MANSOOR, JIM K.; ELDRIDGE, MARLOWE W.; YONEDA, KEN Y.; SCHELEGLE, ED S.; WOOD, STEVE C.
Ascent to altitude is characterized by reductions in the PIO2 leading to changes in breathing pattern that are often accompanied by sensations of dyspnea, often described as “air hunger” or “breathlessness”(21). The mechanisms responsible for sensations of dyspnea in normal healthy individuals have not been fully elucidated. Ascent to altitude presents the individual with a variety of stimuli, including hypoxia because of the reduced barometric pressure, cold, and decreases in relative humidity, which may result in different or additional mechanisms being responsible for dyspneic sensations. For example, both subclinical interstitial edema and clinically relevant alveolar edema can occur with ascent to altitude, particularly if accompanied by exercise (10). The lung edema can stimulate a variety of pulmonary afferent fibers (5) that could potentially play a role in both the breathing pattern changes and sensations of dyspnea experienced by individuals at altitude. To our knowledge, there has been no attempt made to examine the mechanisms behind sensations of dyspnea experienced by individuals on either acute ascent to altitude or after prolonged acclimatization to altitude.
A variety of mechanisms have been proposed to explain dyspnea. One mechanism proposes that pulmonary receptors may be responsible for dyspneic sensations. Guz et al. (9) showed that bilateral vagal and glossopharyngeal blockade in conscious humans reduced the sensations of respiratory discomfort associated with breath-holding. However, Banner et al. (4) showed similar intensities in sensations of breathlessness in heart-lung transplant patients compared with heart transplant patients and healthy controls. In addition, Winning et al. (22) showed no significant reduction in dyspneic sensations after delivery of bupivacaine aerosol in exercising humans. Although these studies suggest that pulmonary vagal afferents do not play a significant role in sensations of dyspnea at sea level, the role that these receptors play in respiratory-related sensations at altitude has never been studied in humans and may be potentially important. Rapid ascent to altitude combined with heavy exercise can significantly increase pulmonary arterial and wedge pressures (8), which in turn may lead to increases in interstitial (3) or pulmonary edema (20). Lung edema has been shown to be an important stimulus for both pulmonary C-fibers (5) and rapidly adapting receptors (17).
The purpose of this study was to examine respiratory-related sensations in men and women on acute ascent to altitude and after prolonged acclimatization to altitude. We examined the intensity and type of respiratory-related sensations using nine different respiratory-related descriptors adopted from Simon et al. (18) in seven male and five female subjects after acute ascent to 3500 m and after prolonged acclimatization at 5000 m. These sensations were examined in the presence and absence of inhaled aerosolized tetracaine in order to determine if airway pulmonary afferents play a role in these responses. Additionally, we examined these sensations at rest and during exercise to increase the hypoxic stress and in turn the respiratory-related sensations experienced by the subjects.
Seven male subjects (age, 33 ± 9 yr (mean ± SD); weight, 71 ± 5 kg; height, 176 ± 5 cm) and five female subjects (age, 31 ± 5 yr; weight, 57 ± 9 kg; height, 162 ± 7 cm) between the ages of 16 and 41 yr gave their informed written consent to participate in this study, which was approved by the Institutional Review Board at Summa Health System Foundation of Akron, OH. All of the subjects were healthy and free of disease at the start of the study. All but three subjects exercised regularly before the expedition. Six subjects had little experience at altitude, never having been above 2400 m, whereas the other six subjects had been above 3600 m hiking, skiing, or climbing on many occasions (at least 5–10 times). Of those that had been above 3600 m, three had experienced acute mountain sickness. None of the subjects had a history of high altitude pulmonary or cerebral edema before the start of the study.
During the study, one of the male subjects developed high-altitude pulmonary edema and was safely evacuated to Leh Hospital, where he recovered completely. There are no data from this subject beyond 3500 m. There are also no data from a second male subject at sea level because of complications in collecting these data. When possible, their data were included in the data analysis.
Expedition and ascent profile.
The subjects left the United States at different times in the Spring of 1998 and gathered in Delhi, India, on May 30, 1998. Sea level data was collected on five of the subjects in Delhi, India, whereas the sea level data from six subjects were collected at the University of California, Davis (Davis, CA). All of the subjects then flew to the city of Leh in the Ladakh region of northern India. Leh is located at an elevation of approximately 3500 m. The subjects spent the first day in Leh relaxing and sightseeing. On the following 2 d, data were collected on all of the subjects (Fig. 1).
