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Altitude Illness Main

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Other Names

  • Acute High Altitude Illness (AHAI)
  • Altitude Illness
  • High Altitude Illness (HAI)




  • Incidence
    • HACE and HAPE have an estimated incidence of 0.1% to 4%[1]
    • Up to 50–70% of mountaineers develop symptoms of AMS[2]


  • General
    • Hypoxemia occurs at high altitude because there is a lower inspired partial pressure of oxygen (hypoxia) as a result of the decreased barometric pressure
    • This in turn leads to varying degrees of tissue hypoxia
    • Onset of HAI occurs between initial exposure to hypoxia and eventual acclimatization
    • Usually in a time period of hours to days.
  • Altitude definitions[3]
    • High altitude: > 1500 m
    • Very high altitude: 3500 to 5500 m
    • Extreme altitude: >5500 m



  • Acute High Altitude Illness (AHAI)
    • Broad term for the range of pathology that the unacclimatised individual may develop when exposed to hypoxia at high altitude
  • Acute Mountain Sickness (AMS)
    • Constitution of symptoms that occur with altitude without any evidence of neurological dysfunction
    • The most common symptoms include headache, trouble sleeping, fatigue
    • Part of a spectrum of disease that ends with HACE
  • High Altitude Cerebral Edema (HACE)
    • End stage of AMS in which the patient begins to develop neurological signs and sequelae
    • Once the patient has evidence of neurological end organ dysfunction, they have HACE
  • High Altitude Pulmonary Edema (HAPE)
    • Non-cardiogenic pulmonary edema occurring as a result of pulmonary artery hypertension
    • Patients will have signs and symptoms consistent with pulmonary edema


  • Chronic altitude related diseases not discussed here
    • Chronic mountain sickness (Monge disease)
    • High-altitude pulmonary hypertension



  • General
    • Discussion of physiologic response to hypoxia and adaptations to altitude
    • Defined as a series of adjustments by the body to meet the challenge of hypoxemia
    • Acclimatization does not seem to occur above 5000-5500 meters (need citation)
  • Duration/ Time to Acclimatize
    • Varies significantly between individuals
    • Optimally, days to a week, less commonly longer
    • AMS onset occurs during the time between initial hypoxia and onset of acclimatization
    • Some individuals acclimatize quickly, some very slowly and predictably develop AMS; most somewhere in between
  • Systemic changes are well understood, what occurs at the molecular and cellular level is not fully described
    • Thought to be molecular up-regulation of hypoxia inducible factor-1[4]
  • Early Compensatory effects
    • Increased minute ventilation leading to a rise in arterial oxygen saturation (SaO2)
    • Mild diuresis and contraction of plasma volume (more oxygen is carried per unit of blood)
    • Elevated blood flow and oxygen delivery
    • Catecholamine-mediated increases in heart rate and cardiac output
    • Hypoxic pulmonary vasoconstrictor response (HPVR)
  • Polycythemia
    • Definition: increased concentration of erythrocyte
    • Increases oxyegn carrying capacity of blood
    • Process takes several weeks
    • Takes several days before increased production is evident[5]
    • For this reason, polycythemia is not thought to play a large role in rapid acclimitization to altitudes[6]
    • Psuedopolycythemia can occur from reduced thirst drive at low temperature leading to dehydration
  • Hyperventilation
    • Definition: increase in the rate and depth of breathing at altitude
    • Results in increased alveolar ventilation, minute ventilation
    • Advantage is that it lessens the otherewise occuring fall in alveolar pO2
    • On the summit of Mount Everest, alveolar ventilation is increased 5 fold
      • pCO2 drops to 7-8 mm Hg, alveolar pO2 maintains at 35 mm Hg[7]
  • Acide-Base Changes
    • pH increases acutely due to reduction in alveolar pCO2 and subsequent respiratory alkalosis
    • Occurs in both blood and cerebrospinal fluid, the later tends to inhibit hyperventilation
    • Carotid body oxygen sensors initiate a hypoxic ventilator respons to help compensate[8]
    • After a few days, pH of the CSF normalizes as bicarbonate moves out of the CSF
    • A few days later, the pH of blood normalizes from renal excretion of bicarbonate
  • Further adaptations
    • At the tissue level[9]
      • Increases in mitochondrial density
      • Increased capillary-to-fiber ratio
      • Fiber cross sectional area
      • Myoglobin concentration
    • Cerebral circulation[10]
      • Increased flow due to hypoxia-induced cerebral vasodilation,
      • Overall effect of this is tempered by hypocapnia caused by hyperventilation

