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...
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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Periodic breathing recorded the evening of arrival on Pikes Peak during the 1911 Anglo-American Expedition to Pikes Peak (2)
July 12, 1911. Subject: British physiologist John Scott Haldane. The periodic breathing transitions into typical Cheyne-Stokes respiration after Haldane took six forced breaths. (Source: Douglas CG, Haldane JS, Henderson Y, Sch...
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Natural breathing passing into periodic breathing after holding the breath to the breaking point during the 1911 Anglo-American Expedition to Pikes Pe...
July 12, 1911. Subject: American physiologist Yandell Henderson (1873-1944). Natural breathing, slightly periodic and passing into well-marked periodic breathing after holding the breath to the breaking point (13 seconds) on th...
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Periodic breathing during the 1911 Anglo-American Expedition to Pikes Peak
July 15, 1911. Subject British physiologist John Scott Haldane. (Source: Douglas CG, Haldane JS, Henderson Y, Schneider EC. Physiological observations made on Pike's Peak, Colorado, with special reference to adaptation to low b...
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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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Quantitative record of respiration during periodic breathing during the 1911 Anglo-American Expedition to Pikes Peak
Subject: Yandell Henderson (1873-1944), Professor of Physiology at Yale University Medical School. August 13, 1911. Inspiration is indicated by upward deflections. (Source: Douglas CG, Haldane JS, Henderson Y, Schneider EC. Phy...
Periodic breathing increases during acclimatization over 2 weeks at altitudes greater than 3730 m (12,200 ft), despite improved oxygen saturation, which is consistent with a progressive increase in loop gain of the respiratory control system (16).
In 1986, nine Japanese climbers participated in an expedition to the Kunlun Mountains (7167 m; 23,510 ft) in China (96). During sleep at an altitude of 5360 m (17,600 ft), all climbers showed severe desaturation, and seven (78%) manifested periodic breathing. Climbers with a high ventilatory response to hypoxia could maintain their arterial oxygenation during sleep due to hyperventilation induced by periodic breathing. Because of this, periodic breathing during sleep is considered an advantageous adaptation for lowland climbers.
Thirty-four mountaineers ascending Mt Muztagh Ata, in China's Kunlun Range, climbed from 3750 m (12,300 ft) to the summit at 7546 m (24,760 ft) within 19 to 20 days (16). During sleep, nocturnal oxygen saturation decreased, whereas minute ventilation and the number of periodic breathing cycles increased with increasing altitude. At the highest camp (6850 m; 22,500 ft), the median nocturnal oxygen saturation was 64%. Periodic breathing at the highest camp occurred at a mean frequency of 132.3 cycles/hour, but subsequent measurements within 5 to 8 days at 4497 m (14,750 ft) and 5533 m (18,150 ft) revealed increased oxygen saturations but no decrease in periodic breathing. The number of periodic breathing cycles was positively associated with days of acclimatization, whereas symptoms of acute mountain sickness had no independent effect on periodic breathing.
High-altitude headache. The incidence of high-altitude headache increases when arterial oxygen saturation and associated oxygen partial pressure decline with increasing altitude. In a study of acute mountain sickness, headache fulfilling the criteria of migraine increased in frequency (117), although a history of migraine or other headache at low altitude is not a major risk factor for acute mountain sickness.
In a study of 25 people who climbed Mount Jade in Taiwan (Yu Shan or Yushan, also known as Jade Mountain or Mount Yu; at 3952 m or 12,966 ft), spectral analysis of electroencephalographic activity at different frequencies (alpha, beta, theta, delta) showed that, at moderate altitude (2400 m or 7874 ft), the increasing delta power at the P4 electrode on electroencephalography was associated with the headache symptom of acute mountain sickness before ascending to high altitude (27).
Acute mountain sickness. Acute mountain sickness is caused by rapid ascent to high altitude without sufficient acclimatization, whereas chronic mountain sickness may result after prolonged residence at high altitude even in acclimatized persons.
Individuals who reach high altitude by active ascent (eg, hiking) become sicker faster and recover quicker than passive ascenders (eg, driving), possibly a function of differences in body fluid regulation (11). A metaanalysis of the effects of flying to high altitudes (2200 to 4559 m), incorporating 12 observational studies involving collectively 11,021 individuals, found a 4.5-fold steeper increase in the acute mountain sickness incidence for air travel compared with slower ascent modes (eg, hiking or combined car and/or air travel and hiking) (22). The higher acute mountain sickness incidence following transportation by flight versus slower means was confirmed in placebo-treated participants in 10 studies of drug prophylaxis against acute mountain sickness (22). Reduced acclimatization, due to the short time in going from low to high altitude, is likely the main reason for a higher acute mountain sickness risk when flying to high-altitude destinations.
Mountain sickness can be viewed as a failure of acclimatization to high altitude. Successful acute acclimatization to high altitude, mediated in part by the endocrine system, involves hemoconcentration through diuresis to increase the oxygen-carrying capacity of the blood to compensate for the reduced partial pressure of oxygen (137). Factors that interfere with either diuresis, the oxygen-carrying capacity of the blood, or the oxygen requirements of an individual can be expected to predispose to development of mountain sickness. This acclimatization process takes some time (usually days), so reaching high altitude too quickly can also predispose to acute mountain sickness (11; 22).
Among patients admitted to the emergency ward of the Mustang district hospital in Nepal between June 2018 and June 2019, ascent rate was strongly associated with the likelihood of developing severe acute mountain sickness (109).
High-altitude pilgrims typically ascend rapidly, are unprepared for the austere environment, and have multiple comorbidities (06). In rapidly ascending pilgrims, most travelers requiring medical attention are suffering from some form of altitude illnesses. In a prospective study of 56 patients who fell ill during pilgrimage in the Himalayan mountains and presented at the Humla District Hospital in the Tibet "Autonomous Region of China" from September 2019 to August 2022, one was already dead, and among the remainder, mild acute mountain sickness (31%) was the most common altitude-related illness and headache (76%) was the most common complaint. Proper planning and awareness of the need for a slow and gradual ascent profile are necessary to make such high-altitude travel safer.
