Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.

Selected and shared hematological responses to apnea in elite human free divers and northern elephant seals (Mirounga angustirostris).

Despite elite human free divers achieving incredible feats in competitive free diving, there has yet to be a study that compares consummate divers, (i.e. northern elephant seals) to highly conditioned free divers (i.e., elite competitive free-diving humans). Herein, we compare these two diving models and suggest that hematological traits detected in seals reflect species-specific specializations, while hematological traits shared between the two species are fundamental mammalian characteristics. Arterial blood samples were analyzed in elite human free divers (n = 14) during a single, maximal volitional apnea and in juvenile northern elephant seals (n = 3) during rest-associated apnea. Humans and elephant seals had comparable apnea durations (∼6.5 min) and end-apneic arterial Po2 [humans: 40.4 ± 3.0 mmHg (means ± SE); seals: 27.1 ± 5.9 mmHg; P = 0.2]. Despite similar increases in arterial Pco2 (humans: 33 ± 5%; seals: 16.3 ± 5%; P = 0.2), only humans experienced reductions in pH from baseline (humans: 7.45 ± 0.01; seals: 7.39 ± 0.02) to end apnea (humans: 7.37 ± 0.01; seals: 7.38 ± 0.02; P < 0.0001). Hemoglobin P50 was greater in humans compared to elephant seals (29.9 ± 1.5 and 28.7 ± 0.6 mmHg, respectively; P = 0.046). Elephant seals overall had higher carboxyhemoglobin (COHb) levels (5.9 ± 2.6%) compared to humans (0.8 ± 1.2%; P < 0.0001); however, following apnea, COHb was reduced in seals (baseline: 6.1 ± 0.3%; end apnea: 5.6 ± 0.3%) and was slightly elevated in humans (baseline: 0.7 ± 0.1%; end apnea: 0.9 ± 0.1%; P < 0.0002, both comparisons). Our data indicate that during static apnea, seals have reduced hemoglobin P50, greater pH buffering, and increased COHb levels. The differences in hemoglobin P50 are likely due to the differences in the physiological environment between the two species during apnea, whereas enhanced pH buffering and higher COHb may represent traits selected for in elephant seals.NEW & NOTEWORTHY This study uses similar methods and protocols in elite human free divers and northern elephant seals. Using highly conditioned divers (elite free-diving humans) and highly adapted divers (northern elephant seals), we explored which hematological traits are fundamentally mammalian and which may have been selected for. We found differences in P50, which may be due to different physiological environments between species, while elevated pH buffering and carbon monoxide levels might have been selected for in seals.

Differences in Plasma Cannabidiol Concentrations in Women and Men: A Randomized, Placebo-Controlled, Crossover Study.

The potential therapeutic benefits of cannabidiol (CBD) require further study. Here, we report a triple-blind (participant, investigator, and outcome assessor) placebo-controlled crossover study in which 62 hypertensive volunteers were randomly assigned to receive the recently developed DehydraTECH2.0 CBD formulation or a placebo. This is the first study to have been conducted using the DehydraTECH2.0 CBD formulation over a 12-week study duration. The new formulation's long-term effects on CBD concentrations in plasma and urine, as well as its metabolites 7-hydroxy-CBD and 7-carboxy-CBD, were analyzed. The results of the plasma concentration ratio for CBD/7-OH-CBD in the third timepoint (after 5 weeks of use) were significantly higher than in the second timepoint (after 2.5 weeks of use; p = 0.043). In the same timepoints in the urine, a significantly higher concentration of 7-COOH-CBD was observed p < 0.001. Differences in CBD concentration were found between men and women. Plasma levels of CBD were still detectable 50 days after the last consumption of the CBD preparations. Significantly higher plasma CBD concentrations occurred in females compared to males, which was potentially related to greater adipose tissue. More research is needed to optimize CBD doses to consider the differential therapeutic benefits in men and women.

Common carotid artery responses to the cold-pressor test are impaired in individuals with cervical spinal cord injury.

