Systemic O2 Delivery Research Articles

Mechanisms underpinning sympathoexcitation in hypoxia.

Sympathoexcitation is a hallmark of hypoxic exposure, occurring acutely, as well as persisting in acclimatised lowland populations and with generational exposure in highland native populations of the Andean and Tibetan plateaus. The mechanisms mediating altitude sympathoexcitation are multifactorial, involving alterations in both peripheral autonomic reflexes and central neural pathways, and are dependent on the duration of exposure. Initially, hypoxia-induced sympathoexcitation appears to be an adaptive response, primarily mediated by regulatory reflex mechanisms concerned with preserving systemic and cerebral tissue O2 delivery and maintaining arterial blood pressure. However, as exposure continues, sympathoexcitation is further augmented above that observed with acute exposure, despite acclimatisation processes that restore arterial oxygen content ( ). Under these conditions, sympathoexcitation may become maladaptive, giving rise to reduced vascular reactivity and mildly elevated blood pressure. Importantly, current evidence indicates the peripheral chemoreflex does not play a significant role in the augmentation of sympathoexcitation during altitude acclimatisation, although methodological limitations may underestimate its true contribution. Instead, processes that provide no obvious survival benefit in hypoxia appear to contribute, including elevated pulmonary arterial pressure. Nocturnal periodic breathing is also a potential mechanism contributing to altitude sympathoexcitation, although experimental studies are required. Despite recent advancements within the field, several areas remain unexplored, including the mechanisms responsible for the apparent normalisation of muscle sympathetic nerve activity during intermediate hypoxic exposures, the mechanisms accounting for persistent sympathoexcitation following descent from altitude and consideration of whether there are sex-based differences in sympathetic regulation at altitude.

Effects of Normoxia, Hyperoxia, and Mild Hypoxia on Macro-Hemodynamics and the Skeletal Muscle Microcirculation in Anesthetised Rats.

Objectives: Excessive oxygen (O2) administration may have a negative impact on tissue perfusion by inducing vasoconstriction and oxidative stress. We aimed to evaluate the effects of different inhaled oxygen fractions (FiO2) on macro-hemodynamics and microvascular perfusion in a rat model.Methods: Isoflurane-anesthetised spontaneously breathing male Wistar rats were equipped with arterial (carotid artery) and venous (jugular vein) catheters and tracheotomy, and randomized into three groups: normoxia (FiO2 21%, n = 6), hyperoxia (FiO2 100%, n = 6) and mild hypoxia (FiO2 15%, n = 6). Euvolemia was maintained by infusing Lactate Ringer solution at 10 ml/kg/h. At hourly intervals for 4 h we collected measurements of: mean arterial pressure (MAP); stroke volume index (SVI), heart rate (HR), respiratory rate (by means of echocardiography); arterial and venous blood gases; microvascular density, and flow quality (by means of sidestream dark field videomicroscopy on the hindlimb skeletal muscle).Results: MAP and systemic vascular resistance index increased with hyperoxia and decreased with mild hypoxia (p < 0.001 in both cases, two-way analysis of variance). Hyperoxia induced a reduction in SVI, while this was increased in mild hypoxia (p = 0.002). The HR increased under hyperoxia (p < 0.05 vs. normoxia at 3 h). Cardiax index, as well as systemic O2 delivery, did not significantly vary in the three groups (p = 0.546 and p = 0.691, respectively). At 4 h, microvascular vessel surface (i.e., the percentage of tissue surface occupied by vessels) decreased by 29 ± 4% in the hyperoxia group and increased by 19 ± 7 % in mild hypoxia group (p < 0.001). Total vessel density and perfused vessel density showed similar tendencies (p = 0.003 and p = 0.005, respectively). Parameters of flow quality (microvascular flow index, percentage of perfused vessels, and flow heterogeneity index) remained stable and similar in the three groups.Conclusions: Hyperoxia induces vasoconstriction and reduction in skeletal muscle microvascular density, while mild hypoxia has an opposite effect.

