As altitude increases, atmospheric pressure decreases while the percentage of oxygen in air remains constant; thus, the partial pressure of oxygen decreases with increasing altitude. At 5800 m (19,000 ft), the partial pressure of oxygen is about one-half that at sea level, while on the summit of Mt. Everest (8848 m, or 29,032 ft), it is roughly one-third that of sea level (1).
Most people can ascend to 1500 to 2000 m (5000 to 6500 ft) in 1 day without illness, but approximately 25% of those who ascend to 2500 m (8000 ft) (2) and 40% of those who ascend to 4340 m (14,000 ft) (3) develop some form of altitude illness, most commonly AMS. Extremely high rates (> 60%) have been reported among religious pilgrims in the Himalayan mountains in Nepal (4) as well as among climbers ascending Mount Kilimanjaro in Kenya and Tanzania (5), settings well known for overly rapid rates of ascent, which is a primary risk factor for the development of altitude illness. Other factors that contribute to developing altitude illness are the maximum altitude reached and the sleeping altitude.
Risk factors
Effects of high altitude vary greatly among individuals. But generally, in people who ascend to altitudes higher than 2000 m (5000 to 6500 ft), risk factors include 1 or more of the following:
History of altitude illness
Maximum altitude reached
Living near sea level
Going too high too fast
Overexertion
Sleeping at too high an altitude
Disorders such as asthma, hypertension, diabetes, coronary artery disease, and mild chronic obstructive pulmonary disease are not risk factors for altitude illness, but hypoxemia at high altitude may exacerbate symptoms caused by some of these disorders (6).
Physical fitness is not protective (7).
Pearls & Pitfalls
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Spending less than a few weeks at altitudes below 3000 m (10,000 ft) does not appear to be dangerous for a pregnant woman or a fetus (8).
References
1. West JB, Boyer SJ, Graber DJ, et al: Maximal exercise at extreme altitudes on Mount Everest. J Appl Physiol Respir Environ Exerc Physiol 55(3):688-698, 1983. doi: 10.1152/jappl.1983.55.3.688
2. Honigman B, Theis MK, Koziol-McLain J, et al: Acute mountain sickness in a general tourist population at moderate altitudes. Ann Intern Med 1993 Apr 15;118(8):587-92. doi: 10.7326/0003-4819-118-8-199304150-00003. Erratum in: Ann Intern Med 120(8):698, 1994.
3. Hackett PH, Rennie D, Levine HD: The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 2(7996):1149-1155, 1976. doi: 10.1016/s0140-6736(76)91677-9
4. Basnyat B, Subedi D, Sleggs J, et al: Disoriented and ataxic pilgrims: An epidemiological study of acute mountain sickness and high-altitude cerebral edema at a sacred lake at 4300 m in the Nepal Himalayas. Wilderness Environ Med 11(2):89-93, 2000. doi: 10.1580/1080-6032(2000)011[0089:daapae]2.3.co;2
5. Davies AJ, Kalson NS, Stokes S, et al: Determinants of summiting success and acute mountain sickness on Mt Kilimanjaro (5895 m). Wilderness Environ Med 20(4):311-317, 2009. doi: 10.1580/1080-6032-020.004.0311
6. Luks AM, Hackett PH: Medical conditions and high-altitude travel. N Engl J Med 386(4):364-373, 2022. doi: 10.1056/NEJMra2104829
7. Sareban M, Schiefer LM, Macholz F, et al: Endurance athletes are at increased risk for early acute mountain sickness at 3450 m. Med Sci Sports Exerc 52(5):1109-1115, 2020. doi: 10.1249/MSS.0000000000002232
8. Jean D, Moore LG: Travel to high altitude during pregnancy: Frequently asked questions and recommendations for clinicians. High Alt Med Biol 13(2):73-81, 2012. https://doi.org/10.1089/ham.2012.102
Pathophysiology of Altitude Illness
Severe acute hypoxemia can cause altered central nervous system function within a matter of minutes, but acute altitude illness develops more slowly, from 1 to 5 days after ascent to a given elevation.
