Isocapnic Hyperventilation Research Articles

Inhibition of nitric oxide synthesis attenuates thermally induced asthma.

To determine whether the inhibition of nitric oxide (NO) synthesis attenuates thermally induced obstruction, we had 10 asthmatic volunteers perform isocapnic hyperventilation with frigid air after inhaling 1 mg of N(G)-monomethyl-L-arginine (L-NMMA) or isotonic saline in a blinded fashion. The challenges were identical in all respects, and there were no differences in baseline lung function [1-s forced expiratory volume (FEV(1)); saline 2.8 +/- 0.3 liters, L-NMMA 2.9 +/- 0.3 liters; P = 0.41] or prechallenge fractional concentration of nitric oxide in the exhaled air (FENO) [saline 23 +/- 6 parts/billion (ppb), L-NMMA 18 +/- 4 ppb; P = 0.51]. Neither treatment had any impact on the FEV(1), pulse, or blood pressure. After L-NMMA, FENO fell significantly (P < 0.0001), the stimulus-response curves shifted to the right, and the minute ventilation required to reduce the FEV(1) 20% rose 53.5% over control (P = 0.02). The results of this study demonstrate that NO generated from the airways of asthmatic individuals may play an important role in the pathogenesis of thermally induced asthma.

Importance of ventilation in modulating the interaction between sympathetic drive and cardiovascular variability

Chemoreflex stimulation elicits both hyperventilation and sympathetic activation, each of which may have different influences on oscillatory characteristics of cardiovascular variability. We examined the influence of hyperventilation on the interactions between changes in RR interval and muscle sympathetic nerve activity (MSNA) and changes in neurocirculatory variability, in 14 healthy subjects. We performed spectral analysis of RR and MSNA variability during each of the following interventions: 1) controlled breathing; 2) maximal end expiratory apnea; 3) isocapnic voluntary hyperventilation; and 4) hypercapnia-induced hyperventilation. MSNA increased from 100% during controlled breathing to 170±25% during apnea (p=.02). RR was unchanged, but normalized low-frequency (LF) variability of both RR interval and MSNA increased markedly (p <.001). During isocapnic hyperventilation, minute ventilation increased to 20.2±1.4 L/min (p<.0001). During hypercapnic hyperventilation, minute ventilation also increased (19.7±1.7 L/min) as did end tidal CO2 (both p<.0001). MSNA remained unchanged during isocapnic hyperventilation (104±7%) but increased to 241±49% during hypercapnic hyperventilation (p<.01). RR interval decreased during both isocapnic and hypercapnic hyperventilation (p < .05). However, normalized LF variability of RR interval and of MSNA decreased (p<.05) during both isocapnic and hypercapnic hyperventilation, despite the tachycardia and heightened sympathetic nerve traffic. In conclusion, marked respiratory oscillations in autonomic drive induced by hyperventilation may induce a dissociation between RR interval, MSNA and neurocirculatory variability, perhaps by suppression of central genesis and/or transmission of low frequency cardiovascular rhythms.

Role of nitric oxide during hyperventilation-induced bronchoconstriction in the guinea pig.

Airway function is largely preserved during exercise or isocapnic hyperventilation in humans and guinea pigs despite likely changes in airway milieu during hyperpnea. It is only on cessation of a hyperpneic challenge that airway function deteriorates significantly. We tested the hypothesis that nitric oxide, a known bronchodilator that is produced in the lungs and bronchi, might be responsible for the relative bronchodilation observed during hyperventilation (HV) in guinea pigs. Three groups of anesthetized guinea pigs were given saline and three groups given 50 mg/kg N(G)-monomethyl-L-arginine (L-NMMA), a potent nitric oxide synthase inhibitor. Three isocapnic ventilation groups included normal ventilation [40 breaths/min, 6 ml/kg tidal volume (VT)], increased respiratory rate only (150 breaths/min, 6 ml/kg VT), and increased respiratory rate and increased volume (100 breaths/min, 8 ml/kg VT). L-NMMA reduced expired nitric oxide in all groups. Expired nitric oxide was slightly but significantly increased by HV in the saline groups. However, inhibition of nitric oxide production had no significant effect on rate of rise of respiratory system resistance (Rrs) during HV or on the larger rise in Rrs seen 6 min after HV. We conclude that nitric oxide synthase inhibition has no effect on changes in Rrs, either during or after HV in guinea pigs.

