Right ventricular performance during acute hypoxic exercise.

Acute hypoxia increases pulmonary arterial (PA) pressures, though its effect on right ventricular (RV) function is controversial. The objective of this study was to characterize exertional RV performance during acute hypoxia. Ten healthy participants (34 ± 10 years, 7 males) completed three visits: visits 1 and 2 included non-invasive normoxic (fraction of inspired oxygen ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) = 0.21) and isobaric hypoxic ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12) cardiopulmonary exercise testing (CPET) to determine normoxic/hypoxic maximal oxygen uptake ( V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ). Visit 3 involved invasive haemodynamic assessments where participants were randomized 1:1 to either Swan-Ganz or conductance catheterization to quantify RV performance via pressure-volume analysis. Arterial oxygen saturation was determined by blood gas analysis from radial arterial catheterization. During visit 3, participants completed invasive submaximal CPET testing at 50% normoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ and again at 50% hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12). Median (interquartile range) values for non-invasive V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ values during normoxic and hypoxic testing were 2.98 (2.43, 3.66) l/min and 1.84 (1.62, 2.25) l/min, respectively (P < 0.0001). Mean PA pressure increased significantly when transitioning from rest to submaximal exercise during normoxic and hypoxic conditions (P = 0.0014). Metrics of RV contractility including preload recruitable stroke work, dP/dtmax , and end-systolic pressure increased significantly during the transition from rest to exercise under normoxic and hypoxic conditions. Ventricular-arterial coupling was maintained during normoxic exercise at 50% V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ . During submaximal exercise at 50% of hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ , ventricular-arterial coupling declined but remained within normal limits. In conclusion, resting and exertional RV functions are preserved in response to acute exposure to hypoxia at an F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12 and the associated increase in PA pressures. KEY POINTS: The healthy right ventricle augments contractility, lusitropy and energetics during periods of increased metabolic demand (e.g. exercise) in acute hypoxic conditions. During submaximal exercise, ventricular-arterial coupling decreases but remains within normal limits, ensuring that cardiac output and systemic perfusion are maintained. These data describe right ventricular physiological responses during submaximal exercise under conditions of acute hypoxia, such as occurs during exposure to high altitude and/or acute hypoxic respiratory failure.

Combined methazolamide and theophylline improves oxygen saturation but not exercise performance or altitude illness in acute hypobaric hypoxia.

NEW FINDINGS: What is the central question of this study? Does the combination of methazolamide and theophylline reduce symptoms of acute mountain sickness (AMS) and improve aerobic performance in acute hypobaric hypoxia? What is the main finding and its importance? The oral combination of methazolamide (100 BID) and theophylline (300 BID) improved arterial oxygen saturation but did not reduce symptoms of AMS and impaired aerobic performance. We do not recommend this combination of drugs for prophylaxis against the acute negative effects of hypobaric hypoxia. ABSTRACT: A limited number of small studies have suggested that methazolamide and theophylline can independently reduce symptoms of acute mountain sickness (AMS) and, if taken together, can improve aerobic exercise performance in normobaric hypoxia. We performed a randomized, double-blind, placebo-controlled, cross-over study to determine if the combination of oral methazolamide and theophylline could provide prophylaxis against AMS and improve aerobic performance in hypobaric hypoxia (∼4875 m). Volunteers with histories of AMS were screened at low altitude (1650 m) and started combined methazolamide (100 mg BID) and theophylline (300 mg BID) treatment, or placebo, 72 h prior to decompression. Baseline AMS (Lake Louise Questionnaire), blood (haemoglobin, haematocrit), cognitive function, ventilatory and pulse oximetry ( SpO2 ) measures were assessed at low altitude and repeated between 4 and 10 h of exposure to hypobaric hypoxia (PB  = 425 mmHg). Aerobic exercise performance was assessed during a 12.5 km cycling time trial (TT) after 4 h of hypobaric hypoxia. Subjects repeated all experimental procedures after a 3-week washout period. Differences between drug and placebo trials were evaluated using repeated measures ANOVA (α = 0.05). The drugs improved resting SpO2 by ∼4% (P < 0.01), but did not affect the incidence or severity of AMS or cognitive function scores relative to placebo. Subjects' performance on the 12.5 km TT was ∼3% worse when taking the drugs (P < 0.01). The combination of methazolamide and theophylline in the prescribed dosages is not recommended for use at high altitude as it appears to have no measurable effect on AMS and can impair aerobic performance.

