Responses of the autonomic nervous system in altitude adapted and high altitude pulmonary oedema subjects

Studies were carried out to ascertain the role of sympatho-parasympathetic responses in the process of adaptation to altitude. The assessment of status of autonomic balance was carried out in a group of 20 young male subjects by recording their resting heart rate, blood pressure, oral temperature, mean skin temperature, extremity temperatures, pupillary diameter, cold pressor response, oxygen consumption, cardioacceleration during orthostasis and urinary excretion of catecholamines; in a thermoneutral laboratory. The same parameters were repeated on day 3 and at weekly intervals for a period of 3 weeks, after exposing them to 3,500 m; and also after return to sea level. At altitude, similar studies were carried out in a group of 10 acclimatized lowlanders, 10 high altitude natives and 6 patients who had recently recovered from high altitude pulmonary oedema. In another phase, similar studies were done in two groups of subjects, one representing 15 subjects who had stayed at altitude (3,500–4,000 m) without any ill effects and the other comprising of 10 subjects who had either suffered from high altitude pulmonary oedema (HAPO) or acute mountain sickness (AMS). The results revealed sympathetic overactivity on acute induction to altitude which showed gradual recovery on prolonged stay, the high altitude natives had preponderance to parasympathetic system. Sympathetic preponderance may not be an essential etiological factor for the causation of maladaptation syndromes.     

Changes in plasma cortisol,blood antidiuretic hormone and urinary catecholamines in high—altitude pulmonary oedema

In 10 subjects susceptible to high altitude pulmonary oedema (HAPO) plasma cortisol and antidiuretic hormone (ADH) and urinary catecholamines were estimated both at sea level and daily during their stay at 3, 500 m (Leh). At high altitude 4 of the subjects developed HAPO, 2 got acute mountain sickness (AMS) and 4 remained unaffected. Plasma cortisol showed a sharp rise on the first day at high altitude in all the subjects. Thereafter, it declined gradually in the unaffected subjects. In the HAPO patients there was a sharp fall in the plasma cortisol level combined with antidiuresis. Changes in plasma ADH and urinary catecholamines were not consistent. It appears that failure in the normal adrenocortical response to altitude stress in susceptible subjects is a factor in precipitating HAPO.     

Lactate during exercise at extreme altitude

Maximal exercise at extreme altitude results in profound arterial hypoxemia and, presumably, extreme tissue hypoxia. The best evidence available indicates that the resting arterial PO2 on the summit of Mount Everest is about 28 torr and that it falls even further during exercise. Nevertheless, some 10 climbers have now reached the summit without supplementary oxygen. Paradoxically, blood lactate for a given work rate at high altitude in acclimatized subjects is essentially the same as at sea level. Because work capacity decreases markedly with increasing altitude, maximal blood lactate also falls. Extrapolation of available data up to 6300 m indicates that a climber who reaches the Everest summit will have no increase in blood lactate. The cause of the low blood lactate during exercise at extreme altitude is not fully understood. One possibility is depletion of plasma bicarbonate in acclimatized subjects, which reduces buffering and results in large increases in H+ concentration for a given release of lactate. The consequent local fall in pH may inhibit enzymes, e.g., phosphofructokinase (EC 2.7.1.56), in the glycolytic pathway.     

高原健康居民某些内分泌激素的变化及其生理意义

本文在海拔10m(青岛)、2260m(青海西宁)和3700m(青海玉树)三个高度,用放射免疫法,测定445例健康人血四碘甲腺原氨酸(T_4)、三碘甲腺原氨酸(T_3)、3,3’,5’三碘甲腺原氨酸(rT3)皮质醇(F)和醛固酮(ALD)含量。结果发现:(1)高海拔地区世居藏族与有15年以上移居史的汉族居民五项测值间无显著差别(P>0.05);(2)高海拔地区居民T_3、T_4、F和ALD含量降低(P<0.05～0.001),而rT3则升高(P<0.01)。这些变化的生理意义,可能反映了高原居民对低氧环境的一种慢性适应机制。在某些高原疾病防治中,适当应用肾上腺皮质激素,可能有一定临床价值。     

Respiratory, circulatory and neuropsychological responses to acute hypoxia in acclimatized and non-acclimatized subjects

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.     