Risk Factors

  • Ascent Rate
    • Rate of ascent one of the main predictors predictor of developing HAI
    • Dose-dependent type response in susceptible individuals
    • Short ascent time increases risk[11]
    • Ascending at a rate of more than 500 m a day above the level of 3000 m[12]
    • Individuals who ascend rapidly above 4,500 m with a previous history of HAPE have a 60% chance of HAPE recurrence[13]
  • Maximum Altitude
    • Major factor for predicting HAI
    • Dose-dependent type response in susceptible individuals
    • Disease can develop based on max altitude: AMS (>2500 m), HAPE (>3000 m), HACE (>4000–5000 m)
  • Increased length of time at altitude
  • Higher sleeping altitude
  • Individual physiological susceptibility to HAI
    • Likely a combination of genetic and environmental variables
    • Normally reside permanently under 900 m[14]
  • Previous history of HAI
    • Increases likelihood of future episodes
  • Physical activity or exertion
    • Exercise is likely to further increase hypoxemia
    • Physical fitness does not appear to offer protection from HAI[15]
  • Dehydration
    • Associated with AMS
    • Unclear whether this is an independent risk factor
  • Abnormal lung function
    • Individuals who display higher oxygen desaturation during exercise at sea level may be more likely to develop AMS[16]
    • Sometimes referred to as hypoxic ventilatory response (HVR)
    • The role of HVR in assessing risk of HAI is not currently well understood
  • Anatomical variations of intracranial volume and space
    • Known as the "tight fit" hypothesis, it may account for the decrease in AMS in patients over age 50 who have greater capacity for cerebral edema
    • More brain allows for less compensation during increased pressures
  • Gender
    • Women are at increased risk of AMS and HACE
    • Men are at increased risk of HAPE[17][18]
  • Other
    • Obesity
    • Younger age
    • Use of sedative drugs, alcohol

More Specific to HAPE

  • Pulmonary circulation/ parenchyma
    • Elevated pulmonary artery pressure and hyper-responsive pulmonary circulation to hypoxia or exercise at sea level[19]
    • Tibetans appear to have hyporesponsive pulmonary circulation to hypoxia compared with lowlanders[20]
    • Abnormal sodium channels in alveolar fluid clearance are also implicated[21]
  • Lung disease
    • Respiratory infections may or may not increase risk of HAPE
    • Chronic lung Disease including pulmonary hypertension, COPD
    • It is not currently thought that Asthma increases risk (need citation)
  • Cardiac disease
    • Cardiac disease including CAD, CHF

Protective Factors

  • Genetic
    • Tibetan and Andean populations have adapted to hypobaria
  • Nitrous Oxides
    • Tibetans have a significantly higher plasma concentration of nitric oxide by-products[22]
    • Impaired nitrous oxide synthesis has been proposed as a genetic risk factor
  • Previous altitude exposure


  • Avoid exposure to hypobaric hypoxic environment
    • For example, in aircraft, use pressurized cabin
    • In high altitude trains to Tibet, supplemental oxygen is provided
    • A 1% increase in oxygen concentration is the equivalent of descending 300 m in altitude[23]
  • Appropriate ascent profile
    • Crucial to prevent HAI
    • Proven effectiveness in multiple studies[24][25]
    • Do not increase sleeping altitude by greater than 300–500 m per day (over 3000 m)
    • Include a rest day every 3 or 4 days above 3000 m to minimize the risk of AMS, allow acclimatization
  • Over-exertion
    • Increases overall risk of HAI, should be avoided
  • "Climb High, Sleep Low"
    • Can reduce hypoxia exposure that can worsen during sleep at altitude due to nocturnal periodic breathing[26]
  • Avoid
    • Drugs that can increase sedation (alcohol, sleep aids)
    • Some climbers have successfully used Zolpidem (ambien) at elevation
  • Perform risk assessment for HAI
    • No such test currently exists that is widely accepted
    • Tannheimer et al measured lowest SaO2 during a run test at high altitude plus time needed to complete the run predicted risk for development of AMS[27]


