMDIs , DPIs require a minimum PIMR of 20–50 L/min . Women of shorter stature, patients with a lower percentage of predicted forced vital capacity ( FVC ), and patients with reduced inspiratory muscle strength are the main patient groups with poor PIFR . In addition, the generation of PIFR depends on the patient's respiratory muscle strength and effort , which may be affected by acute exacerbations, lung overinflation, hypoxemia, and / or muscle atrophy in patients with COPD .

For SMI , the coordination requirement between patient triggering and inspiratory effort is reduced (but not completely eliminated). Scintigraphic studies have shown up to 50% higher lung deposition and lower oropharyngeal deposition with soft-mist inhalation devices compared with chlorofluoroalkane ( CFC ) -based pMDIs . However, a recent meta-analysis reported that approximately 60% of patients using soft-mist inhalation devices experienced device use errors similar to those with pMDIs . The most common errors were breathing errors, hand-to-breath coordination, and difficulty priming the inhaler.

Nebulized drug therapy

A significant number of COPD patients remain breathless despite high-dose pMDIs and DPIs and may benefit from nebulized therapy . Nebulizers are an attractive alternative to handheld inhalation devices for delivering inhaled therapy and have become the cornerstone of inhaled therapy in acute and critical care settings. Nebulizers are now also widely used in clinics, outpatient clinics, and home settings. Current evidence suggests that the efficacy of therapy delivered to COPD patients via nebulizer is similar to that delivered to patients using pMDIs and DPIs . Because nebulizers do not require patients to coordinate between inhalation and triggering , nor do they require any special breathing technique (e.g., full exhalation followed by full inhalation and a breath- hold of several seconds close to total vital capacity ), these devices may be particularly beneficial for patients with cognitive, neuromuscular, or ventilatory impairments, as well as those with suboptimal PIFR . More than 50% of patients use nebulizers rather than other devices because of physical or cognitive impairment. In terms of cost, reports on the use of nebulizers versus inhalation devices have shown different financial impacts on hospitals. A recent retrospective analysis in the United States evaluated respiratory medication costs at 28 health system hospitals after a phased inhalation device to nebulizer program . System-wide drug expenditures decreased by approximately 40% in the first and 2.35 years after implementation compared to before implementation . On the other hand, a cohort study in a US hospital showed that reducing the use of nebulizers and implementing MDI in the hospital resulted in significant annual savings. However, some limitations of this study include the lack of a control group and the possible overestimation of cost savings because some costs were semi-fixed. Considering the effectiveness related to treatment costs, healthcare providers should adopt a personalized approach when treating patients with COPD .

Although some older nebulizer devices have some limitations (lack of portability, long drug administration time), technological advances have led to the recent development of newer nebulizer devices (breath-augmented jet nebulizers , breath-driven jet nebulizers , and vibrating mesh nebulizers ) that reduce drug waste and improve delivery efficiency (Figure 2 ). Table 1 describes the key features, advantages, and disadvantages of these newer nebulizer devices.

Breath-enhanced jet nebulizers ( PARI LC? Sprint [PARI Respiratory Equipment , Midlothian , VA] , NebulTech HDN? [Salter Labs , Arvin , CA] , and SideStream Plus? [Philips , Murrysville , PA] ) are designed to increase the supply of nebulized aerosol only during active inspiration and to expel exhaled air outside the device. Similarly, breath-actuated jet nebulizers , such as the AeroEclipse? II BAN ( Monaghan Medical Corporation , Plattsburgh , NY ), also deliver nebulized aerosol only during inspiration and tend to reduce drug waste during nebulized therapy. Vibrating mesh nebulizers , such as the eFlow? rapid ( PARI Pharma GmbH , Stranberg , Germany ) and Micro Air? NE-U22 ( Omron Healthcare , Bannockburn , IL ), use micropump technology to produce aerosols with fine particle content, which allows for more efficient drug delivery compared to conventional jet nebulizers . The AKITA2? APIXNEB ( PARI Pharma GmbH , Gr?felfing , Germany) mesh nebulizer uses adaptive aerosol delivery technology to coordinate drug delivery based on the patient's breathing pattern .

Nebulizers are a form of aerosol generation that can be used at any age or COPD stage. With recent technological advances, nebulizers will continue to play an important role in the treatment of COPD .

Overview of nebulized therapeutic drugs

A variety of nebulized short-acting and long-acting bronchodilators are available for the treatment of COPD . Overall, these nebulized therapies have shown significant improvements in lung function and reductions in the use of reliever medications.

