High Altitude (1500 to 3500 m [4921 to 11,483 Feet])

The onset of physiologic effects of diminished partial pressure of inspired oxygen (PIO₂) includes decreased exercise performance and increased ventilation (lower PaCO₂) (Box 1-2). Minor impairment exists in arterial oxygen transport (arterial oxygen saturation [SaO₂] at least 90%), but PaO₂ is significantly diminished. Because of the large number of people who ascend rapidly to 2500 to 3500 m (8202 to 11,483 feet), high-altitude illness is common in this range (Table 1-2; see Table 1-1).

TABLE 1-2 Arterial Blood Gases and Altitude*

Very High Altitude (3500 to 5500 m [11,483 to 18,045 Feet])

Maximum arterial oxygen saturation falls below 90% as PaO₂ falls below 50 mm Hg (Figure 1-1; see Table 1-2). Extreme hypoxemia may occur during exercise, sleep, and high-altitude pulmonary edema or other acute lung conditions. Severe altitude illness occurs most commonly in this range.

FIGURE 1-1 Increasing altitude results in decreasing inspired PO₂ (PIO₂), arterial PO₂ (PaO₂), and arterial oxygen saturation (SaO₂). Note that the difference between PIO₂ and PaO₂ narrows at high altitude because of increased ventilation and that SaO₂ is well maintained while awake until over 3000 m (9843 feet).

(Data from Morris A: Clinical pulmonary function tests: A manual of uniform lab procedures, Salt Lake City, 1984, Intermountain Thoracic Society; and Sutton JR, Reeves JT, Wagner PD, et al: Operation Everest II: Oxygen transport during exercise at extreme simulated altitude, J Appl Physiol 64:1309, 1988.)

Extreme Altitude (HIGHER THAN 5500 m [18,045 Feet])

Marked hypoxemia, hypocapnia, and alkalosis characterize extreme altitude. Progressive deterioration of physiologic function eventually outstrips acclimatization. As a result, no permanent human habitation is above 5500 m (18,045 feet). A period of acclimatization is necessary when ascending to extreme altitude; abrupt ascent without supplemental oxygen for other than brief exposures invites severe altitude illness.

Ventilation

By reducing alveolar carbon dioxide, increased ventilation raises alveolar oxygen, improving oxygen delivery (Figure 1-3; see Figure 1-1). This response starts as low as 1500 m (4921 feet) (PIO₂ = 124.3 mm Hg; see Table 1-3) and within the first few minutes to hours of high-altitude exposure. The carotid body, sensing a decrease in PaO₂, through a HIF-mediated process, signals the central respiratory center in the medulla to increase ventilation.^153,281 This carotid body function (hypoxic ventilatory response [HVR]) is genetically determined⁵⁶² but influenced by a number of extrinsic factors. Respiratory depressants such as alcohol and soporifics, as well as fragmented sleep, depress HVR. Agents that increase general metabolism, such as caffeine and coca, as well as specific respiratory stimulants, such as progesterone²⁷⁷ and almitrine,¹⁹² increase HVR. (Acetazolamide, a respiratory stimulant, acts on the central respiratory center rather than on the carotid body.) Physical conditioning apparently has no effect on HVR. Numerous studies have shown that a good ventilatory response enhances acclimatization and performance and that a very low HVR may contribute to illness⁴³³ (see Acute Mountain Sickness and High-Altitude Pulmonary Edema, later). However, over a normal range of values, HVR is not a reliable predictor of susceptibility to altitude illness.

FIGURE 1-3 Change in minute ventilation (), end-tidal carbon dioxide (PACO₂), and arterial oxygen saturation (SaO₂) during 5 days’ acclimatization to 4300 m (14,108 feet). BTPS, Body temperature pressure saturated.

(Modified from Huang SY, Alexander JK, Grover RF, et al: Hypocapnia and sustained hypoxia blunt ventilation on arrival at high altitude, J Appl Physiol 56:602, 1984.)