Isocapnic hyperventilation increases carbon monoxide elimination and oxygen delivery.

Hyperventilation with mixtures of O2 and CO2 has long been known to enhance carbon monoxide (CO) elimination at low HbCO levels in animals and humans. The effect of this therapy on oxygen delivery (DO2) has not been studied. Isocapnic hyperventilation utilizing mechanical ventilation may decrease cardiac output and therefore decrease DO2 while increasing CO elimination. We studied the effects of isocapnic hyperventilation on five adult mechanically ventilated sheep exposed to multiple episodes of severe CO poisoning. Five ventilatory patterns were studied: baseline minute ventilation (RR. VT), twice (2. RR) and four times (4. RR) baseline respiratory rate, and twice (2. VT) and four times (4. VT) baseline tidal volume. The mean carboxyhemoglobin (HbCO) washout half-time (t1/2) was 14.3 +/- 1.6 min for RR. VT, decreasing to 9.5 +/- 0.9 min for 2. RR, 8.0 +/- 0.5 min for 2. VT, 6.2 +/- 0.5 min for 4. RR, and 5.2 +/- 0.5 min for 4. VT. DO2 was increased during hyperventilation compared with baseline ventilation for 2. VT, 4. RR, and 4. VT ventilatory patterns. Isocapnic hyperventilation, in our animal model, did not alter arterial or pulmonary blood pressures, arterial pH, or cardiac output. Isocapnic hyperventilation is a promising therapy for CO poisoning.

Importance of ventilation in modulating interaction between sympathetic drive and cardiovascular variability.

Chemoreflex stimulation elicits both hyperventilation and sympathetic activation, each of which may have different influences on oscillatory characteristics of cardiovascular variability. We examined the influence of hyperventilation on the interactions between changes in R-R interval (RR) and muscle sympathetic nerve activity (MSNA) and changes in neurocirculatory variability, in 14 healthy subjects. We performed spectral analysis of RR and MSNA variability during each of the following interventions: 1) controlled breathing, 2) maximal end-expiratory apnea, 3) isocapnic voluntary hyperventilation, and 4) hypercapnia-induced hyperventilation. MSNA increased from 100% during controlled breathing to 170 +/- 25% during apnea (P = 0.02). RR was unchanged, but normalized low-frequency (LF) variability of both RR and MSNA increased markedly (P < 0.001). During isocapnic hyperventilation, minute ventilation increased to 20.2 +/- 1.4 l/min (P < 0.0001). During hypercapnic hyperventilation, minute ventilation also increased (to 19.7 +/- 1.7 l/min) as did end-tidal CO(2) (both P < 0.0001). MSNA remained unchanged during isocapnic hyperventilation (104 +/- 7%) but increased to 241 +/- 49% during hypercapnic hyperventilation (P < 0.01). RR decreased during both isocapnic and hypercapnic hyperventilation (P < 0.05). However, normalized LF variability of RR and of MSNA decreased (P < 0.05) during both isocapnic and hypercapnic hyperventilation, despite the tachycardia and heightened sympathetic nerve traffic. In conclusion, marked respiratory oscillations in autonomic drive induced by hyperventilation may induce dissociation between RR, MSNA, and neurocirculatory variability, perhaps by suppressing central genesis and/or inhibiting transmission of LF cardiovascular rhythms.

Exhaled nitric oxide and thermally induced asthma.

The purpose of the present study was to determine if nitric oxide (NO) is involved in the pathogenesis of thermally induced asthma. To provide data on this issue, 10 normal and 13 asthmatic subjects performed isocapnic hyperventilation with frigid air while the fractional concentration of NO in the expirate air (FENO) was serially monitored with a chemiluminescence analyzer. FEV1 was measured before and after hyperpnea. Prior to and throughout the challenge, the asthmatics had significantly larger values for FENO (baseline FENO normal, 11 +/- 2 ppb; asthma, 16 +/- 1; p = 0.03). Posthyperpnea, the normal subjects had little change in bronchial caliber (deltaFEV1 baseline to 5 min posthyperpnea, -3.5 +/- 1.5%; p = 0.06), whereas the patients with asthma developed significant airway obstruction (deltaFEV1, -27.7 +/- 2.9%; p = 0.0001). During hyperventilation, the volume of NO rose in both groups. The asthmatic subjects, however, generated approximately 55% more NO/min than did the normal control subjects even though their level of ventilation was approximately 66% less. In contrast to the normal subjects, NO production in the asthmatics continued into the recovery period after the challenge stopped and FENO rose temporally as the airflow limitation developed. These results suggest that NO plays an intimate role in the development of airway obstruction that follows hyperpnea.

