Exercise-induced bronchospasm is a transient increase in airway resistance that occurs following a brief period of vigorous physical exercise. Exercise is an extremely common precipitant of an acute asthmatic response in people of all ages, but it is especially problematic in children, who tend to have high levels of physical activity. Exercise-induced bronchospasm occurs in 80% to 90% of patients with asthma1 and in 40% to 50% of children who have allergic rhinitis but not clinical asthma, an incidence that is probably similar in adults.2 For some people with asthma, exercise is the only trigger.
Exercise- induced bronchospasm usually is diagnosed from a history of cough, shortness of breath, chest pain or tightness, wheezing, or lack of endurance during exercise. Children with exerciseinduced bronchospasm simply may avoid vigorous play, thus masking the problem. When the pattern of symptoms is not clear, diagnosis can be made based on a formal or informal exercise challenge demonstrating a decrease in forced expiratory volume at 1 second (FEVi ) of 10% to 15% or peak expiratory flow rate (PEFR)ofl5%to20%.1-3
Unfortunately, exercise-induced bronchospasm often goes undiagnosed or misdiagnosed. Patients finding themselves "out of breath" after exercising may attribute their condition to having a cold or to "being out of shape." "Locker room coughing" in young athletes following a strenuous workout often is attributed to poor conditioning, but is actually a reliable indicator of exercise-induced bronchospasm. Kyle3 suggests that physicians maintain a high index of suspicion when athletes report multiple antibiotic use during the competitive season because athletes with exercise-induced bronchospasm experience recurrent symptoms of upper respiratory tract infection and bronchitis.
In patients with exercise-induced bronchospasm, progressive airway obstruction typically develops after physical activity ceases. Several minutes into a cooldown or post-exercise period, patients may begin to experience the classic signs and symptoms of acute airway narrowing, including wheezing, dyspnea, and coughing. As shown in the Figure, resistance characteristically peaks at 5 to 10 minutes after activity stops, resulting in a decrease in FEVj or PEFR.2 A decrease in FEVi of 10% to 20% is evidence of mild exercise- induced bronchospasm; a 20% to 40% decrease indicates that the disease is moderately severe, and a 40% or greater decrease is considered severe. The bronchospasm usually resolves within 20 to 45 minutes.4"6 In most cases, exercise-induced bronchospasm is associated with moderate obstruction and is not life threatening.
A distinguishing characteristic of exercise-induced bronchospasm is the tendency toward spontaneous remission. Following continuous or repetitive exercise periods, some patients find that exercise-induced bronchospasm diminishes or completely abates during a refractory period that may last 2 hours after exercising. Exercise-induced bronchospasm is reduced significantly from its initial level during this period.5
Primary factors in the severity of airway obstruction include the intensity of the exertion, the level of ventilation required to meet the demands of the activity, the climate in which the patient is exercising, and the underlying state of airway reactivity.7,8 In general, the response will be amplified if the patient inhales cold or dry air while exercising. Conversely, inhaling humidified air reduces the response. For a given set of inspired-air conditions, more obstruction results from high levels of ventilation than from low levels. Severe obstruction can occur under any climatic conditions in patients with asthma whose airway irritability has increased due to a recent viral respiratory tract infection or exposure to antigens or pollutants.9 Some forms of exercise (eg, running and skating) are more potent triggers than others (eg, swimming).
The International Consensus Report on the Diagnosis and Treatment of Asthma views exercise-induced asthma as one expression of airway hyperresponsiveness and not a special form of asthma. The report notes that the presence of exercise-induced bronchospasm often suggests that the patient's asthma is not well controlled.4
Because this disorder is characterized primarily by bronchial smooth muscle constriction, many researchers prefer the name "exercise-induced bronchospasm" to the more traditional "exercise-induced asthma." Airway inflammation, which is usually a major factor in asthma, is probably not important in most cases of bronchospasm induced by exercise. Kyle3 distinguishes between exercise-induced bronchospasm and exercise-induced anaphylaxis. He points out that both involve proximal airway constriction, and both limit the ability of the distal pulmonary tree to keep up with the work demanded by the body's respiratory needs. Exercise-induced anaphylaxis and exercise- induced bronchospasm also differ in their pathophysiology. Exercise- induced bronchospasm involves bronchoconstriction and pulmonary obstructive limitations. Conversely, exerciseinduced anaphylaxis is associated with upper airway edema and laryngospasm.
Figure. Time course of exercise-induced bronchospasm.
Some studies have suggested the existence of a late-phase bronchoconstriction occurring 4 to 12 hours after the initial exercised-induced exacerbation.10"12 This phenomenon is thought to be analogous to the well-known biphasic asthmatic reaction to allergens, such as dust and pollen, in sensitive individuals. These patients may suffer attacks of asthma many hours after removal of the offending agent from their environment, which is believed to be due to late-phase activation of inflammatory mediators.13*15
Reports have suggested that a biphasic asthmatic reaction to exercise occurred in 30% to 60% of patients with asthma and was especially common in children with exercise-induced wheezing.16 In the most recent evaluation of the phenomenon, however, Rubinstein et al17 concluded that a second asthmatic response occurring long after exercise was uncommon. In their study of 53 patients who had an immediate asthmatic response to exercise in a well-controlled treadmill test, only one patient with laboratory-documented exercise-induced bronchospasm of moderate severity had a delayed response. Although five patients appeared to have a delayed response, the investigators determined that this response also occurred on control days when patients did not exercise. They speculated that what appears to be a delayed asthmatic response to exercise as reported by others might actually represent a decay in pulmonary function related to withdrawal from bronchodilator therapy.
