Michael Yaron, Ryan D. Paterson and Christopher B. Davis

Epidemiology

High-altitude illness represents a spectrum of clinical entities that have hampered the activities of mountaineers, merchants, military forces, aviators, and explorers throughout time. This illness is seen clinically in one of several forms that overlap and share a common pathophysiologic mechanism. Acute mountain sickness (AMS) is the relatively benign and self-limited presentation, whereas high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema (HACE) represent the potentially life-threatening manifestations of high-altitude illness.

Worldwide, it is estimated that approximately 40 million individuals live above 8000 feet, and 25 million live above 10,000 feet.¹ Rather than these high-altitude residents, the groups at risk for acute altitude illnesses are those who ascend into mountainous regions. Mountain sports activities and tourism are attracting increasing numbers of participants each year. This, combined with the rapid ascent, made possible by air transportation results in more unacclimatized individuals at risk for high-altitude illness. More than 1 million visitors travel annually to the remote high mountain ranges of Asia, Africa, and South America.¹ Approximately 35 million visitors travel annually to high-altitude recreation areas in the western United States.¹

The incidence of high-altitude illness depends on many variables, including the rate of ascent, previous altitude exposure, and individual genetic susceptibility.2,3 Sleeping altitude, final altitude reached, and duration of stay at altitude are also risk factors for AMS development.⁴ AMS is common (67% incidence) among mountain climbers on Mt. Rainier who ascend quickly (1 or 2 days) to 14,410 feet.⁵ Trekkers who fly into the Khumbu region to explore the Mt. Everest area have a higher incidence of AMS (47%) compared with those who walk (23%).⁶ Skiers who visit resorts in the western United States from sea level generally fly or drive to the region but sleep at relatively lower altitudes than the other groups mentioned. Among this population, AMS occurs in approximately 25%.⁷ Given the large number of visitors (approximately 25 million) in Colorado each year, this is not a trivial matter. The incidence of HAPE varies from 0.01 to 2% in most studies but has reached 15.5% among soldiers flown directly to 14,500 feet without a chance to acclimatize at a lower altitude.^6,8 The incidence of HACE is lower, and although it frequently occurs with HAPE, it can be seen as an isolated entity. Both HAPE and HACE are more common with a longer duration of visit and higher sleeping altitude.

Age may be a relative risk factor. Most studies of children suggest that they have the same incidence of AMS as adults do.9–12 One small study of tourists in Chile evaluated children 4 to 48 months old and found higher AMS scores and lower oxygen saturations compared with those of their parents.¹³ Younger individuals (<20 years old) are more likely to have HAPE, although HAPE is extremely rare in children younger than 2 years. Gender does not affect the incidence of AMS²; however, women may have less risk for development of HAPE.^6,7,14,15 No relationship appears to exist between AMS development and the menstrual cycle.¹⁶

The number of older travelers visiting mountain resorts is increasing. Many of these individuals have underlying health problems, including lung disease (10%), heart disease (25%), and hypertension (30%). Despite these conditions, the risk for AMS development in adults older than 50 years may be less than in younger age groups.2,17 One study found no difference in the incidence or severity of AMS in climbers older than 50 years compared with a matched cohort of younger climbers.¹⁸ Nevertheless, there are indications that elders may not react well to acute high-altitude exposure. Pulmonary vital capacity decreases almost one third in elders ascending from sea level to 14,000 feet for 1 week, producing a large decrease in both oxygen saturation and maximal oxygen uptake during exercise.

Definitions

Moderate altitude is between 8000 and 10,000 feet of elevation. Although most people do not experience significant arterial oxygen desaturation until they reach higher altitudes, high-altitude illness is common with rapid ascent above 8000 feet, and individuals with underlying medical problems may be predisposed to development of altitude illness at lower levels.

High altitude is between 10,000 and 18,000 feet. Most serious altitude illness occurs at these levels. The pathophysiologic effects of high altitude begin when the oxygen saturation of the arterial blood begins to fall below the 90% level. The sigmoidal shape of the oxyhemoglobin dissociation curve prevents a significant fall of arterial oxygen saturation (SaO₂) in most individuals until an altitude of approximately 12,000 feet. At this altitude, the steep portion of the curve is encountered, and marked oxygen desaturation may occur with relatively small increases in altitude (Fig. 144-1). Some predisposed individuals may desaturate to less than 90% at altitudes as low as 8000 feet.

Extreme altitude is above 18,000 feet. At this height, complete acclimatization generally is not possible, and long visits above this level result in progressive deterioration.