Adaptive remodeling of skeletal muscle energy metabolism in high-altitude hypoxia: Lessons from AltitudeOmics.

Metabolic responses to hypoxia play important roles in cell survival strategies and disease pathogenesis in humans. However, the homeostatic adjustments that balance changes in energy supply and demand to maintain organismal function under chronic low oxygen conditions remain incompletely understood, making it difficult to distinguish adaptive from maladaptive responses in hypoxia-related pathologies. We integrated metabolomic and proteomic profiling with mitochondrial respirometry and blood gas analyses to comprehensively define the physiological responses of skeletal muscle energy metabolism to 16 days of high-altitude hypoxia (5260 m) in healthy volunteers from the AltitudeOmics project. In contrast to the view that hypoxia down-regulates aerobic metabolism, results show that mitochondria play a central role in muscle hypoxia adaptation by supporting higher resting phosphorylation potential and enhancing the efficiency of long-chain acylcarnitine oxidation. This directs increases in muscle glucose toward pentose phosphate and one-carbon metabolism pathways that support cytosolic redox balance and help mitigate the effects of increased protein and purine nucleotide catabolism in hypoxia. Muscle accumulation of free amino acids favor these adjustments by coordinating cytosolic and mitochondrial pathways to rid the cell of excess nitrogen, but might ultimately limit muscle oxidative capacity in vivo Collectively, these studies illustrate how an integration of aerobic and anaerobic metabolism is required for physiological hypoxia adaptation in skeletal muscle, and highlight protein catabolism and allosteric regulation as unexpected orchestrators of metabolic remodeling in this context. These findings have important implications for the management of hypoxia-related diseases and other conditions associated with chronic catabolic stress.

Beneficial Role of Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia.

BACKGROUND: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia. METHODS: Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m. RESULTS: This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O2 release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O2 release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation. CONCLUSIONS: Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.

AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia.

Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia through the so-called oxygen-dependent metabolic regulation, which involves the competitive binding of deoxyhemoglobin and glycolytic enzymes to the N-terminal cytosolic domain of band 3. This mechanism promotes the accumulation of 2,3-DPG, stabilizing the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the Bohr effect. Despite in vitro studies, in vivo adaptations to hypoxia have not yet been completely elucidated. Within the framework of the AltitudeOmics study, erythrocytes were collected from 21 healthy volunteers at sea level, after exposure to high altitude (5260 m) for 1, 7, and 16 days, and following reascent after 7 days at 1525 m. UHPLC-MS metabolomics results were correlated to physiological and athletic performance parameters. Immediate metabolic adaptations were noted as early as a few hours from ascending to >5000 m, and maintained for 16 days at high altitude. Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide, and sulfur/H2S metabolism. Metabolic adaptations were preserved 1 week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory.

Effect of progressive normobaric hypoxia on dynamic cerebral autoregulation.

