High Altitude Exposures Research Articles

Environmental Exposures and Risks During Pregnancy.

The Women in Wilderness Medicine Research Committee of the Wilderness Medical Society conducted a narrative review to address considerations for pregnant individuals in wilderness environments. There is limited evidence behind many opinion-based recommendations on the safety of various environmental exposures in pregnancy. The authors reviewed the literature for the best available evidence, including observational studies, case series, limited controlled trials, and extrapolation from physiological data, as well as evaluating expert consensus statements. The benefits of exposure to natural environments include better pregnancy outcomes and improved maternal mental and physical health. Risks are similar to nonpregnant individuals with the added risks associated with maternal-fetal physiology in wilderness environments and difficulties of evacuation. This narrative review discusses pregnancy-specific concerns in extreme environments, including high altitude, hypothermia, hyperthermia, lightning strikes, envenomations, and common outdoor exposures.

Circulating markers of intestinal barrier injury and inflammation following exertion in hypobaric hypoxia

ABSTRACT Hypoxia induced intestinal barrier injury, microbial translocation, and local/systemic inflammation may contribute to high-altitude associated gastrointestinal complications or symptoms of acute mountain sickness (AMS). Therefore, we tested the hypothesis that six-hours of hypobaric hypoxia increases circulating markers of intestinal barrier injury and inflammation. A secondary aim was to determine if the changes in these markers were different between those with and without AMS. Thirteen participants were exposed to six hours of hypobaric hypoxia, simulating an altitude of 4572 m. Participants completed two 30-minute bouts of exercise during the early hours of hypoxic exposure to mimic typical activity required by those at high altitude. Pre- and post-exposure blood samples were assessed for circulating markers of intestinal barrier injury and inflammation. Data below are presented as mean ± standard deviation or median [interquartile range]. Intestinal fatty acid binding protein (Δ251 [103-410] pg•mL−1; p = 0.002, d = 0.32), lipopolysaccharide binding protein (Δ2 ± 2.4 μg•mL−1; p = 0.011; d = 0.48), tumor necrosis factor-α (Δ10.2 [3-42.2] pg•mL−1; p = 0.005; d = 0.25), interleukin-1β (Δ1.5 [0-6.7] pg•mL−1 p = 0.042; d = 0.18), and interleukin-1 receptor agonist (Δ3.4 [0.4-5.2] pg•mL−1 p = 0.002; d = 0.23) increased from pre- to post-hypoxia. Six of the 13 participants developed AMS; however, the pre- to post-hypoxia changes for each marker were not different between those with and without AMS (p > 0.05 for all indices). These data provide evidence that high altitude exposures can lead to intestinal barrier injury, which may be an important consideration for mountaineers, military personnel, wildland firefighters, and athletes who travel to high altitudes to perform physical work or exercise.

High-altitude exposures and intestinal barrier dysfunction.

Gastrointestinal complaints are often reported during ascents to high altitude (>2,500 m), though their etiology is not known. One potential explanation is injury to the intestinal barrier which has been implicated in the pathophysiology of several diseases. High-altitude exposures can reduce splanchnic perfusion and blood oxygen levels causing hypoxic and oxidative stress. These stressors might injure the intestinal barrier leading to consequences such as bacterial translocation and local/systemic inflammatory responses. The purpose of this mini-review is to 1) discuss the impact of high-altitude exposures on intestinal barrier dysfunction and 2) present medications and dietary supplements which may have relevant impacts on the intestinal barrier during high-altitude exposures. There is a small but growing body of evidence which shows that acute exposures to high altitudes can damage the intestinal barrier. Initial data also suggest that prolonged hypoxic exposures can compromise the intestinal barrier through alterations in immunological function, microbiota, or mucosal layers. Exertion may worsen high-altitude-related intestinal injury via additional reductions in splanchnic circulation and greater hypoxemia. Collectively these responses can result in increased intestinal permeability and bacterial translocation causing local and systemic inflammation. More research is needed to determine the impact of various medications and dietary supplements on the intestinal barrier during high-altitude exposures.

Intra-Individual Test-Retest Variation Regarding Venous Gas Bubble Formation During High Altitude Exposures.

