Search

Background: Although only poor data exist on changes in myocardial blood flow (MBF) under acute hypoxia, patients with known coronary artery disease are advised not to exceed a moderate altitude exposure of about 2000 m above sea level., Methods and Results: We measured MBF with positron emission tomography using O-15--labeled water in 8 healthy human volunteers (aged 26 +/- 3 years [mean +/- SD]) at baseline (450 m above sea level, Zurich, Switzerland) and during acute hypoxic hypoxemia induced by inhalation of 2 hypoxic gas mixtures corresponding to altitudes of 2000 and 4500 m. MBF remained unchanged at 2000 m (increase of 10%, not significant) but increased significantly at 4500 m (62%, P <.001), exceeding the relative increase in rate pressure product., Conclusions: Our results may explain why exposure to an altitude of 2000 m (corresponding to the cabin pressure in most airplanes during flight) is clinically well tolerated, even by patients with reduced coronary flow reserve, such as those with coronary artery disease. However, at an altitude of 4500 m, MBF increases significantly, supporting the recommendation that patients with impaired flow reserve avoid exposure to higher altitudes.

In order to investigate whether vascular endothelial growth factor (VEGF) and inflammatory pathways are activated during acute hypobaric hypoxia in subjects who are susceptible to high-altitude pulmonary oedema (HAPE-S), seven HAPE-S and five control subjects were exposed to simulated altitude corresponding to 4000 m in a hypobaric chamber for 1 day. Peripheral venous blood was taken at 450 m (Zürich level) and at 4000 m, and levels of erythropoietin (EPO), VEGF, interleukin-6 (IL-6) and the acute-phase proteins complement C3 (C3), alpha1-antitrypsin (alpha1AT), transferrin (Tf) and C-reactive protein (CRP) were measured. Peripheral arterial oxygen saturation (SaO2) was recorded. Chest radiography was performed before and immediately after the experiment. EPO increased during altitude exposure, correlating with SaO2, in both groups (r = -0.86, P < 0.001). Venous serum VEGF did not show any elevation despite a marked decrease in SaO2 in the HAPE-S subjects [mean (SD) HAPE-S: 69.6 (9.1)%; controls: 78.7 (5.2)%]. C3 and alpha1AT levels increased in HAPE-S during hypobaric hypoxia [from 0.94 (0.11) g/l to 1.07 (0.13) g/l, and from 1.16 (0.08) g/l to 1.49 (0.27) g/l, respectively; P < 0.05], but remained within the clinical reference ranges. No significant elevations of IL-6, Tf or CRP were observed in either group. The post-exposure chest radiography revealed no signs of oedema. We conclude that VEGF is not up-regulated in HAPE-S and thus does not seem to increase critically pulmonary vascular permeability during the 1st day at high altitude. Furthermore, our data provide evidence against a clinically relevant inflammation in the initial phase of exposure to hypoxia in HAPE-S, although C3 and alpha1AT are mildly induced.

Decreased arterial partial oxygen pressure (PaO2) below a certain level presents a strong stimulus for increasing cerebral blood flow. Although several field studies examined the time course of global cerebral blood flow (gCBF) changes during hypoxia at high altitude, little was known about the regional differences in the flow pattern. Positron emission tomography (PET) with [(15)O]H2O was used on eight healthy volunteers to assess regional cerebral blood flow (rCBF) during short-term exposure to hypoxia corresponding to simulated altitudes of 3,000 and 4,500 m. Scans at the simulated altitudes were preceded and followed by baseline scans at the altitude of Zurich (450 m, baseline-1 and baseline-2). Each altitude stage lasted 20 minutes. From baseline to 4,500 m, gCBF increased from 34.4 +/- 5.9 to 41.6 +/- 9.0 mL x minute(-1) x 100 g(-1) (mean +/- SD), whereas no significant change was noted at 3,000 m. During baseline-2 the flow values returned to those of baseline-1. Statistical parametric mapping identified the hypothalamus as the only region with excessively increased blood flow at 4,500 m (+32.8% +/- 21.9% relative to baseline-1). The corresponding value for the thalamus, the structure with the second largest increase, was 19.2% +/- 16.3%. Compared with the rest of the brain, an excessive increase of blood flow during acute exposure to hypoxia is found in the hypothalamus. The functional implications are at present unclear. Further studies of this finding should elucidate its meaning and especially focus on a potential association with the symptoms of acute mountain sickness.