Environmental Considerations

Barometric pressure decreases logarithmically as the altitude rises. The partial pressure of oxygen (PO₂) in the atmosphere also decreases as altitude rises, but it remains a constant 20.93% of the barometric pressure. The shape of the earth is slightly flat at the poles and bulging at the equator. The atmospheric envelope that surrounds the earth has a similar shape; therefore, the barometric pressure is lower at higher latitudes than it is at the equator. For example, it has been calculated that it would be impossible for a climber to reach the summit of Mt. Everest without supplemental oxygen if the mountain happened to be in a more northern latitude.¹⁹

The atmospheric envelope also undergoes a seasonal tide that causes a variation in its local thickness. This results in barometric pressures that are lower and “relative altitudes” that are higher during the winter season. Local weather can also have a significant effect on barometric pressure from day to day. A low-pressure front can reduce the barometric pressure 12 to 40 mm Hg (500-2500 feet) and result in a significant temporary increase in relative altitude.

Acclimatization

The term acclimatization refers to the series of integrated adaptations that take place at high altitude, which tend to restore the oxygen pressures within the tissues toward normal sea-level values despite the lowered PO₂ of the atmosphere. These processes occur gradually and involve multiple systems from protein synthesis to respiratory, cardiovascular, and hematologic adjustments. Gradual ascents made by mountaineers during several weeks have allowed the successful summiting of many of the world’s highest peaks, including Mt. Everest (29,029 feet), without supplemental oxygen. Without this gradual approach to allow acclimatization, however, rapid exposure to extreme altitude results in loss of consciousness, and death may occur in a matter of minutes.

Acclimatization begins at the altitude that causes the oxygen saturation of arterial blood to fall below sea-level values. The altitude at which this occurs depends on the rate of ascent, the duration of exposure, and the individual’s physiology. People with preexisting conditions that reduce oxygen saturation or content may have a decreased altitude tolerance. Of particular importance are both acute and chronic cardiac and respiratory illnesses. Most healthy, unacclimatized visitors to high altitude will not desaturate significantly (to less than 90%) until they reach elevations higher than 8000 feet.¹

The risk of high-altitude illness also depends on an individual’s inherent ability to acclimatize. Some people acclimatize easily without having any clinical symptoms. Others may transiently have AMS during acclimatization, and a few have marked reactions to altitude exposure, developing severe altitude illness. This variability involves many genetic and epigenetic factors that moderate the process of acclimatization.3,20 Previous successful acclimatization may be predictive of future responses for adults in similar conditions, but this may not be the case for children.²¹

One of the most important physiologic changes that occurs during acclimatization is an increase in minute ventilation, causing a decrease in the partial pressure of carbon dioxide (PACO₂). The alveolar gas equation states that as the PACO₂ decreases, a corresponding increase in PAO₂ occurs, thereby increasing arterial oxygenation (Box 144-1). Thus the level of ventilation determines alveolar oxygen for a given inspired oxygen tension.

When a person arrives at high altitude, the peripheral chemoreceptors in the carotid bodies respond to a decrease in PAO₂ and signal the respiratory control center in the medulla to increase ventilation. This increase in ventilation is known as the hypoxic ventilatory response (HVR), which may be inhibited or stimulated by numerous factors, including ethanol, sleep medications, caffeine, cocoa, prochlorperazine, and progesterone. The magnitude of the HVR varies among individuals and may be genetically predetermined.²²

As ventilation increases, a respiratory alkalosis occurs that acts as a negative feedback system on the central respiratory center, limiting any further increase in ventilation. Within 24 to 48 hours of ascent, the kidneys excrete bicarbonate in an effort to compensate for the alkalosis. As the pH normalizes, ventilation rises slowly, reaching a maximum after 6 to 8 days. This process is enhanced by acetazolamide. The ability to achieve an adequate HVR varies and is related to the ability to acclimatize. A low HVR and relative hypoventilation are implicated in the pathogenesis of both AMS and HAPE.²³ For the majority of people with intermediate HVRs, however, ventilatory drive probably has no predictive value for AMS development.²⁴

The release of catecholamines on ascent stimulates the circulatory system to increase cardiac output. This is manifested by an elevation in heart rate, blood pressure, cardiac output, and venous tone.²⁵ Except at extreme altitudes, acclimatization results in the gradual return of the resting heart rate to near sea-level values. Resting relative tachycardia is evidence of poor acclimatization. As the altitude increases, a decrease in maximal heart rate capacity occurs, and at the limits of acclimatization, maximal and resting heart rates converge.

