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Three Part Question

In [‘intermediate risk’ adults presenting to the emergency department with wheeze] is [salbutamol delivered by a metered-dose inhaler with a spacer] as effective as [salbutamol delivered by nebuliser] with regard to [reducing ED length of stay and rate of hospital admission]?

Clinical Scenario

An adult patient with a mixed background of asthma and chronic obstructive pulmonary disease (COPD) presents to the ED with worsening shortness of breath and wheeze. They report using their salbutamol inhaler multiple times at home, with little improvement. At present, they are not able to speak in full sentences, but their oxygen saturations are normal, and they show no signs of fatigue. You consider prescribing nebulised salbutamol but wonder if there is any evidence to support instead the use of a metered-dose inhaler with spacer.

Search Strategy

An unfiltered database search was conducted using EMBASE and MEDLINE via the Ovid interface to identify relevant studies, utilising the following keyword search:

[Salbutamol.mp OR exp *Albuterol/ OR ventolin.mp OR beta agonist.mp.] AND [Inhaler$.mp] AND [nebuli?er.mp OR exp *"Nebulizers and Vaporizers"/ ] AND {adult.mp]

Following this, the Cochrane database was used to conduct a supplementary search with the same keyword terms. Each relevant paper was then searched using the Google Scholar ‘cited by’ function. This allowed for the identification of any additional studies that had referenced our eligible papers. Lastly, the reference list of each paper was screened to identify any studies missed by our search.

Search Outcome

Our search yielded a total of 445 papers after manual removal of duplicates. 415 were excluded on title and abstract review, as they were not relevant to our clinical question. Of the 30 papers, 18 were excluded after full text review because they were review papers (n=10), not relevant (n=5), irretrievable (n=2) or based on inpatient data (n=1). A further six were excluded because they did not include the relevant outcome data.

