|Year : 2020 | Volume
| Issue : 1 | Page : 8-14
Nebulization in the pandemic of coronavirus disease 2019
Subodh K Katiyar1, Sandeep Katiyar2
1 Department of Tuberculosis and Respiratory Diseases, GSVM Medical College, Kanpur, India
2 Department of Tuberculosis and Respiratory Diseases, GSVM Medical College; Consultant, Department of Pulmonary Medicine, Apollo Spectra Hospital, Kanpur, India
|Date of Submission||05-Jun-2020|
|Date of Acceptance||17-Jun-2020|
|Date of Web Publication||6-Jul-2020|
Dr. Subodh K Katiyar
112/370, Swaroop Nagar, Kanpur - 208 002, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Inhaled therapy is the cornerstone in the management of obstructive airway diseases (OADs). Nebulization is often used for the delivery of bronchodilators and corticosteroids among the elderly and children. The present pandemic of coronavirus disease 2019 (COVID-19), caused by a newly identified, highly contagious, novel coronavirus, called severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), is responsible for great morbidity and mortality globally. There is a great concern regarding person-to-person transmissibility of this virus. There is also a great concern of viral transmission of this virus to the health-care personnel and the bystanders through aerosol-generating procedures including frequently used nebulization therapy. Most of the patients with OAD, during the current pandemic, who were undergoing nebulization therapy, on getting infected with SARS-CoV-2 or on its suspicion, have been shifted to other handheld devices out of fear of transmission of infection. Presently, there exist not enough evidences either on the safety or on the risk of transmissibility of SARS-CoV-2 during nebulization in COVID-19 patients. In addition, there are concerns about nebulization in OAD cases even in the absence of COVID-19 and about the use of inhaled or systemic corticosteroids in these cases. We have made some observations based on all the current information available related to these issues, which may help provide some guidance in the use of nebulizer therapy and also discussed the measures to be taken to minimize the risk of infection, if any, during the procedure.
Keywords: Aerosol-generating procedures, coronavirus disease 2019, nebulization, severe acute respiratory syndrome coronavirus, severe acute respiratory syndrome-coronavirus-2
|How to cite this article:|
Katiyar SK, Katiyar S. Nebulization in the pandemic of coronavirus disease 2019. Indian J Allergy Asthma Immunol 2020;34:8-14
|How to cite this URL:|
Katiyar SK, Katiyar S. Nebulization in the pandemic of coronavirus disease 2019. Indian J Allergy Asthma Immunol [serial online] 2020 [cited 2020 Nov 27];34:8-14. Available from: https://www.ijaai.in/text.asp?2020/34/1/8/289065
| Introduction|| |
The mainstay of therapy in obstructive airway diseases (OAD), including asthma and chronic obstructive pulmonary device (COPD), is inhaled therapy with bronchodilators and corticosteroids, delivered through various available inhalation devices. Handheld inhalers are mostly used in these cases, but drug delivery via nebulizers, is also needed in a good number of cases, especially among the elderly and young children. It is also useful during certain special situations, for example, acute exacerbations, for continuous bronchodilator therapy and large bolus doses. We face a great crisis, in the present time, in the form of the pandemic of coronavirus disease 2019 (COVID-19), caused by the novel human coronavirus, now named severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) (formerly called HCoV-19), which has been responsible for a great morbidity and mortality world over. This is a newly identified pathogen that has not previously been seen to infect humans and is highly contagious and belongs to the same category of viruses such as SARS coronavirus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV), but a different strain with its own characteristics. COVID-19 was first reported in Wuhan, China, in December 2019, and the outbreak has spread quickly across the world. There is a great concern regarding the transmissibility of SARS-CoV-2, from patients having this infection, to their contacts and health-care personnel (HCP) in a health-care setup, during their general care and especially during the aerosol-generating procedures (AGPs). Consequently, there are apprehensions related to the spread of SARS-CoV-2 during nebulization also, not only in COVID-19 patients or their suspects, but also sometimes in non-COVID patients, having preexisting OADs. These apprehensions also relate to the naïve COVID-19 patients requiring inhaled bronchodilators during affection of the lungs. These issues need to be properly addressed for better management of these cases.