NEW FINDINGS: What is the central question of this study? Acute hypoxia reduces dynamic cerebral autoregulation (dCA); however, it is unclear what level of hypoxia is necessary to exert this effect. We sought to investigate whether dCA would be reduced during progressive periods of normobaric hypoxia using a duplex Doppler ultrasound technique to evaluate the volumetric blood flow. What is the main finding and its importance? We showed that dCA decreased linearly as inspired O2 decreased from 21 to 12%. Additionally, symptoms of acute mountain sickness were related to changes in dCA. Our results may provide a sensitive and clinically relevant test to evaluate the risk of acute mountain sickness. Cerebral blood flow is maintained at relatively constant levels over a wide range of perfusion pressures via cerebral autoregulation (CA). Although acute hypoxia reduces dynamic CA, it is unclear what level of hypoxia is necessary to exert this effect. We evaluated dynamic CA during progressive normobaric hypoxia (∼1 h at each of 21, 18, 15 and 12% O2 ) using duplex ultrasonography to measure volumetric changes in common carotid artery blood flow of 11 healthy young men. Dynamic CA was evaluated by the thigh-cuff method and represented as the rate of regulation of vascular conductance. On a separate occasion, symptoms of acute mountain sickness were evaluated during 6 h of prolonged hypoxia (fractional inspired O2 of 14.1%) using the Lake Louise Questionnaire. Repeated-measures ANOVA with linear trend analysis indicated that dynamic CA decreased progressively as fractional inspired O2 was reduced (P < 0.001). Spearman rank order analysis revealed that symptoms of acute mountain sickness were related to changes in the rate of regulation of vascular conductance from 21 to 15% (r = -0.869, P = 0.006) and from 21 to 12% O2 (r = -0.648, P = 0.040), respectively. These results suggest that dynamic CA worsens with progressive hypoxia and that reductions in dynamic CA during moderate to severe hypoxia (<15% O2 ) may be related to the severity of acute mountain sickness.

Reduction in Cerebral Oxygenation After Prolonged Exercise in Hypoxia is Related to Changes in Blood Pressure.

We investigated the relation between blood pressure and cerebral oxygenation (COX) immediately after exercise in ten healthy males. Subjects completed an exercise and recovery protocol while breathing either 21% (normoxia) or 14.1% (hypoxia) O2 in a randomized order. Each exercise session included four sets of cycling (30 min/set, 15 min rest) at 50% of altitude-adjusted peak oxygen uptake, followed by 60 min of recovery. After exercise, mean arterial pressure (MAP; 87±1 vs. 84±1 mmHg, average values across the recovery period) and COX (68±1% vs. 58±1%) were lower in hypoxia compared to normoxia (P<0.001). Changes in MAP and COX were correlated during the recovery period in hypoxia (r=0.568, P<0.001) but not during normoxia (r=0.028, not significant). These results demonstrate that reductions in blood pressure following exercise in hypoxia are (1) more pronounced than in normoxia, and (2) associated with reductions in COX. Together, these results suggest an impairment in cerebral autoregulation as COX followed changes in MAP more passively in hypoxia than in normoxia. These findings could help explain the increased risk for postexercise syncope at high altitude.

Cerebral autoregulation index at high altitude assessed by thigh-cuff and transfer function analysis techniques.

NEW FINDINGS: What is the central question of this study? Whether cerebral autoregulation (CA) is impaired at high altitude and associated with acute mountain sickness remains controversial. We sought to compare two of the most common methods to assess dynamic CA in subjects who ascended to 3424 m and acclimatized. What is the main finding and its importance? We found that CA was reduced at 3424 m when assessed by the classic thigh-cuff inflation-deflation technique, but not when evaluated by transfer function analysis. These findings suggest that the cerebral vasculature of healthy individuals may become less able to buffer a large, abrupt drop in arterial blood pressure, while still maintaining the ability to regulate slow rhythmical oscillations, during periods of moderate hypoxaemia. ABSTRACT: The occurrence and implications of changes in cerebral autoregulation (CA) at high altitude are controversial and confounded by differences in methods used to assess CA. To compare two of the most common methods of dynamic CA assessment, we studied 11 young, healthy sea-level residents (six females and five males; 20.5 ± 2.3 years old) as they ascended to 3424 m and acclimatized over 13 days. A common autoregulation index (ARI) was calculated from the following: (i) transfer function analysis (TFA ARI) of resting oscillations in arterial blood pressure (ABP; finger plethysmography) and middle cerebral artery blood velocity (MCAv; transcranial Doppler); and (ii) MCAv responses following large, abrupt reductions in ABP using the classic thigh-cuff technique (Cuff ARI). Symptoms of acute mountain sickness (AMS) were monitored using the Lake Louise AMS Questionnaire. Cuff ARI scores decreased (P = 0.021) as subjects ascended from low (4.7 ± 1.5) to high altitude (3.2 ± 1.6) and did not change after 13 days of acclimatization (2.9 ± 1.3). The TFA ARI scores were not affected by ascent or acclimatization to 3424 m. Neither Cuff nor TFA ARI scores were correlated with AMS symptoms. These findings suggest that the cerebral vasculature of healthy individuals may become less able to buffer large step changes in ABP, while still maintaining the ability to regulate slow rhythmical oscillations, during periods of moderate hypoxaemia. Given the inherent differences in the autoregulatory stimulus between methods, multiple assessment techniques may be needed to clarify the implications of changes in cerebrovascular regulation at high altitude.

