Introduction
Overview
Acute mountain sickness (or altitude sickness) affects climbers who rapidly ascend to heights of at least 2500 meters (8200 feet). The symptoms of acute mountain sickness include headache, fever, fatigue, nausea, dizziness, anorexia, and sleep disturbances. This article describes the management of acute mountain sickness. Acetazolamide, which reduces the formation of CSF, is the main drug therapy, and additional drugs include nonsteroidal antiinflammatory drugs for headache and dexamethasone for cerebral edema. Oxygen inhalation at 1 L/minute and descent to lower altitudes are recommended.
Key points
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• Acute mountain sickness occurs after ascent to an altitude of at least 2500 meters (8200 feet). |
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• Symptoms include headache, fever, fatigue, nausea, dizziness, anorexia, and sleep disturbances. |
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• If symptoms are not relieved, or with further ascent, cerebral and pulmonary edema may occur. |
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• Treatment is medical, with supplementary oxygen therapy. |
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• If symptoms persist, the affected person should descend to a lower altitude. |
Historical note and terminology
There are two well-known high-altitude syndromes: (1) acute mountain sickness, which occurs within a few hours to a few days at high altitude; and (2) chronic mountain sickness, also called Monge disease, which develops after several years of residence at high altitude (100). Acute mountain sickness (or altitude sickness) affects climbers or other individuals who rapidly ascend to heights of at least 2500 m (8200 ft). Some of the highest mountain passes that can be reached by motorized vehicles contain warnings to individuals regarding the risk of acute mountain sickness.
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Chang La pass, Ladakh in the Himalayan mountains of northern India on the world's "highest motorable road" (5360 m or 17586 ft)
Photograph by Anirvan Shukla on September 28, 2013. (Creative Commons Attribution-Share Alike 3.0 Unported License, https://creativecommons.org/licenses/by-sa/3.0/deed.en.)
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Altitude sickness warning at Chang La pass, Ladakh
Photography by Sistak on August 21, 2009. (Creative Commons Attribution-Share Alike 2.0 Generic License, https://creativecomm ons.org/licenses/by-sa/2.0/deed.en. Photograph edited by Dr. Douglas J Lanska.)
Acute mountain sickness may develop into high-altitude pulmonary edema or high-altitude cerebral edema, but it is still unclear whether these share a common pathophysiology. A subacute form of mountain sickness was described in Indian soldiers in Kashmir who developed pulmonary hypertension and congestive heart failure within a few months of living at altitudes of 5800 to 6700 m (19,000-22,000 ft) (02).
Early reports of high-altitude illness. The first documented report of mountain sickness was reportedly by a Chinese official, Too-Kin, between 37 and 32 BC when he encountered difficulties crossing the Kilik Pass (4827 m; 15840 ft) into what is present-day Afghanistan (52). He described headache and vomiting and gave names such as "the Great Headache Mountain" and "the Little Headache Mountain" to the mountains on his route. In the year 403, a Chinese man crossing into Kashmir, a companion of the Chinese Buddhist monk Fa Hsien (337–c 422 CE; also referred to as Faxian, Fa-Hien, Fa-hsien, and Sehi), died with difficulty in breathing and foam at his mouth, a condition now recognized as high-altitude pulmonary edema (52). Similar cases were described by the Spanish Jesuit missionary Father José de Acosta (1539 or 1540–1600) in 1590 in the high Andes of Peru (01).
José de Acosta (1539-1600)
(Courtesy of Wikimedia Commons. Public domain. Figure restored and edited by Dr. Douglas J Lanska.)
Beginnings of high-altitude medicine. High-altitude physiology and the study of acute and chronic mountain sickness was pioneered by a series of European physiologists from France, Italy, and Great Britain, particularly beginning in the last quarter of the 19th century.
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Apparatus for the experimental study of mountain sickness
(Source: Regnard P La Cure d'Altitude. 2nd edition. Paris: Masson et cie, 1898. Figure edited by Dr. Douglas J Lanska.)
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Pressure room (Sorbonne Physiology Laboratory)
(Source: Regnard P La Cure d'Altitude. 2nd edition. Paris: Masson et cie, 1898. Figure edited by Dr. Douglas J Lanska.)
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Experimental hypobaric chamber or altitude chamber
This experimental hypobaric chamber was used to simulate the effects of high altitude on a dog, especially hypoxia (low oxygen) and hypobaria (low ambient air pressure). (Source: Regnard P La Cure d'Altitude. 2nd edition. Paris...
In 1877, French physiologist Paul Bert (1833–1886), acknowledged as a pioneer in the investigation of the effects of atmospheric pressure on body function, recognized hypoxia as the cause of altitude sickness (13). French physician and physiologist Denis Jourdanet (1815–1892) spent many years in Mexico studying the effects of high altitude (133).
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French zoologist, physiologist, and politician Paul Bert (1833-1866) self-experimenting with hypoxia
Bert is often called the father of high-altitude physiology. Bert provided the first clear statement that the harmful effects of high altitude are caused by the low partial pressure of oxygen in his book La pression barométriq...
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French physician and physiologist Denis Jourdanet (1815-1892) in 1866
Photogravure, after a photograph. Jourdanet spent many years in Mexico studying the effects of high altitude. (West JB, Richalet JP. Denis Jourdanet [1815-1892] and the early recognition of the role of hypoxia at high altitude....