From Leh, the subjects and investigators drove to Tsomuri, a lake located a day’s drive from Leh at an elevation of 4540 m. The next 14 d were spent trekking in the Himalayas between the elevations of approximately 4000 and 5400 m. A high camp was established at the base of Kang Yaze at an elevation of approximately 5000 m, where the final data were collected over the course of 2 d. Subjects thus had 18 d of acclimatization at elevations ranging from 3500–5400 m (Fig. 1).
Research design and general protocol.
Data were collected at three different elevations: sea level, 3500 m, and 5000 m. At each of these elevations, subjects gargled with Dyclone (0.5% dyclonine HCl), a topical anesthetic for mucous membranes, and then inhaled either aerosolized tetracaine or normal saline before data collection. Subjects were randomized in a single-blind fashion to determine which treatment they would receive for that given day, either aerosolized tetracaine or normal saline, and the other treatment was given on the following day. After the aerosol treatment, subjects rated on a 0–10 modified Borg scale the intensity of each of the following respiratory-related descriptors:
“I feel my breathing is rapid.”
“My breath does not go out all the way.”
“My breathing requires more concentration.”
“My breathing is shallow.”
“My breathing requires more work.”
“My chest feels tight.”
“I feel a hunger for more air.”
“My breathing is heavy.”
“I am gasping for breath.”
A zero rating meant an absence of the sensation and a 10 rating meant the sensation was felt as strongly as possible. Heart rate and peripheral O2 saturation (SpO2) was monitored continuously. Subjects then breathed 3% aerosolized saline and a sputum sample was collected for substance P analysis. Each subject then exercised at four different exercise workloads for 3 min, with 3 min of rest between bouts. At the end of each exercise bout, subjects again rated the intensity of respiratory-related descriptors, and heart rates and SpO2 data were recorded. At the end of the exercise bouts, subjects again breathed 3% aerosolized saline and a second sputum sample was collected for substance P analysis.
Before inhaling either tetracaine or saline, subjects gargled with 15 mL of Dyclone for approximately 2 min in order to disguise which aerosolized solution they were receiving. Subjects then inhaled either 5 mL of 0.9% sterile saline as a sham anesthesia or 5 mL of 0.9% sterile saline with 20 mg of tetracaine added for a concentration of 4 mg·mL−1. Subjects inhaled the solutions from either a DeVilbiss 35b or 99 nebulizer over the course of 5–10 min until the nebulizer was empty. Subjects inhaled the aerosolized solution through their mouths while wearing nose clips.
Subjects inhaled 3% saline before and after exercise and brought up sputum from the deep lung to be analyzed for substance P concentration. Because of technical errors, substance P values were not obtained.
Subjects performed step exercise at four different workloads. Male subjects exercised at rates of 22, 26, 32, and 38 steps·min−1, and female subjects exercised at rates of 18, 24, 30, and 36 steps·min−1. The box step height was 30.5 cm. One complete step cycle consisted of stepping from the ground onto the box with both feet, legs extended, and back down to the ground. Subjects were instructed to alternate legs used to step up onto the box to prevent fatigue in one leg. Each work bout lasted 3 min, with 3 min of rest between bouts. Some subjects were not able to finish the last work bout, especially at 5000 m. Only the third work bout was used for the analyses. The average power for this work bout was 85.8 ± 12.7 W for female subjects and 113.7 ± 8.3 W for male subjects.
All data were initially analyzed using a three-way ANOVA with repeated measures (StatView 5, SAS Institute, Inc., Cary, NC). Independent factors for this initial analysis were barometric pressure (sea level vs 3500 m for acute altitude exposure or sea level vs 5000 m for prolonged altitude exposure), gender (male vs female), and treatment (saline vs tetracaine). Separate three-way ANOVAs were performed for acute and prolonged altitude exposure and for rest and exercise. The third exercise bout was used for all exercise analyses. After this initial analysis, it was found that there was no significant effect of tetracaine on any of the variables studied; as a consequence, all data were reanalyzed using a two-way ANOVA with repeated measures. In order to identify mean differences, multiple paired t-tests were performed using an appropriate Bonferroni correction factor. The level of significance was set at P ≤ 0.05. All data are presented as means ± SD.
Acute exposure to 3500 m.
