Hypoxic Gas Research Articles

NIMG-23. A NOVEL APPROACH TO PERFUSION MRI STUDIES IN BRAIN TUMOR PATIENTS USING ENDOGENOUS DEOXYHEMOGLOBIN AS A CONTRAST AGENT: A PROOF-OF-CONCEPT STUDY

Abstract BACKGROUND Assessment of resting perfusion in brain tumors is clinically relevant and relies on dynamic susceptibility contrast magnetic resonance imaging using gadolinium contrast. Preliminary studies have introduced the use of controlled hemoglobin desaturation by means of a transient hypoxic stimulus during echo-planar imaging(EPI) as a surrogate for gadolinium for resting perfusion assessment in healthy subjects. In this proof of concept study, we investigated whether this approach is feasible in brain tumors and warrant further validation. METHODS A computer controlled gas blender was used to induce transient and standardized hypoxic stimulus in isocapnic conditions during EPI acquisition in a heterogenous cohort of tumor patients. The induced blood-oxygen-level-dependent(BOLD) signal changes determined by transit of a bolus of deoxygenated blood in the brain vasculature were used as a surrogate of gadolinium to calculate cerebral blood volume(CBV), cerebral blood flow(CBF) and mean transit time(MTT) using a global arterial input functions obtained through the BOLD signal measured over the middle cerebral artery as previously described by Poublanc et al. Perfusion parameters were calculated in the whole-brain voxel-by-voxel and in automatically segmented region of interest(ROI) using SPM, AFNI, Verbena softwares and MATLAB in-house written scripts. RESULTS Nine patients were included. MTT, rCBV, rCBF were calculated voxel-per-voxel. Obtained maps were overlayed on the co-registered T1 MRI scans and compared to T1CE and FLAIR to identify perfusion patterns in tumor ROIs (contrast enhancement, edema, necrosis). The deoxy-hemoglobin BOLD MRI perfusion were compared to clinical DSC-MRI when available and showed high qualitative agreement. CONCLUSION Transient and precise hemoglobin desaturation by controlled hypoxic gas modulation is safe and repeatable in brain tumor patients. The induced BOLD signal change allows measurement of resting perfusion, which qualitatively closely mimic gadolinium perfusion in different brain tumors. Deoxyhemoglobin-based perfusion warrant further quantitative validation against gadolinium in a larger cohort of heterogenous tumor patients.

Reaction of young physically active men with early repolarization phenomena on a cycle of inhalations of a hypoxic gas mixture

Aim: To examine a reaction of young physically active men with early repolarization phenomena (ERP) on an inhalation of a hypoxic gas mixture (IHGM).Material and Methods.17 men (6 with ERP & 11 without it) participated in our study. ECG, echocardiography, clinical blood test and erythropoietin blood test were carried out to every of them initially and on the 1-st and 10-th days after the IHGM.Results. It was found that end systolic volume was 13,8% more (р = 0,01) and ejection fraction was 8% less (р = 0,01) in ERP group than in non ERP group. These indicators were not change after IHGM. In ERP group on 1-st day after IHGM erythropoietin concentration was 79% more (р = 0,027) and on a 10-th day was 64% more (р = 0,003) than in non-ERP group. In ERP group high fluorescent reticulocyte count on a 1-st day after IHGM was 69% more (р = 0,03) and middle fluorescent reticulocyte count on a 10-th day after IHGM was 13% more (р = 0,04) than in non-ERP group. On a 10-th day after IHGM hematocrit and hemoglobin concentration were 5% (р = 0,01) and 12% (р = 0,01) less than in non ERP group.Conclusion. Thus, men with ERP have a pronounced reaction of the erythropoiesis system on normobaric hypoxia.

Metabolic and hormonal responses to acute high-load resistance exercise in normobaric hypoxia using a saturation clamp.

