NIHR Signal Combination inhaler treatment in emergency departments may reduce admissions for asthma attacks

Published on 30 May 2017

Using a combination of two inhaled drugs to open the airways may modestly reduce the need to admit an adult with asthma attack to hospital, though the underlying evidence is weak.

The first-line treatment for an asthma attack is an inhaled β2 agonist, like salbutamol. This Cochrane review compared emergency department treatment with this drug alone, or combined with an inhaled short-acting anticholinergic, like ipratropium bromide.

Pooled results from 16 trials included found that combination therapy would mean about 65 fewer patients per 1000 are admitted to hospital. As most underlying trials were conducted outside the NHS, the admission rates are likely to be quite different in the UK.

Short-term minor adverse effects were more common with combined therapy.

The evidence suggests combination treatment is most effective in severe attacks and this is consistent with current UK guideline recommendations.

Asthma places a large burden on the NHS and reducing hospital admissions may spare resources. Further study could usefully explore the optimal drug dose and delivery method in a UK setting.   

Why was this study needed?

Asthma is a chronic condition affecting one in 12 adults in the UK. The NHS spends about £1 billion a year treating people with asthma.

Every day 185 people each day are admitted to hospital with an asthma attack. This is when airways become acutely inflamed and narrowed in response to certain triggers like infections, allergens or tobacco smoke, causing sudden breathlessness and wheezing.

Doctors give inhaled β2 agonist drugs, like salbutamol, as first-line treatment for an asthma attack (usually alongside oxygen and steroids). Guidelines recommend giving an inhaled short-acting anticholinergic drug, usually ipratropium bromide, in more severe cases or those that haven’t responded to the β2 agonist.

Previous research has shown that combining both inhaled drugs might reduce the need for children having an asthma attack being admitted to hospital. This Cochrane review aimed to find out whether this is true for adults.

What did this study do?

Researchers identified 21 randomised controlled trials and controlled clinical trials (2724 adults) that compared combined β2 agonists and anticholinergics with β2 agonists alone, in the emergency department treatment of asthma attack.

Most trials used salbutamol and ipratropium bromide and administered treatment via a nebuliser. Drug dose varied between trials, with some giving single doses and others multiple. Studies were conducted in 11 countries, with one from the UK.

The main outcome was admission to hospital after emergency department treatment. Other outcomes included adverse events and lung function test results.

Most of the studies had unclear risk of bias, with uncertainties around method of randomisation, blinding, and whether all outcomes were assessed and reported. If admitting physicians were aware of treatment allocation, for example, it is possible that the admission rates could have been exaggerated. However, the overall direction of effect for hospital admission was similar across trials.   

What did it find?

  • Combination treatment using both an inhaled β2agonist and anticholinergic reduced the risk of hospital admission. Seventeen per cent of participants receiving combination therapy were admitted to hospital compared with 23% receiving a β2 agonist alone (risk ratio [RR] 0.72, confidence intervals [CI] 0.59 to 0.87; 16 studies, 2120 people). Overall this is equivalent to 65 fewer admissions per 1000.         
  • Combination treatment increased the risk of adverse events. There were about 13 adverse events in every 100 people receiving an inhaled β2 agonist alone and around 18 per 100 people receiving the combination therapy (OR 2.03, CI 1.28 to 3.20; 11 studies, 1392 people). Adverse events were short-term and included dry mouth, tremor, anxiety and palpitations, though there was limited data to reliably analyse rates of individual adverse events. No deaths were reported in any study.
  • In subgroup analyses, combination inhaled therapy was more effective in reducing hospital admissions for people with severe asthma attacks (RR 0.56, 95% CI 0.43 to 0.72; seven studies, 599 adults). No difference was found for moderately severe (RR 0.88, 95% CI 0.69 to 1.11; seven studies, 1409 adults) and mild attacks (RR 1.88, 95% CI 0.37 to 9.54; two studies, 112 adults).

Benefits and risks of combined inhalers for acute asthma

What does current guidance say on this issue?

