Christoph Siebenmann

Cutaneous Vasoconstriction Affects Near-infrared Spectroscopy Determined Cerebral Oxygen Saturation during Administration of Norepinephrine

Background: Perioperative optimization of spatially resolved near-infrared spectroscopy determined cerebral frontal lobe oxygenation (scO2) may reduce postoperative morbidity. Norepinephrine is routinely administered to maintain cerebral perfusion pressure and, thereby, cerebral blood flow, but norepinephrine reduces the scO2. We hypothesized that norepinephrine-induced reduction in scO2 is influenced by cutaneous vasoconstriction. Methods: Fifteen healthy male subjects (25 ± 5 yr, mean ± SD) were studied during: hyperventilation (1.5 kPa end-tidal PcO2 reduction), whole-body heating, administration of norepinephrine (0.15 &mgr;g · kg−1 · min−1; with and without end-tidal carbon dioxide correction), and hypoxia (FiO2: 0.12%). Arterial (saO2), skin, and internal jugular venous oxygen saturations (sjO2) were recorded, and the average cerebral capillary oxygen saturation (scapO2) was calculated. Results: This study indicates that scO2 is influenced by skin oxygen saturation because whole-body heating increased scO2 by 3.6% (2.1–5.1%; 95% CI) and skin oxygen saturation by 3.1% (1.3–4.9%), whereas scapO2 remained unaffected. Conversely, hyperventilation decreased scO2 by 2.1% (0.4–3.7%) and scapO2 by 5.3% (3.8–6.9%), whereas skin oxygen saturation increased 1.8% (0.5–3.1%). In response to hypoxia, scO2 (10.2%; 6.6–13.7%), scapO2 (7.9%; 6.4–9.4%), and skin oxygen saturation (8.9%; 6.3–11.6%) all decreased. With administration of norepinephrine there was a 2.2% (1.0–4.3%) decrease in skin oxygen saturation and scO2 decreased 6.2% (4.2–8.0%), with scapO2 remaining unaffected. Conclusion: The results confirm that spatially resolved near-infrared spectroscopy detects cerebral deoxygenation with systemic hypoxic exposure and hyperventilation. However, a commonly used vasopressor norepinephrine disturbs skin oxygen saturation to an extent that influences scO2.

“Live high–train low” using normobaric hypoxia: a double-blinded, placebo-controlled study

The combination of living at altitude and training near sea level [live high-train low (LHTL)] may improve performance of endurance athletes. However, to date, no study can rule out a potential placebo effect as at least part of the explanation, especially for performance measures. With the use of a placebo-controlled, double-blinded design, we tested the hypothesis that LHTL-related improvements in endurance performance are mediated through physiological mechanisms and not through a placebo effect. Sixteen endurance cyclists trained for 8 wk at low altitude (<1,200 m). After a 2-wk lead-in period, athletes spent 16 h/day for the following 4 wk in rooms flushed with either normal air (placebo group, n = 6) or normobaric hypoxia, corresponding to an altitude of 3,000 m (LHTL group, n = 10). Physiological investigations were performed twice during the lead-in period, after 3 and 4 wk during the LHTL intervention, and again, 1 and 2 wk after the LHTL intervention. Questionnaires revealed that subjects were unaware of group classification. Weekly training effort was similar between groups. Hb mass, maximal oxygen uptake (VO(2)) in normoxia, and at a simulated altitude of 2,500 m and mean power output in a simulated, 26.15-km time trial remained unchanged in both groups throughout the study. Exercise economy (i.e., VO(2) measured at 200 W) did not change during the LHTL intervention and was never significantly different between groups. In conclusion, 4 wk of LHTL, using 16 h/day of normobaric hypoxia, did not improve endurance performance or any of the measured, associated physiological variables.