Cervical spinal cord injury (SCI) leads to autonomic cardiovascular dysfunction that underlies the three- to fourfold elevated risk of cardiovascular disease in this population. Reduced common carotid artery (CCA) dilatory responsiveness during the cold-pressor test (CPT) is associated with greater cardiovascular disease risk and progression. The cardiovascular and CCA responses to the CPT may provide insight into cardiovascular autonomic dysfunction and cardiovascular disease risk in individuals with cervical SCI. Here, we used CPT to perturb the autonomic nervous system in 14 individuals with cervical SCI and 12 uninjured controls, while measuring cardiovascular responses and CCA diameter. The CCA diameter responses were 55% impaired in those with SCI compared with uninjured controls (P = 0.019). The CCA flow, velocity, and shear response to CPT were reduced in SCI by 100% (P < 0.001), 113% (P = 0.001), and 125% (P = 0.002), respectively. The association between mean arterial pressure and CCA dilation observed in uninjured individuals (r = 0.54, P = 0.004) was absent in the SCI group (r = 0.22, P = 0.217). Steady-state systolic blood pressure (P = 0.020), heart rate (P = 0.003), and cardiac contractility (P < 0.001) were reduced in those with cervical SCI, whereas total peripheral resistance was increased compared with uninjured controls (P = 0.042). Relative cerebral blood velocity responses to CPT were increased in the SCI group and reduced in controls (middle cerebral artery, P = 0.010; posterior cerebral artery, P = 0.026). The CCA and cardiovascular responsiveness to CPT are impaired in those with cervical SCI.NEW & NOTEWORTHY This is the first study demonstrating that CCA responses during CPT are suppressed in SCI. Specifically, CCA diameter, flow, velocity, and shear rate were reduced. The relationship between changes in MAP and CCA dilatation in response to CPT was absent in individuals with SCI, despite similar cardiovascular activation between SCI and uninjured controls. These findings support the notion of elevated cardiovascular disease risk in SCI and that the cardiovascular responses to environmental stimuli are impaired.

Blunted hypoxic pulmonary vasoconstriction in apnoea divers.

NEW FINDINGS: What is the central question of this study? Does the hyperbaric, hypercapnic, acidotic, hypoxic stress of apnoea diving lead to greater pulmonary vasoreactivity and increased right heart work in apnoea divers? What is the main finding and its importance? Compared with sex- and age-matched control subjects, divers experienced significantly less change in total pulmonary resistance in response to short-duration isocapnic hypoxia. With oral sildenafil (50 mg), there were no differences in total pulmonary resistance between groups, suggesting that divers can maintain normal pulmonary artery tone in hypoxic conditions. Blunted hypoxic pulmonary vasoconstriction might be beneficial during apnoea diving. ABSTRACT: Competitive apnoea divers dive repetitively to depths >50 m. During the final portions of ascent, divers experience significant hypoxaemia. Additionally, hyperbaria during diving increases thoracic blood volume while simultaneously reducing lung volume and increasing pulmonary artery pressure. We hypothesized that divers would have exaggerated hypoxic pulmonary vasoconstriction, leading to increased right heart work owing to their repetitive hypoxaemia and hyperbaria, and that the administration of sildenafil would have a greater effect in reducing pulmonary resistance in divers. We recruited 16 divers (Divers) and 16 age- and sex-matched non-diving control subjects (Controls). Using a double-blinded, placebo-controlled, cross-over design, participants were evaluated for normal cardiac and lung function, then their cardiopulmonary responses to 20-30 min of isocapnic hypoxia (end-tidal partial pressure of O2  = 50 mmHg) were measured 1 h after ingestion of 50 mg sildenafil or placebo. Cardiac structure and cardiopulmonary function were similar at baseline. With placebo, Divers had a significantly smaller increase in total pulmonary resistance than Controls after 20-30 min isocapnic hypoxia (change -3.85 ± 72.85 vs. 73.74 ± 91.06 dyns cm-5 , P = 0.0222). With sildenafil, Divers and Controls had similar blunted increases in total pulmonary resistance after 20-30 min of hypoxia. Divers also had a significantly lower systemic vascular resistance after sildenafil in normoxia. These data indicate that repetitive apnoea diving leads to a blunted hypoxic pulmonary vasoconstriction. We suggest that this is a beneficial adaption allowing for increased cardiac output with reduced right heart work and thus reducing cardiac oxygen utilization in hypoxaemic conditions.

Temporal changes in pulmonary gas exchange efficiency when breath-hold diving below residual volume.