We assessed metabolic and hormonal responses to high-load resistance exercise under varying normobaric hypoxia conditions with a saturation clamp. Employing a counterbalanced, crossover test design, ten well-trained men participated in three exercise trials with normoxic or hypoxic gas mixtures to maintain arterial oxygen saturation at -90% and 80% [moderate (MH) and severe (SH) hypoxia, respectively]. The resistance exercise regimen comprised five sets of 10 repetitions of barbell back squats at 70% of one repetition maximum, with 1-min rest between sets. Metabolic and hormonal responses were measured before normoxia or hypoxia exposures (Pre 1), 15min after the exposures (Pre 2), and at 0-, 15-, and 30-min post-exercises (T0, T15, and T30, respectively). Compared to Pre 2, blood lactate concentrations and growth hormone values were elevated at T0, T15, and T30 (p ≤ 0.001), while testosterone values increased at T0 in all conditions (p ≤ 0.009). Epinephrine values increased significantly from Pre 2 to T0 in SH only (p < 0.001). SH had significantly higher blood lactate concentrations (p = 0.023), growth hormone (p = 0.050), and epinephrine (p = 0.020) values at T30 compared to NM. Cortisol values were elevated above Pre 2at T15 in MH and SH, while lower testosterone values were noted at T0 and T15 for SH compared to NM and MH (all p ≤ 0.05). Severe simulated hypoxia, achieved through a saturation clamp during barbell back squats, may enhance metabolic and hormonal responses, particularly 30min post-session. Nevertheless, the acute effects of hypoxia exposure seem to be overridden by the impact of high-load resistance exercise.

Effect of interval hypoxytherapy on the immune status of hypertensive patients

In recent years, the role of sluggish nonspecific inflammation in the pathogenesis of hypertension has been proven. Oxidative stress that develops in hypertension leads to damage of endothelial glycocalyx with impaired barrier and adaptive functions of endothelium. Activation of transcription factor NF-kB leads to increased synthesis of free oxygen radicals, adhesion molecules (VCAM-1, ICAM-1, P-selectin, E-selectin) and proinflammatory cytokines (TNFα, IL-1, IL-6), triggering the inflammatory process in the endothelium. Modern antihypertensive drugs, affecting various pathogenetic mechanisms of arterial hypertension development, do not fully affect the immune component of arterial hypertension. Therefore, the search for various methods affecting the immunologic reactivity of hypertensive patients remains relevant in our time. The aim of the study was to reveal the effect of interval hypoxytherapy on the state of immunologic reactivity of patients with hypertension stage I. One hundred seventy male patients of 30-45 years old (mean age 38.36±1.64 years) with hypertension stage I (n = 170) who underwent combined treatment including drug therapy and normobaric interval hypoxic therapy in hypoxia-normoxia mode (oxygen content in hypoxic gas mixture was 20.9%) were examined. Indices of redox status and immunologic reactivity before and after interval hypoxytherapy were studied. Having a significant antioxidant effect, interval hypoxytherapy led to the subsidence of oxidative stress, which was indicated by an increase in the activity of superoxide dismutase and glutathione peroxidase in blood erythrocytes and a decrease in the content of malonic dialdehyde in blood as a result of a decrease in the generation of free oxygen radicals and suppression of lipid peroxidation processes. Interval hypoxytherapy resulted in a statistically significant increase in the initially decreased content of CD3+T lymphocytes (p 0.05), CD3+CD4+T lymphocytes (p 0.02), CD3+CD8+T lymphocytes (p 0.02). Initially increased number of B-lymphocytes CD19+, CD16+ lymphocytes, CD95+ lymphocytes significantly decreased. An important result of interval hypoxytherapy was a pronounced anti-inflammatory effect: statistically significant decrease in the content of pro-inflammatory interleukins IL-1β (p 0.02), IL-6 (p 0.01) and increase in the content of anti-inflammatory cytokines IL-4 (p 0.005) and IL-10 (p 0.005), which led to the subsidence of sluggish nonspecific inflammation. Suppression of oxidative stress and normalization of immunological reactivity of hypertensive patients after interval hypoxytherapy led to the subsidence of sluggish nonspecific inflammation, reduction of endothelial dysfunction and restoration of the structure and tone of the vascular wall with a decrease in blood pressure and improvement of the clinical course of hypertension.

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.

A novel rat lung transplantation model using venoarterial extracorporeal membrane oxygenation support

