Human erythropoietin response to hypocapnic hypoxia,normocapnic hypoxia,and hypocapnic normoxia

This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO₂ to the hypoxic gas. On separate days, eight healthy male subjects were exposed to 2 h each of hypocapnic hypoxia, normocapnic hypoxia, hypocapnic normoxia, and normal breathing of room air (control experiment). During the control experiment, serum-EPO showed significant variations (ANOVAP = 0.047) with a 15% increase in mean values. The serum-EPO measured in the other experiments were corrected for these spontaneous variations in each individual. At 2 h after ending hypocapnic hypoxia (10% O₂ in nitrogen), mean serum-EPO increased by 28% [baseline 8.00 (SEM 0.84) U · 1⁻¹, post-hypoxia 10.24 (SEM 0.95) U · 1⁻¹, P = 0.005]. Normocapnic hypoxia was produced by the addition of CO₂ (10% Co₂ with 10% O₂) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVAP > 0.05). Hypocapnic normoxia, produced by hyperventilation of room air, elicited a normoxic increase in the haemoglobin oxygen affinity without changing serum-EPO. Among the measured blood gas and acid-base parameters, only the partial pressures of oxygen in arterial blood during hypocapnic hypoxia were related to the peak values of serum-EPO (r = −0.81,P = 0.01). The present human EPO responses to hypoxia were lower than those which have previously been reported in rodents and humans. In contrast with the earlier rodent studies, it was found that human EPO production could not be triggered by short-term increases in pH and haemoglobin oxygen affinity per se, and the human EPO response to hypoxia could be suppressed by concomitant normocapnia without acidosis.     

Combined action of hypoxia and hypercapnia on functional state of the respiratory center

Discharges of bulbar respiratory neurons and electrical activity of the diaphragm and intercostal muscles were studied and pO₂, pCO₂, pH, and the oxygen saturation of the arterial blood were determined in cats anesthetized with pentobarbital and exposed to the combined action of hypoxia and hypercapnia. During inhalation of a hypoxic gas mixture the developing hypocapnia disturbed the firing pattern of the respiratory neurons and respiration of the Cheyne-Stokes type was established. Addition of 2% CO₂ to the hypoxic gas mixture restored the arterial blood gas composition to its initial level, prevented the development of hypocapnia, and prevented the disturbance of the rhythmic firing pattern of the respiratory neurons. Addition of 5% CO₂ to the hypoxic gas mixture had a negative action: respiratory unit activity was first stimulated, then inhibited, metabolic and respiratory acidosis was induced, and asphyxia developed.     

Effect of picrotoxin on organism’s resistance to acute severe hypoxia

Organism’s resistance to acute severe hypoxia (3% O₂) was studied after administration of GABA_A receptor antagonist picrotoxin and adenosine receptor antagonist euphylline (aminophylline) and after neutralization of secondary hypocapnia by adding 7% CO₂ to the hypoxic mixture. Administration of picrotoxin to anesthetized rats increased animal resistance to hypoxia. The resistance to hypoxia decreased after treatment with euphylline. Neutralization of secondary hypocapnia by adding 7% CO₂ to the hypoxic mixture had no effect on animal lifespan. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 2, pp. 136–140, February, 2008     

The effects of sildenafil and acetazolamide on breathing efficiency and ventilatory control during hypoxic exercise