The Diagnostic Value of Isocapnic Hyperventilation of Cold Air in Adults with Suspected Asthma

Background Asthmatic patients frequently suffer cold-weather-associated respiratory symptoms. The sensitivity, specificity, accuracy and diagnostic value of isocapnic hyperventilation of cold air(IHCA) using a multistep method was investigated in patients suspected to have asthma. Method One hundred and 29 adult patients who had an IHCA performed between july 1999 and December 2000, had an methacholine bronchoprovocation test because of a clinical suspicion of asthma. Results According to strict criteria, 50 were defined as asthmatics and 79 as symptomatic nonashmatics. There were no differences in age, sex and smoking state between the asthmatic and symptomatic nonasthmatic groups. There was a significant decrease in the percentage reduction in the forced expiratory volume in 1 second(FEV1) after the IHCA between the asthmatics(-10.0±6.8%) and the symptomatic nonasthmatics(-2.3±2.5%). The factors associated with a reactivity to IHCA were FEV1/FVC, FEF25-75/FVC and FEV1(% of predicted). The accuracy was highest using a 7% fall in FEV1; the sensitivity was 76% and the specificity 96%. Conclusion IHCA is a specific, although not a sensitive, test for diagnosing asthma in adult patients. Furthermore, the diagnostic cut-off value of the different methods of IHCA need to be determined.

Airway function after cyclooxygenase inhibition during hyperpnea-induced bronchoconstriction in guinea pigs.

Airway function deteriorates significantly on cessation of exercise or isocapnic hyperventilation challenges but is largely preserved during the challenge in humans and guinea pigs. PGE(2), an endogenous bronchodilator, might be responsible for the preservation of lung function during hyperventilation (HV). We hypothesized that PGE(2) might have a protective effect during HV, partially explaining the minimal changes in respiratory system resistance (Rrs) usually seen during HV in humans and guinea pigs. Therefore, changes in Rrs were measured during and after HV in anesthetized, mechanically ventilated guinea pigs treated with flurbiprofen (FBN) or placebo. With HV, there was an initial bronchodilation that was unaffected by FBN. Rrs then increased with time during HV, an effect that was blocked by FBN. After HV, Rrs increased further in all groups, but the increase in Rrs was less in the FBN-treated groups. FBN treatment reduced the PGE(2) concentration slightly in lung lavage fluid compared with placebo. We found no enhancement or refractoriness of the Rrs response to repeat bouts of HV and no effect of FBN treatment on the response of Rrs to repeat HV. These results suggest that a constrictor PG is released during and possibly after HV and that the post-HV increase in Rrs is the sum of effects of the PG released during HV and a second constrictor mechanism operating after HV. We found no evidence for bronchodilator PG during or after HV in the guinea pig.

Indirect bronchial hyperresponsiveness in asthma: mechanisms, pharmacology and implications for clinical research.

Bronchial hyperresponsiveness (BHR), an abnormal increase in airflow limitation following the exposure to a stimulus, is an important pathophysiological characteristic of bronchial asthma. Because of heterogeneity of the airway response to different stimuli, the latter have been divided into direct and indirect stimuli. Direct stimuli cause airflow limitation by a direct action on the effector cells involved in the airflow limitation, while indirect stimuli exert their action essentially on inflammatory and neuronal cells that act as an intermediary between the stimulus and the effector cells. This manuscript reviews the clinical and experimental studies on the mechanisms involved in indirect BHR in patients with asthma. Pharmacological stimuli (adenosine, tachykinins, bradykinin, sodium metabisulphite/sulphur dioxide, and propranolol) as well as physical stimuli (exercise, nonisotonic aerosols, and isocapnic hyperventilation) are discussed. The results of the different direct and indirect bronchial challenge tests are only weakly correlated and are therefore not mutually interchangeable. Limited available data (studies on the effects of allergen avoidance and inhaled corticosteroids) suggest that indirectly acting bronchial stimuli (especially adenosine) might better reflect the degree of airway inflammation than directly acting stimuli. It remains to be established whether monitoring of indirect BHR as a surrogate marker of inflammation (in addition to symptoms and lung function) is of clinical relevance to the long-term management of asthmatic patients. This seems to be the case for the direct stimulus methacholine. More work needs to be performed to find out whether, indirect stimuli are more suitable in asthma monitoring than direct ones. Recommendations on the application of indirect challenges in clinical practice and research will shortly be available from the European Respiratory Society Task Force.

