What Is Altitude Illness

Altitude illness means acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE). In rare cases, altitude sickness can be life-threatening. If you develop HAPE or HACE, you are at risk for complications such as coma or even death. Get treatment as soon as possible to reduce your risk.

Many people who ascend to moderate or high altitudes experience the effects of acute altitude sickness. Symptoms of this sickness typically begin 6-48 hours after the altitude exposure begins, and include headache, nausea, lethargy, dizziness and disturbed sleep.

Everest base camp found that use of an antioxidant vitamin supplement (providing 1,000 mg of vitamin C, 400 IU of vitamin E, and 600 mg of lipoic acid daily) significantly improved symptoms of altitude sickness as compared to placebo.

Other Names

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

General

  • 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

Terminology

Acute

  • Acute High Altitude Illness (AHAI)
    • A broad term for the range of pathology that the unacclimatized 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 diseases 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

  • Chronic altitude-related diseases are not discussed here
    • Chronic mountain sickness (Monge disease)
    • High-altitude pulmonary hypertension
  • High Altitude Training
    • A detailed discussion of training at altitude

Acclimatization

  • 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
  • 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, but 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 leads 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 the oxygen-carrying capacity of the blood
    • The 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 acclimatization 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
    • The advantage is that it lessens the otherwise occurring fall in alveolar pO2
    • On the summit of Mount Everest, alveolar ventilation is increased 5 fold
      • pCO2 drops to 7-8 mm Hg, and alveolar pO2 maintains at 35 mm Hg[7]
  • Acid-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,
      • The overall effect of this is tempered by hypocapnia caused by hyperventilation
  • Ascent Rate
    • Rate of ascent is one of the main predictor’s predictors of the development 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
    • The major factor for predicting HAI
    • Dose-dependent type response in susceptible individuals
    • The 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
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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 the risk of HAPE
    • Chronic lung diseases including pulmonary hypertension, COPD
    • It is not currently thought that Asthma increases the risk (need citation)
  • Cardiac disease
    • Cardiac diseases 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

Prevention

  • 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)
  • Perform risk assessment for HAI
    • No such test currently exists that is widely accepted
    • Tannheimer et al measured the lowest SaO2 during a run test at a high altitude plus the time needed to complete the run predicted risk for development of AMS[27]
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AMS/HACE

  • Pharmacoprophylaxis
    • Generally speaking, not required if an 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 the 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
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HAPE

  • 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