Italian physiologist Angelo Mosso. In 1894, Italian physiologist Angelo Mosso (1846–1910) was among the first to conduct serious and systematic investigations at high altitude. Mosso led a series of scientific expeditions in which he and his colleagues studied many aspects of high-altitude physiology using remarkably simple, though effective, tools. Among these included an experiment performed by his brother, Ugolino Mosso (1854–1909), to measure the quantity of carbonic acid eliminated in half an hour by a medical student. Mosso documented a case of mountain illness at an altitude of 4559 m (14,960 ft) in the Italian Alps bordering Switzerland and was probably the first to record periodic breathing at high altitude (101).
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Italian physiologist Angelo Mosso (1846-1910)
In 1898, Mosso documented a case of mountain illness at an altitude of 4559 m (14960 ft) on the Italian Alps bordering Switzerland (Source: Academy of Sciences of Turin via Wikimedia Commons. Public domain. Figure restored and ...
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Gas-meter, valves, and gutta-percha mask for measurement of the amount of air inspired
Gutta percha is a plastic substance from a Malaysian tree called a percha tree. (Source: Mosso A. Life of man on the high Alps. Kiesow EL, trans. London: T Fisher Unwin, 1898.)
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Roman balance used on the Monte Rosa expedition
(Source: Mosso A. Life of man on the high Alps. Kiesow EL, trans. London: T Fisher Unwin, 1898.)
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Experiment to measure the quantity of carbonic acid eliminated in half an hour
Image depicts an experiment performed by Italian Professor Ugolino Mosso (1854-1909) at the Regina Margherita Hut to measure the quantity of carbonic acid eliminated in half an hour by a medical student, Beno Bizzozero. (Source...
Mosso's experiments with "rarefied air." Mosso performed experiments on the cerebral circulation, including experiments on two boys who had sustained head injuries. Mosso concluded that "[a]rtificial air, owing to its rarefaction, produces the same effects as those due to a diminution of barometric pressure. We may, therefore, conclude that mountain-sickness is not caused by the mechanical action or the diminished weight of the atmosphere, but by its rarefaction, which acts chemically on the metabolism of the nervous system" (101).
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Cerebral pulse of the boy Cesare Lasagno
Cesare Lasagno, a 14-year-old blacksmith's apprentice, had sustained a wound to the middle of his forehead and a skull fracture after falling from the second story while leaning on his stomach over the bannisters, and "sliding ...
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Emanuele Favre da Bramans (Savoy) with his brain exposed due to an ax blow
Emanuel Favre, a 13-year-old boy had been accidentally struck in the head with an axe while "helping his master to chop wood ... by laying the branches on the block, he had bent too far forwards and the axe of the master struck...
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Emanuel Favre shown with apparatus to register the "cerebral pulse during the respirator of artificial air."
(Source: Mosso A. Life of man on the high Alps. Kiesow EL, trans. London: T Fisher Unwin, 1898:248. Public domain.)
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Circulation of the blood in the brain of the boy Emanuel Favre
Emanuel Favre, a 13-year-old boy had been accidentally struck in the head with an axe while "helping his master to chop wood ... by laying the branches on the block, he had bent too far forwards and the axe of the master struck...
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Continuation of the experiment on circulation of the blood in the brain of the boy Emanuel Favre
C (Top): Cerebral pulse immediately after the subject stopped breathing the artificial air. D (Bottom): Curve registered 2 minutes later. (Source: Mosso A. Life of man on the high Alps. Kiesow EL, trans. London: T Fisher Unwin,...
Mosso's high-altitude physiology laboratory at Capanna Regina Margherita. To facilitate his studies, Mosso established a simple high-altitude laboratory at Capanna Regina Margherita (Queen Margherita Hut). The construction of this high-altitude hut on Monte Rosa, in Italian territory near the international border between Italy and Switzerland, had been directed by the Italian Alpine Club in 1889. The hut was prebuilt in the valley, then brought part of the way by mule and the remainder by mountaineers, before being assembled at an onsite mountain hut for alpinists. It was opened in 1893 in the presence of Margherita of Savoy (1851–1926), Queen of Italy, a dedicated mountaineer to whom the hut is dedicated. The hut soon became an important research center for Mosso's studies of high-altitude medicine. A new hut, built around 1898, was also used by Mosso and various colleagues. Then, because the hut was quite small, a newer, lower-altitude research center ("Istituto Mosso") was built near the Salati Pass, in Valsesia Valley (Alagna Valsesia), in 1907 at an elevation of about 2900 meters (9500 ft). The prior Margherita Hut was dismantled in the late 1970s and was replaced in 1980 by the current hut on the summit of Punta Gnifetti, a subpeak of Monte Rosa. At 4554 m (14,940 ft), it is the highest building in Europe. The hut continues to serve as a research station for high-altitude medicine, but it also serves as a simply equipped.
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Construction of the Regina Margherita hut
(Source: Zuntz N, Loewy A, Müller F, Caspari W. Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen : Ergebnisse experimenteller Forschungen im Hochgebirge und Laboratorium. Berlin: Bong & Co., 1906. Public do...
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Apparatus with lever (kymograph) for the tracing of the respiratory movements
The circle beneath the lever represents theoretically the section of the thorax. (Source: Mosso A. Life of man on the high Alps. Kiesow EL, trans. London: T Fisher Unwin, 1898:32. Public domain.)
