Postexertional airway rewarming and thermally induced asthma. New insights into pathophysiology and possible pathogenesis.

To determine if postexercise thermal events play a role in exercise-induced asthma (EIA), nine normal and eight asthmatic subjects on three occasions exercised while they inhaled frigid air. During the recovery period, either cold air, air at room temperature and humidity, or air at body conditions was administered in a random fashion. On a fourth occasion, body-condition air was given during exercise. Pulmonary mechanics were measured before and after each challenge. No changes in mechanics developed when air at body conditions was inhaled during exercise, however, increasing the heat content of the air during recovery produced progressively greater obstruction in both groups. On a separate occasion, seven asthmatics hyperventilated frigid air and either recovered spontaneously or had their ventilation slowly reduced. Controlling ventilation markedly attenuated the obstructive response. These data demonstrate that the severity of EIA is dependent not only on airway cooling but also upon the rapidity and magnitude of airway rewarming postchallenge.

Cold-induced bronchoconstriction: role of cutaneous reflexes vs. direct airway effects.

To determine the relative contributions of direct airway vs. reflex cutaneous thermal receptor stimulation in cold-induced bronchoconstriction, we isolated these two aspects of cold exposure in 10 asthmatics and 13 normal subjects. Ice packs were applied to the skin of the face, chest, thigh, and upper arm in random sequence while serially measuring specific conductance. In this fashion a limited mapping of skin-mediated bronchoconstriction was established. Warm packs were applied to the same areas of control for any potential nonspecific stimulatory effects. Cooling the skin induced bronchoconstriction to a similar degree in both groups; this effect was very small, did not induce symptoms, and was only seen with stimulation of the face. At another time, the subjects performed isocapnic hyperventilation of frigid air to ascertain their response to direct airway cooling. A moderate but significant correlation existed between skin and airway sensitivity; however, the magnitude of the two responses differed markedly. Breathing cold air at rest had no effect on lung function; however, elevating ventilation promptly produced bronchial narrowing. Hence, in a cold environment, the most potent stimulus for the development of airway obstruction in asthmatics derives from a direct airway effect.

Sympathoadrenal response to repetitive exercise in normal and asthmatic subjects.

To explore the role of catecholamine release in the pathogenesis of exercise-induced asthma, we had seven asthmatic and seven normal subjects undergo three hourly exercise challenges that were matched for inspired air temperature, minute ventilation, and relative work loads. Pulmonary mechanics and plasma epinephrine and norepinephrine were measured before, at end exercise, and serially after each challenge. There were no differences in the pattern of sympathoadrenal response of asthmatic and normal subjects, and both groups released sufficient quantities of epinephrine and norepinephrine into the peripheral circulation to allow these compounds to function as circulating hormones. As the catecholamines rose with repetitive exercise, progressive bronchodilation occurred in the asthmatics at the end of the work load, thus decreasing the apparent magnitude of the obstructive response. In addition to their effects on airway smooth muscle, the alpha-adrenergic actions of both catecholamines may have reduced airway wall hyperemia and edema. These data demonstrate that asthmatics do not have a defect in catecholamine release during exercise and that the physiological expression of exercise-induced asthma can be modulated by the sympathoadrenal epiphenomena that are associated with physical exertion.

Effect of exercise on nonspecific airway reactivity in asthmatics.

To investigate whether exercise increases the responsivity of the tracheobronchial tree to nonspecific stimuli, 11 atopic asthmatics underwent serial challenges with aerosolized methacholine before and 4 and 24 h after an asthma attack induced by cycle ergometry while breathing cold air (mean +/- SE = -11 +/- 1 degree C). Bronchodilator therapy was withheld the day before and throughout each study day. There were no significant differences in base-line lung function before exercise or any of the three methacholine bronchoprovocations. Exercise produced a 25 +/- 3% maximal fall in 1-s forced expiratory volume (FEV1) within 15 min. This attack was not associated with either an immediate or a delayed increase in methacholine sensitivity. The provocation concentration of methacholine required to reduce the FEV1 20% from saline control at base line and 4 and 24 h after exercise were 0.8 +/- 0.5, 0.9 +/- 0.5, and 1.1 +/- 0.8 mg/ml, respectively. This was not significant by a one-way analysis of variance (F = 0.078, P = NS). These data demonstrate that exercise-induced asthma does not produce an increase in nonspecific bronchial reactivity. Hence, if mediators are elaborated with exercise as has been suggested, they appear to function differently than when released by antigen.

