The physiological effects of hypobaric hypoxia versus normobaric hypoxia: a systematic review of crossover trials

Much hypoxia research has been carried out at high altitude in a hypobaric hypoxia (HH) environment. Many research teams seek to replicate high-altitude conditions at lower altitudes in either hypobaric hypoxic conditions or normobaric hypoxic (NH) laboratories. Implicit in this approach is the assumption that the only relevant condition that differs between these settings is the partial pressure of oxygen (PO2), which is commonly presumed to be the principal physiological stimulus to adaptation at high altitude. This systematic review is the first to present an overview of the current available literature regarding crossover studies relating to the different effects of HH and NH on human physiology. After applying our inclusion and exclusion criteria, 13 studies were deemed eligible for inclusion. Several studies reported a number of variables (e.g. minute ventilation and NO levels) that were different between the two conditions, lending support to the notion that true physiological difference is indeed present. However, the presence of confounding factors such as time spent in hypoxia, temperature, and humidity, and the limited statistical power due to small sample sizes, limit the conclusions that can be drawn from these findings. Standardisation of the study methods and reporting may aid interpretation of future studies and thereby improve the quality of data in this area. This is important to improve the quality of data that is used for improving the understanding of hypoxia tolerance, both at altitude and in the clinical setting

Trainability of cold induced vasodilatation in fingers and toes

Subjects that repeatedly have to expose the extremities to cold may benefit from a high peripheral temperature to maintain dexterity and tissue integrity. Therefore, we investigated if repeated immersions of a hand and a foot in cold water resulted in increased skin temperatures. Nine male and seven female subjects (mean 20.4; SD 2.2 years) immersed their right (trained) hand and foot simultaneously in 8°C water, 30 min daily for 15 days. During the pre and post-test (days 1 and 15, respectively) the left (untrained) hand and foot were immersed as well. Pain, tactile sensitivity and skin temperatures were measured every day. Mean (SD) toe temperature of the trained foot increased from 9.49°C (0.89) to 10.03°C (1.38) (p < 0.05). The trained hand, however, showed a drop in mean finger temperature from 9.28°C (0.54) to 8.91°C (0.44) (p < 0.001) and the number of cold induced vasodilation (CIVD) reactions decreased from 52% during the first test to 24% during the last test. No significant differences occurred in the untrained extremities. Pain diminished over time and tactile sensitivity decreased with skin temperature. The combination of less CIVD responses in the fingers after training, reduced finger skin temperatures in subjects that did show CIVD and the reduced pain and tactile sensitivity over time may lead to an increased risk for finger cold injuries. It is concluded that repeated cold exposure of the fingers does not lead to favorable adaptations, but may instead increase the injury risk

A Randomly-Controlled Study on the Cardiac Function at the Early Stage of Return to the Plains after Short-Term Exposure to High Altitude

High altitude acclimatization and adaptation mechanisms have been well clarified, however, high altitude de-adaptation mechanism remains unclear. In this study, we conducted a controlled study on cardiac functions in 96 healthy young male who rapidly entered the high altitude (3700 m) and returned to the plains (1500 m) after 50 days. Ninety eight healthy male who remained at low altitude were recruited as control group. The mean pulmonary arterial pressure (mPAP), left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), cardiac function index (Tei index) were tested. Levels of serum creatine kinase isoform MB (CK-MB), lactate dehydrogenase isoenzyme-1 (LDH-1), endothelin-1 (ET-1), nitrogen oxide (NO), serum hypoxia-inducible factor-1α (HIF-1α), 8-iso-prostaglandin F2α (8-iso PGF2α), superoxide dismutase (SOD) and malonaldehyde (MDA) were measured at an altitude of 3700 m and 1500 m respectively. The results showed that after short-term exposure to high altitude mPAP and Tei index increased significantly, while LVEF and LVFS decreased significantly. These changes were positively correlated with altitude. On the 15th day after the subjects returned to low altitude, mPAP, LVEF and LVFS levels returned to the same level as those of the control subjects, but the Tei index in the returned subjects was still significantly higher than that in the control subjects (P<0.01). We also found that changes in Tei index was positively correlated with mPAP, ET-1, HIF-1α and 8-iso PGF2α levels, and negatively correlated with the level of NO, LVEF, LVFS, CK-MB and LDH-1. These findings suggest that cardiac function de-adapts when returning to the plains after short-term exposure to high altitude and the function recovery takes a relatively long time

A Four-Way Comparison of Cardiac Function with Normobaric Normoxia, Normobaric Hypoxia, Hypobaric Hypoxia and Genuine High Altitude.

There has been considerable debate as to whether different modalities of simulated hypoxia induce similar cardiac responses.This was a prospective observational study of 14 healthy subjects aged 22-35 years. Echocardiography was performed at rest and at 15 and 120 minutes following two hours exercise under normobaric normoxia (NN) and under similar PiO2 following genuine high altitude (GHA) at 3,375m, normobaric hypoxia (NH) and hypobaric hypoxia (HH) to simulate the equivalent hypoxic stimulus to GHA.All 14 subjects completed the experiment at GHA, 11 at NN, 12 under NH, and 6 under HH. The four groups were similar in age, sex and baseline demographics. At baseline rest right ventricular (RV) systolic pressure (RVSP, p = 0.0002), pulmonary vascular resistance (p = 0.0002) and acute mountain sickness (AMS) scores were higher and the SpO2 lower (p<0.0001) among all three hypoxic groups (GHA, NH and HH) compared with NN. At both 15 minutes and 120 minutes post exercise, AMS scores, Cardiac output, septal S', lateral S', tricuspid S' and A' velocities and RVSP were higher and SpO2 lower with all forms of hypoxia compared with NN. On post-test analysis, among the three hypoxia groups, SpO2 was lower at baseline and 15 minutes post exercise with GHA (89.3±3.4% and 89.3±2.2%) and HH (89.0±3.1 and (89.8±5.0) compared with NH (92.9±1.7 and 93.6±2.5%). The RV Myocardial Performance (Tei) Index and RVSP were significantly higher with HH than NH at 15 and 120 minutes post exercise respectively and tricuspid A' was higher with GHA compared with NH at 15 minutes post exercise.GHA, NH and HH produce similar cardiac adaptations over short duration rest despite lower SpO2 levels with GHA and HH compared with NH. Notable differences emerge following exercise in SpO2, RVSP and RV cardiac function

