Breathing Hypoxic Gas Research Articles

Feasibility of Delivering 5-Day Normobaric Hypoxia Breathing in a Hospital Setting.

Beneficial effects of breathing at [Formula: see text] < 0.21 on disease outcomes have been reported in previous preclinical and clinical studies. However, the safety and intra-hospital feasibility of breathing hypoxic gas for 5 d have not been established. In this study, we examined the physiologic effects of breathing a gas mixture with [Formula: see text] as low as 0.11 in 5 healthy volunteers. All 5 subjects completed the study, spending 5 consecutive days in a hypoxic tent, where the ambient oxygen level was lowered in a stepwise manner over 5 d, from [Formula: see text] of 0.16 on the first day to [Formula: see text] of 0.11 on the fifth day of the study. All the subjects returned to an environment at room air on the sixth day. The subjects' [Formula: see text], heart rate, and breathing frequency were continuously recorded, along with daily blood sampling, neurologic evaluations, transthoracic echocardiography, and mental status assessments. Breathing hypoxia concentration dependently caused profound physiologic changes, including decreased [Formula: see text] and increased heart rate. At [Formula: see text] of 0.14, the mean [Formula: see text] was 92%; at [Formula: see text] of 0.13, the mean [Formula: see text] was 93%; at [Formula: see text] of 0.12, the mean [Formula: see text] was 88%; at [Formula: see text] of 0.11, the mean [Formula: see text] was 85%; and, finally, at an [Formula: see text] of 0.21, the mean [Formula: see text] was 98%. These changes were accompanied by increased erythropoietin levels and reticulocyte counts in blood. All 5 subjects concluded the study with no adverse events. No subjects exhibited signs of mental status changes or pulmonary hypertension. Results of the current physiologic study suggests that, within a hospital setting, delivering [Formula: see text] as low as 0.11 is feasible and safe in healthy subjects, and provides the foundation for future studies in which therapeutic effects of hypoxia breathing are tested.

Efficiency of interval hypoxia-hyperoxytherapy in the rehabilitation of patients with nonspecific musculosceletal low back pain: results of а randomized placebo-controlled study

BACKGROUND: Considering the high prevalence and social significance of nonspecific musculoskeletal lower back pain, the use of innovative non-drug rehabilitation methods, particularly interval hypoxia-hyperoxytherapy, is relevant. AIM: To evaluate the efficiency of the interval hypoxia-hyperoxytherapy in the complex medical rehabilitation of patients with nonspecific musculoskeletal lower back pain. MATERIALS AND METHODS: This randomized placebo-controlled study enrolled 62 patients (male, n=35; female n=27, aged 34–63 years) with nonspecific musculoskeletal lower back pain. All patients were randomized into two groups. The study group (n=34) received 10 procedures of hypoxia–hyperoxytherapy, and the comparison group (n=28) received 10 placebo procedures of breathing therapy. All groups underwent a 2-week standard rehabilitation program: 10 procedures of low-intensity laser therapy and low-frequency electrostatic therapy and 10 group sessions of physical exercises. The study group was breathing hypoxic (FiO2 13%–15%) and hyperoxic (FiO2 up to 40%) gas mixture through a mask in the interval mode using “ReOxy.” The duration of 1–4 procedures was 30 min and 5–10 procedures took 40 min. The placebo procedures were performed using masks with atmospheric air hole. Rehabilitation diagnosis by domains b28013, b7303, b7600, and d4500 of the International Classification of Functioning, Disability and Health (ICF), back pain and general health on a 100-mm visual analog scale, Lequesne index, 10-m walking test, Spielberger–Khanin reactive anxiety test, and Beck depression inventory were evaluated at baseline and week 2. RESULTS: After 2 weeks the values of the qualifiers of ICF domains significantly improved in the study group, back pain decreased by 65.2% (р 0.01), the Lequesne index by 76.1% (р 0.01), the 10-m walking test by 42.4% (р 0.05), the reactive anxiety level by 50.5% (р 0.01), and depression symptoms by 69.7% (р 0.01), whereas the general health improved by 71.2% (р 0.01), with statistically significant differences from the comparison group in all parameters (р 0.05). CONCLUSION: 2-week rehabilitation program, including interval hypoxia-hyperoxytherapy, reduces back pain and improves rehabilitation diagnosis based on the ICF, general health, functional status and psychoemotional state in patients with nonspecific musculoskeletal lower back pain.

The effect of breathing hypoxic gas (15% FIO2 ) on physiological and behavioral outcomes during simulated driving in healthy subjects.