Hyperventilation alters arterial baroreflex control of heart rate and muscle sympathetic nerve activity

Interactions between mechanisms governing ventilation and blood pressure (BP) are not well understood. We studied in 11 resting normal subjects the effects of sustained isocapnic hyperventilation on arterial baroreceptor sensitivity, determined as the alpha index between oscillations in systolic BP (SBP) generated by respiration and oscillations present in R-R intervals (RR) and in peripheral sympathetic nerve traffic [muscle sympathetic nerve activity (MSNA)]. Tidal volume increased from 478 +/- 24 to 1,499 +/- 84 ml and raised SBP from 118 +/- 2 to 125 +/- 3 mmHg, whereas RR decreased from 947 +/- 18 to 855 +/- 11 ms (all P < 0.0001); MSNA did not change. Hyperventilation reduced arterial baroreflex sensitivity to oscillations in SBP at both cardiac (from 13 +/- 1 to 9 +/- 1 ms/mmHg, P < 0.001) and MSNA levels (by -37 +/- 5%, P < 0.0001). Thus increased BP during hyperventilation does not elicit any reduction in either heart rate or MSNA. Baroreflex modulation of RR and MSNA in response to hyperventilation-induced BP oscillations is attenuated. Blunted baroreflex gain during hyperventilation may be a mechanism that facilitates simultaneous increases in BP, heart rate, and sympathetic activity during dynamic exercise and chemoreceptor activation.

Leukotriene bronchoconstriction induced by allergen and exercise.

Airway hyperresponsiveness to a wide variety of bronchoconstrictor agonists is a characteristic finding in patients with current, symptomatic asthma. The agonists include inhaled pharmacological agonists, such as histamine (1) acting on airway H 1 receptors, the cholinergic agonist methacholine (2) acting on airway M 3 receptors, the cysteinyl-leukotrienes (3) acting on airway Cys-LT 1 receptors, and the stimulatory prostaglandins (PG)D 2 (4) and PGF 2a (5) likely acting on airway TP receptors. These agonists are considered to be direct stimuli causing bronchoconstriction in individuals with asthma, because their action is directly on specific airway receptors. Airway hyperresponsiveness is also present to a number of physical stimuli such as exercise (6), isocapnic hyperventilation of cold, dry air (7), and hypo- and hypertonic aerosols (8). The bronchoconstriction that develops after exposure to the physical stimuli is indirect, because it occurs through the release of constrictor mediators from cells within the airways, which subsequently act on their specific receptors to mediate bronchoconstriction. Another important indirect stimulus for bronchoconstriction in many individuals with asthma is environmental allergens. The responses after inhaled allergens are often quite different from those after the other indirect stimuli, in that the acute bronchoconstrictor responses are often followed by the development of late-phase bronchoconstrictor responses (9), airway inflammation (10), and an increase in airway hyperresponsiveness (11). The focus of this article is to evaluate the evidence that the cysteinyl-leukotrienes (LT) C 4 , D 4 , and E 4 are released in asthmatic airways and are the main cause of bronchoconstriction after exposure to exercise and environmental allergens, and of the changes in airway hyperresponsiveness after the inhalation of allergen.

Thermally induced asthma and airway drying.

The purpose of this study was to determine whether mucosal dehydration causes thermally induced asthma. To provide data on this point, we studied the effects on lung function of progressive water loss (WL) from the respiratory tract by having eight subjects perform isocapnic hyperventilation for 1, 2, 4, and 8 min at a constant level (V E = 57.5 +/- 6.3 L/min [mean +/- SEM]) while they breathed dry air at frigid (TI = -12.5 +/- 2.7 degrees C) (cold trial) and ambient (24.3 +/- 0.7 degrees C) (warm trial) temperatures. Expired temperatures (TE) were continuously monitored, and WL from the intrathoracic airways was calculated from published relationships. FEV1 was measured before and after each challenge. Each inspirate produced stimulus-response decrements in FEV1, but the effect of cold air was greater (% Delta cold8min = 30.0 +/- 4.7%, warm = 16.0 +/- 4.4%; p = 0.01). Water loss, however, was significantly less in the cold experiment because TE was lower (WL cold8min = 4.8 +/- 0.4 g, warm = 7.1 +/- 0.7 g; p = 0.001; TE cold8min = 22.8 +/- 2.3 degrees C, warm 30.9 +/- 1.5 degrees C; p = 0.003). The FEV1 decreased as WL rose, but the largest intrathoracic losses were associated with the smallest obstructive response (% DeltaFEV1 cold8min = 30%, WL = 4.7 mg; % DeltaFEV1 warm8min = 16%, WL = 7.1 mg; p = 0.002). These data show that removal of water from the lower respiratory tract, and by inference the development of a hyperosmolar periciliary fluid, do not appear to be the primary causes of thermally induced asthma.