Developmental,genetic, and environmental components of aerobic capacity at high altitude

The aerobic capacity of 268 subjects (158 males and 110 females) was evaluated in La Paz, Bolivia situated at 3,750 m. The sample included 1) 39 high altitude rural natives (all male); 2) 67 high altitude urban natives (32 male, 35 female); 3) 69 Bolivians of foreign ancestry acclimatized to high altitude since birth (37 male, 32 female); 4) 50 Bolivians of foreign ancestry acclimatized to high altitude during growth (25 male, 25 female); and 5) 43 non-Bolivians of either European or North American ancestry acclimatized to high altitude during adulthood (25 male, 18 female). Data analyses indicate that 1) high altitude urban natives, acclimatized to high altitude since birth or during growth, attained higher aerobic capacity than subjects acclimatized to high altitude during adulthood; 2) age at arrival to high altitude is inversely related to maximum oxygen consumption (V?O² max) expressed in terms L/min or ml/min/kg of lean body mass, but not in terms of ml/min/kg of body weight; 3) among subjects acclimatized to high altitude during growth, approximately 25% of the variability in aerobic capacity can be explained by developmental factors; 4) as inferred from evaluations of skin color reflectance and sibling similarities, approximately 20 to 25% of the variability in aerobic capacity at high altitude can be explained by genetic factors; 5) except among the non-Bolivians acclimatized to high altitude during adulthood, the aerobic capacity of individuals with high occupational activity level is equal to the aerobic capacity of high altitude rural natives; and 6) the relationship between occupational activity level and aerobic capacity is much greater among subjects acclimatized to high altitude before the age of 10 years than afterwards. Together these data suggest that the attainment of normal aerobic capacity at high altitude is related to both developmental acclimatization and genetic factors but its expression is highly mediated by environmental factors, such as occupational activity level and body composition. © 1995 Wiley-Liss, Inc.     

High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein

Hypoxic pulmonary vasoconstriction is associated with but may not be sufficient for the development of high-altitude pulmonary oedema (HAPO). Hypoxia is known to induce an inflammatory response in immune cells and endothelial cells. It has been speculated that hypoxia-induced inflammatory cytokines at high altitude may contribute to the development of HAPO by causing capillary leakage in the lung. We were interested if such an inflammatory response, possibly involved in a later development of HAPO, is detectable at high altitude in individuals without HAPO. We examined the plasma levels of interleukin 6 (IL-6), interleukin 1 receptor antagonist (IL-1ra) and C-reactive protein (CRP) in two independent studies: study A, Jungfraujoch, Switzerland, three overnight stays at 3458 m, n=12; study B: Capanna Regina Margherita, Italy, 3 overnight stays at 3647 m and one overnight stay at 4559 m, n=10. In both studies, probands showed symptoms of acute mountain sickness but no signs of HAPO. At the Jungfraujoch, IL-6 increased from 0.1+/-0.03 pg/ml to 2. 0+/-0.5 pg/ml (day 2, P=0.03), IL-1ra from 101+/-21 to 284+/-73 pg/ml (day 2, P=0.01), and CRP from 1.0+/-0.4 to 5.8+/-1.5 micrograms/ml (day 4, P=0.01). At the Capanna Margherita, IL-6 increased from 0. 5+/-0.2 pg/ml to 2.0+/-0.8 pg/ml (P=0.02), IL-1ra from 118+/-25 to 213+/-28 pg/ml (P=0.02), and CRP from 0.4+/-0.03 to 3.5+/-1.1 micrograms/ml (P=0.03). IL-8 was below the detection limit of the ELISA (<25 pg/ml) in both studies. The increase of IL-6 and IL-1ra in response to high altitude was delayed and preceded the increase of CRP. We conclude that: (1) circulating IL-6, IL-1ra and CRP are upregulated in response to hypobaric hypoxic conditions at high altitude, and (2) the moderate systemic increase of these inflammatory markers may reflect considerable local inflammation. The existence and the kinetics of high altitude-induced cytokines found in this study support the hypothesis that inflammation is involved in the development of HAPO.     

Altitude diuresis: endocrine and renal responses to acute hypoxia of acclimatized and non-acclimatized subjects

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.     