Determinants of time trial performance and maximal incremental exercise in highly trained endurance athletes

Human endurance performance can be predicted from maximal oxygen consumption (Vo(2max)), lactate threshold, and exercise efficiency. These physiological parameters, however, are not wholly exclusive from one another, and their interplay is complex. Accordingly, we sought to identify more specific measurements explaining the range of performance among athletes. Out of 150 separate variables we identified 10 principal factors responsible for hematological, cardiovascular, respiratory, musculoskeletal, and neurological variation in 16 highly trained cyclists. These principal factors were then correlated with a 26-km time trial and test of maximal incremental power output. Average power output during the 26-km time trial was attributed to, in order of importance, oxidative phosphorylation capacity of the vastus lateralis muscle (P = 0.0005), steady-state submaximal blood lactate concentrations (P = 0.0017), and maximal leg oxygenation (sO(2LEG)) (P = 0.0295), accounting for 78% of the variation in time trial performance. Variability in maximal power output, on the other hand, was attributed to total body hemoglobin mass (Hb(mass); P = 0.0038), Vo(2max) (P = 0.0213), and sO(2LEG) (P = 0.0463). In conclusion, 1) skeletal muscle oxidative capacity is the primary predictor of time trial performance in highly trained cyclists; 2) the strongest predictor for maximal incremental power output is Hb(mass); and 3) overall exercise performance (time trial performance + maximal incremental power output) correlates most strongly to measures regarding the capability for oxygen transport, high Vo(2max) and Hb(mass), in addition to measures of oxygen utilization, maximal oxidative phosphorylation, and electron transport system capacities in the skeletal muscle.

Effect of Short-Term Acclimatization to High Altitude on Sleep and Nocturnal Breathing

STUDY OBJECTIVE Objective physiologic data on sleep and nocturnal breathing at initial exposure and during acclimatization to high altitude are scant. We tested the hypothesis that acute exposure to high altitude induces quantitative and qualitative changes in sleep and that these changes are partially reversed with acclimatization. DESIGN Prospective observation. SETTING One night in a sleep laboratory at 490 meters, the first and the third night in a mountain hut at 4559 meters. PARTICIPANTS Sixteen healthy mountaineers. INTERVENTION Altitude exposure. MEASUREMENTS Polysomnography, questionnaire evaluation of sleep and acute mountain sickness. RESULTS Compared to 490 m, median nocturnal oxygen saturation decreased during the 1st night at 4559 m from 96% to 67%, minute ventilation increased from 4.4 to 6.3 L/min, and the apnea-hypopnea index increased from 0.1 to 60.9/h; correspondingly, sleep efficiency decreased from 93% to 69%, and slow wave sleep from 18% to 6% (P < 0.05, all instances). During the 3rd night at 4559 m, oxygen saturation was 71%, slow wave sleep 11% (P < 0.05 vs. 1st night, both instances) and the apnea/hypopnea index was 86.5/h (P = NS vs. 1st night). Symptoms of AMS and of disturbed sleep were significantly reduced in the morning after the 3rd vs. the 1st night at 4559 m. CONCLUSIONS In healthy mountaineers ascending rapidly to high altitude, sleep quality is initially impaired but improves with acclimatization in association with improved oxygen saturation, while periodic breathing persists. Therefore, high altitude sleep disturbances seem to be related predominantly to hypoxemia rather than to periodic breathing.

Twenty-eight days at 3454-m altitude diminishes respiratory capacity but enhances efficiency in human skeletal muscle mitochondria

