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Indirect challenges cause the release of endogenous mediators that cause the airway smooth muscle to contract and the airways to narrow. Airway sensitivity to indirect challenges is reduced or even totally inhibited by treatment with inhaled corticosteroids (ICS), so a positive response to an indirect stimulus is believed to reflect active airway inflammation. The indirect challenges commonly used in pulmonary function laboratories include exercise, eucapnic voluntary hyperpnea, hypertonic (4.5%) saline, and mannitol. Exercise was the first test to be standardized and was used to identify exercise-induced bronchoconstriction (EIB). The inhibition of EIB in young children by sodium cromoglycate led to the concept that mast cells were important very early in the onset of asthma. All of these indirect challenges are associated with the release of mast cell mediators (eg, prostaglandins, leukotrienes, and histamine). The hypertonic saline and mannitol challenges arose from the concept that EIB was caused by an increased osmolarity of the airway surface with release of mediators. These osmotic aerosols simplified testing with indirect challenges in the laboratory, improving the potential to identify currently active asthma. Although hyperresponsiveness to indirect challenges is frequently associated with a sputum eosinophilia, it is not a prerequisite because the mast cell is the most important source of mediators. The mechanism for ICS reducing hyperresponsiveness to indirect challenges likely involves both mast cells and eosinophils. Indirect challenges are appropriate to inform further on both the pathogenesis of asthma and the role of antiinflammatory agents in its treatment.

This study was aimed at the following: (1) the prevalence of airway hyperresponsiveness (AHR) and exercise-induced bronchoconstriction (EIB) in swimmers and winter sport athletes according to the previously recommended regulatory sport agencies criteria, (2) the relationship between respiratory symptoms and AHR/EIB, (3) the impact of the chosen cutoff value for AHR on its prevalence, and (4) the effect on the prevalence of the positive eucapnic voluntary hyperpnea (EVH) test of using the highest vs the lowest spirometric post-EVH values to calculate the magnitude of the airway response. We compared the prevalence of respiratory symptoms with responses to methacholine challenge and EVH in 45 swimmers, 45 winter sport athletes, and 30 controls. Two methacholine challenge cutoffs for AHR were analyzed: ≤ 4 mg/mL (the sport agencies' criteria for AHR) and ≤ 16 mg/mL. Sixty percent of swimmers, 29% of winter sport athletes, and 17% of controls had evidence of EIB or AHR (with the ≤ 4 mg/mL criteria). Among athletes with a methacholine provocative concentration inducing a 20% decrease in the FEV 1 between 4 and 16 mg/mL, 43% of swimmers and 100% of winter sport athletes were symptomatic ( P 1 value measured at each time point post-EVH was used to identify maximal response for calculation of airway response, although these prevalences were higher if we used the lowest value. This study suggests that AHR/EIB is frequent in swimmers, whereas the frequently reported respiratory symptoms in winter sport athletes are often not related to AHR/EIB. Furthermore, the choice of methods for assessing methacholine challenge and EVH responses influences the prevalences of AHR and EIB. Trial registration: clinicaltrials.gov; Identifier NCT 00686491 and NCT 00686452.

To determine whether the duration of the apnea-hyperpnea cycle is longer in patients with congestive heart failure (CHF) and obstructive sleep apnea (OSA) than in patients with OSA alone, and whether this is related to prolonged circulation time.Retrospective study.Sleep laboratory of a university teaching hospital.Male patients with OSA and CHF (n = 22) or without CHF (n = 18) underwent overnight polysomnography.Hyperpnea duration, time to peak tidal volume (Vt), and lung-to-ear circulation time (LECT) were measured in all patients. Compared to the non-CHF patients, those with CHF had significantly longer hyperpneas (25.7 +/- 7.8 s vs 17.6 +/- 5.6 s, p0.001) and LECT (14.9 +/- 3.4 s vs 9.0 +/- 1.8 s, p0.001) [mean +/- SD]. There was also a significant relationship between LECT and hyperpnea duration (r = 0.67, p0.001).In patients with CHF, prolonged lung-to-chemoreceptor circulation time influences the cycling characteristics of OSA such that it prolongs hyperpnea and sculpts a pattern resembling Cheyne-Stokes respiration. These findings further suggest that the increased tendency to periodic breathing in CHF may predispose to, or alter the physiologic manifestations of OSA.

