Clinical Evidence Concise
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Asthma and Other Wheezing Disorders in Children
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Am Fam Physician. 2006 Dec 1;74(11):1901-1905.
What are the effects of treatments for acute asthma in children?
Oxygen (in the Absence of Evidence From Randomized Controlled Trials, Categorization Is Based on Observational Evidence and Strong Consensus Belief That Oxygen Is Beneficial)
A randomized controlled trial (RCT) comparing oxygen treatment and no oxygen treatment for acute severe asthma would be considered unethical. One prospective cohort study and clinical experience support the need for oxygen in patients with acute asthma.
Inhaled Ipratropium Bromide Plus a Beta2 Agonist (in the Emergency Department)
One systematic review showed that, compared with a beta2 agonist alone, multiple doses of inhaled ipratropium bromide plus an inhaled beta2 agonist (fenoterol or salbutamol) reduced hospital admissions and improved lung function in children 18 months to 17 years of age with severe asthma exacerbations. In children with mild to moderate asthma exacerbations, a single dose of inhaled ipratropium bromide plus a beta2 agonist (fenoterol, salbutamol, or terbutaline) improved lung function for up to two hours but did not reduce hospital admissions compared with a beta2 agonist alone.
Metered Dose Inhaler Plus Spacer Devices for Delivery of Beta2 Agonists (as Effective as Nebulizers)
One systematic review including children with acute but not life-threatening asthma who were old enough to use a spacer showed no significant difference in hospital admission rates with a metered dose inhaler plus a spacer compared with nebulized beta2 agonists (fenoterol, salbutamol, or terbutaline) or beta agonist (orciprenaline). Children using a metered dose inhaler with a spacer may have shorter stays in emergency departments, less hypoxia, and lower pulse rates compared with children receiving nebulized beta2 agonists.
One systematic review showed that, compared with placebo, adding systemic corticosteroids to usual treatment with salbutamol, terbutaline, or theophylline increased the likelihood of hospital discharge after four hours and reduced the frequency of relapse within one to three months in children hospitalized with acute asthma.
Inhaled Corticosteroids (High Dose)
We found one systematic review that identified four RCTs comparing high-dose inhaled corticosteroids with oral corticosteroids in children. Three RCTs showed no significant difference in hospital admissions between nebulized budesonide or dexamethasone and oral prednisolone plus other routine treatment in children with mild to moderate asthma. One RCT including children with moderate to severe asthma showed that oral prednisolone reduced hospital admissions and improved lung function at four hours compared with inhaled fluticasone. A subsequent RCT including children four to 16 years of age showed that nebulized fluticasone improved lung function over seven days compared with oral prednisolone. One RCT including children five to 16 years of age hospitalized with severe asthma showed no significant difference between nebulized budesonide and oral prednisolone in lung function after 24 hours or 24 days of hospitalization.
LIKELY TO BE BENEFICIAL
One systematic review examined adding intravenous theophylline to the treatment of patients one to 19 years of age hospitalized with severe asthma who were receiving oxygen, using bronchodilators, and taking glucocorticoids; it improved lung function and symptom scores six to eight hours after treatment compared with adding placebo, but it showed no significant difference in the number of bronchodilator treatments required or length of hospital stay. A subsequent RCT including children one to 17 years of age admitted to the intensive care unit with severe asthma showed that adding intravenous theophylline decreased the time it took to reach a clinical asthma score of 3 or less compared with salbutamol, ipratropium, and methylprednisolone alone, but it showed no significant difference in length of stay in the intensive care unit. Theophylline can cause serious adverse effects if therapeutic blood concentrations are exceeded.
Inhaled Ipratropium Bromide Plus Salbutamol (After Initial Stabilization)
One RCT including children hospitalized with initially stabilized severe asthma showed no significant difference in clinical asthma scores during the first 36 hours of hospitalization between nebulized ipratropium bromide and placebo plus salbutamol (a beta2 agonist) and a corticosteroid (hydrocortisone or prednisone). The RCT showed a significant increase in heart rate after the addition of ipratropium bromide compared with placebo.
What is the effect of single-agent prophylaxis in children taking inhaled beta agonists as needed for asthma?