The pathogenesis of acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) remain unclear despite considerable research in this area. The diseases likely have the same pathophysiology and fall on a continuum of severity, with HACE representing the extreme of the spectrum.
Some features differ between these disorders. AMS may involve activation of the trigeminovascular system due to a variety of stimuli, while HACE involves blood-brain barrier leakage and increased intracranial pressure (1).
High-altitude pulmonary edema (HAPE) is caused by hypoxia-induced elevation of pulmonary artery pressure, which causes interstitial and alveolar pulmonary edema, resulting in impaired oxygenation. Small-vessel hypoxic vasoconstriction is patchy, causing elevated pressure, capillary wall damage, and capillary leakage in less constricted areas. Other factors, such as sympathetic overactivity, may also be involved (2).
Long-time high-altitude residents can develop HAPE when they return after a brief stay at low altitude, a phenomenon referred to as reentry pulmonary edema. Reports suggest that long-term high-altitude residents can also develop noncardiogenic pulmonary edema—referred to as high-altitude resident HAPE—even if they do not descend to and then return from a lower elevation (3, 4).
Acclimatization
Acclimatization is an integrated series of responses that allow the body to tolerate the hypoxia at high altitude. This is different from the process of adaptation, which refers to phenotypic traits that are subject to the effects of natural selection and increase the ability of long-term residents, such as peoples who have lived for long periods of time on the Tibetan plateau or Ethiopian highlands, to survive at high altitude (5). Most people acclimatize reasonably well to altitudes of up to 3000 m (10,000 ft) within a few days. The higher the altitude, the longer acclimatization takes. However, no one can fully acclimatize to long-term residence at altitudes > 5100 m (> 17,000 ft).
Features of acclimatization include sustained hyperventilation, which raises the alveolar and arterial PO2 but also causes respiratory alkalosis. Blood pH tends to normalize within days as bicarbonate is excreted in urine; as pH normalizes, ventilation can increase further. Cardiac output increases initially and returns to baseline values over time; red blood cell mass and tolerance for aerobic work also increase over a period of several weeks.
Pathophysiology references
1. Luks AM, Ainslie PN, Lawley JS, et al: In High Altitude Medicine and Physiology, edited by Ward, Milledge, and West. 6th Edition. Boca Raton, FL. CRC Press.
2. Swenson, ER, Bartsch P: High-altitude pulmonary edema. Compr Physiol 2012. 2(4): 2753-2773.
3. Scoggin CH, Hyers TM, Reeves JT, et al: High-altitude pulmonary edema in the children and young adults of Leadville, Colorado. N Engl J Med 297(23):1269-1272, 1977. doi: 10.1056/NEJM197712082972309
4. Ebert-Santos C: High-altitude pulmonary edema in mountain community residents. High Alt Med Biol 18(3):278-284, 2017. doi: 10.1089/ham.2016.0100
5. Simonson TS: Altitude adaptation: A glimpse through various lenses. High Alt Med Biol 16(2):125-137, 2015.
Symptoms and Signs of Altitude Illness
Acute mountain sickness is by far the most common form of altitude illness.
Acute mountain sickness (AMS)
AMS is unlikely unless altitude is above 2400 m (8000 ft), but it can develop at lower elevations in some highly susceptible people. It is characterized by headache plus at least 1 of the following: fatigue, gastrointestinal symptoms (anorexia, nausea, vomiting), or persistent dizziness. Poor sleep was previously considered a symptom of AMS but is no longer considered 1 of the diagnostic criteria. Symptoms typically develop 6 to 10 hours after ascent and, in most cases, subside in 24 to 48 hours (1). AMS is common at ski resorts, and some people affected by it mistakenly attribute it to excessive alcohol intake (hangover) or a viral illness.