ObjectivesExtracorporeal membrane oxygenation (ECMO) has become an important life support technique during lung transplantation. We aimed to develop a rat model for lung transplantation using venoarterial (VA) ECMO support. MethodsAdult male Sprague-Dawley rats weighing 400 to 450 g were used in this study. ECMO circuits were created by obtaining venous access from the femoral vein with subsequent extracorporeal oxygen exchange, which was then returned to the circulatory system through the left carotid artery (ie, VA-ECMO). Simultaneously, the donor lungs were retrieved and immersed in cold, low-potassium dextran lung preservation solution. Orthotopic left lung transplantation supported by VA-ECMO was performed. Thereafter, a respiratory failure rat model was constructed using ventilation with a hypoxic and hypercapnic gas mixture, consisting of 6% oxygen, 8% carbon dioxide, and 86% nitrogen, before lung transplantation. Similarly, left lung transplantation supported by VA-ECMO was performed in rats with respiratory failure. Arterial blood gas levels were measured at designated time points throughout the experiment. ResultsWe found that VA-ECMO provided sufficient oxygenation and carbon dioxide removal to allow for smooth left lung transplantation in healthy rats and those with respiratory failure. ConclusionsWe established a rat model for lung transplantation using VA-ECMO. Left lung transplantation using VA-ECMO support is also feasible and safe in rat models of respiratory failure. These models provide efficient and economical models for translational medicine for lung transplantation using ECMO. Moreover, it will be invaluable to evaluate the physiological and pathophysiological roles of ECMO during lung transplantation.

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.

Performance of a Wearable Ring in Controlled Hypoxia: A Prospective Observational Study.

Over recent years, technological advances in wearables have allowed for continuous home monitoring of heart rate and oxygen saturation. These devices have primarily been used for sports and general wellness and may not be suitable for medical decision-making, especially in saturations below 90% and in patients with dark skin color. Wearable clinical-grade saturation of peripheral oxygen (SpO2) monitoring can be of great value to patients with chronic diseases, enabling them and their clinicians to better manage their condition with reliable real-time and trend data. This study aimed to determine the SpO2 accuracy of a wearable ring pulse oximeter compared with arterial oxygen saturation (SaO2) in a controlled hypoxia study based on the International Organization for Standardization (ISO) 80601-2-61:2019 standard over the range of 70%-100% SaO2 in volunteers with a broad range of skin color (Fitzpatrick I to VI) during nonmotion conditions. In parallel, accuracy was compared with a calibrated clinical-grade reference pulse oximeter (Masimo Radical-7). Acceptable medical device accuracy was defined as a maximum of 4% root mean square error (RMSE) per the ISO 80601-2-61 standard and a maximum of 3.5% RMSE per the US Food and Drug Administration guidance. We performed a single-center, blinded hypoxia study of the test device in 11 healthy volunteers at the Hypoxia Research Laboratory, University of California at San Francisco, under the direction of Philip Bickler, MD, PhD, and John Feiner, MD. Each volunteer was connected to a breathing apparatus for the administration of a hypoxic gas mixture. To facilitate frequent blood gas sampling, a radial arterial cannula was placed on either wrist of each participant. One test device was placed on the index finger and another test device was placed on the fingertip. SaO2 analysis was performed using an ABL-90 multi-wavelength oximeter. For the 11 participants included in the analysis, there were 236, 258, and 313 SaO2-SpO2 data pairs for the test device placed on the finger, the test device placed on the fingertip, and the reference device, respectively. The RMSE of the test device for all participants was 2.1% for either finger or fingertip placement, while the Masimo Radical-7 reference pulse oximeter RMSE was 2.8%, exceeding the standard (4% or less) and the Food and Drug Administration guidance (3.5% or less). Accuracy of SaO2-SpO2 paired data from the 4 participants with dark skin in the study was separately analyzed for both test device placements and the reference device. The test and reference devices exceeded the minimum accuracy requirements for a medical device with RMSE at 1.8% (finger) and 1.6% (fingertip) and for the reference device at 2.9%. The wearable ring meets an acceptable standard of accuracy for clinical-grade SpO2 under nonmotion conditions without regard to skin color. ClinicalTrials.gov NCT05920278; https://clinicaltrials.gov/study/NCT05920278.

Carotid body-mediated peripheral chemoreflex drive sets exercise tolerance in adult mice