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A "hydro-sphygmograph" for transferring a radial pulse through a water jacket around the arm to a kymograph recording device
(Source: Mosso A. Life of man on the high Alps. Kiesow EL, trans. London: T Fisher Unwin, 1898:53. Public domain.)
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"A corner of the alpine laboratory" showing various physiological instruments
(Source: Mosso A. Life of man on the high Alps. Kiesow EL, trans. London: T Fisher Unwin, 1898:191. Public domain.)
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Drawing of the new Regina Margherita Observatory constructed in 1898 on the summit of Monte Rosa (4560 m or 14,960 ft)
Regina Margherita Observatory was used for studies of high-altitude physiology by Italian physiologist Angelo Mosso (1846-1910) and colleagues. Drawing by an engineer, Girola. (Source: Mosso A. Life of man on the high Alps. Kie...
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Capanna Regina Margherita in 1903
(Source: A Mosso: Das internationale physiologische Laboratorium auf dem Monte Rosa. In: Die Umschau 8, 1904, S 5-9. Public domain.)
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Capanna Margherita in the Italian Alps
Capanna Margherita continues to be used for research in high-altitude medicine. Aerial photograph taken on February 28, 1995. (Photo credits: ETH Library Zurich, photo archive/Stiftung Luftbild Schweiz. Photographer: Swissair P...
The 1911 Anglo-American Expedition to Pikes Peak. The most important high-altitude expedition of the early 20th century was the 1911 Anglo-American Expedition to Pikes Peak, which included British physiologists John S Haldane FRS (1860–1936) and Claude Gordon Douglas (1882–1963) from Oxford; Yandell Henderson (1873–1944), Professor of Physiology at Yale University Medical School; and Edward Christian Schneider (1874–1954), Professor of Biology at Colorado College (in Colorado Springs, Colorado). At the time, Haldane was already famous for his intrepid self-experimentation, which led to many important discoveries about the nature of gases and their effects on the human body. Pikes Peak, just outside Colorado Springs, was an excellent site because of its substantial altitude of 4300 m (14,100 ft), convenient access via a cog railway, and comfortable living accommodation (132). Measurements were first made at sea level, then on the summit for 5 weeks, and then again at sea level.
British physician and physiologist John S Haldane FRS (1860-1936) in 1920
Haldane was famous for his intrepid self-experimentation, which led to many important discoveries about the nature of gases and their effect on the human body. Half-length photograph, seated at desk, full face. Interior view of...
The wide range of studies conducted during the expedition included descriptions of acute mountain sickness, studies of the hemoglobin dissociation curve at high altitude, assessments of the volume and gas content of exhaled air at rest and with varying intensity of exercise at high altitude, studies of periodic breathing, and studies of the cardiac response to high altitude (and hypoxia) (39). They also showed (in an appendix) the observations made by J Richards, Mining Engineer, concerning the increase of hemoglobin percentage at a high altitude in Bolivia. One error was the conclusion that the arterial P(O(2)) could considerably exceed the alveolar value, implying oxygen secretion by the lung (132).
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Interior of laboratory for the 1911 Anglo-American Expedition to Pikes Peak
Alveolar CO2 pressure (thick line); alveolar O2 pressure (thin line). Horizontal interrupted lines represent the mean normal alveolar CO2 and oxygen pressures at sea level (ie, Oxford and New Haven). (Source: Douglas CG, Haldan...
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Hemoglobin dissociation curve from the 1911 Anglo-American Expedition to Pikes Peak
The continuous line represents the dissociation curve of oxyhemoglobin in the blood of British physiologist Claude Gordon Douglas (1882-1963) and John Scott Haldane, determined in Oxford in the presence of 40 mm pressure of CO2...
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Alveolar CO2 and O2 pressures as a function of altitude from the 1911 Anglo-American Expedition to Pikes Peak
(Thick line) alveolar CO2 pressure; (thin line) alveolar O2 pressure; (horizontal interrupted lines) mean normal alveolar and oxygen pressures at sea level (ie, Oxford and New Haven, Connecticut). Measurements for Claude Gordon...
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Determination of the total respiratory exchange while walking on a section of flat ground between railroad rails from the 1911 Anglo-American Expediti...
C Gordon Douglas is shown breathing into a "Douglas bag." Historically, gas exchange was measured by the "Douglas bag method," which involved collecting exhaled air in large, impermeable canvas bags from which gas fractions and...
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Determination of the total respiratory exchange while walking on the highest portion of the 1-in-4 grade on the cog railway from the 1911 Anglo-Americ...
C Gordon Douglas is shown breathing into a "Douglas bag." (Source: Douglas CG, Haldane JS, Henderson Y, Schneider EC. Physiological observations made on Pike's Peak, Colorado, with special reference to adaptation to low baromet...
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Response of high-altitude periodic breathing to administration of oxygen during the 1911 Anglo-American Expedition to Pikes Peak
July 16, 1911. Subject: John Scott Haldane. Natural periodic breathing abolished by administration of oxygen. Reappearance of periodic breathing on withdrawing the oxygen. Subject breathing through valves throughout. (Source: D...
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Rates of oxygen consumption with exercise at high altitude during the 1911 Anglo-American Expedition to Pikes Peak
(x, continuous line) Experiments on Pikes Peak; (filled circle, interrupted line) experiments in Oxford, grass track; (dotted circle, dotted line) experiments in Oxford, laboratory. (Source: Douglas CG, Haldane JS, Henderson Y,...
