Leon-Velarde, Fabiola, Marco Maggiorini, John T. Reeves, Almaz Aldashev, Ingrid Asmus, Luciano Bernardi, Ri-Li Ge, Peter Hackett, Toshio Kobayashi, Lorna G. Moore, Dante Penaloza, Jean-Paul Richalet, Robert Roach, Tianyi Wu, Enrique Vargas, Gustavo Zubieta-Castillo, and Gustavo Zubieta-Calleja. Consensus on high altitude diseases. High Alt Med Biol 6:147-157, 2005.-This is an international consensus statement of an ad hoc committee formed by the International Society for Mountain Medicine (ISMM) at the VI World Congress on Mountain Medicine and High Altitude Physiology (Xining, China; 2004) and represents the committee's interpretation of the current knowledge with regard to the most common chronic and subacute high altitude diseases. It has been developed by medical and scientific authorities from the committee experienced in the recognition and prevention of high altitude diseases and is based mainly on published, peer-reviewed articles. It is intended to include all legitimate criteria for choosing to use a specific method or procedure to diagnose or manage high altitude diseases. However, the ISMM recognizes that specific patient care decisions depend on the different geographic circumstances involved in the development of each chronic high altitude disease. These guidelines are established to inform the medical services on site who are directed to solve high altitude health problems about the definition, diagnosis, treatment, and prevention of the most common chronic high altitude diseases. The health problems associated with life at high altitude are well documented, but health policies and procedures often do not reflect current state-of-the-art knowledge. Most of the cases of high altitude diseases are preventable if on-site personnel identify the condition and implement appropriate care.
Pesce, Carlos, Conxita Leal, Hernan Pinto, Gabriela Gonzalez, Marco Maggiorini, Michael Schneider, and Peter Bartsch. Determinants of acute mountain sickness and success on Mount Aconcagua (6962 m). High Alt Med Biol. 6:158-166, 2005.-To investigate the determinants of acute mountain sickness (AMS) and of summiting in expedition-style mountaineering, 919 mountaineers (15.4% female) leaving Aconcagua Provincial Park at the end of an expedition to Mt. Aconcagua (6962 m) via the normal route were retrospectively evaluated by questionnaires. Symptoms of AMS were reported from the day when mountaineers felt worst. The prevalence of AMS, defined as a Lake Louise Score (self-assessment) > 4, was 39%. Low AMS scores were associated with faster ascent rates. The following parameters were independent predictors for AMS: no susceptibility for AMS (odds ratio, OR, 0.24; 95% confidence interval 0.17 to 0.35) more than 10 exposures per year above 3000 m (OR 0.60; 0.41 to 0.86), and previous exposures above 6000 m (OR, 0.48; 0.33 to 0.68). This last variable increased the OR for summiting 3.7-fold while female gender reduced this OR to 0.41 (0.25 to 0.67). Susceptibility and few exposures to high altitude are major predictors for AMS on Aconcagua, but AMS does not substantially reduce the chances for summiting. Those who are often in the mountains and who have already climbed to altitudes above 6000 m and are not susceptible for AMS have the best options for summiting Aconcagua.
Hypoxia-mediated oxidative stress has been implicated in the pathophysiology of high altitude maladaptations. To explore whether prolonged exposure to high altitude can trigger an adaptive response to oxidative stress and restore redox homeostasis in the body, the study was conducted to evaluate biochemical variables related to oxidative stress and antioxidant status in humans at sea level (190 m) and following 3- and 13-month sojourns at altitude (4500 m). After 3 months at altitude, whole-blood thiobarbituric acid reactive substances (TBARS) were significantly higher (65.6%), nonenzymatic antioxidants like ascorbic acid and caeruloplasmin were significantly lower (41% and 22%, respectively) and plasma total antioxidant status (TAS), glutathione levels, and superoxide dismutase activity were marginally altered as compared to their basal values. After 13 months at altitude, TBARS levels regressed back to preexposure levels. Plasma total antioxidant status (TAS) improved by 21%, glutathione levels by 32.8%, and plasma bilirubin by 35.8% as compared to sea level. Average concentrations of ascorbic acid and caeruloplasmin were 18% and 37% higher as compared to the subjects studied after a 3-month stay at high altitude. In addition, there was a progressive rise in erythrocytic superoxide dismutase activity and persistent hyperurecemia. The study observed that on prolonged exposure to high altitude humans could mount an effective adaptive response to oxidative stress by activating the antioxidant defense. Hence, strengthening the antioxidant defense could be an effective strategy to prevent free-radical-mediated pathophysiological alterations and quicken acclimatization to oxidative stress.
