E.R. McFadden

Effect of long-term salmeterol treatment on exercise-induced asthma.

BACKGROUND With long-term administration of salmeterol, the extent of protection afforded by the drug against experimental precipitants of asthma such as methacholine and adenosine may decrease. Whether this effect extends to a clinically relevant stimulus such as exercise is unknown. METHODS We performed a random-order, double-blind, crossover trial in 20 patients with exercise-induced asthma. Each patient received inhaled salmeterol or placebo twice daily for a month, with a one-week washout period between treatments. The patients performed cycle ergometry while breathing frigid air 30 minutes after the morning dose and 9 hours later on the 1st, 14th, and 29th study days. The primary end point was the extent of the decrease in forced expiratory volume in 1 second (FEV1) 10 minutes after exertion. RESULTS With placebo, significant airway narrowing developed at all times (mean [+/-SE] decrease from base line in FEV1, 19+/-2 percent in the morning and 18+/-2 percent in the evening). The morning dose of salmeterol attenuated the degree of bronchoconstriction at all times (decrease in FEV1 on day 1, 5+/-2 percent; on day 14, 10+/-3 percent; and on day 29, 9+/-3 percent; P=0.10). Its ability to act throughout the day, however, decreased with long-term administration (decrease in FEV1 from morning to evening on day 1, 6+/-2 percent; on day 14, 15+/-3 percent; and on day 29, 14+/-3 percent; P=0.003). CONCLUSIONS Protection against exercise-induced asthma is maintained with long-term administration of salmeterol, but the length of time that the drug remains active after a single dose decreases.

Protocol therapy for acute asthma: Therapeutic benefits and cost savings☆

BACKGROUND To evaluate the therapeutic and financial benefits of protocol therapy for acute asthma using standard medications. MATERIALS AND METHODS This study employed a sequential design in which the influence of an asthma care path on hospital admissions, length of stay (LOS) in the emergency department, and return visits were evaluated for 1 year. This information was contrasted with similar data obtained from the 8 months immediately before the protocol was implemented (preprotocol) and a 12-month period after strict adherence to it had declined (admixture). RESULTS In all, 526 acute exacerbations of asthma were treated with the care path, and 429 and 558 episodes were evaluated during the preprotocol and admixture periods, respectively. There were no significant differences between the presenting clinical or physiologic features of any group. With the protocol, 77% of the patients resolved their symptoms within 1:47 +/- 0.02 hours:minutes of arrival in the emergency department with a 2% return rate within 24 hours. The algorithms used quickly identified those needing hospitalization. Patients not meeting the criteria for discharge after receiving the treatments employed typically did not resolve their symptoms for days (average hospital stay 4.1 +/- 0.2 days). Compared with the preprotocol period, the care path significantly reduced the LOS by 50 minutes, the number of urgent and intensive care unit admissions by 27% and 41%, respectively, and the frequency of return visits within 24 hours by 66%. Charges to patients and third-party payors decreased

Exercise-induced anaphylaxis: a distinct form of physical allergy

395,000. When adherence to the protocol diminished, LOS, admissions, and returns rose significantly toward preprotocol values and the financial benefits were lost. CONCLUSIONS Asthma protocol therapy, based primarily upon aggressive use of sympathomimetics in association with serial monitoring of key indices of improvement, provides prompt and efficient relief for acute exacerbations of asthma. Such an approach yields significant financial benefit while quickly identifying individuals who require hospitalization, and it also detects physician practice patterns that can have potentially detrimental impacts on patient care.