Observing over caution and being too apprehensive, many patients with COVID-19 and respiratory disease have been switched over to handheld devices, such as metered-dose inhalers (MDIs), as an alternative to nebulizers for the delivery of the drugs, especially albuterol. There also has been increased use of these inhalers in patients with COVID-19 and their suspects to help with their respiratory issues. This had led to a sharp rise in the use of albuterol MDIs, leading to their acute shortages in the United States, creating a crisis and panic for some time. This abrupt switch results in many patients having the inability to effectively use the new device, to get the full benefits of inhaler therapy. This may happen because of their inadequate hand–mouth coordination, poor inspiratory strength, or other impediments to the use of handheld devices.,
Currently, there are not enough evidences, in the form of reports and studies on the issues of either safety or on the risk involved in the transmission of SARS-CoV-2, due to nebulization in the cases of COVID-19. We have made some observations based on all the current information available related to these issues, which may help provide some guidance in the use of nebulizer therapy in the present scenario. We have also utilized some findings on the research available related to SARS-CoV and MERS-CoV, closely related virus. However, with the prolonged spell of the COVID-19, some more evidences may be generated which may provide us with a better guidance in future. In the current scenario, nebulization therapy is being viewed as a procedure which has a potential risk to transmit SARS-CoV-2, to susceptible HCP and bystander hosts. The evidences that we have in the present time, favor the risk of transmission of infection directly from nebulization to be low. However, measures are to be adopted to break this transmission chain of infection, if any, to further minimize the risk.
| Aerosol-Generating Procedures|| |
These procedures (AGPs) may expose HCPs to pathogens causing acute respiratory infection including the current SARS-CoV-2 and earlier SARS-CoV. Some of the procedures performed on patients are more likely to generate higher concentrations of infectious respiratory aerosols than by coughing, sneezing, talking, or breathing. These AGPs potentially put HCPs and others at an increased risk for pathogen exposure and infection. Nebulization has not been a part of this main list. Furthermore, development of a comprehensive list of AGPs for health-care settings has not been possible because there is neither sufficient supporting data nor expert consensus, to create a definitive and comprehensive list of AGPs. There are also challenges in determining if reported transmissions during AGPs are due to aerosols or other exposures.,,
As per CDC guidance, the following procedures should be considered in AGPs, due to the creation of uncontrolled respiratory secretions:
- Open suctioning of airway secretions
- Sputum induction
- Cardiopulmonary resuscitation
- Endotracheal intubation and extubation
- Noninvasive ventilation (e.g., bi-level Positive Airway Pressure [BiPAP], continuous positive airway pressure)
- Manual ventilation.
There are limited data on whether other procedures may generate infectious aerosols and represent a transmission risk. These may include but are not limited to:
- Nebulizer administration
- High-flow oxygen delivery
- Nasal endoscopy or endoscopic sinus surgery
- Flexible laryngoscopy
- Trans-sphenoidal surgeries
- Nasogastric or naso-jejunal tube placement.
Tran et al. in a systemic review tried to evaluate the risk of transmission of acute respiratory infections from AGPs for patients undergoing these procedures compared with the risk of transmission to HCWs caring for patients and not undergoing AGPs. Procedures which were found to have an increased risk of transmission included tracheal intubation, noninvasive ventilation, and manual ventilation before intubation. Other intubation-associated procedures, endotracheal aspiration, suction of body fluids, bronchoscopy, nebulizer treatment, administration of oxygen, high-flow oxygen, manipulation of O2 mask or BiPAP mask, defibrillation, chest compressions, insertion of nasogastric tube, and collection of sputum were not found to be significant. They concluded that some procedures potentially capable of generating aerosols have been associated with an increased risk of SARS-CoV transmission to HCPs, with the tracheal intubation being the most consistent across multiple studies.
Aerosols that are generated during nebulization, the smaller ones (0.1 μm to 5 μm), penetrate as far as the alveolar ducts but may also be deposited at any point in the respiratory tract. Among the larger ones, some return to the reservoir feeding tube, whereas others settle on the walls of the baffle and some are released into the environment during expiration. However, this exhaled-out aerosol is not likely to contain the infective virus in it because this has been generated in the nebulization chamber. Unless it is contaminated with the bronchial secretions generated from inside, which may happen while coughing, sneezing, etc., the risk of infection is low or is unlikely.
According to the Public Health Agency of Canada, only aerosols with a larger diameter (10–100 μm) can be deposited on influenza receptors in host cells, which are predominantly found in the upper airway in the nasopharyngeal mucosa. Transmission of the human influenza virus occurs on the exposure of a susceptible host to a sufficient concentration (infectious dose of virus) and its attachment to the receptor of viable human strain viral particles. Thus, the transmission usually can only occur with the larger particles when the susceptible host and infectious source are within close proximity (<2 m). The contribution of close-range exposure to smaller droplet nuclei to the transmission of influenza is unknown, but may be more prominent under special conditions (e.g., AGPs).