Nevertheless, the pathogenesis of acute mountain sickness remains incompletely understood, although hypoxia at high altitude appears to be an important triggering factor. Partial pressure of oxygen falls 30%, from 159 mmHg at sea level to 112 mmHg at a height of 2900 m (9500 ft), and a 50% decrease from sea level occurs at an altitude of 5500 m (18,000 ft), which is the highest level of continuous human habitation (69). Residence above this level leads to some manifestations of chronic mountain sickness. Stormy weather is another aggravating factor because a low-pressure front is equivalent to several hundred feet of additional altitude.
Although hypoxia associated with altitudes of less than 3000 m (10,000 ft) above mean sea level has reportedly no apparent effect on aircrews, oxygen saturation (SpO2) in helicopter aircrew decreased significantly at altitudes over 1500 m (5000 ft), most markedly at 4000 m (13,000 ft) (104). Symptoms may be subtle and often involve cognitive impairment or lightheadedness.
A study in human volunteers found that hypoxia stimulates cerebral oxidative-nitrative stress (04). Both hypoxia and hyperoxia may alter the production of reactive oxygen species (ROS) by changing mitochondrial oxygen, and the resulting high ROS levels may cause oxidative stress and cell damage (102). Altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. Because mitochondrial oxygen depends on the balance between O2 transport and utilization, a mathematical model of O2 transport and utilization in skeletal muscle can be used to predict conditions that cause abnormally high ROS generation (23). From this model, ROS generation in exercising normal muscle switches to high levels at approximately 5000 meters (approximately 16,000 ft), which is the altitude above which permanent human residence is impossible.
Hypobaria may affect development of acute mountain sickness above the level induced by hypoxia alone (38; 37).
Acute mountain sickness is not associated with cerebral edema formation on MRI during simulated high altitude (95). Although passive hypoxia exposures for 8 hours slightly increased gray- and white-matter volumes and the apparent diffusion coefficient, these changes were more pronounced during active hypoxia exposures (ie, with exercise) and were unrelated to acute mountain sickness, suggesting that acute mountain sickness and high-altitude cerebral edema have different pathogenic mechanisms.
Despite an anapyrexia phenomenon (ie, decrease in body temperature below normal) during acute exposure to hypoxia (36), a low-grade fever is, nevertheless, a common manifestation of acute mountain sickness. Fever in acute mountain sickness, even including that occurring at moderate altitudes (eg, 3100 m or approximately 10,000 ft), has been attributed to a systemic inflammatory reaction that is associated with declining arterial oxygen saturation (113) that apparently counteracts the hypoxia-induced anapyrexia.
Acute mountain sickness on exposure to high-altitude hypoxia can sometimes evolve to either high-altitude pulmonary edema or high-altitude cerebral edema.
Acute mountain sickness on exposure to high-altitude hypoxia can sometimes evolve to either high-altitude pulmonary edema or high-altitude cerebral ed...
After recovery or if there is no altitude illness, the evolution towards an increase of hemoglobin, hematocrit, and red blood cells and the formation of more capillaries makes high-altitude residents resistant to several diseas...
After recovery, or if there is no altitude illness, the evolution towards an increase of hemoglobin, hematocrit, and red blood cells and the formation of more capillaries makes high-altitude residents resistant to several diseases and can even lead to extended longevity (145).
High-altitude pulmonary edema. The pathophysiology of high-altitude pulmonary edema is not entirely clear, but pulmonary capillary pressure remains normal, indicating a noncardiac origin. Hypoxia-induced pulmonary hypertension is a well-documented contributing factor. Alveolar hypoxia results in hypoxic pulmonary vasoconstriction, also known as the von Euler-Liljestrand mechanism (or reflex), a physiological response that distributes pulmonary capillary blood flow to alveolar areas of high oxygen partial pressure (134; 88; 125). Increased pulmonary artery pressure with uneven vasoconstriction and regional overperfusion leads to pulmonary vascular stress failure and capillary leak, causing pulmonary edema. The edema fluid has a high content of protein, red cells, and leukocytes, resembling the fluid characteristics in neurogenic pulmonary edema. The accumulation of this protein-rich fluid in the alveolar space implies an increase in the permeability of the pulmonary vascular epithelium that overwhelms the lung's capacity for removing fluid from the alveoli. Hypoxia, in addition to pulmonary hypertension, plays a part in the increased permeability. The result is that pulmonary edema causes deterioration of oxygen diffusion and decreased oxygen saturation.
The role of pulmonary hypertension in high-altitude pulmonary edema is supported by the effectiveness of nifedipine and nitric oxide in reducing pulmonary hypertension and thereby relieving pulmonary edema. In addition, impaired sodium-driven clearance of alveolar fluid may also have a pathogenic role in high-altitude pulmonary edema (14). Beta-adrenergic agonists upregulate the clearance of alveolar fluid by stimulating transepithelial sodium transport (116). In a double-blind, randomized, placebo-controlled study, prophylactic inhalation of the beta-adrenergic agonist salmeterol decreased the incidence of high-altitude pulmonary edema in susceptible subjects by more than 50% during exposure to high altitudes (4559 m, or approximately 14,960 ft, reached in less than 22 hours).
Among dwellers and travelers of the Ecuadorian Andes after sojourning at high altitude (over 3000 m), patients with high-altitude pulmonary edema (N = 58) were compared to a NO HAPE group (N = 713) (115). High-altitude dwellers, particularly children and the elderly, were relatively prone to high-altitude pulmonary edema. High-altitude pulmonary edema prevalence was strongly related to median corpuscular hemoglobin concentration. Residence at middle altitude was inversely related to the odds of suffering high-altitude pulmonary edema. Elevated mean corpuscular hemoglobin concentration (MCHC) was likely an adaptation of Andean highlanders to high altitude and may be useful as a biomarker of high-altitude pulmonary edema risk.