Six papers met our inclusion criteria and underwent analysis: three double-blinded randomised controlled trials (RCTs) (2,4,6), one open-label randomised trial (5), and two observational studies (1,3). Adults with acute asthma and acute exacerbations of COPD (AECOPD) were included. The results are summarised in Table 1.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Newman et al. 2002 USA	Adult patients presenting with acute exacerbation of asthma to a large, urban ED. N = 1,481 Mean age: 36 Male: 41.2% Nebuliser group “Phase 1” (n=617) received exclusively nebulised Albuterol. MDIS group “Phase 2” (n = 864) received an initial 5 puffs of Albuterol via MDIS (AeroChamber), followed by 3-5 puffs every 30 minutes, as required.	Single-centre prospective cohort study	Rate of hospital admission	No statistically significant difference in rate of hospital admission between MDIS and nebuliser group – 13.2% vs. 14.6% respectively (p = > 0.1).	Researchers were unblinded to treatment allocation. Criteria for hospital admission not provided. Non-standardised treatment in nebuliser group for first three months of study. 22.6% of patients in “Phase 2” received nebulised Salbutamol; no subgroup analysis provided for MDIS-only patients
			ED length of stay	Statistically significant reduction in ED LOS in MDIS group compared to nebuliser group – 164 minutes vs. 175 minutes respectively (p = 0.007).
Levitt et al. 1995 USA	Adult patients presenting with acute bronchospastic exacerbation to an urban ED. N = 40 Mean age: not provided Male: not provided Nebuliser group (n = 20) received 15mg/hr of albuterol via continuous-flow nebulization for 5 minutes, followed by four puffs of saline (placebo) - this sequence was repeated until one of three end points was reached. MDIS group (n= 20) received continuous-flow nebulization of saline (placebo) for 5 minutes, followed by four puffs of albuterol via MDIS - this sequence was repeated until one of three end points was reached.	Single-centre double-blinded randomised controlled trial	Rate of hospital admission	No statistically significant difference in rate of hospital admission between MDIS and nebuliser group – 42% vs. 30% respectively (p = 0.4309).	Mean age significantly differed between MDIS and nebuliser groups (p = 0.004). Significant heterogeneity between MDIS and nebuliser groups – 45% asthma patients vs. 80% asthma patients respectively. Excluded patients with a history of allergic reaction, thus excluding a significant subset of atopic patients with comorbid asthma and allergy. Excluded patients with a history of angina and congestive heart failure without justification. Criteria for hospital admission not provided.
Lee et al. 2005 Hong Kong	Adult patients presenting with acute exacerbation of asthma or COPD to an urban ED. N = 565 Mean age: 59 (NEB), 59 (MDIS) Male: 66% (NEB), 70% (MDIS) Nebuliser group (n = 346) November 2002 (pre-SARS) – all patients treated 1st line with nebulised salbutamol. MDIS group (n = 219) November 2003 (post-SARS) – all patients treated 1st line with salbutamol via MDIS.	Single-centre retrospective chart review	Rate of hospital admission	Significantly lower rate of hospital admission in the MDIS group compared to the nebuliser group – 47% vs. 61% respectively (p = 0.002).	Retrospective chart review reliant on patient notes that may be incomplete. Non-standardised salbutamol dosing used in both groups (based on clinical judgement and patient demographics). Excluded patients with ‘serious co-morbidities’ such as stroke, heart or renal failure, and other respiratory co-morbidities without justification. Findings may be accounted for by the change in patient preferences post-SARS epidemic (occurred mid-study), resulting in reluctance to be admitted to hospital.
Dhuper et al. 2011 USA	Adult patients presenting with acute exacerbation of asthma to two urban EDs. N = 58 Mean age: not provided Male: 29% Nebuliser group (n = 29) received six puffs of placebo via MDIS (AireLite), followed by 2.5mg of nebulised Albuterol every hour, until the decision to admit or discharge was made. MDIS group (n = 29) received 540 µg Albuterol via MDIS (AireLite), followed by 3ml of nebulised normal saline solution every hour, until the decision to admit or discharge was made.	Multi-centre double-blinded randomised controlled trial	Rate of hospital admission	No statistically significant difference in rate of hospital admission between MDIS and nebuliser group – 7% vs. 3% respectively (p = 0.55).	Excluded patients with smoking pack history of >20 years, over 70 years, or diagnosed with “co-existent systemic diseases” without justification. Patients only included if they could ‘perform peak flow maneuvers with good effort’ – thereby excluding severe exacerbations. Patients were managed by non-physician respiratory therapists.
			ED length of stay	The median ED LOS was equivalent in the nebuliser and MDIS group at 2 hours. The LOS interquartile range was 1-2.5 hrs for those receiving nebuliser and 1.5-3 hrs for the MDIS group (p = 0.78).
Raimondi et al. 1997 Argentina	Adult patients presenting with severe acute exacerbation of asthma to an urban ED. N = 18 Mean age: 37 (NEB), 34 (MDIS) Male: 56% (NEB), 33% (MDIS) Nebuliser group (n = 9) received 5mg of oxygen-driven nebulised Albuterol on arrival in ED, every 30 minutes for 2 hours, then hourly for 4 hours. MDIS group (n = 9) received 400µg Albuterol via MDIS (AeroChamber) on arrival in ED, every 30 minutes for 2 hours, then hourly for 4 hours.	Prospective open-label randomised trial	Rate of hospital admission	Admission rate in both the MDIS and nebuliser group was zero.	Participants were unblinded to treatment allocation. Excluded patients who were pregnant, had a history of smoking, co-existing cardiorespiratory disease, or those over 65 years old without justification. All patients received a single dose of 8mg IV dexamethasone upon arrival in ED.
Rodrigo et al. 1993 Uruguay	Adult patients presenting with acute exacerbation of asthma to ED with an FEV1 <50% predicted. N = 97 Mean age: 32 (NEB) Male: 46% (NEB), 49% (MDIS) Nebuliser group (n = 48) received 1.5mg of oxygen-driven nebulised Salbutamol at 15-minute intervals, followed by four puffs of placebo via MDIS at 10-minute intervals. MDIS group (n= 49) received 4 puffs of 100µg Salbutamol via MDIS (Volumatic spacer) with 10-minute intervals between each puff, followed by 4ml of nebulised saline at 15-minute intervals.	Double-blinded randomised controlled trial	Rate of hospital admission	No statistically significant difference in hospital admissions between the MDIS and nebuliser group – 10.2% vs. 8.33% respectively (p = 0.95).	Excluded participants who were pregnant, over 50 years old, had a history of chronic cough or had “other medical diseases” without justification.
			ED length of stay	No statistically significant difference in ED LOS between the MDIS and nebuliser group – 2.19 hrs vs. 1.94 hrs respectively (p = 0.68).