Effects of acute hypoxia on cerebrovascular responses to carbon dioxide.

In normoxic conditions, a reduction in arterial carbon dioxide tension causes cerebral vasoconstriction, thereby reducing cerebral blood flow and modifying dynamic cerebral autoregulation (dCA). It is unclear to what extent these effects are altered by acute hypoxia and the associated hypoxic ventilatory response (respiratory chemoreflex). This study tested the hypothesis that acute hypoxia attenuates arterial CO2 tension-mediated regulation of cerebral blood flow to help maintain cerebral O2 homeostasis. Eight subjects performed three randomly assigned respiratory interventions following a resting baseline period, as follows: (1) normoxia (21% O2); (2) hypoxia (12% O2); and (3) hypoxia with wilful restraint of the respiratory chemoreflex. During each intervention, 0, 2.0, 3.5 or 5.0% CO2 was sequentially added (8 min stages) to inspired gas mixtures to assess changes in steady-state cerebrovascular CO2 reactivity and dCA. During normoxia, the addition of CO2 increased internal carotid artery blood flow and middle cerebral artery mean blood velocity (MCA Vmean), while reducing dCA (change in phase = -0.73 ± 0.22 rad, P = 0.005). During acute hypoxia, internal carotid artery blood flow and MCA Vmean remained unchanged, but cerebrovascular CO2 reactivity (internal carotid artery, P = 0.003; MCA Vmean, P = 0.031) and CO2-mediated effects on dCA (P = 0.008) were attenuated. The effects of hypoxia were not further altered when the respiratory chemoreflex was restrained. These findings support the hypothesis that arterial CO2 tension-mediated effects on the cerebral vasculature are reduced during acute hypoxia. These effects could limit the degree of hypocapnic vasoconstriction and may help to regulate cerebral blood flow and cerebral O2 homeostasis during acute periods of hypoxia.

AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery.

Cerebral hypoxaemia associated with rapid ascent to high altitude can be life threatening; yet, with proper acclimatization, cerebral function can be maintained well enough for humans to thrive. We investigated adjustments in global and regional cerebral oxygen delivery (DO2) as 21 healthy volunteers rapidly ascended and acclimatized to 5260 m. Ultrasound indices of cerebral blood flow in internal carotid and vertebral arteries were measured at sea level, upon arrival at 5260 m (ALT1; atmospheric pressure 409 mmHg) and after 16 days of acclimatization (ALT16). Cerebral DO2 was calculated as the product of arterial oxygen content and flow in each respective artery and summed to estimate global cerebral blood flow. Vascular resistances were calculated as the quotient of mean arterial pressure and respective flows. Global cerebral blood flow increased by ∼70% upon arrival at ALT1 (P < 0.001) and returned to sea-level values at ALT16 as a result of changes in cerebral vascular resistance. A reciprocal pattern in arterial oxygen content maintained global cerebral DO2 throughout acclimatization, although DO2 to the posterior cerebral circulation was increased by ∼25% at ALT1 (P = 0.032). We conclude that cerebral DO2 is well maintained upon acute exposure and acclimatization to hypoxia, particularly in the posterior and inferior regions of the brain associated with vital homeostatic functions. This tight regulation of cerebral DO2 was achieved through integrated adjustments in local vascular resistances to alter cerebral perfusion during both acute and chronic exposure to hypoxia.

Effect of acute hypoxia on blood flow in vertebral and internal carotid arteries.