Acute Moderate Hypoxia Reduces One-Legged Cycling Performance Despite Compensatory Increase in Peak Cardiac Output: A Pilot Study.

In severe hypoxia, single-leg peak oxygen uptake (VO2peak) is reduced mainly due to the inability to increase cardiac output (CO). Whether moderate altitude allows CO to increase during single-leg cycling, thereby restoring VO2peak, has not been extensively investigated. Five healthy subjects performed an incremental, maximal, two-legged cycle ergometer test, and on separate days a maximal incremental one-leg cycling test in normoxia and in moderate hypoxia (fraction of inspired oxygen (FiO2) = 15%). Oxygen uptake, heart rate, blood pressure responses, power output, and CO (PhysioFlow) were measured during all tests. Moderate hypoxia lowered single-leg peak power output (154 ± 31 vs. 128 ± 26 watts, p = 0.03) and oxygen uptake (VO2) (36.8 ± 6.6 vs. 33.9 ± 6.9 mL/min/kg, p = 0.04), despite higher peak CO (16.83 ± 3.10 vs. 18.96 ± 3.59 L/min, p = 0.04) and systemic oxygen (O2) delivery (3.37 ± 0.84 vs. 3.47 ± 0.89 L/min, p = 0.04) in hypoxia compared to normoxia. Arterial–venous O2 difference (a–vDO2) was lower in hypoxia (137 ± 21 vs. 112 ± 19 mL/l, p = 0.03). The increases in peak CO from normoxia to hypoxia were negatively correlated with changes in mean arterial pressure (MABP) (p < 0.05). These preliminary data indicate that the rise in CO was not sufficient to prevent single-leg performance loss at moderate altitude and that enhanced baroreceptor activity might limit CO increases in acute hypoxia, likely by reducing sympathetic activation. Since the systemic O2 delivery was enhanced and the calculated a–vDO2 reduced in moderate hypoxia, a potential diffusion limitation cannot be excluded.

Polymerized Hemoglobin Maintains Cardiac Function After Extreme Anemia

BackgroundBlood transfusion as a treatment for anemia is vital in ensuring oxygen (O2) carrying capacity. However, fears of blood shortages and adverse reactions to stored blood transfusion have driven the development of oxygen carrying alternatives to blood. One class of alternatives to blood for transfusion medicine are hemoglobin (Hb) based oxygen carriers (HBOCs), which have been in development for decades. A recent advancement in the development of HBOCs is the discovery that their O2 affinity can be tightly regulated by locking Hb in the T state (low O2 affinity), or R state (high O2 affinity). By regulating O2 affinity, O2 extraction by tissues can be controlled, and targeted O2 delivery to hypoxic tissues is made possible. As the heart is one of the most sensitive organs to changes in oxygenation due to its high metabolic rate, the objective of this study was to test the efficacy of high and low O2 affinity HBOCs in maintaining cardiac function and systemic O2 delivery during severe anemia.MethodsPolymerized hemoglobin (PolyHb), the most scalable method of producing HBOCs, was synthesized in the high and low O2 affinity state (R and T, respectively) with glutaraldehyde and then subjected to 8–9 cycles of diafiltration as previously described. This resulted in a PolyHb solution containing only polymerized Hb molecules &gt; 500kDa suspended in Lactated Ringers solution. Rats were instrumented with a pressure‐volume catheter to monitor cardiac function. Severe anemia was induced via a 50% isovolumic hemodilution with 5% human serum albumin. Rats were then resuscitated by a 40% isovolumic infusion of a 10 g/dL solution of R PolyHb, T PolyHb, or fresh blood (drawn from the animal during the first exchange).ResultsSevere anemia resulted in impaired cardiac function and O2 delivery. Transfusion of fresh blood, T PolyHb, and R PolyHb restored vascular resistance, blood pressure, and cardiac contractility. T PolyHb also promoted increased O2 extraction and myocardial energy utilization. Severe anemia did not cause significant changes in blood electrolytes relative to baseline. Severe anemia resulted in blood acidification that only recovered for animals resuscitated with T PolyHb. Furthermore, resuscitation with T PolyHb resulted in higher arterial pO2 and lower pCO2 than other groups. R PolyHb increased lactate and glucose, suggesting that the high O2 affinity prevented proper O2 release to some tissues, despite maintaining cardiac function.ConclusionsBoth T and R PolyHb maintain myocardial O2 extraction compared to fresh blood. T PolyHb appears to be the optimal molecule for increasing O2 delivery during anemic conditions. Although R PolyHb apparently decreased systemic O2 extraction during anemia, it can be potentially useful to increase O2 uptake in the lungs during hypoxic‐hypoxia. This study indicates that PolyHb is as efficacious as fresh blood in restoring cardiac function and oxygenation in rats during severe anemia.Support or Funding InformationThis work was supported by the NIH Heart Lung and Blood Institute under Grants T32‐HL105373, R01‐HL126945, and R01‐HL138116.

