MiniCAT-RT3 WK3 PICO-Inhaler vs Nebulizer

Clinical Question: As in the past, please briefly outline the scenario and state your clinical question as concisely and specifically as possible

5 y/o M with history of asthma comes in with wheeze and SOB consistent with exacerbation of asthma. Inhaled beta agonists are mainstay of treatment for bronchospasm and can be administered via metered dose inhaler or nebulizer

For pediatric patients is metered dose inhaler with spacer more effective than nebulizer for administration of beta agonist in ED for non life-threatening acute asthma exacerbations?

PICO Question:

Identify the PICO elements – this should be a revision of whichever PICO you have already begun in a previous week

P	I	C	O
Asthma	Metered dose inhaler	Nebulizer	Symptoms resolution
Pediatrics	Inhaler	Nebulized beta agonist	Bronchodilation
Asthma exacerbation	Inhaler with spacer	Wet nebulizer	Improved breathing
Wheezing	Inhaler with holding chamber		Resolution of wheezing
Acute asthma	Inhaler with valved holding chamber
	Metered dose inhaler with spacer
	Metered dose inhaler with valved holding chamber

Search Strategy:

Outline the terms used, databases or other tools used, how many articles returned, and how you selected the final articles to base your CAT on.  This will likewise be a revision and refinement of what you have already done.

PubMed:

• pediatrics, asthma exacerbation, metered dose inhaler, nebulizer – 218

Cochrane Library

• asthma exacerbation, metered dose inhaler, nebulizer – 36

Google Scholar

• pediatrics, asthma exacerbation, metered dose inhaler, nebulizer – 776
  • Since 2017 – 185

JAMA Pediatrics

• Asthma exacerbation, metered dose inhaler, nebulizer – 16
• Narrowed search by focusing on systematic reviews and RCT as these would provide the highest levels of evidence to answer my question. There were a lot of older articles published before 2000 so I tried to focus on the most recent publications. There were also many that evaluated other treatment modalities and medications for asthma exacerbations in the ED, I avoided those in favor of publications that specifically focused on metered dose inhaler with spacer and nebulizer for beta agonist administration in emergency departments. Focused on articles that mentioned pediatric populations, particularly those that included 5 year olds or preschool aged children.

Articles Chosen (4 or more) for Inclusion (please copy and paste the abstract with link):

Article 1:

Cates CJ, Welsh EJ, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2013 Sep 13;2013(9):CD000052. doi: 10.1002/14651858.CD000052.pub3. PMID: 24037768; PMCID: PMC7032675.

Abstract:

Background: In acute asthma inhaled beta(2)-agonists are often administered by nebuliser to relieve bronchospasm, but some have argued that metered-dose inhalers with a holding chamber (spacer) can be equally effective. Nebulisers require a power source and need regular maintenance, and are more expensive in the community setting.

Objectives: To assess the effects of holding chambers (spacers) compared to nebulisers for the delivery of beta(2)-agonists for acute asthma.

Search methods: We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies to identify additional trials. Date of last search: February 2013.

Selection criteria: Randomised trials in adults and children (from two years of age) with asthma, where spacer beta(2)-agonist delivery was compared with wet nebulisation.

Data collection and analysis: Two review authors independently applied study inclusion criteria (one review author for the first version of the review), extracted the data and assessed risks of bias. Missing data were obtained from the authors or estimated. Results are reported with 95% confidence intervals (CIs).

Main results: This review includes a total of 1897 children and 729 adults in 39 trials. Thirty-three trials were conducted in the emergency room and equivalent community settings, and six trials were on inpatients with acute asthma (207 children and 28 adults). The method of delivery of beta(2)-agonist did not show a significant difference in hospital admission rates. In adults, the risk ratio (RR) of admission for spacer versus nebuliser was 0.94 (95% CI 0.61 to 1.43). The risk ratio for children was 0.71 (95% CI 0.47 to 1.08, moderate quality evidence). In children, length of stay in the emergency department was significantly shorter when the spacer was used. The mean duration in the emergency department for children given nebulised treatment was 103 minutes, and for children given treatment via spacers 33 minutes less (95% CI -43 to -24 minutes, moderate quality evidence). Length of stay in the emergency department for adults was similar for the two delivery methods. Peak flow and forced expiratory volume were also similar for the two delivery methods. Pulse rate was lower for spacer in children, mean difference -5% baseline (95% CI -8% to -2%, moderate quality evidence), as was the risk of developing tremor (RR 0.64; 95% CI 0.44 to 0.95, moderate quality evidence).