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Apparatus arrangement to determine total respiratory exchange after cessation of work in the 1911 Anglo-American Expedition to Pikes Peak
Arrangement of apparatus for determining the total respiratory exchange at different intervals after the cessation of work at high altitude. Tubes are connected to four separate Douglas bags. (Source: Douglas CG, Haldane JS, He...
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Recoil apparatus to measure systolic discharge of the heart from the 1911 Anglo-American Expedition to Pikes Peak
Recoil apparatus to measure systolic discharge of the heart consists of a plank supported on rubber stoppers. The recording lever magnifies the recoil movements 60 times. (Source: Douglas CG, Haldane JS, Henderson Y, Schneider ...
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Total oxygen capacity and total amount of hemoglobin over time in response to changes in altitude during the 1911 Anglo-American Expedition to Pikes P...
Ordinates represent percentages of the average values obtained before ascending the Peak (Oxford and Colorado Springs) on the particular subject. The continuous thick line represents the total oxygen capacity or total amount of...
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Increase of hemoglobin percentage at a high altitude in Bolivia
Observations by J Richards, Mining Engineer. (Source: Douglas CG, Haldane JS, Henderson Y, Schneider EC. Physiological observations made on Pike's Peak, Colorado, with special reference to adaptation to low barometric pressures...
British physiologist and clinical pathologist Mabel FitzGerald (1872–1973) was invited to be a member of the expedition but did not join the men on the summit. Instead, she visited various mining camps in Colorado at lower altitudes where she conducted classic studies of alveolar gas partial pressures and hemoglobin values (46; 45; 130; 132; 54; 129; 128).
Nathan Zuntz. German physiologist Nathan Zuntz (1847–1920) was a pioneer of modern altitude physiology and aviation medicine. For his high-altitude respiratory physiology experiments, and particularly for studies of hypoxia, Zuntz utilized a pneumatic chamber of the Jewish Hospital in Berlin (146). In 1885, Zuntz and German physician and pharmacologist August Julius Geppert (1856–1937) invented a respiratory gas analyzer, the Zuntz-Geppert'schen Respirationsapparat (Zuntz-Geppert respiratory apparatus).
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Sir Joseph Barcroft
(Source: Mascart J. Impressions et observations dans un voyage à Tenerife, Paris: Flammarion, 1912. Wellcome Collection. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. I...
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Pneumatic chamber of the Jewish Hospital in Berlin
(Krankenhaus der jüdischen Gemeinde zu Berlin.)
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German physician and pharmacologist August Julius Geppert (1856-1937)
(Source: Pagel J. Biographisches Lexikon hervorragender Ärzte des neunzehnten Jahrhunderts: Mit einer historischen einleitung. Berlin: Urban & Schwarzenberg, 1901. Public domain.)
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Zuntz-Geppert gas analyzer apparatus
The recording and sampling apparatus is shown on the left and the air analysis apparatus at the right. (Source: Zuntz N, Loewy A, Müller F, Caspari W. Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen : Ergebnis...
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Zuntz-Geppart apparatus for gas analysis (schematic diagram)
(Source: Carpenter TM. A Comparison of methods for determining the respiratory exchange of man. Washington, DC: The Carnegie Institution of Washington, 1915:56. Public domain.)
From 1893, many of his field studies were conducted at the Capanna Regina Margherita international research station at the apex of Monte Rosa, Italy, where he worked with German physiologist Adolf Loewy (1862–1936), Italian physiologist Angelo Mosso (1846–1910), and Austrian Arnold Durig (1872–1961) (56). For his field studies, Zuntz devised a portable gas exchange measuring device (Gasuhr) that he sometimes combined with a portable kymograph for simultaneous registration of pulse and respiratory movements (146)
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Zuntz's portable dry gas meter with gas collection tube
A gas exchange measuring device. (Source: Zuntz N, Loewy A, Müller F, Caspari W. Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen : Ergebnisse experimenteller Forschungen im Hochgebirge und Laboratorium. Berlin...
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German physiologist Adolf Loewy (1862-1936), marching with Zuntz portable gas exchange measuring device
Loewy, ready to begin marching with the Zuntz portable gas exchange measuring device. (Source: Zuntz N, Loewy A, Müller F, Caspari W. Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen: Ergebnisse experimenteller...
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German physiologist Adolf Loewy (1862-1936) using Zuntz portable gas meter
German physiologist Adolf Loewy (1862-1936) shown combining measurement of respiration with the Zuntz portable gas meter with simultaneous registration of pulse and respiratory movements using a kymograph. (Source: Zuntz N, Loe...
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Top view of the portable gas meter
(Source: Zuntz N, Loewy A, Müller F, Caspari W. Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen : Ergebnisse experimenteller Forschungen im Hochgebirge und Laboratorium. Berlin: Bong & Co., 1906. Public do...
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Zuntz's apparatus using a kymograph for recording respiratory movements
(Source: Zuntz N, Loewy A, Müller F, Caspari W. Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen : Ergebnisse experimenteller Forschungen im Hochgebirge und Laboratorium. Berlin: Bong & Co., 1906. Public do...
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Gradual transition of breathing to the Cheyne-Stokes form (according to Mosso)
(Source: Zuntz N, Loewy A, Müller F, Caspari W. Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen : Ergebnisse experimenteller Forschungen im Hochgebirge und Laboratorium. Berlin: Bong & Co., 1906. Public do...
