PB and ambient on top of Mount Everest are approximately one third of their values at sea level
Unlike a column of water, which is relatively noncompressible and has a uniform density, the column of air in the atmosphere is compressible and has a density that decreases exponentially ascending from sea level. Half of the mass of the earth's atmosphere is contained in the lowest 5500 m. Another quarter is contained in the next 5500 m (i.e., 5500 to 11,000 m of altitude). In other words, at higher and higher altitudes, the number of gas molecules pressing down on a mountain climber also falls exponentially; PB falls by half for each ~5500 m of ascent (Fig. 61-6).
FIGURE 61-6 Altitude dependence of PB and in dry air.
Everest Base Camp
At an altitude of 5500 m—which also happens to be the altitude of the first base camp used in most ascents of Mount Everest—PB is half the value at sea level (PB ≅ 380 mm Hg), as is the ambient ( ≅ 80 mm Hg). At this altitude, arterial O2 delivery (arterial blood O2 content × cardiac output) can still meet O2 demands in most healthy, active persons, even during mild physical activity. However, the body's compensatory responses to reduced ambient at high altitude vary among individuals. Thus, exposure to an altitude of 5500 m is problematic for a significant portion of the population.
Peak of Mount Everest
The peak of Mount Everest—8848 m above sea level—is the highest point on earth. PB at the peak is ~255 mm Hg, approximately one third that at sea level, and the ambient is only ~53 mm Hg. For a climber at the peak of Mount Everest, the of the humidified inspired air entering the alveoli is even lower, because of the effects of water vapor ( = 47 mm Hg at 37°C). Therefore, inspired = 21% × (255 − 47) = 44 mm Hg, compared with 149 mm Hg at sea level (see Table 26-1). Hypoxia is thus a major problem at the summit of Mount Everest.
Pressurized cabins in passenger planes maintain an ambient pressure equivalent to ~1800 m of altitude (~79% of sea-level pressure) in cross-continental flights, or ~2400 m of altitude (~74% of sea-level pressure) in transoceanic flights. Considering that most people do not need supplemental O2 in the inspired air at Denver (~1500 m) or at some ski resorts (~3000 m), most airline passengers are not bothered by the slight reduction in arterial O2 saturation (89% saturation at 3000 m) associated with these airline cabin pressures. However, passengers with chronic obstructive pulmonary disease (see Box 27-2) may need to carry supplemental O2 onto the plane even if they do not require it at sea level.
Up to modest altitudes, arterial O2 content falls relatively less than PB due to the shape of the Hb-O2 dissociation curve
Although PB and ambient decrease by the same fraction with increasing altitude, the O2 saturation of Hb in arterial blood decreases relatively little at altitudes up to ~3000 m. The reason is that at this altitude, arterial is 60 to 70 mm Hg, which corresponds to the relatively flat portion of the O2-Hb dissociation curve (see Fig. 29-3), so that arterial O2 content is little affected. Thus, the characteristics of Hb protect the arterial O2 content, despite modest reductions of . At higher altitudes, where arterial O2 content falls more steeply, aviators are advised to breathe supplemental O2.
Although the amount of O2 in the blood leaving the lung is important, even more important is the amount of O2 that the systemic tissues extract. This uptake is the product of cardiac output and the arteriovenous (a-v) difference in O2 content (see Equation 29-7). At sea level, arterial is ~100 mm Hg, corresponding to an Hb saturation of ~97.5%, whereas the mixed-venous is ~40 mm Hg, corresponding to an Hb saturation of ~75%. The difference between the arterial and the venous O2 contents is ~22.5% of Hb's maximal carrying capacity for O2. However, at an altitude of 3000 m, arterial is only ~60 mm Hg, which may correspond to an Hb saturation of only 88%. This reduction in blood O2 content is called hypoxemia. Assuming that everything else remains the same (e.g., O2 utilization by the tissues, hematocrit, 2,3-bisphosphoglycerate levels, pH, cardiac output), then the mixed a-v difference in Hb saturation must still be 22.5%. Thus, the mixed-venous blood at 3000 m must have an Hb saturation of 88% − 22.5% = 65.5%, which corresponds to a of ~33 mm Hg. As a result, the a-v difference of O2 partial pressure is much larger at sea level (100 − 40 = 60 mm Hg) than at 3000 m (60 − 33 = 27 mm Hg), even though the a-v difference in O2 content is the same. The reason for the discrepancy is that the O2-Hb dissociation curve is steeper in the region covered by the values at high altitude. N61-22
Contributed by Arthur DuBois
The oxygen tension or (partial pressure, ) in mixed-venous blood—a measure of average end-capillary —is normally 40 mm Hg, sufficient to allow O2 to diffuse into the tissue cells. Although mitochondria can use O2 down to very low levels, the radial O2 diffusion gradient between capillary blood and cell surfaces becomes barely sufficient when the mixed-venous is ≤20 mm Hg. A sign of tissue hypoxia would be lactic acidosis.
Oxygen electrodes measure in arterial or venous blood samples. The difference between arterial and mixed-venous is a measure of the average axial O2 gradient along systemic capillaries. Note that finger pulse oximeters measure the oxyhemoglobin saturation in the pulsating (i.e., arterial) blood that rushes into the tissue of the finger (see Box 29-2).