High-altitude cerebral edema (HACE)
HACE occurs rarely, anywhere from 1 to 5 days following ascent. Marked cerebral edema manifests as headache and diffuse encephalopathy with confusion, drowsiness, stupor, and coma. Gait ataxia is a reliable early warning sign (2, 3). Seizures, focal deficits (eg, cranial nerve palsy, hemiplegia), fever, and meningeal signs are uncommon and should prompt concern for other diagnoses. Papilledema may be present but is not necessary for diagnosis. Coma and death may occur within a few hours unless HACE is treated promptly.
High-altitude pulmonary edema (HAPE)
HAPE typically develops 24 to 96 hours after rapid ascent to > 2400 m (> 8000 ft) and is responsible for most deaths due to altitude illness. It may be preceded by AMS, but can also develop in isolation in people who were not manifesting other evidence of altitude illness.
Initially, patients have dyspnea on exertion, decreased exertion tolerance, and dry cough. Later, dyspnea is present with simple activities or at rest. Pink or bloody sputum and respiratory distress are late findings. On examination, cyanosis, tachycardia, tachypnea, and low-grade fever (< 38.5° C) are common. Focal or diffuse crackles (sometimes audible without a stethoscope) are usually present. HAPE may worsen rapidly; coma and death may occur within hours unless HAPE is treated promptly (4).
Other manifestations
Peripheral and facial edema are common at high altitude even in the absence of altitude illness.
Headache, without other symptoms of AMS, is also common.
Retinal hemorrhages can develop at altitudes as low as 2700 m (9000 ft) and are common at altitudes > 4800 m (> 16,000 ft). They are not a harbinger of severe altitude illness and are usually asymptomatic unless they occur in the macular region, in which case they typically present as painless loss of vision; they resolve over weeks without sequelae (4, 5). With symptomatic hemorrhages, descent is indicated, and further ascent is contraindicated until hemorrhages have resolved. Ophthalmology evaluation is warranted following descent for all patients with symptomatic high-altitude retinal hemorrhages (6).
People who have had radial keratotomy or LASIK may have significant visual disturbances at altitudes > 5000 m (> 16,000 ft). These symptoms disappear rapidly after descent (7).
Chronic mountain sickness (Monge's disease) is a disease that affects long-time high-altitude residents; it is characterized by excessive polycythemia, fatigue, dyspnea, aches and pains, and cyanosis (5). The disorder often involves alveolar hypoventilation (89).
Monge's disease is common in the Andes Mountains but has also been seen in high-altitude communities in Colorado (10). In other areas of the world (for example, in Tibet), lowlanders who have relocated to higher elevations develop a different form of chronic altitude illness marked by pulmonary hypertension and right ventricular dilation and hypertrophy, without overproduction of red blood cells.
Symptoms and signs references
1. Roach RC, Hackett PH, Oelz O, et al: The 2018 Lake Louise acute mountain sickness score. High Alt Med Biol 19(1):4-6, 2018. doi: 10.1089/ham.2017.0164
2. Dickinson JG: High-altitude cerebral edema: Cerebral acute mountain sickness. Semin Respir Med 5:151-158, 1983. doi:10.1055/s-2007-1011445
3. Houston CS, Dickinson J: Cerebral form of high-altitude illness. Lancet 2(7938):758-761, 1975. doi: 10.1016/s0140-6736(75)90735-7
4. Swenson ER, Bartsch P: High-altitude pulmonary edema. Compr Physiol 2012. 2(4): 2753-2773
5. Barthelmes D, Bosch MM, Merz TM, et al: Delayed appearance of high altitude retinal hemorrhages. PLoS One6(2):e11532, 2011. doi: 10.1371/journal.pone.0011532
6. Bosch MM, Barthelmes D, Landau K: High altitude retinal hemorrhages--an update. High Alt Med Biol13(4):240-244, 2012. doi: 10.1089/ham.2012.1077
7. Mader TH, White LJ: Refractive surgery safety at altitude. High Alt Med Biol. 2012 Mar;13(1):9-12. doi: 10.1089/ham.2011.1100
8. Penaloza D, Arias-Stella J: The heart and pulmonary circulation at high altitudes: Healthy highlanders and chronic mountain sickness. Circulation 115(9):1132-1146, 2007. doi: 10.1161/CIRCULATIONAHA.106.624544
9. Richalet JP, Rivera M, Bouchet P, et alAm J Respir Crit Care Med 172(11):1427-1433, 2005. doi: 10.1164/rccm.200505-807OC