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High-altitude physiological instruments, including the Zuntz portable gas meter at left
(Source: Zuntz N, Loewy A, Müller F, Caspari W. Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen : Ergebnisse experimenteller Forschungen im Hochgebirge und Laboratorium. Berlin: Bong & Co., 1906. Public do...
With his assistant, Austrian physiologist Hermann von Schrötter (1870–1928) and German meteorologists Arthur Berson (1859-1942) and Reinhard Süring (1866–1950), he made two high-altitude balloon ascents that reached an altitude of 5000 meters in 1902.
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German meteorologist Arthur Berson (1859-1942)
(Source: Emden R. Illustrierte aeronautische Mitteilungen. Deutsche Zeitschrift für Luftschiffahrt. Fachzeitschrift für alle Interessen der Flugtechnik mit ihren Hülfswissenschaften, für aeronautische Industrie und Unternehmung...
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German meteorologist Reinhard Süring (1866-1950)
(Source: Hildebrandt A. Die Luftschiffahrt nach ihrer geschichtlichen und gegenwärtigen Entwicklung. München and Berlin: R. Oldenbourg, 1907. Public domain.)
In 1906, Zuntz published a classic monograph that summarized his high-altitude research: Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen (High-Altitude Climate and Mountaineering and their Effect on Humans) (146).
In 1910, Zuntz participated in a scientific expedition to the Pico de Teide volcano (summit at 3715 m or 12,188 ft) in the Canary Islands with Schrötter and Austrian physiologist Arnold Durig (1872–1961) and British physiologist Joseph Barcroft (1872–1947).
Participants of an expedition to Teneriffa, including Austrian physiologist Arnold Durig (1872-1961), British physiologist Sir Joseph Barcroft FRS (18...
Back row from left to right: British respiratory physiologist Claude Gordon Douglas FRS (1882-1963), German biochemist Carl Neuberg (1877-1956), French astronomer and mathematician Jean Mascart (1872-1935; at Tenerife to observ...
High-altitude studies of Sir Joseph Barcroft FRS in Peru 1921–1922. British physiologist Sir Joseph Barcroft FRS (1872–1947) is best known for his studies at high altitude and the oxygenation of blood (133; 86).
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British physiologist Sir Joseph Barcroft FRS (1872-1947)
Barcroft is best known for his studies at high altitude and the oxygenation of blood (West 2013; Longo 2016).
References:
West JB. Joseph Barcroft's studies of high-altitude physiology. Am J Physiol Lung Cell...
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German physiologist Nathan Zuntz (1847-1920) in 1910
(Source: Mascart J. Impressions et observations dans un voyage à Tenerife. Paris: Ernest Flammarion, 1912. Public domain.)
In the winter of 1921 to 1922, Barcroft and colleagues made observations on the effect of high altitude on the physiological processes of the human body, which were carried out in the Peruvian Andes, chiefly at Cerro de Pasco (07). They studied the relation of oxygen pressure in alveolar air to that in arterial blood at different altitudes for different members of the expedition, documenting fairly marked oxygen desaturation in the blood at 14,200 feet compared to results at sea level, as well as considerable interindividual variation at high altitude. Barcroft documented a rapid rise in the concentration of red blood cells while expedition members were at high altitude but then a return to baseline levels after return to sea level. At high altitudes, a "trifling amount" of exercise dramatically increased blood flow. At high altitudes, exercise caused a precipitous drop in oxygen saturation of the blood, or what Barcroft termed a "descent of position of utilisation in [the] oxygen dissociation curve when muscular work was undertaken." One factor that complicated assessments was that blood volume changed in a complicated fashion that seemed to be related to ambient temperature: when expedition members passed through tropical climes to and from Peru, their blood volumes increased by about 1.5 liters when their vascular beds expanded (ie, from cutaneous vasodilation).
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Fingers somewhat "clubbed" in natives, unassociated with cardiac or pulmonary lesions
(Source: Barcroft J, Binger CA, Bock AV, et al. Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pasco. Philos Trans R Soc Lo...
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Cabin on S.S. "Victoria" converted into laboratory
(Source: Barcroft J, Binger CA, Bock AV, et al. Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pasco. Philos Trans R Soc Lo...
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View of mobile laboratory made from luggage car on Central Railway of Peru (1)
(Source: Barcroft J, Binger CA, Bock AV, et al. Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pasco. Philos Trans R Soc Lo...
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View of mobile laboratory made from luggage car on Central Railway of Peru (2)
(Source: Barcroft J, Binger CA, Bock AV, et al. Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pasco. Philos Trans R Soc Lo...
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Relation of oxygen pressure in alveolar air (°) to that in arterial blood (x) at different altitudes (Meakins)
(Source: Barcroft J, Binger CA, Bock AV, et al. Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pasco. Philos Trans R Soc Lo...
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Relation of oxygen pressure in alveolar air to that in arterial blood (x) at different altitudes for different members of the expedition
(Source: Barcroft J, Binger CA, Bock AV, et al. Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pasco. Philos Trans R Soc Lo...
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Increase in red blood corpuscles while several expedition members were at high altitude
Increase in red blood corpuscles (millions per ml. of blood) while several expedition members were at high altitude (center peaks). The vertical lines represent the dates on which the party left and returned to Lima, Peru (505 ...
