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To breathe or not to breathe
Journal of Wilderness Medicine, 5,251-253 (1994)
EDITORIAL*
To breathe or not to breathe Anyone who has ever had the misfortune of suffering from Acute Mountain Sickness (AMS) would never question the reality of this affliction. During the first night following rapid ascent to high altitude, being awakened from a restless sleep with a splitting headache, followed by a wave of nausea and perhaps vomiting, is an experience never to be forgotten. Of the millions who visit the mountainous regions of the western United States, approximately one person in four will experience AMS; it is very common. AMS strikes those guilty of "going too high too fast," and "too high" is any altitude above 8000 ft (2400 m). In considering the pathogenesis of AMS, the initiating event is unquestionably rapid ascent to high altitude. Unlike decompression sickness in divers, exposure to the decreased atmospheric pressure per se is probably of little consequence at moderate altitude. Rather, it is the associated decrease in the partial pressure of oxygen, i.e., atmospheric hypoxia, that is the culprit. From an evolutionary viewpoint, defenses against hypoxia probably developed to cope with airway obstruction. Impairment of ventilation would result in a fall in airway paz combined with an increase in airway PCO z. The resulting hypoxemia would stimulate the carotid chemoreceptors while, concurrently, hypercapnic acidosis would provide central stimulation. Together, the responses would produce a powerful increase in the effort to breathe. However, when exposed to atmospheric hypoxia, the respiratory control system is presented with a dilemma. Increased ventilation in response to hypoxemia now lowers airway PCO z, and the normal COz stimulus is withdrawn, thereby counteracting the hypoxic stimulus. Hence, "to breathe or not to breathe?" Those who develop AMS seem to favor the "not to breathe" option, for they exhibit less increase in ventilation, i.e., relative hypoventilation, and more severe hypoxemia than do their more fortunate colleagues. Because relative hypoventilation implies not only a greater fall in paz but also less fall in PCO z, the potential role of changes in PCO z in the pathogenesis of AMS should also be considered, as COz relates to the way in which the body handles fluid. Recall that one of the earliest responses following ascent to altitude is a rise in hematocrit. This results from removal of water from the plasma, i.e., hemoconcentration, followed by diuresis. The latter accounts in part for the usual loss of body weight at altitude. It has been observed that persons who have a diuresis and lower body weight are less likely to develop AMS [1]. Conversely, persons who gain weight at altitude, i.e., retain fluid, are more prone to develop not only the usual symptoms of AMS but also more serious manifestations, including high altitude pulmonary edema (HAPE) and cerebral edema (HACE). This has led to the concept that altitude illness, in general, reflects abnormal fluid retention, i.e., "the edemas of altitude" [2]. Fluid retention appears to be linked to changes in COz. We demonstrated that the usual 'Because of a production error, Matsuzawa et a\"s article that was referenced in R. F. Grover's editorial "To breathe or not to breathe" (J Wild Med 1994; 5, 143-145) was not published with it. We regret the error and any inconvenience that it caused. We are printing the editorial and the article in this issue as was intended by the Editors. 0953-9859 © 1994 Chapman & Hall
252
Editorial