Nitric oxide in red blood cell adaptation to hypoxia.

Nitric oxide (NO) appears to be involved in virtually every aspect of cardiovascular biology. Most attention has been focused on the role of endothelial-derived NO in basal blood flow regulation by relaxing vascular smooth muscle; however, it is now known that NO derived from red blood cells (RBCs) plays a fundamental role in vascular homeostasis by enhancing oxygen (O2) release at the cellular and physiological level. Hypoxia is an often seen problem in diverse conditions; systemic adaptations to hypoxia permit people to adjust to the hypoxic environment at high altitudes and to disease processes. In addition to the cardiopulmonary and hematologic adaptations that support systemic O2 delivery in hypoxia, RBCs assist through newly described NO-based mechanisms, in line with their vital role in O2 transport and delivery. Furthermore, to increase the local blood flow in proportion to metabolic demand, NO regulates membrane mechanical properties thereby modulating RBC deformability and O2 carrying-releasing function. In this review article, we focus on the effect of NO bioactivity on RBC-based mechanisms that regulate blood flow and RBC deformability. RBC adaptations to hypoxia are summarized, with particular attention to NO-dependent S-nitrosylation of membrane proteins and hemoglobin (S-nitrosohemoglobin). The NO/S-nitrosylation/RBC vasoregulatory cascade contributes fundamentally to the molecular understanding of the role of NO in human adaptation to hypoxia and may inform novel therapeutic strategies.

Esmolol acutely alters oxygen supply-demand balance in exercising muscles of healthy humans

Beta‐adrenoreceptor antagonists (β blockers) reduce systemic O2 delivery and blood pressure (BP) during exercise, but the subsequent effects on O2 extraction within the active limb muscles are unknown. In this study, we examined the effects of the fast‐acting, β 1 selective blocker esmolol on systemic hemodynamics and leg muscle O2 saturation (near infrared spectroscopy, NIRS) during submaximal leg ergometry. Our main hypothesis was that esmolol would augment exercise‐induced reductions in leg muscle O2 saturation. Eight healthy adults (6 men, 2 women; 23–67 year) performed light and moderate intensity bouts of recumbent leg cycling before (PRE), during (β 1‐blocked), and 45 min following (POST) intravenous infusion of esmolol. Oxygen uptake, heart rate (HR), BP, and O2 saturation (SmO2) of the vastus lateralis (VL) and medial gastrocnemius (MG) muscles were measured continuously. Esmolol attenuated the increases in HR and systolic BP during light (−12 ± 9 bpm and −26 ± 12 mmHg vs. PRE) and moderate intensity (−20 ± 10 bpm and −40 ± 18 mmHg vs. PRE) cycling (all P < 0.01). Exercise‐induced reductions in SmO2 occurred to a greater extent during the β 1‐blockade trial in both the VL (P = 0.001 vs. PRE) and MG muscles (P = 0.022 vs. PRE). HR, SBP and SmO2 were restored during POST (all P < 0.01 vs. β 1‐blocked). In conclusion, esmolol rapidly and reversibly increases O2 extraction within exercising muscles of healthy humans.