INTRODUCTION: Hypobaric decompression sickness remains a problem during high-altitude aviation. The prevalence of venous gas emboli (VGE) serves as a marker of decompression stress and has been used as a method in evaluating the safety/risk associated with aviation profiles and/or gas mixtures. However, information is lacking concerning the variability of VGE formation when exposed to the same hypobaric profile on different occasions. In this paper, intra-individual test-retest variation regarding bubble formation during repeated hypobaric exposures is presented. The data can be used to determine the sample size needed for statistical power.METHOD: A total of 19 male, nonsmoking subjects volunteered for altitude exposures to 24,000 ft (7315 m). VGE was measured using ultrasound scanning and scored according to the Eftedal-Brubakk (EB) scale. Intraindividual test-retest variation in bubble formation (maximum VGE) was evaluated in subjects exposed more than once to hypobaric pressure. The statistical reliability was examined between paired exposures using the Intraclass Correlation test. G*Power version 3.1.9.6 was used for power calculations.RESULTS: During repeated 20-30 and 70-min exposures to 24,000 ft, 42% (N = 19, CI 23-67%) and 29% (N = 7, CI 5-70%) of the subjects varied between maximum EB scores < 3 and ≥ 3. The sample size needed to properly reject statistical significance of 1 EB step nominal difference between two paired exposures varied between 29-51 subjects.CONCLUSION: The large intraindividual test-retest variations in bubble grades during repeated hypobaric exposures highlight the need for relatively large numbers of subjects to reach statistical power when there are no or small differences in decompression stress between the exposures.Ånell R, Grönkvist M, Eiken O, Elia A, Gennser M. Intra-individual test-retest variation regarding venous gas bubble formation during high altitude exposures. Aerosp Med Hum Perform. 2022; 93(1):46-49.

Hyperoxic Effects on Decompression Strain During Alternating High and Moderate Altitude Exposures.

INTRODUCTION: In fighter aircraft, long-duration high-altitude sorties are typically interrupted by refueling excursions to lower altitude. In normoxia, excursions to moderate cabin altitude may increase the occurrence of venous gas emboli (VGE) at high cabin altitude. The aim was to investigate the effect of hyperoxia on VGE and decompression sickness (DCS) during alternating high and moderate altitude exposure.METHODS: In an altitude chamber, 13 healthy men were exposed to three different conditions: A) 90 min at 24,000 ft (7315 m) breathing normoxic gas (54% O₂; H-NOR); B) 90 min at 24,000 ft breathing hyperoxic gas (90% O₂; H-HYP); and C) three 30-min exposures to 24,000 ft interspersed by two 30-min exposures to 18,000 ft (5486 m) breathing 90% O₂ (ALT-HYP). VGE occurrence was evaluated from cardiac ultrasound imaging. DCS symptoms were rated using a scale.RESULTS: DCS occurred in all conditions and altogether in 6 of the 39 exposures. The prevalence of VGE was similar in H-NOR and H-HYP throughout the exposures. During the initial 30 min at 24,000 ft, the prevalence of VGE was similar in ALT-HYP as in the other two conditions, whereas, after the first excursion to 18,000 ft, the VGE score was lower in ALT-HYP than in H-NOR and H-HYP.DISCUSSION: Hyperoxic excursions from 24,000 to 18,000 ft reduces VGE occurrence, presumably by facilitating diffusive gas exchange across the bubble surfaces, increasing the share of bubble content contributed by oxygen. Still, the excursions did not abolish the DCS risk.Ånell R, Grönkvist M, Gennser M, Eiken O. Hyperoxic effects on decompression strain during alternating high and moderate altitude exposures. Aerosp Med Hum Perform. 2021; 92(4):223230.

Altitude Cardiomyopathy Is Associated With Impaired Stress Electrocardiogram and Increased Circulating Inflammation Makers

Many sea-level residents suffer from acute mountain sickness (AMS) when first visiting altitudes above 4,000 m. Exercise tolerance also decreases as altitude increases. We observed exercise capacity at sea level and under a simulated hypobaric hypoxia condition (SHHC) to explore whether the response to exercise intensity represented by physiological variables could predict AMS development in young men. Eighty young men from a military academy underwent a standard treadmill exercise test (TET) and biochemical blood test at sea level, SHHC, and 4,000-m altitude, sequentially, between December 2015 and March 2016. Exercise-related variables and 12-lead electrocardiogram parameters were obtained. Exercise intensity and AMS development were investigated. After exposure to high altitude, the count of white blood cells, alkaline phosphatase and serum albumin were increased (P < 0.05). There were no significant differences in exercise time and metabolic equivalents (METs) between SHHC and high-altitude exposures (7.05 ± 1.02 vs. 7.22 ± 0.96 min, P = 0.235; 9.62 ± 1.11 vs. 9.38 ± 1.12, P = 0.126, respectively). However, these variables were relatively higher at sea level (8.03 ± 0.24 min, P < 0.01; 10.05 ± 0.31, P < 0.01, respectively). Thus, subjects displayed an equivalent exercise tolerance upon acute exposure to high altitude and to SHHC. The trends of cardiovascular hemodynamics during exercise under the three different conditions were similar. However, both systolic blood pressure and the rate–pressure product at every TET stage were higher at high altitude and under the SHHC than at sea level. After acute exposure to high altitude, 19 (23.8%) subjects developed AMS. Multivariate logistic regression analysis showed that METs under the SHHC {odds ratio (OR) 0.355 per unit increment [95% confidence intervals (CI) 0.159−0.793], P = 0.011}, diastolic blood pressure (DBP) at rest under SHHC [OR 0.893 per mmHg (95%CI 0.805−0.991), P = 0.030], and recovery DBP 3 min after exercise at sea level [OR 1.179 per mmHg (95%CI 1.043−1.333), P = 0.008] were independently associated with AMS. The predictive model had an area under the receiver operating characteristic curve of 0.886 (95%CI 0.803−0.969, P < 0.001). Thus, young men have similar exercise tolerance in acute exposure to high altitude and to SHHC. Moreover, AMS can be predicted with superior accuracy using characteristics easily obtainable with TET.