Study objective: For the 2002 Winter Olympic Games, athletes were required to submit objective evidence of asthma or exercise-induced bronchoconstriction (EIB) for approval to inhale a 2-agonist. Eucapnic voluntary hyperventilation (EVH) was recommended as a laboratory challenge that would identify airway hyperresponsiveness (AHR) consistent with EIB. The objective was to compare the change in FEV1 provoked by EVH with that provoked by exercise in cold weather athletes. Design: Spirometry was measured before and for 15 min after challenges. The two challenges were performed in random order at least 24 h apart. Setting: EVH was performed in the laboratory at 19°C, and exercise took place in the field in the cold (2°C, 45% relative humidity). Participants: Thirty-eight athletes (25 female subjects; median age, 16 years). Interventions: For the EVH, athletes inhaled dry air containing 5% carbon dioxide for 6 min at a target ventilation equivalent to 30 times baseline FEV1. Exercise was performed by cross-country skiing, ice skating, or running for 6 to 8 min. Measurements and results: AHR consistent with EIB was defined as > 10% fall in FEV1 from baseline after challenge. Eleven athletes were exercise positive (EX) [FEV1 fall, 20.5 7.3%], and 17 athletes were EVH positive (FEV1 fall, 14.5 4.5%) [mean SD]. Of 19 subjects with AHR, 58% were identified by exercise and 89% were identified by EVH. EVH identified 9 of 11 subjects who were EX and a further 8 subjects with potential for EIB. The average ventilation during EVH was 28 times FEV1. Conclusion: Performing EVH for 6 min in the laboratory had a greater chance of identifying AHR in these athletes compared with 6 to 8 min of field exercise in the cold. The EVH test will be useful to evaluate elite summer sports athletes whose widely different forms of exercise provide an “equipment” challenge to any laboratory.

Although nocturnal Cheyne-Stokes respiration alternating between hyperpnea and hypopnea has been considered a sign of severe heart failure, the clinical status of cardiac patients who exhibit oscillatory ventilation during wakefulness has not been clarified. This study was carried out to determine the relation between oscillatory ventilation during wakefulness and exercise capacity in patients with chronic heart disease. We also evaluated retrospectively whether the presence of oscillatory ventilation influences the long-term prognosis in these patients.A total of 164 patients with left ventricular dysfunction performed a symptom-limited incremental exercise test. Respiratory gas exchange was measured on a breath-by-breath basis throughout the test. Oscillatory ventilation was defined when clear ventilatory oscillation of at least two consecutive cycles was identified at rest before exercise testing and the difference between the peak and nadir of oscillating ventilation was30% of the mean value of ventilation.Oscillatory ventilation was noted in 45 of 164 cardiac patients (27%), and the magnitude (mean +/- SD) of oscillation in these patients was 45.5 +/- 16.9%. Patients with oscillatory ventilation had significantly lower left ventricular ejection fraction than those without it (40.7 +/- 12.7% vs 44.9 +/- 11.6%, p0.05). However, parameters of exercise capacity such as the peak oxygen uptake (O(2)), the slope of the increase in O(2) relative to the increase in work rate (DeltaO(2)/DeltaWR), and the ratio of the increase in ventilation to the increase in carbon dioxide output (DeltaE/DeltaCO(2)) were not significantly different between the two groups. The mortality rate during 1,797 +/- 599 days of follow-up did not differ between the groups (p = 0.65).Oscillatory ventilation present at rest before cardiopulmonary exercise testing is not significantly related to the peak O(2), DeltaO(2)/DeltaWR, DeltaE/DeltaCO(2), or prognosis in patients with left ventricular dysfunction.