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Reticulated cells in Bock's blood over time as a function of altitude
(1000s per ml. of blood) (Source: Barcroft J, Binger CA, Bock AV, et al. Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pas...
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Blood flow (liters per minute.) over time as a function of rest or exercise
(Source: Barcroft J, Binger CA, Bock AV, et al. Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pasco. Philos Trans R Soc Lo...
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Meakins' curves showing descent of position of utilization in oxygen dissociation curve when muscular work was undertaken by Meakins at 14,200 feet
(Source: Barcroft J, Binger CA, Bock AV, et al. Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pasco. Philos Trans R Soc Lo...
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Blood volume for different members of the expedition over time
Note that each individual has their own portion of the y-axis (on either the right or left side). The increase was about 1.5 liters and the peak corresponded to passing through tropical climes, when their vascular beds expanded...
Clinical manifestations
Presentation and course
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• Initial symptoms of acute mountain sickness are headache, fever, fatigue, nausea, dizziness, anorexia, and sleep disturbances. |
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• If untreated, acute mountain sickness may proceed to high-altitude cerebral edema or high-altitude pulmonary edema. |
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• Chronic mountain sickness manifests by hypoxemia, polycythemia, high hemoglobin levels, and migraine headaches in permanent residents at altitudes above 4000 m (approximately 13,000 ft). |
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• Acute mountain sickness is usually a benign condition, but the more advanced forms can be accompanied by severe morbidity and death. |
High-altitude illness has protein manifestations, including high-altitude headache, acute mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema (67). Although high-altitude headache and acute mountain sickness are comparatively benign, high-altitude pulmonary edema and high-altitude cerebral edema may be fatal if not promptly addressed with emergent descent to a lower altitude and institution of supportive and corrective therapy (66).
Symptoms of acute mountain sickness. Common symptoms of acute mountain sickness include headache, fever, fatigue, nausea, dizziness, anorexia, and sleep disturbances. These are observed with a rapid ascent to 2500 m (8200 ft) or higher. Acute mountain sickness without headache has been reported at an altitude of below 3000 m (approximately 10,000 ft) and can be triggered by chronic stress or excessive exertion (44). Similar symptoms may be observed during high-altitude flights if the cabins are not adequately pressurized. If untreated, acute mountain sickness may progress to high-altitude pulmonary edema or high-altitude cerebral edema.
High-altitude pulmonary edema. Symptoms of high-altitude pulmonary edema include dyspnea and dry cough that changes to productive cough. Signs include tachycardia, cyanosis, and pink-tinged frothy sputum. High-altitude pulmonary edema is diagnosed in the presence of at least two of four symptoms (dyspnea at rest, cough, weakness or decreased exercise performance, chest tightness or congestion) and two of four signs (crackles or wheezing in at least one lung field, central cyanosis, tachypnea, or tachycardia).
Physical examination reveals rales on chest auscultation, the “high-altitude pulmonary edema tongue” or "HAPE tongue," very low pulse oximetry (SpO2), and, in advanced cases, bloody sputum (143; 144). The so-called "high-altitude pulmonary edema tongue" is white with irregularly distributed bright red areas suggesting local desquamation (143; 144). Although not always present, it can be seen in both children and adults and may resemble lingual changes with some viral infections, including COVID-19 (143; 144). These lingual features are highly suggestive of high-altitude pulmonary edema, especially in someone just arriving at high altitude who presents with cough (144).
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Child with HAPE tongue (local desquamation with irregularly distributed bright red areas) at 3500 m (1)
HAPE: high-altitude pulmonary edema. (Source: Zubieta-Calleja G, Zubieta-DeUrioste N. The oxygen transport triad in high-altitude pulmonary edema: a perspective from the high Andes. Int J Environ Res Public Health 2021;18[14]:7...
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Child with HAPE tongue (local desquamation with irregularly distributed bright red areas) at 3500 m (2)
HAPE: high-altitude pulmonary edema. (Source: Zubieta-Calleja G, Zubieta-DeUrioste N. The oxygen transport triad in high-altitude pulmonary edema: a perspective from the high Andes. Int J Environ Res Public Health 2021;18[14]:7...
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Child with HAPE tongue (local desquamation with irregularly distributed bright red areas) at 3500 m (3)
Oxygen is being delivered by nasal cannula. HAPE: high-altitude pulmonary edema. (Source: Zubieta-Calleja G, Zubieta-DeUrioste N. The oxygen transport triad in high-altitude pulmonary edema: a perspective from the high Andes. I...
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Adult with HAPE tongue (local desquamation with irregularly distributed bright red areas) at 3500 m
Oxygen is being delivered by nasal cannula. HAPE: high-altitude pulmonary edema. (Source: Zubieta-Calleja G, Zubieta-DeUrioste N. The oxygen transport triad in high-altitude pulmonary edema: a perspective from the high Andes. I...
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Child with HAPE tongue (local desquamation with irregularly distributed bright red areas) at 3500 m (4)
Before treatment (top): oxygen is being delivered by nasal cannula. After treatment (bottom): the lingual abnormalities have resolved, and the child no longer required supplemental oxygen. HAPE: high-altitude pulmonary edema. (...
