Millions of people annually visit mountainous areas of the western United States at altitudes of >2440 m (>8000 ft). In addition, tens of thousands travel to high-altitude regions in other parts of the world. Adventure travel to mountainous regions is booming.¹ Physicians working or traveling in or near these locations are likely to encounter high-altitude illness or preexisting conditions that are exacerbated by altitude. Although the focus of this chapter is hypoxia-related problems, patients in the mountain environment may require care for associated illnesses such as hypothermia (see chapter 209, “Hypothermia”), frostbite (see chapter 208, “Cold Injuries”), trauma, ultraviolet keratitis, dehydration, and lightning injury (see chapter 218, “Electrical and Lightning Injuries”).

High altitude (>2440 m [>8000 ft]) is a hypoxic environment. Because the concentration of oxygen in the troposphere remains constant at 21%, the partial pressure of oxygen (P_O2) decreases as a function of the barometric pressure. In Denver at 1610 m (5280 ft), air pressure is 17% less than at sea level. The air of Aspen, Colorado, 2440 m (8000 ft), has 26% less oxygen than sea level. At 5490 m (18,000 ft), there is half the available oxygen, whereas on top of Mount Everest, there is only one third. Oxygen supplementation prevents symptoms of altitude illness during hypobaric exposure, and therefore, hypoxia, not hypobaria per se, is responsible for illness.

Altitude may be divided into stages according to physiologic effects. Intermediate altitude, 1520 to 2440 m (5000 to 8000 ft), produces decreased exercise performance and increased alveolar ventilation without major impairment in arterial oxygen transport. Acute mountain sickness (AMS) occurs at and above 2130 to 2440 m (7000 to 8000 ft) and sometimes at lower altitudes in particularly susceptible individuals. Patients who have limitations in ventilatory response such as some neuromuscular diseases or those with preexisting hypoxemia may become more symptomatic in this range of altitude. High altitude, 2440 to 4270 m (8000 to 14,000 ft), is associated with decreased arterial oxygen saturation (Sa_O2); marked hypoxemia may occur during exercise and sleep. Most cases of altitude-related medical problems occur in this elevation range, because of the availability of overnight tourist facilities located at these heights. Very high altitude, 4270 to 5490 m (14,000 to 18,000 ft), is uncommon in the United States but is encountered by visitors to the mountainous regions of South America and the Himalayas. Abrupt ascent can be dangerous, and a period of acclimatization is required to prevent illness. Extreme altitude, >5490 m (>18,000 ft), is experienced only by mountain climbers and is accompanied by severe hypoxemia and hypocapnia. At this height, progressive physiologic deterioration eventually outstrips acclimatization, and sustained human habitation is impossible. Because hypoxemia is maximal during sleep, the sleeping altitude is the critical altitude to consider.

Acutely hypoxic individuals become dizzy, faint, and rapidly unconscious if hypoxic stress is sufficient (Sa_O2 <65%). Captain Hawthorne Gray, in an attempt to set the record for highest hot air balloon flight in 1927, lost consciousness and died when his balloon rose to >12,200 m (>40,000 ft). However, individuals given days to weeks to acclimatize can tolerate surprising degrees of hypoxemia and function quite well. Although the fundamental process of this acclimatization takes place in the metabolic machinery of cells and mitochondria, acute “stress” responses are critical while allowing cells time to adjust.

VENTILATION

The primary initial adaptation is defense of alveolar P_O2 through increased ventilation. The hypoxic ventilatory response is modulated by the carotid body, which senses a decrease in arterial oxygenation and signals the central respiratory center in the medulla to increase ventilation. The vigor of this inborn response relates to successful acclimatization and increased performance. Respiratory depressants or stimulants may affect hypoxic ventilatory drive, as does chronic hypoxia, which eventually blunts the response. A low hypoxic drive may allow extreme hypoxemia to develop during sleep. Initial hyperventilation is attenuated quickly by respiratory alkalosis, which acts as a brake on the respiratory center. As renal excretion of bicarbonate compensates for the respiratory alkalosis, pH returns toward normal, and ventilation continues to increase. The process of maximizing ventilation, termed ventilatory acclimatization, culminates after 4 to 7 days at a given altitude. With continuing ascent to higher altitudes, the central chemoreceptors reset to progressively lower values of partial pressure of carbon dioxide, and the completeness of acclimatization can be gauged by the partial pressure of arterial carbon dioxide. Acetazolamide, which forces a bicarbonate diuresis, greatly facilitates this process. An appreciation of the normal values for blood gases and acid-base status with acclimatization at various altitudes is necessary to distinguish abnormalities (Table 221-1).