High-altitude cerebral edema. Vasogenic and cytotoxic mechanisms are proposed for high-altitude cerebral edema, and venous hypertension is a possible contributory factor (136). Primary intracranial events in high-altitude cerebral edema (cerebral edema, hypoxic cerebral vasodilatation, and elevated cerebral capillary hydrostatic pressure) elevate peripheral sympathetic activity that acts neurogenically in the lungs to cause high-altitude pulmonary edema. These events also act on the kidneys to promote salt and water retention.
Hypoxia leads to capillary leak. Fluid flux is influenced by the hydrostatic pressure in the presence of a more permeable blood-brain barrier. With progression of extracellular vasogenic edema, the intercapillary distance increases, compromising cellular perfusion and potentially rendering the cells ischemic. This may produce further cellular edema and increased intracranial pressure. This cytotoxic mechanism, which has been used in the past to explain high-altitude cerebral edema, may become operational at a later stage and may be preventable by the earlier treatment of vasogenic edema. This concept is supported by the effectiveness of dexamethasone in treating high-altitude cerebral edema.
Animal experiments have shown that hypoxia-induced cerebral edema and neuronal apoptosis are associated with increased expression of the neuropeptide corticotrophin releasing factor (CRF), which acts on corticotropin-releasing hormone receptor 1 (CRFR1) to trigger signaling of cyclic AMP/protein kinase A (cAMP/PKA) in cortical astrocytes, leading to activation of water channel aquaporin-4 (AQP4) and cerebral edema (29). These effects can be blocked by a CRFR1 antagonist.
High-altitude anterior ischemic optic neuropathy. An inadequate autoregulatory response to hypoxia, especially in the setting of exertion at altitude in a patient with increased individual susceptibility, may lead to reduced blood supply to the optic nerve head and nonarteritic anterior ischemic optic neuropathy (05; 31; 127; 17).
High-altitude retinopathy (HAR). High-altitude retinopathy is an ocular disorder that occurs on ascent to high altitude (59). Retinal vascular dilatation, retinal edema, and hemorrhage are common clinical signs; typically, these do not or only slightly affect vision, but rare cases develop serious permanent vision loss. Hypobaric hypoxia plays an aggravating role in promoting the development of the disease. High-altitude retinopathy is associated with acute mountain sickness (AMS) and high-altitude cerebral edema (HACE). Overperfusion of microvascular beds is a key pathophysiologic change in high-altitude retinopathy and early-stage acute mountain sickness (139).
High-altitude cerebral venous thrombosis (CVT). In a systematic review, nine studies with collectively 75 cases of cerebral venous thrombosis at high altitude (3000 to 8848 m) were identified, with a male to female ratio of 7.3:1 (76). Headache and seizure were the most common clinical presentations. Smoking, drinking habits, and the use of oral contraceptive pills were the most commonly identified risk factors for the development of cerebral venous thrombosis. Various underlying hypercoagulable states were also present among cases of cerebral venous thrombosis associated with high altitude exposure.
Physical exercise at high altitude. Physical exercise at high altitude increases the incidence and severity of acute mountain sickness, probably by exercise-induced exaggeration of arterial hypoxemia. Increased ventilatory response to a hypoxic environment is a normal acclimatization response, and alterations in the response, such as inappropriate hypoventilation, have been implicated in the pathogenesis of acute mountain sickness. Support for this hypothesis comes from the prophylactic effectiveness of acetazolamide, a drug that increases ventilation.
Predisposing conditions. Persons with conditions that exacerbate exercise-induced arterial hypoxemia (eg, obesity, physical exhaustion, chronic obstructive pulmonary disease, and sickle cell anemia) may face increased risks of acute mountain sickness at high altitude. Individuals with low baseline insulin sensitivity and low baseline erythropoietin levels are also more susceptible to the development of acute mountain sickness (122). Neurologic disability (eg, spinal cord injury, multiple sclerosis, and traumatic brain injury), a history of acute mountain sickness, and prior occurrence of headache at high altitude may also be risk factors for acute mountain sickness (73).
Genetic factors contribute to the capacity to rapidly acclimatize to high altitude, but the underlying mechanisms have not been elucidated (94). In a case-control study, sequencing showed a significant association between the rs1008348 polymorphism and susceptibility to acute mountain sickness in a Han Chinese population, suggesting that this single nucleotide polymorphism might be a risk factor (85).
Other predisposing factors for acute mountain sickness include use of certain substances and medications, including alcohol or sedative consumption, and use of oral contraceptives. Oral contraceptive use decreases levels of circulating progesterone by preventing ovulation, but this can inhibit ventilation and promote diuresis, inflammation, and contraction of respiratory smooth muscle—all factors that may increase the risk of acute mountain sickness, although the risk appears to be fairly small (61).
In a cohort study among young, healthy, foreign, Spanish-language students arriving to Cusco (3350 m), Peru, between 2012 and 2016, acute mountain sickness affected two out of five travelers (24). Obesity and female sex were associated with increased risk, drinking coca leaf tea for prevention did not decrease the risk, and acetazolamide prophylaxis was associated with decreased risk.
Chronic mountain sickness (Monge disease). A major hallmark of patients suffering from chronic mountain sickness is excessive erythrocytosis (polycythemia), which is responsible for considerable morbidity and even mortality in early adulthood (03). Changes in expression levels of erythrocyte and immune-related genes are associated with high altitude polycythemia (43); the upregulated genes in high-altitude polycythemia are mainly enriched in processes such as erythrocyte differentiation, development, and homeostasis, whereas the down-regulated genes were mainly enriched in categories such as immunoglobulin production and the classical pathway of complement activation. A separate study found that a group of long noncoding RNAs (lncRNAs) regulate erythropoiesis in Monge disease, but not in the population at similar altitude without chronic mountain sickness (03). Among these lncRNAs is LINC02228 (long intergenic noncoding RNA 2228; also known as hypoxia-induced kinase-mediated erythropoietic regulator or HIKER), which, under hypoxia, targets CSNK2B (casein kinase II, beta). CSNK2B encodes a regulatory subunit of casein kinase II (CK2), which is present in high levels in the brain where it may play a role in dopamine signaling. A downregulation of HIKER downregulated CSNK2B, remarkably reducing erythropoiesis; furthermore, an upregulation of CSNK2B on the background of HIKER downregulation rescued erythropoiesis defects. Pharmacologic inhibition of CSNK2B drastically reduced erythroid colonies, and knockdown of CSNK2B in zebrafish led to a defect in hemoglobinization. Thus, HIKER regulates erythropoiesis in Monge disease and acts through at least one specific target, CSNK2B, a casein kinase.
