Activity performed early after arrival at altitude may be associated with a number of short-term physiologic changes affecting the cardiorespiratory system in both healthy and diseased subjects. Aerobic exercise capacity is decreased at high altitudes due to a decreased arterial content secondary to decreased inspiratory partial pressure of oxygen, as well as a decreased maximal cardiac output secondary to reduced maximal heart rate. Tissue hypoxia develops from the significant decrease in oxygen availability in inspired air and results in physiologic compensatory adaptations at rest, which are more pronounced during exercise.
According to Dalton's law, the partial pressure of a gas in a mixture = the fractional concentration of gas × total pressure of system. The oxygen concentration at all altitude is similar, that is, 21%, although the partial pressure changes. At sea level (at standard pressure), this means that the ambient partial pressure of oxygen = (fractional concentration of oxygen in atmosphere) × (atmospheric pressure) = 0.21 × 760 mm Hg = 160 mm Hg. At 3,050 m (10,000 ft), this calculation = 0.21 × 523 mm Hg = 110 mm Hg. Simply put, the partial pressure of oxygen gas is decreased at altitude. Thus, hypoxia at altitude is caused by the inhalation of oxygen-poor air from this reduction in the partial pressure of oxygen and is termed hypobaric hypoxia.
The initial response to altitude is an attempt to get more oxygen into the lungs by increasing the minute-volume via increasing respiratory rate and inspiratory volume. Pulmonary vascular resistance increases 50% to 300% within 5 minutes of exposure to altitude triggered by inhibition of oxygen-sensitive potassium channels called hypoxic pulmonary vasoconstriction or the generalized Euler-Liljestrand reflex. These openings depolarize the pulmonary artery smooth muscle cells and activate L-type voltage-gated calcium channels. Calcium then enters the cells and mediates vasoconstriction. However, this mechanism may not explain all of the effects seen. Hypoxic pulmonary vasoconstriction mediates ventilation-perfusion matching in the lungs at altitude and reduces shunt fraction (percentage of the blood put out by the heart that is not completely oxygenated), to optimize systemic arterial oxygen tension. There is also an increase in the alveolar to pulmonary arterial oxygen gradient.
This elevated alveolar-arterial oxygen difference that is seen in subjects who are in conditions of extreme hypoxia may represent a degree of subclinical high-altitude pulmonary edema (HAPE) or a functional limitation in pulmonary diffusion.
This initial hyperventilation leads to a decrease in intravascular carbon dioxide and respiratory alkalosis that shifts the oxygen-hemoglobin dissociation curve to the left, facilitating increased oxygen binding to hemoglobin in the lungs. Unfortunately, after a few hours at altitude, there is an increase in red cell 2,3-diphosphoglycerate, which shifts the curve back to the right. This results in more oxygen release to the muscles and organs yet makes it more difficult for the oxygen to bind to hemoglobin in the lungs.
One measure of the amount of oxygen available for use within the body is arterial oxygen saturation (SaO 2), which is the percentage of binding sites of hemoglobin molecules that are carrying oxygen. At sea level, 0 m, SaO 2 is 98% to 100%. Upon rapid ascent of an unacclimatized person to 4,300 m (14,190 ft), SaO 2 falls to about 80% and partial pressure of arterial oxygen is 40 mm Hg, meaning that the oxygen content of the blood is lower than at sea level, that is, less oxygen is being carried in the blood.  Given that oxygen delivery is the product of cardiac output and arterial oxygen content, cardiac output (stroke volume × heart rate) must be increased for oxygen delivery to be maintained. Therefore, at any given level of submaximal exercise at altitude, the cardiac output is generally higher than at sea level. Because of the small changes in stroke volume, cardiac output is increased by a rising heart rate. At rest, increases of 10% to 30% in heart rate have been documented at altitudes up to 4,300 m (14,190 ft) with the major determining factor being rate of ascent.
In acute exposure, heart rate is elevated at rest with a minimum reduction in stroke volume. However, there is a reduction in the maximal heart rate response and consequently a lower peak cardiac output. The decrease in heart rate at maximal exercise in prolonged exposure to hypoxia is related to changes in the autonomic nervous system: the desensitization of the ß-adrenergic pathway and the up-regulation of the muscarinic pathway, both using G-protein systems, contribute to limit the myocardial oxygen consumption in face of reduced oxygen availability during maximal exercise.
Fluid changes also occur. Within hours of being at altitude, there is a rapid reduction in plasma volume secondary to increased respiratory, urinary, and cutaneous losses. This results in an increased hematocrit and, thus, an augmentation in the oxygen-carrying capacity of the blood per unit volume. Thus, the stroke volume remains unchanged or may even decrease with the lower plasma volume.
In addition, after rapid ascent to high altitude, parasympathetic nervous system activities are suppressed and significant sympathetic responses, both systemically and regionally, predominate. Specifically, direct (stimulation of the adrenal medulla) and indirect (chemoreceptor reflexes and altered baroreceptor function) effects result in the release of epinephrine within minutes to hours of exposure to hypobaric hypoxia. The higher the altitude, the lower the arterial saturation, and the higher the arterial epinephrine concentration. These elevated epinephrine levels further enhance cardiac output. Epinephrine also causes vasodilation in skeletal muscle blood vessels and bronchodilation in the lungs. The net effect on blood pressure is zero, that is, there is no significant difference between systolic, diastolic, or mean brachial arterial blood pressure between sea level and high altitude. [28,29] Together, these effects serve to promote peripheral oxygen transfer and delivery. Most investigators have found little change in resting plasma norepinephrine levels at altitude.
Diastolic function at altitude has been studied using tissue Doppler imaging. After rapid ascent to high altitude, several studies of healthy men and women at rest have noted the following changes in echocardiographic parameters: up to a 3-fold increase in mean pulmonary artery pressure, altered right and left ventricular diastolic function with prolonged isovolumic relaxation time, maintained right ventricular systolic function, and improved left ventricular systolic function. Similar findings were noted in healthy subjects exercising at high altitude.
Metabolism is also altered; the increase in epinephrine stimulates glycogenolysis, resulting in increased glucose use during rest and exercise causing significantly greater increase in blood lactate levels at altitude than at sea level—the lactate paradox. Although greater use of glucose maximizes the energy yield per unit oxygen, it results in a more rapid depletion of the limited reserves of stored carbohydrate.
MEDSCAPE General Abstract