Hypoxia is mainly caused by cardiopulmonary disease or high-altitude exposure. We used a driving simulator to investigate whether breathing hypoxic gas influences driving behaviors in healthy subjects. Fifty-two healthy subjects were recruited in this study, approved by the Science and Engineering Ethical Committee. During simulated driving experiments, driving behaviors, breathing frequency, oxygen saturation (SpO2 ), and heart rate variability (HRV) were analyzed. Each subject had four driving sessions; a 10-min practice and three 20-min randomized interventions: normoxic room air (21% FIO2 ) and medical air (21% FIO2 ) and hypoxic air (equal to 15% FIO2 ), analyzed by repeated measures ANOVA. Driving behaviors and HRV frequency domains showed no significant change. Heart rate (HR; p < 0.0001), standard deviation of the RR interval (SDRR; p = 0.03), short-term HRV (SD1; p < 0.0001), breathing rate (p = 0.01), and SpO2 (p < 0.0001) were all significantly different over the three gas interventions. Pairwise comparisons showed HR increased during hypoxic gas exposure compared to both normoxic interventions, while SDRR, SD1, breathing rate, and SpO2 were lower. Breathing hypoxic gas (15% FiO2 , equivalent to 2710 m altitude) may not have a significant impact on driving behavior in healthy subjects. Furthermore, HRV was negatively affected by hypoxic gas exposure while driving suggesting further research to investigate the impact of breathing hypoxic gas on driving performance for patients with autonomic dysfunction.

Perceived Exertion And Dyspnea While Cycling During A Hypoxic And Hyperoxic Placebo

Rating of Perceived Exertion (RPE) is used to subjectively quantify and monitor the perception of physical activity, breathlessness or dyspnea, and leg discomfort (RPElegs) during exercise. However, it is unknown how perceptions of exertion can be influenced by expectation of difficulty. PURPOSE: We asked if the placebo and nocebo effects could alter dyspnea and RPEleg by telling subjects they were receiving different concentrations of oxygen during exercise. We hypothesized that subjects would rate their dyspnea and RPElegs higher when they believed they were breathing hypoxic gas and lower when they believed they were breathing hyperoxic gas relative to room air. METHODS: Thirty healthy, active subjects (19 M, 11 F) with normal pulmonary function participated. Prior to exercise, we read a script to ensure subjects understood hypoxic and hyperoxic gas might make breathing feel more difficult and easier, respectively, but intentionally made no mention about RPEleg. Then during 5-minute submaximal cycling trials (60% peak work rate), we deceived subjects by telling them they were breathing different hypoxic (17% and 15% O2) and hyperoxic (23% O2) gas concentrations, when in fact they breathed room air (21% O2). At the end of each trial, we asked subjects for their dyspnea and RPEleg. RESULTS: Cardiorespiratory variables were similar between the trials, however dyspnea and RPElegs changed in a dose-response manner depending on the O2 concentration participants believed they breathed. When subjects believed they were breathing 15% O2, they significantly increased their dyspnea +0.70 ± 0.2 Borg units (p = 0.03) compared to room air, whereas RPElegs did not significantly change +0.35 ± 0.1 Borg units (p = 0.70). When comparing the most severe hypoxic condition, 15% O2, to the 23% hyperoxic condition, subjects significantly increased their dyspnea +1.05 ± 0.4 Borg units (p = 0.003) but did not significantly change RPElegs + 0.55 ± 0.2 Borg units (p = 0.46). CONCLUSION: We found that dyspnea during exercise is susceptible to expectancy, without any accompanying physiological changes. Given that a single unit in dyspnea is considered a minimal clinically important difference, our findings show that the effect of expectation must be considered when interpreting sensations of breathlessness. Support: NSERC

Сlinical Efficacy of Individually Dosed Intermittent Hypoxia-Hyperoxic Therapy in Osteoarthritis Patients with Post-Covid Syndrome

Aim. To evaluate the clinical efficiency of the individually dosed interval hypoxia-hyperoxic therapy in the medical rehabilitation of patients with osteoarthritis (OA), having post-COVID syndrome. Material and methods. 50 patients with OA (84% females, age of 43 to 68 years) where included in the randomized placebo-controlled study. Coronavirus infection COVID-19 were diagnosed from 12 to 26 weeks before the study. Patients had at least 6 symptoms of post-COVID syndrome. All patients were randomized into 3 groups. 18 patients of the study group received 10 hypoxia-hyperoxic therapy procedures, 15 comparison group patients – 10 placebo procedures, 14 control group patients – only standard rehabilitation. The study group patients were breathing hypoxic (FiO2 13–15%) and hyperoxic (FiO2 up to 40%) gas mixture through the mask in the interval mode using device ReOxy. The duration of 1–4 procedures was 30 min, 5–10 procedures – 40 min. The placebo procedures were performed using the mask with the atmospheric air hole. The standard rehabilitation program in all groups for 2 weeks included: 10 group sessions of physical exercises with elements of breathing exercises, 10 procedures of magnetic therapy for joints, 10 sodium chloride baths. Joint pain and general health on 100-mm visual analog scale, Lequesne and WOMAC indexes, Spielberger-Khanin reactive anxiety test, Beck depression inventory and breathlessness on Modified Borg scale were evaluated at baseline (control point T0) and at 2 weeks (control point T1). Results and discussion. After 2 weeks (T1) in the study group, pain decreased by 51.4% (p &lt; 0.01), Lequesne index – by 34.8% (p &lt; 0.05), WOMAC – by 44.7% (p &lt; 0.05), reactive anxiety level – by 23.7% (p &lt; 0.05), depression symptoms – by 52.9% (p &lt; 0.01), breathlessness – by 71.2% (p &lt; 0.01), general health improved by 52.1% (р &lt; 0.01). In the study group, there were statistically significant differences from the control group in all parameters (р &lt; 0.05) and from the comparison group in most indicators (р &lt; 0.05), excluding the Lequesne index. These results are consistent with the data of modern studies of efficiency of hypoxic conditioning. Conclusion. 2-week rehabilitation program, including interval hypoxia-hyperoxic therapy, reduces pain, breathlessness, depression and reactive anxiety symptoms, improves general health and functional status in patients with OA, having post-COVID syndrome.