Nebulized short-acting beta- agonists ( SABAs ) and short-acting muscarinic antagonists ( SAMAs )

Nebulized short-acting bronchodilators are widely used in the treatment of patients with acute COPD exacerbations in the hospital setting. Clinical studies of the nebulized SABAs albuterol sulfate and levalbuterol hydrochloride have demonstrated improvements in forced expiratory volume in 1 second ( FEV1 ) compared with placebo. No significant differences were observed between the two treatments in terms of efficacy, cost, adverse event rates, or hospitalizations. Regarding nebulized SAMAs , nebulized ipratropium bromide showed significant improvements in FEV1 within 15–30 minutes, which lasted for 4–5 hours. In addition, clinical studies of ipratropium bromide - salbutamol have demonstrated improvements in FEV1 compared with either albuterol or ipratropium alone . Ipratropium bromide - salbutamol has also shown a mean time to peak FEV1 of 1.5 hours and lasts for approximately 4 hours.

Nebulized long-acting beta- agonists ( LABAs )

Nebulized arformoterol tartrate and formoterol are given twice daily for maintenance treatment of patients with COPD . Aformoterol significantly improved the mean percentage change in FEV1 over 12 weeks compared with placebo and was well tolerated. A 12 -month Phase IV study showed no increased risk of respiratory death or hospitalization associated with COPD exacerbations. Nebulized formoterol significantly increased FEV1 over 12 weeks compared with placebo , and its efficacy and safety were similar to formoterol administered via DPI .

Nebulized LAMA

Nebulized glycopyrrolate is a twice-daily inhalation solution administered via a mesh nebulizer using the eFlow?CS nebulizer ( PARI Pharma GmbH , Stranberg , Germany ) and was approved by the U.S. Food and Drug Administration ( FDA ) for the maintenance treatment of COPD in 2017. Glycopyrrolate /eFlow?CS has an MMAD of 3.7 μm , making it optimal for bronchodilation.

Overall, the Phase III trial showed that glycopyrrolate significantly improved lung function in patients with moderate to severe COPD with acceptable safety (Table 2 ).

In two 12- week phase III trials ( GOLDEN 3 [NCT02347761] and GOLDEN 4 [NCT0237774] ), glycopyrrolate significantly improved FEV1 compared with placebo , and the incidence of adverse events was lowest in patients who received inhaled glycopyrrolate 25 μg twice daily in both phase III trials . Discontinuations due to adverse events were more common in the placebo group than in the glycopyrrolate group, and the incidence of cardiovascular adverse events and major adverse cardiovascular events ( MACE ) was low in both trials. In a 48 -week safety study ( GOLDEN 5 [NCT02276222] ), the incidence of overall and serious adverse events was similar among patients who received inhaled glycopyrrolate or tiotropium (active control); however, fewer MACEs were reported in patients who received glycopyrrolate .

Revenacin is a once-daily inhalation solution that is administered via a standard jet nebulizer using the PARI LC? Sprint nebulizer ( PARI Pharma GmbH , Starnberg , Germany ) and the PARI Trek? S compressor ( PARI Respiratory Equipment , Midlothian , VA , USA ). The MMAD of the PARI LC? Sprint nebulizer/PARI Trek? S compressor is reported to be 3.8 μm , which is the optimal particle size for bronchodilation. In 2018 , the US Food and Drug Administration approved Revenacin for the maintenance treatment of COPD . Overall, the Phase III trial showed that Revenacin significantly improved lung function and had an acceptable safety profile in patients with moderate to severe COPD (Table 2 ).

In two 12- week phase III trials (Studies 0126 [NCT02459080] and 0127 [NCT0252510] ), revenacin significantly improved baseline FEV1 values compared with placebo, with similar overall rates of adverse events and serious adverse events in the revenacin and placebo groups. The incidence of cardiovascular AEs and MACE was low. In a 52 -week phase III safety trial (Study 0128 [NCT02518139] ), revenacin demonstrated significant improvement from baseline in trough FEV1 that was comparable to that achieved with tiotropium (active control). In patients taking concomitant inhaled LABA±ICS , the effect of revenacin on trough FEV1 was comparable to that in patients not taking these drugs. AEs and serious AEs were comparable across all treatment groups. The incidence of cardiovascular AEs and MACE was low across all treatment groups, with only one MACE (atrial fibrillation) considered possibly / probably related to revenacin 175 μg . In a 28- day phase IIIb trial (Study 0149 [NCT0309546] ), revenacin and tiotropium (active control) effectively improved baseline FEV1 and FVC trough values, numerically favoring revenacin over tiotropium. In a prespecified subgroup analysis, revenacin significantly improved trough FEV1 and FVC values compared with tiotropium in patients with severe to very severe COPD ( i.e. , FEV1 < 50% predicted ) , who comprised 80% of the patients enrolled . Few adverse events were reported for revenacin or tiotropium, with only one serious adverse event ( COPD exacerbation) reported for tiotropium . In a 42- day phase IIIb trial (Study 0167 [NCT03573817] ), continuous and combination administration of revenacin / formoterol via a standard jet nebulizer was well tolerated, with fewer revenacin / formoterol-related adverse events than placebo/formoterol. Revenacin / formoterol (administered either sequentially or in combination) resulted in a statistically significant improvement from baseline in trough FEV1 compared with placebo / formoterol.