To investigate the role of fluid shifts during the short-term adjustment to acute hypobaric hypoxia (AHH), the changes in lower limb (LV) and forearm volumes (FV) were measured using a strain-gauge plethysmograph technique in ten healthy volunteers exposed to different altitudes (450 m, 2500 m, 3500 m, 4500 m) in a hypobaric chamber. Arterial blood pressure, heart rate, arterial oxygen saturation (SaO2), endtidal gases, minute ventilation and urine flow were also determined. A control experiment was performed with an analogous protocol under normobaric normoxic conditions. The results showed mean decreases both in LV and FV of 0.52 (SD 0.39) ml x 100 ml(-1) and -0.65 (SD 0.32) ml x 100 ml(-1), respectively, in the hypoxia experiments [controls: LV 0.28 (SD 0.37), FV 0.41 (SD 0.47) ml x 100 ml(-1)]. Descent to normoxia resulted in further small but not significant decreases in mean LV [-0.02 (SD 0.11) ml x 100 ml(-1)], whereas mean FV tended to increase slightly [ + 0.02 (SD 0.14) ml x 100 ml(-1)]; in the control experiments mean LV and FV decreased continuously during the corresponding times [-0.19 (SD 0.31), -0.18 (SD 0.10) ml x 100 ml(-1) , respectively]. During the whole AHH, mean urine flow increased significantly from 0.84 (SD 0.41) ml x min(-1) to 3.29 (SD 1.43) ml x min(-1) in contrast to the control conditions. We concluded that peripheral fluid volume shifts form a part of the hypoxia-induced acute cardiovascular changes at high altitude. In contrast to the often reported formation of peripheral oedema after prolonged exposure to hypobaric hypoxia, the results provided no evidence for the development of peripheral oedema during acute induction to high altitude. However, the marked increase in interindividual variance in SaO2 and urine flow points to the appearance of the first differences in the short-term adjustment even after 2 h of acute hypobaric hypoxia.

The functional characteristics at rest in responding to stepwise acute exposure to simulated altitude (6000 m) were compared in 10 acclimatized mountaineers (highlanders), residents of Zermatt (1616 m) working at an altitude up to about 4000 m, and in 11 nonacclimatized control subjects (lowlanders) living and working in Zurich (450 m). In comparison with the lowlanders, the highlanders showed at altitude significantly greater hyperventilation, lower heart rate and systolic blood pressure, smaller haemoconcentration, lower urodilatin secretion and natriuresis, and a preserved neuropsychological ability (attentiveness) and vasomotor tone (diastolic blood pressure); the critical altitude at which hypoxic short-term adaptation became insufficient was 6000 m. The lowlanders, however, manifested reduced tolerance of hypoxia, i.e. insufficient short-term adjustment with subjective and objective distress coinciding with the first signs of hypoxia of the central nervous system, already apparent at and above 4000 m. It was concluded that the functional differences between highlanders and lowlanders in responding to acute gradual hypoxia indicated factors contributing to altitude acclimatization.

Health at altitude depends on the success of functional adjustments. Only the success of the short-term adjustments including increased tidal volume, acceleration of circulation, centralization of blood volume, hemoconcentration and adjustment of de diuresis to reduce cardiac volume overload render acclimatization possible. During these long-term adjustments, which always remain incomplete at altitudes above 2000 to 3000 m, mainly the cardiovascular economy and the respiratory efficiency are improved. Failure of the short-term adjustments excludes acclimatization and may be due to reduced physical capacity or to excessive physical activity (too fast too high). It is associated with sympathetic cardiac volume overload, central hypoxia, antidiuresis and distress which result in acute mountain sickness. Health at altitude may be preserved by moderating the ascent, the duration and the physical activity there.

Respiratory, circulatory and neuropsychological responses to stepwise, acute exposure at rest to simulated altitude (6,000 m) were compared in ten acclimatized recumbent mountaineers 24 days, SD 11 after descending from Himalayan altitudes of at least 4,000 m with those found in ten non-acclimatized recumbent volunteers. The results showed that hypoxic hyperpnoea and O2 consumption at high altitudes were significantly lower in the mountaineers, their alveolar gases being, however, similar to those of the control group. In the acclimatized subjects the activation of the cardiovascular system was less marked, systolic blood pressure, pulse pressure, heart rate and thus (calculated) cardiac output being always lower than in the controls; diastolic blood pressure and peripheral vascular resistance, however, were maintained throughout in contrast to the vasomotor depression induced by central hypoxia which occurred in the non-acclimatized subjects at and above 4,000 m [alveolar partial pressure of O2 less than 55-50 mmHg (7.3-6.6 kPa)]. It was concluded that in the acclimatized subjects at high altitude arterial vasodilatation and neurobehavioural impairment, which in the non-acclimatized subjects reflect hypoxia of the central nervous system, were prevented; that acclimatization to high altitude resulted in a significant improvement of respiratory efficiency and cardiac economy, and that maintaining diastolic blood pressure (arterial resistance) at and above 4,000 m may represent a useful criterion for assessing hypoxia acclimatization.