Prabhakar, Nanduri R., and Frank J. Jacono. Cellular and molecular mechanisms associated with carotid body adaptations to chronic hypoxia. High Alt Med Biol. 6:112-120, 2005.-Chronic hypoxia leads to adaptations in the respiratory system manifested as a persistent increase in resting ventilation, termed ventilatory acclimatization to hypoxia (VAH). Increased afferent nerve activity from carotid bodies and the ensuing reflex activation of ventilation are critical for eliciting VAH. In this review we highlight recent information on the cellular and molecular mechanisms associated with chronic hypoxia-induced functional and structural changes in the carotid body. Chronic hypoxia leads to hypersensitivity of the carotid bodies and induces morphological changes, including enlargement of the organ, hyperplasia of glomus cells, and neovascularization. Enhanced hypoxic sensitivity is due to alterations in ion current densities, as well as changes in neurotransmitter dynamics and recruitment of additional neuromodulators (endothelin-1, ET-1) in glomus cells. Morphological alterations are in part due to upregulation of growth factors (e.g., VEGF). VAH is markedly attenuated in mice partially deficient in HIF-1 transcription factor, which regulates several downstream genes, including VEGF, ET-1, and Ca2+ channels. The finding that VAH is also blunted in mice deficient in the fosB gene led to the suggestion that the magnitude and time course of VAH depend on complex interactions between more than one transcription factor, resulting in coordinated regulation of several downstream genes and their protein products.
Remillard, Carmelle V., and Jason X.-J. Yuan. High altitude pulmonary hypertension: role of K+ and Ca2+ channels. High Alt Med Biol 6:133-146, 2005.-Global alveolar hypoxia, as experienced at high-altitude living, has a serious impact on vascular physiology, particularly on the pulmonary vasculature. The effects of sustained hypoxia on pulmonary arteries include sustained vasoconstriction and enhanced medial hypertrophy. As the major component of the vascular media, pulmonary artery smooth muscle cells (PASMC) are the main effectors of the physiological response(s) induced during or following hypoxic exposure. Endothelial cells, on the other hand, can sense humoral and hemodynamic changes incurred by hypoxia, triggering their production of vasoactive and mitogenic factors that then alter PASMC function and growth. Transmembrane ion flux through channels in the plasma membrane not only modulates excitation-contraction coupling in PASMC, but also regulates cell volume, apoptosis, and proliferation. In this review, we examine the roles of K+ and Ca2+ channels in the pulmonary vasoconstriction and vascular remodeling observed during chronic hypoxia-induced pulmonary hypertension.
We examined the effects of the 5-phosphodiesterase (5-PDE) inhibitor sildenafil on pulmonary arterial pressure and some oxygen transport and cardiopulmonary parameters in humans during exposure to hypobaric hypoxia at rest and after exercise. In a double-blind study, 100 mg sildenafil or placebo was administered orally to 14 healthy volunteers 45 min before exposure to 5,000 m of simulated altitude. Arterial oxygen saturation (SaO(2)), heart rate (HR), tidal volume (VT), respiratory rate (RR), left ventricular ejection fraction (EF), and pulmonary arterial pressure (PAP) were measured first at rest in normoxia, at rest and immediately after exercise during hypoxia, and after exercise in normoxia. The increase in systolic PAP produced by hypoxia was significantly decreased by sildenafil at rest from 40.9 +/- 2.6 to 34.9 +/- 3.0 mmHg (-14.8%; p = 0.0046); after exercise, from 49.0 +/- 3.9 to 42.9 +/- 2.6 mmHg (-12.6%; p = 0.003). No significant changes were found in normoxia either at rest or after exercise. Measurements of the effect of sildenafil on exercise capacity during hypoxia did not provide conclusive data: a slight increase in SaO(2) was observed with exercise during hypoxia, and sildenafil did not cause significant changes in ventilatory parameters under any condition. Sildenafil diminishes the pulmonary hypertension induced by acute exposure to hypobaric hypoxia at rest and after exercise. Further studies are needed to determine the benefit from this treatment and to further understand the effects of sildenafil on exercise capacity at altitude.