Hypoxia changes the regional distribution of cerebral blood flow and stimulates the ventilatory chemoreflex, thereby reducing CO2 tension. We examined the effects of both hypoxia and isocapnic hypoxia on acute changes in internal carotid (ICA) and vertebral artery (VA) blood flow. Ten healthy male subjects underwent the following two randomly assigned respiratory interventions after a resting baseline period with room air: (i) hypoxia; and (ii) isocapnic hypoxia with a controlled gas mixture (12% O2; inspiratory mmHg). In the isocapnic hypoxia intervention, subjects were instructed to maintain the rate and depth of breathing to maintain the level of end-tidal partial pressure of CO2 ( ) during the resting baseline period. The ICA and VA blood flow (velocity × cross-sectional area) were measured using Doppler ultrasonography. The was decreased (-6.3 ± 0.9%, P < 0.001) during hypoxia by hyperventilation (minute ventilation +12.9 ± 2.2%, P < 0.001), while was unchanged during isocapnic hypoxia. The ICA blood flow was unchanged (P = 0.429), while VA blood flow increased (+10.3 ± 3.1%, P = 0.010) during hypoxia. In contrast, isocapnic hypoxia increased both ICA (+14.5 ± 1.4%, P < 0.001) and VA blood flows (+10.9 ± 2.4%, P < 0.001). Thus, hypoxic vasodilatation outweighed hypocapnic vasoconstriction in the VA, but not in the ICA. These findings suggest that acute hypoxia elicits an increase in posterior cerebral blood flow, possibly to maintain essential homeostatic functions of the brainstem.

AltitudeOmics: effects of 16 days acclimatization to hypobaric hypoxia on muscle oxygen extraction during incremental exercise.

Acute altitude exposure lowers arterial oxygen content ([Formula: see text]) and cardiac output ([Formula: see text]) at peak exercise, whereas O2 extraction from blood to working muscles remains similar. Acclimatization normalizes [Formula: see text] but not peak [Formula: see text] nor peak oxygen consumption (V̇o2peak). To what extent acclimatization impacts muscle O2 extraction remains unresolved. Twenty-one sea-level residents performed an incremental cycling exercise to exhaustion near sea level (SL), in acute (ALT1) and chronic (ALT16) hypoxia (5,260 m). Arterial blood gases, gas exchange at the mouth and oxy- (O2Hb) and deoxyhemoglobin (HHb) of the vastus lateralis were recorded to assess arterial O2 content ([Formula: see text]), [Formula: see text], and V̇o2. The HHb-V̇o2 slope was taken as a surrogate for muscle O2 extraction. During moderate-intensity exercise, HHb-V̇o2 slope increased to a comparable extent at ALT1 (2.13 ± 0.94) and ALT16 (2.03 ± 0.88) compared with SL (1.27 ± 0.12), indicating increased O2 extraction. However, the HHb/[Formula: see text] ratio increased from SL to ALT1 and then tended to go back to SL values at ALT16. During high-intensity exercise, HHb-V̇o2 slope reached a break point beyond which it decreased at SL and ALT1, but not at ALT16. Increased muscle O2 extraction during submaximal exercise was associated with decreased [Formula: see text] in acute hypoxia. The significantly greater muscle O2 extraction during maximal exercise in chronic hypoxia is suggestive of an O2 reserve.NEW & NOTEWORTHY During incremental exercise muscle deoxyhemoglobin (HHb) and oxygen consumption (V̇o2) both increase linearly, and the slope of their relationship is an indirect index of local muscle O2 extraction. The latter was assessed at sea level, in acute and during chronic exposure to 5,260 m. The demonstrated presence of a muscle O2 extraction reserve during chronic exposure is coherent with previous studies indicating both limited muscle oxidative capacity and decrease in motor drive.

Differential blood flow responses to CO2 in human internal and external carotid and vertebral arteries.