Acute exposure to altitude of approximately 3500 m resulted in an increase in resting heart rate in both male and female subjects (Table 1). This increase in resting heart rate approached statistical significance (P = 0.06). SpO2 at rest on acute exposure to 3500 m was significantly lower than at sea level. Acute mountain sickness scores using the Lake Louise scoring system were higher for female subjects than for male subjects on acute exposure to altitude.
Heart rate and rating of perceived exertion (RPE) during exercise at 3500 m was significantly higher than during sea level exercise (Table 1). Additionally, SpO2 was lower during exercise at 3500 m than at sea level. These findings indicate both a physiological hypoxic stress as well as a psychological or perceived whole-body stress.
Subjects also perceived a change in the intensity of specific respiratory-related sensations when going from sea level to 3500 m. Of the nine respiratory-related sensation descriptors, the descriptor “I feel my breathing is rapid” was rated higher at 3500 m than at sea level during rest (Fig. 2). During exercise at 3500 m, subjects rated four respiratory-related descriptors as being more intense than at sea level: “I feel my breathing is rapid,” “I feel a hunger for more air,” “My breathing is heavy,” and “My chest feels tight.” These higher ratings may be an indication that dyspnea on acute exposure to altitude is associated with respiratory sensations of rapid, heavy breathing, air hunger, and chest tightness. Inhalation of tetracaine had no effect on any of the dependent variables.
Prolonged acclimatization to 5000 m.
After 18 d of acclimatization at elevations between 3500 and 5400 m, resting heart rates of male and female subjects remained higher at 5000 m compared with sea level, but this difference was not significant (Table 1). SpO2 was significantly lower at 5000 m than at sea level during rest. In the only comparison made between 3500 m and 5000 m, acute mountain sickness scores at rest were significantly lower after prolonged acclimatization than after acute exposure to altitude.
Interestingly, there was no significant difference between exercise heart rates at 5000 m and sea level (Table 1). SpO2 during exercise, however, was significantly lower at 5000 m than at sea level. In addition, RPE during exercise was higher at 5000 m than at sea level.
It is also interesting to note that after acclimatization, none of the respiratory-related sensation descriptors were significantly different in intensity than that perceived at sea level during rest. During exercise at 5000 m, however, four respiratory-related sensation descriptors were rated as being significantly more intense than at sea level: “I feel my breathing is rapid,” “I feel a hunger for more air,” “My breathing is heavy,” and “I am gasping for breath” (Fig. 3). The first three, namely, rapid, heavy, and air hunger, were also rated by subjects as being more intense than at sea level during acute exposure to 3500 m. The descriptor “My chest feels tight” was no longer perceived as more intense than at sea level during exercise after acclimatization, but subjects felt a sensation related to gasping during exercise at 5000 m. Again, tetracaine had no significant effect on any of the dependent variables.
The purpose of this study was to examine respiratory-related sensations after acute exposure and prolonged acclimatization to altitude. We examined the intensity and type of respiratory-related sensations in the presence and absence of aerosolized tetracaine during rest and exercise at sea level, after acute ascent to 3500 m, and after 18 d of acclimatization at 5000 m. This is the first study that we are aware of that has attempted to differentiate respiratory-related sensations at altitude and also examine the role played by airway receptors in these sensations.
The respiratory response to altitude consists of hyperventilation caused by hypoxic stimulation of peripheral chemoreceptors. This response occurs on acute exposure to altitude and continues after acclimatization (20). Because of this physiological response, individuals often become aware of respiratory-related sensations, termed “dyspnea.” The terms “breathlessness” and “air hunger” are often used generically by researchers to describe the respiratory-related sensations experienced by individuals at altitude (21) and during exercise (1). In this study, we attempted to differentiate between respiratory-related sensations at sea level and altitude during rest and exercise by having subjects rate the intensity of nine different respiratory-related sensation descriptors adopted from Simon et al. (18) in the presence and absence of airway anesthesia with tetracaine. We found that during resting conditions after acute exposure to 3500 m subjects rated “I feel my breathing is rapid” significantly higher than at sea level, and that this difference was no longer significant after acclimatization at 5000 m. This indicates that healthy subjects at rest only experience a dyspneic sensation after acute exposure to altitude, and that the mechanisms responsible adapt on acclimatization. Others have also shown adaptation of respiratory-related sensations with prolonged altitude exposure (7,14,15,21). Interestingly, the descriptors “I feel a hunger for more air” and “I am gasping for breath,” descriptors similar to air hunger and breathlessness, were not significantly different from sea level at either 3500 m or 5000 m during rest.