NEW FINDINGS: What is the central question of this study? How does deep breath-hold diving impact cardiopulmonary function, both acutely and over the subsequent 2.5 hours post-dive? What is the main finding and its importance? Breath-hold diving, to depths below residual volume, is associated with acute impairments in pulmonary gas exchange, which typically resolve within 2.5 hours. These data provide new insight into the behaviour of the lungs and pulmonary vasculature following deep diving. ABSTRACT: Breath-hold diving involves highly integrative and extreme physiological responses to both exercise and asphyxia during progressive elevations in hydrostatic pressure. Over two diving training camps (Study 1 and 2), 25 breath-hold divers (recreational to world-champion) performed 66 dives to 57 ± 20 m (range: 18-117 m). Using the deepest dive from each diver, temporal changes in cardiopulmonary function were assessed using non-invasive pulmonary gas exchange (indexed via the O2 deficit), ultrasound B-line scores, lung compliance and pulmonary haemodynamics at baseline and following the dive. Hydrostatically induced lung compression was quantified in Study 2, using spirometry and lung volume measurement, enabling each dive to be categorized by its residual volume (RV)-equivalent depth. From both studies, pulmonary gas exchange inefficiency - defined as an increase in O2 deficit - was related to the depth of the dive (r2  = 0.345; P < 0.001), with dives associated with lung squeeze symptoms exhibiting the greatest deficits. In Study 1, although B-lines doubled from baseline (P = 0.027), cardiac output and pulmonary artery systolic pressure were unchanged post-dive. In Study 2, dives with lung compression to ≤RV had higher O2 deficits at 9 min, compared to dives that did not exceed RV (24 ± 25 vs. 5 ± 8 mmHg; P = 0.021). The physiological significance of a small increase in estimated lung compliance post-dive (via decreased and increased/unaltered airway resistance and reactance, respectively) remains equivocal. Following deep dives, the current study highlights an integrated link between hydrostatically induced lung compression and transient impairments in pulmonary gas exchange efficiency.

Effects of circulating extracellular microvesicles from spinal cord-injured adults on endothelial cell function.

People with spinal cord injury (SCI) have three- to four-fold greater risk of cardiovascular disease (CVD) compared with those without SCI. Although circulating extracellular microvesicles are key effectors of vascular health and disease, how their functional phenotype might be altered with SCI is unknown. The aim of the present study was to determine the effects of microvesicles isolated from SCI adults on endothelial cell inflammation and oxidative stress as well as endothelial nitric oxide (NO) synthase (eNOS) activation and tissue-type plasminogen activator (t-PA) expression. Eighteen young and middle-aged adults were studied: 10 uninjured (7M/3F; age: 39 ± 3 years) and 8 cervical level spinal cord injured (SCI; 7M/1F; 46 ± 4 years; cervical injury: C3: n=1; C5: n=4; C6: n=3). Circulating microvesicles were isolated, enumerated and collected from plasma by flow cytometry. Human umbilical vein endothelial cells (HUVECs) were cultured and treated with microvesicles from either the uninjured or SCI adults. Microvesicles from SCI adults did not affect cellular markers or mediators of inflammation and oxidative stress. However, microvesicles from the SCI adults significantly blunted eNOS activation, NO bioavailability and t-PA production. Intercellular expression of phosphorylated eNOS at Ser1177 and Thr495 sites, specifically, were ∼65% lower and ∼85% higher, respectively, in cells treated with microvesicles from SCI compared with uninjured adults. Decreased eNOS activity and NO production as well as impaired t-PA bioavailability renders the vascular endothelium highly susceptible to atherosclerosis and thrombosis. Thus, circulating microvesicles may contribute to the increased risk of vascular disease and thrombotic events associated with SCI.

Alterations in resting cerebrovascular regulation do not affect reactivity to hypoxia, hyperoxia or neurovascular coupling following a SCUBA dive.

NEW FINDINGS: What is the central question of this study? What are the characteristics of cerebral blood flow (CBF) regulation following a single SCUBA dive to a depth of 18 m sea water with a 47 min bottom time. What is the main finding and its importance? Acute alterations in CBF regulation at rest, including extra-cranial vasodilatation, reductions in shear patterns and elevations in intra-cranial blood velocity were observed at rest following a single SCUBA dive. These subtle changes in CBF regulation did not translate into any functional changes in cerebrovascular reactivity to hypoxia or hyperoxia, or neurovascular coupling following a single SCUBA dive. ABSTRACT: Reductions in vascular function during a SCUBA dive - due to hyperoxia-induced oxidative stress, arterial and venous gas emboli and altered endothelial integrity - may also extend to the cerebrovasculature following return to the surface. This study aimed to characterize cerebral blood flow (CBF) regulation following a single SCUBA dive to a depth of 18 m sea water with a 47 min bottom time. Prior to and following the dive, participants (n = 11) completed (1) resting CBF in the internal carotid (ICA) and vertebral (VA) arteries (duplex ultrasound) and intra-cranial blood velocity (v) of the middle and posterior cerebral arteries (MCAv and PCAv, respectively) (transcranial Doppler ultrasound); (2) cerebrovascular reactivity to acute poikilocapnic hypoxia (i.e. FIO2 , 0.10) and hyperoxia (i.e. FIO2 , 1.0); and (3) neurovascular coupling (NVC; regional CBF response to local increases in cerebral metabolism). Global CBF, cerebrovascular reactivity to hypoxia and hyperoxia, and NVC were unaltered following a SCUBA dive (all P > 0.05); however, there were subtle changes in other cerebrovascular metrics post-dive, including reductions in ICA (-13 ± 8%, P = 0.003) and VA (-11 ± 14%, P = 0.021) shear rate, lower ICAv (-10 ± 9%, P = 0.008) and VAv (-9 ± 14%, P = 0.028), increases in ICA diameter (+4 ± 5%, P = 0.017) and elevations in PCAv (+10 ± 19%, P = 0.047). Although we observed subtle alterations in CBF regulation at rest, these changes did not translate into any functional changes in cerebrovascular reactivity to hypoxia or hyperoxia, or NVC. Whether prolonged exposure to hyperoxia and hyperbaria during longer, deeper, colder and/or repetitive SCUBA dives would provoke changes to the cerebrovasculature requires further investigation.