Background and study objectives: Measurement of twitch transdiaphragmatic pressure (TwPdi) during bilateral phrenic nerve stimulation is presently the best method to detect diaphragmatic fatigue in humans. The stimulation methods that are currently employed (ie, transcutaneous electrical stimulation [TES] and cervical magnetic stimulation [CMS]) have limitations. Bilateral anterolateral magnetic stimulation of the phrenic nerves (BAMPS) was recently described. The purpose of this study was to determine whether BAMPS can reliably detect diaphragmatic fatigue, and to compare the results with BAMPS with those obtained with the other stimulation techniques. Subjects: Twelve healthy subjects participated in the study. Methods: TwPdi was measured during TES, CMS, and BAMPS before and 10, 30, and 60 min after a potentially fatiguing task. Voluntary hyperpnea to task failure was used as the fatiguing task because this task has previously been shown to reliably produce contractile fatigue of the diaphragm. To determine the reproducibility of BAMPS, TwPdi was measured before and after a nonfatiguing task in 10 of the subjects. Results: TwPdi fell significantly after the hyperpneic task with all three stimulation techniques, and the amount by which TwPdi fell after hyperpnea was not significantly different for the different stimulation techniques. The percentage fall in TwPdi after hyperpnea was significantly correlated between stimulation techniques (CMS vs BAMPS, r 0.72; TES vs BAMPS, r 0.84; and TES vs CMS, r 0.67). The mean ( SE) within-subject, between-trial coefficient of variation for TwPdi during BAMPS was 5.1 0.1%. Conclusion: BAMPS is highly reproducible and at least as good at detecting diaphragmatic fatigue as the other stimulation techniques. (CHEST 2002; 121:452– 458)

Study objective: To elucidate the mechanism of hyperpnea and tachypnea, which are the common findings in cardiopulmonary patients. Rational: Recently, it was found that activating pulmonary afferents by directly injecting hypertonic saline solution into the lung periphery causes a vagally mediated neural hyperpnea and tachypnea, ie, the excitatory lung reflex. Since reactive oxygen species are released during a variety of pulmonary diseases, we examined whether hydrogen peroxide (H2O2), a common mediator in cardiopulmonary diseases, can initiate the same excitatory lung reflex. Measurements and results: We recorded phrenic efferent activity in anesthetized, open chest, artificially ventilated rabbits as an index of respiratory drive and examined the respiratory responses to injections of H2O2 (10 mmol in 0.1 mL). The responses were compared with those to hypertonic saline solution (8.1%, 0.1 mL). H2O2 and hypertonic saline solution increased both the rate (mean [6 SEM], 43 6 8% and 61 6 10%, respectively; n 5 30; p 5 0.001) and the amplitude of phrenic bursts (12 6 2% and 20 6 4%, respectively; n 5 30; p 5 0.033). These responses were abolished by bilateral vagotomy. Conclusion: H2O2 can initiate the excitatory lung reflex. Therefore, mediator(s) released in pulmonary diseases could be one of the mechanisms causing hyperpnea and tachypnea. (CHEST 1999; 116:1365‐1368)

Background Alterations in respiratory mechanics predispose healthy obese individuals to low lung volume breathing, which places them at risk of developing expiratory flow limitation (EFL). The high ventilatory demand in endurance-trained obese adults further increases their risk of developing EFL and increases their work of breathing. The objective of this study was to investigate the prevalence and magnitude of EFL in fit obese (FO) adults via measurements of breathing mechanics and ventilatory dynamics during exercise. Methods Ten (seven women and three men) FO (mean ± SD, 38 ± 5 years, 38% ± 5% body fat) and 10 (seven women and three men) control obese (CO) (38 ± 5 years, 39% ± 5% body fat) subjects underwent hydrostatic weighing, pulmonary function testing, cycle exercise testing, and the determination of the oxygen cost of breathing during eucapnic voluntary hyperpnea. Results There were no differences in functional residual capacity (43% ± 6% vs 40% ± 9% total lung capacity [TLC]), residual volume (21% ± 4% vs 21% ± 4% TLC), or FVC (111% ± 13% vs 104% ± 15% predicted) between FO and CO subjects, respectively. FO subjects had higher FEV 1 (111% ± 13% vs 99% ± 11% predicted), TLC (106% ± 14% vs 94% ± 7% predicted), peak expiratory flow (123% ± 14% vs 106% ± 13% predicted), and maximal voluntary ventilation (128% ± 15% vs 106% ± 13% predicted) than did CO subjects. Peak oxygen uptake (129% ± 16% vs 86% ± 15% predicted), minute ventilation (128 ± 35 L/min vs 92 ± 25 L/min), and work rate (229 ± 54 W vs 166 ± 55 W) were higher in FO subjects. Mean inspiratory (4.65 ± 1.09 L/s vs 3.06 ± 1.21 L/s) and expiratory (4.15 ± 0.95 L/s vs 2.98 ± 0.76L/s) flows were greater in FO subjects, which yielded a greater breathing frequency (51 ± 8 breaths/min vs 41 ± 10 breaths/min) at peak exercise in FO subjects. Mechanical ventilatory constraints in FO subjects were similar to those in CO subjects despite the greater ventilatory demand in FO subjects. Conclusion FO individuals achieve high ventilations by increasing breathing frequency, matching the elevated metabolic demand associated with high fitness. They do this without developing meaningful ventilatory constraints. Therefore, endurance-trained obese individuals with higher lung function are not limited by breathing mechanics during peak exercise, which may allow healthy obese adults to participate in vigorous exercise training.