Decreases in Mixed Venous Blood O2 Saturation in Cardiac Surgery Patients Following Extubation.

Decreases in mixed venous O2 saturation (SvO2) have been reported to occur in postcardiac surgery patients during weaning from mechanical ventilation. Our aim was to establish whether the physiological mechanism responsible for this phenomenon was a decrease in systemic O2 delivery (DO2) or an increase in global O2 consumption ( O 2). We studied 21 mechanically ventilated, postoperative cardiac patients for 30 minutes before and 60 minutes after extubation. We monitored continuously arterial O2 saturation by pulse oximetry (SaO2) and central venous O2 saturation (ScvO2) with an oximetry catheter. Mixed venous O2 saturation (SvO2) and cardiac output were also measured continuously with an oximetry pulmonary artery catheter. Systemic O2 delivery and O 2 were calculated according to accepted formulae. Immediately following extubation, ScvO2 and SvO2 decreased rapidly (P < .01). Systemic O2 consumption increased from 65 (57) mL·min-1 to 194 (66) mL·min-1 (P < .05) with no changes in DO2. Consequently, systemic O2 extraction rose from 38% (8%) to 45% (9%; P < .01). Preoperative left ventricular ejection fraction correlated with the decline in SvO2 postextubation. All patients weaned successfully. Decreases in SvO2 after discontinuation of ventilatory support in postcardiac surgery patients occur as O 2 increases in response to greater energy requirements by muscles of ventilation that are not initially matched by increases in DO2.

Effects of dobutamine on intestinal microvascular blood flow heterogeneity and O2 extraction during septic shock.

Derangements of microvascular blood flow distribution might contribute to disturbing O2 extraction by peripheral tissues. We evaluated the dynamic relationships between the mesenteric O2 extraction ratio ([Formula: see text]) and the heterogeneity of microvascular blood flow at the gut and sublingual mucosa during the development and resuscitation of septic shock in a swine model of fecal peritonitis. Jejunal-villi and sublingual microcirculation were evaluated using a portable intravital-microscopy technique. Simultaneously, we obtained arterial, mixed-venous, and mesenteric blood gases, and jejunal-tonometric measurements. During resuscitation, pigs were randomly allocated to a fixed dose of dobutamine (5 µg·kg-1·min-1) or placebo while three sham models with identical monitoring served as controls. At the time of shock, we observed a significant decreased proportion of perfused intestinal-villi (villi-PPV) and sublingual percentage of perfused small vessels (SL-PPV), paralleling an increase in [Formula: see text] in both dobutamine and placebo groups. After starting resuscitation, villi-PPV and SL-PPV significantly increased in the dobutamine group with subsequent improvement of functional capillary density, whereas [Formula: see text] exhibited a corresponding significant decrease (repeated-measures ANOVA, P = 0.02 and P = 0.04 for time × group interactions and intergroup differences for villi-PPV and [Formula: see text], respectively). Variations in villi-PPV were paralleled by variations in [Formula: see text] (R2 = 0.88, P < 0.001) and these, in turn, by mesenteric lactate changes (R2 = 0.86, P < 0.001). There were no significant differences in cardiac output and systemic O2 delivery throughout the experiment. In conclusion, dynamic changes in microvascular blood flow heterogeneity at jejunal mucosa are closely related to the mesenteric O2 extraction ratio, suggesting a crucial role for microvascular blood flow distribution on O2 uptake during development and resuscitation from septic shock.NEW & NOTEWORTHY Our observations suggest that dynamic changes in the heterogeneity of microvascular blood flow at the gut mucosa are closely related to mesenteric O2 extraction, thus supporting the role of decreasing functional capillary density and increased intercapillary distances on alterations of O2 uptake during development and resuscitation from septic shock. Addition of a low-fixed dose of dobutamine might reverse such flow heterogeneity, improving microcirculatory flow distribution and tissue O2 consumption.

