CADTH Health Technology Review

Medication Administration With Inhalers or Nebulizers

Rapid Review

Authors: Khai Tran, Aleksandra Grobelna

Key Messages

• Delivery of medication via metered-dose inhalers to children or adults with asthma, or adults with chronic obstructive pulmonary disease at emergency departments or intensive care units, may be as effective as nebulizers in terms of clinical parameters and health care resource use.

• Limited data on adverse events showed no significant differences between metered-dose inhalers and nebulizers.

• No evidence was found on the clinical effectiveness of dry powder inhalers in comparison with nebulizers or metered-dose inhalers.

• No evidence was found on the cost-effectiveness of medication administration via metered-dose inhalers, nebulizers, or dry powder inhalers in comparison with each other.

• No evidence-based guidelines with recommendations regarding the comparative use of metered-dose inhalers, dry powder inhalers, or nebulizers for administration of medication were identified.

Context and Policy Issues

The Canadian Chronic Disease Surveillance System estimated that about 3.8 million Canadians aged 1 year or older were living with asthma, and about 2.0 million Canadians aged 35 years or older were living with chronic obstructive pulmonary disease (COPD), in 2011 to 2012.¹ Medication administration through aerosol delivery is a crucial component for caring patients with respiratory distress such as asthma and COPD when they present at acute care settings such as emergency departments (EDs) or intensive care units (ICUs).² There are 3 classes of medical aerosol devices: nebulizers, pressurized metered-dose inhalers (MDI), and dry power inhalers (DPI).³ Nebulizers are further divided by design into pneumatic jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers.³ In addition, there are different types, brands, and models of nebulizers with different performance characteristics.⁴

Nebulizers are popular aerosol-generating devices in acute care settings.⁴ The advantages of nebulizers are the ability to be used with a broad range of drug solutions and the convenience for patients who have difficulties coordinating themselves or following instructions such as infants, small children, and very old, debilitated, or distressed patients.⁴ The disadvantages of nebulizers are that the equipment may be large and cumbersome and requires a power source to operate, that there is potential for drug exposure to patients’ eyes (with face mask delivery) or to caregivers standing nearby, and that there is potential for contamination with improper handling or inadequate cleaning.⁴

The MDI was designed to deliver precise doses of specific drug formulations.⁴ The device consists of a canister, the medication, a propellant, a metering valve, a mouthpiece, and an actuator.⁴ Unlike nebulizers, an MDI does not require drug preparation, and its internal components are difficult to contaminate.⁴ Other advantages of MDIs are that the device is portable, convenient with multiple doses contained in a single device, and reproducible in terms of emitted doses.⁴ Several disadvantages of MDIs include the requirement of patients’ hand-breath coordination, activation, proper inhalation, and breath-hold, fixed-drug concentrations and doses, and negative reactions to propellants in some patients.⁴

The DPI was developed to overcome the hand-breath coordination required in the MDI and is propellant free, whereby drug delivery to the lungs is driven by inspiration.⁴ The device is portable, with a built-in dose counter.⁴ However, the patient’s inspiratory flow should be high enough to draw the drug from the device.⁴ Further, patients should know how the device works and how to use it for its proper application; for instance, they should not exhale into the mouthpiece, as humidity can impact the effect of the medication.⁴

Historically, it was believed that nebulizers were more effective than inhalers, and nebulizers have been the preferred choice of clinicians to treat patients in acute and critical care settings.^2,4 However, with the advantages and disadvantages of each type of aerosol devices, it is unclear which 1 is more effective than the others, especially given that there are multiple factors to consider such as clinical settings, device and drug availability, devices with the ability to deliver multiple medications versus a single medication, patients’ ability to use a selected device correctly, drug administration time, costs, resource utilization, and patient and caregiver satisfaction.⁵

The aim of this report is to summarize the evidence regarding the clinical effectiveness and cost-effectiveness of nebulizers, MDIs, and DPIs in comparison with each other for administration of medication in hospital or ED settings. This report also aims to summarize the recommendations from evidence-based guidelines regarding the comparative use of these devices.