The reduced arterial oxygen tension at high altitude impairs the ability to work. Acetazolamide improves arterial oxygen saturation (SaO₂) by increasing ventilation but is associated with an increased work and cost of breathing. Depending on the settings, sildenafil can also increases SaO₂ possibly through a reduction in pulmonary hypertension and interstitial edema, which could improve ventilation–perfusion matching. The objective of this study is to determine the effects of acetazolamide and sildenafil on ventilatory control and breathing efficiency (V _E/VCO₂) during submaximal steady-state hypoxic exercise in healthy individuals. Following 18 h of hypoxic exposure in an altitude tent at an oxygen concentration of 12.5% (simulated altitude of 4,300 m), 15 participants performed 10 min of hypoxic exercise on a stationary bicycle at 40% of their sea level peak oxygen uptake (VO₂) while randomly receiving sildenafil 40 mg (SIL), acetazolamide 125 mg (ACZ) or a placebo (PLA). There was no difference in VO₂ during exercise between conditions while SaO₂ was greater with acetazolamide compared to both placebo and sildenafil. Acetazolamide increased ventilation (PLA 49.0 ± 3.2, SIL 47.7 ± 3.1, ACZ 52.1 ± 3.0 l/min) and reduced end-tidal CO₂ (P _ETCO₂) (PLA 32.1 ± 0.8, SIL 32.8 ± 0.9, ACZ 29.2 ± 0.7 mmHg) compared to placebo and sildenafil. Breathing was less efficient with acetazolamide (increased V _E/VCO₂) in comparison to placebo and sildenafil (PLA 41.5 ± 1.0, SIL 40.4 ± 1.3, ACZ 45.4 ± 1.0) while sildenafil did not change V _E/VCO₂ during hypoxic exercise. In conclusion, acetazolamide increased ventilation and reduced breathing efficiency while sildenafil did not affect breathing efficiency despite a trend toward a blunted ventilatory response, possibly due to a reduction in pulmonary hypertension and/or ventilatory drive, during submaximal hypoxic exercise in healthy individuals.     

Combined endogenous MR biomarkers to predict basal tumor oxygenation and response to hyperoxic challenge

Hypoxia is a common feature of solid tumors, which translates into increased angiogenesis, malignant phenotype cell selection, change in gene expression and greater resistance to radiotherapy and chemotherapy. Therefore, there is a need for markers of hypoxia to stratify patients, in order to personalize treatment to improve therapeutic outcome. However, no modality has yet been validated for the screening of hypoxia in routine clinical practice. Magnetic resonance imaging (MRI) R₁ and R₂* relaxation parameters are sensitive to tissue oxygenation: R₁ is sensitive to dissolved oxygen and R₂* is sensitive to intravascular deoxyhemoglobin content. Two rat tumor models with distinct levels of hypoxia, 9L–glioma and rhabdomyosarcoma, were imaged for R₁ and R₂* under air and carbogen (95% O₂ and 5% CO₂) breathing conditions. It was observed that the basal tumor oxygenation level had an impact on the amplitude of response to carbogen in the vascular compartment (R₂*), but not in the tissue compartment (R₁). In addition, the change in tissue oxygenation estimated by ΔR₁ correlated with the change in vascular oxygenation estimated by ΔR₂*, which is consistent with an increase in oxygen supply generating an elevated tumor pO₂. At the intra‐tumoral level, we identified four types of voxel to which a hypoxic feature was attributed (mild hypoxia, severe hypoxia, normoxia and vascular steal), depending on the carbogen‐induced change in R₁ and R₂* values for each voxel. The results showed that 9L–gliomas present more normoxic fractions, whereas rhabdomyosarcomas present more hypoxic fractions, which is in accordance with a previous study using ¹⁸F–fluoroazomycin arabinoside (¹⁸F–FAZA) and electron paramagnetic resonance (EPR) oximetry. The response of the combined endogenous MRI contrasts to carbogen challenge could be a useful tool to predict different tumor hypoxic fractions.     

The effect of hypoxia on performance during 30 s or 45 s of supramaximal exercise