Nebulized ICS

The GOLD guidelines recommend initial treatment with a LABA/ICS combination in patients with frequent exacerbations and eosinophil counts >300 cells /μL or in patients with a history of asthma and COPD . In addition, patients who experience exacerbations during LAMA/LABA treatment can be upgraded to LABA/LAMA/ICS therapy. A recent report points to the benefits of triple inhaler therapy for COPD. In patients with COPD , fluticasone furoate / umeclidinium / vilanterol triple therapy reduced moderate or severe COPD exacerbations and hospitalizations compared with fluticasone furoate /vilanterol or umeclidinium / vilanterol . To date , few studies have been conducted on nebulized ICS therapy in patients with COPD . Meta-analyses have shown that high-dose nebulized budesonide 4–8 mg/ day is noninferior to the change in FEV1 from baseline to end of treatment compared with systemic corticosteroids. Nebulized budesonide has a lower incidence of hyperglycemia than systemic corticosteroids.

Nebulized antibiotics

Some COPD patients with chronic bronchial infections may have an infectious phenotype, and chronic infections are associated with exacerbations. Recent studies have shown that frequent use of some antibiotics can reduce exacerbations. However, to date, there have been few studies on the use of nebulized antibiotics in COPD , with only four reports investigating the efficacy of nebulized antibiotics in patients with COPD . Dal Negro et al. evaluated the effect of nebulized tobramycin ( 300 mg twice daily for 2 weeks) on the incidence of exacerbations and proinflammatory markers in patients with severe to very severe COPD who harbored Pseudomonas aeruginosa. Tobramycin reduced the incidence of exacerbations by 42% compared with the previous 6 months, and proinflammatory markers were significantly reduced after 2 weeks. Soltaninejad et al. evaluated the effect of nebulized gentamicin ( 80 mg twice daily for 5 days) compared with placebo on lung function in patients with acute exacerbations of COPD . Gentomycin treatment resulted in significant improvements in FVC and FEV1 compared with placebo . Bruguera Avila and colleagues evaluated the effect of nebulized polymyxin solution ( 80 mg twice daily for 1 year) on the number of severe exacerbations requiring hospitalization and the length of hospital stay in patients with COPD . Polymyxin reduced the number of hospitalizations per person per year from 2.0 to 0.9 and had a shorter length of stay ( 23.3 days vs. 10.9 days). Together, these studies suggest that nonmedicated antibiotics have a potential therapeutic role in patients with COPD who have drug-resistant pathogens. However, a phase II study evaluating the efficacy of nebulized levofloxacin ( 240 mg twice daily for 5 days every 28 days for 9-12 cycles) in patients with COPD showed no significant reduction in the exacerbation rate and no increase in the time to the next exacerbation compared with placebo. It is suspected that the “ pulse ” treatment regimen may be suboptimal. However, the impact of pulse antibiotics remains uncertain and further research is needed.

Rpl554 aerosol therapy in development

RPL554 is a dual inhibitor of phosphodiesterase 3 ( PD3 ) and PD4 enzymes and is currently being developed as an aerosolized formulation for maintenance treatment of COPD and for the treatment of acute exacerbations of COPD in the hospital setting . In four proof-of-concept clinical studies, RPL554 demonstrated bronchodilatory and anti-inflammatory effects and was well tolerated.