One hypothesis to explain the rapid neural component of exercise hyperpnea contends that afferent stimuli originating in the ventricles of the heart act reflexly on the respiratory center at the onset of exercise, ie, "cardiodynamic hyperpnea." Orthotopic cardiac transplantation (Tx) results in the loss of afferent information from the ventricles. Thus, Tx possibly results in transient hypercapnia and hypoxemia in deafferented heart transplant recipients (HTR) at the onset of exercise due to hypoventilation. To examine the cardiodynamic hypothesis, we collected serial arterial blood gas (ABG) samples during both the transient and the steady-state responses to moderate cycle exercise in 5 HTRs (55 +/- 7 years) 14 +/- 7 months post-Tx and 5 control subjects matched with respect to gender, age, and body composition. Forced vital capacity, forced expiratory volume in 1 s, total lung capacity, and diffusion capacity did not differ (por = 0.05) between groups. Resting arterial PO2, PCO2, and pH did not differ between groups (por = 0.05). The ABGs were drawn every 30 s during the first 5 min and at 6, 8, and 10 min of constant load square wave cycle exercise at 40 percent of the peak power output (watts). Absolute and relative changes in arterial PO2, PCO2, and pH were similar (por = 0.05) between HTR and the control group at all measurement periods during exercise. Heart rate (%HRmax reserve), rating of perceived exertion, and reductions in plasma volume (% delta from baseline) did not differ between HTR and control during exercise at 40 percent of peak power output (por = 0.05). Our results demonstrate that there is no discernible abnormality in ABG dynamics during the transient response to exercise at 40 percent of peak power output in patients with known cardiac denervation. These data do not support the cardiodynamic hyperpnea hypothesis of ventilatory control in humans. The absence of hypercapnia in HTRs is further evidence for the existence of redundant mechanisms capable of stimulating exercise hyperpnea.

To determine if the concentration of nitric oxide (NO) in the lungs increases with hyperpnea by contrasting calculated production (ie, the product of the fractional expired NO concentration [FeNO] and minute ventilation [Ve]) [Vno] with the amount of NO in equilibrium with the conducting airways (eNOair) and the amount of NO diffusing from the alveoli (eNOalv).Observational study.University teaching hospital.Normal subjects.Measurements were made in 16 healthy people during and after 4 min of tidal breathing (10 L/min) and isocapnic hyperventilation of 60 L/min.FeNO was measured by collecting the exhaled air during the last minute of each trial and passing it through a chemiluminescence analyzer. The expired NO levels in the plateau phases of slow (30 mL/s) and fast (200 mL/s) single-breath exhalations were also obtained before and after hyperventilation. The Vno (mean +/- SEM) increased from 89.8 +/- 12.3 to 329.1 +/- 36.2 nL/min as Ve rose (p0.001). However, neither the quantities of eNOair nor eNOalv changed with hyperventilation (eNOair range before to after, 34.9 +/- 7.7 to 30.9 +/- 6.4 parts per billion [ppb], p = 0.96; eNOalv range before to after, 7.3 +/- 1.5 to 6.5 +/- 1.1 ppb, p = 0.97).These data demonstrate that the amount of NO in equilibrium with the airway walls and alveoli are not altered by hyperpnea. Rather, the apparent augmentation in Vno in such circumstances appears to be an arithmetic artifact.