One systematic review showed that prophylactic inhaled corticosteroids improved symptoms and lung function compared with placebo in children with asthma. Several RCTs showed that inhaled corticosteroids slightly reduce growth rate compared with placebo, although studies with long-term follow-up suggest attainment of normal adult height. Inhaled corticosteroids have been associated with rare reports of adrenal suppression. One RCT including children six to 16 years of age showed no significant difference in improvement of asthma symptoms between inhaled beclomethasone and theophylline but found less use of bronchodilators and oral corticosteroids with inhaled beclomethasone. Small RCTs have shown inhaled corticosteroids to be more effective than sodium cromoglycate in improving symptoms and lung function. RCTs in children five to 16 years of age have shown that inhaled corticosteroids (beclomethasone, budesonide, or fluticasone) were more effective than an inhaled long-acting beta2 agonist (salmeterol) or inhaled nedocromil at improving symptoms and lung function in children with asthma.
Two RCTs including children six to 12 years of age taking usual medication showed that adding inhaled nedocromil reduced asthma symptom scores, asthma severity, and bronchodilator use and improved lung function compared with placebo. One large RCT including children five to 12 years of age with mild to moderate asthma showed no significant difference in lung function, hospital admission rates, or symptom scores between adding nedocromil and adding budesonide or placebo, but it showed that budesonide was superior to nedocromil and that nedocromil was superior to placebo in several measures of asthma symptoms and morbidity.
Oral Leukotriene Receptor Antagonists (Montelukast)
One RCT including children six to 14 years of age showed that oral montelukast (a leukotriene receptor antagonist) increased from baseline the mean morning forced expiratory volume in one second and reduced total daily beta2 agonist use compared with placebo, but it showed no significant difference in daytime asthma symptom score or in nocturnal awakenings because of asthma. Another RCT including children two to five years of age showed that oral montelukast improved average daytime symptom scores and reduced the need for rescue oral steroid courses compared with placebo, but it showed no significant difference in average overnight asthma symptom scores. We found no RCTs directly comparing oral montelukast with inhaled corticosteroids.
TRADE-OFF BETWEEN BENEFITS AND HARMS
Inhaled Long-Acting Beta2 Agonist (Salmeterol)
Two RCTs including children four to 14 years of age showed that inhaled salmeterol (a long-acting beta2 agonist) improved lung function compared with placebo, and it provided limited evidence that inhaled salmeterol reduced the need for inhaled salbutamol. One RCT comparing inhaled salmeterol with beclomethasone showed that salmeterol was associated with a significant deterioration in bronchial reactivity. Another RCT showed that inhaled beclomethasone was more effective at increasing lung function and reducing rescue use of salbutamol than salmeterol.
One small RCT including children six to 15 years of age receiving usual care showed that oral theophylline increased mean morning peak expiratory flow rate and reduced the mean number of acute nighttime attacks and doses of bronchodilator used compared with placebo. Another RCT including children six to 16 years of age showed no significant difference in improvement of asthma symptoms between oral theophylline and inhaled beclomethasone, but it showed greater use of bronchodilators and oral corticosteroids with theophylline over one year. Theophylline has serious adverse effects (e.g., cardiac arrhythmia, convulsions) if therapeutic blood concentrations are exceeded.
Inhaled Sodium Cromoglycate
One systematic review provided no evidence that inhaled sodium cromoglycate prophylaxis was effective in reducing asthma symptoms in patients one to 18 years of age. Several small comparative RCTs showed that sodium cromoglycate was less effective than inhaled corticosteroids in improving symptoms and lung function.
What are the effects of additional prophylactic treatments in patients with childhood asthma that is inadequately controlled by standard doses of inhaled corticosteroids?
Increased Dose of Inhaled Corticosteroid (Beclomethasone)
One RCT including children six to 16 years of age taking inhaled beclomethasone that compared a double dose of inhaled corticosteroid (beclomethasone) with placebo showed no significant difference in lung function, symptom scores, exacerbation rates, or bronchial reactivity but found a reduction in growth velocity at one year.
Adding Long-Acting Beta2 Agonists
One RCT including children six to 16 years of age showed that adding inhaled salmeterol (a long-acting beta2 agonist) to the patient’s treatment increased peak expiratory flow rates in the first few months, but it showed no increase after one year. A second short-term RCT including children four to 16 years of age also showed increased morning peak expiratory flow rates and more symptom-free days at three months with the addition of salmeterol. A third RCT showed that adding formoterol to the patient’s treatment improved lung function after three months of treatment compared with placebo but showed no significant difference in symptom scores or use of rescue medication.
Adding Oral Theophylline
One small RCT showed that, compared with adding placebo, adding theophylline to previous treatment increased the proportion of symptom-free days and reduced the use of additional beta agonists (orciprenaline) and additional corticosteroids (beclomethasone or prednisolone) over four weeks. We found insufficient evidence to weigh these short-term benefits against possible long-term harms. A second small RCT using lower-dose theophylline showed no benefit.