Modifications of skeletal muscle mitochondria following exposure to high altitude (HA) are generally studied by morphological examinations and biochemical analysis of expression. The aim of this study was to examine tangible measures of mitochondrial function following a prolonged exposure to HA. For this purpose, skeletal muscle biopsies were obtained from 8 lowland natives at sea level (SL) prior to exposure and again after 28 d of exposure to HA at 3454 m. High‐resolution respirometry was performed on the muscle samples comparing respiratory capacity and efficiency. Exercise capacity was assessed at SL and HA. Respirometric analysis revealed that mitochondrial respiratory capacity diminished in complex I‐ and complex II‐specific respiration in addition to a loss of maximal state‐3 oxidative phosphorylation capacity from SL to HA, all independent from alterations in mitochondrial content. Leak control coupling, respiratory control ratio, and oligomycin‐induced leak respiration, all measures of mitochondrial efficiency, improved in response to HA exposure. SL respiratory capacities correlated with measures of exercise capacity near SL, whereas mitochondrial efficiency correlated best with exercise capacity following HA. This data demonstrate that 1 mo of exposure to HA reduces respiratory capacity in human skeletal muscle; however, the efficiency of electron transport improves.—Jacobs, R. A., Siebenmann, C., Hug, M., Toigo, M., Meinild, A.‐K., Lundby, C. Twenty‐eight days at 3454‐m altitude diminishes respiratory capacity but enhances efficiency in human skeletal muscle mitochondria. FASEB J. 26, 5192–5200 (2012). www.fasebj.org

Red Cell Volume Expansion at Altitude: A Meta-analysis and Monte Carlo Simulation.

INTRODUCTION Altitude acclimatization is associated with a rapid increase in hematocrit. The time course and the contribution of the red cell volume expansion are not clear. The purpose of the present meta-analysis was to explore how much altitude exposure is required to induce polycythemia in healthy lowlanders. METHODS A systematic review was performed of 66 published articles (including 447 volunteers) identified through literature search. We performed a mixed-model random-effects meta-analysis and a Monte Carlo simulation on the extracted data. RESULTS The following results were obtained in this study: 1) the red cell volume expansion for a given duration of exposure is dependent on altitude (P < 0.0001), that is, that the increase in red cell volume was accelerated at higher altitudes; and 2) the extent of the erythropoietic response depends on the initial red cell volume (P < 0.0001). It seems that exposure time must exceed 2 wk at an altitude of more than 4000 m to exert a statistically significant effect. At lower altitudes, longer exposure times are needed with altitudes lower than 3000 m not yielding an increase within 4 wk. CONCLUSIONS Red cell volume response to hypoxia is generally slow, although it accelerates with increasing altitude. This, in combination with a dependency on initial red cell volume, suggests that, for example, athletes may need to spend more time at altitude to see an effect on red cell volume than commonly recommended.

Limitations to oxygen transport and utilization during sprint exercise in humans: evidence for a functional reserve in muscle O2 diffusing capacity

Severe acute hypoxia reduces sprint performance. Muscle V̇O2 during sprint exercise in normoxia is not limited by O2 delivery, O2 offloading from haemoglobin or structure‐dependent diffusion constraints in the skeletal muscle of young healthy men. A large functional reserve in muscle O2 diffusing capacity exists and remains available at exhaustion during exercise in normoxia; this functional reserve is recruited during exercise in hypoxia. During whole‐body incremental exercise to exhaustion in severe hypoxia, leg V̇O2 is primarily dependent on convective O2 delivery and less limited by diffusion constraints than previously thought. The kinetics of O2 offloading from haemoglobin does not limit V̇O2 peak in hypoxia. Our results indicate that the limitation to V̇O2 during short sprints resides in mechanisms regulating mitochondrial respiration.

Hemoglobin mass and intravascular volume kinetics during and after exposure to 3,454 m altitude.