BLOOD

Within 2 hours of ascent to altitude, serum erythropoietin level increases and results in increased red cell mass over days to weeks. This adaptation has no importance during initial acclimatization when acute altitude illness develops; however, excessive red cell mass may develop over a period of weeks to months leading to chronic mountain polycythemia. Shifts in the oxyhemoglobin dissociation curve are thought to be minimal at altitude because of balancing physiologic effects. Hypoxia causes an increase in the level of 2,3-diphosphoglyceric acid and shifts the curve to the right. Respiratory alkalosis shifts the curve to the left. Naturally occurring left-shifted hemoglobin is advantageous at high altitude; a given partial pressure of oxygen will yield higher oxygen saturation and facilitate loading of oxygen onto hemoglobin in the pulmonary capillary.

FLUID BALANCE

Peripheral venous constriction on ascent to altitude causes an increase in central blood volume that triggers baroreceptors to suppress secretion of antidiuretic hormone and aldosterone and induces a diuresis. Combined with the bicarbonate diuresis from the respiratory alkalosis, the result is decreased plasma volume and a hyperosmolality (serum osmolality of 290 to 300 mOsmol/L) that results from a reset of the osmolar center of the brain. The hemoconcentration also increases oxygen-carrying capacity of the blood. Clinically, diuresis and hemoconcentration are considered a healthy response, whereas antidiuresis is associated with AMS and may contribute to edema formation.

CARDIOVASCULAR SYSTEM

Stroke volume decreases initially, and increased heart rate maintains cardiac output. Maximum exercising heart rate declines at altitude proportional to the decrease in maximum oxygen consumption (VO₂max). Cardiac muscle in healthy persons can withstand extreme levels of hypoxemia (partial pressure of arterial oxygen [Pa_O2] of <30 mm Hg) without evidence of ST-segment changes or ischemic events. Blood pressure typically increases mildly on ascent secondary to increased sympathetic tone, but labile blood pressure is also possible.

The pulmonary circulation constricts with exposure to hypoxia. Although pulmonary vasoconstriction is advantageous during conditions of regional alveolar hypoxia, such as pneumonia, it poses a disadvantage during the global hypoxia of altitude exposure, increasing to a variable degree pulmonary vascular resistance and pulmonary artery pressure. A hyperreactive response increases susceptibility to high-altitude pulmonary edema.

Cerebral blood flow transiently increases on ascent to altitude (despite the hypocapnic alkalosis), which increases oxygen delivery to the brain. This response, however, is limited by the increase in cerebral blood volume, which may increase intracranial pressure and aggravate symptoms of altitude illness.

EXERCISE CAPACITY

Exercise capacity, as measured by VO₂max, drops dramatically on ascent to altitude, approximately 10% for each 1000-m (3280-ft) altitude gain above 1500 m (4920 ft). During acclimatization, submaximal endurance increases appreciably after 10 days, but VO₂max does not. The mechanism of this decrement might be lack of adequate oxygen supply to the muscle cells due to the low driving pressure for diffusion of oxygen from the capillary. Another theory suggests that the CNS limits muscle activity to preserve its own oxygenation.

LIMITATIONS TO ACCLIMATIZATION

There are limits to acclimatization. Even those who are by nature good acclimatizers cannot tolerate the hypoxia of extreme altitude for long. Miners in South America report that they cannot live at altitudes >5800 m (>19,000 ft) because of weight loss, increasing lethargy, poor-quality sleep, weakness, and headache. High-altitude mountaineers cannot survive for more than a few days at >8000 m (>26,200 ft) without supplemental oxygen because of rapid deterioration of physiologic functioning. Considerable weight loss due to loss of fat and lean body mass is unavoidable. Other factors limiting the ability to adapt to extreme altitude include right ventricular strain from excessive pulmonary hypertension, intestinal malabsorption, impaired renal function, polycythemia leading to microcirculatory sludging, and prolonged cerebral hypoxia. Even at more modest altitudes, some individuals acclimatize poorly due to genetic and epigenetic factors. One phenotype is blunted carotid body function that leads to inadequate ventilation at high altitude.