High-altitude cerebral edema. In 1975, a cerebral form of mountain sickness in which cerebral edema predominated was described in a series of patients (68). Although some degree of pulmonary edema is present in high-altitude cerebral edema, it is overshadowed by more dramatic neurologic symptoms. High-altitude cerebral edema is characterized by a change in mental status or the development of ataxia in a person with acute mountain sickness (138). The clinical manifestations include severe headaches, ataxic gait, hallucinations, cranial nerve palsies, hemiplegia, and seizures. Impairment of consciousness may occur, ranging from drowsiness to coma. Neurologic symptoms can progress from mild symptoms to unconsciousness within 12 to 72 hours. Seizures may occur at high altitude without any clinical evidence of acute mountain sickness. Transient focal neurologic signs may manifest at high altitude without associated acute mountain sickness or other concurrent illness. Marked hyperventilatory response to hypoxia can cause hypocapnic cerebral vasoconstriction that leads to localized areas of cerebral ischemia resulting in transient focal neurologic impairment.
Chronic mountain sickness. Chronic mountain sickness is manifested by hypoxemia, polycythemia, high hemoglobin levels, and headaches in those who live permanently in altitudes above 4000 m (approximately 13,000 ft). Among 54 men living permanently at high altitude (5100 m), lower nocturnal oxygen saturation (SpO2) and higher nocturnal blood pressure variability were associated with the severity of chronic mountain sickness (108). Cardiovascular complications of living at very high altitude include pulmonary hypertension, right heart enlargement, and congestive heart failure. These patients usually have cognitive impairment.
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Stratification of nocturnal oxygen saturation (SpO2) in highlanders at 5,100 m according to chronic mountain sickness (CMS) status
Nocturnal SpO2 levels are calculated from nocturnal pulse oximetry recordings and represent the percentage of recording time spent at a specific SpO2 value. The percentage of total recording time with a Sp...
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Stratification of nocturnal SpO2 in healthy subjects according to the altitude of residency
Nocturnal SpO2 levels are calculated from nocturnal pulse oximetry recordings and represent percentage of recording time spent at a given SpO2 value. Distribution of SpO2 during the night differ...
Prognosis and complications
Acute mountain sickness is usually a relatively benign condition, but the more advanced forms with high-altitude cerebral edema and high-altitude pulmonary edema can be accompanied by severe morbidity, and death may result if prompt treatment is not instituted. Those who survive a comatose state from high-altitude cerebral edema may have memory and gait deficits that persist for months.
Biological basis
Etiology and pathogenesis
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• Acute mountain sickness is caused by an ascent to high altitude without sufficient acclimatization. |
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• Hypoxia is a contributing factor in the pathogenesis of acute mountain sickness. |
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• High-altitude cerebral edema is likely due to vasogenic as well as cytotoxic mechanisms, and venous hypertension is a possible contributory factor. |
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• Cerebral edema increases peripheral sympathetic activity that acts neurogenically in the lungs to cause high-altitude pulmonary edema. |
Physiologic responses to high altitude. Partial pressure of oxygen of inspired air (PIO2) can be expressed in terms of the fraction of inspired oxygen (FIO2), the barometric pressure (PB), and water vapor pressure (47 mmHg): PIO2 = FIO2 × (PB – 47 mmHg), or 0.21 × (760 – 47) = 149 mmHg at sea level. Atmospheric pressure decreases with altitude whereas the O2 fraction remains constant to about 85 km (53 mi), so PIO2 also decreases with altitude. In fact, barometric pressure and PIO2 decrease exponentially with increasing altitude. PIO2 is about half of the sea level value at 5500 m (18,000 ft), the altitude of the Mount Everest base camp, and less than a third at 8849 m (29,032 ft), the summit of Mount Everest.
Barometric pressure-to-altitude relationship showing important high-altitude landmarks
Important high-altitude landmarks: the cities of Denver (1610 m or 5280 ft) and La Paz (3100 to 4100 m or 10,200 to 13,500 ft); Mount Chacaltaya (5270 m or 17,290 ft); Mount Sajama (6542 m or 21,463 ft; the highest Bolivian mou...
Although the hemoglobin dissociation curve is fairly flat at lower elevations, a climber moves onto the steep portion of the curve at higher elevations, so much less oxygen can be transported to tissues. On the "plateau" portion of the oxyhemoglobin dissociation curve, there is a minimal reduction of oxygen transported; this range extends until the PIO2 falls to approximately 50 mmHg. In contrast, on the "steep" portion of the oxyhemoglobin dissociation curve, a small change in PIO2 causes a marked change in the oxygen-carrying capacity of the blood.
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Hemoglobin dissociation curve showing different PaO2-SpO2 levels at sea level, in Bolivia, and atop Mount Everest
(Source: Zubieta-Calleja G, Zubieta-DeUrioste N. The oxygen transport triad in high-altitude pulmonary edema: a perspective from the high Andes. Int J Environ Res Public Health 2021;18[14]:7619. Creative Commons Attribution [CC...
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Hemoglobin dissociation curve from the 1911 Anglo-American Expedition to Pikes Peak
The continuous line represents the dissociation curve of oxyhemoglobin in the blood of British physiologist Claude Gordon Douglas (1882-1963) and John Scott Haldane, determined in Oxford in the presence of 40 mm pressure of CO2...
When PIO2 drops, the body attempts to compensate (altitude acclimatization) through a series of changes that may take days to weeks, or even months for extreme altitudes. Rapid changes include an increase in heart rate, respiratory rate, and respiratory depth. In addition, nonessential body functions are suppressed (eg, food digestion efficiency declines) as the body optimizes cardiopulmonary function. Additional red blood cells are produced much more slowly.