We had subjects exercise during this study in an attempt to increase their hypoxic stress. Our subjects had significant reductions in oxygen saturations because of both altitude and exercise (Table 1). During exercise at both 3500 m and 5000 m, subjects rated three respiratory-related sensation descriptors significantly higher than at sea level: “I feel my breathing is rapid,” “My breathing is heavy,” and “I feel a hunger for more air.” Subjects also rated “My chest feels tight” and “I am gasping for breath” significantly higher at 3500 m and 5000 m, respectively, during exercise. It is clear from these results that subjects experienced rapid heavy breathing, and also air hunger (“I feel a hunger for more air”) both during acute altitude exposure and after prolonged acclimatization, as well as breathlessness (“I am gasping for breath”) at 5000 m during exercise. These data seem to indicate that the greater the hypoxic stress, the greater the intensity and variation in dyspneic sensations. This is consistent with studies by Del Volgo and Noel-Jorand (7), who found that exercise in combination with ascent to higher altitudes increased “breathing discomfort” over resting conditions, and Ward and Whipp (19), who found that hypoxia during exercise leads to greater “respiratory difficulty” than exercise alone at the same level of ventilation.
The mechanisms responsible for dyspneic sensations have not been fully elucidated. Most theories suggest that input into the CNS from some peripheral afferent receptor and/or central pathway is responsible for respiratory-related sensations (2). One such pathway that has been considered in the genesis of dyspnea is stimulation of pulmonary receptors. Winning et al. (22) showed that breathlessness with exercise and CO2 inhalation was not abolished by inhalation of aerosolized bupivacaine, suggesting that pulmonary afferents in the larger airways are not responsible for dyspneic sensations. Additionally, heart-lung transplant patients are known to experience dyspneic sensations in the absence of an intact vagus nerve (4). With ascent to altitude, however, pulmonary arterial pressures increase (12), which may cause an increase in interstitial water (3,8,12). Increases in interstitial water have been shown to stimulate both rapidly adapting receptors (5,13,17) as well as pulmonary C-fibers (5,16). These fibers, when stimulated, are known to contribute to alterations in breathing pattern (5,16). The extent to which these fibers contribute to sensations of dyspnea when stimulated above basal levels is unknown.
In order to determine whether lung C-fibers become more active and contribute to dyspneic sensations with ascent to altitude, we attempted to measure substance P in induced sputum and block lung afferents with tetracaine. Because of technical difficulties, we were not able to obtain reliable measures of substance P in the induced sputum of our subjects. Tetracaine inhalation had no effect on respiratory-related sensations, suggesting that airway lung afferents, either after acute altitude exposure or prolonged acclimatization, play no role in the genesis of dyspnea at altitude. We do not know, however, the extent to which tetracaine inhalation blocked the variety of pulmonary afferent receptors. It is entirely possible that deeper airway or parenchymal afferent receptors, such as pulmonary C-fibers (J receptors), were not blocked by tetracaine inhalation (6,11,22) and continued to contribute to respiratory-related sensations.
We would like to acknowledge the guides and Sherpas at Rimo Expeditions of Leh, India, who were invaluable in carrying out this research.
This work was supported by Summa Health System Foundation, Akron, OH; a Scholarly Activity & Artistic Grant from the University of the Pacific; and a grant from the Hibbard Williams Research Fund from the University of California, Davis.
Address for correspondence: Jim K. Mansoor, Ph.D., Physical Therapy Department, School of Pharmacy and Health Sciences, University of the Pacific, 3601 Pacific Ave., Stockton, CA 95211; E-mail: email@example.com.
1. Adams, L., and A. Guz. Dyspnea on exertion. In: Exercise: Pulmonary Physiology and Pathophysiology, B. J. Whipp and K. Wasserman (Eds.). New York: Marcel Dekker, 1991, pp. 449–494.
2. American Thoracic Society. Dyspnea: mechanisms, assessment, and management—a consensus statement. Am. J. Respir. Crit. Care Med. 159: 321–340, 1999.
3. Anholm, J. D., E. N. Milne, P. Stark, J. C. Bourne, and P. Friedman. Radiographic evidence of interstitial pulmonary edema after exercise at altitude. J. Appl. Physiol. 86: 503–509, 1999.