The hematopoietic response to high-altitude acclimatization consists of an increase in both hemoglobin and the number of red blood cells. An early increase of up to 15% occurs in mean corpuscular hemoglobin concentration after rapid ascent to high altitude. This is primarily a result of a fluid shift into the extravascular space. Long-term acclimatization leads to an increase in plasma volume and total blood volume. Erythropoietin is secreted in response to hypoxemia within hours of ascent, which in turn stimulates the production of red blood cells, leading to new circulatory red blood cells in 4 or 5 days.²⁶ During the next 2 months, red blood cell mass increases in proportion to the degree of hypoxemia.²⁷

Hypoxemia also results in an increase in 2,3-diphosphoglycerate, causing a rightward shift of the oxyhemoglobin dissociation curve, which favors a release of oxygen from the blood to the tissues. This is counteracted by the leftward shift of the oxyhemoglobin dissociation curve caused by the respiratory alkalosis from hyperventilation. The result is a net null change in the oxyhemoglobin curve and an increase in oxygen-hemoglobin binding in the lung, which raises SaO₂.28,29 Some individuals with mutant hemoglobin and high oxygen-hemoglobin affinity are found to acclimatize more efficiently than their normal counterparts at moderate altitudes.³⁰

Pathophysiology

The clinical syndromes of high-altitude illness are not discrete entities but represent a spectrum of intertwined pathophysiologic mechanisms. AMS and HACE appear to represent differing manifestations of altitude illness on the same continuum, whereas HAPE appears to have a somewhat independent pathophysiologic mechanism.

The symptoms of AMS develop several hours after arrival at high altitude, whereas the development of HAPE and HACE generally requires several days of altitude exposure. Because hypobaric hypoxemia occurs within minutes of arrival, it cannot be the direct cause of high-altitude illness. Instead, it appears to be the initiating factor for a complex pathologic process that leads to the development of the various clinical syndromes. The proposed mechanisms for the development of AMS, HAPE, and HACE are represented schematically in Figure 144-2.

A poor HVR resulting in relative hypoventilation may be due to either the individual’s genetic predisposition or extrinsic factors, such as medications, that decrease the ventilatory drive. Whenever the HVR is decreased, the protective effects of hyperventilation are lost and the hypoxemia of high-altitude exposure is exacerbated.

The centrally mediated periodic breathing associated with high-altitude exposure may result in periods of apnea during sleep, causing severe arterial oxygen desaturation, which further exacerbates hypoxemia.³¹ Significant hypoxemia initiates multiple systemic responses that involve the circulatory, pulmonary, endocrine, and central nervous systems.

Hypoxemia alters fluid homeostasis, resulting in a generalized fluid retention followed by the shift of fluid into the intracellular spaces. This is manifested by peripheral edema, decreased urinary output, and increased body weight in patients with AMS. Several different mechanisms may account for these fluid shifts, including arginine vasopressin levels and sympathetic stimulation that may be centrally mediated.32,33 Arginine vasopressin levels are elevated in some cases of AMS and HAPE and decreased in others.^34,35 Aldosterone, plasma renin, and atrial natriuretic levels are higher in people with AMS.^35–37

The hypoxemia that results from high-altitude exposure also causes an increase in pulmonary artery resistance, leading to pulmonary hypertension and elevated capillary pressures that play the cardinal role in the development of HAPE. Exercise and cold stress at altitude may increase hypoxemia and exacerbate pulmonary hypertension.38,39 Pulmonary blood volumes and pulmonary hypertension are increased by sympathetic nervous system stimulation and catecholamine release.^40,41 In HAPE-susceptible individuals, pulmonary hypertension becomes severe, and an uneven distribution of pulmonary vasoconstriction results in overperfusion, increased capillary pressures, distention, and leakage in the remaining vessels.^42–45 This explains the patchy nature of the infiltrate seen on a chest radiograph with HAPE (Fig. 144-3). The mechanism for the uneven vasoconstriction in HAPE may be due to decreased nitric oxide bioavailability at the pulmonary tissue level, also leading to increased endothelial leakage and extracellular edema.^46–48 Overperfusion of a restricted vascular bed as the pathogenesis of HAPE is supported by the observation that people born with congenital unilateral absence of a pulmonary artery are susceptible to HAPE.⁴⁹ These individuals deliver their entire cardiac output to one lung, predisposing them to overperfusion injury.