No difference in plantar flexion maximal exercise power output between men and women

Background Maximal oxygen consumption \( \dot{V}O_{{2{\text{MAX}}}} \) can be lower in women compared to men during traditional, systemic exercise even when corrected for differences in fat free mass (FFM). One potential source for lower \( \dot{V}{\text{O}}_{{2{\text{MAX}}}} \) might be inherent differences in muscle in men and women. Exercising isolated muscle such as plantar flexion provides the opportunity to study muscle function independent of systemic O2 delivery limitations. It was hypothesized that women would have lower plantar flexion power output (PO) than men even when corrected to calf FFM.

Altered cardiorespiratory response to exercise in overweight and obese women with polycystic ovary syndrome.

In polycystic ovary syndrome (PCOS), cardiovascular risk is increased. Peak O2 uptake (V˙O2peak) predicts the cardiovascular risk. We were the first to examine the contribution of systemic O2 delivery and arteriovenous O2 difference to V˙O2peak in overweight and obese women with PCOS. Fifteen overweight or obese PCOS women and 15 age‐, anthropometry‐, and physical activity‐matched control women performed a maximal incremental cycling exercise test. Alveolar gas exchange (volume turbine and mass spectrometry), arterial O2 saturation (pulse oximetry), and cardiac output (CO) (impedance cardiography) were monitored. Hb concentration was determined. Arterial O2 content and arteriovenous O2 difference (C(a‐v)O2) (Fick equation) were calculated. Insulin resistance was evaluated by homeostasis model assessment (HOMA‐IR). PCOS women had lower V˙O2peak than controls (40 ± 6 vs. 46 ± 5 mL/min/kg fat‐free mass [FFM], P = 0.011). Arterial O2 content was similarly maintained in the groups throughout the exercise test (P > 0.05). Linear regression analysis revealed a pronounced response of CO to increasing V˙O2 in PCOS women during the exercise test: A ∆CO/∆V˙O2 slope was steeper in PCOS women than in controls (β = 5.84 vs. β = 5.21, P = 0.004). Eventually, the groups attained similar peak CO and peak CO scaled to FFM (P > 0.05). Instead, C(a‐v)O2 at peak exercise was lower in PCOS women than in controls (13.2 ± 1.6 vs. 14.8 ± 2.4 mL O2/100 mL blood, P = 0.044). HOMA‐IR was similar in the groups (P > 0.05). The altered cardiorespiratory responses to exercise in overweight and obese PCOS women indicate that PCOS per se is associated with alterations in peripheral adjustments to exercise rather than with limitations of systemic O2 delivery.

Regulation of cardiac output in hypoxia.

This brief review addresses the regulation of cardiac output (Q) at rest and during submaximal exercise in acute and chronic hypoxia. To preserve systemic O2 delivery in acute hypoxia Q is increased by an acceleration of heart rate, whereas stroke volume (SV) remains unchanged. Tachycardia is governed by activation of carotid and aortic chemoreceptors and a concomitant reduction in arterial baroreflex activation, all balancing sympathovagal activity toward sympathetic dominance. As hypoxia extends over several days a combination of different adaptive processes restores arterial O2 content to or beyond sea level values and hence Q normalizes. The latter however occurs as a consequence of a decrease in SV whereas tachycardia persists. The diminished SV reflects a lower left ventricular end-diastolic volume which is primarily related to hypoxia-generated reduction in plasma volume. Hypoxic pulmonary vasoconstriction may contribute by increasing right ventricular afterload and thus decreasing its ejection fraction. In summary, the Q response to hypoxia is the result of a complex interplay between several physiological mechanisms. Future studies are encouraged to establish the individual contributions of the different components from an integrative perspective.

Impaired Skeletal Muscle Oxygenation and Exercise Tolerance in Pulmonary Hypertension.