Evaluation of Role Played by Mediators of Immediate Hypersensitivity in Exercise-induced Asthma

Seven individuals with exercise-induced anaphylaxis under natural circumstances, characterized by the appearance of pruritic cutaneous erythema and urticaria and associated vascular collapse and/or upper respiratory tract symptoms and signs of angioedema, were subjected to a controlled period of exercise in a laboratory. Experimental challenge consisted of running in an occlusive suit on a treadmill of moving grade with maintenance or acceleration of speed for 5 to 17 min. Cutaneous pruritus and erythema without urticaria developed in four of the subjects and progressed to angioedema in two of them; the other three subjects were unaffected. Repeat challenge of three of the abnormal responders elicited a clinical response similar to that of the previous exercise challenge. In those subjects with a clinical response to exercise challenge, mean change from baseline levels of histamine to peak levels was 7.0 +/- 3.0 ng/ml (mean +/- SEM), whereas in the group without clinical symptoms the mean change from baseline was an increase of 0.6 +/- 1.6 ng/ml (mean +/- SEM). The abnormal elevations in serum histamine during the seven exercise-induced symptomatic episodes returned to normal in about 20 min while clinical signs were also subsiding. There were no changes in pulmonary function. Exercise-induced anaphylaxis is clinically separable from cholinergic urticaria and represents a distinct form of physical allergy.

Airway cooling in asthmatic and nonasthmatic subjects during nasal and oral breathing

To determine whether mediators of immediate hypersensitivity played a role in the pathogenesis of exercise-induced asthma, we measured the concentration of histamine and neutrophil-chemotactic activity present in systemic arterial blood during thermal challenges in five asymptomatic asthmatics. Because exercise-induced asthma has been shown to be a result of respiratory heat loss and because respiratory heat loss during isocapnic hyperventilation has been shown to give identical responses, we chose the latter provocational method in order to minimize increases in cardiac output that might interfere with the interpretation of mediator concentrations in arterial blood. Multiple aspects of pulmonary mechanics were also recorded before and after provocation. The results of these studies were then compared with the effects observed when the same subjects inhaled aerosols of specific antigens on the same day. Each challenge produced identical alterations in lung function, and neither was associated with consistent changes in arterial histamine. However, antigen provocation evoked a sustained and prolonged release of neutrophil chemotactic activity in each subject, whereas isocapnic hyperventilation with cold air was without effect. These data strongly suggest that mast-cell derived mediators are not involved in the development or maintenance of the bronchial obstruction that follows exercise in asthmatics.

Administration of budesonide once daily by means of Turbuhaler to subjects with stable asthma

It has been suggested that nasal breathing attenuates the airway obstruction that follows physical exertion in asthmatics. In an effort to determine the reason for this protection, we had nine asymptomatic asthmatics and five normal subjects inhale subfreezing air at equal ventilations through either their noses or mouths in a random fashion while we measured the temperature in the retrotracheal esophagus (Trt). Pulmonary mechanics recorded before and after voluntary eucapnic hyperventilation simulating moderately heavy workloads demonstrated a mean fall in forced expiratory volume in one second (as a representative variable) of 28.6% +/- 4.8% (SEM) and 7.5% +/- 1.9% from control in the oral and nasal challenges, respectively, in the asthmatic subjects (p less than 0.001). Measurement of Trt during hyperventilation showed a mean fall of 2.7 degrees +/- 0.05 degree C with nasal breathing in this group (p less than 0.0001) and a linear relationship between the degree of airway cooling and the severity of subsequent bronchoconstriction (r=0.81). The normal subject showed similar changes in temperature but did not change their lung function. These data demonstrate that nasal ventilation minimizes airway cooling in both normal and asthmatic individuals through more efficient conditioning of inspired air, and it is through this mechanism that this form of respiration protects against exercise-induced bronchospasm.