Arterial CO2 serves as a mediator of cerebral blood flow(CBF), and its relative influence on the regulation of CBF is defined as cerebral CO2 reactivity. Our previous studies have demonstrated that there are differences in CBF responses to physiological stimuli (i.e. dynamic exercise and orthostatic stress) between arteries in humans. These findings suggest that dynamic CBF regulation and cerebral CO2 reactivity may be different in the anterior and posterior cerebral circulation. The aim of this study was to identify cerebral CO2 reactivity by measuring blood flow and examine potential differences in CO2 reactivity between the internal carotid artery (ICA), external carotid artery (ECA) and vertebral artery (VA). In 10 healthy young subjects, we evaluated the ICA, ECA, and VA blood flow responses by duplex ultrasonography (Vivid-e, GE Healthcare), and mean blood flow velocity in middle cerebral artery (MCA) and basilar artery (BA) by transcranial Doppler (Vivid-7, GE healthcare) during two levels of hypercapnia (3% and 6% CO2), normocapnia and hypocapnia to estimate CO2 reactivity. To characterize cerebrovascular reactivity to CO2,we used both exponential and linear regression analysis between CBF and estimated partial pressure of arterial CO2, calculated by end-tidal partial pressure of CO2. CO2 reactivity in VA was significantly lower than in ICA (coefficient of exponential regression 0.021 ± 0.008 vs. 0.030 ± 0.008; slope of linear regression 2.11 ± 0.84 vs. 3.18 ± 1.09% mmHg−1: VA vs. ICA, P <0.01). Lower CO2 reactivity in the posterior cerebral circulation was persistent in distal intracranial arteries (exponent 0.023 ± 0.006 vs. 0.037 ± 0.009; linear 2.29 ± 0.56 vs. 3.31 ± 0.87% mmHg−1: BA vs. MCA). In contrast, CO2 reactivity in ECA was markedly lower than in the intra-cerebral circulation (exponent 0.006 ± 0.007; linear 0.63 ± 0.64% mmHg−1, P <0.01). These findings indicate that vertebro-basilar circulation has lower CO2 reactivity than internal carotid circulation, and that CO2 reactivity of the external carotid circulation is markedly diminished compared to that of the cerebral circulation, which may explain different CBF responses to physiological stress.

A simple method to clamp end-tidal carbon dioxide during rest and exercise.

Carbon dioxide regulates ventilation and cerebral blood flow during exercise. There are significant limitations in breathing systems designed to control end-tidal gas concentrations when used during high-intensity exercise. We designed a simple, inexpensive breathing system which controls end-tidal carbon dioxide (PET CO2) during exercise from rest to peak work capacity (W(max)). The system is operated by an investigator who, in response to breath-by-breath PET CO2, titrates flow of a 10 % CO(2), 21 % O(2) mixture into an open-ended 5-L inspiratory reservoir. To demonstrate system efficacy, nine fit male subjects performed two maximal, incremental exercise tests (25 W min(-1) ramp) on a cycle ergometer: a poikilocapnic control trial in which PET CO2 varied with work intensity, and an experimental trial, in which we planned to clamp PET CO2 at 50 mmHg. With our breathing system, we maintained PET CO2 at 51 ± 2 mmHg throughout exercise (rest, 50 ± 2; W(max), 52 ± 5 mmHg; mean ± SD) despite large changes in ventilation (range 27-65 at rest, 134-185 L min(-1) BTPS at W (max)) and carbon dioxide production (range 0.3-0.7 at rest, 4.5-5.5 L min(-1) at W (max)). This simple, inexpensive system achieves PET CO2 control at rest and throughout exercise.

Health risk for athletes at moderate altitude and normobaric hypoxia.

Altitudes at which athletes compete or train do usually not exceed 2000-2500 m. At these moderate altitudes acute mountain sickness (AMS) is mild, transient and affects at the most 25% of a tourist population at risk. Unpublished data included in this review paper demonstrate that more intense physical activity associated with high-altitude training or mountaineering does not increase prevalence or severity of AMS at these altitudes. These conclusions can also be extended to the use of normobaric hypoxia, as data in this paper suggest that the severity of AMS is not significantly different between hypobaric and normobaric hypoxia at the same ambient pO(2). Furthermore, high-altitude cerebral or pulmonary oedema do not occur at these altitudes and intermittent exposure to considerably higher altitudes (4000-6000 m) used by athletes for hypoxic training are too short to cause acute high-altitude illnesses. Even moderate altitude between 2000 and 3000 m can, however, exacerbate cardiovascular or pulmonary disease or lead to a first manifestation of undiagnosed illness in older people that may belong to the accompanying staff of athletes. Moderate altitudes may also lead to splenic infarctions in healthy athletes with sickle cell trait.