Exercise tolerance (EXT) has been primarily explained by individual body/physical features, partly neglecting the complex cardiorespiratory response needed to cope with exercise. While in healthy conditions most people display good EXT, the presence of exercise intolerance (EXINT) has also been documented. More importantly, EXINT increases in several pathological conditions. Despite the precise mechanism underpinning EXINT is not fully understood. It is well known that exaggerated sympathetic outflow to skeletal muscle impairs proper muscle function and that activation of the carotid body (CB) chemoreceptors elicits a robust increase in sympathetic activity. Therefore, it is plausible to hypothesize that an exaggerated CB-chemoreflex drive may impair EXT. Accordingly, we aimed to determine: i) differences in CB-chemoreflex drive between EXT and EXINT mice, and ii) the role played by the CB-chemoreflex on setting EXINT. Male C57/BL6 mice (n=24) were used to study chemoreflex function using whole-body plethysmography. Exercise tolerance/intolerance was determined by a three-day maximal performance exercise test. CB-chemoreflex drive was assessed by allowing the mice to breathe hypoxic gas (FiO2~5%). We found that the incidence of EXINT among healthy mice was ~30%. Notably, compared to EXT mice, animals with EXINT exhibited a heightened CB-mediated chemoreflex drive as evidenced by larger increases in the hypoxic ventilatory responses (HVR). Indeed, HVR was ~1.4-fold larger in EXINT compared to the values obtained in EXT mice (VE: 17 ± 1.6 vs. 12 ± 3.2, mL/min, EXINT vs. EXT, respectively). Then, we tested whether high chemoreflex drive was associated with EXINT. For this, we reduced the chemosensory drive by using the Dejour´s maneuver (FiO2~35%) while EXINT mice continues to exercise. We found that chemoreflex unloading in EXINT markedly improves exercise tolerance. Indeed, exercise tolerance was almost fully restored by reducing chemoreflex drive in EXINT. Our findings underscore the potential role of heightened CB-chemoreflex on setting exercise tolerance. Supported by Fondecyt 1220950. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Male histone deacetylase 6 (HDAC6) knockout mice have enhanced ventilatory responses to hypoxic challenge.

Histone deacetylase 6 (HDAC6) is a class II histone deacetylase that is predominantly localized in the cytoplasm of cells. HDAC6 associates with microtubules and regulates acetylation of tubulin and other proteins. The possibility that HDAC6 participates in hypoxic signaling is supported by evidence that 1) hypoxic gas challenges cause microtubule depolymerization, 2) expression of hypoxia inducible factor alpha (HIF-1α) is regulated by microtubule alterations in response to hypoxia, and 3) inhibition of HDAC6 prevents HIF-1α expression and protects tissue from hypoxic/ischemic insults. The aim of this study was to address whether the absence of HDAC6 alters ventilatory responses during and/or after hypoxic gas challenge (10% O2, 90% N2 for 15min) in adult male wildtype (WT) C57BL/6 mice and HDAC6 knock-out (KO) mice. Key findings were that 1) baseline values for frequency of breathing, tidal volume, inspiratory and expiratory times, and end expiratory pause were different between knock-out mice and wildtype mice, 2) ventilatory responses during hypoxic challenge were more robust in KO mice than WT mice for recorded parameters including, frequency of breathing, minute ventilation, inspiratory and expiratory durations, peak inspiratory and expiratory flows, and inspiratory and expiratory drives, and 3) responses upon return to room-air were markedly different in KO compared to WT mice for frequency of breathing, minute ventilation, inspiratory and expiratory durations, end expiratory pause (but not end inspiratory pause), peak inspiratory and expiratory flows, and inspiratory and expiratory drives. These data suggest that HDAC6 may have a fundamentally important role in regulating the hypoxic ventilatory response in mice.

Presurgical Use of Hypoxic Mixture for Systemic Perfusion Improvement in Neonates With Complex Congenital Heart Disease: A Systematic Review and Meta-Analysis.

Oxygen therapy is essential for the survival of preterm babies and critically ill newborns; however, it has the potential to cause harm through hypoxemia or hyperoxemia. Newborns with complex congenital heart diseases (CHD) suffer from oxygen fluctuations due to the disease and its treatments, altering pre and postnatal development. The objective of this study is to evaluate the evidence for using a hypoxic mixture to decrease pulmonary over-circulation and improve systemic perfusion before surgical interventions in newborns with complex CHD that course with pulmonary over-circulation and systemic hypoperfusion. A search was conducted in PubMed, EMBASE, LILACS, Scielo, Taylor and Francis, SAGE, and Science Direct databases from 2000 to 2022 by two independent authors, including articles with hypoxic mixture treatment in observational studies or trials, with pre-treatment and post-treatment measurements in the same patient, or two groups or more comparisons. Six articles were selected, with a total of 75 patients. The primary outcome was improved systemic circulation and decreased pulmonary over-circulation measured directly with Qp/Qs and indirectly with oxygen saturation and cerebral near-infrared spectroscopy (NIRS). In addition, we performed a meta-analysis for oxygen saturation and cerebral NIRS. Oxygen saturation was the value uniformly reported; three studies reported a significantly lower oxygen saturation after the hypoxic mixture. The cerebral NIRS was measured in 4 studies, with inconsistent results. After using the hypoxic mixture, the Qp/Qs calculation was lower in the two studies but was not statistically significant. The meta-analysis for oxygen saturation showed a fixed effect post-hypoxic therapy of -0.7 (-1.06; -0.35), p < 0.001. The meta-analysis of two studies that measured cerebral NIRS did not show a statistically significant difference at 12 and 24 hours. In conclusion, this is the first systematic review and meta-analysis regarding the pre-operative use of hypoxic gas mixtures for newborns with complex congenital heart disease. Treatment results in lower oxygen saturations, but there is a lack of evidence of improvement in systemic perfusion. The utilization of this therapy is controversial, and better evidence is necessary.