Other factors influence ventilation on ascent to high altitude. As ventilation increases, hypocapnia produces alkalosis, which acts as a braking mechanism on the central respiratory center and limits a further increase in ventilation. To compensate for the alkalosis, within 24 to 48 hours of ascent the kidneys excrete bicarbonate, decreasing the pH toward normal; ventilation increases as the braking effect of the alkalosis is removed. Ventilation continues to increase slowly, reaching a maximum only after 4 to 7 days at the same altitude (see Figure 1-3). The plasma bicarbonate concentration continues to drop and ventilation to increase with each successive increase in altitude. Persons with lower oxygen saturation at altitude have higher serum bicarbonate values; whether the kidneys might be limiting acclimatization or whether this reflects poor respiratory drive is not clear.¹⁰² This process is greatly facilitated by acetazolamide (see Acetazolamide Prophylaxis, later).

The paramount importance of hyperventilation is readily apparent from the following calculation: the alveolar PO₂ on the summit of Mt Everest (about 33 mm Hg) would be reached at only 5000 m (16,404 feet) if alveolar PCO₂ stayed at 40 mm Hg, limiting an ascent without supplemental oxygen to near this altitude. Table 1-2 gives the measured arterial blood gas levels resulting from acclimatization to various altitudes.

Circulation

The circulatory pump is the next step in the transfer of oxygen, moving oxygenated blood from the lungs to the tissues.

Blood

Hematopoietic Responses to Altitude

Ever since the observation in 1890 by Viault⁵⁵⁰ that hemoglobin concentration was higher than normal in animals living in the Andes, scientists have regarded the hematopoietic response to increasing altitude as an important component of the acclimatization process. On the other hand, hemoglobin values apparently have no relationship to susceptibility to high-altitude illness.

In response to hypoxemia, erythropoietin is secreted by the kidneys and stimulates bone marrow production of red blood cells.⁴⁸³ The hormone is detectable within 2 hours of ascent, nucleated immature red blood cells can be found on a peripheral blood smear within days, and new red blood cells are in circulation within 4 to 5 days. Over a period of weeks to months, red blood cell mass increases in proportion to the degree of hypoxemia. Iron supplementation can be important; women who take supplemental iron at high altitude approach the hematocrit values of men at altitude²⁰² (Figure 1-4).

FIGURE 1-4 Hematocrit changes on ascent to altitude in men and in women with and without supplemental iron.

(Modified from Hannon JP, Chinn KS, Shields JL: Effects of acute high altitude exposure on body fluids, Fed Proc 28:1178, 1969.)

The increase in hemoglobin seen 1 to 2 days after ascent is due to hemoconcentration secondary to decreased plasma volume, rather than a true increase in red blood cell mass. This results in a higher hemoglobin concentration at the cost of decreased blood volume, a trade-off that might impair exercise performance. Longer-term acclimatization leads to an increase in plasma volume as well as in red blood cell mass, thereby increasing total blood volume. Overshoot of the hematopoietic response causes excessive polycythemia, which may impair oxygen transport because of increased blood viscosity. Although the “ideal” hematocrit at high altitude is not established, phlebotomy is often recommended when hematocrit values exceed 60% to 65%. During the American Medical Research Expedition to Mt Everest (AMREE), hematocrit was reduced by hemodilution from 58% ± 1.3% to 50.5% ± 1.5% at 5400 m (17,717 feet) with no decrement in maximum oxygen uptake and increased cerebral functioning.⁴⁶⁵

Oxyhemoglobin Dissociation Curve

The oxygen dissociation curve (ODC) plays a crucial role in oxygen transport. The sigmoidal shape of the curve allows well-maintained SaO₂ up to 3000 m (9843 feet), despite significant decreases in PaO₂ (see Figure 1-1). Above 3000 m (9843 feet), small changes in PaO₂ cause large changes in SaO₂ (Figure 1-5). Because PaO₂ determines diffusion of oxygen from capillary to cell, small changes in PaO₂ can have clinically significant effects. This is often confusing for clinicians because SaO₂ appears relatively well preserved. At high altitude, small changes in PaO₂ lead to lower O₂ uptake that can have a large effect on systemic hypoxemia, and thus on clinical status, while the SaO₂ may appear relatively unchanged.

FIGURE 1-5 Oxygen-hemoglobin dissociation curve showing effect of 10-mm Hg decrement in arterial partial pressure of oxygen (PaO₂) on arterial oxygen saturation (SaO₂) at sea level (A) and near 4400 m (14,436 feet) (B). Note the much larger drop in SaO₂ at high altitude.

