Prophylactic salbutamol use for pediatric exercise-induced bronchoconstriction

Abstract

Question

An 8-year-old child was seen in our clinic for shortness of breath and wheezing after running at school. He was clinically healthy with no other symptoms consistent with asthma. His parents read that in adults, salbutamol could be taken before exercise to prevent shortness of breath and wheezing, but were unsure whether this also applied to children. Is salbutamol safe and effective for preventing exercise-induced bronchoconstriction (EIB) in pediatric patients?

Answer

Effective management of EIB in children supports greater participation in physical activity, which is important for physical and emotional well-being. Pediatric studies found salbutamol is safe and effective for preventing EIB in children when administered 15 to 30 minutes before exercise. Children can develop a tolerance to salbutamol if used frequently; therefore, salbutamol should be used less than once per day to maintain effectiveness. If children require salbutamol more often, additional therapies to manage airway inflammation can be considered.

Exercise-induced bronchoconstriction (EIB) is a transient narrowing of the lower airways that occurs during or after physical activity,¹ and can occur in individuals with or without asthma.² Approximately 9% of children and adolescents aged 5 to 18 years experience EIB, with the average prevalence rising to 15% in athletes and 46% in those with asthma.²

While the pathophysiology is unknown, proposed mechanisms include the osmotic and thermal-vascular theories.³ Both are based on the physiological demands of exercise, which require a greater volume of inspired air to be humidified and warmed to body temperature. In the osmotic theory, water diffuses into the inspired air, increasing the airway-surface fluid osmolality and drawing fluid out of the epithelial cells. This leads to the production and release of pro-inflammatory eicosanoids (signalling molecules), histamines, and neurokinins, which promotes airway smooth muscle contraction and inflammation. In the thermal-vascular theory, EIB is thought to be due to rewarming of cool ambient air that initially causes airway vasoconstriction followed by vasodilation and airway edema.

Patients experiencing EIB may have shortness of breath, coughing, wheezing, and exercise limitations.³ If untreated, EIB can decrease performance during physical activity, limit participation in activities, and add to anxiety and emotional burden.⁴ Given the importance of physical activity for overall well-being, any barrier to participation is concerning. As such, adequate management of EIB is important to maintain an affected child’s quality of life.

Diagnostic workup

The criterion standard for diagnosing EIB is an exercise challenge test where the patient performs spirometry before and after the test to measure changes in forced expiratory volume in 1 second (FEV₁).¹ A 10% to 15% decrease in FEV₁ after exercising is considered a positive test result. Some guidelines suggest EIB severity may be correlated with the magnitude of the FEV₁ decrease where a 10% to 25% FEV₁ decrease is considered mild, a 25% to 50% decrease is moderate, and a decrease of greater than 50% is severe.¹

Treatment of EIB

Inhaled salbutamol is considered first-line therapy for EIB.⁵ Salbutamol is a short-acting β₂-agonist that promotes smooth muscle relaxation and bronchodilation. Salbutamol acts quickly (<5 minutes) and lasts for 4 to 6 hours.⁵ Salbutamol is typically taken before exercise via a metered-dose inhaler (MDI) and spacer. The standard dose is 200 μg (2 puffs of the inhaler, 100 μg per puff).⁶

Several studies demonstrate the preventive effect of salbutamol for EIB in adults with mild to moderate asthma.^7-11 A 2001 study included 27 adults aged 18 to 50 years, randomized into 3 treatment arms: salbutamol MDI, salbutamol dry powder inhaler (DPI), or placebo administered 30 minutes before exercise.⁷ Treatment with salbutamol MDI (mean [standard deviation (SD)] FEV₁ decrease=8.5% [13.8%]) or salbutamol DPI (mean [SD] FEV₁ decrease=13.4% [13.2%]) led to a smaller decrease in FEV₁ compared to placebo (39.4% [17.6%], P<.01).

Among 10 athletes (mean age 20.9 years), mean (standard error of the mean) FEV₁ decreased by 4% (5.2%) with inhaled salbutamol taken 15 minutes before exercise, compared to 14.3% (11.1%) with placebo (P<.05).⁸ In 24 adults aged 18 to 45 years, salbutamol MDI led to a mean decrease in FEV₁ of 15.4%, contributing to greater prevention of EIB compared to placebo (mean FEV₁ decrease=33.7%, P<.01).⁹

In a study of 12 adults aged 19 to 41 years with asthma, both salbutamol and formoterol, a long-acting β₂-agonist, significantly mitigated the decrease in FEV₁ 2 hours after treatment compared to placebo (P<.01).¹⁰ The mean decrease in FEV₁ was 14.1% with salbutamol, 7.7% with formoterol, and 32.7% with placebo.

