Effects of altitude on plasma oxygen uptake

The standard atmospheric pressure of 760 mmHg (101 kPa) at sea level reflects the weight exerted by the gas molecules that make up the air, under gravitational force. As one ascends from sea level, the air becomes progressively less compressed and so the constituent gas molecules become less tightly packed. In consequence, a given volume of inspired air contains fewer molecules of all gases, including oxygen. The relationship between altitude and atmospheric pressure is not a strictly linear one because the air volume increases in 3 dimensions but, in rough terms, pressure falls by around 100 mmHg for every 1000 m (3300 ft) of ascent up to 3000 m (10 000 ft) (Fig. 12.1).

Figure 12.1 Effects of altitude on atmospheric pressure and calculated alveolar oxygen tension (P_AO₂). P_AO₂ values have been estimated as ([21%.P_atmos–47] – 50) and represent the theoretical values that result from atmospheric pressure alone, disregarding any physiological compensations that occur. Note that in this theoretical situation P_AO₂ falls to zero at an altitude of 8000 m (26 000 ft) although, with acclimation, numerous individuals have climbed to the summit of Mt Everest at 8843 m (29 000 ft).

The absolute change in oxygen availability imposed by a given ascent can be calculated easily. Since oxygen represents 21% of normal air, the partial pressure of oxygen (PO₂) at sea level is (21%.760) or 160 mmHg. Once inspired, the air becomes saturated with water vapour (partial pressure 47 mmHg) so that the total gas pressure is reduced to 713 mmHg and PO₂ falls to (21%.713) or 150 mmHg. In the alveoli, the oxygen is diluted further by approximately 50 mmHg, due primarily to the presence of carbon dioxide, resulting in a local PO₂ (P_AO₂) of around 100 mmHg: at equilibrium with the plasma, arterial PO₂ (PaO₂) is, therefore, usually also around 100 mmHg.

At an atmospheric pressure of 560 mmHg, which corresponds to an altitude of around 2300 m (7600 ft) or just higher than Mexico City, P_AO₂ can be estimated to be around 60 mmHg (21%.[560–47] – 50). Many of the major ski resorts like Aspen and Zermatt involve slopes at heights in excess of 3500 m (11 000 ft), where atmospheric pressure is 500 mmHg and so P_AO₂ will be around (21%.[500–47] – 50) or 45 mmHg, while permanent settlements in the Himalayas and Andes are found as high as 5000 m (17 500 ft) where atmospheric pressure is only 390 mmHg and calculated P_AO₂ is around 25 mmHg.

Effects of altitude on oxygen carriage

Because of the sigmoid shape of the haemoglobin dissociation curve, the falls in PaO₂ associated with acute exposure to altitudes up to around 2000 m (6700 ft) cause only a slight reduction in haemoglobin saturation (Fig. 12.2) and so do not reduce oxygen delivery at rest. During exercise, however, the combination of reduced binding and reduced pulmonary capillary transit time leads to a greater degree of desaturation that is proportional both to altitude and to cardiac output. Thus, the threshold altitude for oxygen limitation of maximum exercise in sedentary individuals is typically around 1500 m (5000 ft), but, in trained athletes with substantially greater cardiac outputs, maximum work capacity begins to fall at much lower altitudes (Johnson et al 1994). In the only Summer Olympics held at a significant altitude, in Mexico City in 1968, winning times for all track events longer than 800 m were well above the existing records.

Figure 12.2 Relationship between altitude, arterial oxygen tension (PaO₂), haemoglobin saturation and blood oxygen carriage. Note that at the altitude where PaO₂ reaches the threshold for peripheral hypoxia receptor activation (60 mmHg) blood oxygen carriage is reduced only marginally from the sea level value.

Respiratory stimulation

The reduced oxygen carriage associated with moderate altitude results in more rapid fatigue during exercise, but no respiratory compensation occurs because ventilation is still driven by the central chemoreceptors. These respond to rises in local proton concentration (that is, reduced pH) secondary to arterial carbon dioxide diffusing into the hindbrain, but are insensitive to hypoxia. The peripheral chemoreceptors responsible for monitoring arterial oxygen status are triggered only when PaO₂ falls to around 60 mmHg which, as we saw earlier (p. 145), corresponds to an approximate altitude of 2300 m or 7600 ft. At or above this height, chemoreceptor stimulation initiates increased minute ventilation the magnitude of which depends both on the initial PaO₂ and on whether increased ventilation is able to restore PaO₂ to a value above 60 mmHg.

This acute ventilatory compensation for hypoxia occurs very rapidly, but is itself able to produce only a moderate improvement in oxygen availability. The reason is that increased ventilation necessarily results in carbon dioxide being blown off at a greater rate than before, leading to a fall in arterial carbon dioxide (PaCO₂) (hypocapnia) and, therefore, to a rise in hindbrain pH and reduced central chemoreceptor drive, inhibiting the stimulant effect of the hypoxic drive.