Limb muscle dysfunction is documented in pulmonary arterial hypertension (PAH), but little is known regarding muscle oxygen (O2) supply and its possible effects on exercise tolerance in PAH. Ten patients with PAH and 10 matched controls underwent progressive maximal cardiopulmonary exercise test, voluntary and nonvolitional dominant quadriceps muscle strength measures, and nondominant quadriceps biopsy to assess maximal oxygen uptake, muscle function, and lower limb fiber type and capillarity, respectively. Both groups then performed normoxic and hyperoxic submaximal intensity exercise protocol at the same absolute workload during which muscle O2 supply was assessed by measuring changes in myoglobin-deoxyhemoglobin level (Δ[Mb-HHb]) and tissue oxygenation index in the dominant quadriceps using near-infrared spectroscopy. Changes in cardiac output, estimated systemic O2 delivery, and systemic O2 saturation were also assessed noninvasively throughout both submaximal exercises. Patients with PAH displayed lower maximal oxygen uptake (P < 0.01), skeletal muscle strength (P < 0.05), and capillarity (P = 0.01). Throughout the normoxic submaximal exercise protocol, Δ[Mb-HHb] (P < 0.01) was higher whereas changes in tissue oxygenation index (P < 0.01) and systemic O2 saturation (P = 0.01) were lower in patients with PAH compared with those in controls. Conversely, changes in cardiac output and estimated systemic O2 delivery were similar between groups. Muscle oxygenation remained unchanged with O2 supplementation. Among variables known to influence tissue oxygenation, only quadriceps capillarity density correlated with Δ[Mb-HHb] (r = -0.66, P < 0.01), which in turn correlated with maximal oxygen uptake (r = -0.64, P < 0.01), 6-min walked distance (r = -0.74, P = 0.01), and both voluntary (r = -0.46, P = 0.04) and nonvolitional (r = -0.50, P = 0.02) quadriceps strength. Capillary rarefaction within the skeletal muscle influences exercise tolerance and quadriceps strength at least partly through impaired muscle oxygen supply in PAH.

Localized increase of tissue oxygen tension by magnetic targeted drug delivery

Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy-methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg−1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to increase O2 in tumors, enhancing the efficacy of radiation therapies.

Hypovolemia explains the reduced stroke volume at altitude

During acute altitude exposure tachycardia increases cardiac output (Q) thus preserving systemic O2 delivery. Within days of acclimatization, however, Q normalizes following an unexplained reduction in stroke volume (SV). To investigate whether the altitude-mediated reduction in plasma volume (PV) and hence central blood volume (CBV) is the underlying mechanism we increased/decreased CBV by means of passive whole body head-down (HDT) and head-up (HUT) tilting in seven lowlanders at sea level (SL) and after 25/26 days of residence at 3454 m. Prior to the experiment on day 26, PV was normalized by infusions of a PV expander. Cardiovascular responses to whole body tilting were monitored by pulse contour analysis. After 25/26 days at 3454 m PV and blood volume decreased by 9 ± 4% and 6 ± 2%, respectively (P < 0.001 for both). SV was reduced compared to SL for each HUT angle (P < 0.0005). However, the expected increase in SV from HUT to HDT persisted and ended in the same plateau as at SL, albeit this was shifted 18 ± 20° toward HDT (P = 0.019). PV expansion restored SV to SL during HUT and to an ∼8% higher level during HDT (P = 0.003). The parallel increase in SV from HUT to HDT at altitude and SL to a similar plateau demonstrates an unchanged dependence of SV on CBV, indicating that the reduced SV during HUT was related to an attenuated CBV for a given tilt angle. Restoration of SV by PV expansion rules out a significant contribution of other mechanisms, supporting that resting SV at altitude becomes reduced due to a hypovolemia.