Vascular dysfunction following breath-hold diving.

The pathogenesis of predominantly neurological decompression sickness (DCS) is multifactorial. In SCUBA diving, besides gas bubbles, DCS has been linked to microparticle release, impaired endothelial function, and platelet activation. This study focused on vascular damage and its potential role in the genesis of DCS in breath-hold diving. Eleven breath-hold divers participated in a field study comprising eight deep breath-hold dives with short surface periods and repetitive breath-hold dives lasting for 6 h. Endothelium-dependent vasodilation of the brachial artery, via flow-mediated dilation (FMD), and the number of microparticles (MPs) were assessed before and after each protocol. All measures were analyzed by two-way within-subject ANOVA (2 × 2 ANOVA; factors: time and protocol). Absolute FMD was reduced following both diving protocols (p < 0.001), with no interaction (p = 0.288) or main effect of protocol (p = 0.151). There was a significant difference in the total number of circulating MPs between protocols (p = 0.007), where both increased post-dive (p = 0.012). The number of CD31+/CD41- and CD66b+ MP subtypes, although different between protocols (p < 0.001), also increased by 41.0% ± 56.6% (p = 0.050) and 60.0% ± 53.2% (p = 0.045) following deep and repetitive breath-hold dives, respectively. Both deep and repetitive breath-hold diving lead to endothelial dysfunction that may play an important role in the genesis of neurological DCS.

Acute heat stress reduces biomarkers of endothelial activation but not macro- or microvascular dysfunction in cervical spinal cord injury.

Cardiovascular diseases (CVD) are highly prevalent in spinal cord injury (SCI), and peripheral vascular dysfunction might be a contributing factor. Recent evidence demonstrates that exposure to heat stress can improve vascular function and reduce the risk of CVD in uninjured populations. We therefore aimed to examine the extent of vascular dysfunction in SCI and the acute effects of passive heating. Fifteen participants with cervical SCI and 15 uninjured control (CON) participants underwent ultrasound assessments of vascular function and venous blood sampling for biomarkers of endothelial activation (i.e., CD62e+) and apoptosis (i.e., CD31+/42b-) before and after a 60-min exposure to lower limb hot water immersion (40°C). In SCI, macrovascular endothelial function was reduced in the brachial artery [SCI: 4.8 (3.2)% vs. CON: 7.6 (3.4)%, P = 0.04] but not the femoral artery [SCI: 3.7 (2.6)% vs. CON: 4.0 (2.1)%, P = 0.70]. Microvascular function, via reactive hyperemia, was ~40% lower in SCI versus CON in both the femoral and brachial arteries ( P < 0.01). Circulating concentrations of CD62e+ were elevated in SCI versus CON [SCI: 152 (106) microparticles/µl vs. CON: 58 (24) microparticles/µl, P < 0.05]. In response to heating, macrovascular and microvascular function remained unchanged, whereas increases (+83%) and decreases (-93%) in antegrade and retrograde shear rates, respectively, were associated with heat-induced reductions of CD62e+ concentrations in SCI to levels similar to CON ( P = 0.05). These data highlight the potential of acute heating to provide a safe and practical strategy to improve vascular function in SCI. The chronic effects of controlled heating warrant long-term testing. NEW & NOTEWORTHY Individuals with cervical level spinal cord injury exhibit selectively lower flow-mediated dilation in the brachial but not femoral artery, whereas peak reactive hyperemia was lower in both arteries compared with uninjured controls. After 60 min of lower limb hot water immersion, femoral artery blood flow and shear patterns were acutely improved in both groups. Elevated biomarkers of endothelial activation in the spinal cord injury group decreased with heating, but these biomarkers remained unchanged in controls.

Competitive apnea and its effect on the human brain: focus on the redox regulation of blood-brain barrier permeability and neuronal-parenchymal integrity.

