Abstract
Introduction
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild to moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 100 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta2 agonists (plus ipratropium bromide, pressured metered-dose inhalers, short-acting continuous nebulised, short-acting intermittent nebulised, short-acting iv, and inhaled formoterol); corticosteroids (inhaled); corticosteroids (single oral, combined inhaled, and short courses); education about acute asthma; generalist care; helium–oxygen mixture (heliox); magnesium sulphate (iv and adding isotonic nebulised magnesium to inhaled beta2 agonists); mechanical ventilation; oxygen supplementation (controlled 28% oxygen and controlled 100% oxygen); and specialist care.
Key Points
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. These people have an increased risk of death.
Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
Inhaled short-acting beta2 agonists are considered the mainstay of treatment for acute asthma.
In people with an acute attack of asthma, supplementation of beta2 agonists with low oxygen concentrations, systemic corticosteroids (short courses), additional beta2 agonists (various routes of administration), or ipratropium bromide improves symptoms.
Inhaled corticosteroids seem to improve lung function in people with acute asthma. However, we don't know whether inhaled corticosteroids are as effective as systemic corticosteroids at improving symptom severity, lung function, and hospital admissions.
Inhaled plus oral corticosteroids and oral corticosteroids alone may have similar effects in preventing relapse.
Beta2 agonists delivered from a metered-dose inhaler using a spacer are as effective at improving lung function as those given by a nebuliser or given iv. Giving beta2 agonists iv is more invasive than giving beta2 agonists by nebuliser.
In people with severe acute asthma, continuous nebulised short-acting beta2 agonists may also improve lung function more than intermittent nebulised short-acting beta2 agonists.
The inhaled long-acting beta2 agonist formoterol seems to be at least equivalent to the short-acting beta2 agonists salbutamol and terbutaline in terms of pulmonary function in moderate to severe acute asthma treatment. On the basis of research undertaken in people with chronic asthma, the FDA has recommended minimising the use of long-acting beta agonists because of an increased risk of asthma exacerbations, hospital admissions, and death. The FDA acknowledges that they do have an important role in helping some patients control asthma symptoms.
We don't know if iv magnesium sulphate, nebulised magnesium alone, or adding nebulised magnesium to inhaled beta2 agonists improves lung function in people with acute asthma.
We don't know whether helium–oxygen mixture (heliox) is more effective at improving lung function compared with usual care.
Mechanical ventilation may be life saving in severe acute asthma, but it is associated with high levels of morbidity.
Specialist care of acute asthma may lead to improved outcomes compared with generalist care.
We don't know whether education to help self-manage asthma improves symptom severity, lung function, or quality of life, but it may reduce hospital admissions.
Clinical context
About this condition
Definition
Asthma is characterised by variable airflow obstruction and airway hyper-responsiveness. Symptoms include dyspnoea, cough, chest tightness, and wheezing. The normal diurnal variation of peak expiratory flow rate (PEFR) is increased in people with asthma. Acute asthma is defined here as an exacerbation of underlying asthma requiring urgent treatment. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions in no particular order.
Incidence/ Prevalence
The reported prevalence of asthma has been increasing worldwide, but may have currently reached a plateau.[1] [2] [3] About 10% of people have suffered an attack of asthma, but epidemiological studies have also found marked variations in prevalence between and within countries.[4] [5] [6]
Aetiology/ Risk factors
Most people with asthma are atopic. Exposure to certain stimuli initiates inflammation and structural changes in airways causing airway hyper-responsiveness and variable airflow obstruction, which in turn cause most asthma symptoms. There are many such stimuli; the more important include environmental allergens, occupational sensitising agents, and respiratory viral infections.[7] [8]
Prognosis
About 10% to 20% of people presenting to the emergency department with asthma are admitted to hospital. Of these, less than 10% receive mechanical ventilation.[9] [10] Those who are ventilated are at 19-fold increased risk of ventilation for a subsequent episode.[11] It is unusual for people to die unless they have suffered respiratory arrest before they reach hospital.[12] One prospective study of 939 people discharged from emergency care found that 106/641 (17%, 95% CI 14% to 20%) relapsed by 2 weeks.[13]
Aims of intervention
To minimise or eliminate symptoms; to maximise lung function; to prevent exacerbations; to minimise the need for medication; to minimise adverse effects of treatment; and to provide enough information and support to facilitate self-management of asthma.
