Christoph Siebenmann

Institute of Mountain Emergency Medicine

In lowlanders, high altitude (HA) acclimatization induces hemoconcentration by reducing plasma volume (PV) and increasing total hemoglobin mass (Hb mass ). Conversely, Tibetan highlanders living at HA are reported to have a similar hemoglobin concentration ([Hb]) as lowlanders near sea level and we investigated whether this reflects alterations in...

During acute hypoxic exposure, cerebral blood flow (CBF) increases to compensate for the reduced arterial oxygen content (CaO2). Nevertheless, as exposure extends, both CaO2 and CBF progressively normalize. Haemoconcentration is the primary mechanism underlying the CaO2 restoration and may therefore explain, at least in part, the CBF normalization....

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 autonom...

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo‐controlled approach to prevent nPB by increasing inspiratory CO2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single‐blinded,...

Background An increasing number of hypertensive persons travel to high altitude (HA) while using antihypertensive medications such as beta-blockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In an...

Lowlanders sojourning for more than 1 day at high altitude (HA) experience a reduction in plasma volume (PV) that increases haemoglobin concentration and thus restores arterial oxygen content. If the sojourn extends over weeks, an expansion of total red cell volume (RCV) occurs and contributes to the haemoconcentration. While the reduction in PV wa...

Blood volume (BV) is an important clinical parameter and is usually reported per kg of body mass (BM). When fat mass is elevated, this underestimates BV/BM. One aim was to study if differences in BV/BM related to sex, age, and fitness would decrease if normalized to lean body mass (LBM). The analysis included 263 women and 319 men (age: 10–93 years...

Kammerer, Tobias, Anna Walzl, Thomas Müller, Philipp Groene, Giulia Roveri, Rachel Turner, Johanna Roche, Hannes Gatterer, Christoph Siebenmann, and Simon T. Schäfer. Effects of hypobaric hypoxia on coagulation in healthy subjects exposed to 3,500 m altitude. High Alt Med Biol. 24:94-103, 2023. Background: Hypoxia is discussed as a trigger for prot...

Altitude exposure may suppress appetite and hence provide a viable weight-loss strategy. While changes in food intake and availability as well as physical activity may contribute to altered appetite at altitude, herein we aimed to investigate the isolated effects of hypobaric hypoxia on appetite regulation and sensation. Twelve healthy women (age:...

We sought to determine the effects of prolonged moderate hypobaric hypoxia (HH) on cardiac baroreflex sensitivity (cBRS) in young women, and whether these effects are a consequence of the reduced arterial oxygen (O2) tension and/or increased pulmonary ventilation in HH. We hypothesised that HH would reduce cBRS and that this effect would be counter...

We have recently reported that hypobaric hypoxia (HH) reduces plasma volume (PV) in men by decreasing total circulating plasma protein (TCPP). Here, we investigated whether this applies to women and whether an inflammatory response and/or endothelial glycocalyx shedding could facilitate the TCCP reduction. We further investigated whether acute HH i...

The cardiac phenotype of a substantial fraction of the population, i.e., mature women, is mainly unresponsive to endurance training (ET), the most effective intervention to improve cardiorespiratory fitness. This study assessed whether a novel intervention comprising additional haemodynamic stimuli may overcome the generalized limitations to modify...

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant...

Exercise facilitates cerebral lactate uptake, likely by increasing arterial lactate concentration and hence the diffusion gradient across the blood brain barrier. However, non-specific β-adrenergic blockade by propranolol has previously reduced the arterio-jugular venous lactate difference (AV Lac ) during exercise, suggesting β-adrenergic control...

Purpose: Whether blood oxygen (O2) carrying capacity plays a substantial role in determining cardiorespiratory fitness, a strong predictor of mortality, remains uncertain in women and elderly individuals due to the scarcity of experimental investigations. This study experimentally assessed the role of blood O2 carrying capacity on cardiorespirator...