Normally, the particle sizes generated by a nebulizer are in the range of < 10 μm, with majority being in the respirable range (0.1–5 μm), hence their contribution in the transmission of influenza virus is an unlikely probability. Larger particle sizes that can contribute to transmission are either not produced and these, even if generated, are not released in the atmosphere, as most remain inside the system. Even if these manage to leak get out, they drop down soon (get sedimented due to gravity) and are not able even to travel 1–2 m because of their size. The newer generation nebulizers such as vibrating mesh nebulizers (VMN) and ultrasonic ones are better than jet nebulizer because they mostly generate finer particles.
The nebulization time is equally important because the risk may be enhanced, both direct and indirect, with the increasing nebulization time and therefore VMNs have a better drug delivery with the shortest nebulization time as compared to the commonly used jet nebulizers. The technologically advanced nebulizers, including breath-enhanced and breath-actuated, decrease the amount of aerosol lost to the atmosphere during exhalation while increasing the efficiency of drug delivery, thereby increasing the total inhaled drug mass. These will further minimize the risk of spreading infection.
The National Institute for Health and Care Excellence and the UK government guidance from the New and Emerging Respiratory Virus Threats Advisory Group advise the continued use of nebulizers because the administration of medication via nebulization is not considered to represent a significant infectious risk. This is because the aerosol produced during nebulizer treatment is not patient derived but is generated from fluid from the nebulizer chamber, and therefore, does not carry patient-derived viral particles. If a particle in the aerosol comes into contact with a patient's contaminated mucous membrane, it will cease to be airborne and therefore, will not be part of an aerosol. It is uncertain whether potential associations between performing this common procedure and increased risk of infection might be due to aerosols generated by the procedure or due to increased contact between those administering the nebulized medication and infected patients.,
| Transmission Risk of Severe Acute Respiratory Syndrome-Coronavirus-2|| |
The primary concern during nebulization in a COVID-19 patient is the potential risk of release and spread of SARS-CoV-2 in the form of aerosolized respiratory droplets. Unfortunately, an assessment of the available data about the risks of infection in the nebulizer treatment during an epidemic of respiratory viruses reveals very limited information. Being a recent disease caused by a new virus, reports and studies on SARS-CoV-2 related to risk on the spread of infection to HCW, caregivers, and bystanders are only few, but likely to become available in future as the pandemic prolongs further. However, we also have some information related to SARS-CoV, which may be useful in the present context also, because both are closely related infections with quite similar disease profile.
In a study in specific relation to the 2002–2003 SARS-CoV outbreak, in a patient with SARS, undergoing treatment with a humidifier and large-volume nebulizer, there was no evidence of SARS-CoV-specific nucleic acid material in all the air samples taken from the vicinity of the patient, 30 cm above the patient's head. A 2012 review article on AGPs concluded that there was no significant evidence of transmission risk of SARS-CoV related to nebulizers. Utilizing evidences from the SARS outbreak, they have assessed three cohort studies and found no statistically significant risk of SARS-CoV transmission to HCP caring for patients undergoing nebulizer treatment.
In the 2019–2020 SARS-CoV-2 pandemic, the first US case of community-acquired COVID-19 was confirmed on February 26, 2020, in a patient hospitalized in Solano County, California, who earlier was not a suspect, and none of the HCP wore personal protective equipment (PPE) at the time of patient care in the hospital. The patient underwent multiple AGPs, including nebulization treatment, BiPAP ventilation, and bronchoscopy. A report by the CDC, related to this patient, revealed that 121 HCPs were exposed to SARS-CoV-2, out of which 43 developed symptoms and were tested for SARS-CoV-2; of these three had positive test results. All these three HCPs had unprotected contact with the patient, thus making it difficult to determine the degree of involvement of nebulization in SARS-CoV-2 transmission in this instance. More research to determine the risks associated with specific procedures and the protectiveness of different types of PPE, as well as the extent of short-range aerosol transmission of SARS-CoV-2, is needed.,
In general, as per the CDC, there are no currently known links between performing nebulized treatments and an increased risk of SARS-CoV-2 infection. It is difficult to ascertain whether the possible risk of transmission is causally related to the use of a nebulizer or increased contact between the infected person and the HCP administering the treatment. The CDC recommends early recognition and isolation of the patients with possible infection of SARS-CoV-2 and proper use of PPE by HCP.,
The current United Kingdom guidance on infection prevention from COVID-19 does not list nebulizers as a potential transmission risk, due to the fact that the aerosol generated by the device is derived from the medication fluid within the nebulizer chamber and not from the patient.