The Impact of Breathing Hypoxic Gas and Oxygen on Pulmonary Hemodynamics in Patients With Pulmonary Hypertension

BackgroundPure oxygen breathing (hyperoxia) may improve hemodynamics in patients with pulmonary hypertension (PH) and allows to calculate right-to-left shunt fraction (Qs/Qt), whereas breathing normobaric hypoxia may accelerate hypoxic pulmonary vasoconstriction (HPV). This study investigates how hyperoxia and hypoxia affect mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with PH and whether Qs/Qt influences the changes of mPAP and PVR.Study Design and MethodsAdults with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) underwent repetitive hemodynamic and blood gas measurements during right heart catheterization (RHC) under normoxia [fractions of inspiratory oxygen (FiO2) 0.21], hypoxia (FiO2 0.15), and hyperoxia (FiO2 1.0) for at least 10 min.ResultsWe included 149 patients (79/70 PAH/CTEPH, 59% women, mean ± SD 60 ± 17 years). Multivariable regressions (mean change, CI) showed that hypoxia did not affect mPAP and cardiac index, but increased PVR [0.4 (0.1–0.7) WU, p = 0.021] due to decreased pulmonary artery wedge pressure [−0.54 (−0.92 to −0.162), p = 0.005]. Hyperoxia significantly decreased mPAP [−4.4 (−5.5 to −3.3) mmHg, p < 0.001] and PVR [−0.4 (−0.7 to −0.1) WU, p = 0.006] compared with normoxia. The Qs/Qt (14 ± 6%) was >10 in 75% of subjects but changes of mPAP and PVR under hyperoxia and hypoxia were independent of Qs/Qt.ConclusionAcute exposure to hypoxia did not relevantly alter pulmonary hemodynamics indicating a blunted HPV-response in PH. In contrast, hyperoxia remarkably reduced mPAP and PVR, indicating a preserved vasodilator response to oxygen and possibly supporting the oxygen therapy in patients with PH. A high proportion of patients with PH showed increased Qs/Qt, which, however, was not associated with changes in pulmonary hemodynamics in response to changes in FiO2.

Интервальная гипокси-гипероксическая терапия в комплексной реабилитации пациентов с остеоартритом

The purpose — to evaluate the clinical efficiency of the individually dosed interval hypoxic-hyperoxic therapy in the medical rehabilitation of patients with osteoarthritis (OA). Material and methods. 68 patients with OA (81% females, aged 44 to 69 years) were included in the randomized controlled study. 35 study group patients received 10 hypoxic-hyperoxic therapy procedures, 33 control group patients – only standard rehabilitation. The study group patients were breathing hypoxic (FiO2 13–15%) and hyperoxic (FiO2 up to 40%) gas mixture through a mask in the interval mode using ReOxy device. The duration of 1–4 procedures was 30 min, 5–10 procedures — 40 min. The patients of both groups underwent a 2-week standard rehabilitation program: 10 group sessions of physical exercises, 10 procedures of magnetic therapy for joints, 10 sodium chloride baths. Results. After 2 weeks, joint pain on a 100 mm visual analog scale in the study group decreased by 54% (p &lt; 0.01), Lequesne index — by 35.7% (p &lt; 0.05), WOMAC index — by 49.6% (p &lt; 0.05), Spielberger — Khanin reactive anxiety test — by 30.1% (p &lt; 0.05), depression symptoms by Beck depression inventory — by 60.8% (p &lt; 0.01). In the study group there were statistically significant differences from the control group in all parameters (р &lt; 0.05). Conclusion. The 2-week rehabilitation program, including interval hypoxic-hyperoxic therapy, reduces pain, depression and reactive anxiety symptoms, improves functional status in patients with OA.

Acute Hemodynamic Effect of Acetazolamide in Patients With Pulmonary Hypertension Whilst Breathing Normoxic and Hypoxic Gas: A Randomized Cross-Over Trial.