Inhaled furosemide attenuates hyperpnea-induced obstruction and intra-airway thermal gradients.

Inhaled furosemide attenuates exercise- and isocapnic hyperventilation-induced asthma; however, the mechanism for this phenomenon is unknown. Because the magnitude of the intra-airway thermal gradient that develops between the cooling of hyperpnea and the rewarming that occurs once hyperventilation ceases is directly related to the severity of thermally induced obstruction in humans, we wondered if furosemide blunted these temperature changes. To explore this issue, eight asthmatic subjects had tracheobronchial airstream temperature measures as they performed isocapnic hyperventilation with frigid air alone (HV) or with pretreatment with inhaled saline (S + HV) or 45 +/- 3 (SE) mg of furosemide (F + HV). HV and S + HV resulted in similar degrees of obstruction, whereas the mechanical decrements after F + HV were significantly less. In concert with this protective effect, F + HV resulted in less airstream cooling during hyperventilation and slower rewarming in the recovery period. Because the major source of heat to the airways is provided by its microcirculation, inhaled furosemide may be acting as a topical vasodilator serving to enhance heat availability and thus reducing the effective thermal burden of hyperpnea.

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.

Integrated response of the upper and lower respiratory tract of asthmatic subjects to frigid air.

To evaluate the influence of cold air hyperpnea on integrated upper and lower airway behavior, 22 asthmatic volunteers hyperventilated through their mouths (OHV) and noses (NHV) while pulmonary and nasal function were determined individually and in combination. In the isolated studies, OHV at a minute ventilation of 65 +/- 3 l/min lowered the 1-s forced expiratory volume (FEV(1)) 24 +/- 2% (P < 0. 001) and NHV (40 l/min) induced a 31 +/- 9% (P < 0.001) increase in nasal resistance (NR). In the combined studies, oral hyperpnea reduced the FEV(1) (DeltaFEV(1) 26 +/- 2%, P < 0.001) and evoked a significant rise in NR (DeltaNR 26 +/- 9%, P = 0.01). In contrast, NHV only affected the upper airway. NR rose 33 +/- 9% (P = 0.01), but airway caliber did not change (DeltaFEV(1) 2%, P = 0.27). The results of this investigation demonstrate that increasing the transfer of heat and water in the lower respiratory tract alters bronchial and nasal function in a linked fashion. Forcing the nose to augment its heat-exchanging activity, however, reduces nasal caliber but has no effect on the intrathoracic airways.

Re-examination of the late asthmatic response to exercise.

To determine the nature of the delayed response to exercise, we had 20 atopic asthmatics perform cycle ergometry on 2 occasions while breathing either frigid or hot-humid air in a random fashion. The latter served as a sham control. Forced expiratory volume in one second (FEV1) was measured serially for 10 h after each trial. Subjects developing a second wave of obstruction after recovery from the initial asthma attack were rechallenged on a third day with methacholine and followed in an identical fashion. Cold-air exercise produced an immediate 28% fall in FEV1 for the group as a whole, after which 2 distinct patterns of recovery developed. In 13 subjects, the initial obstruction resolved over several hours. Thereafter, lung function remained constant. In the remaining 7 subjects, the early attack was followed by an initial improvement and then progressive deterioration. This pattern occurred at the same times and to the same magnitude both in the hot-humid experiment in which the initial obstruction was absent, and when the obstruction was induced with methacholine. Based on these observations, it appears that the late asthmatic reaction that follows physical exertion in some subjects is a nonspecific epiphenomenon that is neither dependent upon the existence of an early response nor is unique to exercise.

Comparison of intraairway temperatures in normal and asthmatic subjects after hyperpnea with hot, cold, and ambient air.

To determine how the inhalation of hot dry, frigid, and room temperature air influences airway heat transfers, we obtained single-breath temperature washout curves in eight asthmatic and eight normal subjects before and during periods of hyperpnea. The order of study was randomly determined, and the thermal events with each inspirate were correlated with their effects on lung function. Each inspired air condition produced significant airway cooling in both groups. Cold air evoked the greatest response, followed thereafter by hot dry and then room air. Only the asthmatic subjects developed airway obstruction. These data demonstrate that hot dry gases facilitate evaporative cooling and do not keep the airways warm as has been previously suggested. It appears the airway cooling is a normal part of respiration and develops whenever air is inhaled that requires the transfer of heat and/or water to bring the inspirate to body conditions.

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.

Intrathoracic airstream temperatures during acute expansions of thoracic blood volume.