Prevention
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• Gradual ascent and acclimatization are the cornerstones of prevention for acute mountain sickness. |
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• Inhibitors of prostaglandin synthesis (ie, cyclooxygenase inhibitors, such as aspirin and nonsteroidal anti-inflammatory agents) are helpful in the treatment and prevention of high-altitude headache, although the quality of supporting evidence is low. |
Gradual ascent and acclimatization are the cornerstones of prevention for acute mountain sickness. Higher ascent and a faster rate of ascent increase the risk of altitude illness (106). A prior history of acute mountain sickness has been suggested as a risk factor but is not a reliable predictor of subsequent episodes of high-altitude illness (93). Therefore, a history of acute mountain sickness cannot serve as a guide for prophylactic strategies for high-altitude ascent.
Remote ischemic preconditioning (ie, in a normobaric hypoxic chamber [equivalent to 4000 m] for 6 hours multiple times per day for 2 to 3 days) combined with acetazolamide exerts a powerful antihypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes (84).
High-altitude headache. In the past, the increase in cerebral blood flow during acute hypoxia was thought to be the main cause of high-altitude headache, but more recent findings have given greater weight to the sensitization of intracranial pain-sensitive structures and the role of prostaglandins as mediators between hypoxia and high-altitude headache (20; 21; 19). Inhibitors of prostaglandin synthesis (ie, cyclooxygenase inhibitors, such as aspirin and nonsteroidal anti-inflammatory agents) are helpful in the treatment and prevention of high-altitude headache (20), although the quality of supporting evidence is low. In a small randomized, double-blind, placebo-controlled trial (29 subjects), pretreatment with aspirin prevented headache without improving oxygenation and instead raised the headache threshold, as indicated by toleration of lower values of oxygen saturation (20). Pretreatment with aspirin was also associated with less pronounced cardiorespiratory responses to short-term exercise at high altitude. Aspirin may prevent high-altitude headache by diminishing the elevations of prostaglandins that would otherwise result from acute hypoxia, with consequent decreases in ergoreceptor activation and accompanying sympathetic stimulation.
Acute mountain sickness. Gradual ascent and acclimatization are the cornerstones of prevention for acute mountain sickness. Ideally, coming from sea level, one should rest for a couple of days at an altitude of 2500 m (approximately 8200 ft) to facilitate acclimatization and then repeat the rest breaks periodically during further ascent. A high-carbohydrate diet and moderate physical activity facilitate acclimatization.
Acetazolamide. Acetazolamide is the drug of choice for prophylaxis of acute mountain sickness (103; 72; 24) and is also helpful in alleviating high-altitude periodic breathing (58), although the operant mechanisms have not been fully elucidated (123). A Cochrane review of 28 randomized-controlled and crossover trials collectively involving 2345 participants found that acetazolamide is an effective pharmacological agent to prevent acute high-altitude illness in dosages of 250 to 750 mg/day based on evidence of moderate quality (103). Acetazolamide is associated with an increased risk of paresthesia, but there are few reports of other adverse events.
Separate meta-analyses from 11 to 22 trials reached similar conclusions to the Cochrane review. These studies concluded that acetazolamide at 125, 250, and 375 mg twice daily (bid) significantly reduced the incidence of acute mountain sickness compared to placebo (87; 111; 48; 49). However, there was no significant association between efficacy and dose of acetazolamide, timing at the start of acetazolamide treatment, mode of ascent, acute mountain sickness assessment score, timing of acute mountain sickness assessment, baseline altitude, or endpoint altitude.
Different studies have reached different conclusions on whether day-of-ascent dosing is either more or less effective at preventing the development of acute mountain sickness or severe acute mountain sickness. Similar rates of severe acute mountain sickness and overall symptom severity for the two approaches, improved convenience, and likely greater compliance may support day-of-ascent use (83; 82).
Acetazolamide 62.5 mg twice daily has been proposed as an alternative to the typically recommended dose of 125 mg twice daily for the prevention of acute mountain sickness (97). However, the lower dose is less effective than 125 mg twice daily for the prevention of acute mountain sickness. Therefore, due to the increased risk of developing acute mountain sickness and no demonstrable symptomatic or physiologic benefits, acetazolamide 62.5 mg twice daily should not be recommended for acute mountain sickness prevention (81).
Dexamethasone. Early studies of generally poor quality suggested that dexamethasone may be effective for prophylaxis of symptoms associated with acute mountain sickness accompanying rapid ascent to altitudes above 4300 m (14,000 ft) (42).
A Cochrane review evaluated the preventive benefits of dexamethasone in seven parallel studies collectively involving 205 participants (103). The data did not show significant benefits of dexamethasone at any dosage based on four trials collectively involving 176 participants, with evidence deemed of low quality. Included studies did not report events of high-altitude pulmonary edema or high-altitude cerebral edema, although the evidence concerning adverse events was deemed of very low quality.
Dexamethasone can be considered, with significant reservations, for persons without contraindications who are intolerant of acetazolamide, for whom acetazolamide is ineffective, or who must make forced, rapid ascents to high altitude for a short period of time with a guaranteed retreat route (41; 42).
