Effects of Altitude
Studies of the effects of chronic hypoxemia can be performed in the laboratory by decreasing either the concentration of inspired oxygen or the barometric pressure in a hypobaric chamber. Nature has provided a third option, high altitude, which allows examination of the effects of chronic hypoxemia in individuals under varying conditions.
Thus, studies of high-altitude physiologists are of interest not only to mountaineers and aviators but also to physicians. Knowledge gained on mountain peaks may give insight into the pathophysiology of patients with cyanotic heart disease or chronic lung disease. Finally, physicians caring for patients who already have hypoxemia should understand the alterations provoked by changes in altitude that may affect these patients while they are living in or visiting mountainous regions or traveling by air.
High altitude has generally been defined as an elevation above 2500-3000 m (approximately 8200-10,000 ft). In healthy persons, clinically significant changes are difficult to demonstrate at elevations lower than this. Many people live at high altitude and perform normal activities. Worldwide, more than 140 million people live more than 2500 m above sea level; of these, 80 million live in Asia, and 35 million live in the Andean mountains (where the major population density is at elevations exceeding 3500 m). 
Mountaineers and aviators have experimented with humans’ ability to function and survive at extreme altitudes. The conquests of Mount Everest (8884 m [about 29,140 ft]) without supplemental oxygen were a stringent test of survival ability in a severely hypoxemic environment. At that altitude, nearly all of the available oxygen is required to support basal metabolism, and the climbing rate near the summit drops to 2 m/min.
From sea level to high altitude, the percentage of oxygen remains constant at 20.93%; therefore, barometric pressure determines the partial pressure of oxygen (PO2) in ambient air. Barometric pressure decreases as one rises in altitude and moves toward the poles. The changing position of the sun in relation to the equator affects barometric pressure, producing a seasonal atmospheric tide.
At sea level (barometric pressure, 760 mm Hg), the PO2 of ambient air is 159 mm Hg (ie, 760 mm Hg × 0.2093). As air passes through the respiratory tract, it is saturated with water vapor, which makes the inspired PO2 149 mm Hg (ie, [760 – 47 mm Hg] × 0.2093).
The alveolar PO2 (PAO2) is calculated as follows:
PAO2 = [(PB – PH2 O) FiO2] – [PACO2 (FiO2 + 1 – FiO2/R)],
where PB is the ambient barometric pressure, PH2 O is the pressure water vapor exerts at body temperature, FiO2 is the fraction of inspired oxygen, PACO2 is the alveolar partial pressure of carbon dioxide, and R is the respiratory exchange ratio.
Humans have shown an ability to adapt for short periods to a barometric pressure one third that of sea level on Mount Everest without supplemental oxygen. At that elevation, the calculated PAO2 is 35 mm Hg, and the arterial PO2 (PaO2) is 28 mm Hg. Humans can permanently live at 5100 m (16,700 ft), where the barometric pressure is approximately one half that of sea level. Although cold, low humidity, increased solar radiation, and poor economic conditions limit the ability to survive at high altitude, hypoxia is the most important factor.
Changes in oxygen transport
At sea level, the PO2 available in the atmosphere and the oxygen demands of mitochondria are large. At each stage of the oxygen transport system, PO2decreases; this phenomenon is figuratively called the oxygen cascade.
At high altitudes, the decrease in barometric pressure reduces the amount of oxygen initially available in the environment, making the slope of the cascade considerably less steep than it otherwise is. Mechanisms that compensate for the decreased availability of oxygen in the environment include changes in the intracellular enzyme systems to allow them to function at low levels of oxygen and changes in the oxygen transport system to increase the amount of oxygen delivered. The latter is the primary compensatory mechanism. 
An increased hypoxic ventilatory response is an important means of acclimatization for a sea-level resident who aspires to participate in activities at high altitude. Mountain climbers with an increased hypoxic ventilatory response are better able to climb to great heights, presumably because of the increased availability of alveolar oxygen; this capacity may also have a downside. A low hypoxic ventilatory response has been implicated in acute mountain sickness, excessive polycythemia, and low birth weight.
After a person acclimatizes, hyperventilation may occur at a PaO2 as high as 90 mm Hg. The hypoxic ventilatory response persists for the sea-level resident who continues to remain at high altitude. At extreme altitudes, marked respiratory alkalosis develops to maintain a PAO2 of more than 35 mm Hg. In a decompression chamber with conditions equal to those at Mount Everest, PaCO2 is 8 mm Hg.
Therefore, native high-altitude residents can perform a given physical activity with a relatively small ventilatory requirement; hence, they have less dyspnea than others do. This advantage increases their capacity to perform work at high altitude.
This outcome is unlike that observed in the native highlander, whose response remains blunted for years. An important distinction between the native highlander and the patient with cyanotic congenital heart disease (CHD) may be that although they both have arterial hypoxemia, the highlander has a lowered PAO2, whereas the patient with cyanotic CHD has a normal PAO2.
A 32% decrease in coronary blood flow has been observed after 10 days at 3100 m (10,200 ft).  However, no evidence of myocardial ischemia is observed. This finding is presumably due to increased extraction of oxygen from coronary arterial blood and reduced oxygen requirements secondary to decreased cardiac work. Left ventricular (LV) dysfunction has been suggested; however, echocardiographic indices of LV contractility are normal and chamber sizes are reduced at altitude.