hemoconcentration at altitude did not occur if hypocapnia was prevented by adding CO 2 to the atmosphere in a decompression chamber [3]. Furthermore, preventing the fall in PC0 2 also increased the severity of AMS symptoms [4]. Subsequently, we observed among trekkers in Nepal a relative hypoventilation, i.e., higher PC0 2 and lower arterial saturation, and a failure to lose weight (presumably due to fluid retention) in those who developed AMS [1]. Hence, changes in CO 2 as well as in O 2 appear to be determinants of AMS, and both are related to the ventilatory response to high altitude. Just as individual variability is intrinsic to physiological control mechanisms in general, so it is to the control of ventilation. Among individuals, there is a broad spectrum of both hypoxic ventilatory response (HVR) and hypercapnic ventilatory response (HCVR) [5]. This variable chemosensitivity to acute stimuli is reflected in the ventilatory acclimatization to the chronic hypoxia of high altitude. Differences in HVR will provide variable stimulation, whereas differences in HCVR will provide variable inhibition from falling CO 2 [6,7]. The net change in ventilation on ascent will be determined by the relative strengths of these two opposing factors. A weak HVR will permit hypoxemia to persist with minimal fall in PC0l> a combination that favors the development of AMS [8,9]. The dilemma "to breathe (and lessen hypoxia) or not to breathe (and preserve a more normal PC0 2 and pH)" is particularly evident during sleep and is manifest as alternate periods of hyperventilation and apnea, i.e., periodic breathing (PB). This is associated with cyclic variations in arterial O 2 saturation. Although the increases in saturation result from transient hyperventilation, the subsequent declines in saturation are not simply a reflection of the temporary suspension of breathing, as they cannot be reproduced by breath holding while awake [10], although the actual mechanism is unclear. So the question may be asked, does PB with recurring drops in saturation accentuate the greater hypoxemia produced by sleep itself with regular breathing? If this were to occur, PB might then contribute to the severity of AMS. In the present issue of Wilderness Medicine, Matsuzawa et al. [11] have examined this question. They exposed a group of young men to simulated high altitude and sought correlations between the severity of AMS and the degree of arterial desaturation, particularly during sleep, the incidence of PB during sleep, and respiratory chemosensitivity at sea level. They have confirmed previous reports that arterial saturation falls during sleep at altitude [11,12], but the magnitude of desaturation mayor may not correlate with the severity of AMS [12,13]. Further, Kobayashi et al. found that desaturation during sleep correlated with HVR, whereas Powles and Sutton [13] failed to detect such a correlation. However, Kobayashi et al. as well as others [14] found no evidence that PB either accentuated sleep hypoxemia or increased the severity of AMS. Kobayashi et al. also found no correlation between the extent of PB and either HVR or HCVR. Although Lahiri and Barnard [15] reported a correlation between PB and HVR, this pattern depended on the inclusion of a group of highland Sherpas with very low HVR; for the lowlanders sojourning at high altitude, there was no such correlation. Anecdotally, we also observed virtually no PB in Sherpas sleeping at high altitude, even though a larger group of Sherpas had HVR comparable to that of western lowlanders, i.e., not blunted [16]. One final comment should be made on the relationships (or lack of same) between hypoxemia and PB during sleep, severity of AMS, respiratory chemosensitivity, and ventilatory acclimatization to high altitude. Acetazolamide is recognized as being effective in minimizing AMS and HAPE, and of improving the quality of sleep by lessening both hypoxemia and PB [17]. These benefits result in part from the inhibition of carbonic anhydrase, which promotes a bicarbonate diuresis, resulting in a metabolic acidosis
Editorial
253