A new guinea-pig model for acute inhalation studies on combined effects of cold air and pollutants

We have developed a new small animal model for acute inhalation studies on combined effects of cold air and gaseous urban air pollutants. The anaesthetised, tracheostomised and paralysed guinea-pig was placed inside a small, sealed whole-body-box, in which it was ventilated mechanically by using cyclic negative pressure (P box) for active expansion of the chest. During a 2-h normal ventilation with warm humid air ( n=6), there was a need for increasing P box with time to maintain the fixed tidal volume (V t) of 11 ml/kg. No such need was seen in the experiments with 15-min periods of isocapnic hyperventilation at 80 and 120 breaths/min ( n=13). During the 2-h normal ventilation and in experiments with hyperventilation, there was a gradual increase in heart rate and small gradual decreases in Pa CO 2 and pH with time. Cold air+SO 2 2.5 ppm produced a significantly stronger bronchoconstriction (ΔV t=−30.3±7.2%, n=6, P<0.05) than clean cold dry air (ΔV t=−10.6±1.3%, n=6) and cold air+NO 2 2.5 ppm (ΔV t=−13.2±3.3%, n=6), although these three exposure conditions produced similar decreases in tracheal air and retrotracheal tissue temperatures. With the present guinea-pig model, the combined respiratory effects of cold air and gaseous urban air pollutants can be investigated in a highly controlled manner.

The diagnostic value of cold air hyperventilation in adults with suspected asthma

The diagnostic value of isocapnic hyperventilation of cold air (IHCA) is not fully established. All 342 adult patients in whom IHCA had been performed because of a clinical suspicion of asthma between 1992 and 1994 were analysed retrospectively in the authors' hospital. In addition, 26 healthy subjects were recruited. According to strict criteria, the patients were divided into asthmatics and symptomatic non-asthmatics. For the calculations of sensitivity, specificity and accuracy, the symptomatic non-asthmatic group served as a control. The post-test probability of asthma after IHCA was determined for all the possible pre-test probabilities by applying Bayes' theorem. A linear regression model was used to investigate the factors associated with the reactivity to IHCA. A single 4-min IHCA and skin prick tests were performed in the healthy subjects. Of the 287 patients in the final analysis, 113 were defined as asthmatics and 174 as symptomatic non-asthmatics. The accuracy was highest using a 9·0% fall in forced expiratory volume in 1 s (FEV 1) as a cut-off value; the specificity was then 86·8% and the sensitivity 31·9%. The authors found IHCA to be a useful diagnostic test only if the pre-test probability of asthma is between 0·30 and 0·56. The positive final diagnostic gain of IHCA is 22% at its best, but the negative gain is negligible for all possible pre-test probabilities. Factors associated with reactivity to IHCA were young age and, to a lesser extent, a history of cold-weather-associated respiratory symptoms and pre-challenge bronchial obstruction. If a rigid cut-off value for a positive response is used in all age groups, the specificity of IHCA is good but the sensitivity is unacceptably low in adults. The diagnostic value of IHCA might increase if age is taken into account when defining the cut-off value.

Hypoxic Ventilatory Response and Breathlessness Following Hypocapnic and Isocapnic Hyperventilation

