The inhaled route has been used for centuries to administer various substances and drugs. Inhaled drugs are deposited directly in the respiratory tract, and therefore achieve higher concentrations with faster onset of action and fewer side effects than when used systemically. The 3 modalities commonly used are pressurized metered-dose inhalers, dry powder inhalers, and nebulizers. As a general rule, nebulizers are not recommended if the drug can be administered using other devices.1–4 The European Respiratory Society2 recommends them for patients who require high doses of bronchodilators, when they need to inhale drugs that only exist in this form (antibiotics or dornase alfa), or when they are unable to use other inhalation devices.2

Medicinal products for inhalation are developed with specific characteristics that are different to their systemically administered analogs. The efficacy of nebulization depends on many factors, including the characteristics of the medicinal product (size, shape, density, and surface tension of the particle), the anatomy of the airway, the patient's inhalation technique, and the nebulization system.1 The size of the particles produced by a nebulizer depends on the properties of the solution and the flow rate. The higher the flow rate, the smaller the size of the particles in the aerosol. Particles of between 1 and 5μm are most likely to reach the correct sites in the bronchial tree and achieve the sought-after therapeutic effect.1–4 Nebulization devices or systems are composed of a nebulization chamber containing the liquid to be nebulized and from which the aerosol is generated, and an energy source to produce the mist. There are 3 types of nebulizers for clinical use: ultrasonic, jet (pneumatic) and mesh. Their main characteristics are summarized in Table 1. Nebulized drugs should preferably be administered using the nebulizers with which the clinical trials were conducted. Patients should be trained in their use, cleaning and maintenance. Technological development in recent years has led to new devices that optimize lung deposition and reduce the time needed to administer the treatment.1,4,5 In this review we will focus on currently available or investigational drugs for use in nebulization in adult patients.

Various systematic reviews have shown that the 3 types of devices commonly used to administer inhaled bronchodilators and corticosteroids (pressurized inhalers, dry powder inhalers, and nebulizers) have a similar efficacy when used correctly.2–4,6,7 However, clinical practice has shown that some patients (particularly the elderly) with physical or mental limitations, or with serious disease, are unable to correctly use dry powder or pressurized metered-dose inhalers.8 These patients, together with those who prefer nebulizers to other inhalers, could benefit from nebulized drug delivery.2,3,9–13

Short-acting bronchodilators are those most often used in nebulization, with drugs such as salbutamol and ipratropium bromide being currently available. Their combined use has been found to obtain a 24% improvement in the FEV1 compared to salbutamol alone, and a 37% improvement with respect to ipratropium bromide alone, in patients with chronic obstructive pulmonary disease (COPD).14 This treatment can improve quality of life even with concomitant use of another inhaler.15 Formoterol is the only long-acting bronchodilator available (as formoterol fumarate or arformoterol), although not in Spain. Various studies have demonstrated its effectiveness in the treatment of patients with COPD.16–18

Nebulized corticosteroids,19–28 principally budesonide20–23 (although also flunisolide,24 fluticasone,25 and beclomethasone26,27), can be considered an effective alternative in patients with asthma or COPD who are unwilling or unable to use other inhalation devices (Table 2). In a study of elderly patients with asthma or COPD who found it difficult to use other devices, Marcus et al.28 observed less use of systemic corticosteroids and fewer visits to the emergency department when long term treatment was maintained with nebulized corticosteroids. Maltais et al.22 compared the efficacy of nebulized budesonide and systemic corticosteroids in patients with COPD exacerbations and found no differences in FEV1 improvement, hospital stay, or adverse effects. The use of higher or more frequent doses could be a safe alternative to systemic corticosteroids, without their accompanying side effects.23

Nebulized antibiotics (NAB) (penicillin and streptomycin) were first used for the treatment of bronchial infection in the 1950s.29,30 These early attempts gave way to the use of a wider range of NABs, prepared from their intravenous formulation, essentially in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa (PA) infection. They have also been used for the treatment of bronchial infection in non-CF bronchiectasis (NCFB), COPD, and in ventilator-associated pneumonia (VAP). All this has driven the commercialization of specific antibiotic preparations for nebulization (Table 3) and the launch of clinical trials with different antibiotics for inhalation (some in dry power form, which will not be discussed here) in different diseases.29–33 NABs should preferably be administered using the nebulizers with which the trials were conducted.1–4,33,34