Authors’ conclusions: Nebuliser delivery produced outcomes that were not significantly better than metered-dose inhalers delivered by spacer in adults or children, in trials where treatments were repeated and titrated to the response of the participant. Spacers may have some advantages compared to nebulisers for children with acute asthma.

https://www-ncbi-nlm-nih-gov.york.ezproxy.cuny.edu/pmc/articles/PMC7032675/

Article 2:

Castro-Rodriguez JA, Rodrigo GJ. beta-agonists through metered-dose inhaler with valved holding chamber versus nebulizer for acute exacerbation of wheezing or asthma in children under 5 years of age: a systematic review with meta-analysis. J Pediatr. 2004 Aug;145(2):172-7. doi: 10.1016/j.jpeds.2004.04.007. PMID: 15289762.

Abstract:
Objective: To compare the efficacy of beta-agonists given by metered-dose inhaler with a valved holding chamber (MDI+VHC) or nebulizer in children under 5 years of age with acute exacerbations of wheezing or asthma in the emergency department setting.

Study design: Published (1966 to 2003) randomized, prospective, controlled trials were retrieved through several different databases. The primary outcome measure was hospital admission.

Results: Six trials (n=491) met criteria for inclusion. Patients who received beta-agonists by MDI+VHC showed a significant decrease in the admission rate compared with those by nebulizer (OR, 0.42; 95% CI, 0.24-0.72; P=.002); this decrease was even more significant among children with moderate to severe exacerbations (OR, 0.27; 95% CI, 0.13-0.54; P=.0003). Finally, measure of severity (eg, clinical score) significantly improved in the group who received beta-agonists by MDI+VHC in comparison to those who received nebulizer treatment (standardized mean difference, -0.44; 95% CI, -0.68 to -0.20; P=.0003).

Conclusions: The use of an MDI+VHC was more effective in terms of decreasing hospitalization and improving clinical score than the use of a nebulizer in the delivery of beta-agonists to children under 5 years of age with moderate to severe acute exacerbations of wheezing or asthma.

https://www-sciencedirect-com.york.ezproxy.cuny.edu/science/article/pii/S0022347604002835?via%3Dihub

Article 3:

Ploin D, Chapuis FR, Stamm D, Robert J, David L, Chatelain PG, Dutau G, Floret D. High-dose albuterol by metered-dose inhaler plus a spacer device versus nebulization in preschool children with recurrent wheezing: A double-blind, randomized equivalence trial. Pediatrics. 2000 Aug;106(2 Pt 1):311-7. doi: 10.1542/peds.106.2.311. Erratum in: Pediatrics 2000 Oct;106(4):623. PMID: 10920157.

Abstract:

Inhaled albuterol is the most frequently used bronchodilator for acute wheezing, and nebulization is the standard mode of delivery in hospital setting. However, recent guidelines consider spacer devices as an easier to use, and cost-saving alternative and recommend the high-dose metered-dose inhaler bronchodilator.

Objective: To demonstrate clinical equivalence between a spacer device and a nebulizer for albuterol administration.

Design: Randomized, double-blind, parallel group equivalence trial.

Setting: Pediatric emergency wards at 2 tertiary teaching hospitals.

Patients: Sixty-four 12- to 60-month-old children with acute recurrent wheezing (32 per group).

Interventions: Albuterol was administered through the spacer device (50 microg/kg) or through the nebulizer (150 microg/kg) and repeated 3 times at 20-minute intervals. Parents completed a questionnaire.

Outcome measures: Pulmonary index, hospitalization, ease of use, acceptability, and pulse oximetry saturation.

Results: The 90% confidence interval of the difference between treatment groups for the median absolute changes in pulmonary index values between T0 and T60 was [-1; +1] and was included in the equivalence interval [-1.5; +1.5]. Clinical improvement increased with time. Less than 10% of the children (3 in each group) required hospitalization (2 in each group attributable to treatment failure). Parents considered administration of albuterol using the spacer device easier (94%) and better accepted by their children (62%).