SLEEP AT HIGH ALTITUDE

Sleep stages III and IV are reduced at altitude, whereas sleep stage I is increased. More time is spent awake, with a significant increase in arousals, but with only slightly less rapid eye movement time. Frequent nighttime awakenings are a common source of bitter complaints from skiers and others, but they are innocuous and improve with time at altitude. The typical periodic breathing (Cheyne-Stokes respiration) in those sleeping at >2700 m (>8860 ft) consists of 6- to 12-second apneic pauses interspersed with cycles of vigorous ventilation. Intervals of apnea of >20 seconds have been observed at extreme altitudes. Interestingly, the frequent awakenings are not necessarily related to sleep periodic breathing, and they are not related to AMS either. Quality of sleep and arterial oxygenation during sleep improve with acclimatization and with acetazolamide.

High-altitude syndromes are those attributed directly to the hypoxia: acute hypoxia, AMS, pulmonary edema, cerebral edema, retinopathy, peripheral edema, sleeping problems, and a group of neurologic syndromes. Other syndromes occurring at high altitude, which are not necessarily related to hypoxia, include thromboembolic events (which may be attribuTable to dehydration, prolonged incapacitation, polycythemia, and cold), high-altitude pharyngitis and bronchitis, and ultraviolet keratitis. Although the different hypoxic clinical syndromes overlap, all share a fundamental mechanism, all are seen in the same setting of rapid ascent in unacclimatized persons, and all respond to the same essential therapy: descent and oxygen.

ACUTE HYPOXIA

The syndrome of acute hypoxia occurs in the setting of sudden and severe hypoxic insult, such as accidental decompression of a pressurized aircraft cabin or failure of the oxygen system used by a pilot or high-altitude mountaineer. Sudden overexertion precipitating arterial desaturation, acute onset of pulmonary edema, carbon monoxide poisoning, and sleep apnea may result in relatively acute hypoxia as well. Unacclimatized persons become unconscious at an Sa_O2 of 50% to 60%, a Pa_O2 of less than approximately 30 mm Hg, or a jugular venous P_O2 of <15 mm Hg. Acute hypoxia reverses with immediate administration of oxygen, rapid descent, and correction of the underlying cause. Symptoms of acute hypoxia reflect the sensitivity of the CNS to this insult: dizziness, light-headedness, and dimmed vision progressing to loss of consciousness. Hyperventilation increases the time of useful consciousness during acute alveolar hypoxia.

ACUTE MOUNTAIN SICKNESS

AMS is a syndrome characterized by headache along with some combination of GI disturbance, dizziness, fatigue, or sleep disturbance (Table 221-2). It occurs in the setting of more gradual and less severe hypoxic insult than in acute hypoxia syndrome. Its incidence varies by location, ease of access to the high-altitude environment, rate of ascent, and sleeping altitude. One study found a 25% incidence of AMS in physicians attending a continuing-education meeting held at 2100 m (6900 ft) in Colorado. Other studies at resorts at altitudes between 2220 and 2700 m (7280 and 8860 ft) claim an incidence between 17% and 40%, and a sleeping altitude of 2740 m (9000 ft) seems to be a threshold for an increase in attack rate.² Approximately 40% of trekkers in Nepal on the path to Mount Everest experience AMS, and climbers on Mount Rainier have a very high incidence of 70% because of the rapidity of ascent.

In addition to rate of ascent and sleeping altitude, inherent factors determine individual susceptibility to AMS. Blunted carotid body response and low vital capacity are examples. Age has little influence on incidence, with children being as susceptible as adults, although those >50 years of age tend to have less AMS. Women are just as likely to develop mountain sickness but appear to have less pulmonary edema. Obesity has recently been linked to the development of AMS, possibly due to greater nocturnal oxygen desaturation.³ Susceptibility to AMS generally is reproducible in an individual on repeated exposures. Persons living at intermediate altitudes of 1000 to 2000 m (3300 to 6600 ft) already are partially acclimatized and do much better than lowlanders on ascent to higher altitudes. There is no relationship between susceptibility to AMS and physical fitness.