Muscular blood flow in human highlanders and in lowlanders living at altitude (3 800 m) (author's transl)]

Muscular blood flow (MBF) was measured in the tibialis anteiror muscle by the 133Xe washout technique. Measurements were made in lowlanders at sea level, in native highlanders at 3 800 m and in lowlanders who had been living at this altitude for less than 6 months. At rest and during exercise, MBF is smaller in highlanders and in the high altitude visitors than in lowlanders. If, instead of total blood flow, the red cell flow is calculated (by multiplying MBF by the haematocrit) these differences are no longer significant at rest and are minimized during exercice. These results are consistent with reduction of cardiac output and blood supply to other regions in subjects who are acclimatized to altitude.     

Metabolic Adaptations May Counteract Ventilatory Adaptations of Intermittent Hypoxic Exposure during Submaximal Exercise at Altitudes up to 4000 m

Intermittent hypoxic exposure (IHE) has been shown to induce aspects of altitude acclimatization which affect ventilatory, cardiovascular and metabolic responses during exercise in normoxia and hypoxia. However, knowledge on altitude-dependent effects and possible interactions remains scarce. Therefore, we determined the effects of IHE on cardiorespiratory and metabolic responses at different simulated altitudes in the same healthy subjects. Eight healthy male volunteers participated in the study and were tested before and 1 to 2 days after IHE (7×1 hour at 4500 m). The participants cycled at 2 submaximal workloads (corresponding to 40% and 60% of peak oxygen uptake at low altitude) at simulated altitudes of 2000 m, 3000 m, and 4000 m in a randomized order. Gas analysis was performed and arterial oxygen saturation, blood lactate concentrations, and blood gases were determined during exercise. Additionally baroreflex sensitivity, hypoxic and hypercapnic ventilatory response were determined before and after IHE. Hypoxic ventilatory response was increased after IHE (p<0.05). There were no altitude-dependent changes by IHE in any of the determined parameters. However, blood lactate concentrations and carbon dioxide output were reduced; minute ventilation and arterial oxygen saturation were unchanged, and ventilatory equivalent for carbon dioxide was increased after IHE irrespective of altitude. Changes in hypoxic ventilatory response were associated with changes in blood lactate (r = −0.72, p<0.05). Changes in blood lactate correlated with changes in carbon dioxide output (r = 0.61, p<0.01) and minute ventilation (r = 0.54, p<0.01). Based on the present results it seems that the reductions in blood lactate and carbon dioxide output have counteracted the increased hypoxic ventilatory response. As a result minute ventilation and arterial oxygen saturation did not increase during submaximal exercise at simulated altitudes between 2000 m and 4000 m.     

Effect of phosphate supplementation on oxygen delivery at high altitude

In the present communication, effect of low doses of phosphate supplementation on short-term high altitude adaptation has been examined. Studies were carried out in 36 healthy, male, sea-level residents divided in a double blind fashion into drug and placebo treated groups. 3.2 mmol of phosphate were given orally to each subject of the drug treated group once a day for 4 days on arrival at an altitude of 3,500 m. Sequential studies were done in the subjects in both groups on the 3rd, 7th, 14th and 21st day of their altitude stay. Haemoglobin, haematocrit, erythrocyte and reticulocyte counts increased to the similar extent in both groups. Blood pH, pO₂ and adenosine tri-phosphate (ATP) did not differ between the two groups. On 3rd day of the altitude stay, inorganic phosphate and 2,3-diphosphoglycerate (2,3 DPG) levels in the drug treated group increased significantly as compared to the placebo group. No significant difference in inorganic phosphate and 2,3 DPG was observed later on in the two groups. Psychological and clinical tests also indicated that the drug treated subjects felt better as compared to the placebo treated subjects. The present study suggests that low doses of phosphate increases circulating 2,3-DPG concentration which in turn brings about beneficial effect towards short term high altitude adaptation.     