10. Winslow RM, Monge CC: Hypoxia, polycythemia and chronic mountain sickness. 1987. Johns Hopkins University Press.
Diagnosis of Altitude Illness
History and physical examination
For high-altitude pulmonary edema (HAPE), a chest radiograph and blood oxygen levels, if available
Prompt diagnosis and initiation of treatment of high-altitude cerebral edema (HACE) and high-altitude pulmonary edema (HAPE) are essential to prevent coma and death.
Diagnosis of altitude illness is usually based on history and physical examination. Laboratory tests are usually unnecessary and may be unavailable depending on the setting in which illness develops (eg, remote mountain valley versus mountain resort community). However, imaging, when available, may be useful for HAPE and sometimes HACE.
In HAPE, hypoxemia is often severe, with pulse oximetry showing 40 to 70% saturation, depending on the elevation at which the individual becomes ill. Plain chest radiography shows a normal-sized heart and patchy lung edema (1, 2).
HACE can usually be differentiated from other causes of headache and coma (eg, infection, brain hemorrhage, uncontrolled diabetes) by history and clinical findings; if not, CT or MRI imaging of the head may help rule out other causes. MRI of the brain shows evidence of cytotoxic and vasogenic edema. Some of the characteristic findings, such as microhemorrhages and hemosiderin deposition, can persist for many months after illness and thus help confirm HACE after a return from a trip to high altitude (3, 4).
The Lake Louise Acute Mountain Sickness Score is a tool that can be used in diagnosis of AMS but is primarily designed for the purpose of research studies rather than clinical practice (5).
Diagnosis references
1. Vock P, Fretz C, Franciolli M, et al: High-altitude pulmonary edema: findings at high-altitude chest radiography and physical examination. Radiology 170(3 Pt 1):661-666, 1989. doi: 10.1148/radiology.170.3.2916019
2. Bärtsch P, Waber U, Haeberli A, et al: Enhanced fibrin formation in high-altitude pulmonary edema. J Appl Physiol 63(2):752-775, 1985.. doi: 10.1152/jappl.1987.63.2.752
3. Hackett PH, Yarnell PR, Weiland DA, et al: Acute and evolving MRI of high-altitude cerebral edema: Microbleeds, edema, and pathophysiology. AJNR Am J Neuroradiol 40(3):464-469, 2019. doi: 10.3174/ajnr.A5897
4. Schommer K, Kallenberg K, Lutz K, et al: Hemosiderin deposition in the brain as footprint of high-altitude cerebral edema. Neurology 81(20):1776-1779, 2013. doi: 10.1212/01.wnl.0000435563.84986.78
5. Roach RC, Hackett PH, Oelz O, et al: The 2018 Lake Louise acute mountain sickness score. High Alt Med Biol 19(1):4-6, 2018. doi: 10.1089/ham.2017.0164
Treatment of Altitude Illness
For high-altitude cerebral edema (HACE) and high-altitude pulmonary edema (HAPE), immediate descent and treatment with oxygen, medications, and pressurization
Acute mountain sickness (AMS)
High-altitude cerebral edema (HACE) and high-altitude pulmonary edema (HAPE)
Patients should descend to low altitude immediately. Helicopter evacuation may be life-saving (1). If descent is delayed, patients should rest and be given oxygen. If descent is impossible, oxygen (to raise the O2 saturation to > 90%), medications, and pressurization in a portable hyperbaric bag help buy time but are not substitutes for and should not delay descent.
For HACE (and severe AMS)
5, 6).
