Clinical manifestations

Presentation and course

High-altitude illness has protein manifestations, including high-altitude headache, acute mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema (50). Although high-altitude headache and acute mountain sickness are comparatively benign, high-altitude pulmonary edema and high-altitude cerebral edema may be fatal if not promptly addressed with emergent descent to a lower altitude and institution of supportive and corrective therapy (49).

Symptoms of acute mountain sickness. Common symptoms of acute mountain sickness include headache, fever, fatigue, nausea, dizziness, anorexia, and sleep disturbances. These are observed with a rapid ascent to 2500 m (8200 ft) or higher. Acute mountain sickness without headache has been reported at an altitude of below 3000 m (approximately 10,000 ft) and can be triggered by chronic stress or excessive exertion (31). Similar symptoms may be observed during high-altitude flights if the cabins are not adequately pressurized. If untreated, acute mountain sickness may progress to high-altitude pulmonary edema or high-altitude cerebral edema.

High-altitude pulmonary edema. Although some degree of pulmonary edema is present in high-altitude cerebral edema, it may be overshadowed by more dramatic neurologic symptoms. Symptoms of high-altitude pulmonary edema include dyspnea and dry cough that changes to productive cough. Signs include tachycardia, cyanosis, and pink-tinged frothy sputum. High-altitude pulmonary edema is diagnosed in the presence of at least 2 of 4 symptoms (dyspnea at rest, cough, weakness or decreased exercise performance, chest tightness or congestion) and 2 of 4 signs (crackles or wheezing in at least one lung field, central cyanosis, tachypnea, or tachycardia).

Physical examination reveals rales on chest auscultation, the “high-altitude pulmonary edema tongue,” very low pulse oximetry (SpO2), and, in advanced cases, bloody sputum (110; 111). The so-called "high-altitude pulmonary edema tongue" is white with irregularly distributed bright red areas suggesting local desquamation (110; 111). Although not always present, it can be seen in both children and adults and may resemble lingual changes with some viral infections, including COVID-19 (110; 111). These lingual features are highly suggestive of high-altitude pulmonary edema, especially in someone just arriving at high altitude who presents with cough (111).

High-altitude cerebral edema. In 1975, a cerebral form of mountain sickness in which cerebral edema predominated was described in a series of patients (51). High-altitude cerebral edema is characterized by a change in mental status or the development of ataxia in a person with acute mountain sickness (107). The clinical manifestations include severe headaches, ataxic gait, hallucinations, cranial nerve palsies, hemiplegia, and seizures. Impairment of consciousness may occur, ranging from drowsiness to coma. Neurologic symptoms can progress from mild symptoms to unconsciousness within 12 to 72 hours. Seizures may occur at high altitude without any clinical evidence of acute mountain sickness. Transient focal neurologic signs may manifest at high altitude without associated acute mountain sickness or other concurrent illness. Marked hyperventilatory response to hypoxia can cause hypocapnic cerebral vasoconstriction that leads to localized areas of cerebral ischemia resulting in transient focal neurologic impairment.

Chronic mountain sickness. Chronic mountain sickness is manifested by hypoxemia, polycythemia, high hemoglobin levels, and headaches in those who live permanently in altitudes above 4000 m (approximately 13,000 ft). Cardiovascular complications of living at very high altitude include pulmonary hypertension, right heart enlargement, and congestive heart failure. These patients usually have cognitive impairment.

Prognosis and complications

Acute mountain sickness is usually a relatively benign condition, but the more advanced forms with high-altitude cerebral edema and high-altitude pulmonary edema can be accompanied by severe morbidity, and death may result if prompt treatment is not instituted. Those who survive a comatose state from high-altitude cerebral edema may have memory and gait deficits that persist for months.

Biological basis

Etiology and pathogenesis

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.

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.

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 (66). 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. During exercise, with reduced red cell transit time, the arterial partial pressure of oxygen drops substantially as pulmonary oxygen exchange becomes diffusion limited (even in normal individuals).

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. 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 (05).

Sleep disorders at high altitude. Sleep is often disturbed at high altitude, with a high frequency of periodic breathing in conjunction with nocturnal hypoxia (72; 11; 88). This was well illustrated by the earliest recordings by Mosso and colleagues in the 1890s (77). These results were confirmed by the most important recordings from the early 20th century during the 1911 Anglo-American Expedition to Pikes Peak (28).

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 (11).

In 1986, nine Japanese climbers participated in an expedition to the Kunlun Mountains (7167 m; 23,510 ft) in China (72). During sleep at an altitude of 5360 m (17,600 ft), all of the 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 (11). 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 (90), although a history of migraine or other headache at low altitude is not a major risk factor for acute mountain sickness.