(Modified from Severinghaus JW, Chiodi H, Eger EI, et al: Cerebral blood flow in man at high altitude: Role of cerebrospinal fluid pH in normalization of flow in chronic hypoxia, Circ Res 19:274, 1966.)

In 1936, Ansel Keys and colleagues²⁶⁶ demonstrated an in vitro right shift in position of the ODC at high altitude, favoring release of oxygen from blood to tissues. This change, due to increased 2,3-diphosphoglycerate, is proportional to the severity of hypoxemia. In vivo, however, the alkalosis at moderate altitude offsets this, and no net change occurs. In contrast, the marked alkalosis of extreme hyperventilation, as measured on the summit and simulated summit of Mt Everest (PaCO₂ 8 to 10 mm Hg, pH greater than 7.5), shifts the ODC to the left, facilitating oxygen-hemoglobin binding in the lung that raises SaO₂ and is advantageous.⁴⁶² Persons with a very left-shifted ODC, caused by an abnormal hemoglobin (Andrew-Minneapolis), when taken to moderate (3100 m [10,171 feet]) altitude, had less tachycardia and dyspnea and remarkably had no decrease in exercise performance.²⁰⁸ High-altitude adapted animals also have a left-shifted ODC.

Tissue Changes

The next link in the oxygen transport chain is tissue oxygen transfer, which depends on capillary perfusion, diffusion distance, and driving pressure of oxygen from the capillary to the cell. Banchero²⁰ has shown that capillary density in dog skeletal muscle doubled in 3 weeks at a barometric pressure of 435 mm Hg. A recent study in humans noted no change in capillary density or in gene expression thought to enhance muscle vascularity.³¹⁶ Ou and Tenney³⁹⁵ revealed a 40% increase in mitochondrial number but no change in mitochondrial size, whereas the study of Oelz and colleagues³⁹² showed that high-altitude climbers had normal mitochondrial density. A significant drop in muscle size is often noted after high-altitude expeditions because of net energy deficit,^316,319 resulting in increased capillary density and ratio of mitochondrial volume to contractile protein fraction as a result of the atrophy. Although there is no de novo synthesis of capillaries or mitochondria, the net result is a shortening of diffusion distance for oxygen.^316,319

Sleep at High Altitude

Disturbed sleep is common at high altitude. There are multiple causes. Reflecting the great interest in sleep, more than 160 papers in the last 10 years have addressed sleep at altitude. The interested reader is referred to recent reviews.^{67,308,551,561,569} Nearly all subjects complain of disturbed sleep at high altitude, with severity increasing with the altitude. At moderate altitude, sleep architecture is changed, with a reduction in stages 3 and 4 sleep, stage 1 time increased, and little change in stage 2. Overall, there is a shift from deeper sleep to lighter sleep. In addition, more time is spent awake, with significantly increased arousals. Clinicians have reported either slightly less rapid eye movement (REM) time or no change in REM compared with what occurs at low altitude. REM sleep may improve over time at altitude.²⁶⁸ The subjective complaints of poor sleep are out of proportion to the small reduction (if any) in total sleep time and appear to be due to sleep fragmentation. With more extreme hypoxia, sleep time was dramatically shortened and arousals increased, without a change in ratio of sleep stages but with a reduction in REM sleep.¹⁰ The mechanisms of this change in sleep architecture and fragmentation are poorly understood. Periodic breathing appears to play only a minor role in altering sleep architecture at high altitude.⁴⁶¹ The arousals have been linked to periodic breathing in some studies but not in others. Other factors might include change in circadian rhythm and perhaps body temperature.⁹⁸ Obesity may explain susceptibility to both deranged sleep and sleep-disordered breathing in some individuals.¹⁵⁵ Recent studies of infants and children⁵⁹⁰ and athletes in simulated altitude devices used for training also revealed deranged sleep quality in these groups.^269,270,401 Although deranged sleep is a frequent complaint in high-altitude visitors, it seems to have little relation to susceptibility to altitude illness or other serious problems. Symptomatic treatment that avoids respiratory depression is safe (see Treatment under Acute Mountain Sickness, later).