Summary The purpose of this study was to evaluate the effect of hypoxia (10.8±0.6% oxygen) on performance of 30 s and 45 s of supramaximal dynamic exercise. Twelve males were randomly allocated to perform either a 30 s or 45 s Wingate test (WT) on two occasions (hypoxia and room air) with a minimum of 1 week between tests. After a 5-min warm-up at 120 W subjects breathed the appropriate gas mixture from a wet spirometer during a 5-min rest period. Resting blood oxygen saturation was monitored with an ear oximeter and averaged 97.8 ± 1.5% and 83.2 ± 1.9% for the air (normoxic) and hypoxic conditions, respectively, immediately prior to the WT. Following all WT trials, subjects breathed room air for a 10-min passive recovery period. Muscle biopsies from the vastus lateralis were taken prior to and immediately following WT. Arterialized blood samples, for lactate and blood gases, were taken before and after both the warm-up and the performance of WT, and throughout the recovery period. Opencircuit spirometry was used to calculate the total oxygen consumption (Vo₂), carbon dioxide production and expired ventilation during WT. Hypoxia did not impair the performance of the 30-s or 45-s WT.Vo₃ was reduced during the 45-s hypoxic WT (1.71±0.21 I) compared with the normoxic trial (2.16±0.261), but there was no change during the 30-s test (1.22±0.11 vs 1.04±0.171 for the normoxic and hypoxic conditions, respectively). Muscle lactate (LA) increased more during hypoxia following both the 30-s and 45-s WT (67.1±25.0 mmol· kg^–1 dry weight) compared with normoxia (30.8 ± 18.0 mmol · kg^–1 dry weight). Hypoxia did not influence the change in intramuscular adenosine triphosphate, creatine phosphate and glucose-6-phosphate. The performance of WT during hypoxia was associated with a greater decrease in muscle glycogen (P<0.06). Throughout the recovery period, blood LA was lower following the hypoxia (8.43±2.88 mmol · l^–1) comparedwith normoxia (9.15±3.06 mmol · 1^–1). Breathing the hypoxic gas mixture prior to the performance of WT increased blood pH to 7.44±0.03, compared with 7.39±0.03 for normoxia. Blood pH remained higher during the 10-min recovery period following the hypoxic WT trials (7.24±0.08) compared with the normoxic WT (7.22±0.06). BloodP _{CO 2} was reduced prior to and immediately following WT during hypoxia, but there were no differences between the normoxic and hypoxic trials during the 10 min recovery period. These data indicate that more energy was transduced from the catabolism of glycogen to lactate during the hypoxic WT trials, which offset the reduced O₂ availability and maintained performance comparable with normoxic conditions. It is suggested that the induced respiratory alkalosis associated with breathing the hypoxic gas could account for the increased rate of muscle LA accumulation.     

Avian embryos in hypoxic environments

Avian embryos at high altitude do not benefit of the maternal protection against hypoxia as in mammals. Nevertheless, avian embryos are known to hatch successfully at altitudes between 4000 and 6500 m. This review considers some of the processes that bring about the outstanding modifications in the pressure differences between the environment and mitochondria of avian embryos in hypoxic environments. Among species, some maintain normal levels of oxygen consumption ( ) have a high oxygen carrying capacity, lower the air cell-arterial pressure difference (P_AO2−P_aO2) with a constant pH. Other species decrease , increase only slightly the oxygen carrying capacity, have a higher P_AO2−P_aO2 difference than sea-level embryos and lower the P_CO2 and pH. High altitude embryos, and those exposed to hypoxia have an accelerated decline of erythrocyte ATP levels during development and an earlier stimulation of 2,3-BPG synthesis. A higher Bohr effect may ensure high tissue P_O2 in the presence of the high-affinity hemoglobin. Independently of the strategy used, they serve together to promote suitable rates of development and successful hatching of high altitude birds in hypoxic environments.     

The pattern of breathing during hypoxic exercise

Summary Breathing pattern was studied in six subjects in normoxia (F_IO₂=0.21) and hypoxia (F_IO₂=0.12) at rest and during incremental work-rate exercise. Ventilation (V) as well as mean inspiratory flow (V_T/T_I) increased with exercise intensity and were augmented in the hypoxic environment, whereas the ratio between inspiratory (T_I) and total (T_tot) breath durations increased with exercise intensity but was unaffected by hypoxia. The relationship of tidal volume (V_T) and inspiratory time duration (T_I) showed linear, coinciding ranges for the normoxic and hypoxic conditions up to V_T/T_I values of about 2.5 l · s⁻¹. At higher V_T/T_I values T_I continued to decrease, whereas V_T tended to level off, an effect which was more evident in the hypoxic condition. The results suggest that the hypoxic augmentation of exercise hyperpnea is primarily brought about by an enhancement of central inspiratory drive, the timing component being largely unaffected by the hypoxic environment, and that at low to moderate levels of exercise hyperpnea inspiratory off-switch mechanisms are essentially unaffected by moderate hypoxia.     