Aims: To test the acute hemodynamic effect of acetazolamide in patients with pulmonary hypertension (PH) under ambient air and hypoxia.Methods: Patients with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) undergoing right heart catheterization were included in this randomized, placebo-controlled, double-blinded, crossover trial. The main outcome, pulmonary vascular resistance (PVR), further hemodynamics, blood- and cerebral oxygenation were measured 1 h after intravenous administration of 500 mg acetazolamide or placebo-saline on ambient air (normoxia) and at the end of breathing hypoxic gas (FIO2 0.15, hypoxia) for 15 min.Results: 24 PH-patients, 71% men, mean ± SD age 59 ± 14 years, BMI 28 ± 5 kg/m2, PVR 4.7 ± 2.1 WU participated. Mean PVR after acetazolamide vs. placebo was 5.5 ± 3.0 vs. 5.3 ± 3.0 WU; mean difference (95% CI) 0.2 (−0.2–0.6, p = 0.341). Heart rate was higher after acetazolamide (79 ± 12 vs. 77 ± 11 bpm, p = 0.026), pH was lower (7.40 ± 0.02 vs. 7.42 ± 0.03, p = 0.002) but PaCO2 and PaO2 remained unchanged while cerebral tissue oxygenation increased (71 ± 6 vs. 69 ± 6%, p = 0.017). In acute hypoxia, acetazolamide decreased PVR by 0.4 WU (0.0–0.9, p = 0.046) while PaO2 and PaCO2 were not changed. No adverse effects occurred.Conclusions: In patients with PAH/CTEPH, i.v. acetazolamide did not change pulmonary hemodynamics compared to placebo after 1 hour in normoxia but it reduced PVR after subsequent acute exposure to hypoxia. Our findings in normoxia do not suggest a direct acute pulmonary vasodilator effect of acetazolamide. The reduction of PVR during hypoxia requires further corroboration. Whether acetazolamide improves PH when given over a prolonged period by stimulating ventilation, increasing oxygenation, and/or altering vascular inflammation and remodeling remains to be investigated.

Oxygenation pattern and compensatory responses to hypoxia and hypercapnia following bilateral carotid body resection in humans.

Five years after bilateral carotid body resection (bCBR) performed in four patients, the absence of the hypoxic ventilatory response persisted, suggesting no compensatory regrowth. Breathing hypoxic gas mixtures (15% and 12%) results in a lower (by ∼10%) minimal blood oxygen saturation ( ) in bCBR patients compared to heart failure subjects (CHF) with intact peripheral chemoreceptors. After bCBR, patients were characterized by a greater short-term variability in during mild hypoxia in comparison to the CHF group. The ventilatory response to hypercapnia was preserved following bCBR and was sufficient to maintain minimal at levels comparable to controls when combined with hypoxia. Bilateral CBR - a novel treatment modality for sympathetically mediated diseases - should be used with caution due to the risk of significant desaturation even during mild hypoxia equivalent to that experienced during long-haul air travel and high altitude. Carotid body resection has been proposed as a novel treatment for sympathetically mediated diseases but the safety of bilateral carotid body resection (bCBR) for blood oxygenation during hypoxic stress (long-haul flights or high altitude) remains uncertain. Also unknown is whether central ventilatory drive is sufficient to maintain adequate oxygen saturation when exposed to hypercapnia with concomitant hypoxia. Thus, we administered: 15% O2 , 12% O2 , 5% CO2 /12% O2 and 5% CO2 /95% O2 to a group of four patients with congestive heart failure (65±2.9years) in whom bCBR was performed 5years earlier. Ventilatory, haemodynamic and blood oxygen saturation ( ) responses were recorded non-invasively and compared to control groups with intact peripheral chemoreceptors (both healthy and heart failure patients). First, we confirmed that the ventilatory response to hypoxia was eliminated in patients with bCBR, although the increase in cardiac output was preserved. Second, administration of hypoxic gas mixtures resulted in a larger decrease in and greater short-term variability of the leading to a lower minimal for both hypoxia levels in the bCBR group compared to heart failure controls (82.5±1.2% vs. 91.6±2.3% for 15% O2 and 73.8±4.0% vs. 83.7±3.1% for 12% O2 ). Third, in bCBR patients the ventilatory response to hypercapnia was present and sufficient to maintain a minimal at a level comparable to heart failure controls following administration of 5% CO2 /12% O2 (88.7±4.2% vs. 91.1±2.8%). We conclude that bCBR carries a risk of significant oxygen desaturation even during mild hypoxia. Despite preservation of central chemosensitivity, future studies should focus on unilateral CBR or on pharmacological modulation of peripheral chemosensitivity.

Splenic contraction is enhanced by exercise at simulated high altitude

PurposeSplenic contraction increases circulating hemoglobin (Hb) with advantages during hypoxia. As both hypoxia and exercise have been shown to be important separate triggers of splenic contraction we aimed to investigate if the spleen response to simulated high altitude (HA) is enhanced by superimposing exercise.MethodFourteen healthy volunteers (seven females) performed the following protocol in a normobaric environment sitting on an ergometer cycle: 20 min rest in normoxia; 20 min rest while breathing hypoxic gas simulating an altitude of 3500 m; 10 min exercise at an individually set intensity while breathing the hypoxic gas; 20 min rest in hypoxia; and finally 20 min rest in normoxia. Spleen measurements were collected by ultrasonic imaging and venous Hb measured at the end of each intervention.ResultMean ± SD baseline spleen volume during normoxic rest was 280 ± 107 mL, the volume was reduced by 22% during rest in hypoxia to 217 ± 92 mL (p < 0.001) and by 33% during exercise in hypoxia (189 mL; p < 0.001). Hb was 140.7 ± 7.0 g/L during normoxic rest and 141.3 ± 7.4 g/L during hypoxic rest (NS), but increased by 5.3% during hypoxic exercise (148.6 ± 6.3 g/L; p < 0.001). Spleen volume and Hb were stepwise changed back to baseline at cessation of exercise and return to normoxia.ConclusionSplenic contraction is induced by hypoxia and further enhanced by superimposing exercise, and reduced when exercise ceases, in a step-wise manner, showing that the tonic but partial contraction observed in long-term field expeditions to HA may occur also in the short term. This “graded response” may be beneficial during acclimatization to HA, to cope with moderate chronic hypoxia during rest while allowing additional enhancement of oxygen carrying capacity to overcome short bouts of extreme hypoxia caused by exercise.