Static apnea provides a unique model that combines transient hypertension, hypercapnia, and severe hypoxemia. With apnea durations exceeding 5 min, the purpose of the present study was to determine how that affects cerebral free-radical formation and the corresponding implications for brain structure and function. Measurements were obtained before and following a maximal apnea in 14 divers with transcerebral exchange kinetics, measured as the product of global cerebral blood flow (duplex ultrasound) and radial arterial to internal jugular venous concentration differences ( a-vD). Apnea increased the systemic (arterial) and, to a greater extent, the regional (jugular venous) concentration of the ascorbate free radical, resulting in a shift from net cerebral uptake to output ( P < 0.05). Peroxidation (lipid hydroperoxides, LDL oxidation), NO bioactivity, and S100ß were correspondingly enhanced ( P < 0.05), the latter interpreted as minor and not a pathologic disruption of the blood-brain barrier. However, those changes were insufficient to cause neuronal-parenchymal damage confirmed by the lack of change in the a-vD of neuron-specific enolase and human myelin basic protein ( P > 0.05). Collectively, these observations suggest that increased cerebral oxidative stress following prolonged apnea in trained divers may reflect a functional physiologic response, rather than a purely maladaptive phenomenon.-Bain, A. R., Ainslie, P. N., Hoiland, R. L., Barak, O. F., Drvis, I., Stembridge, M., MacLeod, D. M., McEneny, J., Stacey, B. S., Tuaillon, E., Marchi, N., De Maudave, A. F., Dujic, Z., MacLeod, D. B., Bailey, D. M. Competitive apnea and its effect on the human brain: focus on the redox regulation of blood-brain barrier permeability and neuronal-parenchymal integrity.

Cerebrovascular function is preserved during mild hyperthermia in cervical spinal cord injury.

STUDY DESIGN: Experimental study. OBJECTIVES: Compromised cerebrovascular function likely contributes to elevated neurological risk in spinal cord injury (SCI). Passive heating offers many cardiovascular and neurological health benefits; therefore, we aimed to determine the effects of an acute bout of heating on cerebrovascular function in chronic SCI. METHODS: Persons with cervical SCI (n = 15) and uninjured controls (CON; n = 15) completed 60 min of lower limb hot water immersion (40 °C). Assessments of middle cerebral (MCA) and posterior cerebral artery (PCA) velocities, pulsatilities, and neurovascular coupling (NVC) were performed using transcranial Doppler ultrasound. Duplex ultrasonography was used to index cerebral blood flow via the internal carotid artery (ICA), and carotid-femoral pulse-wave velocity (PWV) was measured using tonometry. The NVC response was quantified as the peak hyperemic value during 30-s cycles of visual stimulation. RESULTS: Mean arterial pressure changed differentially with heating [mean (standard deviation); SCI: +6(14) mmHg, CON: -8(12) mmHg; P = 0.01]. There were no differences in any intracranial artery measures (all P > 0.05), except for small (~10%) increases in MCA conductance in CON after heating vs. SCI (interaction P = 0.006). Resting ICA flow was greater in SCI vs. CON (P = 0.03) but did not change with heating in either group (interaction P = 0.34). There were also no between-group differences in the NVC response (ΔPCA conductance) pre- [SCI: 29(19)% vs. CON: 30(9)%] or post-heating [SCI 30(9)% vs. 25(9)%; interaction P = 0.22]. CONCLUSIONS: Mild acute heating does not impair or improve cerebrovascular function in SCI or CON. Thus, further study of the effects of chronic heating interventions are warranted.

Wavelet decomposition analysis is a clinically relevant strategy to evaluate cerebrovascular buffering of blood pressure after spinal cord injury.

The capacity of the cerebrovasculature to buffer changes in blood pressure (BP) is crucial to prevent stroke, the incidence of which is three- to fourfold elevated after spinal cord injury (SCI). Disruption of descending sympathetic pathways within the spinal cord due to cervical SCI may result in impaired cerebrovascular buffering. Only linear analyses of cerebrovascular buffering of BP, such as transfer function, have been used in SCI research. This approach does not account for inherent nonlinearity and nonstationarity components of cerebrovascular regulation, often depends on perturbations of BP to increase the statistical power, and does not account for the influence of arterial CO2 tension. Here, we used a nonlinear and nonstationary analysis approach termed wavelet decomposition analysis (WDA), which recently identified novel sympathetic influences on cerebrovascular buffering of BP occurring in the ultra-low-frequency range (ULF; 0.02-0.03Hz). WDA does not require BP perturbations and can account for influences of CO2 tension. Supine resting beat-by-beat BP (Finometer), middle cerebral artery blood velocity (transcranial Doppler), and end-tidal CO2 tension were recorded in cervical SCI ( n = 14) and uninjured ( n = 16) individuals. WDA revealed that cerebral blood flow more closely follows changes in BP in the ULF range ( P = 0.0021, Cohen's d = 0.89), which may be interpreted as an impairment in cerebrovascular buffering of BP. This persisted after accounting for CO2. Transfer function metrics were not different in the ULF range, but phase was reduced at 0.07-0.2 Hz ( P = 0.03, Cohen's d = 0.31). Sympathetically mediated cerebrovascular buffering of BP is impaired after SCI, and WDA is a powerful strategy for evaluating cerebrovascular buffering in clinical populations.