Adding Oral Leukotriene Receptor Antagonists (Montelukast)
One crossover RCT including children six to 14 years of age with persistent asthma who had been taking inhaled budesonide for at least six weeks showed that adding oral montelukast (a leukotriene receptor antagonist) reduced asthma exacerbations over four weeks compared with adding placebo. This difference was statistically significant but modest in clinical terms.
What are the effects of treatments for acute wheezing in infants?
LIKELY TO BE BENEFICIAL
Short-Acting Beta2 Agonists (Nebulized Salbutamol)
One RCT including infants three months to two years of age showed that nebulized salbutamol improved respiratory rates and clinical symptom scores compared with placebo but showed no significant difference in hospital admission. Another RCT including infants younger than 18 months and children 18 to 36 months of age showed no significant difference in change from baseline clinical symptom scores between nebulized salbutamol and placebo. Nebulized beta2 agonists may cause tachycardia, tremor, and hypocalcemia.
Short-Acting Beta2 Agonists Delivered by Metered Dose Inhaler Plus Spacer vs. Nebulizer
Two RCTs including children five years or younger showed no significant difference in hospital admission with salbutamol delivered through a metered dose inhaler plus spacer and nebulized salbutamol. Another RCT in infants one to 24 months of age showed no significant difference in symptom improvement between terbutaline delivered through a metered dose inhaler plus spacer and nebulized terbutaline. Nebulized beta2 agonists may cause tachycardia, tremor, and hypocalcemia.
Inhaled Ipratropium Bromide
One systematic review of RCTs provided insufficient evidence about the clinical effects of inhaled ipratropium bromide compared with placebo or added to beta2 agonists.
Oral Corticosteroids (Prednisolone)
One small RCT showed no significant difference in daily symptom scores between oral prednisolone and placebo.
Inhaled Corticosteroids (High Dose)
One systematic review showed that high-dose inhaled corticosteroids reduced the requirement for oral corticosteroids compared with placebo, but the difference was not statistically significant. It also showed that the children’s parents had a clear preference for inhaled corticosteroids over placebo. The clinical importance of these results is unclear.
What are the effects of prophylactic treatments for wheezing in infants?
LIKELY TO BE BENEFICIAL
Oral Short-Acting Beta2 Agonists (Salbutamol)
One RCT identified by a systematic review including infants three to 14 months of age showed that oral salbutamol (a short-acting beta2 agonist) reduced treatment failures compared with placebo.
TRADE-OFF BETWEEN BENEFITS AND HARMS
Inhaled Corticosteroids (Higher Dose)
One systematic review and two additional RCTs provided evidence that higher-dose inhaled corticosteroids reduced the severity and frequency of acute wheezing episodes in infants compared with placebo. Higher doses of inhaled corticosteroids have the potential for adverse effects.
Inhaled Ipratropium Bromide
One small RCT identified by a systematic review showed no significant difference in symptom relief between nebulized ipratropium bromide and placebo. The study may have lacked power to exclude a clinically important difference between treatments.
Inhaled Short-Acting Beta2 Agonists (Salbutamol)
Two RCTs identified by a systematic review including infants two years or younger showed no significant improvement in symptoms with inhaled salbutamol compared with placebo.
Inhaled Corticosteroids (Lower-Dose Budesonide)
Two RCTs showed no clear evidence of effectiveness with lower prophylactic doses of inhaled budesonide (a corticosteroid) in children one week to six years of age with recurrent wheezing.
Differentiation between asthma and nonasthmatic, viral-associated wheezing may be difficult; persisting symptoms and signs between acute attacks are suggestive of asthma, as is a personal or family history of atopic conditions such as eczema and hay fever.Childhood asthma is characterized by chronic or recurrent coughing and wheezing. The diagnosis is confirmed by demonstrating reversible airway obstruction, preferably on several occasions over time, in children old enough to perform peak flow measurements or spirometry. Diagnosing asthma in children requires exclusion of other causes of recurrent respiratory symptoms. Acute asthma is a severe exacerbation of asthma symptoms accompanied by tachycardia and tachypnea. The aim of prophylactic treatments of asthma is to minimize persistent symptoms and prevent acute exacerbations.Wheezing in infants is characterized by a high-pitched purring or whistling sound produced mainly on exhalation and commonly is associated with an acute viral infection (e.g., bronchiolitis) or asthma, which are not easily distinguished clinically.