Aspergillus fumigatus infection is the most common infection in lung transplant recipients. Inhaled amphotericin is the most common preventive strategy.104 It has good distribution at pulmonary level105 without modifying surfactant lipid levels,106 and has very low systemic absorption. It comes in 3 presentations: amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B. The latter 2 are the most widely used as they are well tolerated and have better pulmonary distribution.105

Inhaled amphotericin for the prevention of invasive pulmonary aspergillosis has been used with good results in patients with hematological diseases with expected chemotherapy-induced neutropenia.107 It may also be an alternative to itraconazole or voriconazole treatment in patients with CF and allergic bronchopulmonary aspergillosis (ABPA). Proesmans et al.108 treated 7 patients with CF, ABPA, and difficulty in tapering steroids with amphotericin B deoxycholate or amphotericin B lipid complex, demonstrating its efficacy and safety, with improved lung function and only 1 treatment failure.108

The pharmacokinetic results of an aqueous suspension of itraconazole for patients with ABPA have recently been published, reporting high and long-lasting lung tissue concentrations, which enable once daily administration with minimal systemic exposure.109

Nebulized N-acetylcysteine has not been shown to be effective in COPD,10,89,110 CF,33,36,37,111 bronchiectasis,33,67,68 or conclusively in idiopathic pulmonary fibrosis.112 A recent randomized study by Homma et al.113 found that nebulized N-acetylcysteine monotherapy could be useful in patients with early stage idiopathic pulmonary fibrosis, because although there was no improvement in lung function, it did appear to halt deterioration.

Inhalation of dornase alfa (DNase) has been shown to be clearly effective in CF,33,36,37,114 but in bronchiectasis due to other etiologies it may be ineffective or even harmful,115,116 and therefore is not recommended (Table 6).

Inhalation of hypertonic saline solution (HSS) in patients with CF is effective, as it reduces exacerbations, improves quality of life, and slightly improves lung function.33,36,37,117

In patients with NCFB, HSS may reduce sputum viscosity and exacerbations, and improve quality of life and lung function.33,67,68 Nicolson et al.118 compared saline 6% with saline 0.9%, and found that both reduced colonization by microorganisms and exacerbations, while improving quality of life and lung function, with no significant differences between concentrations.118 HSS may also have immunomodulatory effects, and it has been observed that it may reduce interleukin-8 concentrations in sputum and bronchoalveolar lavage.119

Clinical trials are currently ongoing in COPD with HSS120 and BIO-11006 inhalation solution, which could have anti-inflammatory effects and inhibit mucous secretion.121

Alpha-1 antitrypsin (AAT). The role of nebulized AAT as an anti-inflammatory treatment in CF is currently being investigated. In a randomized, double-blind study of 39 patients treated for 4 weeks with inhaled human recombinant AAT, the drug was well tolerated, but had a limited effect on inflammatory markers.122,123 In contrast, Griese et al.124 observed a decrease in the total PA load and in inflammatory markers in induced sputum with the inhalation of AAT. Nebulized l-arginine has recently been used in patients with CF,125 and was found to be safe and well-tolerated, increasing nitric acid production with no evidence of changes in bronchial inflammation.

Magnesium sulfate. Various studies have assessed the role of magnesium sulfate in asthma exacerbation. A recent Cochrane review did not find significant improvements when magnesium sulfate was added to beta-agonist treatment.126 In a subsequent meta-analysis, magnesium sulfate was added to usual treatment with corticosteroids and beta-2 agonists; in adults, this nebulized treatment was associated with a significant effect on pulmonary function and a reduction in hospital admissions.127 Goodacre et al.128 compared the effect of intravenous magnesium sulfate versus nebulized magnesium sulfate and placebo in 1084 adults, and found no benefit in adding it to standard treatment, either in dyspnea or in the rate of hospitalizations. There is currently no evidence that nebulized magnesium sulfate in adult patients has any effect on asthma exacerbation.126,129

Lidocaine. Lidocaine is a drug used as a local anesthetic and antiarrhythmic agent. In addition to its topical use to suppress coughing during fibrobronchoscopy, nebulized lidocaine has been used to treat difficult-to-control cough and asthma. Although it is not commercially available for nebulization, lidocaine hydrochloride solution for injection satisfies the requirements for use in nebulized form.130

Its use in refractory cough has been analyzed in various descriptive studies. However, the diversity of data with respect to dose, inhaled fraction according to the nebulizer used, comorbidities responsible for the cough, and previous treatment make it difficult to establish the ideal dose and to identify patients who could benefit from this treatment.130,131 In a recent study of 99 patients with difficult-to-control cough, using between 3 and 5ml of 4% lidocaine twice or 3 times a day, symptomatic control was achieved in 49% of the cases with no serious side effects.131 Therefore, although lidocaine is not a first choice treatment for persistent cough, it may be an alternative in patients who cannot tolerate or do not respond to other treatments.