Highs and lows of hyperoxia: physiological, performance, and clinical aspects.

Molecular oxygen (O2) is a vital element in human survival and plays a major role in a diverse range of biological and physiological processes. Although normobaric hyperoxia can increase arterial oxygen content ([Formula: see text]), it also causes vasoconstriction and hence reduces O2 delivery in various vascular beds, including the heart, skeletal muscle, and brain. Thus, a seemingly paradoxical situation exists in which the administration of oxygen may place tissues at increased risk of hypoxic stress. Nevertheless, with various degrees of effectiveness, and not without consequences, supplemental oxygen is used clinically in an attempt to correct tissue hypoxia (e.g., brain ischemia, traumatic brain injury, carbon monoxide poisoning, etc.) and chronic hypoxemia (e.g., severe COPD, etc.) and to help with wound healing, necrosis, or reperfusion injuries (e.g., compromised grafts). Hyperoxia has also been used liberally by athletes in a belief that it offers performance-enhancing benefits; such benefits also extend to hypoxemic patients both at rest and during rehabilitation. This review aims to provide a comprehensive overview of the effects of hyperoxia in humans from the "bench to bedside." The first section will focus on the basic physiological principles of partial pressure of arterial O2, [Formula: see text], and barometric pressure and how these changes lead to variation in regional O2 delivery. This review provides an overview of the evidence for and against the use of hyperoxia as an aid to enhance physical performance. The final section addresses pathophysiological concepts, clinical studies, and implications for therapy. The potential of O2 toxicity and future research directions are also considered.

Differential influence of vitamin C on the peripheral and cerebral circulation after diving and exposure to hyperoxia.

We examined if the diving-induced vascular changes in the peripheral and cerebral circulation could be prevented by oral antioxidant supplementation. Fourteen divers performed a single scuba dive to eighteen meter sea water for 47 min. Twelve of the divers participated in a follow-up study involving breathing 60% of oxygen at ambient pressure for 47 min. Before both studies, participants ingested vitamin C (2 g/day) or a placebo capsule for 6 days. After a 2-wk washout, the study was repeated with the different condition. Endothelium-dependent vasodilator function of the brachial artery was assessed pre- and postintervention using the flow-mediated dilation (FMD) technique. Transcranial Doppler ultrasound was used to measure intracranial blood velocities pre- and 90 min postintervention. FMD was reduced by ∼32.8% and ∼21.2% postdive in the placebo and vitamin C trial and posthyperoxic condition in the placebo trial by ∼28.2% ( P < 0.05). This reduction in FMD was attenuated by ∼10% following vitamin C supplementation in the hyperoxic study ( P > 0.05). Elevations in intracranial blood velocities 30 min after surfacing from diving were reduced in the vitamin C study compared with the placebo trial ( P < 0.05). O2 breathing had no postintervention effects on intracranial velocities ( P > 0.05). Prophylactic ingestion of vitamin C effectively abrogated peripheral vascular dysfunction following exposure to 60% O2 but did not abolish the postdive decrease in FMD. Transient elevations of intracranial velocities postdive were reduced by vitamin C. These findings highlight the differential influence of vitamin C on peripheral and cerebral circulations following scuba diving, which are only partly mediated via hyperoxia.

Physiology of static breath holding in elite apneists.

NEW FINDINGS: What is the topic of this review? This review provides an up-to-date assessment of the physiology involved with extreme static dry-land breath holding in trained apneists. What advances does it highlight? We specifically highlight the recent findings involved with the cardiovascular, cerebrovascular and metabolic function during a maximal breath hold in elite apneists. ABSTRACT: Breath-hold-related activities have been performed for centuries, but only recently, within the last ∼30 years, has it emerged as an increasingly popular competitive sport. In apnoea sport, competition relates to underwater distances or simply maximal breath-hold duration, with the current (oxygen-unsupplemented) static breath-hold record at 11 min 35 s. Remarkably, many ultra-elite apneists are able to suppress respiratory urges to the point where consciousness fundamentally limits a breath-hold duration. Here, arterial oxygen saturations as low as ∼50% have been reported. In such cases, oxygen conservation to maintain cerebral functioning is critical, where responses ascribed to the mammalian dive reflex, e.g. sympathetically mediated peripheral vasoconstriction and vagally mediated bradycardia, are central. In defence of maintaining global cerebral oxygen delivery during prolonged breath holds, the cerebral blood flow may increase by ∼100% from resting values. Interestingly, near the termination of prolonged dry static breath holds, recent studies also indicate that reductions in the cerebral oxidative metabolism can occur, probably attributable to the extreme hypercapnia and irrespective of the hypoxaemia. In this review, we highlight and discuss the recent data on the cardiovascular, metabolic and, particularly, cerebrovascular function in competitive apneists performing maximal static breath holds. The physiological adaptation and maladaptation with regular breath-hold training are also summarized, and future research areas in this unique physiological field are highlighted; particularly, the need to determine the potential long-term health impacts of extreme breath holding.