The oxygen cost of breathing in man: effects of altitude, training, and race

The oxygen cost of breathing was determined by an open-circuit method with voluntary hyperventilation over a wide range of volumes. In 11 lowland residents the oxygen cost (ml/1 STPD) of extra ventilation (BTPS) was 3.3 ml/1 at sea level and 2.1 ml/1 after 16 days at 4000 m; the corresponding cost for ventilation STPD was 4.2 ml/1 at altitude and 4.1 ml/1 at sea level. In acclimatized persons at altitude, including both native Indian and European residents, the cost of breathing varied from 2.5 to 3.7 ml/1. On the average, the cost of breathing for acclimatized subjects was 3.1 ml/1 (BTPS), only slightly lower (5 to 10%) than that for lowlanders at sea level. This relatively higher cost with acclimatization, though still lower than at sea level, may reflect pulmonary congestion concomitant with altitude sojourn. Group differences in the cost of breathing could not be ascribed to athletic training, racial background, or permanent altitude residence, nor was there a difference of cost during quiet seated hyperventilation versus cost during free wheel bicycle pedalling. Individual, group, altitude, and acclimatizational differences in the cost of breathing could affect oxygen intake at rest and work, as well as the regulation of ventilation.     

Neuropsychological acclimatization to high altitude

Subjects acclimatized to high altitudes manifest improved manual dexterity as well as trunkal and distal limb co-orbination over un-acclimatized subjects. There is no change in reaction time. Improved attentiveness may contribute to the improved performance, as well as the ability to adapt behaviorally to the numerous physiological consequences of hypoxia. From an ecological and perhaps evolutionary standpoint it matters little whether the adjustment to hypoxia involves intrinsic changes in tissue metabolism (physiological), or results from learning compensatory strategies at altitude (behavioral).     

Age-dependent influence of a moderate altitude (1,350 m) on the rat cardiopulmonary system

The aim of the study was to determine whether a moderate altitude (1,350 m, Strbské Pleso, High Tatras) would act as a hypoxic stimulus on the cardiopulmonary system of young and adult rats. We used three experimental groups of animals differing in the duration of time for which they were kept at the given altitude (60 and 120 days) and the age at which they were acclimatized (from the 5th and the 60th day of life). The controls were kept at an altitude of 200 m (Prague). We found that an altitude of 1,350 m produced a significant increase in blood pressure in the lesser circulation; this response did not depend on the animals' age. Right ventricular enlargement occurred at the same time and was more pronounced in rats which had been acclimatized from infancy. The systemic blood pressure fell mildly, but significantly, only in animals exposed to altitude from adulthood; elevation of the haematocrit was likewise recorded only in this group. The results show that even a moderate altitude influences the cardiopulmonary system of the rat in a manner characteristic of the effect of chronic hypoxic hypoxia.     

Acclimatization to hypoxia modulates the tryptophan 2,3-dioxygenase activity in rats exposed to simulated high altitude.

1. Exposure of rats to an 8000 m altitude increased the hepatic tryptophan 2,3-dioxygenase (EC 1.13.1.12) activity. 2. Acclimatization to hypoxia by a repeated exposure to an altitude of 5000 m induced a marked decrease in liver tryptophan dioxygenase activity after the rats were subjected to an 8000 m altitude, but a pre-exposure to 4000 m altitude showed no effect on the enzyme activity. 3. Plasma tryptophan was rapidly decreased by exposure to 8000 m altitude to the same extent in the acclimatized and non-acclimatized rats. 4. Plasma tryptophan may be utilized as the substrate for tryptophan dioxygenase in liver of the non-acclimatized rats under highly hypoxic conditions; however, acclimatized rats can reserve tryptophan as the substrate for the alternative metabolism other than the degradation pathway in liver.     

Effects of exposure to a simulated altitude of 3,500 m on calves and oxen

Nine calves and nine oxen were divided into 6 groups and exposed in a climatised low pressure chamber to the following conditions: 2 weeks at 400 m and 4 weeks at 3,500 m. High altitude produced the following changes: increases in heart rate and pulmonary artery pressure, both these changes being larger in the calves than in the oxen. During 4 weeks continuous exposure to 3,500 m, heart rate declined, whereas pulmonary arterial pressure rose. There were increments in respiratory rate, blood-pH, leucocyte number, rectal temperature, blood lactate and blood pyruvate, but no changes in the lactate/pyruvate ratio. Increases in erythrocyte number, haemoglobin, haematocrit, blood specific gravity and blood viscosity were more pronounced in the oxen than in the calves. Feed intake in all animals tended to be depressed in the first half of the high altitude periode. Water intake showed a fall during the first day at 3,500 m, but recovered thereafter. It is concluded that in response to high altitude the calves activated preferentially the circulatory, the oxen the erythropoetic system.     