instead of the usual hypocapnic alkalosis. These observations again emphasize the importance of changes in CO 2 as well as in O 2 in ventilatory acclimatization to high altitude and the pathogenesis of AMS. ROBERT F. GROVER, MD
Arroyo Grande, California
References 1. Hackett, P.H., Rennie, D., Hofmeister, S.E., Grover, R.F., Grover, E.B. and Reeves, J.T. Fluid retention and relative hypoventilation in acute mountain sickness. Respiration 1982; 43, 321-9. 2. Hackett, P.H., Rennie, D., Grover, RF. and Reeves, J.T. Acute mountain sickness and the edemas of high altitude: a common pathogenesis? Respir Physiol1981; 46, 383-90. 3. Grover, R.F., Reeves, J.T., Maher, J.T., McCullough, RE., Cruz, J.e., Denniston, J.e. and Cymerman, A Maintained stroke volume but impaired arterial oxygenation in man at high altitude with supplemental CO 2 , eirc Res 1976; 38, 391-6. 4. Maher, J.T., Cymerman, A., Reeves, J.T., Cruz, J.C., Denniston, J.e. and Grover, RF. Acute mountain sickness: increased severity in eucapnic hypoxia. Aviat Space Environ Med 1975; 46, 826-9. 5. Hirshman e.A, McCullough RE. and Weil J.V. Normal values for hypoxic and hypercapnic ventilatory drives in man.] Appl Physiol1975; 38, 1095-8. 6. Moore, L.G., Huang, S.Y., McCullough, R.E., Sampson, J.B., Maher, J.T., Weil, J.V., Grover, R.F., Alexander, J.K. and Reeves, J.T. Variable inhibition by falling CO 2 of hypoxic ventilatory response in humans.] Appl Physiol1984; 56, 207-10. 7. Huang, S.Y., Alexander, J.K., Grover, RF., Maher, J.T., McCullough, RE., McCullough, R.G., Moore, L.G., Sampson, J.B., Weil, J.V. and Reeves, J.T. Hypocapnia and sustained hypoxia blunt ventilation on arrival at high altitude.] Appl Physiol1984; 56, 602-6. 8. Moore, L.G., Harrison, G.L., McCullough, R.E., Micco, AJ., Tucker, A, Weil, J.V. and Reeves, J.T. Low acute hypoxic ventilatory response and hypoxic depression in acute mountain sickness. ] Appl Physiol1986; 60, 1407-12. 9. Kawashima, A, Fujimoto, K., Matsuzawa, Y., Fukushima, M., Kubo, K., Levine, B.D., Kobayashi, T. and Kusama, S. Acute mountain sickness in subjects susceptible to high-altitude pulmonary edema. In: Ueda G., Kusama S. and Voelkel N.F., eds. High-Altitude Medical Science (HAMS). Matsumoto, Japan: Shinshu University, 1988: 269-73. 10. Weil, J.V., Kryger, M.H. and Scoggin, e.H. Sleep and breathing at high altitude. In: Guilleminault e. and Dement W.e., eds. Sleep Apnea Syndromes. New York: Alan R Liss, Inc., 1978: 119-36. 11. Matsuzawa, Y., Kobayashi, T., Fujimoto, K., Yamaguchi, S., Shinozaki, S., Kubo, K., Sekiguchi, M., Hayashi, R, Sakai, A and Ueda, G. Nocturnal periodic breathing and arterial oxygen desaturation in acute mountain sickness. J Wild Med 1994: 5, 269-281. 12. Powles, AC.P., Sutton, J.R, Gray, G.W., Mansell, AL., McFadden, M. and Houston, e.S. Sleep hypoxemia at altitude: its relationship to acute mountain sickness and ventilatory responsiveness to hypoxia and hypercapnia. In: Folinsbee L.J., Wagner, J.A, Borgia, J.F., Drinkwater, B.L., Gliner, J.A and Bedi, J.F., eds. Environmental Stress Individual Human Adaptations. New York: Academic Press. 1978: 373-81. 13. Powles, Ae.P. and Sutton, J.R Sleep at altitude. Semin Respir Med 1983; 5, 175-80. 14. Powles, Ae.P. Sleep at altitude. In: Sutton J.R, Jones N.L. and Houston e.S., eds. Hypoxia: Man atAltitude. New York: Thieme-Stratton, Inc., 1982: 182-5. 15. Lahiri, S. and Barnard, P. Role of arterial chemoreflex in breathing during sleep at high altitude. In: Sutton J.R, Houston e.s. and Jones N.L., eds. Hypoxia, Exercise, and Altitude: Proceedings of the Third BanffInternational Hypoxia Symposium. New York: Alan R Liss, Inc., 1983: 75-85. 16. Hackett, P.H., Reeves, J.T., Reeves, e.D., Grover, RF. and Rennie, D. Control of breathing in Sherpas at low and high altitude.] Appl Physiol1980; 49, 374-9. 17. Hackett, P.H. and Rennie, D. Acute mountain sickness. Semin Resp Med 1983; 3,132-9.