Other preventive measures. A Cochrane review of commonly used classes of drugs for high-altitude illness (ie, acute mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema) considered ibuprofen and budesonide (103). A second Cochrane review of other agents for preventing high-altitude illness examined selective 5-hydroxytryptamine(1D)-receptor agonists (eg, sumatriptan), N-methyl-D-aspartate (NMDA) antagonist, endothelin-1 antagonist, anticonvulsant drugs, and spironolactone (53). A third Cochrane review of miscellaneous and nonpharmacological interventions for the prevention of high-altitude illness examined the use of simulated altitude or remote ischemic preconditioning, the use of positive end-expiratory pressure, supplementation (antioxidants, medroxyprogesterone, iron, or Rhodiola crenulata), erythropoietin, and ginkgo biloba (99). Available evidence from either of these Cochrane reviews to support any of these preventive measures was quite limited due to the low number of studies identified (only one study was identified for most of these agents or measures) and limitations in the quality of the evidence (moderate to low). The absence of large and methodologically sound studies precludes establishing or refuting the efficacy and safety of these agents.
A preliminary randomized, double-blinded, placebo-controlled trial suggests that intravenous iron supplementation may protect against the symptoms of acute mountain sickness in healthy volunteers, possibly because of the ability of iron to influence cellular oxygen-sensing pathways (124).
Elevated serum concentrations of low-density lipoprotein (LDL) are somewhat protective against the development of acute mountain sickness (62; 63). The use of statins, although they lower serum LDL concentrations, may provide some modest protection against development of acute mountain sickness because of their antiinflammatory properties (63).
High-altitude pulmonary edema. Slow ascent remains the primary prevention strategy for high-altitude pulmonary edema. Pharmacological agents are particularly helpful for the prevention of acute mountain sickness and high-altitude pulmonary edema when rapid ascent cannot be avoided or when rapid descent is not possible (72).
Among a group of U.S. Army Special Operations soldiers who tested recommended doses of acetazolamide prophylaxis for acute mountain sickness during six expeditions to elevations between 5800 and 7000 m (19,000 and 23,000 ft), acetazolamide was considered to be an acceptable choice for the prevention of acute mountain sickness in conjunction with a slow, controlled ascent and proper fitness, nutrition, clothing, and gear (32).
In a fast-climbing ascent to 4559 m (14,960 ft), acetazolamide did not significantly reduce the incidence of high-altitude pulmonary edema or differences in hypoxic pulmonary artery pressures compared with placebo, despite reductions in acute mountain sickness and greater ventilation-induced arterial oxygenation (12).
Ibuprofen is slightly inferior to acetazolamide for the prevention of acute mountain sickness and should not be recommended over acetazolamide for rapid ascent (18).
Wilderness Medical Society Guidelines for the Prevention of Acute Altitude Illness
The key evidence-based guidelines for the prevention of acute altitude illness from an expert panel convened by the Wilderness Medical Society are as follows (90; 91):
Gradual ascent. Gradual ascent, defined as a slow increase in sleeping elevation, is recommended to prevent acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema. When feasible, staged ascent (ie, spending 6 to 7 days at a moderate altitude of approximately 2200 to 3000 m before proceeding to higher altitude) and preacclimatization (ie, repeated exposures to hypobaric or normobaric hypoxia in the days and week preceding high-altitude travel) can be considered as a means for the prevention of acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema.
Medication options for acute mountain sickness prevention. Acetazolamide should be strongly considered in travelers at moderate or high risk of acute mountain sickness with ascent to high altitude. Dexamethasone can be used as an alternative to acetazolamide for adult travelers at moderate or high risk of acute mountain sickness. Ibuprofen can be used for the prevention of acute mountain sickness in persons who do not wish to take acetazolamide or dexamethasone or who have allergies or intolerance to these medications. The following should NOT be used for acute mountain sickness prevention: inhaled budesonide; Ginkgo biloba; and acetaminophen.
Medication options for high-altitude pulmonary edema prevention. Nifedipine is recommended for the prevention of high-altitude pulmonary edema in people who are susceptible to high-altitude pulmonary edema. Tadalafil can be used for the prevention of high-altitude pulmonary edema in known susceptible individuals who are not candidates for nifedipine. Dexamethasone can be used for the prevention of high-altitude pulmonary edema in known susceptible individuals who are not candidates for either nifedipine or tadalafil. There are no data to determine whether acetazolamide might be useful in this regard. However, acetazolamide can be considered for the prevention of "reentry high-altitude pulmonary edema " (ie, high-altitude pulmonary edema on return to high altitude for someone who previously lived at high altitude but traveled to a lower altitude) in people with a history of the disorder.
Table 1. Wilderness Medical Society Risk Categories for Acute Mountain Sickness in Unacclimatized Individuals
|
Risk category |
Description
|
|
Low |
• No history of AMS and ascending to 2800 m |
|
• Taking at least 2 days to arrive at 2500 to 3000 m, with subsequent increases in sleeping elevation less than 500 m/day plus an extra day for acclimatization every 1000 m
|
|
Moderate |
• History of AMS and ascending to 2500 to 2800 m in 1 day |
|
• No history of AMS and ascending to more than 2800 m in 1 day |
|
• Ascending more than 500 m/day (in sleeping elevation) above 3000 m, but with an extra day for acclimatization every 1000 m
|
|
High |
• History of AMS and ascending to more than 2800 m in 1 day |
|
• History of HACE or HAPE |
|
• Ascending to more than 3500 m in 1 day |
|
• Ascending more than 500 m/day (in sleeping elevation) above 3000 m without extra days for acclimatization
|
|
Abbreviations: AMS, acute mountain sickness; HACE, high-altitude cerebral edema; HAPE, high-altitude pulmonary edema
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|
Notes |
(1) Altitudes listed refer to the altitude at which the person sleeps. |
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(2) Ascent is assumed to start from elevations less than 1200 m. |
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(3) The risk categories described pertain to unacclimatized individuals.