The 2016 British Thoracic Society and Scottish Intercollegiate Guidelines Network guideline on the management of asthma recommends high-dose inhaled β2 agonists as the first-line treatment of asthma attack. If symptoms are severe, treatment should be given via a nebuliser driven by oxygen. Guidelines recommend adding the anticholinergic ipratropium bromide to the nebuliser for patients with severe or life-threatening asthma, or those with poor initial response to β2 agonists alone.

It is also recommended that oral steroids are given as soon as possible to all people with asthma attack.

What are the implications?

The findings support current guidelines on giving both an inhaled β2 agonist and anticholinergic to people with severe asthma attack or those not getting rapid relief from a β2 agonist.

Although patients receiving both drugs were more likely to experience adverse events, these were short-term and minor and probably outweighed by the benefits in reducing the severity of the attack. Costs of giving both drugs would be small and could be offset by savings from reduced hospital admissions.

Exploration of the best doses and delivery method in UK studies could optimise emergency treatment of asthma attacks for the NHS.

Citation and Funding

Kirkland SW, Vandenberghe C, Voaklander B, et al. Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma. Cochrane Database Syst Rev. 2017;1:CD001284.

This project was funded by the National Institute for Health Research via Cochrane infrastructure funding to the Cochrane Airways group.

Bibliography

Asthma UK. What is asthma? London: Asthma UK; 2016.

Asthma UK. Asthma facts and statistics. London: Asthma UK; 2016.

Booker R. Pharmacology of bronchodilators. Clinical archive article. Warwick: Nursing Times; 2004.

British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. SIGN: Edinburgh; 2016.

Grifths B, Ducharme FM. Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children. Cochrane Database Syst Rev. 2013;(8):CD000060.  

NHS Choices. Asthma attack: what to do. London: Department of Health; 2016.

Why was this study needed?

Asthma is a chronic condition affecting one in 12 adults in the UK. The NHS spends about £1 billion a year treating people with asthma.

Every day 185 people each day are admitted to hospital with an asthma attack. This is when airways become acutely inflamed and narrowed in response to certain triggers like infections, allergens or tobacco smoke, causing sudden breathlessness and wheezing.

Doctors give inhaled β2 agonist drugs, like salbutamol, as first-line treatment for an asthma attack (usually alongside oxygen and steroids). Guidelines recommend giving an inhaled short-acting anticholinergic drug, usually ipratropium bromide, in more severe cases or those that haven’t responded to the β2 agonist.

Previous research has shown that combining both inhaled drugs might reduce the need for children having an asthma attack being admitted to hospital. This Cochrane review aimed to find out whether this is true for adults.

What did this study do?

Researchers identified 21 randomised controlled trials and controlled clinical trials (2724 adults) that compared combined β2 agonists and anticholinergics with β2 agonists alone, in the emergency department treatment of asthma attack.

Most trials used salbutamol and ipratropium bromide and administered treatment via a nebuliser. Drug dose varied between trials, with some giving single doses and others multiple. Studies were conducted in 11 countries, with one from the UK.

The main outcome was admission to hospital after emergency department treatment. Other outcomes included adverse events and lung function test results.

Most of the studies had unclear risk of bias, with uncertainties around method of randomisation, blinding, and whether all outcomes were assessed and reported. If admitting physicians were aware of treatment allocation, for example, it is possible that the admission rates could have been exaggerated. However, the overall direction of effect for hospital admission was similar across trials.   

What did it find?

  • Combination treatment using both an inhaled β2agonist and anticholinergic reduced the risk of hospital admission. Seventeen per cent of participants receiving combination therapy were admitted to hospital compared with 23% receiving a β2 agonist alone (risk ratio [RR] 0.72, confidence intervals [CI] 0.59 to 0.87; 16 studies, 2120 people). Overall this is equivalent to 65 fewer admissions per 1000.         
  • Combination treatment increased the risk of adverse events. There were about 13 adverse events in every 100 people receiving an inhaled β2 agonist alone and around 18 per 100 people receiving the combination therapy (OR 2.03, CI 1.28 to 3.20; 11 studies, 1392 people). Adverse events were short-term and included dry mouth, tremor, anxiety and palpitations, though there was limited data to reliably analyse rates of individual adverse events. No deaths were reported in any study.
  • In subgroup analyses, combination inhaled therapy was more effective in reducing hospital admissions for people with severe asthma attacks (RR 0.56, 95% CI 0.43 to 0.72; seven studies, 599 adults). No difference was found for moderately severe (RR 0.88, 95% CI 0.69 to 1.11; seven studies, 1409 adults) and mild attacks (RR 1.88, 95% CI 0.37 to 9.54; two studies, 112 adults).