4. Banner, N. R., M. H. Lloyd, R. D. Hamilton, J. A. Innes, A. Guz, and M. H. Yacoub. Cardiopulmonary response to dynamic exercise after heart and combined heart-lung transplantation. Br. Heart J. 61: 215–23, 1989.
5. Coleridge, H. M., and J. C. G. Coleridge. The control of breathing, part I: reflexes evoked from tracheobronchial tree and lungs. In: Handbook of Physiology, Section 3: The Respiratory System, A. P. Fishman, N. S. Cherniack, J. G. Widdicombe, and S. R. Geiger (Eds.). Bethesda, MD: American Physiological Society, 1986, pp. 395–429.
6. Cross, B. A., A. Guz, S. K. Jain, S. Archer, J. Stevens, and F. Reynolds. The effect of anaesthesia of the airway in dog and man: a study of respiratory reflexes, sensations and lung mechanics. Clin. Sci. Mol. Med. 50: 439–454, 1976.
7. Del Volgo, M. J., and M. C. Noel-Jorand. The respiratory sensation at high altitude. Arch. Int. Physiol. Biochim. Biophys. 100: 113–119, 1992.
8. Eldridge, M. W., A. Podolsky, R. S. Richardson, et al. Pulmonary hemodynamic responses to exercise in subjects with prior high altitude pulmonary edema. J. Appl. Physiol. 81: 911–921, 1996.
9. Guz, A., M. I. M. Noble, J. H. Eisele, and D. Trechard. Experimental results of vagal block in cardiopulmonary disease. In: Breathing: Hering-Breuer Centenary Symposium, R. Porter (Ed.). London: Churchill, 1970, pp. 315–328.
10. Hackett, P. H., and R. C. Roach. High altitude pulmonary edema. J. Wilderness Med. 1: 3–26, 1990.
11. Hamilton, R. D., A. J. Winning, and A. Guz. Blockade of ‘alveolar’ and airway reflexes by local anesthetic aerosol in dogs. Respir. Physiol. 67: 159–170, 1987.
12. Hultgren, H. N. High altitude pulmonary edema: hemodynamic aspects. Int. J. Sports Med. 18: 20–25, 1997.
13. Kappagoda, C. T., G. C. W. Man, and K. K. Teo. Behaviour of canine pulmonary vagal afferent receptors during sustained acute pulmonary venous pressure elevation. J. Physiol. 394: 249–265, 1987.
14. Noel-Jorand, M. C., and H. Burnet. Changes in human respiratory sensation induced by acute high altitude hypoxia. Neuroreport 5: 1562–1566, 1994.
15. Noel-Jorand, M. C., and H. Burnet. The sensation of respiration in men experiencing high-altitude chronic hypoxia. Biol. Psychol. 43: 1–12, 1996.
16. Paintal, A. S. The mechanism of excitation of type J receptors and the J reflex. In: Breathing: Hering-Breuer Centenary Symposium, R. Porter (Ed.). London: Churchill, 1970, pp. 59–71.
17. Ravi K., K. K. Teo, and C. T. Kappagoda. Stimulation of rapidly adapting pulmonary stretch receptors by pulmonary lymphatic obstruction in dogs. Can. J. Physiol. Pharmacol. 66: 630–636, 1988.
18. Simon, P. M., R. M. Schwartzstein, J. W. Weiss, K. Lahive, V. Fencl, M. Teghtsoonian, and S. E. Weinberger. Distinguishable sensations of breathlessness induced in normal volunteers. Am. Rev. Respir. Dis. 140: 1021–1027, 1989.
19. Ward, S. A., and B. J. Whipp. Effects of peripheral and central chemoreflex activation on the isopneic rating of breathing in exercise in humans. J. Physiol. 411: 27–43, 1989.
20. West, J. B. Physiological Basis of Medical Practice. Baltimore: Williams & Wilkins, 1990, pp. 588–592.
21. Wilson, R. C., W. L. G. Oldfield, and P. W. Jones. Effect of residence at altitude on the perception of breathlessness on return to sea level in normal subjects. Clin. Sci. 84: 159–167, 1993.
22. Winning, A. J., R. D. Hamilton, S. A. Shea, C. Knott, and A. Guz. The effect of airway anaesthesia on the control of breathing and the sensation of breathlessness in man. Clin. Sci. 68: 215–225, 1985.
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