Oxygen‐sensitive MRI assessment of tumor response to hypoxic gas breathing challenge

Oxygen-sensitive MRI has been extensively used to investigate tumor oxygenation based on the response (R2 * and/or R1 ) to a gas breathing challenge. Most studies have reported response to hyperoxic gas indicating potential biomarkers of hypoxia. Few studies have examined hypoxic gas breathing and we have now evaluated acute dynamic changes in rat breast tumors. Rats bearing syngeneic subcutaneous (n=15) or orthotopic (n=7) 13762NF breast tumors were exposed to a 16% O2 gas breathing challenge and monitored using blood oxygen level dependent (BOLD) R2 *and tissue oxygen level dependent (TOLD) T1 -weighted measurements at 4.7T. As a control, we used a traditional hyperoxic gas breathing challenge with 100% O2 on a subset of the subcutaneous tumor bearing rats (n=6). Tumor subregions identified as responsive on the basis of R2 * dynamics coincided with the viable tumor area as judged by subsequent H&E staining. As expected, R2 * decreased and T1 -weighted signal increased in response to 100% O2 breathing challenge. Meanwhile, 16% O2 breathing elicited an increase in R2 *, but divergent response (increase or decrease) in T1 -weighted signal. The T1 -weighted signal increase may signify a dominating BOLD effect triggered by 16% O2 in the relatively more hypoxic tumors, whereby the influence of increased paramagnetic deoxyhemoglobin outweighs decreased pO2 . The results emphasize the importance of combined BOLD and TOLD measurements for the correct interpretation of tumor oxygenation properties.

Acute hemodynamic changes by breathing hypoxic and hyperoxic gas mixtures in pulmonary arterial and chronic thromboembolic pulmonary hypertension

BackgroundThere is insufficient evidence to counsel patients with pulmonary hypertension undergoing altitude or air travel. We thus aimed to study hemodynamic response of patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH) during changes in inspiratory oxygen partial pressure. Methods and resultsConsecutive patients undergoing right heart catheterization had hemodynamic assessments whilst breathing ambient air (normoxia, FiO2 0.21, at altitude 490 m), nitrogen-enriched air (hypoxia, FiO2 0.16, simulated altitude 2600 m) and oxygen (hyperoxia, FiO2 1.0), each for 10 min. Data from patients with PAH/CTEPH with mean pulmonary artery pressure (mPAP) ≥25 mmHg, pulmonary artery wedge pressure ≤15 mmHg, were compared to data from controls, mPAP <20 mmHg.28 PAH/CTEPH-patients, 15 women, median age (quartiles) 62y (49;73), mPAP 35 mmHg (31;44), PaO2 7.1 kPa (6.8;9.3) and 16 controls, 12 women, 60y (52;69), mPAP 18 mmHg (16;18), PaO2 9.5 kPa (8.5;10.6) were included. Hypoxia reduced the PaO2 in PAH/CTEPH-patients by median of 2.3 kPa, in controls by 3.3 kPa, difference (95%CI) in change 1.0 (0.02 to 1.9), p < 0.05. Corresponding changes in pulmonary vascular resistance, mPAP and cardiac output were nonsignificant in both groups. Hyperoxia decreased mPAP in PAH/CTEPH-patients by 4 mmHg (2 to 6), in controls by 2 mmHg (0 to 3), difference in change 3 mmHg (0 to 5), p < 0.05. ConclusionsIn patients with PAH/CTEPH, very short-term exposure to moderate hypoxia similar to 2600 m altitude or during commercial air travel did not deteriorate hemodynamics. These results encourage studying the response of PAH/CTEPH during daytrips to the mountain or air travel.

Skeletal Muscle Pyruvate Dehydrogenase Phosphorylation and Lactate Accumulation During Sprint Exercise in Normoxia and Severe Acute Hypoxia: Effects of Antioxidants.

Compared to normoxia, during sprint exercise in severe acute hypoxia the glycolytic rate is increased leading to greater lactate accumulation, acidification, and oxidative stress. To determine the role played by pyruvate dehydrogenase (PDH) activation and reactive nitrogen and oxygen species (RNOS) in muscle lactate accumulation, nine volunteers performed a single 30-s sprint (Wingate test) on four occasions: two after the ingestion of placebo and another two following the intake of antioxidants, while breathing either hypoxic gas (PIO2 = 75 mmHg) or room air (PIO2 = 143 mmHg). Vastus lateralis muscle biopsies were obtained before, immediately after, 30 and 120 min post-sprint. Antioxidants reduced the glycolytic rate without altering performance or VO2. Immediately after the sprints, Ser293- and Ser300-PDH-E1α phosphorylations were reduced to similar levels in all conditions (~66 and 91%, respectively). However, 30 min into recovery Ser293-PDH-E1α phosphorylation reached pre-exercise values while Ser300-PDH-E1α was still reduced by 44%. Thirty minutes after the sprint Ser293-PDH-E1α phosphorylation was greater with antioxidants, resulting in 74% higher muscle lactate concentration. Changes in Ser293 and Ser300-PDH-E1α phosphorylation from pre to immediately after the sprints were linearly related after placebo (r = 0.74, P < 0.001; n = 18), but not after antioxidants ingestion (r = 0.35, P = 0.15). In summary, lactate accumulation during sprint exercise in severe acute hypoxia is not caused by a reduced activation of the PDH. The ingestion of antioxidants is associated with increased PDH re-phosphorylation and slower elimination of muscle lactate during the recovery period. Ser293 re-phosphorylates at a faster rate than Ser300-PDH-E1α during the recovery period, suggesting slightly different regulatory mechanisms.