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes.

High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.

Evolution and Preservation of Venous Gas Emboli at Alternating High and Moderate Altitude Exposures.

INTRODUCTION: The evolution and preservation of venous gas emboli (VGE), as markers of decompression stress, were investigated during alternating high- and moderate altitude exposures, thus, simulating a fighter aircraft high-altitude flight, interrupted by refueling excursions to lower altitudes.METHODS: Eight men served as subjects during three normoxic simulated altitude exposures: High = 90 min at 24,000 ft; High-Low = three × 30 min at 24,000 ft, interspersed by two 30-min intervals at 15,000 ft; Low = 90 min at 15,000 ft. VGE scores were assessed by cardiac ultrasound, using a 5-grade scale. Respiratory nitrogen exchange was measured continuously using a modified closed-circuit electronic rebreather.RESULTS: Both High and High-Low induced persistent VGE, with no inter-condition difference either at rest [median (range): High: 1 (0-3), High-Low: 2 (0-3)] or during unloaded knee-bends [High: 3 (1-4), High-Low: 3 (0-4)], whereas VGE was considerably less in Low, both at rest [0 (0-1)] and during knee-bends [0 (0-2)]. In High-Low, VGE decreased temporarily during the 15,000-ft excursions, but resumed pre-excursion values upon return to 24,000 ft. During the final descent to ground level, VGE were more persistent following High-Low than High. In both High and Low, nitrogen was continuously washed out at altitude, whereas in High-Low, the washout at 24,000 ft was interrupted by nitrogen uptake at 15,000 ft.DISCUSSION: In normoxic conditions, long-duration flying at a cabin altitude of 24,000 ft is associated with substantial VGE occurrence, which is not abolished by intermittent excursions to a cabin altitude of 15,000 ft.Ånell R, Grönkvist M, Gennser M, Eiken O. Evolution and preservation of venous gas emboli at alternating high and moderate altitude exposures. Aerosp Med Hum Perform. 2020; 91(1):11-17.

Is decision making in hypoxia affected by pre-acclimatisation? A randomized controlled trial

IntroductionDecision making is impaired in hypoxic environments, which may have serious or even lethal consequences for mountaineers. An acclimatisation period prior to high altitude exposures may help to overcome adverse effects of hypoxia.Thus, we investigated possible effects of short-term pre-acclimatisation on decision making in hypoxia. MethodsIn a randomized controlled study design, 52 healthy participants were allocated to a hypoxia group (HG: short-term pre-acclimatisation by the use of intermittent hypoxia 7×1h at FiO2=12.6%, equivalent to 4500m) or a control group (CG: sham pre-acclimatisation 7×1h at FiO2=20.9%, equivalent to 600m). The number of risky decisions was assessed using the Game of Dice Task at four time points during a 12-hours stay in hypoxia (FiO2=12.6%). Results42 (HG: 27, CG: 25) participants completed the study. The number of risky decisions was significantly (p=0.048 as determined by 4×2 ANCOVA) reduced in the hypoxia group compared to the control group, partial η2=0.11, when the age-effect on decision making was controlled. Self-reported positive affective valence prior to decision making was negatively related to the number of risky decisions, r<−0.38. ConclusionShort-term pre-acclimatisation might influence decision making in hypoxia in a positive way and might be considered as a risk-reducing preparation method prior to exposures to hypoxic environments. Positive affective states seem to have a medium-sized protective effect against risky decision making.