At high altitude, the fall in arterial causes a reflex hyperventilation that lowers arterial and thus tissue and thereby increases the affinity of Hb for oxygen. By itself, this Bohr effect (see p. 652) would further lower tissue . Conversely, raising tissue raises tissue by displacing O2 from Hb.
At very high altitudes, still another factor comes into play. The uptake of O2 by pulmonary-capillary blood slows at high altitudes, which reflects the smaller O2 gradient from alveolus to blood (see Fig. 30-10D). As a result, at sufficiently high altitudes, particularly during exercise, O2 may no longer reach diffusion equilibrium between alveolar air and pulmonary-capillary blood by the time the blood reaches the end of the capillary. Thus, at increasing altitude, not only does alveolar —and hence the maximal attainable arterial —fall in a predictable way, but also the actual arterial may fall to an even greater extent because of a failure of pulmonary-capillary blood to equilibrate with alveolar air.
During the first few days at altitude, compensatory adjustments to hypoxemia include tachycardia and hyperventilation
A reduction in arterial stimulates the peripheral chemoreceptors (see pp. 710–713) and causes an immediate increase in ventilation, which has two effects. First, it brings alveolar (and thus arterial ) closer to the ambient . Second, hyperventilation blows off CO2, producing a respiratory alkalosis (see p. 680) that inhibits the peripheral but especially the central chemoreceptors and thereby decreases ventilatory drive (see pp. 709–717). Thus, during an acute exposure to an altitude of 4500 m is only about twice that at sea level, whereas the hypoxia by itself would have produced a much larger stimulation. Accompanying the increased ventilatory drive during acute altitude exposure is an increase in heart rate, probably owing to the heightened sympathetic drive that accompanies acute hypoxemia (see p. 545). The resultant increase in cardiac output enhances O2 delivery.
During the next few days to weeks at an elevation of 4500 m, acclimatization causes ventilation to increase progressively by about the same amount as the acute response. As a result, continues to rise, and , to fall. Two mechanisms appear to cause this slower phase of increased ventilation. First, the pH of the cerebrospinal fluid (CSF) decreases, which counteracts the respiratory alkalosis induced by the increase in ventilation and thus offsets the inhibition of central chemoreceptors. However, the time course of the pH decrease in CSF does not correlate tightly with the time course of the increase in ventilation. The pH at the actual site of the central chemoreceptors may fall with the appropriate time course. Long-term hypoxia appears to increase the sensitivity of the peripheral chemoreceptors to hypoxia, and this effect may better account for acclimatization.
In the second mechanism for acclimatization, the kidneys respond over a period of several days to the respiratory alkalosis by decreasing their rate of acid secretion (see pp. 832–833) so that blood pH decreases toward normal (i.e., metabolic compensation for respiratory alkalosis). Another result of this compensation is that the unreabsorbed produces an osmotic diuresis and an alkaline urine. The consequence of reducing both CSF and plasma pH is to remove part of the inhibition caused by alkaline pH and thus allow hypoxia to drive ventilation to higher values.
An extreme case of adaptation to high altitude occurs in people climbing very high mountains. In 1981, a team of physiologists ascended to the peak of Mount Everest. Although on their way up to the summit the climbers breathed supplemental O2, at the summit they obtained alveolar gas samples while breathing ambient air—trapping exhaled air in an evacuated metal container. The alveolar at the summit was a minuscule 7 to 8 mm Hg, or ~20% of the value of 40 mm Hg at sea level. Thus, assuming a normal rate of CO2 production, the climbers' alveolar ventilation would have been 5-fold higher than normal (see pp. 679–680). Because the work of heavy breathing and increased cardiac output at the summit (driven by hypoxia) would increase CO2 production substantially, the increase in alveolar ventilation must have been much greater than 5-fold.
The climbers' alveolar at the peak of Mount Everest was ~28 mm Hg, which is marginally adequate to provide a sufficient arterial O2 content to sustain the resting metabolic requirement at the summit. However, the term resting is somewhat of a misnomer, because the work of breathing and the cardiac output are markedly elevated.
Long-term adaptations to altitude include increases in hematocrit, pulmonary diffusing capacity, capillarity, and oxidative enzymes
Although the increases in ventilation and cardiac output help to maintain O2 delivery during acute hypoxia, they are costly from an energy standpoint and cannot be sustained for extended periods. During prolonged residence at a high altitude, the reduced arterial triggers profound adaptations that enhance O2 delivery to tissues at a cost that is lower than that exacted by short-term compensatory strategies. Many of these adaptations are mediated by an increase in hypoxia-inducible factor 1 (HIF-1), a transcription factor that activates genes involved in erythropoiesis, angiogenesis, and other processes.