The chronicity of acute attacks of asthma—mechanical and therapeutic implications

BACKGROUND Optimal management of chronic, mild-to-moderate asthma with inhaled steroids may include use of the lowest possible doses, as recommended in guidelines, and a reduction in the frequency of daily administration for greater convenience. Lower doses and once daily treatment with inhaled steroids must be rigorously evaluated in controlled clinical trials. OBJECTIVES The objective of this study was to assess the efficacy and safety of once daily treatment with budesonide in subjects with stable asthma. METHODS Once daily budesonide was assessed in 309 adult subjects, including those who were and were not using an inhaled steroid at baseline. The subjects were stratified by inhaled steroid use and randomly assigned to one of 3 treatments: 200 microgram budesonide, 400 microgram budesonide, or placebo administered by means of Turbuhaler once daily in the morning for 6 weeks. Beyond this point, treatment was continued unchanged for another 12 weeks (maintenance) in those receiving 200 microgram budesonide once daily and placebo. In those who received 400 microgram budesonide once daily, the dose was reduced to 200 microgram once daily at week 6 and held constant for the remaining 12 weeks (400/200 microgram group). Primary efficacy endpoints were mean change from baseline in FEV1 and morning peak expiratory flow. RESULTS Once daily budesonide was well tolerated and resulted in significant improvements in all efficacy endpoints, even though baselines were well stabilized. Baseline lung function was elevated with little room for improvement; however, mean increases in FEV1 during the maintenance period were 0.10 L and 0.11 L in the 200 microgram and 400/200 microgram groups, respectively, versus a decrease of -0.09 L in the placebo arm (P <.001). Results for peak expiratory flow were similar. Significant improvements in secondary endpoints, including symptoms, beta-agonist use, and quality of life, also developed with budesonide 200 and 400 microgram once daily. CONCLUSION Inhaled budesonide, in doses as low as 200 microgram, may be an appropriate introductory or maintenance dose in subjects with stable, mild-to-moderate asthma.

Relationship between bronchial responsiveness to hyperventilation with cold and methacholine in asthma

Defects in ventilatory function can persist for considerable periods of time following the amelicoration of the signs and symptoms of acute episodes of asthma. Serial spirographic and lung volume determinations in such patients demonstrate that the pattern of resolution of these abnormalities is such that their subtlest manifestations are depressed flow rates in the mid vital capacity range and/or elevations in residual volumes. These changes are believed to represent the effects of residual obstruction that is located in the airways in the periphery of the lung. Recent studies suggest that this residua is capable of influencing the lungs response to asthmogenic stimulis, and imply that it may be beneficial to place asthmatics on continuous therapy for as long as they have alterations in lung function.

Magnitude and site of airway response to exercise in asthmatics in relation to arterial histamine levels

Twenty-seven subjects with asthma and normal baseline lung function were challenged with aerosols of methacholine (M) and by isocapnic hyperventilation with cold air (HV). Stimulus-effect relationships were determined for each provocational technique on separate days and were expressed as the dose required to produce a 20% fall in forced expired volume in 1 sec (FEV1) obtained by linear interpolation from log stimulus vs. response curves (PD20). Each stimulus was applied with a sufficient intensity to produce a 20% or greater fall in FEV1 in each subject. The PD20 for M correlated significantly with the PD20 for HV (p less than 0.001) when the latter was expressed in liters per minute. The correlation between cumulative M PD20 and HV PD20 expressed as a percent of maximal voluntary ventilation was significant but less strong. We conclude that the airway response to HV reflects nonspecific bronchial hyperresponsiveness and that the dose of HV is best determined as the absolute level of ventilation.

Mechanisms of pulsus paradoxus during resistive respiratory loading and asthma

In order to determine if there is a relationship among arterial histamine levels, state of disease activity, and the magnitude and site of obstruction in exercise-induced asthma, we recorded airway resistance, lung volumes, spirometry, and density dependence of maximum expiratory flow before and after an exercise challenge in 17 asymptomatic individuals. These observations were then related to the concentration of histamine in systemic arterial blood. This study demonstrates that those individuals whose disease process was the most active at the time of investigation had more depressed lung function and higher baseline histamine levels, and responded to the challenge with severe obstruction that involved the airways in the periphery of the lung. In contrast, those subjects whose underlying disease was more quiescent had lower histamine values and the response to provocation was less severe and predominated in the larger airways. In neither group did the postchallenge values for histamine increase. It is suggested that the factor that determines these patterns of response is the state of inflammation of the airways, for which histamine may serve as a marker.