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.

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 (106). 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.

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 (52). 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) (80). Symptoms may be subtle and often involve cognitive impairment or lightheadedness.

A study in human volunteers found that hypoxia stimulates cerebral oxidative-nitrative stress (03). 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 (78). 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 (17). 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 (27; 26).

Acute mountain sickness is not associated with cerebral edema formation on MRI during simulated high altitude (71). 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 (25), 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 (87) 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.

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 (112).

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. 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 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 (09). Beta-adrenergic agonists upregulate the clearance of alveolar fluid by stimulating transepithelial sodium transport (89). 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).

High-altitude cerebral edema. Vasogenic and cytotoxic mechanisms are proposed for high-altitude cerebral edema, and venous hypertension is a possible contributory factor (105). 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 (20). 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 (04; 21; 98; 12).

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 (95). 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 (56).

Genetic factors contribute to the capacity to rapidly and efficiently acclimatize to high altitude, but the underlying mechanisms have not been elucidated (70). 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 particular single nucleotide polymorphism might be a risk factor (63).

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 (44).

Gender, age, or level of physical fitness do not play a significant role in susceptibility to acute mountain sickness.

Epidemiology

Acute mountain sickness affects more than 25% of individuals ascending to 3500 m (approximately 11,500 ft) and more than 50% of those above 6000 m (approximately 19,700 ft); for each increase in altitude of 1000 m (3300 ft) above 2500 m (8200 ft), the prevalence increases by 13% (74). Of the 20 million visitors to ski resorts in the western United States every year, approximately 5 million have some symptoms of acute mountain sickness. About half of climbers passing through 4243 m (13,920 ft) on the Everest route experience symptoms of acute mountain sickness, including headache, anorexia, nausea, vomiting, breathlessness, dizziness, weakness, and insomnia, and approximately 4% develop life-threatening disease (42; 24). The incidence of severe acute mountain sickness in UK military personnel performing adventure training on Mount Kenya at an altitude of 4985 m (approximately 16,350 ft) was 34% (47). Among 275,950 trekkers in Nepal from mid-1987 through 1991, there were 10 deaths from altitude illness, giving a mountain sickness–specific death rate of 3.6 per 100,000 trekkers (92).

From June 2001 through 2003, about 75,000 construction workers worked in a low-barometric-pressure environment to build the Qinghai-Tibetan Railway (107). The new railroad stretches 1118 km (695 miles) from Golmud (2808 m; 9213 ft) to Lhasa (3658 m; 12,000 ft), with more than three quarters of the distance above 4000 m (approximately 13,100 ft), through the Mt Kun Lun and Tanggula ranges. From July 2001 through October 2003, the overall incidence rates of high-altitude pulmonary edema and high-altitude cerebral edema were approximately 0.5% and 0.3%, respectively.

Prevention

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 (82). 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 (69). Therefore, a history of acute mountain sickness cannot serve as a guide for prophylactic strategies for high-altitude ascent.

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 (15; 16; 14). 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 (15), 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 (15). 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 (79; 55). 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 (79). 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 conclusions similar 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 (65; 85; 34; 35). 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 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 (62; 61).

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 (73). 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 (60).

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) (30).

A Cochrane review evaluated the preventive benefits of dexamethasone in seven parallel studies collectively involving 205 participants (79). 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 (29; 30).

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 (79). 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 (39). 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 (75). 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 (96).

Elevated serum concentrations of low-density lipoprotein (LDL) are somewhat protective against the development of acute mountain sickness (45; 46). 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 (46).

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 (55).

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 (22).

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 (07).

Ibuprofen is slightly inferior to acetazolamide for the prevention of acute mountain sickness and should not be recommended over acetazolamide for rapid ascent (13).

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 (67):

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

Differential diagnosis

Confusing conditions

Some subjective symptoms of acute mountain sickness, such as headache and sleep disturbances, may also result from travel-related stress, although symptoms are typically more severe and temporally linked with rapid ascent in high-altitude headache and acute mountain sickness.

