Asthma is a common childhood illness that is caused by narrowing of the small air passages in the lungs. This narrowing is due to swelling and inflammation and to muscles around the air passages becoming tighter. An acute asthma attack results in shortness of breath, cough, wheeze, and chest tightness.
When children have an asthma attack, the standard treatment is to give steroids to reduce inflammation and swelling (usually given by mouth) and inhaled medications to relax the muscles in the air passages (called "bronchodilators"). In this review, we call that standard treatment "first-line" treatment. These medications are well understood to be the best treatments for use in the first instance.
Some children's asthma attacks do not improve with first-line treatment, and more treatment is necessary - usually at the emergency department or hospital; in this review, we call this 'second-line' treatment. However, the best second-line treatment for children who do not respond to first-line treatment is poorly understood. Many treatment options are available, and what is done for children varies from hospital to hospital.
We wanted to look at existing Cochrane Reviews of second-line treatments for children having asthma attacks. We hoped to be able to bring this information together in a useful document and to be able to present the evidence that would help the practitioner make the best treatment decision for each child having an asthma attack when inhaled bronchodilators and oral steroids have not helped with symptoms.
What is the effectiveness and safety of treatment options available for children with acute asthma who do not improve with standard first-line treatment?
We included 13 Cochrane Systematic Reviews on various treatment options, including inhaled medication, intravenous medications, and other therapies. This overview provides the most up-to-date evidence from systematic reviews with meta-analyses of randomised controlled trials on acute severe asthma in children. This overview is current to December 2019.
Quality of the evidence
The quality of these reviews was assessed using a checklist, which helped us assess the risk of bias. Nine of the 13 reviews were considered to be high quality. Four reviews were considered at risk of bias due to concerns with the way studies were identified for inclusion in the reviews. Most of the reviews are out-of-date because they have not been updated since 2016. The quality of evidence for specific comparisons ranged from very low to high, with many results coming from small studies. It is difficult to be confident in making recommendations for clinical practice.
For children with acute severe asthma requiring additional treatment, we found that:
- intravenous magnesium sulfate (a bronchodilator given through a vein) appears to reduce the length of time spent in hospital;
- no evidence suggests that any treatment reduced the risk of being admitted to intensive care;
- some treatments appeared to reduce the risk of hospital admission. These included adding a second type of inhaled bronchodilator treatment (anticholinergic medication such as ipratropium bromide) to standard inhaled treatment (beta-agonist such as salbutamol), giving intravenous magnesium sulfate, and breathing a mixture of helium and oxygen;
- serious adverse events may be reduced by inhaled magnesium sulfate;
- nausea and/or vomiting is more common with aminophylline (another bronchodilator medication given through a vein); and
- adding a second type of inhaled bronchodilator treatment (anticholinergic medication such as Ipratropium bromide) reduces the risk of nausea and tremor but not vomiting.
Recommendations for future research
One of the major problems with existing research is that a small number of patients is included in each study, likely because severe acute asthma in children is relatively uncommon. To work out whether or not a treatment is effective and/or to tell the difference between treatments, a research study must include enough patients receiving each treatment. Therefore, high-quality research into severe acute asthma in children is likely to require studies that include a number of hospitals.
It is also important to be able to compare results across studies. To do this, researchers across the world should agree on a standard way of measuring results in studies of acute severe asthma in children.
This overview provides the most up-to-date evidence on interventions for escalation of therapy for acute exacerbations of asthma in children from Cochrane Reviews of randomised controlled trials. A vast majority of comparisons involved between one and three trials and fewer than 100 participants, making it difficult to assess the balance between benefits and potential harms. Due to the lack of comparative studies between various treatment options, we are unable to make firm practice recommendations. Intravenous magnesium sulfate appears to reduce both hospital length of stay and the risk of hospital admission. Hospital admission is also reduced with the addition of inhaled anticholinergic agents to inhaled beta2-agonists. However, further research is required to determine which patients are most likely to benefit from these therapies.