We investigated whether low arterial oxygen tension (PaO 2 ) or hypoxia-induced plasma volume (PV) contraction, which reduces central blood volume (BV) and atrial distension, explain reduction in circulating atrial natriuretic peptide (ANP) after prolonged hypoxic exposure. Ten healthy males were exposed for four days to hypobaric hypoxia correspon...

Aims/hypothesis: The aim of this parallel-group, double-blinded (study personnel and participants), randomised clinical trial was to assess the interaction between metformin and exercise training on postprandial glucose in glucose-intolerant individuals. Methods: Glucose-intolerant (2 h OGTT glucose of 7.8-11.0 mmol/l and/or HbA1c of 39-47 mmol/...

New findings: What is the central question of this study? Does the ventilatory response to moderate acute hypoxia increase cerebral perfusion independently of changes in arterial oxygen tension in humans? What is the main finding and its importance? The ventilatory response does not increase middle cerebral artery mean blood flow velocity during m...

Key points Acclimatization to hypoxia leads to a reduction in plasma volume (PV) that restores arterial O2 content. Findings from studies investigating the mechanisms underlying this PV contraction have been controversial, possibly as experimental conditions were inadequately controlled. We examined the mechanisms underlying the PV contraction evok...

High altitude exposure typically reduces endothelial function, and this is modulated by hemoconcentration resulting from plasma volume contraction. However, the specific impact of hypobaric hypoxia, independent of external factors (e.g. cold, varying altitudes, exercise, diet, dehydration) on endothelial function is unknown. We examined the tempora...

Heat acclimation is associated with plasma volume (PV) expansion that occurs within the first week of exposure. However, prolonged effects on hemoglobin mass (Hbmass) are unclear as intervention periods in previous studies have not allowed sufficient time for erythropoiesis to manifest. Therefore, Hbmass, intravascular volumes, and blood volume (BV...

Heat acclimation (HA) involves physiological adaptations that directly promote exercise performance in hot environments. However, for endurance-athletes it is unclear if adaptations also improve aerobic capacity and performance in cool conditions, partly because previous randomized controlled trial (RCT) studies have been restricted to short interv...

We have previously shown that the increase in muscle sympathetic nerve activity (MSNA) to contracting muscle during sustained isometric exercise is due primarily to central command, and that the contracting muscle does not exhibit a metaboreflex. Here, we tested the hypothesis that MSNA increases to the contracting muscle also during rhythmic isoto...

We have previously shown that the increase in muscle sympathetic nerve activity (MSNA) to contracting muscle during sustained isometric exercise is due primarily to central command and that contracting muscle does not express a metaboreceptor-driven increase in MSNA. Here we tested the hypothesis that MSNA increases to the contracting muscle also d...

Hypoxia increases heart rate (HR) in humans by sympathetic activation and vagal withdrawal. However, in anaesthetized dogs hypoxia increases vagal activity and reduces HR if pulmonary ventilation does not increase and we evaluated whether that observation applies to awake humans. Ten healthy males were exposed to 15 min of normoxia and hypoxia (10....

Millet and Brocherie argue that responses to altitude could have occurred in our control group living and training at 1000‐1500 m. First, their argumentation is somewhat imprecise since the participants lived at 1035 m and spent 82% of total training time between 550 and 1100 m.¹ Second, their statement is surprising since in one of their own studi...

The purpose of the study was to evaluate the recuperative efficacy of pre-exercise napping on physical capacity after military sustained operations (SUSOPS) with partial sleep deprivation. Before and after a 2-day SUSOPS, 61 cadets completed a battery of questionnaires, and performed a 2-min lunges trial and a 3,000-m running time-trial. After the...

Limb muscle dysfunction in patients with COPD may be associated with local muscle and/or systemic inflammation, and therefore, we investigated whether exercise training altered markers of inflammation and oxidative stress. We obtained vastus lateralis muscle biopsies and venous blood samples from patients with COPD (n=30) before and after 8 weeks o...