Conclusions: The efficacy of albuterol administered using the spacer device was equivalent to that of the nebulizer. Given its high tolerance, repeated 50-microg/kg doses of albuterol administered through the spacer device should be considered in hospital emergency departments as first-line therapy for wheezing.

https://pubmed-ncbi-nlm-nih-gov.york.ezproxy.cuny.edu/10920157/

Article 4:

Payares‐Salamanca, L, Contreras‐Arrieta, S, Florez‐García, V, Barrios‐Sanjuanelo, A, Stand‐Niño, I, Rodriguez‐Martinez, CE. Metered‐dose inhalers versus nebulization for the delivery of albuterol for acute exacerbations of wheezing or asthma in children: A systematic review with meta‐analysis. Pediatric Pulmonology. 2020; 55: 3268‐ 3278. https://doi.org/10.1002/ppul.25077

Abstract

Objectives The benefits of metered‐dose inhalers with a spacer (MDI+S) have increasingly been recognized as an alternative method of albuterol administration for treating pediatric asthma exacerbations. The aim of this systematic review was to compare the response to albuterol delivered through nebulization (NEB) with albuterol delivered through MDI+S in pediatric patients with asthma exacerbations.

Methods We conducted an electronic search in MEDLINE/PubMed, EMBASE, Ovid, and ClinicalTrials. To be included in the review, a study had to a randomized clinical trial comparing albuterol delivered via NEB versus MDI+S; and had to report the rate of hospital admission (primary outcome), or any of the following secondary outcomes: oxygen arterial saturation, heart rate (HR), respiratory rate (RR), the pulmonary index score (PIS), adverse effects, and need for additional treatment.

Results Fifteen studies (n = 2057) met inclusion criteria. No significant differences were found between the two albuterol delivery methods in terms of hospital admission (relative risk, 0.89; 95% confidence interval [CI], 0.55–1.46; I² = 32%; p = .65). There was a significant reduction in the PIS score (mean difference [MD], −0.63; 95% CI, −0.91 to −0.35; I² = 0%; p < .00001), and a significantly smaller increase in HR (better; MD −6.47; 95% CI, −11.69 to −1.25; I² = 0%; p = .02) when albuterol was delivered through MDI+S than when it was delivered through NEB.

Conclusions This review, an update of a previously‐published meta‐analysis, showed a significant reduction in the PIS and a significantly smaller increase in HR when albuterol was delivered through MDI+S than when it was delivered through NEB.