AltitudeOmics: effect of reduced barometric pressure on detection of intrapulmonary shunt, pulmonary gas exchange efficiency, and total pulmonary resistance.

Blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA) occurs in healthy humans at rest and during exercise when breathing hypoxic gas mixtures at sea level and may be a source of right-to-left shunt. However, at high altitudes, QIPAVA is reduced compared with sea level, as detected using transthoracic saline contrast echocardiography (TTSCE). It remains unknown whether the reduction in QIPAVA (i.e., lower bubble scores) at high altitude is due to a reduction in bubble stability resulting from the lower barometric pressure (PB) or represents an actual reduction in QIPAVA. To this end, QIPAVA, pulmonary artery systolic pressure (PASP), cardiac output (QT), and the alveolar-to-arterial oxygen difference (AaDO2) were assessed at rest and during exercise (70-190 W) in the field (5,260 m) and in the laboratory (1,668 m) during four conditions: normobaric normoxia (NN; [Formula: see text] = 121 mmHg, PB = 625 mmHg; n = 8), normobaric hypoxia (NH; [Formula: see text] = 76 mmHg, PB = 625 mmHg; n = 7), hypobaric normoxia (HN; [Formula: see text] = 121 mmHg, PB = 410 mmHg; n = 8), and hypobaric hypoxia (HH; [Formula: see text] = 75 mmHg, PB = 410 mmHg; n = 7). We hypothesized QIPAVA would be reduced during exercise in isooxic hypobaria compared with normobaria and that the AaDO2 would be reduced in isooxic hypobaria compared with normobaria. Bubble scores were greater in normobaric conditions, but the AaDO2 was similar in both isooxic hypobaria and normobaria. Total pulmonary resistance (PASP/QT) was elevated in HN and HH. Using mathematical modeling, we found no effect of hypobaria on bubble dissolution time within the pulmonary transit times under consideration (<5 s). Consequently, our data suggest an effect of hypobaria alone on pulmonary blood flow. NEW & NOTEWORTHY Blood flow through intrapulmonary arteriovenous anastomoses, detected by transthoracic saline contrast echocardiography, was reduced during exercise in acute hypobaria compared with normobaria, independent of oxygen tension, whereas pulmonary gas exchange efficiency was unaffected. Modeling the effect(s) of reduced air density on contrast bubble lifetime did not result in a significantly reduced contrast stability. Interestingly, total pulmonary resistance was increased by hypobaria, independent of oxygen tension, suggesting that pulmonary blood flow may be changed by hypobaria.

Bubble and macroaggregate methods differ in detection of blood flow through intrapulmonary arteriovenous anastomoses in upright and supine hypoxia in humans

Blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) increases in healthy humans breathing hypoxic gas and is potentially dependent on body position. Previous work in subjects breathing room air has shown an effect of body position when Q̇IPAVA is detected with transthoracic saline contrast echocardiography (TTSCE). However, the potential effect of body position on Q̇IPAVA has not been investigated when subjects are breathing hypoxic gas or with a technique capable of quantifying Q̇IPAVA. Thus the purpose of this study was to quantify the effect of body position on Q̇IPAVA when breathing normoxic and hypoxic gas at rest. We studied Q̇IPAVA with TTSCE and quantified Q̇IPAVA with filtered technetium-99m-labeled macroaggregates of albumin (99mTc-MAA) in seven healthy men breathing normoxic and hypoxic (12% O2) gas at rest while supine and upright. On the basis of previous work using TTSCE, we hypothesized that the quantified Q̇IPAVA would be greatest with hypoxia in the supine position. We found that Q̇IPAVA quantified with 99mTc-MAA significantly increased while subjects breathed hypoxic gas in both supine and upright body positions (ΔQ̇IPAVA = 0.7 ± 0.4 vs. 2.5 ± 1.1% of cardiac output, respectively). Q̇IPAVA detected with TTSCE increased from normoxia in supine hypoxia but not in upright hypoxia (median hypoxia bubble score of 2 vs. 0, respectively). Surprisingly, Q̇IPAVA magnitude was greatest in upright hypoxia, when Q̇IPAVA was undetectable with TTSCE. These findings suggest that the relationship between TTSCE and 99mTc-MAA is more complex than previously appreciated, perhaps because of the different physical properties of bubbles and MAA in solution. NEW & NOTEWORTHY Using saline contrast bubbles and radiolabeled macroaggregrates (MAA), we detected and quantified, respectively, hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) in supine and upright body positions in healthy men. Upright hypoxia resulted in the largest magnitude of Q̇IPAVA quantified with MAA but the lowest Q̇IPAVA detected with saline contrast bubbles. These surprising results suggest that the differences in physical properties between saline contrast bubbles and MAA in blood may affect their behavior in vivo.