Background: Respiratory muscle endurance training (hyperpnea training) has been shown to have beneficial effects in patients with COPD. Study objectives: The purpose of this study was to determine whether hyperpnea training, when added to an endurance exercise training program, would lead to additional benefits compared with endurance training alone in patients with COPD. Setting and participants: Patients with COPD entering an 8-week outpatient pulmonary rehabilitation program. Fifteen patients (mean [ SE] FEV1 ,4 5 6% predicted) were randomized to combined therapy, and 14 patients (mean FEV1 ,4 4 4% predicted) were randomized to endurance training. Methods: Peak exercise capacity, exercise endurance time during constant workload cycle exercise, 6-min walk distance, quality of life as measured by the chronic respiratory questionnaire, respiratory muscle strength and endurance, and quadriceps fatigability were measured before and after endurance or combined training. Results: After rehabilitation, peak exercise capacity, exercise endurance time, 6-min walk distance, and quality of life all increased in both groups, but there was no significant difference in the extent of improvement between groups. Mean respiratory muscle endurance increased to a significantly greater extent in the combined therapy group (17.5 2.7 vs 8.5 2.5 min, respectively; p 0.02). Respiratory muscle strength was significantly increased, and quadriceps fatigability was significantly reduced after rehabilitation in the combined therapy group but not in the endurance training group, but the difference between groups did not reach statistical significance. Conclusion: The endurance of the respiratory muscles can be improved by specific training beyond that achieved by endurance training alone in patients with COPD. However, this improvement did not translate into additional improvement in quality of life or exercise performance. (CHEST 2005; 128:1216–1224)

Study objective To determine the effect of an aerobicconditioning program on fitness, respiratory physiology, and restinglung function in patients with mild asthma. Design Prospective cohort study. Setting Outpatientrehabilitation facility. Methods Five patients withmild intermittent asthma and five normal control subjects completed a10-week aerobic conditioning program. Pulmonary function studies andnoninvasive cardiopulmonary exercise tests were performed before andafter the conditioning program. Results After aerobicconditioning, there were significant gains in maximum oxygenconsumption ( V ˙ o 2 max; 22.73 mL/kg/min vs25.29 mL/kg/min, p = 0.01, asthma; 22.94 mL/kg/min vs 27.85mL/kg/min, p = 0.03, control) and anaerobic threshold (0.99 L/min vs1.09 L/min, p = 0.03, asthma; 0.89 L/min vs 1.13 L/min, p = 0.01,control) in both groups. Although FEV 1 was unchanged, themaximum voluntary ventilation (MVV) improved in the asthma group (96.0L/min vs 108.2 L/min, p = 0.08, asthma; 134.0 L/min vs 131.2 L/min,p = 0.35, control). During exercise, minute ventilation( V ˙ e) for each level of work was decreased in theasthma group after conditioning, while little change occurred in thecontrol group (68.48 L/min vs 51.70 L/min at initial V ˙ o 2 max, p = 0.02, asthma; 65.82 L/minvs 63.12 L/min at initial V ˙ o 2 max,p = 0.60, control). A significant decrease in the ventilatoryequivalent ( V ˙ e/oxygen consumption, 40.8 vs 30.4 at V ˙ o 2 max, p = 0.02, asthma; 37.2 vs 35.84 at V ˙ o 2 max, p = 0.02,control) and the dyspnea index ( V ˙ e/MVV) at submaximal(0.44 vs 0.38, p = 0.05, asthma; 0.32 vs 0.38, p Conclusions Exercise rehabilitation improves aerobicfitness in both asthmatic and nonasthmatic participants of a 10-weekaerobic fitness program. Additional benefits of improved ventilatorycapacity and decreased hyperpnea of exercise occurred in patients withmild asthma.