  • Pharmacoprophylaxis
    • Generally speaking, not required if appropriately controlled ascent rate is employed
    • In high risk patients who are susceptible, ascent greater than 3500 m in one day or faster than 300 m per day, acetazolamide is indicated
  • Acetazolamide
    • Proven to be effective in prevention of AMS in multiple studies[28][29]
    • Consider for patients at moderate or high risk of AMS
    • Prophylactic dosage for adults is 125 mg every 12 hours; for children is 2.5 mg/kg (maximum: 125 mg) every 12 hours
    • Initiate the day before ascent; continue two to four days after arrival at the target altitude
    • Still beneficial if start day of ascent
  • Dexamethasone
    • Can prevent AMS, HACE in moderate to high risk patients but does not help with acclimatization
    • Prophylactic dose: 2 mg every six hours or 4 mg every 12 hours (4 mg every 6 hours in high risk situations)
    • Initiate the day before ascent; continue two to four days after arrival at the target altitude
    • If used greater than 10 days, taper down rather than stop abruptly
    • Some recommend reserving it for treatment rather than initiating as a prevention
  • Possibly Ibuprofen
    • Can be used in patients who want to avoid or can't take Acetazolamide, Dexamethasone
    • Recommended dose: 600 mg three times daily
    • Studies comparing ibuprofen to acetazolamide had mixed results: one found similar benefits, another found ibuprofen inferior (need citations)
  • Other considerations
    • Chew coco leaves or coco tea (not studied, no formal recommendations)
  • Other medication options not specifically recommended for AMS include
    • Acetaminophen
    • Antioxidants
    • Dietary nitrates
    • Ginkgo
    • Inhaled budesonide
    • Iron
    • Leukotriene receptor blockers
    • Phosphodiesterase inhibitors
    • Salicylic acid
    • Spironolactone
    • Sumatriptan


  • General
    • Objective of pharmacoprophylaxis is to prevent pulmonary artery hypertension
    • WMS guidelines currently recommend nifedipine
    • Salmeterol, tadalafil, acetazolamide and dexamethasone are not currently recommended for HAPE prophylaxis.
  • Nifedipine
    • Reduces the incidence of HAPO from 63% to 10% when ascending over 4500 m
    • Dose: 20 mg three times daily
    • WMS guidelines recommend using only 60 mg nifedipine modified-release daily (divided in 2 or 3 doses)
    • This should be started 1 day prior to ascent and continued for 5 days
  • Phosphodiesterase-5 inhibitor
    • Tadalafil: 10 mg twice a day provides similar protection to nifedipine
    • Sildenafil is another option, however a recent study showed it increased severity of AMS[30]
  • Acetazolamide
    • Role is unclear
    • One study showed no benefit[29]
  • Dexamethasone
    • Effective prophylactic in HAPE susceptible individuals.
    • See dosing above
  • Salmeterol
    • Effective, but less so than CCB or phosphodiesterase inhibitors
    • One study found it reduced the incidence from 74% to 33% when ascending over 4500 m[31]
    • Dose: 125 µg twice daily