| How to Minimize the Risk of Infection With Nebulization|| |
Nebulization and some of the other procedures performed on patients with known or suspected COVID-19 could generate infectious aerosols or have the potential to do so. In the absence of enough data on their safety or risk involved, they continue to be a potential source of infection. Such procedures that pose a risk should be performed cautiously and avoided if possible. However, based on the available data, nebulizer administration in patients with COVID-19, likely represents a lower infection risk than other AGPs, but close-range viral aerosol generation remains to be a possibility. Based on this potential risk, the CDC and Minnesota Department of Health recommend the following guidance to minimize risk to HCPs:,
- If patient can tolerate and properly use, switch to MDI with a dedicated spacer
- HCPs should wear a N-95 facemask along with an eye protection, gloves, and a gown during treatment
- The number of HCP present during the procedure should be limited to only those essential for patient care and procedure support. Visitors should not be present for the procedure
- Close patient's room door when providing nebulizer treatment
- Upon the setup of nebulizer, have HCPs maintain a safe distance (6 feet or greater), possibly outside the door
- Clean and disinfect procedure room surfaces promptly with recommended disinfectants
- AGPs should preferably be performed in airborne infection isolation rooms, if available
- Patients do not need to be transferred to a higher level of care solely for the purpose of providing nebulizer treatment.
The guidance further notes that HCP should use appropriate hand hygiene when helping patients remove nebulizers and oxygen masks.
Only disposable single-use nebulization units should be used for the purpose of nebulization of a patient in a health-care facility which in no case must be reused. The driving gas to run the unit could be either oxygen or compressed air according to the need in the particular case. These units must be disposed of properly after every use.
A study by Liu et al. of aerosolized SARS-CoV-2 RNA in two Wuhan hospitals during the COVID-19 outbreak found that room ventilation, open space, sanitization of protective apparel, and disinfection of toilet areas effectively reduced the levels of SARS-CoV-2 RNA in the aerosols. They had found the concentration of SARS-CoV-2 RNA in aerosols detected in isolation wards and ventilated patient rooms to be very low, but it was elevated in the patients' toilet areas and some of the public places prone to crowding. Although they could not establish the infectivity of the virus detected in these hospital areas, they proposed that SARS-CoV-2 may have the potential to be transmitted via aerosols.
The COPD Foundation has offered an additional guidance to those using nebulizer to prevent risk of infection spreading around them. The foundation has recommended to use a PARI filter (equivalent to an N95 mask) with nebulizers to filter the patient's exhaled air, and thus limit the risk of virus spread.
| Nebulization at Home in Patients With Covid-19|| |
Nebulizer use at home may be necessary for patients with asthma who are either suspects or are cases of COVID-19. In such instances, the nebulizer may be used in a location that minimizes and preferably avoids exposure to any other members of the household, and preferably a location where air is not recirculated into the home (such as a porch, patio, or garage). It is also important to limit the number of people in the room or location where the nebulizer is used. Nebulizers should be used and cleaned according to the manufacturer's instructions. The caregivers, if any, must use PPE, in such circumstances. If HCPs have to be present during nebulizer use among patients or suspects of COVID-19, follow the precautions when performing AGPs.
| Nebulization of Non-Covid-19-Infected Patient at Home/hospital|| |
From the perspective of an uninfected patient at home, there are no known infection-related hazards that preclude the use of a nebulizer. Patients with asthma but without symptoms or a diagnosis of COVID-19 should continue any required nebulized drugs for their treatment, as recommended by the guidelines.
| Avoid Indiscriminate Use of Nebulizers and Prescribing Metered-Dose Inhalers to Wrong Candidates|| |
There is a belief, not only in several patients but also in some physicians, that nebulized therapy has benefits in the drug delivery as against the use of MDI. Hence, nebulizers are often used indiscriminately by many patients of OAD including the elderly, but it needs to be verified whether it really scores over MDI, with or without a spacer, using the same drugs and dosages. This assumption that nebulizers are superior drug delivery systems than the other handheld devices has been dispelled out by several studies.,,,
Despite several evidences suggesting their lack of superiority or inferiority, compared to MDIs with spacer, the nebulizer is still widely used in many health-care facilities. In the current scenario of SARS-CoV-2 infection, nebulization can prove to be hazardous too. Hence, its use during the current pandemic situation must be restricted only to those patients where other handheld devices cannot be used.