Quadriceps fatigue during hypoxic and ischemic knee-extension exercise is similar in males and females.

Hypoxia is known to increase muscle fatigue via both central and peripheral mechanisms. Females are typically less fatigable than males during isometric fatiguing contractions due to greater peripheral blood flow. However, sex differences in fatigue are blunted during dynamic fatiguing tasks. Thus, this study determined the interactions of sex and hypoxia on knee extensor muscle contractile function during a dynamic, ischemic fatiguing contraction. Electrical stimulation was used to determine contractile properties of the knee extensor muscles in eight males and eight females before and after an ischemic, dynamic fatiguing task while inspiring room air or a hypoxic gas mixture (10% O2:90% N2). Fatigue (assessed as time-to-task failure) was ∼10% greater during the hypoxic condition (94.3 ± 33.4 s) compared with normoxic condition (107.0 ± 42.8 s, P = 0.041) and ∼40% greater for females than males (77.1 ± 18.8 vs. 124.2 ± 38.7, P < 0.001). Immediately after the dynamic fatiguing task, there were reductions in maximal voluntary contraction force (P = 0.034) and electrically evoked twitch force (P < 0.001), and these reductions did not differ based on sex or inspirate. Cerebral tissue oxygenation showed a significant interaction of time and inspirate (P = 0.003) whereby it increased during normoxia and remained unchanged in hypoxia. No sex-related differences in the changes of cerebral tissue oxygenation were observed (P = 0.528). These data suggest that acute hypoxia increases central fatigue during ischemic single-leg exercise resulting in earlier exercise termination, but the effect does not differ based on sex.NEW & NOTEWORTHY Hypoxia exacerbates fatigue via central mechanisms after ischemic single-leg exercise. The greater fatigue observed during ischemic dynamic fatiguing exercise with hypoxia inspirate did not differ between the sexes. Hypoxia-induced central limitations are present in acute ischemic exercise and do not appear different in males and females.

Generalized Calibrated BOLD fMRI for the Relationship between Cerebral Metabolism and Hypertensive Status

AbstractBackgroundElevated blood pressure levels during mid‐life have been found to be associated with an increased susceptibility to developing dementia later in life, particularly vascular dementia. Quantitative imaging biomarkers, such as Oxygen Extraction Fraction (OEF) and Cerebral Metabolism Rate of Oxygen (CMRO2), can be indicators of impaired cerebral metabolism. Calibrated Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) is a multi‐parametric approach utilizing hyperoxic and hypercapnic gas challenges (Figure 1). The impact of hypertension on OEF and CMRO2 has been investigated.MethodA cohort of 84 participants was recruited from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core (Table 1). Among all the covariates, participants with prediabetes and diabetes were considered diabetic, and those who exhibited high blood pressure or were using medication to manage hypertension were classified as hypertensive. The MRI was conducted using a 3T Siemens Skyra MRI scanner with a 32‐channel head coil. Dynamic Pseudocontinuous Arterial Spin Labeling (PCASL) was used to acquire cerebral blood flow (CBF) and BOLD images during respiratory challenges with an end‐tidal forcing system. The ROI values in the frontal lobe, temporal lobe, parietal lobe, and occipital lobe regions were chosen. The correlation between hypertensive status and OEF and CMRO2 in the ROI was analyzed with a linear mixed model, with covariates of age, sex, cognitive status, APOE genotype, diabetic status, and hypertensive status.ResultA negative correlation was found between CBF, OEF, and CMRO2 with hypertensive status in frontal lobe region (Figure 2). Statistical significance was observed for OEF and CMRO2 (p = 0.049 and p = 0.028, respectively), indicating the potential influence of hypertensive status on these biomarkers.ConclusionThe study concludes that there is a significant negative association between hypertensive status and both OEF and CMRO2, particularly in the frontal lobe region. The observed reduction in OEF and CMRO2 is not solely due to decreased CBF, but rather complex and multifactorial processes involving vascular remodeling and altered oxygen metabolism. Additional research is necessary to fully understand the underlying pathophysiological mechanisms that link hypertension to decreased OEF and CMRO2, particularly in the context of regional specificity.

