High Altitude Medicine & Biology

The present case study examined changes in peripheral markers of free radical metabolism and skeletal/myocardial muscle damage 30 h after a mountaineer had survived a lightning storm, having experienced contact with what was considered to be "upward leaders" at 4200 m. Sea-level control data were available between 3 and 8 weeks prior to the altitude sojourn for comparative purposes. Follow-up measurements were obtained for the same individual 3 weeks following the incident after simulated exposure to the combined stresses of inspiratory hypoxia and physical exercise. Venous blood was assayed for molecular markers of skeletal [myoglobin and total creatine phosphokinase (CPK)] and myocardial [cardiac troponin I (cTnI)] muscle damage. Ex-vivo spin trapping with α-phenyl-tert-butylnitrone (PBN) combined with electron paramagnetic resonance (EPR) spectroscopy was incorporated for the direct detection of free radicals. The relative increases [post-exposure/preexposure × 100 (%)] in the concentration of the PBN adduct, myoglobin, and CPK in the "lightning blood" were markedly greater than those observed following the simulation study (PBN: 276 vs. 129%; CPK: 1130 vs. 182%; myoglobin: 205 vs. 115%). In contrast, no changes were observed for cTnI. A marked decrease in the PBN adduct, myoglobin, and CPK was observed within 2 h of completing the simulation study, following oral administration of water and lipid-soluble antioxidant vitamins in normoxia. These findings are the first to document lightning-induced free radical generation and selective damage to skeletal muscle in a high altitude mountaineer. Furthermore, free radicals may contribute to the pathogenesis of lightning injury, and dietary supplementation with antioxidant vitamins may prove of some benefit against associated tissue damage.

The purpose of the present study was to elucidate the influence of intermittent hypobaric hypoxia at rest on endurance performance and cardiorespiratory and hematological adaptations in trained endurance athletes. Twelve trained male endurance runners were assigned to either a hypoxic group (n = 6) or a control group (n = 6). The subjects in the hypoxic group were exposed to a simulated altitude of 4500 m for 90 min, three times a week for 3 weeks. The measurements of 3000 m running time, running time to exhaustion, and cardiorespiratory parameters during maximal exercise test and resting hematological status were performed before (Pre) and after 3 weeks of intermittent hypoxic exposure (Post). These measurements were repeated after the cessation of intermittent hypoxia for 3 weeks (Re). In the control group, the same parameters were determined at Pre, Post, and Re for the subjects not exposed to intermittent hypoxia. The athletes in both groups continued their normal training together at sea level throughout the experiment. In the hypoxic group, the 3000 m running time and running time to exhaustion during maximal exercise test improved. Neither cardiorespiratory parameters to maximal exercise nor resting hematological parameters were changed in either group at Post, whereas oxygen uptake (V_O2) during submaximal exercise decreased significantly in the hypoxic group. After cessation of intermittent hypoxia for 3 weeks, the improved 3000 m running time and running time to exhaustion tended to decline, and the decreased V_O2 during submaximal exercise returned to Pre level. These results suggest that intermittent hypoxia at rest could improve endurance performance and submaximal exercise efficiency at sea level in trained endurance athletes, but these improvements are not maintained after the cessation of intermittent hypoxia for 3 weeks.

We tested the hypothesis that acute hypoxia may alter the circadian pattern of body temperature in adult humans. Six healthy subjects were studied in normoxia, hypoxia (~13% inspired O₂), and again normoxia, each session lasting >24 h and spaced a few days apart, with a constant routine protocol of sustained wakefulness and minimal activity. Some parameters (e.g., tympanic and abdominal temperatures, heart rate) were recorded continuously; others (e.g., oxygen consumption and pulmonary ventilation) were monitored for ~10 min every 2 h. The amplitudes of the circadian oscillation of tympanic, abdominal, and calf skin temperatures were reduced in hypoxia, averaging, respectively, 61%, 80% and 50% of the normoxic amplitude. Oxygen consumption and pulmonary ventilation, which presented a circadian pattern in normoxia, had no longer significant oscillations during hypoxia, whereas the opposite was the case for heart rate and diastolic pressure. Therefore, acute hypoxia can disturb the normal circadian patterns and, specifically, depress those of body temperature. These effects, qualitatively similar to those observed in chronically hypoxic animals and humans, could contribute to sleep disturbances at high altitude.