EDITORIAL*
To breathe or not to breathe Anyone who has ever had the misfortune of suffering from Acute Mountain Sickness (AMS) would never question the reality of this affliction. During the first night following rapid ascent to high altitude, being awakened from a restless sleep with a splitting headache, followed by a wave of nausea and perhaps vomiting, is an experience never to be forgotten. Of the millions who visit the mountainous regions of the western United States, approximately one person in four will experience AMS; it is very common. AMS strikes those guilty of "going too high too fast," and "too high" is any altitude above 8000 ft (2400 m). In considering the pathogenesis of AMS, the initiating event is unquestionably rapid ascent to high altitude. Unlike decompression sickness in divers, exposure to the decreased atmospheric pressure per se is probably of little consequence at moderate altitude. Rather, it is the associated decrease in the partial pressure of oxygen, i.e., atmospheric hypoxia, that is the culprit. From an evolutionary viewpoint, defenses against hypoxia probably developed to cope with airway obstruction. Impairment of ventilation would result in a fall in airway paz combined with an increase in airway PCO z. The resulting hypoxemia would stimulate the carotid chemoreceptors while, concurrently, hypercapnic acidosis would provide central stimulation. Together, the responses would produce a powerful increase in the effort to breathe. However, when exposed to atmospheric hypoxia, the respiratory control system is presented with a dilemma. Increased ventilation in response to hypoxemia now lowers airway PCO z, and the normal COz stimulus is withdrawn, thereby counteracting the hypoxic stimulus. Hence, "to breathe or not to breathe?" Those who develop AMS seem to favor the "not to breathe" option, for they exhibit less increase in ventilation, i.e., relative hypoventilation, and more severe hypoxemia than do their more fortunate colleagues. Because relative hypoventilation implies not only a greater fall in paz but also less fall in PCO z, the potential role of changes in PCO z in the pathogenesis of AMS should also be considered, as COz relates to the way in which the body handles fluid. Recall that one of the earliest responses following ascent to altitude is a rise in hematocrit. This results from removal of water from the plasma, i.e., hemoconcentration, followed by diuresis. The latter accounts in part for the usual loss of body weight at altitude. It has been observed that persons who have a diuresis and lower body weight are less likely to develop AMS [1]. Conversely, persons who gain weight at altitude, i.e., retain fluid, are more prone to develop not only the usual symptoms of AMS but also more serious manifestations, including high altitude pulmonary edema (HAPE) and cerebral edema (HACE). This has led to the concept that altitude illness, in general, reflects abnormal fluid retention, i.e., "the edemas of altitude" [2]. Fluid retention appears to be linked to changes in COz. We demonstrated that the usual 'Because of a production error, Matsuzawa et a\"s article that was referenced in R. F. Grover's editorial "To breathe or not to breathe" (J Wild Med 1994; 5, 143-145) was not published with it. We regret the error and any inconvenience that it caused. We are printing the editorial and the article in this issue as was intended by the Editors. 0953-9859 © 1994 Chapman & Hall
252
Editorial