https://onlinelibrary.wiley.com/doi/abs/10.1002/ppul.25077

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting(# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Cates CJ, Welsh EJ, Rowe BH (2013)	Systematic review	Cochrane Airways Group Trial Register was used to identify 39 RCTs with a total of 1897 children and 729 adults evaluated	The primary outcomes were hospital admission, and length of stay. Secondary outcomes include change in respiratory rate, blood gases, tremor, symptoms score, lung function, use of steroids, relapse rate	Hospital admission rates did not significantly differ in adults or children. Duration of ED visit was significantly shorter for inhaler with spacer than nebulizer. Pulse rate significantly lower when spacer was used. Tremor was more common with nebulizer. No significant difference in lung function, oxygen saturation, respiratory rate, and steroid use.	For some outcomes there were different results between children and adult groups. There was heterogeneity for time spent in ED between studies, but after separating children and adults no heterogeneity was shown. There is uncertainty over the dose and type of beta agonist used in some studies. The study excluded life-threatening asthma exacerbations. The studies were performed under supervision by healthcare professionals and cannot necessarily be applied to treatment of acute asthma exacerbations at home where patients might benefit due to cost of nebulizer and need for access to electricity.
Castro-Rodriguez JA, Rodrigo GJ (2004)	Systematic review and meta analysis	Searched Medline, Embase, and Cochrane Controlled Trials Register. Included 6 randomized trials evaluating 491 children 1-60 months of age. 5 Studies treated with albuterol and 1 with terbutaline.	Disease severity, hospital admission rate, heart rate, respiratory rate	Patients treated for moderate to severe exacerbations with metered-dose inhaler and spacer had significantly lower admission rates with no heterogeneity between studies. Significant decrease in disease severity with metered-dose inhaler and spacer. Significant increase in heart rate with nebulizers.  Low values of heterogeneity (<25%) were found in all comparisons. 3 of 6 trials were considered “high-quality” and those studies also showed highest effect of MDI with spacer in lowering hospital admissions.	Data from all studies was not sufficient to accurately analyze secondary outcomes such as respiratory rate and oxygen saturation. Meta analysis is limited by quality and quantity of data reported. Publication bias and study-selection bias cannot be ruled out, unpublished trials were not used. Life threatening asthma was excluded from this review.
Ploin D, Chapuis FR, Stamm D, Robert J, David L, Chatelain PG, Dutau G, Floret D. (2000)	RCT	64 12-60 month old children were enrolled between December 1995-March 1997 with acute recurrent wheeze at a single pediatric ED.Double blind study, patients randomized in blocks of 4 and given either (1) albuterol via metered dose inhaler with spacer and nebulizer placebo or (2) nebulized albuterol and inhaler with placebo. Within each group they were randomized to receive either inhaler or nebulizer first.	Cardiorespiratory status every 20 minutes, oxygen saturation, heart rate, respiratory rate, parent survey for which was easier to administer and which seemed more effective	Concluded that the 2 treatments were equivalent due to 90% confidence interval between treatment groups for median absolute changes in pulmonary index value. 94% (59/64) of parents said the inhaler with spacer was easier mode of albuterol administration, 3 (5%) preferred the nebulizer, and 1 had no preference. 62% (39/64) of parents said the inhaler with spacer was better accepted by their child, 27% (17/64) preferred the nebulizer, 11% (7/64) had no preference.	Limited by size, study was done at a single center and had only 64 patients. Unbalanced initial symptoms/wheeze severity that as not clearly defined, the treatment effectiveness was evaluated based on change from baseline.
Payares‐Salamanca, L, Contreras‐Arrieta, S, Florez‐García, V, Barrios‐Sanjuanelo, A, Stand‐Niño, I, Rodriguez‐Martinez, CE. (2020)	Systematic review with meta analysis	Searched MEDLINE/PubMed, EMBASE, and Ovid databases through February 2020 to identify 15 studies including 2057 patients under 18 years of age with acute wheezing or asthma exacerbations managed in ED or inpatient. 73.3% of studies enrolled children younger than 5 years.	Primary outcome was hospital admission. Secondary outcomes included pulmonary index score (PIS), SaO2, heart rate, adverse effects including nausea, palpitations, and tremor	No significant difference was found in hospital admission, some evidence of heterogeneity. Significant reduction in PIS for MDS with spacer, no significant heterogeneity. No significant difference in SaO2. Significantly smaller increase in heart rate for MDS with spacer compared to nebulizer. No significant difference for adverse effects including nausea, palpitations, and tremor.	Limited by quality and quantity of available studies and information that they report. Some studies enroll patients with wheeze without acknowledging clear diagnosis of asthma. 6 studies had high risk of bias due to being open-label trials. Also limited because subgroup analysis was not done between age groups. Dose of albuterol delivered via MDI was not standardized between studies compared to dose via nebulizer.

Conclusion(s):
– Briefly summarize the conclusions of each article

– Then provide an overarching conclusion.

Cates et al. – Concluded that there was no significant advantage of wet nebulizer over metered-dose inhaler (MDI) with spacer for administration of beta agonists in treatment of acute asthma. Nebulizers did not prevent hospital admissions and children treated with metered dose inhaler and spacer had significantly shorter ED visits (23-43 minutes). Same cannot be said for adults. MDI with spacer had lower rates of hypoxia, pulse rates, and tremor. MDI with spacer was also cost saving due to reduced cost of medication and equipment and also reduced length of ED stay.

Castro-Rodriguez and Rodrigo – Concluded that for infants and children younger than 5 years with acute exacerbation of wheeze or asthma that were treated with MDI and spacer had lower hospital admission rates and clinical scores than patients treated with the same beta agonist via nebulizer. Difference was greater with more severe wheeze or asthma.

Ploin et al. – Concluded that the 2 treatments were equivalent due to 90% confidence interval between treatment groups for median absolute changes in pulmonary index value. Parent survey showed that there was a strong perception that MDI with spacer was easier to use and better accepted by their children.