Benefits and risks of combined inhalers for acute asthma

What does current guidance say on this issue?

The 2016 British Thoracic Society and Scottish Intercollegiate Guidelines Network guideline on the management of asthma recommends high-dose inhaled β2 agonists as the first-line treatment of asthma attack. If symptoms are severe, treatment should be given via a nebuliser driven by oxygen. Guidelines recommend adding the anticholinergic ipratropium bromide to the nebuliser for patients with severe or life-threatening asthma, or those with poor initial response to β2 agonists alone.

It is also recommended that oral steroids are given as soon as possible to all people with asthma attack.

What are the implications?

The findings support current guidelines on giving both an inhaled β2 agonist and anticholinergic to people with severe asthma attack or those not getting rapid relief from a β2 agonist.

Although patients receiving both drugs were more likely to experience adverse events, these were short-term and minor and probably outweighed by the benefits in reducing the severity of the attack. Costs of giving both drugs would be small and could be offset by savings from reduced hospital admissions.

Exploration of the best doses and delivery method in UK studies could optimise emergency treatment of asthma attacks for the NHS.

Citation and Funding

Kirkland SW, Vandenberghe C, Voaklander B, et al. Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma. Cochrane Database Syst Rev. 2017;1:CD001284.

This project was funded by the National Institute for Health Research via Cochrane infrastructure funding to the Cochrane Airways group.

Bibliography

Asthma UK. What is asthma? London: Asthma UK; 2016.

Asthma UK. Asthma facts and statistics. London: Asthma UK; 2016.

Booker R. Pharmacology of bronchodilators. Clinical archive article. Warwick: Nursing Times; 2004.

British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. SIGN: Edinburgh; 2016.

Grifths B, Ducharme FM. Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children. Cochrane Database Syst Rev. 2013;(8):CD000060.  

NHS Choices. Asthma attack: what to do. London: Department of Health; 2016.

Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma

Published on 12 January 2017

Kirkland, S. W.,Vandenberghe, C.,Voaklander, B.,Nikel, T.,Campbell, S.,Rowe, B. H.