See Also


  1. Basnyat B, Murdoch DR. High-altitude illness. Lancet 2003; 361: 1967–1974.
  2. Hupper T, Gieseler U, Angelini C, Hillebrandt D, Milledge J. Emergency field management of acute mountain sickness, high altitude pulmonary oedema, and high altitude cerebral oedema. In: UIAA Medical Commision (ed.) Consensus statement. 2008. Bern, Switzerland: UIAA
  3. Fulco CS, Rock PD, Cymerman A. Improving athletic performance: is altitude residence or altitude training helpful? Aviat. Space Environ. Med. 2000; 71:162Y71
  4. Webb JD, Coleman ML, Pugh CW: Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing. Cell Mol Life Sci 2009.
  5. Pugh LG. Blood volume and hemoglobin concentration at altitude above 18,000 ft (5,500 m). J Physiol 1964; 170: 344−53.
  6. West JB. The physiological basis of high-altitude diseases. Ann Intern Med 2004; 141: 789−800.
  7. West JB, Hackett PH, Maret KH, et al. Pulmonary gas exchange on the summit of Mount Everest. J Appl Physiol 1983; 55: 678−87.
  8. Lahiri S. Peripheral chemoreceptors and their sensory neurons in chronic states of hypo- and hyperoxygenation. Handbook Physiol Env Physiol 1996; 2: 1183−206
  9. Vogt M, Puntschart A, Geiser J, et al. Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J. Appl. Physiol. 2001; 91:173Y82.
  10. Wilson MH, Newman, S, Imray CH. The cerebral effects of ascent to high altitudes. Lancet. Neurol. 2009; 8:175Y91.
  11. Bloch KE, Turk AJ, Maggiorini M, et al. Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m. High Alt Med Biol 2009; 10: 25–32.
  12. Luks AM, McIntosh SE, Grissom CK, et al. Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness. Wild Environ Med 2010; 21: 146–155.
  13. Bartsch P, Maggiorini M, Mairbaurl H, Vock P, Swenson ER. Pulmonary extravascular fluid accumulation in climbers. Lancet 2002; 360: 571−2.
  14. Honigman B, Theis MK, Koziol-McLain J, et al. Acute mountain sickness in a general tourist population at moderate altitudes. Ann Intern Med 1993; 118: 587–592.
  15. Milledge JS, Beeley JM, Broome J, Luff N, Pelling M, Smith D. Acute mountain sickness susceptibility, fitness and hypoxic ventilatory response. Eur Respir J 1991; 4: 1000–1003.
  16. Richalet JP, Larmignat P, Poitrine E, Letournel M, Canoui-Poitrine F. Physiological risk factors for severe high-altitude illness: a prospective cohort study. Am J Respir Crit Care Med 2012; 185: 192–198.
  17. Sophocles AM Jr. High-altitude pulmonary edema in Vail, Colorado, 1975–1982. High Alt Med Biol 1986; 144: 569−73.
  18. Hultgren HN, Honigman B, Theis K, Nicholas D. High-altitude pulmonary edema at a ski resort. West J Med 1996; 164: 222−7.
  19. Dehnert C, Grunig E, Mereles D, von Lennep N, Bartsch P. Identification of individuals susceptible to high-altitude pulmonary oedema at low altitude. Eur Respir J 2005; 25: 545–551
  20. Groves BM, Droma T, Sutton JR, et al. Minimal hypoxic pulmonary hypertension in normal Tibetans at 3,658 m. J Appl Physiol 1993; 74: 312–318.
  21. Sartori C, Duplain H, Lepori M, et al. High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects. Eur Respir J 2004; 23: 916–920.
  22. Erzurum SC, Ghosh S, Janocha AJ, et al. Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans. Proc Nat Acad Sci U S A 2007; 104: 17593–17598.
  23. West JB. High-altitude medicine. Am J Resp Crit Care Med 2012; 186: 1229–1237.
  24. Hackett PH, Rennie D, Levine HD. The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 1976; 2: 1149–1155.
  25. Bloch KE, Turk AJ, Maggiorini M, et al. Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m. High Alt Med Biol 2009; 10: 25–32.
  26. Rodway GW, Hoffman LA, Sanders MA. High-altitude related disorders Y part 2: prevention, special populations, and chronic medical conditions. Heart Lung. 2003; 33:3Y12
  27. Tannheimer M, Albertini N, Ulmer HV, et al. Testing individual risk of acute mountain sickness at greater altitudes. Milit. Med. 2009; 174:363Y9.
  28. Low EV, Avery AJ, Gupta V, Schedlbauer A, Grocott MP. Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. BMJ 2012; 345: e6779.
  29. 29.0 29.1 Basnyat B, Gertsch JH, Holck PS, et al. Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol 2006; 7: 17–27.
  30. Bates MG, Thompson AA, Baillie JK, et al. Sildenafil citrate for the prevention of high altitude hypoxic pulmonary hypertension: double blind, randomized, placebo-controlled trial. High Alt Med Biol 2011; 12: 207–214.
  31. Sartori C, Allemann Y, Duplain H, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 2002; 346: 1631–1636.
Created by:
John Kiel on 13 June 2019 05:34:31
Last edited:
22 June 2022 15:15:12