|
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Modified from (90) |
Diagnostic workup
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• Acute mountain sickness by itself generally does not require any diagnostic workup as the symptoms subside spontaneously by acclimatization, descent to a lower altitude, or therapeutic measures. |
| |
• A clinical diagnosis of high-altitude pulmonary edema should be made in appropriate patients at altitude who exhibit at least two relevant symptoms or complaints (ie, chest tightness or pain, cough, dyspnea at rest, or decreased exercise tolerance) and at least two relevant exam findings (ie, central cyanosis, tachycardia, tachypnea, and, if chest auscultation is possible, rales/wheezes). |
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• Acute mountain sickness or high-altitude pulmonary edema usually precede high-altitude cerebral edema, but high-altitude cerebral edema may occur without these. |
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• In patients with acute mountain sickness, the onset of high-altitude cerebral edema is usually indicated by vomiting, headache that does not respond to nonsteroidal anti-inflammatory drugs, hallucinations, and stupor. |
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• Although high-altitude cerebral edema must be distinguished from conditions with similar symptoms, it should be the working diagnosis when a consistent pattern of signs and symptoms develop while ascending to a high altitude until proven otherwise. |
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• MRI in patients with high-altitude cerebral edema may show variable degrees of edema in subcortical white matter and the splenium of the corpus callosum. |
High-altitude headache as defined by the International Headache Society is a headache that appears within 24 hours after ascent to 2500 m (8200 ft) or higher (65). In addition, evidence of causation must be demonstrated by at least two of the following: (1) headache developed in temporal relation to ascent; (2) headache significantly worsened in parallel with continuing ascent and/or headache resolved within 24 hours following descent to below 2500 m (8200 ft); (3) the headache has at least two of the following characteristics: bilateral location; mild or moderate intensity; and aggravation by exertion, movement, straining, coughing and/or bending. High-altitude headache can appear in isolation or as part of acute mountain sickness.
Acute mountain sickness consists of nonspecific symptoms that occur at altitudes of at least 2500 m (8200 ft) in unacclimatized individuals, typically with a delay in onset of 4 to 12 hours after arrival at a new altitude. The symptoms are usually most pronounced after the first night spent at a new altitude and resolve spontaneously when appropriate measures are taken. The most common symptom is headache, but this is not universally present. Other symptoms include anorexia or nausea, dizziness/lightheadedness, fatigue/lassitude, and insomnia. Acute mountain sickness by itself generally does not require any diagnostic workup as the symptoms subside spontaneously by acclimatization, descent to a lower altitude, or therapeutic measures.
The Lake Louise Acute Mountain Sickness scoring system has been a useful research tool since it was first published in 1991, but its various formulations were never intended as diagnostic criteria for acute mountain sickness (112). The Lake Louise Acute Mountain Sickness score for an individual is the sum of the scores for the component symptoms (headache, gastrointestinal symptoms, fatigue/weakness, and dizziness/lightheadedness), with each symptom receiving a score of 0 to 3, from not present (0) to severe and incapacitating (3). Initially, sleep disturbance was included as a component symptom, but this was removed in the 2018 revision because disturbed sleep at altitude is more likely due to altitude hypoxia rather than being a clear manifestation of acute mountain sickness (112). According to the Lake Louise Acute Mountain Sickness scoring system, a determination of acute mountain sickness for research purposes requires a headache score of at least 1 point and a total score of at least 3 points, although the absence of headache does not exclude a diagnosis of acute mountain sickness for clinical purposes (112). Although sufficient research is lacking to divide the total score into severity levels, mild acute mountain sickness is 3 to 5 points, moderate acute mountain sickness is 6 to 9 points, and severe acute mountain sickness is 10 to 12 points. For individuals with acute mountain sickness, an "Acute Mountain Sickness Clinical Functional Score" can also be assigned on a scale of 0 to 3 based on the impact of those symptoms: 0 indicates no impact on activities; 1 indicates that symptoms, though present, did not force any change in activity or itinerary; 2 indicates that either ascent had to be terminated or that an individual was forced to descend, but on their own power; and 3 indicates that an individual had to be evacuated to a lower altitude (112). Since the 2018 revision, several criticisms have been raised, and critics have suggested the following (28; 110; 131): (1) headache should not be a mandatory requirement for the diagnosis of acute mountain sickness, for research purposes or otherwise; (2) sleep disruption does contribute to the diagnosis of acute mountain sickness; (3) gastrointestinal symptoms and dizziness are weaker contributors to the diagnosis of acute mountain sickness; (4) dizziness/lightheadedness may result from a hyperresponsiveness to hypoxia and not to acute mountain sickness itself; and (5) the current questionnaire has a tendency to overestimate acute mountain sickness by including high-altitude headache cases.
A clinical diagnosis of high-altitude pulmonary edema should be made in appropriate patients at altitude who exhibit at least two relevant symptoms or complaints (ie, chest tightness or pain, cough, dyspnea at rest, or decreased exercise tolerance) and at least two relevant exam findings (ie, central cyanosis, tachycardia, tachypnea, and, if chest auscultation is possible, rales/wheezes) (70). High-altitude pulmonary edema may also manifest with cough, frothy pink sputum, and orthopnea (ie, a sensation of breathlessness in the recumbent position, relieved by sitting or standing) (79).
Table 2. Wilderness Medical Society Severity Classification of Acute Mountain Sickness
|
Severity |
Symptoms |
Symptom intensity |
Signs |
Lake Louise AMS Score
|
|
Mild |
• Headache |
Mild |
None |
3–5 |
|
• At least one of the following: |
|
|
|
|
|
- Dizziness |
|
|
|
|
|
- Fatigue |
|
|
|
|
|
- Lassitude |
|
|
|
|
|
- Nausea/vomiting
|
|
|
|
|
Moderate to severe |
• Headache |
Moderate to severe |
None |
6–12 |
|
• At least one of the following: |
|
|
|
|
|
- Dizziness |
|
|
|
|
|
- Fatigue |
|
|
|
|
|
- Lassitude |
|
|
|
|
|
- Nausea/vomiting
|
|
|
|
|
HACE |
• Worsening from moderate-to-severe AMS |
Moderate to severe |
• Altered mental status |
Not applicable |
|
• Ataxia |
|
• Encephalopathy |
|
• Severe lassitude
|
|
Abbreviations: AMS, acute mountain sickness; HACE, high-altitude cerebral edema
|
|
Note: For the Lake Louise Score, see (112)
|
|
Modified from (90) |
If available, (1) arterial blood gas analysis typically demonstrates severe hypoxemia and respiratory alkalosis, (2) chest x-ray may show patchy alveolar infiltrates with a normal-sized mediastinum/heart, (3) ultrasound may show B-lines consistent with pulmonary edema, and (4) ECG may show signs of right axis deviation or ischemia. In a patient with infiltrates on chest x-ray, rapid correction of clinical status and SpO2 with supplemental oxygen is pathognomonic of high-altitude pulmonary edema.