Incidence and Prevalence
Surveys have shown an increase in the proportion of children diagnosed with asthma. The increase is higher than can be explained by an increased readiness to diagnose asthma. One cross-sectional questionnaire study from Aberdeen, Scotland, surveyed children eight to 13 years of age: 2,510 children in 1964 and 3,403 children in 1989. Over 25 years, asthma diagnoses increased from 4 to 10 percent.1 The increase in the prevalence of childhood asthma from the 1960s to the 1980s was accompanied by an increase in hospital admissions over the same period. This was a sixfold increase in England and Wales.2
Wheezing in Infants
Wheezing is common and seems to be increasing, although the magnitude of any increase is not clear. The Scottish cross-sectional study showed that the prevalence of wheezing rose from 10 percent in 1964 to 20 percent in 1989, and episodes of shortness of breath rose from 5 to 10 percent over the same period.1 Difficulties in defining clear groups (phenotypes) and the transient nature of the symptoms, which often resolve spontaneously, have confounded many studies.
Asthma is more common in children with a personal or family history of atopy, increased severity and frequency of wheezing episodes, and presence of variable airway obstruction or bronchial hyper-responsiveness. Precipitating factors for symptoms and acute episodes include infection, house dust mites, allergens from pets, exposure to tobacco smoke, and anxiety.
Wheezing in Infants
Most wheezing episodes in infancy are precipitated by viral respiratory infection.
A British longitudinal study of children born in 1970 showed that 29 percent of five-year-olds who were wheezing in the previous year were still wheezing at 10 years of age.3 Another study followed a group of children in Melbourne, Australia, from seven years of age (in 1964) into adulthood. The study showed that a large proportion (73 percent) of 14-year-olds with infrequent symptoms had few or no symptoms by 28 years of age, whereas two thirds of 14-year-olds with frequent wheezing still had recurrent attacks at 28 years of age.4
Wheezing in Infants
One cohort study (826 infants followed from birth to six years of age) suggests that there may be at least three prognostic categories for wheezing in infants: (1) persistent wheezers (14 percent of total, with risk factors for atopic asthma such as elevated immunoglobulin E levels and a maternal history of asthma) who initially suffered wheezing during viral infections that persisted into school age; (2) transient wheezers (20 percent of total, with reduced lung function as infants but no early markers of atopy) who suffered wheezing during viral infections but stopped wheezing after three years of age; and (3) late-onset wheezers (15 percent of total) who did not wheeze when they were younger than three years but had developed wheezing by school age.5 Another retrospective cohort study showed that 14 percent of children with one attack and 23 percent of children with four or more attacks in the first year of life had experienced at least one wheezing illness in the previous year by 10 years of age.3
Administering inhaled treatments to young children can be difficult. Inconsistencies in results could reflect the effects of the different drugs, delivery devices, and dosages used and the differences in the pattern of wheezing illnesses and treatment responses among young children.
editor’s note: Fenoterol is undergoing investigation in the United States as a bronchodilating agent. It has been available outside the United States as a metered dose inhaler, a solution for nebulization, a powder for inhalation, and an oral preparation. Salbutamol is called albuterol and orciprenaline is called metaproterenol in the United States. Sodium cromoglycate commonly is called cromolyn sodium in the United States.
search date: October 2004
Adapted with permission from Keeley D, McKean M. Asthma and other wheezing disorders in children. Clin Evid. 2006;15:68–3.
1. Russell G, Ninan TK. Respiratory symptoms and atopy in Aberdeen school children: evidence from two surveys 25 years apart. BMJ. 1992;304:873–5.
2. Kabesh M, Von Mutius E. Epidemiology and public health. In: Silverman M, ed. Childhood Asthma and Other Wheezing Disorders. 2nd ed. London, U.K.: Arnold, 2002.
3. Park ES, Golding J, Carswell F, et al. Pre-school wheezing and prognosis at 10. Arch Dis Child. 1986;61:642–6.
4. Kelly WJ, Hudson I, Phelan PD, et al. Childhood asthma in adult life: a further study at 28 years of age. BMJ. 1987;294:1059–62.
5. Martinez FD, Wright AL, Taussig L, et al. Asthma and wheezing in the first six years of life. N Engl J Med. 1995;333:133–8.
This is one in a series of chapters excerpted fromClinical Evidence Concise, published by the BMJ Publishing Group, Tavistock Square, London, U.K.Clinical Evidence Concise is printed twice a year and is updated monthly online. Each topic is revised every 12 months, and subscribers should view the most up-to-date version at http://www.clinicalevidence.com. If interested in contributing toClinical Evidence Concise, e-mail: CEcommissioning@bmj.com. The complete text for this topic also is available as a PDF at http://www.aafp.org/afp/20061201/bmj.html. The evidence on this topic is available at http://www.clinicalevidence.com/ceweb/conditions/chd/0302/0302.jsp.
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