Oxygen therapy improves cerebral oxygen delivery and neurovascular function in hypoxaemic chronic obstructive pulmonary disease patients.

NEW FINDINGS: What is the central question of this study? How does oxygen therapy influence cerebral blood flow, cerebral oxygen delivery and neurovascular function in chronic obstructive pulmonary disease patients? What is the main finding and its importance? Oxygen therapy improves cerebral oxygen delivery and neurovascular function in chronic obstructive pulmonary disease patients. This improvement in cerebral oxygen delivery and neurovascular function might provide a physiological link between oxygen therapy and a reduced risk of cerebrovascular disease (e.g. stroke, mild cognitive impairment and dementia) in chronic obstructive pulmonary disease. ABSTRACT: We investigated the role of hypoxaemia in cerebral blood flow (CBF), oxygen delivery (CDO2 ) and neurovascular coupling (coupling of CBF to neural activity; NVC) in hypoxaemic chronic obstructive pulmonary disease (COPD) patients (n = 14). Resting CBF (duplex ultrasound), peripheral oxyhaemoglobin saturation (SpO2; pulse-oximetry) and NVC (transcranial Doppler) were assessed before and after a 20 min wash-in of supplemental oxygen (∼3 l min-1 ). The peripheral oxyhaemoglobin saturation increased from 91.0 ± 3.3 to 97.4 ± 3.0% (P < 0.01), whereas CBF was unaltered (593.0 ± 162.8 versus 590.1 ± 138.5 ml min-1 ; P = 0.91) with supplemental O2 . In contrast, both CDO2 (98.1 ± 25.7 versus 108.7 ± 28.4 ml dl-1 ; P = 0.02) and NVC were improved. Specifically, the posterior cerebral artery cerebrovascular conductance was increased to a greater extent after O2 normalization (+40%, from 20.4 ± 9.9 to 28.0 ± 10.4% increase in conductance; P = 0.04), whereas the posterior cerebral artery cerebrovascular resistance decreased to a greater extent during O2 normalization (+22%, from -16.7 ± 7.3 to -21.4 ± 6.6% decrease in resistance; P = 0.04). The cerebral vasculature of COPD patients appears insensitive to oxygen, because CBF was unaltered in response to O2 supplementation leading to improved CDO2 . In patients, the improvements in CDO2 and neurovascular function with supplemental O2 may underlie the cognitive benefits associated with O2 therapy.

2D speckle tracking echocardiography of the right ventricle free wall in SCUBA divers after single open sea dive.

The presence of circulating gas bubbles and their influence on pulmonary and right heart hemodynamics was reported after uncomplicated self-contained underwater breathing apparatus (SCUBA) dive(s). Improvements in cardiac imaging have recently focused great attention on the right ventricle (RV). The aim of our study was to evaluate possible effects of a single air SCUBA dive on RV function using 2D speckle tracking echocardiography in healthy divers after single open sea dive to 18 meters of seawater, followed by bottom stay of 47 minutes with a direct ascent to the surface. Twelve experienced male divers (age 39.5 ± 10.5 years) participated in the study. Echocardiographic assessment of the right ventricular function (free wall 2 D strain, tricuspid annular planes systolic excursion [TAPSE], lateral tricuspid annular peak systolic velocity [RV s`] and fractional area change [FAC]) was performed directly prior to and 30, 60, 90 and 120 minutes after surfacing. Two-dimensional strain of all three segments of free right ventricular wall showed a significant increase in longitudinal shortening in post-dive period for maximally 26% (basal), 15.4% (mid) and 16.3% (apical) as well as TAPSE (11.6%), RV FAC (19.2%), RV S` (12.7%) suggesting a rise in systolic function of right heart. Mean pulmonary arterial pressure (mean PAP) increased post-dive from 13.3 mmHg to maximally 23.5 mmHg (P = .002), indicating increased RV afterload. Our results demonstrated that single dive with significant bubble load lead to increase in systolic function and longitudinal strain of the right heart in parallel with increase in mean PAP.