For HAPE
78). When promptly treated by descent, patients usually recover from HAPE within 24 to 48 hours. Exertion should be avoided during descent.
Some patients with HAPE in areas with adequate medical resources (eg, a ski resort community) and family or friends who can adequately monitor them can be discharged with supplemental oxygen (9). People who have had 1 episode of HAPE are likely to have another and should be so warned.
Pearls & Pitfalls
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Treatment references
1. Luks AM, Beidleman BA, Freer L, et al: Wilderness Medical Society clinical practice guidelines for the prevention, diagnosis, and treatment of acute altitude illness: 2024 Update. Wilderness Environ Med35(1_suppl):2S-19S, 2024. doi: 10.1016/j.wem.2023.05.013
2. Bärtsch P, Swenson ER: Clinical practice: Acute high-altitude illnesses. N Engl J Med 368:2294-2302, 2013. doi: 10.1056/NEJMcp1214870
3. Grissom CK, Roach RC, Sarnquist FH, et alAnn Intern Med 116(6):461-465, 1992. doi: 10.7326/0003-4819-116-6-461
4. Levine BD, Yoshimura K, Kobayashi T, et alN Engl J Med 321(25):1707-1713, 1989. doi: 10.1056/NEJM198912213212504
5. Dickinson J: High altitude cerebral edema: Cerebral acute mountain sickness. Semin Respir Med 5:151-761, 1983. doi:10.1055/s-2007-1011445
6. Houston CS, Dickinson J: Cerebral form of high-altitude illness. Lancet 2(7938):758-61, 1975. doi: 10.1016/s0140-6736(75)90735-7
7. Oelz O, Maggiorini M, Ritter M, et alLancet 2(8674):1241-1244, 1989. doi: 10.1016/s0140-6736(89)91851-5
8. Maggiorini M, Mélot C, Pierre S, et al: High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation. 2001;103(16):2078-2083. doi:10.1161/01.cir.103.16.2078
9. Zafren K, Reeves JT, Schoene R: Treatment of high-altitude pulmonary edema by bed rest and supplemental oxygen. Wilderness Environ Med 7(2):127-132, 1996. doi: 10.1580/1080-6032(1996)007[0127:tohape]2.3.co;2
Prevention of Altitude Illness
Slow ascent
Although physical fitness enables greater exertion at altitude, it does not protect against any form of acute altitude illness (1, 2). Maintaining adequate fluid intake does not prevent acute mountain sickness (AMS) but does preserve exercise performance and protect against dehydration, the symptoms of which closely resemble AMS (3). Opioids, benzodiazepines, and heavy alcohol consumption, particularly shortly before sleep, should be avoided.
Ascent
The most important measure is a slow ascent (4, 5). Above 3000 m (10,000 ft), climbers should not increase their sleeping altitude by more than approximately 300 to 500 m (1000 to 1600 ft) per day and should include a rest day (ie, sleep at the same altitude) every 3 to 4 days (6). If a single day's ascent must exceed 500 m (eg, due to logistics or terrain features), they should add in rest days to achieve an average rate of < 500 m (1600 ft) per day over the entire ascent. During rest days, climbers can engage in physical activity and ascend to higher altitudes but should return to the lower level for sleep. Climbers vary in ability to ascend without developing symptoms; a climbing party should be paced for its slowest member.
Acclimatization is gradually lost after a few days at low altitude, and climbers returning to high altitude after this duration should once more follow a graded ascent.
Medications
125 mg orally every 12 hours reduces the incidence of altitude illness (7). Acetazolamide should be started the night before ascent; it acts by inhibiting carbonic anhydrase and thus increasing ventilation (8). Acetazolamide 125 mg orally at bedtime reduces the amount of periodic breathing (almost universal during sleep at high altitude), thus limiting sharp falls in blood oxygen.