It is also important to recognize that neurologic disorders may be precipitated or acutely exacerbated by a high-altitude environment, and these disorders may require different treatment than that for acute mountain sickness or high-altitude cerebral edema. For example, on ascent to 5200 m (17,000 ft), a young man with no prior history of acute mountain sickness developed a severe headache associated with nausea, fatigue, anorexia, and difficulty sleeping and was, therefore, given a presumptive diagnosis of acute mountain sickness (23). However, when he failed to improve on descent to a lower altitude, neurologic investigations revealed that he had pituitary apoplexy instead. In another case, a 32-year-old man trekked to the South Everest Base Camp (5364 m, or 17,600 ft) in Nepal (94). On the last day of the ascent, he noticed dysesthesias in his right leg and descended by helicopter but had a generalized seizure shortly after descent, followed by right hemiparesis and speech arrest. Without the availability of cerebral imaging, he was given intravenous dexamethasone with marked clinical improvement, including regaining the ability to speak. MRI later revealed a left frontotemporal meningioma with compression of brain parenchyma and minimal paralesional edema.

Acute mountain sickness must not be confused with high-altitude cerebral edema. Isolated acute mountain sickness exhibits no neurologic findings and is self-limited. High-altitude cerebral edema, which usually develops between 24 and 72 hours after a gain in altitude, is characterized by worsened mental status or ataxia, typically occurs in association with acute mountain sickness or high-altitude pulmonary edema, and is a medical emergency that may end fatally if not promptly addressed.

In cases of fever at moderate or high altitude, the differential diagnosis must include acute mountain sickness.

Acute mountain sickness should be differentiated from altitude decompression sickness, which usually affects aviators rapidly ascending to high altitude in nonpressurized aircraft or experiencing sudden cabin depressurization. Symptoms and signs of altitude decompression sickness are due to embolization of gas bubbles (typically nitrogen gas bubbles) in the blood. This condition is like the decompression sickness affecting divers who ascend to the surface rapidly. Both forms of decompression sickness are managed by recompression. Altitude decompression sickness is not encountered during mountain climbing (except potentially in the rare circumstance in which an aviator makes an emergency landing at a significant altitude on a mountain).

High-altitude cerebral edema needs to be distinguished from cerebral edema associated with other intracranial disorders, but the temporal association with ascent to high altitude, absence of history of neurologic disorders or head injury, and relief of symptoms on descent should readily differentiate high-altitude cerebral edema from other conditions. Patients with intracranial space-occupying lesions may show manifestations of increased intracranial pressure on ascent to high altitude.

The absence of previous cardiac disease, temporal association with ascent, and response to agents such as acetazolamide help in differentiation. Right ventricular enlargement and heart failure may develop in patients with subacute mountain sickness. Erythrocytosis or secondary polycythemia in chronic mountain sickness needs to be differentiated from polycythemia vera.

Diagnostic workup

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 (48). 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 (86). 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 (86). 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 (86). 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 (86). Since the 2018 revision, several criticisms have been raised, and critics have suggested the following (19; 84): (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; and (4) dizziness/lightheadedness may result from a hyperresponsiveness to hypoxia and not to acute mountain sickness itself.

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) (53). 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) (58).

Table 2. Wilderness Medical Society Severity Classification of Acute Mountain Sickness

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.

Acute mountain sickness or high-altitude pulmonary edema usually precede high-altitude cerebral edema, but high-altitude cerebral edema may occur without these (05). 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 (91; 05; 58). 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 (105).

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 (18; 81; 57; 59; 68). Reported causes of mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) include high-altitude cerebral edema, infection, antiepileptic drug withdrawal, and cesarean section (81).

Management

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 (18). 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)] (14). Dexamethasone has also been recommended for prophylaxis and treatment of high-altitude headache (14), 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 (43).

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) (108). 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 (36).

Acute mountain sickness. 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 (54). 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 (41). However, the quality of evidence supporting the use of acetazolamide for the treatment of acute mountain sickness is poor (97). 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. 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 (83; 109). Dexamethasone, calcium channel blockers, and phosphodiesterase inhibitors have been advocated for the treatment of high-altitude pulmonary edema (55), but according to the current available literature, neither phosphodiesterase-5 inhibitors, calcium channel blockers (eg, nifedipine), nor dexamethasone significantly alters the outcome (109; 10).

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 (93). These treatments have generally been considered, recommended, or used based on analogy with other disorders. Acetazolamide reduces the rate of CSF formation and, combined 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 (67):

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.

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.

Special considerations

A systematic review of various studies related to the effect of older age (60 years and older) on the risk of acute mountain sickness reported conflicting results (37).

Pregnancy

Pregnant women can usually tolerate travel up to an altitude of 4000 (approximately 13,000 ft) with no change in delivery of oxygen to the placenta. Risk to the fetus is insignificant during short-term exposure to moderate altitudes. Women with high-risk and late-term pregnancies are advised not to travel to altitudes higher than 2500 m (8200 ft).