The importance of the excessive rise in pulmonary artery pressure in HAPE is emphasized because lowering of the pressure during ascent prevents HAPE.⁵⁰ This implicates increased vascular pressure rather than inflammation as the primary cause of the vascular leak. The resultant mechanical shear forces lead to endothelial damage and changes in membrane permeability.⁴⁸ Inflammatory mediators appear to be a secondary response to the mechanical injury caused by overperfusion.^44,51 Once the vascular leak occurs and alveolar fluid accumulates, a defect in transepithelial sodium transport impairs the clearance of alveolar fluid and contributes to HAPE development.^52–54 Alveolar fluid clearance is upregulated by beta-adrenergic agonists, and inhaled beta-agonists may successfully prevent and treat HAPE.^54,55

Preexisting inflammation may also be a risk factor for HAPE. A preexisting respiratory infection during ascent to high altitude increases susceptibility to HAPE, particularly in children.⁵⁶ Inflammation may “sensitize” the pulmonary endothelium to mechanical injury and increase susceptibility to alveolar fluid accumulation and HAPE during ascent.

The clinical manifestations of AMS and HACE are the result of central nervous system dysfunction. The mechanistic theories involve altered cerebral hemodynamics and inflammatory mediators.57,58 It is known that the vasodilatory response to hypoxemia causes an increase of cerebral blood flow and volume.^59,60 The resulting hypoxemia leads to impaired vascular autoregulation, causing increased pressure transmission to the brain’s capillary beds.^33,61,62 In addition, systemic hypertension from strenuous exercise at high altitude may overwhelm the brain vasculature, resulting in transcapillary leakage and vasogenic edema. In susceptible individuals, these hemodynamic changes are likely to contribute to clinical manifestations of AMS and HACE.^63–65

Additional circumstances, however, may be necessary for the development of vasogenic edema and clinical symptoms. Inflammatory mediators may contribute to edema formation. Vascular endothelial growth factor, the inducible form of nitric oxide synthase, reactive cytokines, and free radical formation may mediate brain endothelial permeability. The roles that these play in the pathophysiologic process of altitude illness remain unclear.57,66–69

Whereas vasogenic edema has been implicated in the origin of AMS, magnetic resonance imaging (MRI) reveals signal changes present in subjects with and without clinical AMS. Thus the significance of vasogenic edema in AMS is questioned.⁷⁰ In patients with HACE, MRI studies reveal white matter changes consistent with vasogenic edema that correlate with symptoms.⁷¹ Despite the unclear role of vasogenic edema, a breakdown of the blood-brain barrier remains the leading theory in AMS and HACE pathophysiology and is most likely due to a combination of mechanical factors and biochemical mediation of permeability.^59,72

MRI data do reveal that cytotoxic edema is also present in severe AMS.73,74 Cytotoxic edema results from hypoxic cell damage most often associated with ischemic hypoxic insults. Failure of the adenosine triphosphate–dependent sodium pump allows sodium to accumulate within the cells, increasing intracellular water to maintain the osmotic equilibrium. Cytotoxic intracellular water accumulation may not be the primary mechanism for the development of HACE but rather the result of the increased cell ischemia initially caused by hemodynamic changes, vasogenic edema, biochemical mediators, and increased ratios of brain volume to intracranial space.^71,75

Hypobaria also appears to play a role in the development of AMS. Sea-level experiments that expose subjects to hypoxia alone do not result in AMS; however, when hypoxia is combined with hypobaria, AMS does occur.76,77 Although microbubble formation and fluid retention may be a mechanism, the exact pathophysiologic role of hypobaria in altitude illness is unclear.⁷⁷

These responses to hypoxia and altitude exposure occur in both susceptible individuals and those who remain free of AMS. Thus there must be an overall factor in a subject at risk for AMS that fails to compensate for the changes associated with altitude exposure. The “tight fit” hypothesis is proposed to explain AMS development and its inherent individual susceptibility.59,78 This theory suggests that the development of AMS and HACE is due to a lack of intracranial space to accommodate increasing volume from brain swelling and edema that develop at altitude.⁵⁸ The adequacy of the space to buffer changes in brain and cerebrospinal fluid (CSF) volume plays a key role in determining which individuals have symptoms of altitude illness. As brain volume increases from increased cerebral blood volume, the volume-buffering capacity of the central nervous system may prevent an immediate rise of intracranial pressure. As brain volume increases, the intracranial CSF is displaced through the foramen magnum into the space available in the spinal canal. Increased absorption of CSF by the arachnoid villi and decreased CSF production also occur. Individuals with less intracranial and intraspinal CSF buffering capacity have less compliance and become more symptomatic (i.e., develop AMS) from mild brain swelling. This tight fit hypothesis is supported by lumbar puncture, MRI, and computed tomography studies.^59,78–80

Acute Mountain Sickness