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Thorax and abdominal x-rays in a patient with high-altitude pulmonary edema at 3500 m
(1) Four days after arrival at high altitude. Note the distention of cases (high-altitude gas expansion). (2) Two days later, after treatment. (Source: Zubieta-Calleja G, Zubieta-DeUrioste N. The oxygen transport triad in high-...
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Chest x-rays in a child with HAPE followed by recovery over 2 days
(A) HAPE chest x-rays in a child with bilateral irregular focal cotton-like edema areas surrounded by functioning lung areas. (B) Recovery of the child after 2 days following treatment, showing complete clearance without sequel...
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Chest x-rays in an adult with HAPE followed by improvement over 4 days
HAPE in an adult showing unilateral big, cotton-like images with a favorable evolution in 4 days. HAPE: high-altitude pulmonary edema. (Source: Zubieta-Calleja G, Zubieta-DeUrioste N. The oxygen transport triad in high-altitude...
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Severe HAPE in an adult evolving favorably (3500 m) in spite of cardiomegaly
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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José de Acosta (1539-1600)
(Courtesy of Wikimedia Commons. Public domain. Figure restored and edited by Dr. Douglas J Lanska.)
Acute mountain sickness or high-altitude pulmonary edema usually precede high-altitude cerebral edema, but high-altitude cerebral edema may occur without these (08). In patients with acute mountain sickness, the onset of high-altitude cerebral edema is usually indicated by vomiting, headache that does not respond to nonsteroidal anti-inflammatory drugs, hallucinations, ataxia, and declining level of arousal progressing to stupor (118; 08; 79). Although high-altitude cerebral edema must be distinguished from conditions with similar symptoms, it should be the working diagnosis when a consistent pattern of signs and symptoms develop while ascending to a high altitude until proven otherwise (136).
Neuroimaging. MRI in patients with high-altitude cerebral edema may show variable degrees of edema and microhemorrhages in the subcortical white matter and the splenium of the corpus callosum (25; 105; 77; 80; 92; 34). Reported causes of mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) include high-altitude cerebral edema, infection, antiepileptic drug withdrawal, and cesarean section (105).
In a cross-sectional study among 49 trekkers rescued from high altitudes in the Nepal Himalayas with clinically suspected high-altitude cerebral edema, MRI showed the following findings: (1) 57% showed no abnormal signal changes; (2) 29% showed various white matter high-signal-intensity areas on T2 and FLAIR images without restricted diffusion; (3) 12% had findings highly suggestive of high-altitude cerebral edema, including five patients with high signal intensity on T2-weighted images and restricted diffusion in the splenium of corpus callosum, three of whom had features of microhemorrhage, and an additional patient, who had normal brain morphology and intensity on T1, T2, and FLAIR images but showed innumerable variable-sized microhemorrhages on susceptibility weighted imaging; and (4) one patient had features of subacute lacunar infarcts (74).
Management
| |
• Descent to a lower elevation is the best treatment for all forms of acute altitude illness. |
| |
• For acute mountain sickness management, use oxygen inhalation, nonsteroidal antiinflammatory drugs for headache, antiemetics for nausea, and acetazolamide. If there is no relief, descend to lower altitudes. |
| |
• For cerebral edema management, evacuate to a hospital. |
Descent to a lower elevation is the best treatment for all forms of acute altitude illness, but this is not required with high-altitude headache and isolated acute mountain sickness.
High-altitude headache. High-altitude headache is probably part of the spectrum of acute mountain sickness, but for management purposes, it can be considered separately. Hypoxia-induced cerebral vasodilation is a probable cause of high-altitude headache (25). High-altitude headache can be prevented or relieved by stopping ascent, administration of oxygen, acetazolamide, and use of analgesics [acetaminophen (500-1000 mg)] or anti-inflammatory analgesics [nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen) or high-dose aspirin (1 gm)] (19). Dexamethasone has also been recommended for prophylaxis and treatment of high-altitude headache (19), but the evidence is less convincing. The most beneficial effects, however, may be achieved by the combination of acetazolamide and aspirin or a nonsteroidal anti-inflammatory agent, although this is presumptive based on available information.
A small randomized, controlled clinical treatment trial of ibuprofen (400 mg) versus acetaminophen (1000 mg) for high-altitude headache found no significant difference between these drugs (60).
Ibuprofen is modestly helpful in preventing high-altitude headache. In a meta-analysis incorporating three randomized-controlled clinical trials collectively involving 407 subjects, high-altitude headache occurred in 101 of 239 subjects (42%) who received ibuprofen and 96 of 168 (57%) who received placebo (RR = 0.79) (140). The absolute risk reduction was 15%, and the number needed to treat to prevent one high-altitude headache was 7. The incidence of severe high-altitude headache was also significantly lower in the ibuprofen treatment group (RR = 0.40). Severe high-altitude headache occurred in 3% of those treated with ibuprofen compared with 10% of those who received placebo. The absolute risk reduction was 8%, and the number needed to treat to prevent one severe high-altitude headache was 13. One included randomized controlled trial reported one participant with black stools and three participants with stomach pain in the ibuprofen group, whereas seven participants reported stomach pain in the placebo group.
A prospective, double-blind, randomized, placebo-controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high-altitude headache found that ibuprofen and acetazolamide were similarly effective in preventing high-altitude headache (50).
Acute mountain sickness. Of 366 trekkers on the Everest Base Camp Trek, Nepal, about one in five experienced acute mountain sickness, but only 1% showed adequate knowledge concerning specific first aid strategies (26).