Research Questions

1. What is the clinical effectiveness of medication administration via metered-dose inhalers versus nebulizers?

2. What is the cost-effectiveness of medication administration via metered-dose inhalers versus nebulizers?

3. What is the clinical effectiveness of medication administration via dry powder inhalers versus nebulizers?

4. What is the cost-effectiveness of medication administration via dry powder inhalers versus nebulizers?

5. What is the clinical effectiveness of medication administration via dry powder inhalers versus metered-dose inhalers?

6. What is the cost-effectiveness of medication administration via dry powder inhalers versus metered-dose inhalers?

7. What are the evidence-based guidelines regarding dry powder inhalers, nebulizers, and metered-dose inhalers for medication administration?

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources including MEDLINE, the Cochrane Database of Systematic Reviews, the international HTA database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were metered-dose inhalers, dry powder inhalers, and nebulizers. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2016 and September 23, 2021.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed, and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, if they were duplicate publications, or if they were published before 2016. Primary studies retrieved by the search were excluded if they were captured in 1 or more included systematic reviews (SRs). Guidelines with unclear methodology and those that did not provide recommendations regarding the comparative use of MDIs, DPIs, or nebulizers for administration of medication were also excluded.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)⁶ for SRs, and the Downs and Black checklist⁷ for randomized and non-randomized studies. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 516 citations were identified in the literature search. Following screening of titles and abstracts, 499 citations were excluded, and 17 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 12 publications were excluded for various reasons, and 7 publications met the inclusion criteria and were included in this report. These comprised 2 SRs, 4 RCTs, and 1 non-randomized study. Appendix 1 presents the PRISMA⁸ flow chart of the study selection.

Summary of Study Characteristics

The detailed characteristics of the included SRs^9,10 (Table 2) and primary clinical studies^11-15 (Table 3) are provided in Appendix 2.

Study Design

The SR by Roncada et al. (2018)⁹ identified and included 9 RCTs (N = 1,307) in the meta-analyses. The RCTs were published between 1993 and 2006. The SR by van Geffen et al. (2016)¹⁰ identified and included 8 RCTs (N = 250) in the meta-analysis. The RCTs were published between 1985 and 2007.

The 5 included primary studies comprised 4 RCTs^11-14 and 1 prospective cohort study.¹⁵ The RCTs^11-14 were published between 2016 and 2019, while the prospective cohort study¹⁵ was published in 2021.

Country of Origin

The SRs were conducted by authors from Brazil⁹ and the Netherland.¹⁰ The primary studies were conducted by authors from Paraguay,¹¹ US,^12,15 Egypt,¹³ and Sweden.¹⁴

Patient Population

Patients in the RCTs included in the SR by Roncada et al. (2018)⁹ were children with mild-to-moderate asthma exacerbations treated at EDs. Patients in the included RCTs had mean age of 6.8 years, and 55% were male. Patient baseline characteristics were similar between treatment groups in term of age, heart rate, respiratory rate, O₂ saturation, asthma clinical score, and forced expiratory volume in the first second (FEV₁).

Patients in the RCTs included in the SR by van Geffen et al. (2016)¹⁰ were adult patients with COPD exacerbations treated at EDs. Three of the 8 included RCTs reported the mean age which were 55, 68, and 71 years; the other 5 RCTs did not provide age information. Other patient baseline characteristics were only reported as comparable between groups without any details provided.

Patients in the included primary studies were children with mild-to-moderate^12,14,15 or moderate-to-severe¹¹ asthma exacerbations treated at EDs^11,12,14,15 or adult patients with asthma treated at ICU.¹³ The mean age of the children ranged from 23 months to 10 years, and the percentage of male ranged from 36 to 69. The adult population had a mean age of 61 years, and 50% of the population were male.

Interventions and Comparators

The SR by Roncada et al. (2018)⁹ included RCTs comparing the administration of a bronchodilator (i.e., salbutamol) by 2 inhalation techniques (i.e., MDI and nebulizer) for asthma treatment at pediatric ED units. The SR by van Geffen et al. (2016)¹⁰ included RCTs comparing pressurized MDIs with a spacer versus nebulizers as devices delivering different beta₂-agonists and anticholinergics for the treatment of adult patients with COPD exacerbations in hospital ED settings.