PATHOPHYSIOLOGY OF EXERCISEINDUCED BRONCHOSPASM
In a review of the current concepts of the pathophysiology of exercise-induced bronchospasm, McFadden18 points out that most evidence supports the idea of exercise-induced bronchospasm as a vascular phenomenon resulting from hyperventilation of cool, dry air. To bring the air to body conditions of temperature and humidity, more heat and water must move from the mucosal surface of the lung to the air. As the quantities of heat and water being transferred increase, so does the subsequent obstructive response. The converse is also true. When the level of ventilation is low and the temperature and humidity of the inspired air are high, the magnitude of the bronchospasm is diminished.
The role of mediators of immediate hypersensitivity in exercise-induced bronchospasm is unclear. While thermal stimuli can cause sensitized mast cells to degranulate in the skin and release mediators such as histamine, similar mast cell involvement in exerciseinduced bronchospasm is controversial.18 According to McFadden,9 if the late response to exercise is an artifact, as proposed by Rubenstein et al,17 the question of the release of mediators associated with it, as well as with the early response, must be reexamined. McFadden9 reviews other inconsistencies in the literature that undermine the mediator hypothesis.
MANAGING EXERCISE-INDUCED BRONCHOSPASM
Proper management of exercise-induced bronchospasm should allow patients to participate in any physical activity without interference from symptoms of asthma. Management of exercise-induced bronchospasm consists of three major aspects: pharmacologic therapy, athletic conditioning, and education.
The Expert Panel Report of the National Asthma Education Program (NAEP) recommends that patients with exercise- induced bronchospasm use short-acting inhaled beta-agonists as premedication 5 to 60 minutes prior to exercise. Since the efficacy of these medications abates with time, patients are advised to take them just before exercising. The medication can be repeated as needed after 2 hours if exercise continues.2
Proper use of short-acting inhaled beta-agonists has been shown to reduce asthmatic symptoms in more than 80% of exercise-induced bronchospasm patients for up to 4 to 6 hours.19 As an alternative therapy, the NAEP also recommends the use of cromolyn (two puffs) immediately before exercising. Patients who still experience symptoms with exercise despite following these regimens are usually helped by increasing the dosage of the beta2-agonist (two puffs) or by using both a β2-agonist and cromolyn (two or four puffs).2 The long-acting inhaled β2-agonist salmeterol has shown efficacy in exercise-induced bronchospasm, but it is not indicated for children under age 12 and is not recommended by NAEP.
Because exercise in younger children (<5 years) is more often spontaneous than organized, specific preplanning for exercise-induced bronchospasm management is more difficult. Young children with frequent exercise-related wheeze or cough should be managed as moderate asthmatics by the NAEP recommendations. Those children able to use a metered dose inhaler with a spacer can be treated with an inhaled, anti-inflammatory drug (cromolyn, nedocromil, or corticosteroid) plus either regular or intermittent use of an inhaled short-acting beta-agonist. Younger children who use a home nebulizer should receive cromolyn with or without a bronchodilator as regular prophylactic management. For some children, regular use of long-acting theophylline sprinkles orally as maintenance therapy may be more appropriate, supplementing with an oral or inhaled beta-agonist as needed for breakthrough symptoms.
Patients with low aerobic fitness may benefit from a program of athletic conditioning to improve muscle and exercising efficiency. Such conditioning may help decrease a patient's level of ventilation for a given degree of exertion, but it will not modify exerciseinduced bronchospasm for a given level of ventilation.20
Kyle3 recommends that the first step in management of athletes with exercise-induced bronchospasm and low aerobic fitness should be a prescribed exercise regimen. They should be instructed to avoid exercising in cold, dry environments and to warm up for a prolonged period before an event. He also points out that some athletes experience a refractory period after the initial exercise-induced bronchospasm attack during which they are resistant to additional episodes of bronchospasm. If athletes are aware of this refractory period, they can occasionally take advantage of it by engaging in strenuous pre-event exercise.
Exercise-induced bronchospasm is a highly manageable disorder that should rarely limit patients1 activities provided they understand the nature of their condition and what they can do to minimize its effects. Asthmatic attacks limit behavior not only at the time of the attack, but also between attacks due to the fear they engender of future attacks. It is not unusual for children with exercise- induced bronchospasm to limit their exercise or avoid it altogether, thus missing out on some of the great joys of childhood.
In addition to prescribing medication, the physician can help dispel the myths about exercise-induced bronchospasm and help patients over the obstacles that the disease places in their path. Treatment involves not only drugs, but also confidence building. The idea that with proper care and conditioning, exercise-induced bronchospasm need not prevent children and adolescents from participating in nearly any level of athletic activity, up to and including Olympic or professional sports, should be firmly planted in their minds.