hemoconcentration at altitude did not occur if hypocapnia was prevented by adding CO 2 to the atmosphere in a decompression chamber [3]. Furthermore, preventing the fall in PC0 2 also increased the severity of AMS symptoms [4]. Subsequently, we observed among trekkers in Nepal a relative hypoventilation, i.e., higher PC0 2 and lower arterial saturation, and a failure to lose weight (presumably due to fluid retention) in those who developed AMS [1]. Hence, changes in CO 2 as well as in O 2 appear to be determinants of AMS, and both are related to the ventilatory response to high altitude. Just as individual variability is intrinsic to physiological control mechanisms in general, so it is to the control of ventilation. Among individuals, there is a broad spectrum of both hypoxic ventilatory response (HVR) and hypercapnic ventilatory response (HCVR) [5]. This variable chemosensitivity to acute stimuli is reflected in the ventilatory acclimatization to the chronic hypoxia of high altitude. Differences in HVR will provide variable stimulation, whereas differences in HCVR will provide variable inhibition from falling CO 2 [6,7]. The net change in ventilation on ascent will be determined by the relative strengths of these two opposing factors. A weak HVR will permit hypoxemia to persist with minimal fall in PC0l> a combination that favors the development of AMS [8,9]. The dilemma "to breathe (and lessen hypoxia) or not to breathe (and preserve a more normal PC0 2 and pH)" is particularly evident during sleep and is manifest as alternate periods of hyperventilation and apnea, i.e., periodic breathing (PB). This is associated with cyclic variations in arterial O 2 saturation. Although the increases in saturation result from transient hyperventilation, the subsequent declines in saturation are not simply a reflection of the temporary suspension of breathing, as they cannot be reproduced by breath holding while awake [10], although the actual mechanism is unclear. So the question may be asked, does PB with recurring drops in saturation accentuate the greater hypoxemia produced by sleep itself with regular breathing? If this were to occur, PB might then contribute to the severity of AMS. In the present issue of Wilderness Medicine, Matsuzawa et al. [11] have examined this question. They exposed a group of young men to simulated high altitude and sought correlations between the severity of AMS and the degree of arterial desaturation, particularly during sleep, the incidence of PB during sleep, and respiratory chemosensitivity at sea level. They have confirmed previous reports that arterial saturation falls during sleep at altitude [11,12], but the magnitude of desaturation mayor may not correlate with the severity of AMS [12,13]. Further, Kobayashi et al. found that desaturation during sleep correlated with HVR, whereas Powles and Sutton [13] failed to detect such a correlation. However, Kobayashi et al. as well as others [14] found no evidence that PB either accentuated sleep hypoxemia or increased the severity of AMS. Kobayashi et al. also found no correlation between the extent of PB and either HVR or HCVR. Although Lahiri and Barnard [15] reported a correlation between PB and HVR, this pattern depended on the inclusion of a group of highland Sherpas with very low HVR; for the lowlanders sojourning at high altitude, there was no such correlation. Anecdotally, we also observed virtually no PB in Sherpas sleeping at high altitude, even though a larger group of Sherpas had HVR comparable to that of western lowlanders, i.e., not blunted [16]. One final comment should be made on the relationships (or lack of same) between hypoxemia and PB during sleep, severity of AMS, respiratory chemosensitivity, and ventilatory acclimatization to high altitude. Acetazolamide is recognized as being effective in minimizing AMS and HAPE, and of improving the quality of sleep by lessening both hypoxemia and PB [17]. These benefits result in part from the inhibition of carbonic anhydrase, which promotes a bicarbonate diuresis, resulting in a metabolic acidosis
Editorial
253