Wilderness dermatology: mountain exposures

Exploring the mountains is a highly rewarding past time; however, certain high-altitude exposures can lead to dermatologic manifestations. In this review article, the authors will describe cold, solar, and severe weather that one may experience when spending time outdoors. Factors such as increased ultraviolet radiation, temperature extremes, and low partial pressure of oxygen, along with human physiologic parameters also contribute to disease severity and presentation. This review article will address the diagnosis, treatment, and prevention of high-altitude dermatology exposures.

Nrf2 activation: A potential strategy for the prevention of acute mountain sickness

Reactive oxygen species (ROS) formed during acute high altitude exposure contribute to cerebral vascular leak and development of acute mountain sickness (AMS). Nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) is a transcription factor that regulates expression of greater than 90% of antioxidant genes, but prophylactic treatment with Nrf2 activators has not yet been tested as an AMS therapy. We hypothesized that prophylactic activation of the antioxidant genome with Nrf2 activators would attenuate high-altitude-induced ROS formation and cerebral vascular leak and that some drugs currently used to treat AMS symptoms have an additional trait of Nrf2 activation. Drugs commonly used to treat AMS were screened with a luciferase reporter cell system for their effectiveness to activate Nrf2, as well as being tested for their ability to decrease high altitude cerebral vascular leak in vivo. Compounds that showed favorable results for Nrf2 activation from our screen and attenuated high altitude cerebral vascular leak in vivo were further tested in brain microvascular endothelial cells (BMECs) to determine if they attenuated hypoxia-induced ROS production and monolayer permeability. Of nine drugs tested, with the exception of dexamethasone, only drugs that showed the ability to activate Nrf2 (Protandim, methazolamide, nifedipine, amlodipine, ambrisentan, and sitaxentan) decreased high-altitude-induced cerebral vascular leak in vivo. In vitro, Nrf2 activation in BMECs before 24h hypoxia exposure attenuated hypoxic-induced hydrogen peroxide production and permeability. Prophylactic Nrf2 activation is effective at reducing brain vascular leak from acute high altitude exposures. Compared to acetazolamide, methazolamide may offer better protection against AMS. Nifedipine, in addition to its known vasodilatory activities in the lung and protection against high altitude pulmonary edema, may provide protection against brain vascular leak as well.

Off Target therapeutic effects of commonly used drugs to treat acute mountain sickness

IntroductionAcute mountain sickness is a syndrome that effects ~60% of individuals ascending to high altitude, yet the etiology is still unclear. It has been proposed that reactive oxygen species (ROS) formed from acute high altitude exposure contribute to brain vascular leak and development of AMS. NF‐E2‐related factor 2 (Nrf2) is a transcription factor that regulates expression of greater than 90% of antioxidant genes.HypothesisWe postulated that some drugs currently used to treat AMS symptoms could induce Nrf2 activation and that by increasing anti‐oxidant status would decrease vascular damage from oxidative stress in hypoxic conditions.MethodsA MCF7 cell line stably transfected with a luciferase gene driven by an antioxidant response element, the known Nrf2 promoter, was used to screen. Drugs that showed favorable Nrf2 activation were further tested in brain microvascular endothelial cells to determine if they attenuated hypoxia induced ROS production and permeability. Finally, compounds were tested for their ability to induce Nrf2 and decrease brain leak (measured by Evans blue dye) in male Spraque Dawly rats exposed to high altitude (48 h, 19,000 ft).ResultsOf 9 drugs tested, Nifedipine and Methazolamide showed strong NRF2 activation. Cells in hypoxic conditions increased hydrogen peroxide production by two fold from normoxic. Pre‐treatment with Methazolamide, Nifedipine, and Protandim decreased ROS production back to normoxic concentrations. This response was blocked by siRNA against Nrf2. Resistance was decreased after 24 hr hypoxic exposure, which was restored to normoxic values with pre‐treatments of Protandim, Methazolamide, and Nifedipine. Only drugs that showed Nrf2 activation in‐vitro, decreased brain vascular leak, in‐vivo.ConclusionNrf2 activators are effective at reducing brain vascular leak from acute high altitude exposures.