Four included primary studies^11,12,14,15 compared MDIs with nebulizers for the treatment of children with asthma exacerbations at EDs, and 1 primary study¹³ compared MDIs with nebulizers for the treatment of adult patients with asthma at ICU. Types of MDIs included MDIs with a valved-holding chamber,¹¹ MDIs with AeroChamber Vent with or without humidification,¹³ and MDIs with a spacer.¹⁴ Two studies^12,15 did not report the type of MDIs used. Types of nebulizers included breath-actuated nebulizers¹² and vibrating mesh nebulizers with or without humidification.¹³ Three studies^11,14,15 did not report the type of nebulizers used. The types of bronchodilators used for the treatment of asthma were salbutamol plus ipratropium bromide,¹¹ albuterol,^12,15 and salbutamol alone.¹⁴ One study¹³ did not report the type of medications used.

Outcomes

The clinical outcomes considered in the included SRs^9,10 and primary studies^11-15 can be broadly categorized as clinical parameters, health care resource use, and adverse events (AEs).

The clinical parameters included the heart rate,^9,11,13,14 respiratory rate,^9,13,14 O₂ saturation,^9-11,14 asthma severity score,^9,11-13 change in FEV₁,¹⁰ change in the dyspnea score in the first 24 hours after dosing,¹⁰ O₂ partial pressure,¹³ CO₂ partial pressure,¹³ pH,¹³ and skeletal muscle strength (i.e., grip).¹⁵ The asthma severity score evaluates the respiratory rate, presence of wheezing, cyanosis, chest retractions, and transcutaneous O₂ saturation, with scores ranging from 0 to 15 points (i.e., mild exacerbation: < 7; moderate exacerbation: 8 to 11; severe exacerbation: ≥ 12).

Outcomes on health care resource use included ED or ICU length of stay,^12-14 hospital admission rate,^10-12,14 length of hospital stay,¹⁰ and mechanical ventilation days.¹³

One SR¹⁰ and 1 primary study¹² reported on AEs.

Summary of Critical Appraisal

Additional details regarding the strengths and limitations of the included SRs^9,10 (Table 4) and primary clinical studies^11-15 (Table 5) are provided in Appendix 3.

Both SRs^9,10 were explicit in their objectives and inclusion criteria for the review, selection of the study designs for inclusion, and included a comprehensive literature search strategy. Providing details of the literature search strategy increases the reproducibility of the review. Study selection and data extraction were performed in duplicate in 1 SR,¹⁰ but no such details were reported in the other SR.⁹ Performing these activities in duplicate reduces the likelihood of missing relevant studies and making errors in data extraction. One SR¹⁰ provided a list of excluded studies, the reasons for exclusion, and the sources of funding for the included studies, while the other SR did not.⁹ Not having a list of, or the justifications for, the excluded studies makes it impossible to assess whether any relevant articles were excluded and if so, for what reasons. Funding received from industry can introduce bias in favour of the intervention. One SR¹⁰ assessed the methodological quality of the included studies using the Cochrane risk of bias tool, while the other SR⁹ did not. Therefore, it was not possible to assess the trustworthiness of the meta-analysis findings from the latter SR.⁹ Both SR^9,10 used the software Review Manager (RevMan) in the meta-analyses, and the authors of both SRs provided a discussion of the heterogeneity observed in the results, which was the main limitation of the meta-analyses. The review authors of both SRs^9,10 declared that no funding was received for the reviews. Conflicts of interest were also declared in both SRs.^9,10 Overall, 1 SR⁹ was of moderate methodological quality, and the other¹⁰ was of high methodological quality.

With respect to reporting, all primary studies including 4 RCTs^11-14 and 1 prospective cohort study¹⁵ clearly described the objective of the study, the interventions of interest, the main outcomes, and the main findings of the study. The baseline characteristics of the patients included in the study were clearly described in all studies, except in 1 study.¹³ Without a clear description of patient baseline characteristics, it was not possible to assess if there were potential confounders that could potentially affect the interpretation of the results. Three studies^11,13,14 had no patients lost to follow-up, 1 study¹⁵ did not report on patients lost to follow-up, and 1 study¹² had about 9% of patients excluded due to various types of violation. The characteristics of these patients were not reported, and the analyses did not account for those patients. Not accounting for patients lost to follow-up in the analyses may have resulted in risk of attrition bias. Actual P values (i.e., P values) and the random variability in the data for the main outcomes (e.g., confidence interval, standard deviation, or interquartile range) were reported in all included studies.^11-15 Regarding external validity, it was unclear if the patients were representative of the entire population from which they were recruited in 4 included studies,^11,13-15 as their study populations were relatively small (i.e., 50 to 103 patients in total). For internal validity, 2 RCTs^12,13 were non-blinded, 1 RCT¹⁴ had only the assessors blinded, and 1 RCT¹¹ was double-blinded to the investigators and patients. The lack of blinding may result in risk of bias for selection, performance, and detection. Three RCTs^12-14 did not report allocation concealment, the lack of which may result in risk of selection bias. The prospective cohort study¹⁵ may have been prone to high risk of bias for selection, performance, and detection due to the nature of the observational study design. However, confounding variables were identified and adjusted for in the analyses of this study.¹⁵ Appropriate statistical tests were used to assess the main outcomes, and reliable and validated outcome measures were used, in all studies.^11-15 Patients in different intervention groups appeared to be recruited from the same population and over the same period of time in all studies, except in 1 study.¹⁵ Two^13,15 of the 5 included studies did not report whether sample size calculations were performed, and it is unclear whether the non-significant differences in certain outcomes were because the studies were underpowered for those outcomes. Patient compliance was not reported in all included studies.^11-15 Overall, 3 included studies^11,12,14 were of moderate methodological quality, and 2 studies^13,15 were of low methodological quality.