Studies with nebulized lidocaine in asthma patients have not shown clear results; some have found an improvement in lung function and a reduction in the use of corticosteroids for symptom control,130,132 although others have not managed to reproduce these data,130,133 suggesting that further studies are required to consider this option in patients who require high doses of oral corticosteroids for symptom control.

Furosemide. This has also been used to relieve dyspnea via nebulized administration. It has been effective in patients with advanced cancer and severe dyspnea who do not respond to opiates. Various studies reviewing the effects of nebulized furosemide in patients with airway obstruction have found that it has a slight bronchodilator effect, or at least is capable of arresting bronchoconstriction.134 A recent randomized clinical trial of 100 patients with exacerbation of COPD in which the addition of inhaled furosemide to conventional treatment was compared, found a significant improvement in FEV1, dyspnea, pH, blood pressure and heart rate in the furosemide group.135

Prostanoids. In pulmonary arterial hypertension (PAH), there are 2 drugs within the prostanoid group that can be inhaled: iloprost and treprostinil.136 Iloprost is an analog of prostacyclin authorized in Spain as inhaled treatment in adults with PAH and functional class III. Although there was an initial improvement in functional grade, in the long-term only a few patients remained stable with iloprost in monotherapy.137 There are studies that support its efficacy in combination with bosentan and sildenafil, and also as an alternative to intravenous or subcutaneous prostanoids.132 Recent studies have explored the usefulness of iloprost in patients with acute respiratory distress syndrome (ARDS) and PAH, reporting improvement in gas exchange without any detriment to respiratory or hemodynamic parameters.138,139

Inhaled treprostinil was approved by the FDA in 2009 for patients with PAH and functional class III. Its effectiveness was initially demonstrated in patients who remained symptomatic despite treatment with bosentan and sildenafil,140 and it has also been used as an alternative to intravenous or subcutaneous prostanoids.141

Tuberculostatics. Some attempts have been made to treat multi-resistant tuberculosis via the inhaled route, such as with dry powder capreomycin, or formulations of various tuberculostatics such as liposomal capreomycin,142 isoniazide or rifampicin that have shown good levels via aerosol delivery in experimental animals.143 However, some characteristics of tuberculous lesions, such as the existence of poorly aerated areas or growth of microorganisms in biofilms, reduce the efficacy of nebulized therapy.

Anticoagulants. Impaired alveolar fibrin turnover is a fundamental aspect of severe pneumonia. Clinical studies suggest that natural coagulation inhibitors exert lung-protective effects via anticoagulant and possibly anti-inflammatory pathways. In experimental animals, the aerosolized administration of activated protein C, plasma anti-thrombin and heparin significantly reduced pulmonary coagulopathy, with no changes in systemic coagulation. Plasma anti-thrombin treatment inhibits the spread of S. pneumoniae and histopathological damage in the lung. It has not been possible to confirm this effect in pneumonia caused by PA. In a systematic review144 of preclinical and clinical trials on nebulized anticoagulants, only 3 clinical trials on nebulized heparin were identified.145–147 These found an improvement in survival in patients with acute lung injury associated with smoke inhalation, and also a reduction in the number of days on mechanical ventilation.

Surfactant. One meta-analysis148 that analyzed the administration of exogenous surfactant in ARDS found that it might improve oxygenation but not mortality. However, a wide variety of routes of administration were used in this meta-analysis, which concluded that the bronchoscopic route may be most promising, as the rate of pulmonary deposition using the nebulized route only reaches 4%–5%.149

Nebulized drugs are an effective therapeutic alternative in multiple respiratory diseases. Effective, rapid administration nebulization devices are currently available. The future will doubtless bring innovative drugs and new evidence that will allow us to resolve the many uncertainties that still exist.

Casilda Olveira has participated in expert committees and training activities promoted and funded by Chiesi, Gilead, Novartis and Praxis.

Adolfo Domenech has participated in training activities promoted and funded by Astra, Boehringer, Esteve, Glaxo, Novartis and Menarini.

Ana Muñoz has participated in training activities promoted and funded by Astra.