Dynamic oxygen challenge evaluated by NMR T1 and T2* – insights into tumor oxygenation

There is intense interest in developing non‐invasive prognostic biomarkers of tumor response to therapy, particularly with regard to hypoxia. It has been suggested that oxygen sensitive MRI, notably blood oxygen level‐dependent (BOLD) and tissue oxygen level‐dependent (TOLD) contrast, may provide relevant measurements. This study examined the feasibility of interleaved T₂*‐ and T₁‐weighted oxygen sensitive MRI, as well as R₂* and R₁ maps, of rat tumors to assess the relative sensitivity to changes in oxygenation. Investigations used cohorts of Dunning prostate R3327‐AT1 and R3327‐HI tumors, which are reported to exhibit distinct size‐dependent levels of hypoxia and response to hyperoxic gas breathing. Proton MRI R₁ and R₂* maps were obtained for tumors of anesthetized rats (isoflurane/air) at 4.7 T. Then, interleaved gradient echo T₂*‐ and T₁‐weighted images were acquired during air breathing and a 10 min challenge with carbogen (95% O₂–5% CO₂). Signals were stable during air breathing, and each type of tumor showed a distinct signal response to carbogen. T₂* (BOLD) response preceded T₁ (TOLD) responses, as expected. Smaller HI tumors (reported to be well oxygenated) showed the largest BOLD and TOLD responses. Larger AT1 tumors (reported to be hypoxic and resist modulation by gas breathing) showed the smallest response. There was a strong correlation between BOLD and TOLD signal responses, but ΔR₂^* and ΔR₁ were only correlated for the HI tumors. The magnitude of BOLD and TOLD signal responses to carbogen breathing reflected expected hypoxic fractions and oxygen dynamics, suggesting potential value of this test as a prognostic biomarker of tumor hypoxia. Copyright © 2015 John Wiley & Sons, Ltd.     

Impact of acute hypobaric hypoxia on blood flow distribution in brain

Aim: Acute hypobaric hypoxia is well known to alter brain circulation and to cause neuropsychological impairment. However, very few studies have examined the regional changes occurring in the brain during acute exposure to extreme hypoxic conditions. Methods: Regional cerebral blood flow (rCBF) response to hypoxia was investigated in six healthy subjects exposed to either normobaric normoxia or hypobaric hypoxia with ambient pressure/inspired oxygen pressure of 101/21 kPa and 50/11 kPa respectively. After 40 min at the desired pressure they were injected ^99mTc‐HMPAO and subsequently underwent single photon emission computed tomography. Regional cerebral blood flow distribution changes in the whole brain were assessed by Statistical Parametric Mapping, a well established voxel‐based analysis method. Results: Hypobaric hypoxia increased rCBF distribution in sensorymotor and prefrontal cortices and in central structures. PCO₂ correlated positively and SatO₂ negatively with rCBF in several temporal, parahippocampal, parietal and central structures. Conclusions: These findings underscore the specific sensitivity of the frontal lobe to acute hypobaric hypoxia and of limbic and central structures to blood gas changes emphasizing the involvement of these brain areas in acute hypoxia.     