To investigate the etiology of posthyperventilation (post-HV) hypoxemia following voluntary hyperventilation (VHV), we examined the effects of hypocapnic (hypo-CO2) and isocapnic (iso-CO2) VHV on the hypoxic ventilatory response (O2-response) and on the sensation of breathlessness during the O2-response. O2-responses and visual analog scale (VAS) scores for estimating breathlessness in 10 normal subjects during the O2-response under iso-CO2 conditions and under hypo-CO2 conditions immediately following voluntary maximal HV of 3 min duration were examined. Although there was no significant difference in the post-HV ventilation levels following hypo-CO2 vs iso-CO2 VHV, the VAS scores at the start of the O2-response following hypo-CO2 VHV (30.2+/-24.2 mm) were significantly higher (p<0.05) than the VAS scores at the start of the O2-response following iso-CO2 VHV (13.7+/-8.4 mm). However, VHV did not have a significant effect on the O2-response at 2 min after the VHV when the arterial O2 saturation (SaO2) was below 90%. The nonsteady-state hypo-CO2 induced by VHV greatly attenuated the O2-response below 90% SaO2 and VAS scores at 70% SaO2. Elevated VAS scores immediately following the hypo-CO2 VHV, which might be independent of actual breathing levels, and the attenuation of the O2-response following the hypo-CO2 VHV were not due to input from lung and chest wall mechanoreceptors induced by the hyperpnea itself, but rather to the hypo-CO2 induced by hyperpnea.

Effect of inhaled beclomethasone dipropionate on isocapnic hyperventilation with cold air in asthmatics, measured with forced oscillation technique

Isocapnic hyperventilation with cold air (IHCA) is a reliable technique for assessing indirect bronchial hyperresponsiveness in patients with asthma. Impedance measurement of the respiratory system by the forced pseudorandom noise oscillation technique is a sensitive technique to assess changes in bronchial tone after IHCA. The aim of this study was to evaluate the effect of 6 weeks of treatment with beclomethasone dipropionate, 1,000 microg x day-1, on IHCA in asthmatic patients, measured with both forced oscillation technique and flow-volume recordings. Forty patients with mild asthma were included in this double-blind, placebo-controlled parallel-group study. Stratification on the basis of sex was performed to overcome differences in airway diameter. At entry and every 2 weeks during the treatment period, IHCA was performed and patient diaries were evaluated. Characteristic changes in forced oscillation parameters after IHCA were observed in all patients. After 6 weeks of treatment, BDP-treated patients showed statistically significant differences in impedance measurements after IHCA, manifested by significant attenuation of resistance at 8 Hz (p<0.01), slope of the frequency-resistance curve (p<0.01), reactance at 8 Hz (p=0.01), and resonant frequency (f0) (p<0.02). Flow-volume recordings showed only a statistically significant change in the decrease of inspiratory vital capacity (IVC) (p=0.01). Furthermore, a significant correlation was observed between serum immunoglobulin E (IgE) levels and the effect of BDP on IHCA, measured with forced oscillation technique. In this study, beclomethasone dipropionate, 1,000 microg x day(-1) for 6 weeks, decreased indirect bronchial hyperresponsiveness as assessed by cold air bronchoprovocation in asthmatic patients. The forced oscillation technique proved a more sensitive method of detecting changes in bronchial tone than flow-volume recordings.

Effects of the combination of skin cooling and hyperpnea of frigid air in asthmatic and normal subjects.

To investigate whether reducing integumental temperature influences pulmonary mechanics and interacts with inhaling cold air, 10 normal and 10 asthmatic subjects participated in a three-part trial in which cooling the skin of the head and thorax and isocapnic hyperventilation of frigid air were undertaken as isolated challenges and then administered in combination. Integumental cooling for 30 min caused airway obstruction to develop in both populations [change in 1-s forced expiratory volume (delta FEV1) asthmatic subjects = 10% ; normal subjects = 6%)]. Hyperventilation, however, only affected the asthmatic subjects (delta FEV1 asthmatic subjects = 18%; normal subjects = 3%). In contrast to expectations, the combined challenge did not produce a summation effect (delta FEV1 asthmatic subjects = 21%; normal subjects = 7%). These data demonstrate that the skin of the trunk and head is cold sensitive and when stimulated causes similar degrees of bronchial narrowing in both normal subjects and patients with airway disease independent of any ventilatory effect. They also indicate that cooling of the skin does not add to the obstructive consequences of hyperpnea.

Exercise-induced asthma and the use of hypertonic saline aerosol as a bronchial challenge.