The influence of combined effects of hyperbaria and hyperoxia on human heart rate variability during exercise strain

With the participation of 8 male volunteers, the dynamics of values of heart rate autonomic regulation were studied at response to physical load on a bicycle ergometer twice: both respirating by the room air under normobaric environment and simulating effects of the altered hyperoxic respiratory gas mixture (HRGM) by the rebreathe respiration methods from a rebreather at the high-pressure chamber (at «depth» 7 m). The devices and methods of Holter electrocardiogram monitoring were used under 24 hours research. The specialized software to analyze the data was used. The electrocardiogram (ECG) and calculated time series of cardiac intervals data obtained were subjected to mathematical processing to calculate statistical and spectral values of heart rate variability (HRV). Additionally, the geometric and nonlinear analysis methods of HRV were investigated. It has been established that influencing factors (compound and pressure of the HRGM) affect the autonomic regulation of heartbeats both at rest and during physical load. Clinical practitioners the HRV values are studied at rest and during strictly regulated tests, i.e. in stationary conditions. The analysis of non-stationary processes, for example, when it is necessary to continuously analyze data, the so-called transient processes under increasing psychological stress, to assess changes in the autonomic regulation of the heart during breathing of gas mixtures with different compositions (hypoxic therapy, hyperbaric oxygenation, etc.), and, especially during physically upload are used the methods of nonlinear and geometric analysis of HRV that are independent of the degree of nonstationary processes and, to some extent, of artifactual cardiac intervals. During the breathing the respiratory gas mixtures with an increased substance of O2 under conditions of high pressure, the activity of the parasympathetic branches of the autonomic nervous system (ANS) significantly increases. The nonlinear dynamics indexes reflect significant differences in the activity of autonomic components under experimental conditions in the direction of strengthening the parasympathetic links of the ANS. The use of nonlinear analysis values is more acceptable when evaluating obtained of non-stationary processes. In general, the study confirms that the regulatory response to the effects of hyperbaria and hyperoxia when performing a bicycle ergometer test with stepwise increase exercise strain is manifested by the prevalence of the activity of the parasympathetic part of the ANS autonomic regulation of cardiac rhythm compared to regular room air and barometric pressure.

On the Relationship of Natural and Modified Radioresistance with Mast Cell Reactivity

This study was caused by accumulation of the data concerning: 1) relationship between the general reactivity of the body and radioresistance; 2) essential role of mast cells in the formation of radiobiological effects; 3) significant individual features of body radioresistance. Purpose of the study was to identify the relationship of radioresistance indicators with the state of body reactivity, manifested by constitutionally determined features of connective tissue mast cells. Natural radioresistance and modifying effect of hypoxia, hyperoxia and indralin radioprotector were considered. The study was performed on 369 white male rats weighing 215–240 g. To determine the individual characteristics of radioresistance, total and cranio-caudal irradiation of animals was performed. As a hypoxic test, hypoxic gas mixture with 8% oxygen content was used. The criteria of radioresistance were 5- and 30-day survival, weight loss, early transient disability. Index of reactivity of skin mast cells was considered as the diagnostic sign. Relationship features between the level of mast cell reactivity and radioresistance indicators were revealed. It has been shown that the minimum level of natural radioresistance is typical for animals with a high index of mast cell response to hypoxia. The modifying effect of hypoxia during irradiation was manifested in all animals. Also, the highest level of modified radioresistance was observed in rats with average values of the mast cell reactivity index. At the same time, When indralin was used, its radioprotective effect was most pronounced in the group of animals with the maximum reaction of mast cells. The radiomodifying effect of oxygen is mostly expressed in rats with the maximum values of the mast cell reactivity index and is characterized by a decrease in 5-day survival and average life expectancy. The relationship between the characteristics of mast cells and radioresistance can serve as a basis for the development of methods for predicting individual natural and modified radioresistance.