Does 'altitude training' increase exercise performance in elite athletes?

The general practice of altitude training is widely accepted as a means to enhance sport performance despite a lack of rigorous scientific studies. For example, the scientific gold-standard design of a double-blind, placebo-controlled, cross-over trial has never been conducted on altitude training. Given that few studies have utilised appropriate controls, there should be more scepticism concerning the effects of altitude training methodologies. In this brief review we aim to point out weaknesses in theories and methodologies of the various altitude training paradigms and to highlight the few well-designed studies to give athletes, coaches and sports medicine professionals the current scientific state of knowledge on common forms of altitude training. Another aim is to encourage investigators to design well-controlled studies that will enhance our understanding of the mechanisms and potential benefits of altitude training.

Effects of hypobaric hypoxia on cerebral autoregulation.

BACKGROUND AND PURPOSE: Acute hypoxia is associated with impairment of cerebral autoregulation (CA), but it is unclear if altered CA during prolonged hypoxia is pivotal to the development of cerebral pathology, such as that seen in acute mountain sickness (AMS). This investigation evaluated relationship between CA and AMS over 9 hours of hypobaric hypoxia. METHODS: Fifty-five subjects (41 males, 14 females) were studied in normoxia (PB=625 mm Hg) and after 4 and 9 hours of hypobaric hypoxia (PB=425 mm Hg; approximately 4875 m). Resting, beat-by-beat changes in arterial blood pressure, and middle cerebral artery blood flow velocity were recorded at each time point while breathing room air. Transfer function analyses were used to estimate autoregulation indices (ARI). In 29 subjects, ARI during isocapnic hyperoxia and cerebral vasomotor reactivity during modified rebreathing were also determined to isolate effects of hypoxia and CO2 reactivity on CA. RESULTS: Self-reported Lake Louise AMS Questionnaire scores > or = 3 with headache were used to differentiate between AMS-positive (n=27) and AMS-negative (n=28) subjects (P<0.01). ARI decreased and CO2 reactivity increased in both groups at 4 hours (P<0.01) and did not progress at 9 hours, despite increased incidence and severity of AMS (P<0.01). Impairments in ARI were alleviated with isocapnic hyperoxia at 4 and 9 hours (P<0.01) and were not related to CO2 reactivity. CONCLUSIONS: These results indicate that hypoxia directly impairs CA but that impaired CA does not play a pivotal role in the development of AMS.

Improving biologic predictors of cycling endurance performance with near-infrared spectroscopy derived measures of skeletal muscle respiration: E pluribus unum.

The study aim was to compare the predictive validity of the often referenced traditional model of human endurance performance (i.e. oxygen consumption, VO2 , or power at maximal effort, fatigue threshold values, and indices of exercise efficiency) versus measures of skeletal muscle oxidative potential in relation to endurance cycling performance. We hypothesized that skeletal muscle oxidative potential would more completely explain endurance performance than the traditional model, which has never been collectively verified with cycling. Accordingly, we obtained nine measures of VO2 or power at maximal efforts, 20 measures reflective of various fatigue threshold values, 14 indices of cycling efficiency, and near-infrared spectroscopy-derived measures reflecting in vivo skeletal muscle oxidative potential. Forward regression modeling identified variable combinations that best explained 25-km time trial time-to-completion (TTC) across a group of trained male participants (n = 24). The time constant for skeletal muscle oxygen consumption recovery, a validated measure of maximal skeletal muscle respiration, explained 92.7% of TTC variance by itself (Adj R2  = .927, F = 294.2, SEE = 71.2, p < .001). Alternatively, the best complete traditional model of performance, including VO2max (L·min-1 ), %VO2max determined by the ventilatory equivalents method, and cycling economy at 50 W, only explained 76.2% of TTC variance (Adj R2  = .762, F = 25.6, SEE = 128.7, p < .001). These results confirm our hypothesis by demonstrating that maximal rates of skeletal muscle respiration more completely explain cycling endurance performance than even the best combination of traditional variables long postulated to predict human endurance performance.