Improved breath alcohol analysis in patients with depressed consciousness

Many patients in pre-hospital and emergency care are under the influence of alcohol. In addition, some of the more common pathological conditions can introduce a behaviour that can be mistaken to be related to alcohol inebriation. Fast quantitative determination of the breath alcohol concentration (BrAC) in emergency patients facilitates triage and medical assessment, but shallow expirations performed by non-cooperative patients reduce the measurement reliability. The aim of this study was to evaluate if breath alcohol analysis in non-cooperative patients can be improved with use of simultaneous measurement of the expired carbon dioxide (CO₂). With prototypes of a handheld breath alcohol analyser based on infrared transmission spectroscopy the alcohol and CO₂ concentration in expired breath from 37 cooperative and non-cooperative patients were measured. The results show that enhanced breath sampling with use of a pump and estimation of the end expiratory BrAC with use of the ratio between the measured partial pressure of CO₂ ( P_\textCO2 P_{{{\text{CO}}_{2} }} ) and a reference value of the alveolar P_\textCO2 P_{{{\text{CO}}_{2} }} , provided adequate correlation with the blood alcohol concentration (BAC). This pre-clinical study has shown that breath alcohol analysis in shallow expirations from non-cooperative patients can be improved with use of CO₂ as a tracer gas.     

Changes in hemodynamics and respiration in animals with different resistance to acute hypoxia

We studied the effects of acute hypoxia on hemodynamics and respiration in cats. The animals were divided into high-, low- and medium-resistant to hypoxia by the time of respiratory arrest after breathing with 3% O₂ gas mixture. In high-resistant animals, hemodynamic indices remained at a high level throughout the hypoxic episode, while in low-resistant cats they decreased shortly after the onset of hypoxia. It is suggested that the peculiarities of hemodynamic regulation play an important role in individual resistance to acute hypoxia. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 9, pp. 286–290, September, 1999     

Enhanced chemosensitivity after intermittent hypoxic exposure does not affect exercise ventilation at sea level

The purpose of the present study was to test the hypothesis that the ventilatory response to exercise at sea level may increase after intermittent hypoxic exposure for 1 week, accompanied by an increase in hypoxic or hypercapnic ventilatory chemosensitivity. One group of eight subjects (hypoxic group) were decompressed in a chamber to 432 torr (where 1 torr=1.0 mmHg, simulating an altitude of 4,500 m) over a period of 30 min and maintained at that pressure for 1 h daily for 7 days. Oxygen uptake and pulmonary ventilation (V_E) were determined at 40%, 70%, and 100% of maximal oxygen uptake at sea level before (Pre) and after (Post) 1 week of daily exposures to hypoxia. The hypoxic ventilatory response (HVR) was determined using the isocapnic progressive hypoxic method as an index of ventilatory chemosensitivity to hypoxia, and the hypercapnic ventilatory response (HCVRSB) was measured by means of the single-breath carbon dioxide method as an index of peripheral ventilatory chemosensitivity to hypercapnia. The same parameters were measured in another group of six subjects (control group). In the hypoxic group, resting HVR increased significantly (P<0.05) after intermittent hypoxia and HCVRSB increased at Post, but the change was not statistically significant (P=0.07). In contrast, no changes in HVR and HCVRSB were found in the control group. There were no changes in either V_E or the ventilatory equivalent for oxygen during maximal and submaximal exercise at sea level throughout the experimental period in either group. These results suggest that the changes in resting hypoxic and peripheral hypercapnic chemosensitivities following short-term intermittent hypoxia have little effect on exercise ventilation at sea level. Electronic Publication     

Changes in hemodynamics and respiration in rats with different resistance to acute hypoxia

Effects of acute hypoxia on hemodynamics and respiration were studied in acute experiments on narcotized rats. The animals were divided into groups characterized by high, low-, and medium- resistance to hypoxia by the time of respiration arrest during inhalation of gas mixture containing 3% O₂. Hemodynamic parameters of highly resistant animals were higher than in low-resistant rats throughout the entire hypoxic period. The development of a rare (with prolonged inspiratory phase) respiratory rhythm in highly resistant rats is an adaptive reaction, which allows them longer tolerate hypoxia compared to low-resistant animals. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 138, No. 7, pp. 24–28, July, 2004     

Amelioration of hypoxia-induced striatal 5-HT(2A) receptor, 5-HT transporter and HIF1 alterations by glucose, oxygen and epinephrine in neonatal rats