With increasing hypoxia, the maximum heart rate decreases by 1 beat/min for every 130 m (about 430 ft) above 3100 m (10,200 ft). The decreased cardiac output, stroke volume, and exercise capacity noted at high altitude may be due to decreased preload secondary to a reduction in plasma volume associated with arrival at high altitude.
In general, systemic blood pressure is slightly lower at high altitude than it is at sea level. This difference is thought to be secondary to the vasodilatory effects of hypoxia on the systemic vascular smooth muscle. The incidence of hypertension at high altitude has been reported to be less than that the rate at sea level.
Oxygen-hemoglobin dissociation curve
Tissue PO2 (tPO2) varies little over a PAO2 range of 70-100 mm Hg. As might be expected at high altitude, a PAO2 of 40-70 mm Hg is associated with rapid unloading of oxygen for small changes in oxygen tension. Some suggest that increased oxygen affinity or left-shifting of the oxygen-hemoglobin dissociation curve may be beneficial at high altitude. As with fetal hemoglobin, a leftward shift facilitates oxygen loading in a hypoxic environment. Others suggest that a rightward shift may increase the ability of the blood to unload oxygen at the tissue level.
In summary, at each stage of the oxygen transport system, considerable changes occur to facilitate oxygen delivery. The extent to which the patient with cyanosis makes use of these or similar mechanisms can be a focus of future research.
No less important than the transport system is the transport vehicle—namely, the red blood cell (RBC). During the first 1-2 weeks at high altitude, plasma volume decreases, raising the hemoglobin concentration by 1-2 g/dL. In addition, within hours of exposure to altitude, RBC production increases because production of erythropoietin is heightened. However, the overall response is slow, taking months to reach equilibrium.
The degree of polycythemia is directly related to the altitude, up to an elevation of 3660 m (12,000 ft). Above this altitude, the hemoglobin concentration increases rapidly. However, if the systemic arterial saturation falls below 60%, erythropoietic activity decreases. In subjects living at 4540 m (14,900 ft), total blood volume gradually rises from 80 to nearly 100 mL/kg, a change that represents an increase in RBC volume as plasma volume decreases. Monge disease (chronic mountain sickness) is associated with excessive erythropoiesis.
Polycythemia is associated with hyperviscosity and declining oxygen transport. A further rise in hemoglobin is observed with age at high altitude. At altitude, climbers with polycythemia exhibit reduced maximal oxygen consumption, even on 100% oxygen. This observation suggests that peripheral extraction of oxygen from blood is limited by its reduced flow. Phlebotomy and hemodilution experiments in mountain climbers and autologous RBC transfusions in athletes have not yielded information about the ideal hematocrit for any given altitude.
The platelet count decreases by 7% after 2 days at 2990 m (9800 ft) and by 25% after 2 days at 5370 m (17,600 ft). Some suggest that exposure to high altitude induces a hypercoagulable state in humans.
Increased fibrinogen levels and a decreased clot lysis time were noted in 38 soldiers living at high altitude for 2 years, as compared with control subjects at sea level.  Soldiers with clinical evidence of pulmonary arterial hypertension had somewhat low levels of fibrinogen, high levels of platelet factor III, and increased platelet adhesiveness. This evidence suggests that conversion to fibrin, and possibly platelet deposition, were occurring in these subjects.
Most visitors to high altitude notice initial weight loss, which has been attributed to reduced dietary intake, enhanced water loss, and loss of stored body fat. Anorexia is a common complaint of visitors to even moderate altitude. At high altitude, appetite and caloric intake decrease dramatically in unacclimatized persons, who generally find fat distasteful and prefer sweets. Fluid losses result from the insensible water losses associated with hyperventilation and low humidity, as well as diuresis induced by hypoxia and the cold environment.
Changes in sensory, motor, and mental function
Because the retina of the eye has a great requirement for oxygen, vision is the first sense altered with the lack of oxygen. This phenomenon is demonstrated by diminished night vision even at altitudes below 3000 m (about 9600 ft). At 3048 m (10,000 ft), people require more time to learn a new task than they do at low elevations. At 6100 m (20,000 ft), impairments in sensory, perceptual, and motor performance have been demonstrated. 
One year after the American Medical Research Expedition to Everest, reductions in finger-tapping speed persisted. Also observed were declines in visual long-term memory and verbal learning, along with increased aphasic errors during neuropsychological testing after climbs to high altitude. This finding prompted some to surmise whether climbs to extreme altitude cause brain damage.
On initial exposure to altitude, cerebral blood flow (CBF) decreases because of vasoconstriction associated with hypocarbia. However, when PaO2 decreases to 50-60 mm Hg, CBF increases. Blood flow appears to be regionally uneven, increasing at the brainstem level at the expense of cortical flow. This mechanism may possibly explain the increased vulnerability of the cortex to hypoxia.
A surprising observation is that the climbers with a high ventilatory response to hypoxia have the most impairment. The hypocapnia associated with hyperventilation possibly causes a marked decrease in CBF that offsets any beneficial effects of increased oxygenation.