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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).

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.



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. 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.

Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre

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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.
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