Summary of Findings

Appendix 4 presents the main study findings of the SRs^9,10 and primary clinical studies.^11-15 The findings are presented by outcome, which are clinical parameters (Table 6), health care resource use (Table 7), and AEs (Table 8).

Clinical Effectiveness of Medication Administration via Metered-Dose Inhalers Versus Nebulizers

Clinical Parameters in Pediatric Patients With Asthma Exacerbations Treated in EDs By MDIs Versus Nebulizers

Meta-analysis results of the SR by Roncada et al. (2018)⁹ found no statistically significant differences between MDIs with a spacer and nebulizers to administer a Beta₂ agonist (i.e., salbutamol) in children with mild-to-moderate asthma exacerbations for the heart rate, respiratory rate, O₂ saturation (P = 0.98), and asthma severity score.

The RCT by Iramain et al. (2018)¹¹ showed that children with moderate-to-severe asthma exacerbations in the MDI group had a statistically significantly lower heart rate than those in the nebulizer group from 30 minutes of treatment (P < 0.003) up to until 4 hours of treatment (P < 0.00001). Both groups received ipratropium bromide between salbutamol treatments. Further, the MDI group had statistically significantly higher O₂ saturation than those in the nebulizer group from 90 minutes of treatment (P < 0.00001) up to 4 hours of treatment (P < 0.00001). The asthma severity score was statistically significantly better (i.e., lower) from 60 minutes of treatment (P < 0.00001) up to 4 hours of treatment (P < 0.00001) in the MDI group than in the nebulizer group.

The RCT by Snider et al. (2018)¹² found no statistically significant differences in post-treatment asthma severity scores between MDIs and breath-actuated nebulizers that delivered albuterol to children with mild-to-moderate asthma exacerbations treated at EDs.

The RCT by Mitselou et al. (2016),¹⁴ comparing MDI-spacers with nebulizers in delivering salbutamol to children with virus-induced wheezing or mild-to-moderate asthma exacerbations treated at EDs, found no statistically significant differences between groups in the heart rate, respiratory rate, and O₂ saturation.

The prospective cohort study by Burger et al. (2020),¹⁵ comparing MDIs and nebulizers as the route of administration in delivering albuterol for treatment of children with mild-to-moderate asthma exacerbations at EDs, showed that children treated with nebulizer-delivered albuterol were associated with decreased skeletal muscle strength (measured by hand grip); whereas albuterol administration via MDIs was associated with no change in skeletal muscle strength. After adjustment for age and pre-treatment asthma severity scores, children treated with nebulizers had a 12.9% decrease in skeletal muscle strength compared with those treated with MDIs.

Clinical Parameters in Adult Patients With Asthma Exacerbations Treated in ICU By MDIs Versus Nebulizers

The RCT by Moustafa et al. (2017)¹³ found no statistically significant differences in various clinical parameters (i.e., heart rate, respiratory rate, asthma severity score, O₂ partial pressure, CO₂ partial pressure, and pH) between MDIs and nebulizers with or without humidification for the treatment of adult patients with asthma exacerbations at ICU.