Periodic Breathing

Periodic breathing is most common in early and light sleep, may occur during wakefulness when drowsy, and does not occur in REM sleep. The pattern is characterized by hyperpnea followed by apnea (Figure 1-6) and is caused by a battle for control of breathing between peripheral chemoreceptors (carotid body) and the central respiratory center. Respiratory alkalosis during hyperpnea acts on the central respiratory center, causing apnea. During apnea, SaO₂ decreases, carbon dioxide increases, and the carotid body is stimulated, causing a recurrent hyperpnea and apnea cycle. The apnea is central, not associated with snoring, and occurs with absence of rib cage movement. Persons with high hypoxic ventilatory response have more periodic breathing,⁵⁵ with mild oscillations in SaO₂,²⁸² whereas persons with low hypoxic ventilatory response have more regular breathing overall but may suffer periods of apnea with extreme hypoxemia distinct from periodic breathing.¹⁹² As acclimatization progresses, periodic breathing lessens but does not disappear, especially over 5000 m (16,404 feet), and sleep SaO₂ increases (Figure 1-7; see Figure 1-6).^10,55,524 Periodic breathing has not been implicated in the etiology of high-altitude illness, but nocturnal oxygen desaturation has been implicated.^55,133,150 Eichenberger and colleagues¹³⁰ have also reported greater periodic breathing in persons with HAPE, secondary to lower SaO₂. As with fragmented sleep, intensity of periodic breathing is quite variable. Total sleep time with periodic breathing can vary from 1% to over 90%.⁵⁹⁸ Most studies report no association between periodic breathing and AMS.⁵⁵ This may relate to the fact that persons with periodic breathing tend to have higher HVR and greater average ventilation and oxygenation.⁵⁶¹

FIGURE 1-6 Respiratory patterns and arterial oxygen saturation (SaO₂) with placebo and acetazolamide in two sleep studies of a subject at 4200 m (13,780 feet). Note pattern of hyperpnea followed by apnea during placebo treatment, which is changed with acetazolamide.

(Modified from Hackett PH, Roach RC, Harrison GL, et al: Respiratory stimulants and sleep periodic breathing at high altitude: Almitrine versus acetazolamide, Am Rev Respir Dis 135:896, 1987.)

FIGURE 1-7 Sleep oxygenation improves with acclimatization to same altitude. Top line is maximum, and bottom line is minimum arterial oxygen saturation (SaO₂) in an acclimatized person. Shaded area is maximum and minimum SaO₂ values for new arrival at 5360 m (17,585 feet).

(Modified from Sutton JR, Gray GW, Houston CS, et al: Effects of acclimatization on sleep hypoxemia at altitude. In West JB, Lahiri S, editors: High altitude man, Bethesda, Md, 1984, American Physiological Society, pp 141-146.)

Exercise

Maximal oxygen consumption drops dramatically on ascent to high altitude.^151,434 Maximal oxygen uptake () falls from sea level by approximately 10% for each 1000 m (3281 feet) of altitude gained above 1500 m (4921 feet). Persons with the highest sea level values have the largest decrement in at high altitude, but overall performance at high altitude is not consistently related to sea level .^392,428,566 In fact, many of the world’s elite mountaineers have quite average values, in contrast with other endurance athletes.³⁹² Acclimatization at moderate altitudes enhances submaximal endurance time but does not enhance (Figure 1-8).¹⁵¹

FIGURE 1-8 On ascent to altitude, maximum oxygen consumption () decreases and remains suppressed. In contrast, endurance time (minutes to exhaustion at 75% of altitude-specific ) increases with acclimatization.

(Modified from Maher JT, Jones LG, Hartley LH: Effects of high altitude exposure on submaximal endurance capacity of men, J Appl Physiol 37:895, 1974.)

Oxygen transport during exercise at high altitude becomes increasingly dependent on the ventilatory pump. The marked rise in ventilation produces a sensation of breathlessness, even at low work levels. The following quotation is from a high-altitude mountaineer:

In contrast to the increase in ventilation with exercise, at increasing altitudes in OEII, cardiac function and cardiac output were maintained at or near sea level values for a given oxygen consumption (workload).⁴¹⁷ Recent work has attributed the altitude-induced drop in to the lower PIO₂, impairment of pulmonary gas exchange, and reduction of maximal cardiac output and peak leg blood flow, each explaining about one-third of the loss in .⁷⁶ However, mechanisms to explain the impairment of gas exchange and the lower blood flow remain elusive. Wagner⁵⁵⁶ proposes that the pressure gradient for diffusion of oxygen from capillaries to the working muscle cells may be inadequate. Another concept is that increased cerebral hypoxia from exercise-induced desaturation is the limiting factor.^{91,241,356,519,520} Mountaineers, for example, become light-headed and their vision dims when they move too quickly at extreme altitude (Figure 1-9).⁵⁶⁴

FIGURE 1-9 Calculated changes in the PO₂ of alveolar gas and arterial and mixed venous blood as oxygen uptake is increased for a climber on the summit of Mt Everest_. Unconsciousness develops at a mixed venous PO₂ of 15 mm Hg. P_B, Barometric pressure; DMO₂, muscle diffusing capacity; , maximum oxygen consumption.

(Modified from West JB: Climbing Mt. Everest without oxygen: An analysis of maximal exercise during extreme hypoxia, Respir Physiol 52:265, 1983.)

Neurologic Syndromes

Neurologic syndromes reflect both nervous system sensitivity to hypoxia and effects of compensatory mechanisms. Although brain adenosine triphosphate (ATP) production and overall metabolism remain intact during moderate hypoxia, impaired synthesis of neurotransmitters can produce cerebral symptoms such as lassitude, malaise, and cognitive defects. Compensatory cerebral vasodilation at altitude appears to be the trigger for altitude headache and contributes to development of AMS and HACE. However, much of the pathophysiology of AMS and HACE remains a mystery. Focal neurologic deficits without cerebral edema are also difficult to explain; cerebral artery spasm and watershed hypoxia have both been invoked. Understanding the exact etiology of these neurologic syndromes will parallel advances in neuroscience; the emphasis in altitude illness is finally and appropriately on the brain.⁴³⁸

Acute Cerebral Hypoxia

Acute, profound hypoxia, although of greatest interest in aviation medicine, may also occur on terra firma when ascent is too rapid or when hypoxia abruptly worsens. Carbon monoxide poisoning, pulmonary edema, sudden overexertion, sleep apnea, or a failed oxygen delivery system may rapidly exaggerate hypoxemia. Unacclimatized persons will lose consciousness from acute hypoxia at SaO₂ of 40% to 60% or a PaO₂ of less than about 30 mm Hg or mixed venous PO₂ of 15 mm Hg. Tissandier, the sole survivor of the flight of the balloon Zenith in 1875, gave a graphic description of the effects of acute hypoxia:

The ascent to over 8000 m (26,247 feet) took 3 hours, and the descent less than 1 hour. When the balloon landed, Tissandier’s two companions were dead.

The prodigious work that Paul Bert conducted in an altitude chamber during the 1870s showed that lack of oxygen, rather than an effect of isolated hypobaria, explained the symptoms experienced during rapid ascent to extreme altitude.

Bert goes on to describe the symptoms of acute exposure to hypoxia:

Bert was also able to both prevent and immediately resolve symptoms by breathing oxygen. Modern studies of acute hypoxic exposure use the measurement of time of useful consciousness; that is, the time until a subject can no longer take corrective measures, such as putting on an oxygen mask. With exposure to 8500 m (27,887 feet), that time is 60 seconds during moderate activity and 90 seconds at rest.

Acute hypoxia can be quickly reversed by immediate administration of oxygen, rapid pressurization or descent, or correction of an underlying cause, such as relief of apnea, removal of a carbon monoxide source, repair of an oxygen delivery system, or cessation of overexertion. Hyperventilation increases time of useful consciousness during severe hypoxia.

High-Altitude Headache

The term high-altitude headache (HAH) has been used in the literature for decades, and studies directed toward the pathophysiology and treatment of HAH have been reported. Obviously these are to an extent also studies of AMS. Headache lends itself to investigation better than do some other symptoms, because headache scores have been well validated.²⁴⁴ Headache is generally the first unpleasant symptom consequent to altitude exposure and is sometimes the only symptom.²¹⁴ It may or may not be the harbinger of AMS, which is defined as the presence of headache plus at least one of four other symptoms, in the setting of an acute altitude gain.⁴³⁵ One could even argue that it is the headache itself that causes other symptoms such as anorexia, nausea, lassitude, and insomnia, as is commonly seen in migraine or tension headaches, and that mild AMS is essentially due to headache. The International Headache Society²⁰⁶ has defined high-altitude headache as headache with at least two of the following characteristics: (1) bilateral; (2) frontal or frontotemporal; (3) dull or pressing quality; (4) mild or moderate intensity; and (5) aggravated by exertion, movement, straining, coughing, or bending. In addition, the headache must occur with an ascent to altitude greater than 2500 m (8202 feet), develop within 24 hours after ascent, and resolve within 8 hours after descent.