Study objectives To investigate the etiology of posthyperventilation (post-HV) hypoxemia following voluntary hyperventilation (VHV), we examined the effects of hypocapnic (hypo-CO 2 ) and isocapnic (iso-CO 2 ) VHV on the hypoxic ventilatory response (O 2 -response) and on the sensation of breathlessness during the O 2 -response. Methods O 2 -responses and visual analog scale (VAS) scores for estimating breathlessness in 10 normal subjects during the O 2 -response under iso-CO 2 conditions and under hypo-CO 2 conditions immediately following voluntary maximal HV of 3 min duration were examined. Results Although there was no significant difference in the post-HV ventilation levels following hypo-CO 2 vs iso-CO 2 VHV, the VAS scores at the start of the O 2 -response following hypo-CO 2 VHV (30.2±24.2 mm) were significantly higher (p 2 -response following iso-CO 2 VHV (13.7±8.4 mm). However, VHV did not have a significant effect on the O 2 -response at 2 min after the VHV when the arterial O 2 saturation (SaO 2 ) was below 90%. The nonsteady-state hypo-CO 2 induced by VHV greatly attenuated the O 2 -response below 90% SaO 2 and VAS scores at 70% SaO 2 . Conclusions Elevated VAS scores immediately following the hypo-CO 2 VHV, which might be independent of actual breathing levels, and the attenuation of the O 2 -response following the hypo-CO 2 VHV were not due to input from lung and chest wall mechanoreceptors induced by the hyperpnea itself, but rather to the hypo-CO 2 induced by hyperpnea.

Although periodic breathing consisting of alternating hyperpnea and hypopnea has been recognized in heart failure patients, its mechanism has not been clarified. We hypothesized that heart failure patients who have oscillations in ventilation will also be found to have oscillations in pulmonary blood flow, as reflected in left ventricular ejection fraction. To test this hypothesis, we analyzed continuously gas exchange and left ventricular ejection fraction during exercise in cardiac patients who exhibited periodic breathing. Out of 48 consecutive patients with reduced left ventricular function who performed a symptom-limited incremental exercise test using an upright cycle ergometer, we selected 5 patients who exhibited clear ventilatory oscillations during exercise. These patients repeated the same exercise test on another day for measuring gas exchange and left ventricular ejection fraction continuously. Oscillatory changes were noted both in left ventricular ejection fraction and in ventilation in these patients. These observations offer support for the hypothesis that fluctuations in pulmonary blood flow are primarily responsible for the periodic breathing seen in heart failure patients.

Studies of the limited exercise capacity in patients with COPD have not assessed the recovery phase, although the phenomenon of increased oxygen uptake after exercise has been thoroughly investigated in normal subjects. Therefore, we compared the recovery of gas exchange variables and HR after maximal cycle ergometry in 16 patients with varying seventies of airflow obstruction and ten aged control subjects. Aerobic capacity was reduced in the patients with COPD, and the rates of recovery of VE, Vo,, Vco,, excess Vco,, and HR were all significantly slower in the patients with COPD than in the controls. When expressed as the half-time for recovery, patients with COPD had values which were approximately twice that of control subjects for gas exchange and HR. The extent of recovery was similar in patients and controls. We conclude that in patients with COPD, postexercise relative hyperpnea and hypermetabolism are significantly prolonged. In addition, impaired elimination of increased body stores of carbon dioxide may contribute to impaired adjustment to acid-base disorders in these patients. (Chest 1990; 97:276-79)