To estimate the separate and combined effects of reduced P-B and 02 levels on body fluid balance and regulating hormones, measurements were made during reduced P-B (altitude, ALT; P-B = 432 mm Hg, F-IO2 = 0.207), reduced inspired O-2 concentration (normobaric hypoxia, HYX; P-B = 614 mm. Hg, F-IO2 = 0.142), and lowered ambient pressure without hypoxia (normoxic hypobaria HYB; P-B = 434 mm Hg, F-IO2 = 0.296). Nine fit and healthy young men were exposed to these conditions for 10 h in a decompression chamber. Lake Louise AMS scores, urine collections, and blood samples were obtained every 3 h, with recovery measurements 2 h after exposure. AMS was significantly greater during ALT than HYX, as previously reported (J. Appl. Physiol. 81:1908-1910. 1996), because the combination of reduced P-B and P-O2 over the 10 h favored fluid retention by reducing urine volume, while plasma volume (PV) remained higher than during HYX At ALT the plasma Na+ fell significantly at 6 h, probably from dilution of extracellular fluid, and antidiuretic hormone (ADH) was highest (p = 0.006 versus HYB). The PV, urine flow, free water clearance, and plasma renin activity (PRA) rose significantly during recovery from ALT as AMS symptoms subsided, suggesting increased intravascular fluid and reduced adrenergic tone. During HYB, the plasma aldosterone (ALDO) and K+ levels were significantly elevated, and PRA was highest and ADH lowest, without fluid retention. During HYX, fluid balance was similar to HYB, but PV and ALDO were significantly lower, and ALDO increased significantly in recovery from HYX The fluid retention at ALT in AMS-susceptible subjects appears related to a synergistic interaction involving reduced P-B and ADH and ALDO.
Changes in heart rate variability induced by an intermittent exposure to hypoxia were evaluated in athletes unacclimatized to altitude. Twenty national elite athletes trained for 13 days at 1200 m and either lived and slept at 1200 m (live low, train low, LLTL) or between 2500 and 3000 m (live high, train low, LHTL). Subjects were investigated at 1200 m prior to and at the end of the 13-day training camp. Exposure to acute hypoxia (11.5% 02) during exercise resulted in a significant decrease in spectral components of heart rate variability in comparison with exercise in normoxia: total power (p < 0.001), low-frequency component. LF (p < 0.001), high-frequency component, HF (p < 0.05). Following acclimatization, the LHTL group increased its LF component (p < 0.01) and LF/HF ratio during exercise in hypoxia after the training period. In parallel, exposure to intermittent hypoxia caused an increased ventilatory response to hypoxia. Acclimatization modified the correlation between the ventilatory response to hypoxia at rest and the difference in total power between normoxia and hypoxia (r(2) = 0.65, p < 0.001). The increase in total power, LF component, and LF/HF ratio suggests that intermittent hypoxic training increased the response of the autonomic nervous system mainly through increased sympathetic activity.
We examined the effect of dietary supplementation with L-arginine on breath condensate VEGF, exhaled nitric oxide (NO), plasma erythropoietin, symptoms of acute mountain sickness, and respiratory related sensations at 4342 In through the course of 24 h in seven healthy male subjects. Serum L-arginine levels increased in treated subjects at time 0, 8, and 24 h compared with placebo, indicating the effectiveness of our treatment. L-arginine had no significant effect on overall Lake Louise scores compared with placebo. However, there was a significant increase in headache within the L-arginine treatment group at 12 h compared with time 0, a change not seen in the placebo condition between these two time points. There was a trend (p = 0.087) toward greater exhaled NO and significant increases in breath condensate VEGF with L-arginine treatment, but no L-arginine effect on serum EPO. These results suggest that L-arginine supplementation increases HIF-1 stabilization in the lung, possibly through a NO-dependent pathway. In total, our observations indicate that L-arginine supplementation is not beneficial in the prophylactic treatment of AMS.
Rapid extrication is the most important determinant of survival in avalanche victims. To facilitate rapid localization of avalanche victims by uninjured companions, avalanche transceivers are widely used during off-piste and backcountry activities. Despite their widespread use, the influence of transceivers on survival probability in avalanche accidents is controversial. The aim of this retrospective study was to analyze the influence of transceivers on the mortality of avalanche victims. There were 194 accidents in Austria from 1994 to 2003, involving 278 totally buried victims, which were analyzed. Avalanche transceivers were used by 156 (56%) victims and were associated with a significant reduction in median burial time from 102 to 20 min (p < 0.001), as well as a significant reduction in mortality from 68.0% to 53.8% (p = 0.011). This reduction was due to a decrease in mortality during backcountry activities involving ski tourers in free alpine areas (from 78.9% to 50.4%, p < 0.001). Transceivers did not reduce mortality during off-piste activities beside or near organized ski slopes (67.7% with versus 58.5% without transceiver, not significant). Mortality of persons using a transceiver is significantly higher if burial depth exceeds 1.5 m. Despite a significant reduction, mortality still exceeds 50% even with the use of transceivers. Therefore, in addition to the use of emergency equipment like transceivers, avalanche avoidance measures are critically important. The fairly modest influence of the use of transceivers on survival probability may be due to the highly efficient mountain rescue service in the Austrian Alps. In remote areas the reduction in mortality will probably be far more pronounced.