Recent studies have attempted to characterize the clinical features and incidence of headache at altitude (Table 1-4). Silber and co-workers⁴⁹⁶ found that 50 of 60 trekkers (83%) in Nepal up to 5100 m (16,732 feet) developed at least one headache when over 3000 m (9843 feet). Older persons were less susceptible; women and those with headaches in daily life had more severe headaches, but no more headaches than others. Of those with headache, 52% did not have AMS by the Lake Louise criteria. The clinical features were widely variable. In general, the headaches were bilateral, generalized, dull, exacerbated by exertion or movement, often occurring at night, and resolved within 24 hours. Thus the headaches had some features of increased intracranial pressure (ICP). Persons with history of migraine did not have a higher incidence of headache. Various medications alleviated the headaches, especially mild ones, 70% of the time.

TABLE 1-4 Clinical Characteristics of Headache

Serrano-Duenas⁴⁸⁹ also described in detail HAH in 98 climbers in the Andes. Persons with history of primary headache were excluded. He found the following characteristics: holocranial, 65.6%; pulsatile-burst type quality, 75.3%; oscillating evolution, 36.7%; increasing with exercise, 49.5%; relieved by rest, 41.8%; concurrent symptoms referred to: anorexia, 26.8%, irritability, 26.5%, and finally pessimism and anxiety feelings, 33.2% and 29.5%, respectively. Headaches were worse after a night’s sleep, more common in men, were of moderate intensity, and responded to analgesics.

In general, the literature suggests that HAH can be prevented by the use of nonsteroidal antiinflammatory drugs^65,72,157 and acetaminophen²⁰⁴ as well as the drugs commonly used for prophylaxis of AMS, acetazolamide and dexamethasone. Some agents appear more effective than do others, with ibuprofen and aspirin apparently superior to naproxen.^65,70,73 A serotonin agonist (sumatriptan, a 5-HT₁ [serotonin type 1] receptor agonist) was reported to be effective for HAH prevention and/or treatment in some studies,^69,243,544 but not in others.²⁸ Flunarizine, a specific calcium antagonist used for treatment of migraine, was not effective in one study.⁴⁴ Interestingly, oxygen is often immediately effective for HAH (within 20 minutes) in subjects with and without AMS, indicating a rapidly reversible mechanism of the headache.^26,191

The response to many different agents might reflect multiple components of the pathophysiology, or merely the nonspecific nature of analgesics. As Sanchez del Rio and Moskowitz⁴⁶³ have pointed out, different inciting factors for headache may result in a final common pathway, such that the response to different therapies is not necessarily related to the initial cause of the headache. They have provided a useful multifactorial concept of the pathogenesis of HAH, based on current understanding of headaches in general.⁴⁶³ They suggest that the trigeminovascular system is activated at altitude by both mechanical and chemical stimuli (vasodilation, nitric oxide [NO] and other noxious agents), and in addition, the threshold for pain is likely altered at high altitude (Figure 1-10).⁴⁶³ If AMS and especially HACE ensue, then altered intracranial dynamics may also play a role, via compression or distension of pain-sensitive structures. A recent study provided evidence against sustained trigeminovascular activity,¹⁴ but more study will hopefully bring better understanding of the pathophysiology of these often debilitating headaches, and new treatments as well.

FIGURE 1-10 Proposed pathophysiology of high-altitude headache. CNS, Central nervous system; eNOS, endothelial nitric oxide synthase; NO, nitric oxide.

(Modified from Sanchez del Rio M, Moskowitz MA: High altitude headache. In Roach RC, Wagner PD, Hackett PH, editors: Hypoxia: Into the next millennium, New York, 1999, Plenum/Kluwer Academic Publishing, pp 145-153.)

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