Infections and acute mountain sickness (AMS) are common at high altitude, yet their precise etiologies remain elusive and the potential for differential diagnosis is considerable. The present study was therefore designed to compare clinical nonspecific symptoms associated with these pathologies and basic changes in free radical and amino-acid metabolism. Nineteen males were examined at rest and after maximal exercise at sea level before (SL₁/SL₂) and following a 20 ± 5 day ascent to Kanchenjunga base camp located at 5100 m (HA). Four subjects with symptoms consistent with an ongoing respiratory and recent gastrointestinal infection were also diagnosed with clinical AMS on the evening of day 1 at HA. These and six other subjects recovering from symptoms consistent with a respiratory infection presented with a greater increase (HA minus SL₁) in AMS scores and resting venous concentration of lipid hydroperoxides (LH) and in total creatine phosphokinase and ratio of free tryptophan/branched chain amino acids, and greater decrease in glutamine (Gln) compared to healthy controls (n = 9, p < 0.05). The decrease in Gln was consistently related to the altitude/exercise-induced increase in LH (r = -0.69/r = -0.45; p < 0.05) and altitude-induced increase in myoglobin (r = -0.73, p < 0.05). These findings highlight the potential for the misdiagnosis of altitude illness due to the similarity of nonspecific constitutional symptoms associated with infection and AMS. Both conditions were characterized by parallel changes in peripheral biomarkers related to free-radical, skeletal muscle damage and amino acid metabolism. While clearly not establishing cause and effect, free radical-mediated changes in peripheral amino acid metabolism known to influence immune and cerebral serotoninergic function may enhance susceptibility to and/or delay recovery from altitude illness.

Our purpose was to study the preventive effect of the calcium channel blocker flunarizine on headache, postural ataxia, and memory deficits occurring during decompression to high altitude in a randomized, placebo-controlled, double-blind study. After 7-day pretreatment with the study drugs, 20 healthy men were investigated at 490 m and 0.5, 2, 4, and 6 h later at a simulated altitude of 4559 m. Headache severity was evaluated on a 4-point scale. Sway path and anteroposterior and lateral sway were recorded with open and closed eyes by static posturography. Short- and long-term memory was studied by testing the recall of verbal and figural material immediately and 2 h after presentation, respectively. Blood pressure (BP) and arterial oxygen saturation (Sa_O2) were also assessed. Headache scores showed a trend to be lower in the flunarizine group that was significant after 4 and 6 h. Headache scores expressed as difference from baseline values showed a nonsignificant trend to be lower at 4 and 6 h in subjects treated with flunarizine. Postural stance, memory, BP, and Sa_O2 were similar in both treatment groups. Although the low number of investigated subjects may have prevented the detection of a significant therapeutic effect of flunarizine, the present data do not show that flunarizine is effective for prevention of headache, postural ataxia, and neurocognitive deficits occurring at simulated high altitude.

To test the hypothesis that the changes in hypoxic ventilatory response (HVR) of men and women mountaineers on induction to HA by trekking is not influenced by gender, isocapnic HVR as ΔV_E/ΔSa_O2 was studied in eight men and eight women mountaineering trainees initially at 2100 m, then during 6 to 7 days of sojourn at 4350 m, and retested again on return to 2100 m. Results indicated that HVR at 2100 m increased significantly at 4350 m in both sexes, and the values reverted to baseline level within 4 to 5 days between leaving high altitude (4350 m) and restudy at 2100 m. No sex differences were observed at 2100- or at 4350-m altitude, indicating that men and women have a similar level of chemosensitive response as measured by HVR during induction to HA.

The male reproductive functions of the members of the Masherbrum (7821 m) Expedition in 1999 were examined via semen analyses and endocrine tests. Specimens were collected from three subjects who had stayed above 5100 m for 21 to 24 days and above 6700 m for 4 to 5 days before departure and 1 month, 3 months, and 2 yr after returning from the expedition. Semen analyses showed no change in the semen volume. Sperm counts decreased after 1 month and had not recovered after 3 months, but they had recovered after 2 yr in all subjects. An increase in abnormally shaped sperm was also observed after 1 month, but had nearly recovered to the preexpedition state after 3 months. Endocrine tests revealed slightly decreased testosterone in the blood after 1 month, which had decreased still further after 3 months. The tests were completely normal after 2 yr. We suggest that a high altitude sojourn may induce reversible spermatogenic and Leydig cell dysfunction.

One essential factor in the development of high altitude pulmonary edema (HAPE) is elevated pulmonary artery pressure, possibly due to a lack of nitric oxide (NO) in pulmonary vessels. NOS3 gene polymorphisms (G894T, T-786C, and CA-repeats ≥38) might be linked to decreased NO synthesis and increased susceptibility to HAPE, while the C242T polymorphism of the CYBA gene [encoding for the NAD(P)H oxidase subunit p22phox] may increase NO availability and thus convey resistance to HAPE. To test this hypothesis, we genotyped 51 mountaineers susceptible and 52 mountaineers not susceptible to HAPE. Genotyping revealed similar genotype frequencies of the G894T and the T-786C NOS3 polymorphism in both groups (G894T: susceptibles, 39.2% GG, 47.1% GT, 13.7% TT; nonsusceptibles, 48.0% GG, 44.0% GT, 8.0% TT; p = 0.54. T-786C: susceptibles, 45.1% TT, 39.2% TC, 15.7% CC; nonsusceptibles, 53.8% TT, 40.4% TC, 5.8% CC; p = 0.28). Genotype frequencies of the C242T CYBA polymorphism were 43.1% CC, 47.1 % CT, and 9.8% TT in HAPE susceptibles and 38.0% CC, 52.0 % CT, and 10.0% TT (p = 0.92) in nonsusceptibles. There was also no difference between the two groups in the number of CA repeats (p = 0.57), and individuals with ≥38 CA repeats were not more likely to develop HAPE (p = 1.0). Haplotype analysis for the NOS3 polymorphisms also revealed no association with HAPE. The results of this study suggest that none of these genetic variants plays a substantial role in the pathogenesis of HAPE in Caucasians, but does not exclude epistatic effects that might still involve the genetic systems studied here.