Athma is characterized by repeated episodes of bronchoconstriction, often triggered by environmental stimuli. Since much of the therapy of asthma is aimed at preventing these episodes of bronchoconstriction, understanding the mechanisms by which environmental stimuli cause bronchoconstriction has obvious clinical importance. This review will discuss the general mechanisms by which inhaled agents can cause bronchoconstriction and what little is known about the specffic mechanisms of action of non-immunologic stimuli. Some of the well-recognized nonimmunologic stimuli to bronchoconstriction are listed in Table 1. These stimuli are all capable of causing marked bronchoconstriction in subjects with asthma, but have little effect on normal human subjects. Although at high concentrations some of these stimuli do produce measurable bronchoconstriction in animals, the relevance of these effects to realistic environmental exposures is uncertain. Thus, the major source of useful information on the mechanisms of action of these agents is experiments conducted on human subjects with asthma. The ethical and technical constraints of such experiments largely explain the limited nature of present understanding of these mechanisms. Three of the stimuli listed in Table 1 are virtually certain to cause clinically significant effects in patients with asthma. These three stimuli: exercise, fbg (distilled water aerosol), and the air pollutant sulfur dioxide, have been the most extensively studied and form the basis of subsequent discussion in this review. Exercise has been well recognized as a cause of clinically important bronchoconstriction in patients with asthma since at least the 17th century.’ Over the past ten years, studies from several laboratories have confirmed that the bronchoconstrictor effects of exercise can be mimicked by voluntary hyperpnea at an equivalent minute ventilation, suggesting that exercise-induced asthma is at least in part due to the local effects of exercise-induced hyperpnea on the airways.2 Studies reporting that hyperpnea-induced bronchoconstriction could be ameliorated by inhalation of warm humid air and potentiated by inhalation of cold dry air led to the suggestion that airway cooling might be the actual stimulus to exercise-induced bronchoconstriction.58 Recently, largely due to the pioneering studies of Anderson and co-workers,9 this notion has been questioned. In particular, the observation from three separate laboratories that the water content of inspired air was an important determinant of the magnitude of exercise or hyperpnea-induced bronchoconstriction, whereas the temperature was not, supported the hypothesis that exercise-induced bronchoconstriction might be due to airway drying rather than airway cooling.’#{176} Recent evidence based on direct calculations of airway heat loss and airway water loss during hyperpuea with dry air at two widely different temperatures (21#{176}C and 39#{176}C) suggests that neither heat loss nor water loss alone is likely to explain hyperpnea-induced bronchoconstriction and that it is therefore likely that both stimuli contribute to this effect. The recognition that fog may be an important stimulus to bronchoconstriction is considerably more recent. Nonetheless, over the past ten years reports from several laboratories have shown that inhalation of an aerosol of water (the major constituent of natural fog) rapidly causes bronchoconstriction in most subjects with asthma.’3’4 Distilled water aerosol causes bronchoconstriction on the basis of its low osmolarity since increasing the osmolarity of the inhaled aerosol by addition of dextrose or a variety of chemically unrelated solutes prevents fog-induced bronchoconstriction.’3 Interestingly, inhalation of hyperosmolar aerosols is also a potent stimulus to bronchoconstriction.14’5 Although hyperosmolar aerosols are not generally encountered in the environment, this effect provides support for the notion that airway water loss can

In order to investigate the effect of resistive breathing training on ventilatory muscular endurance, we examined the maximal sustained ventilatory capacity in ten patients with chronic obstructive pulmonary disease (COPD) before and after a six-week program of resistive breathing training. In addition, we investigated the effect of altered breathing strategy on resistive breathing performance. The patients performed two 15-minute sessions of resistive breathing daily for six weeks using an inspiratory resistive device (Pflex). Before and after the training, we found no significant change in spirometric data, pulmonary volumes, maximal inspiratory pressure, and maximal expiratory pressure. Of the ten patients, seven failed to show an improvement in their performance of resistive breathing. Furthermore, the maximal sustained ventilatory capacity was unchanged after the resistive breathing training. After the completion of the training program, seven of the patients participated in an additional experiment in which they were instructed to take long slow inspirations while breathing through the resistive device. With this change in breathing pattern, five of the seven were able to improve their performance of resistive breathing. Analysis of the breathing strategy showed that a reduction in the peak mouth pressure, breathing frequency, and external resistive work with a longer inspiratory time was beneficial. We conclude that (1) neither resistive breathing performance nor ventilatory muscular endurance, as measured by sustained hyperpnea, is improved by resistive breathing training performed according to the current instructions with the resistive device, and (2) alterations in breathing strategy have a profound effect on the performance of resistive breathing. The lack of details of breathing strategy in previous studies of resistive breathing makes it difficult to determine if previously demonstrated improvements were due to a real enhancement of ventilatory muscular performance or merely secondary to a different strategy.

We compared the duration of the protective effect of two beta-adrenoceptor agonists, fenoterol (200 micrograms) and salbutamol (200 micrograms), the anticholinergic agent ipratropium (80 micrograms), and the combination of fenoterol (200 micrograms) and ipratropium (80 micrograms) against challenge by eucapnic voluntary hyperventilation (EVH). Twelve patients with asthma performed EVH for two or four min at 60 percent maximal voluntary ventilation, 30 min, 2 and 4 h after treatment. All treatments (Rx) produced significant bronchodilation after 30 min. The Rx containing a beta-adrenoceptor agonist maintained this bronchodilation for at least 2 h. While all the Rx with a beta-adrenoceptor agonist significantly reduced the fall in forced expiratory volume in one second after EVH at 30 min, only the combination of fenoterol and ipratropium provided significant protection after 2 h. We advise that the duration of protective effect of beta-adrenoceptor agonists is short and patients with moderate to severe exercise-induced asthma may be better controlled by combination therapy.