Clinical Parameters in Adult Patients With COPD Exacerbations Treated in EDs By MDIs Versus Nebulizers

In the SR by van Geffen et al. (2016),¹⁰ comparing bronchodilators delivered by MDIs versus nebulizers for COPD exacerbations in adults treated in EDs, 1 included RCT showed no statistically significant difference in O₂ saturation between the groups at different time points (i.e., 30 minutes, 6 hours, 24 hours, 48 hours, or 10 days). For the change in FEV₁ 1 hour after dosing, 2 RCTs found no statistically significant difference between the groups. For the change in FEV₁ closest to 1 hour after dosing, a meta-analysis of 4 RCTs showed a statistically significant difference of 83 mL in favour of the nebulizer treatment (P = 0.03). For the change in the dyspnea score in the first 24 hours after dosing, 4 included RCTs reported no statistically significant difference between the groups.

Health Care Resource Use in Pediatric Patients With Asthma Exacerbations Treated in EDs By MDIs Versus Nebulizers

The RCT by Iramain et al. (2018)¹¹ showed that statistically significantly fewer children with an asthma severity score of at least 7 in the MDI group needed to be hospitalized at the end of 4 hours of treatment compared with those in the nebulizer group (5.8% versus 27.5%; P = 0.003).

The RCT by Snider et al. (2018)¹² found no statistically significant differences in ED length of stay and hospital admission rates between MDIs and breath-actuated nebulizers that delivered albuterol to children with mild-to-moderate asthma exacerbations treated at EDs, after adjustment for baseline asthma severity, ipratropium, and elevated versus standard dosing of albuterol.

The RCT by Mitselou et al. (2016)¹⁴ found no statistically significant difference in ED length of stay and hospital admission rates between MDI-spacers and nebulizers in delivering salbutamol to children with virus-induced wheezing or mild-to-moderate asthma exacerbations treated at EDs.

Health Care Resource Use in Adult Patients With Asthma Exacerbations Treated in ICU By MDIs Versus Nebulizers

The RCT by Moustafa et al. (2017)¹³ found that patients with asthma treated with vibrating mesh nebulizers had statistically significantly shorter ICU length of stay by about 1.42 days compared to those treated with MDIs (P = 0.039), with or without humidification. However, there was no statistically significant difference between the groups in mechanical ventilation days.

Health Care Resource Use in Adult Patients With COPD Exacerbations Treated in EDs By MDIs Versus Nebulizers

In the SR by van Geffen et al. (2016),¹⁰ 1 RCT showed no statistically significant difference in hospital admission rates, and the other RCT showed no statistically significant difference in the length of hospital stay between the groups.

Adverse Events in Pediatric Patients With Asthma Exacerbations Treated in EDs By MDIs Versus Nebulizers

The RCT by Snider et al. (2018)¹² found that there was a statistically significantly higher incidence of tachycardia in the nebulizer group compared with the MDI group (P = 0.002) for the treatment of children with mild-to-moderate asthma exacerbations in EDs. There were no statistically significant differences between the groups in nausea or vomiting.

Adverse Events in Adult Patients With COPD Exacerbations Treated in EDs By MDIs Versus Nebulizers

In the SR by van Geffen et al. (2016),¹⁰ 3 RCTs reported AEs. One RCT reported 2 AEs in the nebulizer group, but the nature of the events was not reported. One RCT reported that there was 1 patient developing a marked fall in saturation from 88% to 73%, 15 minutes after taking the nebulizer treatment. One RCT reported 2 patients developing a pneumothorax and 1 patient requiring mechanical ventilation in the nebulizer group, and 3 patients developing a pneumothorax in the MDI group. The authors of the SR¹⁰ concluded that there were no significant differences between the groups concerning AEs in these studies.

Cost-Effectiveness of Medication Administration Via Metered-Dose Inhalers Versus Nebulizers

No studies comparing the cost-effectiveness of medication administration with MDIs versus nebulizers were identified; therefore, no summary can be provided.

Clinical Effectiveness of Medication Administration Via Dry Powder Inhalers Versus Nebulizers

No studies comparing the clinical effectiveness of medication administration with DPIs versus nebulizers were identified; therefore, no summary can be provided.

Cost-Effectiveness of Medication Administration Via Dry Powder Inhalers Versus Nebulizers

No studies comparing the cost-effectiveness of medication administration with DPIs versus nebulizers were identified; therefore, no summary can be provided.

Clinical Effectiveness of Medication Administration Via Dry Powder Inhalers Versus Metered-Dose Inhalers

No studies comparing the clinical effectiveness of medication administration with DPIs versus MDIs were identified; therefore, no summary can be provided.