Patients allergic to sulfa medications have a small risk of cross-reactivity to acetazolamide; a supervised trial of acetazolamide should be considered for these patients before they make a trip to altitudes remote from medical care. Acetazolamide should not be given to patients with a history of anaphylaxis to sulfa medications. Acetazolamide may cause numbness and paresthesias of the fingers; these symptoms are benign but can be annoying. Carbonated drinks taste flat to people taking acetazolamide.
2 mg orally every 6 hours (or 4 mg orally every 12 hours) is an alternative to acetazolamide (9).
Low-flow oxygen during sleep at altitude is effective but inconvenient and may pose logistic difficulties.
Prevention references
1. Milledge JS, Beeley JM, Broome J, et al: Acute mountain sickness susceptibility, fitness and hypoxic ventilatory response. Eur Respir J 4(8):1000-10003, 1991.
2. Sareban M, Schiefer LM, Macholz F, et al: Endurance athletes are at increased risk for early acute mountain sickness at 3450 m. Med Sci Sports Exerc 52(5):1109-1115, 2020. doi: 10.1249/MSS.0000000000002232
3. Castellani JW, Muza SR, Cheuvront SN, et al: Effect of hypohydration and altitude exposure on aerobic exercise performance and acute mountain sickness. J Appl Physiol (1985) 109(6):1792-800, 2010. doi: 10.1152/japplphysiol.00517.2010.
4. Luks AM, Beidleman BA, Freer L, et al: Wilderness Medical Society clinical practice guidelines for the prevention, diagnosis, and treatment of acute altitude illness: 2024 Update. Wilderness Environ Med35(1_suppl):2S-19S, 2024. doi: 10.1016/j.wem.2023.05.013
5. Bartsch P, Swenson ER: Clinical practice: Acute high-altitude illnesses. N Engl J Med 368:2294-2302, 2013. doi: 10.1056/NEJMcp1214870
6. Luks AM: Clinician's corner: What do we know about safe ascent rates at high altitude? High Alt Med Biol 13(3):147-152, 2012. doi: 10.1089/ham.2012.1055
7. Basnyat B, Gertsch JH, Holck PS, et alHigh Alt Med Biol (1):17-27, 2006. doi: 10.1089/ham.2006.7.17
8. Fischer R, Lang SM, Leitl M, et alEur Respir J 23(1):47-52, 2004. doi: 10.1183/09031936.03.00113102
9. Ellsworth AJ, Larson EB, Strickland DAm J Med 83(6):1024-1030, 1987. doi: 10.1016/0002-9343(87)90937-5
10. Bärtsch P, Maggiorini M, Ritter M, et alN Engl J Med 325(18):1284-1289, 1991. doi: 10.1056/NEJM199110313251805
11. Maggiorini M, Brunner-La Rocca HP, Peth S, et al: Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: A randomized trial. Ann Intern Med 145(7):497-506, 2006. doi: 10.7326/0003-4819-145-7-200610030-00007
Key Points
About 20% of people who ascend to 2500 m (8000 ft) and 40% of those who ascend to 3000 m (10,000 ft) in 1 day develop some form of altitude illness, the most common form of which is acute mountain sickness (AMS).
AMS causes headache plus fatigue, gastrointestinal symptoms (anorexia, nausea, vomiting), or persistent dizziness.
High-altitude cerebral edema (HACE) causes headache, ataxia, and encephalopathy.
High-altitude pulmonary edema (HAPE) causes dyspnea, decreased exertion tolerance, and dry cough initially which can progress to dyspnea with simple activities or at rest, profound fatigue, cyanosis, and a cough productive of blood sputum in the more severe stages.
Diagnose altitude illness based on clinical findings.
Arrange immediate descent for patients with HACE, HAPE, or very severe AMS.
More Information
The following English-language resource may be useful. Please note that The Manual is not responsible for the content of this resource.
Luks AM: Physiology in medicine: A physiologic approach to prevention and treatment of acute high-altitude illnesses. J Appl Physiol (1985) 18(5):509-519, 2015. doi: 10.1152/japplphysiol.00955.2014