A good proportion of elderly patients having asthma or COPD are likely to be the candidates for the use of nebulizers for their regular medication. Many of these elderly patients are unable to use MDI satisfactorily due to impaired cognitive function or memory loss, weak fingers, or poor coordination. The presence of arthritis or joint pain; loss of physical strength; neuromuscular conditions such as Parkinson's disease; stroke; osteoporosis and kyphosis; worsening hypoxia or hypercapnia, etc., are some of the conditions where nebulization may have no substitute in management.,,,,,, It will be inappropriate to prescribe other handheld devices under such circumstances.
In recent times, a shift has been seen toward increasing use of MDIs with spacers in the place of nebulizers. Many of the patients with COVID-19 and respiratory disease are being switched to handheld devices, such as MDIs, for the delivery of their medications in the place of nebulization. This abrupt switch in some patients having the inability to effectively use the new device, may make them land up with problems because of poor delivery of drugs to the lungs.
Further, inhalation technique used with MDIs can substantially influence the clinical response to inhaled medications. An early study of cognitively impaired patients who were instructed on inhaler use showed that 1 day after training, 50% of patients with borderline cognitive impairment could not operate an MDI correctly and 100% of patients with mild dementia could not operate an MDI correctly. These unaddressed challenges to inhaler selection contribute to inappropriate use of inhalers in 41%–69% of patients with OAD, with critical errors in at least 88% of patients., Besides these physical and mental deficits, some patients may require nebulization for some technical reasons such as severe airway obstruction requiring high doses of drugs or who need continuous bronchodilator therapy.,,
| Asthma Care during the Covid-19 Pandemic|| |
Not much is known about any relationship between asthma and COVID-19 and how does the SARS-CoV-2 affect asthma. In general, asthma does not increase the risk of developing COVID-19, but there may be a higher risk of developing severe illness in patients having moderate-to-severe asthma if effected by COVID-19. There has also been no evidence that asthma could be a risk factor to develop acute respiratory distress syndrome, a complication of COVID-19, if co-infection occurs in some of the cases. However, any of the respiratory viruses, including SARS-CoV, can trigger the asthma symptoms, requiring better control with increased dose of bronchodilators and anti-inflammatory drugs (inhaled corticosteroids). In a situation where an asthmatic develops COVID-19, the patient may continue taking his/her usual medication, including inhaled corticosteroids, and if required, in enhanced doses.
Based on what we currently know about COVID-19, the selection of therapeutic options through guideline-recommended treatment of asthma has not been affected. Continuation of ICS is particularly important for patients already using it because there is no evidence of increased risk of COVID-19 morbidity with the use of ICS. There is abundance of data showing reduced risk of asthma exacerbation with maintenance of asthma controller therapy. Patients with asthma but without symptoms or a diagnosis of COVID-19 should continue any required nebulizer treatments. Selection of therapeutic options through guideline-recommended treatment of asthma exacerbations has not been affected by what we currently know about COVID-19.
Systemic corticosteroids could be used to treat an asthma exacerbation as per the guidelines and current standards of care, even if it is caused by COVID-19. Short-term use of systemic corticosteroids to treat asthma exacerbations should be continued. There is currently no evidence to suggest that short-term use of systemic corticosteroids to treat asthma exacerbations increases the risk of developing severe COVID-19, whereas there is an abundance of data to support the use of systemic steroids for moderate or severe asthma exacerbations.
| Summary|| |
Presently, there are apprehensions about the spread of SARS-CoV-2 infection through the use of nebulizers in COVID-19 patients. All the existing knowledge concerning evidences against and in favor of transmission of infection through nebulization, though not too many, are discussed. Other AGPs that have the potential to transmit the disease have been highlighted. Currently, no definitely known links between performing nebulization therapy and an increased risk of SARS-CoV-2 infection exist. It is also difficult to ascertain whether the possible risk of transmission is causally related to the use of a nebulizer or increased contact between the infected person and the HCP administering the treatment. However, considering its potential to spread infection, measures to minimize it including the use of PPE are discussed besides the status of management of asthma in the view of COVID-19 disease and to avoid indiscriminate use of nebulization in the present epidemic.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
World Health Organization 2020 Coronavirus Disease 2019 (COVID-19) Pandemic. FAQ on COVID-19 and Related Health Topics. [Last accessed on 2020 May 02].