Combined altitude depleted oxygen vis-à-vis hypobaric hypoxia: Efficacy in hypoxia indoctrination

Introduction: The Combined Altitude and Depleted Oxygen (CADO), as an alternate method for hypoxia indoctrination, has the dual advantages of exposing to an altitude less than the threshold for decompression sickness, a known risk in training using Hypobaric Hypoxia (HH) while accounting for the pressure changes due to altitude, a limitation of using normobaric hypoxia. Objectives: This study aimed to evaluate the efficacy of CADO in hypoxia indoctrination by comparing it with the time-tested gold standard method of HH. Material and Methods: Forty subjects were exposed to both CADO and HH, simulating 25,000 ft for a maximum period of 5 min. CADO was achieved by combining exposure to an altitude of 10,000 ft in the hypobaric chamber and breathing a hypoxic gas mixture of 10.3% oxygen and 89.7% nitrogen. Physiological parameters (oxygen saturation, heart rate, and respiratory rate) and psychomotor performance (dual task test component of pSuMEDhA) were compared between the two exposures. The incidence and severity of subjective symptoms were also compared at the end of exposures. Results: No significant difference was observed in the physiological parameters and psychomotor performance during the two exposures. Out of the 24 common symptoms of hypoxia assessed, there was a higher incidence of 20 symptoms in subjects exposed to HH compared to CADO. The severity of 15 symptoms was also found to be significantly greater (P &lt; 0.05) in subjects exposed to HH. Conclusion: The similarity of physiological changes in CADO and HH shows the potential application of CADO as a tool for hypoxia demonstration. However, in view of decreased incidence and severity of subjective symptoms in CADO compared to HH, CADO cannot be considered equivalent to the gold standard (HH) for hypoxia indoctrination for high-risk individuals, namely, aircrew and combat free fall personnel. CADO as a modality can be used as a tool for hypoxia demonstration for persons not involved in flying duties and for high-altitude research.

0050 Pediatric OSA and neurodevelopment

Abstract Introduction Pediatric OSA and its associated sleep disorders occur in up to 7% of children. Whereas the sequelae of the disease are well characterized, the underpinnings of its phenotypes are poorly understood. This is mainly because of a lack of comprehensive model of the disease in the young. Here I present the neurobehavioral phenotype of pediatric OSA utilizing a preclinical murine model. Methods This proposal represents a departure from prior models and is embedded in the sculpting of the IH model. 1) Human polysomnographic data: We studied human data in children with OSA 2) Murine oximetry data: we create murine oximetry curves 3) Cross Species Curve Fitting: We cross fit those across species 4) Optimization of hypoxic gas throughputs: We then optimized this for the hypoxia chamber we are using Results We examined 4 behavioral tasks over a number of time periods to establish the temporality needed for hippocampal task ablation, as the hippocampus is the center of learning and memory in mammals. 2 tasks were hippocampal dependent: a) Novel object recognition b) Object place recognition. 2 tasks were hippocampal independent: 1) Hot plate: 2) OFA. We utilized 3 time periods initially: exposure from p14 to p23 (9 days acute), to p35 (21 days intermediate), and p70 (56 days, chronic). There was no deterioration in hippocampal tasks from p14 to p35, however at p70 we noted task ablation. We therefore systematically worked backwards, until we discovered the 'tipping point' where hippocampal task ablation is observed is p49 (35 days of exposure). Prior to this, we note no task ablation, however after this time point, hippocampal task ablation is preserved. Conclusion We have demonstrated a tractable, temporal model for pediatric OSA over a systematic set of time points to show when hippocampal deficits from the OSA stimulus manifest phenotypically. We have further isolated these deficits to the hippocampus of developing mice, which is the mammalian center of learning, memory, and retrieval. Support (if any) Arvind has previously received support from AASM and BCM OOR. He is currently supported by 1K08HL161263-01 from NHLBI.

Neural and physiological state dependency of opioid induced respiratory depression