Background Echocardiography is usually performed with the subject/patient lying in the left lateral position (LLP), because the acoustic window is better in this than in the supine position (SP). The aim was to investigate cardiac responses to rotational changes of position in the transversal plane, from SP to LLP while horizontal, and from leaning...

Live high – train low (LHTL) using hypobaric hypoxia was previously found to improve sea-level endurance performance in well-trained individuals, however confirmatory controlled data in athletes are lacking. Here we test the hypothesis that natural-altitude LHTL improves aerobic performance in cross-country skiers, in conjunction with expansion of...

Background: Changes in left ventricular (LV) torsion have been related to LV geometry in patients with concomitant long-standing myocardial disease or pulmonary hypertension (PH). We evaluated the effect of acute high altitude-induced isolated PH on LV geometry, volumes, systolic function, and torsional mechanics. Methods: Twenty-three volunteer...

In this CORP article we present the theory and practical aspects of the carbon monoxide (CO) rebreathing method for the determination of total hemoglobin mass in humans. With CO rebreathing, a small quantity of CO is diluted in O2 and rebreathed for a specified time period, during which most of the CO is absorbed and bound to circulating hemoglobin...

Humans ascending to high altitude (HA) experience a reduction in arterial oxyhemoglobin saturation and, as a result, arterial O2 content (CaO2). As HA exposure extends, this reduction in CaO2 is counteracted by an increase in arterial hemoglobin concentration. Initially, hemoconcentration is exclusively related to a reduction in plasma volume (PV),...

Carbon monoxide (CO) increases middle cerebral artery mean flow velocity (MCAVmean), but the effect of CO on the near-infrared spectroscopy (NIRS) determined cerebral oxygenation (ScO2) is not detailed. In our study, 11 non-smoking subjects breathed 100% O2 through a closed circuit. A CO2 scrubber with CO (1.5 mL kg−1) was added to the circuit. Two...

The main aim of the present study was to quantify the magnitude of differences introduced when estimating a given blood volume compartment (e.g. plasma volume) through the direct determination of another compartment (e.g. red cell volume) by multiplication of venous haematocrit and/or haemoglobin concentration. However, since whole body haematocrit...

Cerebral blood flow (CBF) is regulated to secure brain O2 delivery while simultaneously avoiding hyperperfusion; however, both requisites may conflict during sprint exercise. To determine whether brain O2 delivery or CBF is prioritized, young men performed sprint exercise in normoxia and hypoxia (PIO2 = 73 mmHg). During the sprints, cardiac output...

Key points: Heart rate is increased in chronic hypoxia and we tested whether this is the result of increased sympathetic nervous activity, reduced parasympathetic nervous activity, or a non-autonomic mechanism. In seven lowlanders, heart rate was measured at sea level and after 2 weeks at high altitude after individual and combined pharmacological...

Background: To measure nitrogen (N2) wash-out and uptake requires elaborate set-ups, especially when doing the measurements at increased or decreased ambient pressure. Here we present a transportable device for quantifying N2 turnover in humans which can be used at different ambient pressures. Methods: A modified close-circuit electronic rebreat...

Aim: Experiments have indicated that skin perfusion in mice is sensitive to reductions in environmental O2 availability. Specifically, a reduction in skin-surface PO2 attenuates transcutaneous O2 diffusion, and hence epidermal O2 supply. In response, epidermal HIF-1α expression increases and facilitates initial cutaneous vasoconstriction and subse...

Introduction and Methods: Acute exposure to high altitude increases pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR). The evolution of Ppa and PVR with continuous hypoxic exposure remains, however, elusive. To test the hypothesis that altitude exposure leads to a persistent elevation in Ppa and PVR throughout acclimatization...