Decrease in barometric pressure after ascent leads to a series of physiologic responses, some of which are mediated by hypoxia-inducible factors (89). Ascent to high altitude leads to a decrease in the partial pressure of oxygen at all points along the oxygen transport cascade, with secondary physiologic responses affecting multiple organ systems over varying time frames. The lower alveolar partial pressure of oxygen slows the rate of oxygen diffusion across the alveolar-capillary membrane. Especially during exercise, with reduced red cell transit time, the arterial partial pressure of oxygen (PaO2) drops substantially as pulmonary oxygen exchange becomes diffusion limited (even in normal individuals).
With increasing altitude, the partial pressure of inspired oxygen (PIO2) decreases and, consequently, the arterial oxygen pressure (PaO2) decreases (47).
Arterial blood gas values by altitude based on aggregated data
The size of each bubble is proportional to the standard error of each of the 51 studies shown in the figure. The 95% confidence interval (gray area) is the standard error of the estimate (ie, the standard error of the point est...
A metaanalysis of 51 studies found that the mean point estimate was a reduction of 1.60 kPa in PaO2 per kilometer of vertical ascent (47). Arterial hypoxemia triggers an increase in minute ventilation (known as the ventilatory response to hypoxia), which is mediated by the carotid bodies. The ventilatory response to hypoxia produces an initial uncompensated respiratory alkalosis (47). Lower and upper limits of normal for PaO2, PaCO2, and pH based on individual participant data were also calculated (47).
Lower and upper limits of normal for PaO2, PaCO2, and pH based on individual participant data
A total of 13 studies were included in the analysis. Dots represent individual participant data, continuous lines represent means, and dashed lines represent 90% confidence intervals. The lower dashed line represents the lower ...
Over several days, renal excretion of bicarbonate leads to a compensatory metabolic acidosis, which contributes to later increases in ventilation. In response to acute hypoxia, cardiac output increases because of a sympathetically triggered increase in heart rate, which serves to maintain tissue oxygen delivery despite the lower arterial partial pressure of oxygen. Within minutes of exposure to environmental hypoxia, the lower alveolar partial pressure of oxygen also triggers hypoxic pulmonary vasoconstriction, which produces a secondary increase in pulmonary artery pressure.
Hypoxia-induced diuresis and natriuresis are mediated by peripheral chemoreceptors (and not due to changes in levels of renin, angiotensin, aldosterone, or atrial natriuretic peptide). The resulting decrease in plasma volume, in conjunction with the decrease in humidity at high altitude and hyperventilation-induced insensible fluid losses via the respiratory tract, collectively increase the risk of dehydration in those with inadequate compensatory fluid intake.
Hemoglobin concentrations increase within 1 to 2 days of ascent and continue to rise in the weeks that follow. The initial changes are due to the reduced plasma volume from diuresis and natriuresis, whereas later changes are due to increases in red cell mass caused by elevated serum erythropoietin concentrations.
Persons who are not acclimatized to high altitudes and who ascend to 2500 m (8200 ft) are at risk for acute high-altitude illnesses (08).
Hypoxia-inducible factor pathway genes are linked to high-altitude adaptation in both human and nonhuman highland species (10; 142; 78). EPAS1 (endothelial PAS domain protein 1), a target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans (10; 142). A similar association exists between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders (78). This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations (78). CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression (78). Therefore, unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories (78).
Sleep disorders at high altitude. Sleep is often disturbed at high altitude, with a high frequency of periodic breathing in conjunction with nocturnal hypoxia (96; 16; 114). This was well illustrated by the earliest recordings by Mosso and colleagues in the 1890s (101). These results were confirmed by the most important recordings from the early 20th century during the 1911 Anglo-American Expedition to Pikes Peak (39).
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Periodic respiration during sleep at the Regina Margherita Hut (4554 m or 14,941 ft)
The subject was Angelo Mosso's brother, Ugolino Mosso (1854-1909), a lecturer in pharmacology in Turin. (Source: Mosso A. Life of man on the high Alps. Kiesow EL, trans. London: T Fisher Unwin, 1898.)
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Periodic respiration during light sleep at the Regina Margherita Hut (4554 m or 14,941 ft)
The subject was Franioli, keeper of the Regina Margherita Hut. (Source: Mosso A. Life of man on the high Alps. Kiesow EL, trans. London: T Fisher Unwin, 1898.)
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Thoracic excursion as an indicator of respiration
Comparison of recordings in the same person (Chamois, a soldier), showing normal respiration at low altitude (top) and periodic respiration at high altitude (bottom). Subject:(A) Tracing obtained in Turin, Italy (255 m, 837 ft)...
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Gradual transition of breathing to the Cheyne-Stokes form (according to Mosso)
(Source: Zuntz N, Loewy A, Müller F, Caspari W. Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen : Ergebnisse experimenteller Forschungen im Hochgebirge und Laboratorium. Berlin: Bong & Co., 1906. Public do...
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Periodic breathing recorded the evening of arrival on Pikes Peak during the 1911 Anglo-American Expedition to Pikes Peak (1)
July 12, 1911. Subject: British physiologist C Gordon Douglas. (Source: Douglas CG, Haldane JS, Henderson Y, Schneider EC. Physiological observations made on Pike's Peak, Colorado, with special reference to adaptation to low ba...
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