Opioid induced respiratory depression (OIRD) is the major cause of death associated with opioid overdose. Within the brainstem, respiratory activity is generated within the ventrolateral medulla in an opioid-sensitive region known as the PreBötzinger Complex (PreBötC). Within the PreBötC a heterogenous network of neurons under continuous influence by excitatory and inhibitory neuromodulators culminate to form synchronized bursting that results in inspiratory activity. Additionally, the PreBötC network dynamically interacts with the physiological processes that give rise to ventilation. Understanding the interplay between neural and physiological states of the in-vivo system will be key to overcoming OIRD. Here, we tested whether increasing the excitatory state of the PreBötC in-vivo by non-specific K + channel inhibition, or elevated norepinephrine destabilizes breathing, but creates a network state resistant to OIRD. Further, we tested whether the state of upper airway patency following opioid administration influences sensitivity of the PreBötC to OIRD. Following microdialysis into the PreBötC of the non-specific K + channel antagonist, tetraethylammonium (TEA)(10mM), or 1mM norepinephrine ventilation increased and breathing became erratic with variable frequency and tidal volume. However, following 150mg/kg morphine, breathing re-stabilized and returned to near control levels. These results demonstrate that determining the neuromodulatory state of excitability within the PreBötC prior to opioid administration may help to better predict and prevent OIRD. To determine whether the physiological state of the upper-airway following opioid administration can affect sensitivity of the PreBötC to OIRD we tested the ventilatory response to opioids in both airway-intact and tracheostomized mice in-vivo. For these experiments we utilized fentanyl, due to it’s known effects on disrupting upper airway function. Following administration of 500μg/kg fentanyl airway in-tact mice displayed increased upper airway resistance with regular periods of obstructive apnea, severe hypoxemia and reduced breathing frequency that eventually resulted in complete cessation of respiratory activity. Conversely, mice receiving 500μg/kg fentanyl following tracheostomy showed significantly less respiratory suppression and no apneic periods, compared to airway in-tact mice. However, following administration of a hypoxic gas mixture (10% O2) tracheostomized mice experienced terminal apnea in the presence of 500μg/Kg fentanyl. These results demonstrate that hypoxemia experienced following fentanyl administration, which is exacerbated by upper airway constriction may increase the risk of fatal OIRD in-vivo. Together our data suggest that understanding OIRD within the in-vivo system requires the careful investigation of integrative mechanisms between the neural and physiological processes that give rise to overall ventilation. This work was supported by NIH grants: HL154558 (NJB), HL145004 (NEB), HL126523 (JMR), HL144801 (JMR) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Acute Intermittent Hypoxia and Respiratory Strength Training to Improve Respiratory Function in Individuals with Chronic Spinal Cord Injury: Preliminary Outcomes

Spinal cord injury (SCI) disrupts neural pathways to respiratory motor neurons, causing paralysis and breathing impairment, a major cause of illness and death in SCI. Acute intermittent hypoxia (AIH) is a promising therapeutic modality that elicits spinal synaptic plasticity, improving breathing in rodent models of SCI. AIH also elicits plasticity in limb motor systems in both rodent models and humans with chronic SCI, where functional gains are greatest when paired with task-specific training. The impact of similar combinatorial treatments on breathing ability is unknown. Here, we report preliminary breathing outcomes in seventeen adults with chronic SCI who received AIH and task-specific training (respiratory strength training; RST). Seventeen males with chronic SCI (33.7 ± 15 yrs of age; 1-28 yrs post-SCI; 12 cervical, 5 thoracic injuries; C1-T6 AIS A-D). Respiratory function was 52% ± 19% of the age-predicted normative function for expiratory pressure generation and 123% ± 32% of normative values for inspiratory function. Participants completed four random ordered 5-day protocols of AIH, Sham, RST, and AIH+RST, &gt;3 weeks apart. AIH consisted of 15, 1-minute episodes of breathing a hypoxic gas mixture (9% oxygen), interspersed with 1.5-minute episodes of breathing room air (21% oxygen). Thirty minutes after AIH, RST involved both inspiratory and expiratory training; 4 sets of 6-12 breaths with the pressure threshold device set to 80% of each individual’s maximum. Sham treatments replicated AIH but used room air. A linear mixed model was used to test for differences in maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and forced vital capacity (FVC) prior to and 1 day post-intervention. MIP increased 10±15.6% (pre 120±34cmH20, post 129±36 cmH20) 1 day after RST (p=0.001) and 6±10.5% (pre 123±34cmH20; post 131±34cmH20) 1 day after AIH+RST (p=0.04), but did not change after AIH or Sham. MIP increased by &gt;10% in 5/17 participants following AIH+RST and 9/17 participants following RST. Neither MEP nor FVC changed following any block. Although there were no significant differences between AIH+RST and RST intervention blocks, there was a medium effect size (0.44). Since RST and AIH+RST preliminary outcomes suggest functional respiratory benefit, future steps will determine if the combinatorial treatment elicits greater gains. Examination of biomarkers associated with outcomes will provide insight into outcome variability. Department of Defense CDMRP W81XWH1810718 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.