Erratum to: Haemodynamic responses to dehydration in the resting and exercising human leg

In the originally published article systemic O2 delivery values reported in Fig. 3 are incorrect. The correct calculation for systemic O2 delivery (L min ) = arterial O2 content (mL L) * cardiac output (L min). The error in the manuscript was due to a miscalculation in the unit conversion from mL to L resulting in an erroneously high systemic O2 delivery across all conditions of dehydration/ rehydration and rest and exercise. Therefore, this error does not change the statistical results, the interpretation of the results nor the implication of the findings. The recalculations for each condition are as follows, control rest = 1.16 ± 0.06 L min, control exercise = 1.52 ± 0.07 L min, 2 % dehydration rest = 1.23 ± 0.03 L min, 2 % dehydration exercise = 1.58 ± 0.07 L min, 3.5 % dehydration rest = 1.37 ± 0.07 L min, 3.5 % dehydration exercise = 1.69 ± 0.06 L min, rehydration rest = 1.29 ± 0.04 L min, rehydration exercise = 1.58 ± 0.05 L min. Accordingly, the systemic O2 delivery panel from Fig. 3 has also changed.

Central versus peripheral control of cardiac output in humans: insight from atrial pacing

Central <i>versus</i> peripheral control of cardiac output in humans: insight from atrial pacing

Exercise capacity and oxygen transport in native Tibetan highlanders with high‐ compared to low‐hemoglobin concentration

Evidence suggests elevated [Hb] at high altitude is a non‐advantageous, possibly misguided, response to high‐altitude hypoxia. In support of that, lower [Hb] is often observed in native high‐altitude resident Tibetans. To determine whether [Hb] in Tibetans is associated with peak VO2 and/or changes in particular step(s) of the O2 transport chain, we compared ventilation, lung diffusional conductance, cardiac output and systemic O2 delivery, and muscle O2 diffusional conductance in 21 Tibetan males with [Hb] ranging from 15.2 g/gl to 22.9 g/dl [Hb] by measuring their ventilation, VO2 and VCO2, heart rate, cardiac output, and arterial PO2, PCO2, pH, P50, and O2 saturation at peak exercise on a cycle ergometer. [Hb] showed a significant negative relationship with VO2/kg (r= −0.45, p&lt; 0.05), cardiac output/kg (r= −0.54, p &lt; 0.01), and diffusion capacity in muscle (DM/kg: r= −0.44, p&lt;0.05) but not lung. Furthermore, VO2/kg was highly positively correlated with DM/kg (r=0.84, p&lt; 2×10‐6), QT/kg (r=0.76, p &lt; 7.5×10‐5), and arterial [H+] (r= 0.52, p &lt; 0.02), and DM/kg was related to QT/kg (r=0.43, p &lt; 0.051). These trends suggest that genetic mutations resulting in reduced [Hb] may convey an advantage in exercise capacity, possibly via higher cardiac function, ventilation, and diffusion capacity in the muscle and support the emerging hypothesis that the polycythemia of altitude is a misguided response to low cellular PO2.

Similar peak VO2 at altitude in native lowland (Han Chinese) and Tibetan highland inhabitants despite different hemoglobin concentration [Hb

Tibetan highlanders exhibit a unique suite of physiological traits, including markedly decreased [Hb] compared to Andean highlanders and high‐altitude sojourners at the same altitude. We performed exercise studies at 4200m in both native lowland Han Chinese males resident at &gt;4000m for at least the past year (n = 7, [Hb]=19+/−0.77 g/dl) and native highland Tibetan males (n = 21, [Hb]=17.7+/−2.07 g/dl, p&lt;0.02 between groups) to determine whether they differed in exercise capacity and/or one or more step(s) of the oxygen transport cascade. During maximal exercise we measured ventilation, VO2 and VCO2, heart rate, cardiac output, arterial PO2, PCO2, pH, HbP50, and arterial O2 saturation and calculated systemic O2 delivery and lung and muscle diffusional conductances (DL, DM). While peak VO2 and arterial blood gas variables were similar between groups, peak cardiac output and index trended lower in Han (both p &lt; 0.11), which combined with higher [Hb], resulted in similar O2 delivery. DL normalized to lung volume trended higher (p &lt; 0.07) in Tibetans, but DM was not different. These results show that in spite of lower [Hb], and thus O2 carrying capacity, Tibetan males can reach the same peak VO2 as Han, and appear to offset lower [Hb] by higher cardiac output, and possibly, lung diffusing capacity. How these differences relate to recently described changes in hypoxia‐sensitive genes in Tibetans remains to be determined.