PATHOPHYSIOLOGY

AMS is due to hypobaric hypoxia, but the exact sequence of events leading to illness is unclear. Cerebral vasodilation appears to be the initiating event. Vasodilation occurs in the brain in all persons ascending to high altitude, thus increasing cerebral blood flow and blood volume. Whether this is solely sufficient to cause the symptoms of mild AMS is unclear. However, in persons who progress to high-altitude cerebral edema, vasogenic edema is evident as increased T2 signal on MRI.⁴ The leaky blood–brain barrier in high-altitude cerebral edema is due either to loss of autoregulation leading to overperfusion, or to increased permeability caused by mediators such as vascular endothelial growth factor or bradykinin. A combination of these two processes is also possible. The fact that dexamethasone so effectively treats AMS also supports the notion of vasogenic edema. An alternative notion is that the trigeminal-vascular system is triggered by hypoxic vasodilation or by noxious agents such as nitric oxide or free oxygen radicals.

CLINICAL FEATURES

The diagnosis of AMS is based on an appropriate setting paired with characteristic symptoms. The setting is rapid ascent of an unacclimatized person to 2000 m (6560 ft) or higher. On arrival the person typically feels light-headed and slightly breathless, especially with exercise. Symptoms develop between 1 and 6 hours later, but sometimes are delayed for 1 or 2 days (especially after a night’s sleep). Symptoms of mild AMS are remarkably similar to those of an alcohol hangover. Headaches are usually bifrontal and worsen with exertion, bending over, or performing a Valsalva maneuver. GI symptoms include anorexia, nausea, and sometimes vomiting, especially in children. The chief constitutional symptoms are lassitude and weakness. The person with AMS can be irriTable and often wants to be left alone. Sleepiness and a deep inner chill also are common. The Lake Louise AMS self-report questionnaire can be helpful in following the severity of the illness (Table 221-2).

As the illness progresses, headache becomes more severe while vomiting and oliguria develop. Lassitude may progress so that the victim requires assistance in eating and dressing. The onset of ataxia and altered level of consciousness heralds high-altitude cerebral edema. Coma may ensue within 12 hours if treatment is delayed. The diagnosis of AMS can be difficult in preverbal children and should be a diagnosis of exclusion.⁵

Physical findings in mild AMS are nonspecific. Heart rate and blood pressure are variable and usually in the normal range, although postural hypotension may be present. Presenting percent Sa_O2 is typically normal or slightly low for a given altitude, and percent Sa_O2 overall correlates poorly with the diagnosis of AMS. Localized rales are detecTable in up to 20% of persons with AMS. Fundoscopy reveals venous tortuosity and dilatation, and retinal hemorrhages are common at altitudes >5000 m (>16,400 ft) and in those with pulmonary and cerebral edema. Facial and peripheral edema sometimes accompanies AMS.

The differential diagnosis in this setting includes hypothermia, carbon monoxide poisoning, pulmonary or CNS infection, dehydration, migraine, and exhaustion. Carbon monoxide poisoning may have a presentation very similar to that of AMS and is not uncommon in mountain towns in the winter. Reduced oxyhemoglobin levels complicate hypoxia from high altitude, and the effects are additive. Hypoxia may trigger a migraine headache in patients with a personal or family history of migraine.⁶ Headache from AMS often dissipates within 10 to 15 minutes with supplemental oxygen administration, unlike headaches from other causes. Providers may find this to be a useful diagnostic maneuver.

The average duration of AMS at a Colorado resort (3000 m or 9840 ft) was 15 hours, with a range of up to 94 hours. Half of those affected with AMS chose to self-medicate.² At higher sleeping altitudes the illness may last much longer, up to weeks if untreated, and is more likely to progress to pulmonary or cerebral edema. Eight percent of those with AMS at 4270 m (14,000 ft) in Nepal developed cerebral or pulmonary edema or both.⁷