Tashkin DP, Barjaktarevic IZ. Nebulized treatments and the possible risk of coronoavirus transmission: where is the evidence? Chronic Obstr Pulm Dis. 2020;7. [In press]. doi: http://doi.org/10.15326/jcopdf.7.3.2020.0161
Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: A systematic review. PLoS One 2012;7:e35797.
Wan GH, Tsai YH, Wu YK, Tsao KC. A large-volume nebulizer would not be an infectious source for severe acute respiratory syndrome. Infect Control Hosp Epidemiol 2004;25:1113-5.
Heinzerling A, Stuckey MJ, Scheur T, Xu K, Perkins KM, Resseger H, et al
. Transmission of COVID-19 to health care personnel during exposures to a hospitalized patient Solano county, California. MMWR Morb Mortal Wkly Rep 2020;69:472-6.
Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 -” United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep 2020;69:382-6. DOI: http://dx.doi.org/10.15585/mmwr.mm6913e2
Liu Y, Ning Z, Chen Y, Guo M, Liu Y, Gali NK,et al
. Aerodynamic analysis of SARSCoV-2 in two Wuhan hospitals. Nature 2020; 582: 557-60.
COPD Foundation. Webinar: COVID-19, COPD and you: Important Strategies from Leading Medical Experts on Managing your Health. Published March 17, 2020. [Last accessed on 2020 Apr 30].
Pounsford JC. Nebulisers for the elderly. Thorax 1997;52 Suppl 2:S53-5.
Mestitz H, Copland JM, McDonald CF. Comparison of outpatient nebulized vs metered dose inhaler terbutaline in chronic airflow obstruction. Chest 1989;96:1237-40.
Turner MO, Patel A, Ginsburg S, FitzGerald JM. Bronchodilator delivery in acute airflow obstruction. A meta-analysis. Arch Intern Med 1997;157:1736-44.
Jenkins SC, Heaton RW, Fulton TJ, Moxham J. Comparison of domiciliary nebulized salbutamol and salbutamol from a metered-dose inhaler in stable chronic airflow limitation. Chest 1987;91:804-7.
Gunawardena KA, Smith AP, Shankleman J. A comparison of metered dose inhalers with nebulizers from the delivery of ipratropium bromide in domiciliary practice. Br J Dis Chest 1986;80:170-8.
Cates C. Spacers and nebulisers for the delivery of beta-agonists in non-life-threatening acute asthma. Respir Med 2003;97:762-9.
Cates CJ, Welsh EJ, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2013;2013:CD000052. doi:10.1002/14651858.CD000052.pub3.
Pedersen S. Inhalers and nebulizers: Which to choose and why. Respir Med 1996;90:69-77.
Chapman KR, Voshaar TH, Virchow JC. Inhaler choice in primary practice. Eur Respir Rev 2005;14:117-22.
Mandelberg A, Chen E, Noviski N, Priel IE. Nebulized wet aerosol treatment in emergency department-is it essential? Comparison with large spacer device for metered-dose inhaler. Chest 1997;112:1501-5.
Moriates C, Feldman L. Nebulized bronchodilators instead of metered-dose inhalers for obstructive pulmonary symptoms. J Hosp Med 2015;10:691-3.
van Geffen WH, Douma WR, Slebos DJ, Kerstjens HA. Bronchodilators delivered by nebuliser versus pMDI with spacer or DPI for exacerbations of COPD. Cochrane Database Syst Rev. 2016:CD011826. doi:10.1002/14651858.CD011826.pub2.
Rau JL. Practical problems with aerosol therapy in COPD. Respir Care 2006;51:158-72.
Allen SC. Competence thresholds for the use of inhalers in people with dementia. Age Ageing 1997;26:83-6.
Johnson DH, Robart P. Inhaler technique of outpatients in the home. Respir Care 2000;45:1182-7.
Vanderman AJ, Moss JM, Bailey JC, Melnyk SD, Brown JN. Inhaler misuse in an older adult population. Consult Pharm 2015;30:92-100.
Bisgaard H, Nikander K, Munch E. Comparative study of budesonide as a nebulized suspension vs. pressurized metered-dose inhaler in adult asthmatics. Respir Med 1998;92:44-9.
Nicolini G, Cremonesi G, Melani AS. Inhaled corticosteroid therapy with nebulized beclometasone dipropionate. Pulm Pharmacol Ther 2010;23:145-55.
Hill JM. Nebulised corticosteroids in the treatment of patients with asthma. Thorax 1999;54:661-3.