Survey of on-site treatment of patients in mountain areas of 14 countries in Europe and North America (nonresponder rate 33%) to compare emergency medical services. Around 37,535 ground rescuers and 747 helicopters are ready for evacuation of casualties and patients in mountain areas. And 1316 physicians and 50,967 paramedics take part in ground and air mountain rescue operations. In Europe, 63.2% of helicopters have a physician on board, 17.8% are staffed with a paramedic, and 19% have no medically trained personnel on board. In North America, 31.6% (p < 0.001) of helicopters are staffed with a doctor, 59.3% (p < 0.001) with a paramedic, and 9.1% (p < 0.001) have no medical personnel. The percentage of on-site treatment according to the recommendations of the International Liaison Committee on Resuscitation (ILCOR) or International Commission for Alpine Rescue (ICAR) varies among all countries (p < 0.001) and is positively related to the percentage of physician-staffed helicopters (r = 0.76, p < 0.001). Paramedics in 90.9% countries are obliged to be medically trained, but physicians only need to have a standardized training in emergency medicine in 50% (p = 0.042). On-site treatment according to ILCOR or ICAR recommendations is performed more often in countries where physicians are regularly involved in mountain rescue operations. However, no conclusions can be drawn from the data as to the efficiency of treatment. The data show a lack of medical education in specific, mountain rescue-related problems. Physicians involved should undergo suitable training.
The purpose of this study was to elucidate the magnitude and the time course of ventilatory changes resulting from a repeated series of hypoxic exposures. Eight healthy males participated in the present study. The subjects spent 1 h/day in normobaric hypoxia (12% inspired oxygen). Inspired minute ventilation ((I)) end-tidal partial pressure of carbon dioxide (PETCO2), and arterial oxygen saturation (SaO(2)) were measured in a hypoxic tent. These measurements were taken for 10 consecutive days (series 1), and were taken again after the subjects had been away from hypoxic exposure for 1 month (series 2). PETCO2 decreased and SaO(2) increased progressively in the hypoxic tent during the 10 days of intermittent hypoxia in series 1. At the onset of series 2 (days 1 to 3), PETCO2 was significantly lower and SaO(2) was significantly higher than those on day 1 during series 1. These results suggest that humans who have had previous hypoxic exposure adapt sooner to hypoxic condition due to an increase in the magnitude of hyperventilation in the first few days of a series of reexposures to hypoxia.
Wilson, David F., Arijit Roy, and Sukhamay Lahiri. Immediate and long-term responses of the carotid body to high altitude. High Alt Med Biol 6:97-111, 2005.-High altitude and the decreased environmental oxygen pressure have both immediate and chronic effects on the carotid body. An immediate effect is to limit the oxygen available for mitochondrial oxidative phosphorylation, and this leads to increased activity on the afferent nerves leading to the brain. In the isolated carotid body preparation, the afferent nerve activity depends on the ratio of carbon monoxide (CO), an inhibitor of respiratory chain function, to oxygen. The CO-induced increase in afferent neural activity is reversed by light, and the wavelength dependence of this reversal shows that the site of CO (and therefore oxygen) interaction is cytochrome a(3) of the mitochondrial respiratory chain. Thus, primary sensing of ambient oxygen pressure is through the oxygen dependence of mitochondrial oxidative phosphorylation. The conductance of ion channels in the cellular membranes may also be sensitive to oxygen pressure and, through this, modulate the sensitivity to oxygen pressure. Longer-term exposure to high altitude results in progressive changes in the carotid body that involve several mechanisms, including cellular energy metabolism and hypoxia inducible factor-1 alpha (HIF-1 alpha). These changes begin within minutes of exposure, but progress such that chronic exposure results in morphological and biochemical alterations in the carotid body, including enlarged cells, increased catecholamine levels, altered cellular appearance, and others. In the chronically adapted carotid body, responses to acute changes in oxygen pressure are enhanced. The adaptive changes due to chronic hypoxia are largely reversed upon return to lower altitudes.