With maintained exposure to the hypoxic environment, the inhibition of central chemoreceptor drive diminishes over the next several days. Most rapidly, there is over 1–2 days’ diffusion of excess bicarbonate ions out of the interstitial fluid around the central chemoreceptors that reduces buffering of interstitial protons. Over the next 2–3 days, renal bicarbonate excretion amplifies this process and restores central pH and respiratory drive to normal despite the maintained hypocapnia, although arterial pH remains slightly more alkaline than normal. As a result of these adjustments, minute ventilation rises progressively over the first week of hypoxic exposure, with an associated progressive increase in work capacity that is due both to the increased inspired air volume and to the fact that the enhanced ventilation has reduced alveolar PCO₂ further and, therefore, the oxygen tension of alveolar air rises. At very high altitudes, the decrease in air density may also contribute to increased capacity for maximum ventilation.

Haematological changes

Over the first few days of exposure to hypoxia, haematological changes increase the capacity of the red blood cell pool to deliver oxygen. The alkalosis produced by hypocapnia increases red cell expression of 2,3-diphosphglycerate (DPG), which shifts the haemoglobin dissociation curve to the right and increases oxygen unloading in the systemic capillaries (Fig. 12.3). Simultaneously, erythropoietin release from the renal medulla in response to hypoxia stimulates red cell production, so that haematocrit rises progressively over the ensuing several weeks.

Figure 12.3 Effect of altitude on the efficiency of DPG expression as an aid to oxygen delivery. Note that the values for PaO₂ represent those occurring at the respective altitudes before any compensation. (a) At altitude 2200 m (PaO₂ 60 mmHg) there is a doubling of oxygen offloading, while onloading is virtually unaffected. The net tissue gain is 6.5 ml oxygen/100 ml blood. (b) At altitude 3500 m (PaO₂ 40 mmHg), by contrast, the improved offloading is almost obviated by reduced onloading. The net tissue gain now is only 1.5 ml oxygen/100 ml blood.

Benefits of adaptation for exercise capacity at high altitude

The spectrum of compensatory processes means that fully acclimated individuals have vastly better capacities for work than when they first arrive at altitude. They are, however, still not able to achieve workloads identical to those that were possible at sea level. The compensations that occur cannot overcome fully the reduced haemoglobin saturation imposed by a low PaO₂ and, in addition, the adaptive processes themselves impose some limits of circulatory efficiency. One problem is that increased haematocrit increases blood viscosity and so increases cardiac workload for a given cardiac output. In addition, the rightwards shift of the haemoglobin dissociation curve induced by DPG has the effect of, under moderate-to-severely hypoxic conditions, reducing pulmonary loading of oxygen as well as increasing the unloading process (Fig. 12.3). Finally, since even slight alkalosis shifts the dissociation curve to the left, the profound hypocapnia seen in fully acclimated individuals may actually reverse the effect of DPG and reduce capillary oxygen unloading.

For athletes who live at low altitudes, a period of acclimation is obviously essential if they are to compete effectively at higher altitudes but, even then, the limits to adaptation described above are likely to restrict their performance. The same limitations are not evident to the same extent in natives of high altitude communities, who appear to possess cardiorespiratory systems that are better adapted to hypoxia. It remains uncertain to what extent these differences from low-level residents are genetically determined and to what extent they are developed during childhood.

Benefits of adaptation for exercise capacity at low altitude

The greatest significance for athletic performance of adaptations to high altitude is its potential effect on performance at low altitude. Here, the positive effects on oxygen delivery of DPG and raised haematocrit can be exploited without interference from reduced ambient oxygen availability or hypocapnia. This scenario has led to training at altitude being adopted as a routine component of preparation for competition of many athletes. Unfortunately, the value of this strategy is limited by the reduced intensity of training that is possible under hypoxic conditions. More convincing results have been obtained by allowing training to be carried out at low altitude and stimulating the haematological adaptations by exposure to a hypoxic environment overnight (Hendricksenn & Meeuwsen 2003).

The potential advantages for performance of adaptations to hypoxia have led to the administration of synthetic erythropoietin in order to increase haematocrit. Leaving aside the illegality, ‘blood doping’ with erythropoietin carries with it very substantial risks. The normal response to hypoxia incorporates both increased red cell mass and increased oxygen carriage efficiency through DPG expression. The red cells produced in response to erythropoietin do not have up-regulated DPG and so, in order to achieve a given increment in tissue oxygen delivery, there needs to be a much greater increment in red cell mass. In consequence, athletes who have taken erythropoietin may have haematocrits of the order of 70%, with massively elevated cardiac workload and a significant risk of cardiac events during exercise, as well as increased risk of venous thrombosis due to red cell clumping (see Chapter 5, p. 55).