Salbutamol was equally effective in preventing EIB when administered as a combination inhaler.¹¹ In a sample of 60 adults with a mean age of 40.5 years, a single dose of salbutamol-budesonide MDI (180 μg and 160 μg, respectively) 30 minutes before performing 6 to 8 minutes of exercise on a treadmill at 80% to 95% of maximum heart rate resulted in a 5.5% reduction of FEV₁ after exercise compared to a 19.0% reduction with placebo (P<.01).¹¹

Research in children

The efficacy of salbutamol for EIB prophylaxis has been observed in the pediatric population.^12-18 Five pediatric studies suggested good tolerability, with no adverse effects.^6,7,14,17,18 Among 46 children aged 4 to 11 years with asthma, a 200-μg salbutamol MDI or DPI prevented EIB more than placebo (P<.01) when taken 15 minutes before exercise.¹²

Children treated with a salbutamol MDI or DPI experienced a 6% mean decrease in FEV₁ following the exercise test, compared to a 23% decrease in the placebo group.¹² An industry-sponsored study of 15 children aged 6 to 11 years with asthma found treatment with salbutamol MDI resulted in a mean (SD) FEV₁ increase of 1.9% (16.4%) after exercise compared to a decrease of 25.5% (16.0%) with placebo (P<.01).¹³ Despite relatively small sample sizes, these results suggest salbutamol is an effective treatment for children experiencing EIB.

Several studies compared salbutamol with agents targeting the inflammatory components of EIB. A 1998 study found salbutamol and a salbutamol-nedocromil combination were both protective against EIB and better than placebo (P<.01) in 12 children with asthma aged 7 to 13 years.¹⁴ The mean (SD) decrease in FEV₁ after exercise was 3.7% (4.4%) with salbutamol, 2.2% (2.7%) with the combination, and 25.7% (18.9%) with placebo. The proposed mechanism is that nedocromil stabilizes the mast cells, preventing release of molecules that lead to inflammation and bronchoconstriction during exercise.¹⁴ Further, salbutamol was better than a mast stabilizer (sodium cromoglycate) in an older study (P<.05).¹⁵

A study in the United States compared salbutamol and montelukast, a leukotriene receptor antagonist, in 11 children with asthma aged 7 to 17 years.¹⁶ A salbutamol MDI taken 15 minutes before exercise prevented EIB in all participants (mean [SD] FEV₁ decrease=0.7% [1.6%]), compared to 5 to 10 mg montelukast capsules taken nightly for 3 to 7 days before the exercise test, which resulted in a larger FEV₁ decrease (18.3% [13.7%], P<.01). These findings reinforce salbutamol’s effectiveness for pretreating EIB, suggesting direct salbutamol-mediated bronchodilation is more effective than targeting inflammatory pathways alone.

Other studies from the United States compared the effectiveness of salbutamol against a long-acting β₂-agonist.^17,18 A 1999 study using a small sample of 24 children aged 4 to 11 years with mild to moderate asthma found treatment with salbutamol led to a smaller decrease in FEV₁ compared to placebo (mean [standard error (SE)] 3.8% [1.5%] vs 13.5% [2.6%], P<.01), and compared to both 25-μg (mean [SE] 5.4% [2.1%]) and 50-μg (mean [SE] 5.6% [2.3%]) doses of salmeterol (P<.03).¹⁷

An industry-sponsored study of 12 children aged 8 to 15 years with asthma found aerosol salbutamol prevented EIB (mean [SD] FEV₁ decrease=18% [18%]) more than placebo (mean [SD] FEV₁ decrease=44% [14%]) 30 minutes after exercise (P<.02).¹⁸ Twelve-microgram formoterol prevented EIB more than both placebo (P<.01) and salbutamol (P<.02). This evidence suggests both salbutamol and long-acting β₂-agonists are effective for acute prevention of EIB. However, these studies predate regulatory guidance that now discourages long-acting β₂-agonist monotherapy due to an increased risk of asthma-related death.¹⁹

Considering salbutamol in children

Studies have demonstrated the efficacy of taking 200 μg of salbutamol to prevent EIB in both pediatric and adult populations^7-18; however, additional studies assessing different medication doses are required to determine an optimal dose. Current guidelines endorse taking 200 μg of salbutamol less than once per day, as frequent use may lead to downregulation of β₂-adrenoceptors, reducing effectiveness for preventing EIB.¹ In these pediatric trials, salbutamol failed to prevent EIB in up to 9% of participants,¹² while others report rates as high as 20%.¹ Patients who find salbutamol ineffective or require it more than once per day may consider supplementary therapy with a daily inhaled corticosteroid or other treatments addressing airway inflammation.¹

Conclusion

Preventing EIB in children is important, and taking 200 μg of salbutamol before exercise is a safe and effective treatment option.

Child Health Update is produced by the Pediatric Research in Emergency Therapeutics (PRETx) program (http://www.pretx.org) at the BC Children’s Hospital in Vancouver, BC. Connor L. Flynn and Dr Wallace B. Wee are members and Dr Ran D. Goldman is Director of the PRETx program. The mission of the PRETx program is to promote child health through evidence-based research in therapeutics in pediatric emergency medicine.