Previous studies have shown that acute hypobaric hypoxia, obtained in a hypobaric chamber, and subsequent reoxygenation, give rise to modifications of the erythrocyte membrane lipid dynamics, resulting in an increased lateral diffusivity of the membrane lipids, and this was interpreted as the result of a modified lipid-protein interaction. The aim of the present study was to determine the effect of the reoxygenation condition in individuals after 3 days at an altitude of 3500 In above sea level. Reoxygenation was a consequence of returning to sea level. Resting blood samples from both conditions were obtained, and erythrocytes were separated and immediately lysed for membrane isolation. We measured the bilayer polarity in membranes with Laurdan, a fluorescent probe. We also measured malondialdehyde in membrane lipids, an indicator of oxidative damage. We found a 12% (p = 0.016, n = 7) increase in the polarity of the membrane bilayer surface, and an increase of 70% (p = 0.005, n = 7) in the formation of malondialdehyde in the membrane after the reoxygenation condition. The membrane bilayer polarity increase is due to an oxidative modification of the phospholipid backbone after reoxygenation. People working and/or recreating at moderate altitude (3500 m) may be at risk of erythrocyte membrane oxidative damage upon returning to sea level, and therefore a better understanding of the processes occurring upon reoxygenation may lead to proposed strategies to minimize this effect.
Stress erythropoiesis is usually considered as a compensatory effort to counteract tissue hypoxia. Its homeostatic importance in anemic hypoxia has not been questioned, but researchers, clinicians, and mountain climbers have had second thoughts on polycythemia as to its appropriateness for hypoxic or altitude hypoxia (HA). Therefore, polycythemia, one of the responses to HA seen in nongenetically adapted mammals, could or could not be considered beneficial. The present study was thus performed to obtain further information on the importance of HA polycythemia on acclimation of mice to HA. To this end, the development of polycythemia was prevented by experimental manipulations (administration of 20 mg/kg/d of the hemolytic drug phenylhydrazine or removal of 0.225 mL/d of blood), and the degree of tissue hypoxia was evaluated from plasma erythropoietin (pEPO) concentration, as determined by immunoassay, in adult female mice exposed to air maintained at 506 mbar (380 mmHg) in a simulated HA (SHA) chamber during at least 23.5 h/d for 9 d. Plasma EPO concentration in those treated hypoxic mice whose hematocrit values remained almost unchanged was between 5.55 and 7.89 times higher (depending on the experimental designs) than in control hypoxic mice allowed to develop HA polycythemia. These results, plus the finding of an inverse relationship between the hematocrit value and pEPO concentration in both the polycythemic and normocythemic SHA-exposed mice indicate that HA polycythemia is highly effective in ameliorating tissue hypoxia under SHA conditions, thus giving support to the concept of the important role of the increased hemoglobin mass in nongenetically adapted animals, whereas a left-shifted oxyhemoglobin dissociation curve confers a good degree of adaptation to HA in genetically adapted animals.
Schobersberger, Wolfgang, Sven Greie, Egon Humpeler, Markus Mittermayr, Dietmar Fries, Beatrix Schobersberger, Erika Artner-Dworzak, Walter Hasibeder, Anton Klingler, and Hanns-Christian Gunga. Austrian Moderate Altitude Study (AMAS 2000): Erythropoietic activity and Hb-O-2 affinity during a 3-week hiking joliday at moderate altitude in persons with metabolic syndrome. High Alt Med Biol 6:167-177,2005.-Moderate altitude hypoxia (1500 to 2500 m) is known to stimulate erythropoiesis and to improve oxygen transport to tissue by a reduction of Hb-O-2 affinity. Whether this adaptation also occurs in tourists with metabolic syndrome has not yet been investigated sufficiently. Thus, we performed a prospective field study to measure erythropoietic parameters and oxygen transport properties in 24 male volunteers with metabolic syndrome during a 3-week holiday program at 1700 m consisting of four guided, individually adapted hiking tours per week. The following examinations were performed: baseline investigations at 500 m (T1); examinations at moderate altitude on day 1 (T2), day 4 (T3), day 9 (T4), and day 19 (T5); and postaltitude tests (T6) 7 to 10 days after return. On day 1 and day 19, a walk on a standardized hiking test route with oxygen saturation (SpO(2)) measure points was performed. Hemoglobin, packed cell volume, and red cell count showed changes over time, with higher values at T5 as compared to baseline. Reticulocyte count and erythropoietin (EPO) were increased at T2 and increased further until T5. EPO declined toward prealtitude values. P50-value (blood P-O2 at 50% hemoglobin oxygen saturation at actual pH) increased during the altitude sojourn (maximum increase at T5 by +0.40 kPa). At T5 all volunteers had a higher Spot before, during, and at the end of the test route compared to T1. During adaptation to moderate altitude, persons with metabolic syndrome exhibit an increase in EPO and a rightward shift of the oxygen dissociation curve that is similar to healthy subjects.