As a result of our recently published studies we have thought that altitude diuresis resulting from hypoxic stimulation of the arterial chemoreceptors reduces the cardiac volume overload. To test this hypothesis, cardiovascular, endocrine and renal responses to stepwise acute exposure to simulated altitude (6,000 m) were compared in ten acclimatized recumbent mountaineers a mean of 24 days, SD 11, after descending from Himalayan altitudes of at least 4,000 m, with those found in ten non-acclimatized recumbent volunteers. The results showed that natriuresis and diuresis typified the renal responses to altitude exposure of both the acclimatized as well as non-acclimatized subjects, as long as altitude was well tolerated. It was concluded that the renal effects were mediated by atrial natriuretic peptide release and slight suppression of arginine-vasopressin (AVP) secretion, that the increased urine flow at altitude offset the cardiac (volume) overload resulting from hypoxic stimulation of the arterial chemoreceptors, and that enhanced AVP secretion, as found in the non-acclimatized subjects at and above 4,000 m, coincided with subjective and objective distress, i.e. with inadequate altitude adjustment owing to insufficient chemoreflex effects and central hypoxia.

The role of the sympatho-adrenal system in the acute respiratory and cardiovascular responses to high altitude was studies in 20 volunteers during ascent to 6,000 m in a low pressure chamber, once without (control) and once with beta-adrenergic blockade. Special attention was paid to the hypoxia-induced ECG changes. Propranolol lowered the level of hypoxia-induced cardiovascular reactions, whereas it had no effect on hypoxic hyperventilation and alveolar gases. At altitude, ECG changes during myocardial depolarization occurred in both the propranolol and the control groups, probably due to the direct effects of hypoxia. During the repolarization phase, propranolol led to an almost complete abolition of S-T depression and to significant reduction of T wave flattening. The minor but still significant flattening of the T wave as well as the relative (to the heart rate) lengthening of Q-T is probably due to the direct effects of hypoxia. Propranolol abolishes or diminishes the signs of cardiac hypoxia by antagonizing the effects of catecholamine release and/or by reducing myocardial oxygen consumption, thus probable increasing the ability to withstand oxygen-want at altitude.

In order to analyze the respiratory, cardiovascular, and ECG responses to acute hypoxic hypoxia, three experimental series were carried out in a randomized manner on 11 healthy, unacclimatized volunteers at rest during standardized stepwise exposure to 6000 m (PAO2 35.2 +/- 2.9 mmHg/4.7 +/- 0.4 kPa) in a low-pressure chamber a) without (control), b) with propranolol, and c) with atropine combined with propranolol. The results show that hypoxic hyperventilation and alveolar gases are not affected by activation of the sympatho-adrenal axis or by parasympathetic withdrawal. Sympathetic activity, however, increases heart rate, stroke volume (pulse pressure), estimated cardiac output and systolic blood pressure, whereas decreased parasympathetic activity increases heart rate and estimated cardiac output, but lowers stroke volume. The fall in peripheral resistance, observed during progressive hypoxia in all three groups, is thought to be due to hypoxia-induced depression of the vasomotor center. At altitude catecholamine secretion and vagal withdrawal synergistically account in the ECG for the R-R shortening, the relative Q-T lengthening, the elevation of the P wave and the ST-T flattening. Probable direct hypoxic effects on the heart are the increase in P-Q duration and the minor but still significant depression of the T wave. It is concluded that at altitude increased sympatho-adrenal and decreased parasympathetic activity is without effect on hypoxic hyperventilation, but accounts for most of the cardiovascular and ECG changes. Diminution of sympathetic activity and imminent vagotonia arising after acute ascent to 6000 m probably reflect hypoxia of the central nervous system.

In order to distinguish the effects of beta-receptor stimulation on the ECG from other factors during short-term adjustment to hypoxic aerohypoxia, the ECG of 19 volunteers were compared during moderately acute, stepwise exposure to high altitude (6,000 m) in a low pressure chamber, once with and once without beta-receptor blockade (propranolol), and after isoprenaline inhalation at ground level. The results show that beta-receptor stimulation accounts mainly for most ECG changes during altitude exposure, i.e., for the shortening of R-R interval, the lengthening of Q-T and in particular for the ST-T flattening, the latter therefore being only an indirect sign of hypoxia. After exclusion of the catecholamines, the minor but still significant ECG changes at altitude (shortening of R-R interval, increase of P wave, prolongation of P-Q, deviation of the R vector, T wave flattening in the left precordial leads) may be attributed to other, so far undefined factors, such as cardiac hypoxia, vagal withdrawal, or increase of pulmonary resistance.

The venous concentrations of epinephrine and norepinephrine and changes in ventilation, respiratory gases, circulation and ECG were determined in 20 young healthy male medical students during standardized stepwise ascent to 6000 m in a low pressure chamber, once without (control) and once with beta-receptor blockade (propranolol). The results show that the plasma concentration of norepinephrine increased significantly as a result of hypoxic hypoxia. The moderate increase in epinephrine was, besides the minor but significant hypoxic influence, mainly due to psychic tension. Since beta-receptor blockade does not prevent the respiratory and circulatory adjustment, beta-adrenergic stimulation is not thought to be necessary at altitude. Propranolol, on the contrary, lowers the hypoxia-induced increase in cardiac output and diminishes the ECG changes, in particular the S-T depression, significantly. By antagonizing the effects of epinephrine and by its central effects, propranolol improves subjective tolerance to altitude, and, on the other hand, by economizing the cardiac work load, the objective ability to withstand oxygen want.