The key to avoiding limitations on activity is compliance with the physician's recommendations regarding proper exercise and the use of bronchodilator medication. Thus, it is important for physicians to educate their patients with exercise-induced bronchospasm about the best ways to exercise and the conditions least likely to promote attacks. Patients should be instructed never to exercise alone, and they should understand how to properly use their medication to prevent attacks. In case of a breakthrough during exercise, patients should know to stop exercising immediately and to inhale a short-acting beta20-agonist bronchodilator.
CLINICAL STUDIES OF BRONCHODILATORS IN EXERCISEINDUCED BRONCHOSPASM
Short-acting inhaled betao-agonists, including albuterol, terbutaline, bitolterofi and metaproterenol, are considered first-line therapy for preventing exercise-induced bronchospasm attacks and for limiting breakthrough attacks.2'4 The mechanism of action of all these agents is direct bronchial smooth muscle relaxation leading to airway dilatation.
Because of its favorable side effect profile, established safety record, and relatively long duration of action (up to 6 hours), albuterol generally is considered to be a first choice among young athletes with exerciseinduced bronchospasm.2'21 The National Asthma Education Program Expert Panel Report recommends use of an inhaled, short-acting beta^-agonist in children as young as 4 or 5 years.2 In a study of 18 asthmatic children (aged 12 to 17 years), for example, albuterol blocked exercise-induced bronchospasm significantly longer than metaproterenol sulfate.22 Albuterol's rapid onset of action means that patients can take their preexercise dose close to the time of exercise (5 to 15 minutes), which enhances spontaneity.
Salmeterol, a longer acting beta2-agonist, has demonstrated efficacy against exercise-induced bronchospasm for up to 12 hours.23'26 Salmeterol has a significantly slower onset of action than albuterol. The relative speeds of action of albuterol and salmeterol in asthma patients subjected to a methacholine test were evaluated in a study by Beach et al.27 They found that the median recovery to 90% and 95% of the baseline FEVj (pre-methacholtne challenge) took 9.6 and 19.4 minutes, respectively, for salmeterol, but only 4.8 and 8.3 minutes, respectively, for albuterol. In an in vitro study, the mean onset of action of salmeterol was 17.6 minutes.28 Salmeterol's long onset of action means patients must take the drug 30 to 60 minutes before exercising, which may make it less convenient for immediate pre-exercise treatment. However, its long duration of action is useful for patients who plan to exercise several hours after treatment or for those who exercise for prolonged periods.
In January 1995, labeling revisions were made by the manufacturer of salmeterol (Serevent, Allen &. HanburysGlaxo Wellcome Ine, Research Triangle Park, North Carolina) in response to reports of serious acute respiratory events, including fatalities. (Allen and Hanburys, personal communication) Physicians were warned not to prescribe salmeterol for acute symptoms or for patients with acutely deteriorating asthma. The revisions indicated that salmeterol was appropriate for patients 1 2 years or older. It should not be used in patients whose asthma can be managed by occasional use of short-acting beta2-agonists, a category to which many exercise-induced bronchospasm patients belong.
There is some controversy as to whether tolerance develops to the protective effects of inhaled agonists with long-term use. Evidence suggests that tolerance may develop to the protective effects of these drugs against different bronchoconstrictor stimuli but not to the bronchodilator response. Ramage et al29 found that salmeterol (50 µg twice daily for 4 weeks) protected against exercise-induced bronchospasm at 6 and 12 hours after the first dose but was ineffective after 4 weeks of continuous dosing.
Exercise -induced bronchospasm is an extremely common disorder, but it is rarely serious. While exet' ciseAnouceà bronchospasm affects both adults and children, it is often more problematic in children because of their higher activity level. Most people with asthma have airway hyperirritability that can lead to exercise-induced bronchospasm, so this disorder should be anticipated in all asthma patients. For some people with asthma, exercise may be the only trigger. Left untreated, exercise- induced bronchospasm can limit activity and disrupt normal life. In most cases, though, exercise-induced bronchospasm is easily prevented for up to 6 hours by inhaling a short-acting beta2 -agonist, such as albuterol, shortly before exercising. These drugs have been shown to safe and effective.
Exercise-induced bronchospasm patients should be encouraged to exercise in a warm, humid, environment free of allergens and pollutants when possible, especially during the winter. If they must exercise in cold, dry weather, they should wear a face mask and try to breathe through their noses. Activities that involve repeated short bursts of effort (eg, tennis, volleyball, and baseball) are preferable to continuous activities such as running or ice skating.
Short-acting ber^-agonists such as albuterol remain the first-line therapy for exercise-induced bronchospasm. The role of long-acting betin-agonists in exercise-induced bronchospasm has not Deen clearly defined. They are not appropriate for children younger than 12 years. Although for adolescents with exerciseinduced bronchospasm the extended protection provided by salmeterol may not be necessary, it may be useful for those who exercise several times a day or those who exercise for prolonged periods. These patients should carry a short-acting beta-agonist inhaler with them to use if a breakthrough attack occurs.
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