Neurological Altitude Decompression Sickness Among U-2 Pilots: 2002–2009

Compared to the previous 47 yr, U-2 pilots reported an increased number of altitude decompression sickness (DCS) incidents with central nervous system (CNS) manifestations during 2002-2009. Due to increasing incident severity during military operations, the U.S. Air Force initiated an investigation to prevent future mishaps. We retrospectively examined all neurological DCS cases observed among U-2 pilots during 2002-2009. Urgency to prevent further pilot losses limited this study to using existing, often incomplete data sources. During 2002-2009, 16 confirmed incidents of CNS DCS occurred with 13 pilots, plus 4 possible incidents with 4 pilots. Significantly, 12 of 16 confirmed incidents occurred at 1 operating location, including 4 of 5 life-threatening cases. This series of cases were of a type and severity rarely found in flight operations and correlated temporally with increased sortie frequency/duration associated with combat operations. Multiple investigations confirmed no defects in aircraft, support equipment, or oxygen supplies. Nor were significant trends observed with age, habitus, environmental exposure, medication use, or cardiac defects. In 11 cases, symptom recognition occurred well after the 4-h point where clinical experience indicated risk should stabilize. Symptoms also recurred days later and responded to repeat hyperbaric oxygen therapy in three of four cases. Finally, neuropsychiatric symptoms persisted in six pilots for years and may represent permanent injury. An increase in U-2 CNS DCS cases probably resulted from more cockpit activity combined with longer, more frequent high-altitude exposures. Adjustments in preoxygenation, cabin altitude, exercise at altitude, and frequency of flights may reduce incidence.

How Do You Approach Seizures in the High Altitude Traveler?

Counseling patients who suffer first-time or break- through seizures can be difficult, particularly when controllable external factors may be contributing to the lowering of their seizure threshold. High altitude as a potential trigger for seizures is a common question in our epilepsy clinics in Colorado, and this article reviews the existing anecdotal literature, presents our local experience with high altitude seizures (HAS), offers possible mechanisms to explain how high altitude may trigger seizures, and suggests an initial work-up and prophylactic strategies for future high altitude exposures.

Correlation of microRNA levels during hypoxia with predicted target mRNAs through genome-wide microarray analysis

BackgroundLow levels of oxygen in tissues, seen in situations such as chronic lung disease, necrotic tumors, and high altitude exposures, initiate a signaling pathway that results in active transcription of genes possessing a hypoxia response element (HRE). The aim of this study was to investigate whether a change in miRNA expression following hypoxia could account for changes in the cellular transcriptome based on currently available miRNA target prediction tools.MethodsTo identify changes induced by hypoxia, we conducted mRNA- and miRNA-array-based experiments in HT29 cells, and performed comparative analysis of the resulting data sets based on multiple target prediction algorithms. To date, few studies have investigated an environmental perturbation for effects on genome-wide miRNA levels, or their consequent influence on mRNA output.ResultsComparison of miRNAs with predicted mRNA targets indicated a lower level of concordance than expected. We did, however, find preliminary evidence of combinatorial regulation of mRNA expression by miRNA.ConclusionTarget prediction programs and expression profiling techniques do not yet adequately represent the complexity of miRNA-mediated gene repression, and new methods may be required to better elucidate these pathways. Our data suggest the physiologic impact of miRNAs on cellular transcription results from a multifaceted network of miRNA and mRNA relationships, working together in an interconnected system and in context of hundreds of RNA species. The methods described here for comparative analysis of cellular miRNA and mRNA will be useful for understanding genome wide regulatory responsiveness and refining miRNA predictive algorithms.

Reduced oxygen due to high‐altitude exposure relates to atrophy in motor‐function brain areas

At high altitudes barometric pressure is reduced and, thus, less oxygen is inhaled. Reduced oxygen concentration in brain tissue can lead to cerebral damage and neurological and cognitive deficits. The present study was designed to explore the effects of high-altitude exposure using a quantitative MRI technique, voxel-based morphometry. We studied nine world-class mountain climbers before (baseline) and after (follow-up) an extremely high-altitude ascent of Everest and K2. We investigated the effects of repeated extremely high-altitude exposures by comparing mountain climbers' scans at baseline with scans of 19 controls. In addition, we measured the effects of a single extremely high-altitude expedition by comparing mountain climbers' scans at baseline and follow-up. A region of reduced white matter density/volume was found in the left pyramidal tract near the primary (BA 4) and supplementary (BA 6) motor cortex when mountain climbers at baseline were compared with controls. Further, when mountain climbers' scans before and after the expedition were compared, a region of reduced grey matter density/volume was found in the left angular gyrus (BA 39). These findings suggest that extremely high-altitude exposures may cause subtle white and grey matter changes that mainly affect brain regions involved in motor activity.

The effect of chronic erythrocyte polycythemia and high altitude upon plasma and blood volumes.

Comparison of two kinds of physiological chronic erythrocytic polycythemias in order to differentiate the specific effect of erythrocytic polycythemia from the general effects of high altitude upon the plasma volume. The two kinds were produced hormonally in female chickens, at sea level, or by protracted high-altitude exposures. It appears that the vascular system of the body may account for an increase in red blood cell mass either by reduction in plasma volume, or by no change in plasma volume, resulting in differential changes in total blood volumes.