Cost-Effectiveness of Medication Administration Via Dry Powder Inhalers Versus Metered-Dose Inhalers

No studies comparing the cost-effectiveness of medication administration with DPIs versus MDIs were identified; therefore, no summary can be provided.

Guidelines

No evidence-based guidelines with recommendations regarding the comparative use of MDIs, DPIs, or nebulizers for administration of medication were identified; therefore, no summary can be provided.

Limitations

The main limitation of both SRs^9,10 was the substantial heterogeneity in patient baseline characteristics and significant variation in the type and dose of bronchodilators, as well as different frequencies of treatment among included studies. There was a lack of standardization of pulmonary function evaluations that were used to show improvements in lung function markers with the use of both inhalation techniques. The SR by van Geffen et al. (2016)¹⁰ included a low number of studies, each of which had relatively small numbers of patients. Some evidence in both SRs^9,10 was relatively old. The oldest study was published in 1993 in 1 SR⁹ and in 1985 in the other SR.¹⁰ This may influence the results, since new devices may work in a different way than those used more than 28 years ago. Important clinical parameters such as hospital readmission in 30 days, change in peak FEV₁, and change in quality of life were not available from the included studies. The type of nebulizers, compressors, and pressurized MDIs used in the studies might influence the results. Thus, these limitations might affect the generalizability of the findings.

A general limitation of the included primary clinical studies was that lung function was not evaluated. There was no follow-up on patients after being discharged from EDs. No data on the age of disease onset, previous severe exacerbations, and hospitalization were reported. The lack of these data prevents assessing whether they might have influenced the results.

This review did not identify any studies involving DPIs. Also, this review did not identify any economic evaluation studies or evidence-based guidelines with recommendations regarding the comparative use of MDIs, DPIs, or nebulizers for administration of medication. The findings in this review may have limited applicability and generalizability to the Canadian context.

Conclusions and Implications for Decision- or Policy-Making

This report identified 2 SRs^9,10 and 5 primary clinical studies,^11-15 including 4 RCTs^11-14 and 1 prospective cohort study.¹⁵

Findings from 1 SR⁹ and 2 RCTs^12,14 involving children with mild-to-moderate asthma exacerbations treated at EDs showed no significant differences between MDIs and nebulizers in post-treatment clinical parameters including the heart rate, respiratory rate, O₂ saturation, and asthma severity score. In this population, evidence from 2 RCTs^12,14 showed no significant differences between MDIs and nebulizers in health care resource use such as ED length of stay and hospital admission rates. One prospective cohort study¹⁵ reported that children treated with nebulizers had a 12.9% decrease in skeletal muscle strength compared with those treated with MDIs. With respect to AEs, 1 RCT¹² reported a significantly higher incidence of tachycardia in the nebulizer group compared with the MDI group, but there were no significant differences between groups in nausea or vomiting.

Findings from 1 RCT¹¹ involving children with moderate-to-severe asthma exacerbations treated at EDs showed that patients in the MDI group had a significantly lower heart rate, higher O₂ saturation level, and better asthma severity score compared with the nebulizer group. Children in the MDI group had a significantly lower rate of hospital admission than those in the nebulizer group.

Findings from 1 RCT¹³ involving adult patients with asthma exacerbations treated in ICU showed no significant differences between MDIs and nebulizers in post-treatment clinical parameters including the heart rate, respiratory rate, asthma severity score, O₂ partial pressure, CO₂ partial pressure, and pH. Patients treated with nebulizers had significantly shorter in ICU length of stay compared to those treated with MDIs, without any significant difference in mechanical ventilation days.

Findings from 1 SR¹⁰ involving adult patients with COPD exacerbations treated at EDs showed no significant differences in O₂ saturation, change in FEV₁ 1 hour after dosing, and change in the dyspnea score between the MDI and nebulizer groups. For health care resource use, there were no significant differences in hospital admission rates or length of hospital stay between the groups. With respect to AEs, the authors of the SR¹⁰ concluded that there were no significant differences between the groups in studies that reported AEs.