Due to the relatively rare incidence of acute severe paediatric asthma, multi-centre research will be required to generate high-quality evidence. A number of existing Cochrane Reviews should be updated, and we recommend that a new review be conducted on the use of high-flow nasal oxygen therapy. Important priorities include development of an internationally agreed core outcome set for future trials in acute severe asthma exacerbations and determination of clinically important differences in these outcomes, which can then inform adequately powered future trials.
Asthma is an illness that commonly affects adults and children, and it serves as a common reason for children to attend emergency departments. An asthma exacerbation is characterised by acute or subacute worsening of shortness of breath, cough, wheezing, and chest tightness and may be triggered by viral respiratory infection, poor compliance with usual medication, a change in the weather, or exposure to allergens or irritants.
Most children with asthma have mild or moderate exacerbations and respond well to first-line therapy (inhaled short-acting beta-agonists and systemic corticosteroids). However, the best treatment for the small proportion of seriously ill children who do not respond to first-line therapy is not well understood. Currently, a large number of treatment options are available and there is wide variation in management.
- To summarise Cochrane Reviews with or without meta-analyses of randomised controlled trials on the efficacy and safety of second-line treatment for children with acute exacerbations of asthma (i.e. after first-line treatments, titrated oxygen delivery, and administration of intermittent inhaled short-acting beta2-agonists and oral corticosteroids have been tried and have failed)
- To identify gaps in the current evidence base that will inform recommendations for future research and subsequent Cochrane Reviews
- To categorise information on reported outcome measures used in trials of escalation of treatment for acute exacerbations of asthma in children, and to make recommendations for development and reporting of standard outcomes in future trials and reviews
- To identify relevant randomised controlled trials that have been published since the date of publication of each included review
We included Cochrane Reviews assessing interventions for children with acute exacerbations of asthma. We searched the Cochrane Database of Systematic Reviews. The search is current to 28 December 2019. We also identified trials that were potentially eligible for, but were not currently included in, published reviews. We assessed the quality of included reviews using the ROBIS criteria (tool used to assess risk of bias in systematic reviews). We presented an evidence synthesis of data from reviews alongside an evidence map of clinical trials. Primary outcomes were length of stay, hospital admission, intensive care unit admission, and adverse effects. We summarised all findings in the text and reported data for each outcome in 'Additional tables'.
We identified 17 potentially eligible Cochrane Reviews but extracted data from, and rated the quality of, 13 reviews that reported results for children alone. We excluded four reviews as one did not include any randomised controlled trials (RCTs), one did not provide subgroup data for children, and the last two had been updated and replaced by subsequent reviews.
The 13 reviews included 67 trials; the number of trials in each review ranged from a single trial up to 27 trials. The vast majority of comparisons included between one and three trials, involving fewer than 100 participants. The total number of participants included in reviews ranged from 40 to 2630. All studies included children; 16 (24%) included children younger than two years of age. Most of the reviews reported search dates older than four years.
We have summarised the published evidence as outlined in Cochrane Reviews. Key findings, in terms of our primary outcomes, are that (1) intravenous magnesium sulfate was the only intervention shown to reduce hospital length of stay (high-certainty evidence); (2) no evidence suggested that any intervention reduced the risk of intensive care admission (low- to very low-certainty evidence); (3) the risk of hospital admission was reduced by the addition of inhaled anticholinergic agents to inhaled beta2-agonists (moderate-certainty evidence), the use of intravenous magnesium sulfate (high-certainty evidence), and the use of inhaled heliox (low-certainty evidence); (4) the addition of inhaled magnesium sulfate to usual bronchodilator therapy appears to reduce serious adverse events during hospital admission (moderate-certainty evidence); (5) aminophylline increased vomiting compared to placebo (moderate-certainty evidence) and increased nausea and nausea/vomiting compared to intravenous beta2-agonists (low-certainty evidence); and (6) the addition of anticholinergic therapy to short-acting beta2-agonists appeared to reduce the risk of nausea (high-certainty evidence) and tremor (moderate-certainty evidence) but not vomiting (low-certainty evidence).
We considered 4 of the 13 reviews to be at high risk of bias based on the ROBIS framework. In all cases, this was due to concerns regarding identification and selection of studies. The certainty of evidence varied widely (by review and also by outcome) and ranged from very low to high.