Payares-Salamanca et al. – Concluded that while MDI with spacer was not significantly superior than nebulizer in terms of admission rates it showed significant reduction in Pulmonary Index Score, and significantly smaller increase in heart rate, while showing no significant difference in SaO2, nausea or other adverse effects compared to nebulizer. They also favor use of MDI with spacer over nebulizer during COVID-19 pandemic as it does not aerosolize particles that can potentially spread virus

Overall conclusion is that MDI with spacer is at least equally as effective as wet nebulizer for treatment of acute asthma exacerbations in children in the ED. MDI with spacer had decreased length of stay in ED, lower rate of admission, and less adverse effects associated with it. Parents also perceived the MDI with spacer to be easier to use and better accepted by their children. This has been demonstrated for mild, moderate, and severe exacerbations but not for life-threatening asthma exacerbations.

Clinical Bottom Line:

Please include an assessment of the following:

– Weight of the evidence

• Cates et al. – I weighed this article as the strongest as it was very large and also the most recent article I included. It was a systematic review, which is the highest level of evidence, and evaluated 39 RCTs containing 1897 children and 729 adults. The results were fairly different between children and adults, and the authors made separate conclusions regarding MDI+spacer use in children and adults. This review built on a previous version of the review by adding studies published 2008-2013.
• Castro-Rodriguez and Rodrigo – This article was the second strongest evidence. It was a systematic review and meta analysis providing the highest level of evidence. I weighed this below the Cates article due to it being a slightly older publication from 2004 including 6 RCTS with 491 subject both of which are less than the Cates article. While they were able to draw clear conclusion about their primary outcomes such as admission rates and disease severity without significant heterogeneity between studies, the meta-analysis was limited by the quality and quantity of data reported which limited their ability to analyze certain secondary outcomes.
• Ploin et al. – Strong evidence as it was a double blind RCT, I weighed it weaker than the other 3 because it only had 64 subjects and was done at a single center. Showed similar results to the other studies, no significant difference was seen between MDI with spacer and nebulizer. This study also directly applied to my 5 year old patient as they evaluated age 12-60 months. They evaluated other important factors for pediatrics population: parent perception and ease of use. They surveyed the parents to determine which device was easier to use and which was seen as better accepted by their children with majority showing preference for MDI with spacer.
• Payares-Salamanca et al – This article had high level of evidence as it is a systematic review published in 2020 that evaluated 15 studies, 3 of which were newer than the Cates et al Cochrane systematic review from 2013 and therefore not included at that time. They had a large sample size of 2057 patients less than 18 years old with acute wheezing or asthma exacerbations managed either in the ED or inpatient. The sample size of each individual study was relatively small, only 5 had more than 100. Majority of studies had children younger than 5 years old. 4 of the included studies had low risk of bias for criteria they evaluated, 6 had high risk of bias, and for 2 studies the risk of bias was unclear. The results were fairly consistent with the previously mentioned review from 2013 with improved outcomes and less adverse effects when MDI with spacer was used compared to nebulizer.

– Magnitude of any effects

• All 4 articles came to similar conclusions, there was no statistically significant difference between MDI with spacer and wet nebulizer for children with acute asthma exacerbation.

– Clinical significance (not just statistical significance)

• All 4 articles provide evidence showing that MDI with spacer was at least as effective as nebulizer. They also showed shorter length of ED visit, lower hospital admission rates and lower adverse effect profile associated with MDI and spacer compared to nebulizer. The authors also alluded to benefits associated with MDI and spacer by pointing out faster rate of administration and parent’s perceived easer of use, as well as bulky equipment and need for electricity when using nebulizer. Faster rate of administration, shorter length of ED stay, and lower rates of hospital admission all contribute to lowering cost. MDI with spacer is favored over nebulizer during COVID-19 pandemic as it does not aerosolize particles that can potentially spread virus None of the studies included life-threatening exacerbations of asthma and none of the authors believed the results could be extrapolated to those patients.

– Any other considerations important in weighing this evidence to guide practice  –

• The results clearly showed MDI with spacer was at least as effective as nebulizer for treating exacerbations of asthma, while also identifying other benefits associated with adverse effects and hospital length of stay. One systematic review found that this was different for adults. Moving forward it is important to identify what age the benefit from MDI with spacer is no longer seen in order to optimize care as pediatric patients become older.