Systemic oxygen transport derived by using continuous measured oxygen consumption after the Norwood procedure−an interim review

The balance between systemic O(2)consumption (VO(2)) and O(2)delivery (DO(2)) is impaired in children after cardiopulmonary bypass surgery, with decreased DO(2)and increased VO(2). The major goal, and the major challenge, of postoperative management has been to match DO(2)to VO(2)in order to sustain cellular metabolism, particularly in neonates after the Norwood procedure. While much effort has been put into augmenting cardiac output and DO(2), VO(2)remains largely ignored. Respiratory mass spectrometry allows the precise and continuous measurement of VO(2). Measured VO(2), using the direct Fick principle, allows for the calculation of each element of systemic O(2)transport in the complex Norwood circulation. The actual measurements of O(2)transport have allowed us, in the past five years or so, to extensively investigate the Norwood physiology in terms of the VO(2)-DO(2)relationship and the factors affecting it in clinical treatments. Therefore, the first objective of this article is to introduce the technique of respiratory mass spectrometry and its adaption to measure VO(2)across paediatric ventilators with continuous flow. The second objective is to give an interim review of the main findings in our studies on systemic O(2)transport in 17 neonates in the first 72h after the Norwood procedure. These findings include the profiles of systemic O(2)transport, the important contribution of VO(2)to the impaired balance of O(2)transport and the complex effects of some routine clinical treatments on the VO(2)-DO(2)relationship (including catecholamines, PaCO(2), Mg(2+)and hyperglycaemia, as well as patient-specific anatomical variations). The influence of systemic O(2)transport on cerebral oxygenation is also introduced. This information may help us to refine postoperative management in neonates after the Norwood procedure. Our initial studies mark the end of the beginning, but much is yet explored. Ultimately, the resultant improved systemic and regional O(2)transport in the early postoperative period may have an important impact on long-term outcomes, thereby improving the quality of life for these vulnerable children.

Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms

Exertional dyspnea limits exercise in some mitochondrial myopathy (MM) patients, but the clinical features of this syndrome are poorly defined, and its underlying mechanism is unknown. We evaluated ventilation and arterial blood gases during cycle exercise and recovery in five MM patients with exertional dyspnea and genetically defined mitochondrial defects, and in four control subjects (C). Patient ventilation was normal at rest. During exercise, MM patients had low Vo(2peak) (28 ± 9% of predicted) and exaggerated systemic O(2) delivery relative to O(2) utilization (i.e., a hyperkinetic circulation). High perceived breathing effort in patients was associated with exaggerated ventilation relative to metabolic rate with high VE/VO(2peak), (MM = 104 ± 18; C = 42 ± 8, P ≤ 0.001), and Ve/VCO(2peak)(,) (MM = 54 ± 9; C = 34 ± 7, P ≤ 0.01); a steeper slope of increase in ΔVE/ΔVCO(2) (MM = 50.0 ± 6.9; C = 32.2 ± 6.6, P ≤ 0.01); and elevated peak respiratory exchange ratio (RER), (MM = 1.95 ± 0.31, C = 1.25 ± 0.03, P ≤ 0.01). Arterial lactate was higher in MM patients, and evidence for ventilatory compensation to metabolic acidosis included lower Pa(CO(2)) and standard bicarbonate. However, during 5 min of recovery, despite a further fall in arterial pH and lactate elevation, ventilation in MM rapidly normalized. These data indicate that exertional dyspnea in MM is attributable to mitochondrial defects that severely impair muscle oxidative phosphorylation and result in a hyperkinetic circulation in exercise. Exaggerated exercise ventilation is indicated by markedly elevated VE/VO(2), VE/VCO(2), and RER. While lactic acidosis likely contributes to exercise hyperventilation, the fact that ventilation normalizes during recovery from exercise despite increasing metabolic acidosis strongly indicates that additional, exercise-specific mechanisms are responsible for this distinctive pattern of exercise ventilation.