Taken together, evidence from the included SRs and primary clinical studies generally suggested that the delivery of medication via MDIs to patients with asthma or COPD at acute care settings may be as effective as nebulizers in terms of clinical parameters and health care resource use. Limited data on device-related AEs were available. No data were identified comparing DPIs with nebulizers or DPIs with MDIs. With the aforementioned limitations of the evidence, interpretation of the findings should be made with caution. More studies are needed to assess the optimal mode of delivery of bronchodilators in patients with respiratory distress, including studies on DPIs. Future studies should also assess patient important outcomes such as AEs and quality of life. Economic evaluation studies are also needed to compare the cost-effectiveness between devices in acute care settings.

References

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11.Iramain R, Castro-Rodriguez JA, Jara A, et al. Salbutamol and ipratropium by inhaler is superior to nebulizer in children with severe acute asthma exacerbation: Randomized clinical trial. Pediatr Pulmonol. 2019;54(4):372-377. PubMed

12.Snider MA, Wan JY, Jacobs J, Kink R, Gilmore B, Arnold SR. A randomized trial comparing metered dose inhalers and breath actuated nebulizers. J Emerg Med. 2018;55(1):7-14. PubMed

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15.Burger C, Vendiola DF, Arnold DH. Nebulized albuterol delivery is associated with decreased skeletal muscle strength in comparison with metered-dose inhaler delivery among children with acute asthma exacerbations. J Am Coll Emerg Physicians Open. 2021;2(2):e12422. PubMed

Appendix 1: Selection of Included Studies

Note that this appendix has not been copy-edited.

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Note that this appendix has not been copy-edited.

Table 2: Characteristics of Included Systematic Reviews

AE = adverse event; bpm = beat per minute; COPD = chronic obstructive pulmonary disease; ED = emergency department; FEV₁ = forced expiratory volume in 1 second; MA = meta-analysis; MDI = metered-dose inhaler; mpm = movements per minute; NR = not reported; O₂ = oxygen; RCT = randomized controlled trial; SAE = serious adverse event; SR = systematic review.

^aThe asthma severity score evaluates the respiratory rate, presence of wheezing, cyanosis, chest retractions, and transcutaneous O₂ saturation, with scores ranging from 0 to 15 points (i.e., mild exacerbation: < 7; moderate exacerbation: 8 to 11; severe exacerbation: ≥ 12).

Table 3: Characteristics of Included Primary Clinical Studies

AE = adverse event; AV = AeroChamber Vent; COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; ED = emergency department; ICU = intensive care unit; min = minute; ITT = intention-to-treat; MDI = metered-dose inhaler; NR = not reported; O₂ = oxygen; pCO₂ = partial pressure of carbon dioxide; pO₂ = partial pressure of oxygen; RCT = randomized controlled trial.

^aThe asthma severity score evaluates the respiratory rate, presence of wheezing, cyanosis, chest retractions, and transcutaneous O₂ saturation, with scores ranging from 0 to 15 points (i.e., mild exacerbation: < 7; moderate exacerbation: 8 to 11; severe exacerbation: ≥ 12).

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 4: Strengths and Limitations of Systematic Reviews Using AMSTAR 2⁶

AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; NR = not reported; PICO = population, intervention, comparator, and outcomes.

Table 5: Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist⁷

CI = confidence interval; ED = emergency department; ICU = intensive care unit; IQR = interquartile range; RCT = randomized controlled trial.

Appendix 4: Main Study Findings

Note that this appendix has not been copy-edited.

Table 6: Summary of Findings by Outcome — Clinical Parameters

bpm = beat per minute; CI = confidence interval; COPD = chronic obstructive pulmonary disease; ED = emergency department; FEV₁ = forced expiratory volume in 1 second; hr = hour; ICU = intensive care unit; IQR = interquartile range; MD = mean difference; MDI = metered-dose inhaler; min = minute; mpm = movements per minute; NR = not reported; O₂ = oxygen; RCT = randomized controlled trial; SR = systematic review; vs. = versus .

Table 7: Summary of Findings by Outcome — Health Care Resource Use

CI = confidence interval; COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; ED = emergency department; ICU = intensive care unit; MDI = metered-dose inhaler; min = minute; OR = odds ratio; RCT = randomized controlled trial; RD = risk difference; RR = relative risk; SR = systematic review.

Table 8: Summary of Findings by Outcome — Adverse Events

AE = adverse event; CI = confidence interval; COPD = chronic obstructive pulmonary disease; ED = emergency department; MDI = metered-dose inhaler; O₂ = oxygen; OR = odds ratio; RCT = randomized controlled trial; SR = systematic review.