In a single-dose, placebo-controlled, six- arm crossover Phase IIa study, nebulized RPL554 ( 6 mg ) and standard doses of short-acting bronchodilators (albuterol, ipratropium) produced significant and clinically meaningful additional bronchodilation ( >60% ; P<0.001 ) and was well tolerated with no increase in adverse events compared with placebo. In a 3- day, randomized, placebo-controlled Phase IIa study, RPL554 ( 1.5 mg or 6 mg ) and tiotropium 18μg produced statistically significant peak FEV1 ( 1.5 mg , 104 mL , P=0.002 ; 6 mg , 127 mL , P<0.0001 ), and RPL554 was well tolerated as an add-on therapy to tiotropium . A 4 -week, placebo-controlled Phase IIb study showed that RPL554 improved lung function ( >200mL ; P<0.001 ) and COPD symptoms ( P≤0.002 ) and was well tolerated at all four doses ( 0.75 mg , 1.5 mg , 3 mg or 6 mg ) compared to placebo.

These studies suggest that RPL554 is a promising treatment for COPD ; however, further studies are needed to determine its ability to elicit anti-inflammatory activity in COPD patients. RPL554 is currently in Phase IIb development, with Phase III trials planned for 2020 .

Important factors to consider when evaluating inhalation device selection for COPD patients include patient characteristics, medication combination, patient preference, and satisfaction. Although inhalation devices present various challenges in effectively delivering therapy, nebulizers offer an alternative route of drug administration for COPD patients that avoids the need for high inspiratory flow rates, manual dexterity, or complex hand-breath coordination.

With quieter, more portable nebulizer devices, patients should be able to access nebulizer therapy with minimal inconvenience. Although nebulizers typically involve a few steps (e.g., assembling the device, inserting the vial into the device, and cleaning, which, in the case of vibrating mesh nebulizers , requires disassembly of the device), patients are generally satisfied with the nebulizers and find them easy and convenient to use with quick action. Suboptimal PIFR ( <60 L/min ) identifies patients who do not respond well to DPIs compared with optimal PIFR ( ≥60 L/min ) . 19–78% of outpatients and 32–52% of inpatients demonstrated suboptimal PIFR before discharge after treatment . Two randomized controlled trials demonstrated that patients with severe to very severe COPD and those with suboptimal PIFR had greater improvements in lung function with nebulized bronchodilators compared with DPIs .

For elderly patients and those with arthritis, musculoskeletal disorders , or neurological conditions, dexterity and grip strength should be considered when prescribing an inhalation device . DPIs may not be suitable for patients with tremors, as jitter or instability of the inhalation device may result in dose loss. Patients with reduced dexterity and weak grip strength may have difficulty actuating pMDI devices. In addition, coordination between inhalation and actuation is a common problem for these patients. Nebulizers can overcome these concerns and therefore may be an appropriate device for these patient groups.

LAMAs have a greater impact on reducing exacerbations and hospitalizations than LABAs. Nebulized LAMAs were not available for primary maintenance treatment of COPD until revifenacin and glycopyrrolate were approved to provide an alternative to inhaled devices . Revifenacin and glycopyrrolate demonstrated significant improvements in lung function with an acceptable safety profile. Combination therapy with LABAs and LAMAs is recommended for patients with severe COPD who have severe symptoms . There are currently no new fixed-dose LAMA/LABA combinations on the market; however, a recent pilot study showed that revifenacin / formoterol administered via a standard jet- jet nebulizer was well tolerated compared with placebo / formoterol . In addition, a recent study showed that revifenacin /formoterol was stable at room temperature for at least 60 minutes when used in combination with albuterol, aformoterol, or budesonide . Further research and development of nebulized dual bronchodilators may be beneficial from a patient compliance perspective. In addition, the benefits of triple therapy ( LABA/LAMA/ICS ) have been demonstrated. Triple therapy has the potential to further reduce COPD exacerbations and hospitalizations compared to dual bronchodilator therapy ( LABA/LAMA ) . The availability of these bronchodilators via nebulization could ensure concomitant delivery . The development of the first nebulized PD3/4 inhibitor may provide another treatment option for patients who have further exacerbations on LABA/LAMA or LABA/LAMA/ICS .

In conclusion, it is important to consider patient characteristics, medication combinations, patient preferences, and satisfaction when recommending and prescribing inhalation devices to patients with COPD . With the development of more advanced nebulizer devices and the recent availability of nebulized LAMA , nebulized therapy may be a suitable alternative to handheld inhalation devices , especially for patients with cognitive, neuromuscular, or ventilatory impairment (and limited assistance from caregivers), as well as those with poor PIFR . Compared with inhalation devices , nebulizers are easy to use and do not require forceful inspiration or complex hand-breath coordination. Given that COPD is a significant cause of chronic morbidity and mortality, and is expected to become the third leading cause of death worldwide by 2030 , the role of nebulizers in the management of patients with COPD is likely to become even more important in the near future.?