Outcomes
Symptom severity (daytime and nocturnal, excluding lung function); lung function, in terms of peak expiratory flow rate (PEFR) and forced expiratory volume in 1 second (FEV1); need for rescue medication such as inhaled beta2 agonists; variability of flow rates; activities of daily living; primary care follow-up; hospital admissions; time in the emergency department; and adverse effects of treatment.
Methods
Clinical Evidence search and appraisal April 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2010, Embase 1980 to April 2010, and The Cochrane Database of Systematic Reviews April 2010 (online) (1966 to date of issue). When editing this review we used The Cochrane Database of Systematic Reviews 2010, issue 2. An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language. Blinded and open RCTs were included. RCTs had to contain 20 or more individuals, of whom 80% or more were followed up. There was no minimum length of follow-up required to include studies. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. This was supplemented by additional material assessing harms from the authors' own search. We have primarily included RCTs in people aged 13 years and older if most people in the trial were adults. Inhaled short-acting beta2 agonists are the mainstay of treatment for acute asthma and there is consensus that they are effective. RCTs comparing them with placebo or no treatment would be unethical. We have therefore focused on assessing different delivery methods for inhaled beta2 agonists and effects of combination treatments compared with inhaled beta2 agonists alone. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Asthma in adults (acute).
| Important outcomes | Hospital admissions, Lung function, Quality of life, Symptom severity (excluding lung function) | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments for acute asthma? | |||||||||
| At least 17 (at least 2998) | Symptom severity (excluding lung function) | Education versus usual care or control | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| At least 7 (at least 1072) | Lung function | Education versus usual care or control | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 20 (at least 3798) | Hospital admissions | Education versus usual care or control | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 6 (515) | Quality of life | Education versus usual care or control | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| 1 (801) | Symptom severity (excluding lung function) | Specialist versus generalist care | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for incomplete reporting of results. Directness points deducted for narrowness of population and uncertainty about intervention |
| 3 (1370) | Hospital admissions | Specialist versus generalist care | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for incomplete reporting of results. Directness points deducted for inclusion of children and narrowness of population, and uncertainty about intervention |
| At least 6 (at least 360) | Lung function | Inhaled short-acting beta2 agonists delivered by metered-dose inhalers plus spacer devices/holding chambers versus delivery by nebulisation | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of people with different airway diseases |
| at least 8 (at least 524) | Hospital admissions | Inhaled short-acting beta2 agonists delivered by metered-dose inhalers plus spacer devices/holding chambers versus delivery by nebulisation | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (110) | Symptom severity (excluding lung function) | Inhaled short-acting beta2 agonists delivered by continuous nebulisation versus delivery by on-demand nebulisation | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (64) | Lung function | Inhaled short-acting beta2 agonists delivered by continuous nebulisation versus delivery by on-demand nebulisation | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (110) | Hospital admissions | Inhaled short-acting beta2 agonists delivered by continuous nebulisation versus delivery by on-demand nebulisation | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| At least 5 (at least 401) | Lung function | Inhaled short-acting beta2 agonists delivered by continuous nebulisation versus delivery by intermittent nebulisation | 4 | 0 | 0 | −1 | 0 | Moderate | Directness point deducted for inclusion of children |
| 8 (461) | Hospital admissions | Inhaled short-acting beta2 agonists delivered by continuous nebulisation versus delivery by intermittent nebulisation | 4 | 0 | 0 | −1 | 0 | Moderate | Directness point deducted for inclusion of children |
| 8 (473) | Lung function | Inhaled formoterol (a long-acting beta2 agonist) versus inhaled short-acting beta2 agonists | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for statistical heterogeneity among RCTs. Directness point deducted for inclusion of RCTs in children in the meta-analysis |
| 3 (173) | Hospital admissions | Inhaled formoterol (a long-acting beta2 agonist) versus inhaled short-acting beta2 agonists | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, use of multiple comparators (salbutamol and terbutaline), and different drug doses. Directness point deducted for inclusion of 1 RCT in children in the meta-analysis |
| At least 5 (at least 384) | Lung function | Inhaled corticosteroids versus placebo | 4 | −1 | +1 | −1 | 0 | Moderate | Quality point deducted for incomplete reporting of results. Consistency point added for dose response. Directness point deducted for inclusion of children |
| 7 (466) | Hospital admissions | Inhaled corticosteroids versus placebo | 4 | 0 | 0 | −1 | +1 | High | Directness point deducted for inclusion of children. Effect-size point added for OR <0.5 |