Skeletal muscle signaling, metabolism, and performance during sprint exercise in severe acute hypoxia after the ingestion of antioxidants.

The aim of this study was to determine if reactive oxygen species (ROS) could play a role in blunting Thr172-AMP-activated protein kinase (AMPK)-α phosphorylation in human skeletal muscle after sprint exercise in hypoxia and to elucidate the potential signaling mechanisms responsible for this response. Nine volunteers performed a single 30-s sprint (Wingate test) in two occasions while breathing hypoxic gas ([Formula: see text] = 75 mmHg): one after the ingestion of placebo and another following the intake of antioxidants (α-lipoic acid, vitamin C, and vitamin E), with a randomized double-blind design. Vastus lateralis muscle biopsies were obtained before, immediately after, and 30- and 120-min postsprint. Compared with the control condition, the ingestion of antioxidants resulted in lower plasma carbonylated proteins, attenuated elevation of the AMP-to-ATP molar ratio, and reduced glycolytic rate (P < 0.05) without significant effects on performance or V̇o2 The ingestion of antioxidants did not alter the basal muscle signaling. Thr172-AMPKα and Thr184/187-transforming growth factor-β-activated kinase 1 (TAK1) phosphorylation were not increased after the sprint regardless of the ingestion of antioxidants. Thr286-CaMKII phosphorylation was increased after the sprint, but this response was blunted by the antioxidants. Ser485-AMPKα1/Ser491-AMPKα2 phosphorylation increased immediately after the sprints coincident with increased Akt phosphorylation. In summary, antioxidants attenuate the glycolytic response to sprint exercise in severe acute hypoxia and modify the muscle signaling response to exercise. Ser485-AMPKα1/Ser491-AMPKα2 phosphorylation, a known mechanism of Thr172-AMPKα phosphorylation inhibition, is increased immediately after sprint exercise in hypoxia, probably by a mechanism independent of ROS.NEW & NOTEWORTHY The glycolytic rate is increased during sprint exercise in severe acute hypoxia. This study showed that the ingestion of antioxidants before sprint exercise in severe acute hypoxia reduced the glycolytic rate and attenuated the increases of the AMP-to-ATP and the reduction of the NAD+-to-NADH.H+ ratios. This resulted in a modified muscle signaling response with a blunted Thr286-CaMKII but similar AMP-activated protein kinase phosphorylation responses in the sprints preceded by the ingestion of antioxidants.

Susceptibility to high-altitude pulmonary edema is associated with a more uniform distribution of regional specific ventilation.

High-altitude pulmonary edema (HAPE) is a potentially fatal condition affecting high-altitude sojourners. The biggest predictor of HAPE development is a history of prior HAPE. Magnetic resonance imaging (MRI) shows that HAPE-susceptible (with a history of HAPE), but not HAPE-resistant (with a history of repeated ascents without illness) individuals develop greater heterogeneity of regional pulmonary perfusion breathing hypoxic gas (O2 = 12.5%), consistent with uneven hypoxic pulmonary vasoconstriction (HPV). Why HPV is uneven in HAPE-susceptible individuals is unknown but may arise from regionally heterogeneous ventilation resulting in an uneven stimulus to HPV. We tested the hypothesis that ventilation is more heterogeneous in HAPE-susceptible subjects (n = 6) compared with HAPE-resistant controls (n = 7). MRI specific ventilation imaging (SVI) was used to measure regional specific ventilation and the relative dispersion (SD/mean) of SVI used to quantify baseline heterogeneity. Ventilation heterogeneity from conductive and respiratory airways was measured in normoxia and hypoxia (O2 = 12.5%) using multiple-breath washout and heterogeneity quantified from the indexes Scond and Sacin, respectively. Contrary to our hypothesis, HAPE-susceptible subjects had significantly lower relative dispersion of specific ventilation than the HAPE-resistant controls [susceptible = 1.33 ± 0.67 (SD), resistant = 2.36 ± 0.98, P = 0.05], and Sacin tended to be more uniform (susceptible = 0.085 ± 0.009, resistant = 0.113 ± 0.030, P = 0.07). Scond was not significantly different between groups (susceptible = 0.019 ± 0.007, resistant = 0.020 ± 0.004, P = 0.67). Sacin and Scond did not change significantly in hypoxia (P = 0.56 and 0.19, respectively). In conclusion, ventilation heterogeneity does not change with short-term hypoxia irrespective of HAPE susceptibility, and lesser rather than greater ventilation heterogeneity is observed in HAPE-susceptible subjects. This suggests that the basis for uneven HPV in HAPE involves vascular phenomena.NEW & NOTEWORTHY Uneven hypoxic pulmonary vasoconstriction (HPV) is thought to incite high-altitude pulmonary edema (HAPE). We evaluated whether greater heterogeneity of ventilation is also a feature of HAPE-susceptible subjects compared with HAPE-resistant subjects. Contrary to our hypothesis, ventilation heterogeneity was less in HAPE-susceptible subjects and unaffected by hypoxia, suggesting a vascular basis for uneven HPV.