Ventilation inhibits sympathetic action potential recruitment even during severe chemoreflex stress.

This study investigated the influence of ventilation on sympathetic action potential (AP) discharge patterns during varying levels of high chemoreflex stress. In seven trained breath-hold divers (age 33 ± 12 yr), we measured muscle sympathetic nerve activity (MSNA) at baseline, during preparatory rebreathing (RBR), and during 1) functional residual capacity apnea (FRCApnea) and 2) continued RBR. Data from RBR were analyzed at matched (i.e., to FRCApnea) hemoglobin saturation (HbSat) levels (RBRMatched) or more severe levels (RBREnd). A third protocol compared alternating periods (30 s) of FRC and RBR (FRC-RBRALT). Subjects continued each protocol until 85% volitional tolerance. AP patterns in MSNA (i.e., providing the true neural content of each sympathetic burst) were studied using wavelet-based methodology. First, for similar levels of chemoreflex stress (both HbSat: 71 ± 6%; P = NS), RBRMatched was associated with reduced AP frequency and APs per burst compared with FRCApnea (both P < 0.001). When APs were binned according to peak-to-peak amplitude (i.e., into clusters), total AP clusters increased during FRCApnea (+10 ± 2; P < 0.001) but not during RBRMatched (+1 ± 2; P = NS). Second, despite more severe chemoreflex stress during RBREnd (HbSat: 56 ± 13 vs. 71 ± 6%; P < 0.001), RBREnd was associated with a restrained increase in the APs per burst (FRCApnea: +18 ± 7; RBREnd: +11 ± 5) and total AP clusters (FRCApnea: +10 ± 2; RBREnd: +6 ± 4) (both P < 0.01). During FRC-RBRALT, all periods of FRC elicited sympathetic AP recruitment (all P < 0.001), whereas all periods of RBR were associated with complete withdrawal of AP recruitment (all P = NS). Presently, we demonstrate that ventilation per se restrains and/or inhibits sympathetic axonal recruitment during high, and even extreme, chemoreflex stress.NEW & NOTEWORTHY The current study demonstrates that the sympathetic neural recruitment patterns observed during chemoreflex activation induced by rebreathing or apnea are restrained and/or inhibited by the act of ventilation per se, despite similar, or even greater, levels of severe chemoreflex stress. Therefore, ventilation modulates not only the timing of sympathetic bursts but also the within-burst axonal recruitment normally observed during progressive chemoreflex stress.

Influence of lung volume on the interaction between cardiac output and cerebrovascular regulation during extreme apnoea.

NEW FINDINGS: What is the central question of this study? Does the reduction in cardiac output observed during extreme voluntary apnoea, secondary to high lung volume, result in a reduction in cerebral blood flow, perfusion pressure and oxygen delivery in a group of elite free divers? What is the main finding and its importance? High lung volumes reduce cardiac output and ventricular filling during extreme apnoea, but changes in cerebral blood flow are observed only transiently during the early stages of apnoea. This reveals that whilst cardiac output is important in regulating cerebral haemodynamics, the role of mean arterial pressure in restoring cerebral perfusion pressure is of greater significance to the regulation of cerebral blood flow. We investigated the role of lung volume-induced changes in cardiac output (Q̇) on cerebrovascular regulation during prolonged apnoea. Fifteen elite apnoea divers (one female; 185 ± 7 cm, 82 ± 12 kg, 29 ± 7 years old) attended the laboratory on two separate occasions and completed maximal breath-holds at total lung capacity (TLC) and functional residual capacity (FRC) to elicit disparate cardiovascular responses. Mean arterial pressure (MAP), internal jugular venous pressure and arterial blood gases were measured via cannulation. Global cerebral blood flow was quantified by ultrasound and cardiac output was quantified by via photoplethysmography. At FRC, stroke volume and Q̇ did not change from baseline (P > 0.05). In contrast, during the TLC trial stroke volume and Q̇ were decreased until 80 and 40% of apnoea, respectively (P < 0.05). During the TLC trial, global cerebral blood flow was significantly lower at 20%, but subsequently increased so that cerebral oxygen delivery was comparable to that during the FRC trial. Internal jugular venous pressure was significantly higher throughout the TLC trial in comparison to FRC. The MAP increased progressively in both trials but to a greater extent at TLC, resulting in a comparable cerebral perfusion pressure between trials by the end of apnoea. In summary, although lung volume has a profound effect on Q̇ during prolonged breath-holding, these changes do not translate to the cerebrovasculature owing to the greater sensitivity of cerebral blood flow to arterial blood gases and MAP; regulatory mechanisms that facilitate the maintenance of cerebral oxygen delivery.