1. To determine the validity of employing intrathoracic heat flux as a reflection of changes in bronchial blood flow, we used a thermal probe to record airstream temperatures within the tracheobronchial tree in five normal and five asthmatic subjects during isocapnic hyperventilation challenges with and without inflation of the lower limb bladders of a pressure suit. 2. During hyperpnoea, airstream temperatures fell progressively in both subject groups. When blood volume was acutely shifted from the legs into the thorax via anti-shock trousers, airstream temperatures within the tracheobronchial tree rose and were significantly higher than the temperature recorded during hyperpnoea alone. In the normal subjects, once hyperpnoea ceased, the rate of airway re-warming was similar whether or not the anti-shock trousers were inflated. In the asthmatic subjects, however, shifting blood into the thorax attenuated the obstructive response to hyperpnoea and slowed the rate of re-warming. 3. These data demonstrate that changes in airway blood volume are reflected in fluctuations in intrathoracic heat exchange and that disruption of the end hyperpnoea thermal gradient attenuates the airway obstruction that follows hyperpnoea. Since the bronchial blood supply is the major source of heat to the airways, this circulation may play an important role in thermally induced asthma.

Vascular volume expansion and thermally induced asthma.

To determine whether a relationship exists between intravenous infusion of isotonic fluid and reactivity to hyperpnoea, eight normal and eight asthmatic subjects underwent rapid intravascular administration of approximately 2 l of warm normal saline, by itself and before and after hyperventilation of cold air. In the asthmatic subjects, saline infusion mirrored the obstruction seen with hyperventilation; whereas, in normal subjects saline produced more bronchial narrowing than hyperventilation. When the two stimuli were given together, the timing of the infusion altered the asthmatic subjects' responses. Giving fluid early in the hyperventilation challenge blunted obstruction, whereas giving it later amplified the airway narrowing. Similar findings, but on a smaller scale, occurred in normal subjects. These data demonstrate that sudden elevations in intrathoracic vascular volume with warm saline produce airway obstruction that is quantitatively similar to that seen with hyperventilation in asthmatic individuals. They also demonstrate that these two stimuli interact together in such a manner that a common mechanism may exist to account for the decrease in airflow.

Lack of interaction of hyperpnoea with methacholine and histamine in asthma.

1. The thermal precipitants of asthma (exercise and hyperventilation) appear to have a unique pathogenesis that does not alter bronchial responsiveness. In the present work, we tested whether hyperpnoea interacts with other constrictor stimuli.2. To provide data on this issue, we exposed 17 subjects with asthma to isocapnic hyperventilation of frigid air (HV), methacholine (METH) and histamine (HIS) alone and in combination.3. With HV (mean ventilation=55.6+/-7.7 litres/min), METH (2.20+/-0.7 mmol/l) and HIS (10.35+/-5.04 mmol/l) alone, the decrements in forced expiratory volume in 1 s (FEV1) from baseline were 27.4+/-3.4, 27.4+/-3.8 and 32.4+/-3% respectively (n=9). Giving the agonists simultaneously did not produce additive effects (Delta FEV1 HV+METH=32.8+/-3.6%; HV+HIS=28.7+/-5.1%). None of the individual or combined responses was significantly different from each other. Changing the sequence of the experiments and giving METH at the height of the HV-induced bronchial narrowing, instead of during hyperpnoea, did not alter the findings (n=8). The maximum fall in FEV1 after both bronchoconstrictors in this experiment (Delta FEV1=32.3+/-4.3%) was not significantly different from either alone (HV=22.8+/-1.0%; METH=27.3+/-1.9%). When METH and HIS were administered together, however (n=5), a positive interaction ensued (METH=1.53+/-0.56 mmol/l, Delta FEV1=15.6+/-4.6%; HIS=4.77+/-2.07 mmol/l, Delta FEV1=18. 8+/-3.1%; METH+HIS Delta FEV1=33.4+/-5.2%; P<0.001 compared with the individual effects).4. These results indicate that HV does not interact with stimuli that directly or indirectly modulate airway calibre. It is unclear if this effect represents protection conferred from increased bronchial blood flow or derives from differences in effector mechanisms between the thermal and pharmacological agonists.

Metabisulfite sensitivity and local dental anesthesia.

A case of sulfite sensitivity first manifesting as urticaria and acute airway obstruction following local anesthesia is described. A positive parenteral provocation test to metabisulfite was observed weeks after recovery of the patient from the clinical event.