Cochrane Database Syst Rev Volume 1 , 2017

BACKGROUND: Inhaled short-acting anticholinergics (SAAC) and short-acting beta(2)-agonists (SABA) are effective therapies for adult patients with acute asthma who present to the emergency department (ED). It is unclear, however, whether the combination of SAAC and SABA treatment is more effective in reducing hospitalisations compared to treatment with SABA alone. OBJECTIVES: To conduct an up-to-date systematic search and meta-analysis on the effectiveness of combined inhaled therapy (SAAC + SABA agents) vs. SABA alone to reduce hospitalisations in adult patients presenting to the ED with an exacerbation of asthma. SEARCH METHODS: We searched MEDLINE, Embase, CINAHL, SCOPUS, LILACS, ProQuest Dissertations & Theses Global and evidence-based medicine (EBM) databases using controlled vocabulary, natural language terms, and a variety of specific and general terms for inhaled SAAC and SABA drugs. The search spanned from 1946 to July 2015. The Cochrane Airways Group provided search results from the Cochrane Airways Group Register of Trials which was most recently conducted in July 2016. An extensive search of the grey literature was completed to identify any other potentially relevant studies. SELECTION CRITERIA: Included studies were randomised or controlled clinical trials comparing the effectiveness of combined inhaled therapy (SAAC and SABA) to SABA treatment alone to prevent hospitalisations in adults with acute asthma in the emergency department. Two independent review authors assessed studies for inclusion using pre-determined criteria. DATA COLLECTION AND ANALYSIS: For dichotomous outcomes, we calculated individual and pooled statistics as risk ratios (RR) or odds ratios (OR) with 95% confidence intervals (CI) using a random-effects model and reporting heterogeneity (I(2)). For continuous outcomes, we reported individual trial results using mean differences (MD) and pooled results as weighted mean differences (WMD) or standardised mean differences (SMD) with 95% CIs using a random-effects model. MAIN RESULTS: We included 23 studies that involved a total of 2724 enrolled participants. Most studies were rated at unclear or high risk of bias.Overall, participants receiving combination inhaled therapy were less likely to be hospitalised (RR 0.72, 95% CI 0.59 to 0.87; participants = 2120; studies = 16; I(2) = 12%; moderate quality of evidence). An estimated 65 fewer patients per 1000 would require hospitalisation after receiving combination therapy (95% 30 to 95), compared to 231 per 1000 patients receiving SABA alone. Although combination inhaled therapy was more effective than SABA treatment alone in reducing hospitalisation in participants with severe asthma exacerbations, this was not found for participants with mild or moderate exacerbations (test for difference between subgroups P = 0.02).Participants receiving combination therapy were more likely to experience improved forced expiratory volume in one second (FEV(1)) (MD 0.25 L, 95% CI 0.02 to 0.48; participants = 687; studies = 6; I(2) = 70%; low quality of evidence), peak expiratory flow (PEF) (MD 36.58 L/min, 95% CI 23.07 to 50.09; participants = 1056; studies = 12; I(2) = 25%; very low quality of evidence), increased percent change in PEF from baseline (MD 24.88, 95% CI 14.83 to 34.93; participants = 551; studies = 7; I(2) = 23%; moderate quality of evidence), and were less likely to return to the ED for additional care (RR 0.80, 95% CI 0.66 to 0.98; participants = 1180; studies = 5; I(2) = 0%; moderate quality of evidence) than participants receiving SABA alone.Participants receiving combination inhaled therapy were more likely to experience adverse events than those treated with SABA agents alone (OR 2.03, 95% CI 1.28 to 3.20; participants = 1392; studies = 11; I(2) = 14%; moderate quality of evidence). Among patients receiving combination therapy, 103 per 1000 were likely to report adverse events (95% 31 to 195 more) compared to 131 per 1000 patients receiving SABA alone. AUTHORS' CONCLUSIONS: Overall, combination inhaled therapy with SAAC and SABA reduced hospitalisation and improved pulmonary function in adults presenting to the ED with acute asthma. In particular, combination inhaled therapy was more effective in preventing hospitalisation in adults with severe asthma exacerbations who are at increased risk of hospitalisation, compared to those with mild-moderate exacerbations, who were at a lower risk to be hospitalised. A single dose of combination therapy and multiple doses both showed reductions in the risk of hospitalisation among adults with acute asthma. However, adults receiving combination therapy were more likely to experience adverse events, such as tremor, agitation, and palpitations, compared to patients receiving SABA alone.

Short-acting β2 agonist bronchodilators, like salbutamol, mimic adrenaline and act quickly to open the airways. They provide immediate symptom relief when a person experiences acute breathlessness and wheezing. By comparison long-acting β2 agonists like salmeterol take longer to work. They are used in the general preventative management of asthma, but are not effective for acute symptoms.

Anticholinergic bronchodilators, like ipratropium bromide, are mostly used in the management of chronic obstructive pulmonary disease. They work by blocking the action of a nerve transmission chemical that causes airways to tighten. Ipratropium bromide is also quite fast acting, so can be used for acute asthma attacks.

Expert commentary

Inhaled short acting bronchodilators are first line therapy in acute asthma attacks. β2 agonists and anticholinergics each act immediately to ease patient’s respiratory distress. For some years national guidance has recommended that emergency physicians use these agents in combination in preference to lone β2 agonists when asthma is severe.

This review supports existing guidance; a variety of combination bronchodilator regimes can   lower hospital admission rates - when compared to single therapy - across a range of emergency department admission policies. It was unclear whether regimes administered by spacer as opposed to nebuliser were equally effective.

Patients experience more frequent short term side effects such as tremor and dry mouth with combination therapy and there was no benefit to combination therapy in less severe asthma

Fiona Lecky, Clinical Professor in Emergency Medicine, University of Sheffield; Honorary Consultant in Emergency Medicine, Salford Royal Hospital; Honorary Chair as Research Director of the Trauma Audit and Research Network, University of Manchester

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