Exercise induced asthma is a common complaint and the prevalence appears to be increasing worldwide. Once confined to the research domain of university teaching hospitals, the study of EIA has extended into the school playground, defence force establishments and sports institutions. Standardized protocols have been developed to study EIA in the laboratory and in the field. A surrogate challenge using eucapnic or isocapnic hyperventilation with dry air is becoming popular because it has advantages over exercise, at least for adults. The stimulus that leads the airways to narrow is caused by the inhalation of dry air during hyperventilation and exercise, during which water is evaporated from the airways in order to condition the inspired air. The mechanism whereby the airways narrow is thought to be due to the dehydrating effects of water loss, particularly in relation to its potential to cause the airways to become hyperosmolar. Mast cell mediators such as histamine and the leucotrienes are probably involved in EIA because specific antagonists reduce severity. As a result of the osmotic theory of EIA, studies were carried out to determine whether subjects with EIA were sensitive to the effects of increasing airway osmolarity by inhalation of hyperosmolar aerosols of sodium chloride. A challenge protocol using an aerosol of 4.5% sodium chloride, generated from an ultrasonic nebulizer, has been used to identify persons with asthma and to assess response to drug therapy. There are many similarities between responses to exercise, hyperventilation and hypertonic saline in the physiological and biochemical responses and the responses to drugs. Challenge with hypertonic saline is easier and cheaper to use because expensive equipment and a source of dry air is not required as with exercise or hyperventilation. The ability to obtain a dose-response curve rather than a single response and the ability to collect inflammatory cells at the same time make challenge with hypertonic saline an attractive technique to study patients suspected of having asthma.

Tracheobronchial Constriction in Asthmatics Induced by Isocapnic Hyperventilation With Dry Cold Air

Although it is well known that isocapnic hyperventilation (IHV) with dry cold air produces airway constriction in asthmatic subjects, the site of airway narrowing is nuclear. To address this issue, we have quantified the tracheal and bronchial response to IHV with dry cold air in 15 patients with mild asthma and 7 healthy control subjects. We employed the acoustic reflection technique to evaluate changes in airway cross-sectional areas caused by IHV with dry cold air. Airway areas were measured during tidal breathing before and 5 to 10, 30, 60, and 90 min following cold air challenge. For analysis purposes, airway areas were divided into three anatomic segments: extrathoracic tracheal segment, intrathoracic tracheal segment, and main bronchial segment. These segments were assessed at a fixed volume below total lung capacity. Maximal and partial expiratory flow-volume curves were also obtained before each set of area measurements. In normal subjects, IHV with dry cold air caused no significant changes in FEV1, flow at 30% of the vital capacity in the partial curve (V30p), or airway areas. In asthmatics, at 5 to 10 min after challenge, we found that FEV1 decreased by 22 +/- 5% (mean +/- SEM) (p < 0.0001), V30p by 33 +/- 8% (p < 0.003), intrathoracic tracheal area by 10.7% +/- 2% (p < 0.03), and main bronchial area by 14 +/- 3% (p < 0.003). At 30 min, tracheal and main bronchial areas were returned to baseline levels; however, FEV1 and V30p were still significantly decreased, by 13 +/- 3% and 16 +/- 4%, respectively. We conclude that in asthmatics, IHV with dry cold air causes both tracheal and bronchial constriction, and that recovery seems to occur first in the central airways.

Mucociliary clearance during and after isocapnic hyperventilation with dry air in the presence of frusemide

We have previously shown that mucociliary clearance (MCC) decreased during and increased after isocapnic hyperventilation (ISH) with dry air, both in asthmatic and healthy subjects. Inhaled frusemide, an inhibitor of the Na+/K+/2Cl- and NaCl co-transporters on the basolateral membrane of the epithelial cell, prevents the airway narrowing provoked by ISH with dry air. The co-transport system controls epithelial cell volume and chloride secretion and, thus, frusemide has the potential to modify the rate of recovery of periciliary fluid volume during and after ISH with dry air, and hence affect MCC. Frusemide also blocks mediator release from mast cells, which may also modify the increase in MCC after ISH. Eleven asthmatic and 11 healthy subjects inhaled frusemide (35.7 +/- 0.44 mg) or its vehicle, from a Fisoneb ultrasonic nebulizer 30 min before ISH with dry air, on two separate occasions. MCC was measured using 99mTc-sulphur colloid and a gamma camera. Frusemide, compared to its vehicle, did not affect MCC during or 45 min after ISH. However, in the presence of frusemide, the onset of the increase of MCC after ISH was significantly delayed for approximately 10 min in the whole right lung (p < 0.002) and central region (p < 0.01) in the asthmatic but not in the healthy subjects. These findings could be explained by frusemide delaying the recovery of the periciliary fluid volume after ISH with dry air and/or interfering with the stimulus that causes the increase in MCC in the asthmatic subjects after ISH.