High altitude (HA) exposure facilitates a rapid contraction of plasma volume (PV) and a slower occurring expansion of hemoglobin mass (Hbmass). The kinetics of the Hbmass expansion has never been examined by multiple repeated measurements, and this was our primary study aim. The second aim was to investigate the mechanisms mediating the PV contraction. Nine healthy, normally trained sea-level (SL) residents (8 males, 1 female) sojourned for 28 days at 3,454 m. Hbmass was measured and PV was estimated by carbon monoxide rebreathing at SL, on every 4th day at HA, and 1 and 2 wk upon return to SL. Four weeks at HA increased Hbmass by 5.26% (range 2.5-11.1%; P < 0.001). The individual Hbmass increases commenced with up to 12 days of delay and reached a maximal rate of 4.04 ± 1.02 g/day after 14.9 ± 5.2 days. The probability for Hbmass to plateau increased steeply after 20-24 days. Upon return to SL Hbmass decayed by -2.46 ± 2.3 g/day, reaching values similar to baseline after 2 wk. PV, aldosterone concentration, and renin activity were reduced at HA (P < 0.001) while the total circulating protein mass remained unaffected. In summary, the Hbmass response to HA exposure followed a sigmoidal pattern with a delayed onset and a plateau after ∼3 wk. The decay rate of Hbmass upon descent to SL did not indicate major changes in the rate of erythrolysis. Moreover, our data support that PV contraction at HA is regulated by the renin-angiotensin-aldosterone axis and not by changes in oncotic pressure.

Hypocapnia during hypoxic exercise and its impact on cerebral oxygenation, ventilation and maximal whole body O2 uptake

With hypoxic exposure ventilation is elevated through the hypoxic ventilatory response. We tested the hypothesis that the resulting hypocapnia reduces maximal exercise capacity by decreasing (i) cerebral blood flow and oxygenation and (ii) the ventilatory drive. Eight subjects performed two incremental exercise tests at 3454 m altitude in a blinded manner. In one trial end-tidal [Formula: see text] was clamped to 40 mmHg by CO(2)-supplementation. Mean blood flow velocity in the middle cerebral artery (MCAv(mean)) was determined by trans-cranial Doppler sonography and cerebral oxygenation by near infra-red spectroscopy. Without CO(2)-supplementation, [Formula: see text] decreased to 30 ± 3 mmHg (P<0.0001 vs isocapnic trial). Although CO(2)-supplementation increased MCAv(mean) by 17 ± 14% (P<0.0001) and attenuated the decrease in cerebral oxygenation (-4.7 ± 0.9% vs -5.4 ± 0.9%; P=0.002) this did not affect maximal O(2)-uptake. Clamping [Formula: see text] increased ventilation during submaximal but not during maximal exercise (P=0.99). We conclude that although hypocapnia promotes a decrease in MCAv(mean) and cerebral oxygenation, this does not limit maximal O(2)-uptake. Furthermore, hypocapnia does not restrict ventilation during maximal hypoxic exercise.

Cardiac output during exercise: A comparison of four methods

Several techniques assessing cardiac output (Q) during exercise are available. The extent to which the measurements obtained from each respective technique compares to one another, however, is unclear. We quantified Q simultaneously using four methods: the Fick method with blood obtained from the right atrium (QFick‐M), Innocor (inert gas rebreathing; QInn), Physioflow (impedance cardiography; QPhys), and Nexfin (pulse contour analysis; QPulse) in 12 male subjects during incremental cycling exercise to exhaustion in normoxia and hypoxia (FiO2 = 12%). While all four methods reported a progressive increase in Q with exercise intensity, the slopes of the Q/oxygen uptake (VO2) relationship differed by up to 50% between methods in both normoxia [4.9 ± 0.3, 3.9 ± 0.2, 6.0 ± 0.4, 4.8 ± 0.2 L/min per L/min (mean ± SE) for QFick‐M, QInn, QPhys and QPulse, respectively; P = 0.001] and hypoxia (7.2 ± 0.7, 4.9 ± 0.5, 6.4 ± 0.8 and 5.1 ± 0.4 L/min per L/min; P = 0.04). In hypoxia, the increase in the Q/VO2 slope was not detected by Nexfin. In normoxia, Q increases by 5–6 L/min per L/min increase in VO2, which is within the 95% confidence interval of the Q/VO2 slopes determined by the modified Fick method, Physioflow, and Nexfin apparatus while Innocor provided a lower value, potentially reflecting recirculation of the test gas into the pulmonary circulation. Thus, determination of Q during exercise depends significantly on the applied method.