instead of the usual hypocapnic alkalosis. These observations again emphasize the importance of changes in CO 2 as well as in O 2 in ventilatory acclimatization to high altitude and the pathogenesis of AMS. ROBERT F. GROVER, MD
Arroyo Grande, California
References 1. Hackett, P.H., Rennie, D., Hofmeister, S.E., Grover, R.F., Grover, E.B. and Reeves, J.T. Fluid retention and relative hypoventilation in acute mountain sickness. Respiration 1982; 43, 321-9. 2. Hackett, P.H., Rennie, D., Grover, RF. and Reeves, J.T. Acute mountain sickness and the edemas of high altitude: a common pathogenesis? Respir Physiol1981; 46, 383-90. 3. Grover, R.F., Reeves, J.T., Maher, J.T., McCullough, RE., Cruz, J.e., Denniston, J.e. and Cymerman, A Maintained stroke volume but impaired arterial oxygenation in man at high altitude with supplemental CO 2 , eirc Res 1976; 38, 391-6. 4. Maher, J.T., Cymerman, A., Reeves, J.T., Cruz, J.C., Denniston, J.e. and Grover, RF. Acute mountain sickness: increased severity in eucapnic hypoxia. Aviat Space Environ Med 1975; 46, 826-9. 5. Hirshman e.A, McCullough RE. and Weil J.V. Normal values for hypoxic and hypercapnic ventilatory drives in man.] Appl Physiol1975; 38, 1095-8. 6. Moore, L.G., Huang, S.Y., McCullough, R.E., Sampson, J.B., Maher, J.T., Weil, J.V., Grover, R.F., Alexander, J.K. and Reeves, J.T. Variable inhibition by falling CO 2 of hypoxic ventilatory response in humans.] Appl Physiol1984; 56, 207-10. 7. Huang, S.Y., Alexander, J.K., Grover, RF., Maher, J.T., McCullough, RE., McCullough, R.G., Moore, L.G., Sampson, J.B., Weil, J.V. and Reeves, J.T. Hypocapnia and sustained hypoxia blunt ventilation on arrival at high altitude.] Appl Physiol1984; 56, 602-6. 8. Moore, L.G., Harrison, G.L., McCullough, R.E., Micco, AJ., Tucker, A, Weil, J.V. and Reeves, J.T. Low acute hypoxic ventilatory response and hypoxic depression in acute mountain sickness. ] Appl Physiol1986; 60, 1407-12. 9. Kawashima, A, Fujimoto, K., Matsuzawa, Y., Fukushima, M., Kubo, K., Levine, B.D., Kobayashi, T. and Kusama, S. Acute mountain sickness in subjects susceptible to high-altitude pulmonary edema. In: Ueda G., Kusama S. and Voelkel N.F., eds. High-Altitude Medical Science (HAMS). Matsumoto, Japan: Shinshu University, 1988: 269-73. 10. Weil, J.V., Kryger, M.H. and Scoggin, e.H. Sleep and breathing at high altitude. In: Guilleminault e. and Dement W.e., eds. Sleep Apnea Syndromes. New York: Alan R Liss, Inc., 1978: 119-36. 11. Matsuzawa, Y., Kobayashi, T., Fujimoto, K., Yamaguchi, S., Shinozaki, S., Kubo, K., Sekiguchi, M., Hayashi, R, Sakai, A and Ueda, G. Nocturnal periodic breathing and arterial oxygen desaturation in acute mountain sickness. J Wild Med 1994: 5, 269-281. 12. Powles, AC.P., Sutton, J.R, Gray, G.W., Mansell, AL., McFadden, M. and Houston, e.S. Sleep hypoxemia at altitude: its relationship to acute mountain sickness and ventilatory responsiveness to hypoxia and hypercapnia. In: Folinsbee L.J., Wagner, J.A, Borgia, J.F., Drinkwater, B.L., Gliner, J.A and Bedi, J.F., eds. Environmental Stress Individual Human Adaptations. New York: Academic Press. 1978: 373-81. 13. Powles, Ae.P. and Sutton, J.R Sleep at altitude. Semin Respir Med 1983; 5, 175-80. 14. Powles, Ae.P. Sleep at altitude. In: Sutton J.R, Jones N.L. and Houston e.S., eds. Hypoxia: Man atAltitude. New York: Thieme-Stratton, Inc., 1982: 182-5. 15. Lahiri, S. and Barnard, P. Role of arterial chemoreflex in breathing during sleep at high altitude. In: Sutton J.R, Houston e.s. and Jones N.L., eds. Hypoxia, Exercise, and Altitude: Proceedings of the Third BanffInternational Hypoxia Symposium. New York: Alan R Liss, Inc., 1983: 75-85. 16. Hackett, P.H., Reeves, J.T., Reeves, e.D., Grover, RF. and Rennie, D. Control of breathing in Sherpas at low and high altitude.] Appl Physiol1980; 49, 374-9. 17. Hackett, P.H. and Rennie, D. Acute mountain sickness. Semin Resp Med 1983; 3,132-9.