| At least 4 (at least 684) | Symptom severity (excluding lung function) | Inhaled corticosteroids versus systemic corticosteroids | 4 | −1 | 0 | −1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of children |
| At least 2 (at least 40) | Lung function | Inhaled corticosteroids versus systemic corticosteroids | 4 | –2 | 0 | –1 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of children |
| 2 (186) | Hospital admissions | Inhaled corticosteroids versus systemic corticosteroids | 4 | −1 | 0 | −1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for inclusion of children |
| 3 (909) | Symptom severity (excluding lung function) | Inhaled plus oral corticosteroids versus oral corticosteroids alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| At least 5 (at least 329) | Symptom severity (excluding lung function) | Systemic corticosteroids versus placebo | 4 | 0 | 0 | 0 | +1 | High | Effect-size point added for RR <0.5 |
| At least 3 (at least 78) | Lung function | Systemic corticosteroids versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 10 (891) | Hospital admissions | Systemic corticosteroids versus placebo | 4 | –1 | 0 | –1 | +1 | Moderate | Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of children. Effect-size point added for RR <0.5 |
| 1 (180) | Symptom severity (excluding lung function) | Oral corticosteroids versus intramuscular corticosteroids | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (88) | Lung function | Oral corticosteroids versus intramuscular corticosteroids | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (74) | Lung function | Different concentrations of controlled oxygen supplementation versus each other | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 18 (2282) | Lung function | Inhaled ipratropium bromide plus beta2 agonists versus inhaled beta2 agonists alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of anticholinergics other than ipratropium bromide |
| 10 (1619) | Hospital admissions | Inhaled ipratropium bromide plus beta2 agonists versus inhaled beta2 agonists alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of anticholinergics other than ipratropium bromide |
| 1 (33) | Lung function | Inhaled magnesium sulphate delivered by nebulisation versus inhaled short-acting beta2 agonists | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for inclusion of children |
| 1 (33) | Hospital admissions | Inhaled magnesium sulphate delivered by nebulisation versus inhaled short-acting beta2 agonists | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for inclusion of children |
| 7 (430) | Lung function | Inhaled magnesium sulphate delivered by nebulisation plus inhaled short-acting beta2 agonists versus inhaled beta2 agonists alone | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for heterogeneity among RCTs. Directness point deducted for combined regimens |
| 6 (356) | Hospital admissions | Inhaled magnesium sulphate delivered by nebulisation plus inhaled short-acting beta2 agonists versus inhaled beta2 agonists alone | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for heterogeneity among RCTs. Directness point deducted for combined regimens |
| 5 (337) | Lung function | Iv short-acting beta2 agonists versus inhaled short-acting beta2 agonists | 4 | 0 | 0 | 0 | 0 | High | |
| At least 9 (at least 910) | Lung function | Iv magnesium sulphate versus placebo | 4 | –1 | –2 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency points deducted for statistical heterogeneity and conflicting results. Directness point deducted for use of co-interventions |
| At least 8 (at least 826) | Hospital admissions | Iv magnesium sulphate versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for use of co-interventions |
| 9 (582) | Lung function | Helium–oxygen mixture (heliox) versus air or oxygen | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and uncertainty about measurement of outcomes |
| 8 (552) | Hospital admissions | Helium–oxygen mixture (heliox) versus air or oxygen | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of children in meta-analysis |
| 1 (30) | Hospital admissions | Mechanical ventilation versus no ventilation | 4 | –1 | 0 | 0 | +1 | High | Quality point deducted for sparse data. Effect-size point added for RR <0.5 |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Diurnal variation
A characteristic of people with asthma is increased variation in peak flow rates and forced expiratory volume in 1 second during the day. The diurnal variation is sometimes expressed as the difference between maximum and minimum values expressed as a fraction of the maximum value.
- Forced expiratory volume in 1 second (FEV1)
The volume breathed out in the first second of forceful blowing into a spirometer, measured in litres.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Life-threatening asthma
An attack of such severity that the person usually requires management in the emergency department. Some people require endotracheal intubation and, usually in the initial stages of resuscitation, cannot inhale bronchodilator treatment.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Peak expiratory flow rate (PEFR)
The maximum rate that gas is expired from the lungs when blowing into a peak flow meter or a spirometer. It is measured at an instant, but the units are expressed as litres per minute.
- Salbutamol
A short-acting beta2 agonist known as albuterol in the US.
- Shared care
Involves sharing care between outpatient specialist and general practitioner.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Asthma and other wheezing disorders in children
Asthma in adults (chronic)
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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