Hypoxic training increases maximal oxygen consumption in Thoroughbred horses well-trained in normoxia.

ABSTRACTHypoxic training is effective for improving athletic performance in humans. It increases maximal oxygen consumption (V̇O2max) more than normoxic training in untrained horses. However, the effects of hypoxic training on well-trained horses are unclear. We measured the effects of hypoxic training on V̇O2max of 5 well-trained horses in which V̇O2max had not increased over 3 consecutive weeks of supramaximal treadmill training in normoxia which was performed twice a week. The horses trained with hypoxia (15% inspired O2) twice a week. Cardiorespiratory valuables were analyzed with analysis of variance between before and after 3 weeks of hypoxic training. Mass-specific V̇O2max increased after 3 weeks of hypoxic training (178 ± 10 vs. 194 ± 12.3 ml O2 (STPD)/(kg × min), P<0.05) even though all-out training in normoxia had not increased V̇O2max. Absolute V̇O2max also increased after hypoxic training (86.6 ± 6.2 vs. 93.6 ± 6.6 l O2 (STPD)/min, P<0.05). Total running distance after hypoxic training increased 12% compared to that before hypoxic training; however, the difference was not significant. There were no significant differences between pre- and post-hypoxic training for end-run plasma lactate concentrations or packed cell volumes. Hypoxic training may increase V̇O2max even though it is not increased by normoxic training in well-trained horses, at least for the durations of time evaluated in this study. Training while breathing hypoxic gas may have the potential to enhance normoxic performance of Thoroughbred horses.

Acute Activation of the Peripheral Chemoreceptors Briefly Induces Cutaneous Vasoconstriction

Recent evidence indicates that five minutes of breathing hypoxic gas elicits cutaneous vasodilation. However, it is unclear if skin blood flow is influenced by a brief hypoxic exposure. PURPOSE: We tested the hypothesis that cutaneous vasodilation is increased following a brief hypoxic exposure. METHODS: Seven healthy participants (2 women, 25 ± 2 years, BMI 26 ± 3 kg/m2) breathed 4–6 breaths of 100% nitrogen. We continuously measured skin blood flow on the ventral side of the forearm (laser Doppler), arterial oxygen saturation (finger pulse oximeter), mean arterial pressure (Finometer), and heart rate (ECG) at baseline and following the hypoxic exposure for one minute, during which data were analyzed in 15 s time bins. Skin blood flow was also normalized to mean arterial pressure (MAP) and expressed as a percentage of the local heating induced maximal cutaneous vascular conductance (%CVCmax). RESULTS: Arterial oxygen saturation was lower at 45 s (89 ± 7%; P < 0.05) and 60 s (90 ± 5%; P < 0.05) vs. baseline (97 ± 1%). Skin blood flow was lower 15 s after the hypoxic exposure when compared to baseline (4.2 ± 0.9 vs. 5.1 ± 0.9 PU, P = 0.001). MAP was greater at 15 s vs. baseline (94 ± 7 vs. 88 ± 7 mmHg; P < 0.05) and returned to baseline values at 30 s. %CVCmax was reduced within the first 15 s following the hypoxic exposure compared to baseline (4.3 ± 1.0 vs. 5.6 ± 1.2%; P < 0.05). Skin blood flow and %CVCmax returned to baseline values 30 s following the hypoxic exposure. Heart rate was significantly greater than baseline (64 ± 9 bpm) at 15 s (76 ± 13 bpm; P < 0.01), 30 s (76 ± 14 bpm; P < 0.01), 45 s (69 ± 11 bpm; P < 0.01), and 60 s (67 ± 11 bpm; P < 0.05). CONCLUSIONS: Contrary to our hypothesis, a brief hypoxic exposure induces cutaneous vasoconstriction and attenuates skin blood flow. This suggests that activation of the peripheral chemoreceptors acutely lowers skin blood flow.

Interactive effects of hypoxia, carbon monoxide and acute lung injury on oxygen transport and aerobic capacity

This study determined how breathing hypoxic gas, reducing circulatory capacitance for O2 by breathing CO, and impairing pulmonary gas exchange by acutely injuring the lungs interact to limit cardiopulmonary O2 delivery, O2 extraction and maximal aerobic capacity (VO2max). Five goats ran on a treadmill at VO2max following oleic-acid induced acute lung injury that impaired pulmonary gas exchange, after partial recovery or with no acute lung injury. Goats breathed normoxic or hypoxic inspired gas fractions (FIO2 0.21 or 0.12) with and without small amounts of CO to maintain carboxyhemoglobin fractions (FHbCO) of 0.02 or 0.30. With the exception of elevated FHbCO with acute lung injury (P=0.08), all combinations of hypoxia, elevated FHbCO and acute lung injury attenuated the reduction in VO2max by 15–27% compared to the sum of each treatment’s individual reduction in VO2max when administered separately. Simultaneous administration of two treatments attenuated the reduction in VO2max by attenuating the decrease in cardiopulmonary O2 delivery, not synergistically increasing O2 extraction.