Comment(s)

Our search returned six studies demonstrating reduced (1,3) or similar (2,4-6) hospital admission and ED length of stay in wheezy patients given salbutamol via MDIS instead of nebulisers. It is our observation that adult patients presenting to ED with wheeze frequently receive nebulised salbutamol, even when their symptoms fall short of the criteria for “life-threatening” asthma (7) or “severe” AECOPD (8). Typically, these intermediate-risk patients would be described as “acute severe asthma” (7) or ‘moderate-to-severe’ AECOPD (8) and guidelines equivocate on the appropriate mode of delivery for their salbutamol. It is inevitable that a proportion of this ‘intermediate-risk’ group will require nebulised bronchodilators, and possibly hospital admission. However, the results of our review suggest that some may be safely treated with MDIS – which would appear to be more compatible with an earlier discharge from ED. One additional advantage of MDIS therapy is that it provides the opportunity to educate patients on inhaler use, thus supporting the continuity of asthma management in the community. Newman et al provided an “asthma bag” to patients, along with a brief counselling program ran by ED nurses. This may have also contributed to the lower rates of relapse observed in the MDIS group (1). The key limitation in our review is the methodological disparity seen among our studies, including the use of different spacer devices, salbutamol dosing, severity criteria, and admission criteria. A pragmatic RCT including only ‘intermediate risk’ patients, using standardised doses of inhaled and nebulised salbutamol is required to objectively answer this clinical question. In the meantime, we recommend on the basis of our review that ED clinicians trial salbutamol via MDIS when patients present with wheeze but have normal oxygen saturations and no clear “life-threatening” (7) or “severe” (8) features.

Clinical Bottom Line

In patients presenting to ED with ‘intermediate-risk’ wheeze, a trial of salbutamol delivered via MDIS may be beneficial in reducing hospital admission and ED length of stay. Clinicians should reserve nebulised salbutamol for patients with severe bronchoconstriction and those in whom MDIS has failed.

References

1. Kenneth B. Newman, Scott Milne, Cathy Hamilton, Kent Hall A Comparison of Albuterol Administered by Metered-Dose Inhaler and Spacer With Albuterol by Nebulizer in Adults Presenting to an Urban Emergency Department With Acute Asthma CHEST 2002;121(4):1036-41
2. M. Andrew Levitt, Elaine F Gambrioli, James B Fink Comparative Trial of Continuous Nebulization Versus Metered-Dose Inhaler in the Treatment of Acute Bronchospasm Annals of Emergency Medicine 1995;26(3):273-7
3. GPC Lee, WY Sung, HT Fung, CW Kam Nebulizer versus Inhaler with Spacer for Beta-Agonist Treatment in Acute Bronchospastic Disease Hong Kong Journal of Emergency Medicine 2005;12(3):133-9
4. Sunil Dhuper, Alpana Chandra, Aziz Ahmed, Sabin Bista, Ajit Moghekar, Rajesh Verma, Cynthia Chong, Chang Shim, Hillel Cohen, Sonia Choksi Efficacy and Cost Comparisons of Bronchodilatator Administration Between Metered Dose Inhalers with Disposable Spacers and Nebulizers for Acute Asthma Treatment The Journal of Emergency Medicine 2011;40(3):247-55
5. Alejandro C. Raimondi, Juan Schottlender, Dora Lombardi, Nester A. Molfino Treatment of Acute Severe Asthma With Inhaled Albuterol Delivered via Jet Nebulizer, Metered Dose Inhaler With Spacer, or Dry Powder CHEST 1997;112(1):24-8
6. Gustavo Rodrigo, Carlos Rodrigo Comparison of salbutamol delivered by nebulizer or metered-dose inhaler with a pear-shaped spacer in acute asthma Current Therapeutic Research 1993;54(6):797-808
7. British Thoracic Society SIGN. British guideline on the management of asthma. 2019
8. National Institute for Health and Care Excellence (NICE). Chronic obstructive pulmonary disease in over 16s: diagnosis and management. 2019