Expression Profiling Reveals Novel Hypoxic Biomarkers in Peripheral Blood of Adult Mice Exposed to Chronic Hypoxia

Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO) mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX), exposed for two weeks to normobaric chronic hypoxia (CH) or two weeks of CH followed by two weeks of normoxic recovery (REC). Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off), 230 genes were identified and separated into four distinct temporal categories. Class I) contained 1 transcript up-regulated in both CH and REC; Class II) contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III) contained 9 transcripts down-regulated both in CH and REC; Class IV) contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1) by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia

Influence of Inhaled Amiloride on Lung Fluid Clearance in Response to Normobaric Hypoxia in Healthy Individuals.

AIM: To investigate the role of epithelial sodium channels (ENaC) on lung fluid clearance in response to normobaric hypoxia, 20 healthy subjects were exposed to 15 hours of hypoxia (fraction of inspired oxygen [FiO2] = 12.5%) on two randomized occasions: (1) inhaled amiloride (A) (1.5 mg/5 mL saline); and (2) inhaled saline placebo (P). Changes in lung fluid were assessed through chest computed tomography (CT) for lung tissue volume (TV), and the diffusion capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) for pulmonary capillary blood volume (VC). Extravascular lung water (EVLW) was derived as TV-VC and changes in the CT attenuation distribution histograms were reviewed. RESULTS: Normobaric hypoxia caused (1) a reduction in EVLW (change from baseline for A vs. P, -8.5% ± 3.8% vs. -7.9% ± 5.2%, p  0.05), and (4) CT attenuation distribution became more negative, leftward skewed, and kurtotic (p < 0.05). CONCLUSION: Acute normobaric hypoxia caused a reduction in lung fluid that was unaffected by ENaC inhibition through inhaled amiloride. Although possible amiloride-sensitive ENaC may not be necessary to maintain lung fluid balance in response to hypoxia, it is more probable that normobaric hypoxia promotes lung fluid clearance rather than accumulation for the majority of healthy individuals. The observed reduction in interstitial lung fluid means alveolar fluid clearance may not have been challenged

Markers of physiological stress during exercise under conditions of normoxia, normobaric hypoxia, hypobaric hypoxia and genuine high altitude.

Purpose To investigate whether there is a differential response at rest and following exercise to conditions of genuine high altitude (GHA), normobaric hypoxia (NH), hypobaric hypoxia (HH) and normobaric normoxia (NN). Method Markers of sympathoadrenal and adrenocortical function (plasma normetanephrine [PNORMET], metanephrine [PMET], cortisol), myocardial injury (highly sensitive cardiac troponin T [hscTnT]) and function (N-terminal brain natriuretic peptide [NT-proBNP]) were evaluated at rest and with exercise under NN, at 3375 m in the Alps (GHA) and at equivalent simulated altitude under NH and HH. Participants cycled for 2 hours {15 minute warm-up, 105 minutes at 55% Wmax (maximal workload)} with venous blood samples taken prior (T0), immediately following (T120) and 2 hours post-exercise (T240). Results Exercise in the three hypoxic environments produced a similar pattern of response with the only difference between environments being in relation to PNORMET. Exercise in NN only induced a rise in PNORMET and PMET. Conclusion Biochemical markers that reflect sympathoadrenal, adrenocortical and myocardial responses to physiological stress demonstrate significant differences in the response to exercise under conditions of normoxia versus hypoxia while NH and HH appear to induce broadly similar responses to GHA and may therefore be reasonable surrogates

Indirect synthesis of methyl and alkylamines from CO2

International audienceIn the past few years C02 has been investigated as a Cl building block for the synthesis of a variety of chemicals and especially methylamines. 1 However due to the inertness of CO 2 , the methylation of amines re~.Juire either the use of activated hydrides (silanes/boranes) whose by-products are not recyc1able, or the use oflarge excess ofH 2 yie1ding poor faradaic efficiencies. On the other hand, great improvements have been made for the 2-e1ectron reduction of CO 2 to CO or HCOO-offering convenient platforms for the indirect synthesis of chemicals form C02. 2 However to the best of our knowledge, neither HCOO-nor CO has been reported for the synthesis of methyl or alkylamines. We therefore report the first ruthenium catalyzed synthesis of methylamines using HCOOH as the unique source of carbon and hydrogen. 3 Thanks to a theoretical and experimental approach,4 we were able to achieve quantitative yield for the methylation of amines. If the use of HCOOH is lin;üted to the synthesis of methylamines, we also deve10ped the synthesis of alkylamines via the homologation of amines, using CO as a building block. 5 Amines bearing an alkyl chain of up to 5 carbons were synthetized from the corresponding methylamines in one pot thanks to a cobalt catalyst