Implications of temperature

Even with ascents that are insufficient to produce significant hypoxia, the effect of altitude on environmental temperature needs to be borne in mind. With every 200 m (660 ft) rise above sea level, air temperature falls by 1.3° C (2.1° F), so that a simple hill walk to a peak standing 1500 m (4900 ft) means exposure to temperatures about 10° C below that at the base. Since increased altitude is also almost inevitably accompanied by greater wind chill and less shelter, hypothermia is an ever-present danger even in moderate climates.

Dehydration

The progressive temperature fall not only has direct implications for thermoregulation, but also greatly affects water balance. As air temperature falls, the air becomes progressively drier, so that at 0° C (32° F) saturated water vapour pressure is only around 30% of its value at 20° C (68° F). When this air is inspired, its temperature rises to that of the body and additional water is lost from the airway mucosa in order to saturate it. Ascent to any altitude, therefore, necessarily involves increased water loss. The extent of this must be proportional to the ventilatory volume, so it becomes an increasing problem with increased exercise intensity and especially when the altitude is sufficient for activation of hypoxic respiratory drive. Respiratory dehydration has a powerful enhancing effect on the susceptibility of an individual to hypothermia, since substantial amounts of body heat are lost in warming cold inspired air, while the depletion of plasma volume potentially limits exercise capacity.

Acute mountain sickness

Individuals who ascend rapidly to altitudes around 3000 m (9800 ft) frequently suffer from a syndrome termed acute mountain sickness, which involves nausea, headache and fatigue, among other symptoms. These symptoms usually appear within 1 or 2 h of ascent and usually disappear over the next several days as acclimation occurs. Several factors may be involved in genesis of acute mountain sickness. Significant dehydration often occurs, because hypoxia and the alkalosis that follows respiratory stimulation appear to inhibit thirst and so exaggerate the increased respiratory water loss associated with altitude. This dehydration probably plays a part in the headache by tightening the connective tissue strands that support the brain. Alkalosis seems also to be a key factor in the other symptoms, since most people can prevent acute mountain sickness except at extreme altitudes by dosing themselves with a carbonic anhydrase inhibitor before ascent.

Pulmonary oedema

A small number of individuals show a more serious acute response to the same levels of ascent that induce acute mountain sickness. In these people, there is damage to the pulmonary capillary wall so that plasma leaks into the lung interstitium and may enter the alveoli. The precise mechanisms that underlie this high-altitude pulmonary oedema are not fully understood, but it almost certainly involves generation of high intracapillary pressures in response to hypoxia. Superficially, this seems counterintuitive. You will remember from Chapter 8 (pp. 94) that capillary hydrostatic pressure in the lung is normally well below the plasma oncotic pressure, so that there is a good safety margin to ensure no fluid extravasation. We also saw in Chapter 8 (pp. 96) that the pulmonary arteriolar smooth muscle possesses hypoxia receptors that induce vasoconstriction in response to reduced alveolar PO₂. In theory, therefore, breathing hypoxic air should cause generalized pulmonary vasoconstriction which, while it will elevate pulmonary arterial pressure, will reduce capillary hydrostatic pressure.

In practice, the likely explanation is that, in the susceptible individuals that suffer high altitude pulmonary oedema, not all areas of the pulmonary arteriolar bed respond equally strongly to the vasoconstrictor effect of hypoxia. Under these circumstances, a disproportionate volume of right cardiac output is directed through the least constricted vessels exposing the capillaries in these areas to an intravascular pressure close to pulmonary arterial pressure (West 2004).

Pulmonary hypertension

Chronic hypoxia also has other disadvantageous consequences that are seen in long-term residents and, in particular, in individuals who have been born at high altitude. The pulmonary vasoconstrictor effect of hypoxia generates an increased afterload for the right ventricle leading to myocardial hypertrophy and the possibility of right heart failure because of inadequate coronary vascularization (see Chapter 8, p. 95). In addition, the relatively low PaO₂ results in reduced efficiency of ductus arteriosus closure after birth (see Chapter 8, p. 102), so that a relatively large number of native highland children have some residual shunting between pulmonary and systemic circulations, which further increases pulmonary afterload.

Key points

As one ascends above sea level, exercise capacity becomes increasingly limited by ventilatory capacity to deliver oxygen to the bloodstream.

The threshold altitude for limiting in sedentary individuals is around 1500 m (5000 ft), but a considerably lower ascent is needed to impair performance in trained athletes with higher cardiac outputs.

Short-term compensations to improve exercise capacity at altitude include increased ventilation triggered by peripheral hypoxia receptors and up-regulation of 2,3-DPG expression in erythrocytes. Over a longer timecourse, these are augmented by increased red cell mass.

The effects of hypoxia can be utilized to improve exercise performance at lower altitudes, with better results produced by exposure to a hypoxic environment for part of the day, but with training performed at a low altitude.

Exposure to altitude is associated with increased risk of dehydration and hypothermia, as well as with the consequences of hypoxia and alkalosis.