Alterations in neurotransmitters and its receptors expression induce brain injury during neonatal hypoxic insult. Molecular processes regulating the serotonergic receptors play an important role in the control of respiration under hypoxic insult. The present study focused on the serotonergic regulation of neonatal hypoxia and its resuscitation methods. Receptor binding assays and gene expression studies were done to evaluate the changes in 5HT_2A receptors and its transporter in the corpus striatum of hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen and epinephrine. Total 5HT and 5HT_2A receptor number was increased in hypoxic neonates along with an up regulation of 5HT_2A receptor and 5HT transporter gene. The enhanced striatal 5HT_2A receptors modulate the ventilatory response to hypoxia. Immediate glucose resuscitation was found to ameliorate the receptor and transporter alterations. Hypoxia induced ATP depletion mediated reduction in blood glucose levels can be encountered by glucose administration and oxygenation helps in overcoming the anaerobic condition. The adverse effect of immediate oxygenation and epinephrine supplementation was also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia.     

Hypoxia augments apnea-induced increase in hemoglobin concentration and hematocrit

Increased hemoglobin concentration (Hb) and hematocrit (Hct), attributable to spleen contraction, raise blood gas storage capacity during apnea, but the mechanisms that trigger this response have not been clarified. We focused on the role of hypoxia in triggering these Hb and Hct elevations. After horizontal rest for 20 min, 10 volunteers performed 3 maximal apneas spaced by 2 min, each preceded by a deep inspiration of air. The series was repeated using the same apneic durations but after 1 min of 100% oxygen (O₂) breathing and O₂ inspiration prior to each apnea. Mean apneic durations were 150, 171, and 214 s for apneas 1, 2, and 3, respectively. Relative to pre-apnea values, the mean post-apneic arterial O₂ saturation nadir was 84.7% after the air trial and 98% after the O₂ trial. A more pronounced elevation of both Hb and Hct occurred during the air trial: after apnea 1 with air, mean Hb had increased by 1.5% (P < 0.01), but no clear increase was found after the first apnea with O₂. After the third apnea with air Hb had increased by 3.0% (P < 0.01), and with O₂ by 2.0% (P < 0.01). After the first apnea with air Hct had increased by 1.9% (P < 0.01) and after 3 apneas by 3.0% (P < 0.01), but Hct did not change significantly in the O₂ trial. In both trials, Hb and Hct were at pre-apneic levels 10 min after apneas. Diving bradycardia during apnea was the same in both trials. We conclude that hypoxia contributes to spleen contraction during apnea, likely through chemosensor-related sympathetic output. There are, however other factors involved that trigger spleen contraction even in the absence of hypoxia.     

Effect of intermittent hypoxia on oxygen uptake during submaximal exercise in endurance athletes

The purpose of the present study was to clarify the following: (1) whether steady state oxygen uptake (O₂) during exercise decreases after short-term intermittent hypoxia during a resting state in trained athletes and (2) whether the change in O₂ during submaximal exercise is correlated to the change in endurance performance after intermittent hypoxia. Fifteen trained male endurance runners volunteered to participate in this study. Each subject was assigned to either a hypoxic group (n=8) or a control group (n=7). The hypoxic group spent 3 h per day for 14 consecutive days in normobaric hypoxia [12.3 (0.2)% inspired oxygen]. The maximal and submaximal exercise tests, a 3,000-m time trial, and resting hematology assessments at sea level were conducted before and after intermittent normobaric hypoxia. The athletes in both groups continued their normal training in normoxia throughout the experiment. O₂ during submaximal exercise in the hypoxic group decreased significantly (P<0.05) following intermittent hypoxia. In the hypoxic group, the 3,000-m running time tended to improve (P=0.06) after intermittent hypoxia, but not in the control group. Neither peak O₂ nor resting hematological parameters were changed in either group. There were significant (P<0.05) relationships between the change in the 3,000-m running time and the change in O₂ during submaximal exercise after intermittent hypoxia. The results from the present study suggest that the enhanced running economy resulting from intermittent hypoxia could, in part, contribute to improved endurance performance in trained athletes.