Effect of altitude on the lung function of high altitude residents of European ancestry

The forced vital capacity (FVC), forced expiratory volume in one second (FEV), and ratio of FEV to FVC (%FEV) of 161 male and 158 female youths of European ancestry who were born at high altitudes and who were residing in La Paz, Bolivia (average altitude of 3,600 m) were examined and compared with those for lowland Europeans and highland Aymara Amerindians. FVC and FEV were significantly larger (p less than .001) in the La Paz Europeans than in two lowland control samples of European ancestry, with the relative differences between samples varying from small (1.5-4.1%) to moderate (7.7-11.9%). It could not be determined whether the enhanced lung volumes of the La Paz European children were acquired through an accelerated development of lung volumes relative to stature during adolescence, as is the case for Amerindian highlanders. After controlling for body and chest size, FVC and FEV were significantly smaller in the La Paz Europeans than in highland Aymara (p less than .001), suggesting that the lung volumes of the Aymara are influenced by factors other than simply growth and development at high altitude. Finally, as found in Amerindians, chest size is an important determinant of intra-individual variation in lung function among highland Europeans.     

Serum erythropoietin in humans at high altitude and its relation to plasma renin

Serum immunoreactive erythropoietin (siEp) was estimated in samples collected from members of two scientific and mountaineering expeditions, to Mount Kongur in Western China and to Mount Everest in Nepal. SiEp was increased above sea-level control values 1 and 2 days after arrival at 3,500 m and remained high on ascent to 4,500 m. Thereafter, while subjects remained at or above 4,500 m, siEp declined, and by 22 days after the ascent to 4,500 m was at control values but increased on ascent to higher altitude. Thus siEp was at a normal level during the maintenance of secondary polycythemia from high-altitude exposure. On descent, with removal of altitude hypoxia, siEp decreased, but despite secondary polycythemia levels remained measurable and in the range found in subjects normally resident at sea level. On Mount Everest, siEp was significantly (P less than 0.01) elevated above preexpedition sea-level controls after 2-4 wk at or above 6,300 m. There was no correlation between estimates of siEp and plasma renin activity in samples collected before and during both expeditions.     

Ventilatory, circulatory, endocrine, and renal effects of almitrine infusion in man: a contribution to high altitude physiology

Diuresis at altitude was thought to be the result of chemoreceptor stimulation leading to a reduction of cardiac volume overload. This hypothesis was tested in ten young, healthy subjects by infusion of almitrine (0.5 mg.kg-1 body mass within 30 min) assuming analogous sites of action, i.e. arterial chemoreceptors and pulmonary vessels, for almitrine as for hypoxic hypoxia. The results show that almitrine increases ventilation, heart rate, systolic blood pressure, central venous pressure and natriuresis, but fails to increase significantly atrial natriuretic peptide plasma concentration and diuresis. It is concluded: (1) that almitrine has similar sites of action as hypoxic hypoxia at about 5000 m, (2) that natriuresis during arterial chemoreceptor stimulation might reduce cardiac volume overload, (3) that the volume excretion hypothesis, in particular the pathways from the cardiac volume overload to the water diuresis, need, for an understanding of the hypoxia-induced diuresis, further direct investigations at altitude.     

Sustained venoconstriction in man supplemented with CO2 at high altitude.

Venoconstriction occurs at high altitude. This study sought to determine whether hypoxia or hypocapnia is the cause of the venoconstriction. Five male subjects were exposed to 4,000-4,400 m (PB 440-465 mmHg) with supplemental 3.77 +/- 0.02% CO2 in a hypobaric chamber for 4 days. Similar alveolar O2 tensions were obtained in four control subjects exposed to 3,500-4,100 m (PB 455-492 mmHg) without CO2. A water-filled plethysmograph was used to determine forearm flow and venous compliance. Systemic blood pressure was measured with the cuff procedure. Catecholamines were measured in 24-h urine collections. Venous compliance fell at high altitude in both groups and was less (P less than 0.01) than control values. Forearm flow and resistance were unaltered at altitude in the group with CO2 supplementation while forearm flow decreased and resistance increased in the hypocapnic group at 72 h of exposure. Urinary catecholamines increased in the group with CO2 and remained unaltered in the hypocapnic group. It is concluded that hypoxia is responsible for decreasing venous compliance, and hypocapnia for increasing resistance and decreasing flow. Group differences observed in urinary catecholamines may be explained by differences in arterial pH.