A few studies have reported increased body temperature (T_o) associated with acute mountain sickness (AMS), but these usually include exercise, varying environmental conditions over days, and pulmonary edema. We wished to determine whether T_o would increase with AMS during early exposure to simulated altitude at rest. Ninety-four exposures of 51 men and women to reduced P_B (423 mmHg = 16,000 ft = 4850 m) were carried out for 8 to 12 h. AMS was evaluated by LL and AMS-C scores near end of exposure, and T_o was measured by oral digital thermometer before altitude and after 1 (A1), 6 (A6), and last (A12) h at simulated altitude. Other measurements included ventilation, O₂ consumption and autonomic indicators of plasma catecholamines, HR, and HR variability. Average T_o increased by 0.5°F from A1 to A12 in all subjects (p < 0.001). Comparison between 16 subjects with lowest AMS scores (mean LL = 1.0, range = 0 to 2.5) and 16 other subjects with highest AMS scores (mean LL = 7.4, range = 5 to 11) demonstrated a transient decline in T_o from A1 to A6 in AMS, in contrast to a rise in non-AMS (p = 0.001). Catecholamines, HR, and HR variability (increased low F/high F ratio) indicated significant elevation of sympathetic activity in AMS, where T_o fell, but no change in metabolic rate. The apparently greater heat loss during early AMS suggests increased hypoxic vasodilation in spite of enhanced sympathetic drive. Greater hypoxic vasodilation and elevated HR in AMS in the absence of other changes suggest that augmentation of β-adrenergic tone may be involved in early AMS pathophysiology.

The aims of this study were to relate heart morphology and functions changes to heart rate variability (HRV) components after acclimatization to high altitude and to define whether preadaptation to hypoxia could modulate HRV responses to acute hypoxic stress. Doppler-echocardiographic studies of the left ventricle were performed in female Wistar rats before, during, and after a 10-week exposure to moderate hypobaric hypoxia (CH rats, ~4000 m simulated) or normoxia (N rats, ~55 m). Right ventricular morphology and function and pulmonary artery pressure were evaluated using heart catheterization. Spectral analysis of HRV was studied after exposure in conscious unrestrained rats in normoxia and during acute hypoxic stress. Necropsy right ventricular hypertrophy and intraventricular and pulmonary artery hypertension were found in CH rats compared with N rats. Echocardiographic left ventricular morphology and functions were similar between the groups after exposures. Compared to the control group, CH rats had similar heart rates and HRV components when measured in normoxia. During acute hypoxic stress, HRV decreased in all rats, but less in CH rats. These results support the hypothesis that long-term mild hypoxia may moderate sympathetic activation induced by acute hypoxia and that right ventricular hypertrophy cannot be the direct cause of such a shift in sympathovagal nerve interaction during acute hypoxic stress.

When lowlanders go to high altitude, the resulting oxygen deprivation impairs mental and physical performance, quality of sleep, and general well-being. This paper compares the effects of ventilatory acclimatization and oxygen enrichment of room air on the improvement of oxygenation as judged by the increase in the alveolar P_O2 and the reduction in equivalent altitude. The results show that, on the average, complete ventilatory acclimatization at an altitude of 5000 m increases the alveolar P_O2 by nearly 8 torr, which corresponds to a reduction in equivalent altitude of about 1000 m, although there is considerable individual variability. By comparison, oxygen enrichment to 27% at 5000 m can easily reduce the equivalent altitude to 3200 m, which is generally well tolerated. Because full ventilatory acclimatization at altitudes up to about 3600 m reduces the equivalent altitude to about 3000 m, oxygen enrichment is not justified for well-acclimatized persons. At an altitude of 4200 m, where several telescopes are located on the summit of Mauna Kea, full acclimatization reduces the equivalent altitude to about 3400 m, but the pattern of commuting probably would not allow this. Therefore, at this altitude, oxygen enrichment would be beneficial but is not essential. At higher altitudes such as 5050 m, where other telescopes are located or planned, the gain in oxygenation from acclimatization is insufficient to produce an adequate mental or physical performance for most work, and oxygen enrichment is highly desirable. Full ventilatory acclimatization requires at least a week of continuous exposure, although much of the improvement is seen in the first 2 days.