If needed, treatment with supplemental oxygen via tank or concentrator can reduce the symptoms of acute mountain sickness. A small uncontrolled trial of continuous positive airway pressure (CPAP) in five subjects suggests that CPAP may reduce symptoms of acute mountain sickness (71). Acetazolamide (eg, 250 mg every 8 to 12 hours) and dexamethasone (4 mg every 6 hours) can be added for individuals with more severe acute mountain sickness or those who fail to respond to conservative measures (55). However, the quality of evidence supporting the use of acetazolamide for the treatment of acute mountain sickness is poor (126). Antiemetics may help with associated nausea and vomiting. Individuals who remain ill despite several days of conservative treatment should descend 500 to 1000 m (1600-3300 ft) until symptoms resolve.
High-altitude pulmonary edema. The primary therapeutic aim of high-altitude pulmonary edema is improvement of oxygenation. Patients with high-altitude pulmonary edema must be immediately and emergently evacuated to a lower altitude, preferably to a hospital, and treated with bed rest and supplemental oxygen (107; 141).
However, in circumstances in which high-altitude pulmonary edema occurs, the reality is that descent is often difficult, and bottled oxygen and hyperbaric chambers are often unavailable. In a comparison of (1) auto-PEEP using a special kind of pursed-lips breathing and (2) bottled oxygen in two patients suffering from high-altitude pulmonary edema, oxygen saturation (SpO2) increased significantly from 65% to 70% to 95% with both therapies (125). Auto-PEEP is universally available, improves SpO2 nearly as well as 3 L/min oxygen, and has a positive effect on oxygenation lasting for approximately 120 minutes after stopping.
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Time course of peripheral oxygen saturation (SpO2; blue) and pulse (grey) in a patient with HAPE at 4870 m (15,978 ft)
The black line indicates the start of supplemental oxygen at an initial flow rate of 3.0 L/min which was reduced to 0.5-1.0 L/min after several minutes. The grey dotted lines show the attempt of pursed lips breathing that had t...
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Time course of SpO2 (blue) and pulse (green) in a patient with HAPE at 4380 m (14,370 ft)
The black lines indicate the beginning and end of Auto-PEEP breathing. (Source: Tannheimer M, Lechner R. Initial treatment of high-altitude pulmonary edema: comparison of oxygen and auto-PEEP. Int J Environ Res Public Health 20...
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How hypoxia induces HAPE with points of attack using supplemental oxygen and auto-PEEP
Pulmonary edema aggravates hypoxia due to enlarged alveolar-capillary diffusion distance. Legend: down arrow, leads to; circled minus sign, reduces; circled plus sign, increases. (Source: Tannheimer M, Lechner R. Initial treatm...
Dexamethasone, calcium channel blockers (eg, nifedipine), and phosphodiesterase inhibitors have been advocated for the treatment of high-altitude pulmonary edema (72), but none of these significantly alters the outcome (141; 15).
High-altitude cerebral edema. Patients with high-altitude cerebral edema must be immediately evacuated to a lower altitude, preferably to a hospital, and treated with bed rest and supplemental oxygen (eg, 6 L/minute initially and 2 L/minute thereafter).
Well-designed controlled clinical trials (and meta-analyses of such studies) of acetazolamide, dexamethasone, and hyperbaric oxygen treatment are lacking (120). These treatments have generally been considered, recommended, or used based on analogy with other disorders. Acetazolamide reduces the rate of CSF formation and, in combination with its diuretic action, contributes to reduction of cerebral edema. Dexamethasone (10 mg intravenously and 4 mg intramuscularly every 6 hours) likely reduces capillary wall permeability, thus, preventing the exudation of fluid into the extracellular space.
Wilderness Medical Society Guidelines for Treatment of Acute Altitude Illness. The key evidence-based guidelines for the treatment of acute altitude illness from an expert panel convened by the Wilderness Medical Society are as follows (90):
1. Descent is effective for any degree of acute mountain sickness / high-altitude cerebral edema and is indicated for individuals with severe acute mountain sickness, acute mountain sickness that fails to resolve with other measures, high-altitude cerebral edema, or high-altitude pulmonary edema.
2. When available, ongoing supplemental oxygen (sufficient to raise SpO2 over 90% or to relieve symptoms) should be used while waiting to initiate descent, when descent is not practical, and during descent in severely ill patients.
3. When available, portable hyperbaric chambers should be used for patients with severe acute mountain sickness, high-altitude cerebral edema, or high-altitude pulmonary edema when descent is infeasible or delayed and supplemental oxygen is not available.
4. Acetazolamide should be considered for the treatment of mild acute mountain sickness.
5. Dexamethasone should be administered for high-altitude cerebral edema and should be considered for the treatment of moderate to severe acute mountain sickness.
6. High-altitude headache can be treated with acetaminophen or ibuprofen.
7. Nifedipine should be used for high-altitude pulmonary edema treatment when descent is impossible or delayed and reliable access to supplemental oxygen or portable hyperbaric therapy is not available. Pulmonary vasodilators (ie, tadalafil or sildenafil) can be used for high-altitude pulmonary edema treatment when descent is impossible or delayed and when supplemental oxygen, portable hyperbaric therapy, and nifedipine are unavailable.
However, although calcium channel blockers (eg, nifedipine) and phosphodiesterase inhibitors have been advocated for the treatment of high-altitude pulmonary edema (72), these have not been shown to significantly alter the outcome (141; 15).
8. Continuous positive airway pressure or expiratory positive airway pressure may be considered for the treatment of high-altitude pulmonary edema when supplemental oxygen or pulmonary vasodilators are not available or as adjunctive therapy in patients not responding to supplemental oxygen alone.
9. The following should NOT be used for the treatment of high-altitude pulmonary edema: diuretics, acetazolamide. Due to insufficient evidence, no recommendation can be made regarding dexamethasone for high-altitude pulmonary edema treatment.
Outcomes
High-altitude headache and acute mountain sickness are usually relatively benign conditions, but the more advanced forms of altitude sickness with high-altitude pulmonary edema and high-altitude cerebral edema can be accompanied by severe morbidity, and death may result if the patient is not immediately evacuated to a lower altitude.