Red blood cell (RBC) mass slowly increases with prolonged hypoxemia. The Hb concentration of blood increases from a sea-level value of 14 to 15 g/dL to >18 g/dL, and hematocrit increases from 40% to 45% to >55%. Normally, the body regulates RBC mass within fairly tight limits. However, renal hypoxia and norepinephrine stimulate the production and release of erythropoietin (EPO) from fibroblast-like cells in the kidney (see pp. 431–433). EPO is a growth factor that stimulates production of proerythroblasts in bone marrow and also promotes accelerated development of RBCs from their progenitor cells. N18-2
Pulmonary Diffusing Capacity
Acclimatization to high altitude also causes a 2- to 3-fold increase in pulmonary diffusing capacity (see p. 668). Much of this increase appears to result from a rise in the blood volume of pulmonary capillaries (see p. 664) and from the associated increase in capillary surface area available for diffusion (see p. 661). This surface area expands even further because hypoxia stimulates an increase in the depth of inspiration. Finally, right ventricular hypertrophy raises pulmonary arterial pressure, thereby increasing perfusion to the upper regions of the lungs (see Fig. 31-9).
Hypoxia causes a dramatic increase in tissue vascularity. Tissue angiogenesis (see pp. 481–482) occurs within days of exposure to hypoxia, triggered by growth factors released by hypoxic tissues. Among these angiogenic factors are vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and angiogenin.
Hypoxia promotes expression of oxidative enzymes in the mitochondria, thereby enhancing the tissues' ability to extract O2 from the blood (see pp. 1220–1222). Thus, acclimatization to high altitude increases not only O2 delivery to the periphery but also O2 uptake by the tissues.
High altitude causes mild symptoms in most people and acute or chronic mountain sickness in susceptible individuals
Symptoms of Hypoxia
The first documented evidence of the ill effects of high altitude was in 35 BC, when Chinese travelers called the Himalayas the “Headache Mountains.” Recreational mountain climbing became popular in the mid-19th century, and with modern transportation, many people can now travel rapidly to mountain resorts. In fact, it is possible to ascend passively from sea level to high altitude in a matter of minutes (e.g., in a balloon) to hours. A rapid ascent may precipitate a constellation of relatively mild symptoms: drowsiness, fatigue, headache, nausea, and a gradual decline in cognition. These uncomfortable effects of acute hypoxia are progressive with increasing altitude. They occur in some people at altitudes as low as 2100 m and occur in most people at altitudes higher than 3500 m. Initially, these symptoms reflect an inadequate response (i.e., compensatory hyperventilation) to hypoxemia, which results in insufficient O2 delivery to the brain. In the longer term, symptoms may stem from mild cerebral edema, which probably results from dilation of the cerebral arterioles leading to increased capillary filtration pressure and enhanced transudation (see p. 468).
Acute Mountain Sickness
Some people who ascend rapidly to altitudes as seemingly moderate as 3000 to 3500 m develop acute mountain sickness (AMS). The constellation of symptoms is more severe than those described in the previous paragraph and includes headache, fatigue, dizziness, dyspnea, sleep disturbance, peripheral edema, nausea, and vomiting. The symptoms usually develop within the first day and last for 3 to 5 days. The primary problem in AMS is hypoxia, and the symptoms probably have two causes. The first is thought to be a progressive, more severe case of cerebral edema. The second cause of the symptoms is pulmonary edema, which occurs as hypoxia leads to hypoxic pulmonary vasoconstriction (see p. 687), which in turn increases total pulmonary vascular resistance, pulmonary-capillary pressure, and transudation. Certain people have an exaggerated pulmonary vascular response to hypoxia, and they are especially susceptible to AMS. Cerebral or pulmonary edema can be fatal if the exposure to hypoxia is not rapidly reversed, first by providing supplemental O2 to breathe and then by removing the individual from the high altitude.
Although being physically fit provides some protection against AMS, the most important factor is an undefined constitutional difference. Persons who are least likely to develop symptoms ventilate more in response to the hypoxia and therefore tend to have a higher and a lower . The higher and lower lead to less cerebral vasodilation, and the higher minimizes pulmonary vasoconstriction. N61-23
Contributed by Emile Boulpaep, Walter Boron
For a discussion of acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), visit http://www.everestnews.com/stories2005/illness01112005.htm (accessed February 2015).
For a discussion of chronic mountain sickness (CMS), see the papers by León-Velarde and colleagues (the consensus statement) and by Zubieta-Castillo and colleagues (an alternative view).
León-Velarde F, Maggiorini M, Reeves JT, et al. Consensus statement on chronic and subacute high altitude diseases. High Alt Med Biol. 2005;6:147–157.
Zubieta-Castillo G Sr, Zubieta-Calleja G Jr, Zubieta-Calleja L. Chronic mountain sickness: The reaction of physical disorders to chronic hypoxia. J Physiol Pharmacol. 2006;57(Suppl 4):431–442.
Chronic Mountain Sickness
After prolonged residence at high altitude, chronic mountain sickness may develop. The cause of this disorder is an overproduction of RBCs—an exaggerated response to hypoxia. In such conditions, the hematocrit can exceed 60%—polycythemia—which dramatically increases blood viscosity and vascular resistance, and increases the risk of intravascular thrombosis. The combination of pulmonary hypoxic vasoconstriction and increased blood viscosity is especially onerous for the right heart, which experiences a greatly increased load. These conditions eventually lead to congestive heart failure of the right ventricle. N61-23