New findings: What is the topic of this review? This review addresses whether a mismatch between cerebral O2 demand and delivery accelerates the development of central fatigue during endurance-type exercise. What advances does it highlight? The difficulty with studying the importance of cerebral O2 availability for exercise performance is to manip...

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 chemorecept...

To determine the contribution of convective and diffusive limitations to (V) over dot(O2 peak) during exercise in humans, oxygen transport and haemodynamics were measured in 11 men (22 +/- 2years) during incremental (IE) and 30s all-out cycling sprints (Wingate test, WgT), in normoxia (Nx, P-IO2: 143mmHg) and hypoxia (Hyp, P-IO2: 73mmHg). Carboxyha...

The role of hypoxia on skeletal muscle mitochondria is controversial. Studies superimposing exercise training with hypoxic exposure demonstrate an increase in skeletal muscle mitochondrial volume density (MitoVD ) over equivalent normoxic training. In contrast, a reduction in both skeletal muscle mass and MitoVD have been reported following mountai...

Hypoxia increases the heart rate (HR) response to exercise but the mechanism(s) remain unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate but not combined inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exercise to exhaustion in normoxia and hypoxia (FIO2 = 12%)...

Aortic occlusion activates cardiac mechanoreceptors that elicits muscle vasodilatation and reduce heart rate (HR). Norepinephrine and phenylephrine reduce HR but whether muscle blood flow increases is not known. Cardiovascular variables were determined in males during administration of norepinephrine (n=15) or phenylephrine (n=7) and during 50° hea...

Controversy exists regarding the effect of high-altitude exposure on cerebrovascular CO2 reactivity (CVR). Confounding factors in previous studies include the use of different experimental approaches, ascent profiles, duration and severity of exposure and plausibly environmental factors associated with altitude exposure. One aim of the present stud...

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 contracti...

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 rebreathi...

Frontal lobe oxygenation (Sc O2 ) is assessed by spatially resolved near-infrared spectroscopy (SR-NIRS) although it seems influenced by extra-cerebral oxygenation. We aimed to quantify the impact of extra-cerebral oxygenation on two SR-NIRS derived Sc O2 . Multiple regression analysis estimated the influence of extra-cerebral oxygenation as exempl...

Erythropoietin (EPO) is mainly synthesized within renal peritubular fibroblasts, and also other tissues such as the liver possess the ability. However, to what extent non-kidney produced EPO contributes to the hypoxia-induced increase in circulating EPO in adult humans remains unclear. We aimed to quantify this by assessing the distribution of EPO...

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 underly...

Purpose: Hemoglobin mass (Hbmass) is commonly assessed using the CO re-breathing method with the subject in the seated position. This may lead to an underestimation of Hbmass as blood in lower extremity veins while seated may not be tagged with carbon monoxide (CO) during the re-breathing period. Methods: To test this hypothesis, CO re-breathing...

Frontal lobe cerebral oxygenation (s c O 2 ) is assessed by spatially resolved near infrared spectroscopy (SR‐NIRS) to exclude the contribution of extra‐cerebral tissue. However, changes in cutaneous blood flow impact s c O 2 but the contribution of the skin to s c O 2 is unknown. This study quantified the influence of cutaneous blood flow on s c O...

Introduction: Altitude acclimatization is associated with a rapid increase in hematocrit. The time course and contribution of the red cell volume expansion is not clear. The purpose of the present meta-analysis is to explore how much altitude exposure is required to induce polycythemia in healthy lowlanders.Methods: A systematic review of 66 publis...

Susceptible subjects ascending rapidly to high altitude develop pulmonary edema (HAPE). We evaluated whether HAPE leads to sleep and breathing disturbances that are alleviated by dexamethasone. Double-blind, randomized, placebo-controlled trial with open-label extension. One night in sleep laboratory at 490 m, 2 nights in mountain hut at 4,559 m. 2...

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 obta...

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 3454m altitude in a blinded...

It remains unclear by which mechanism 'live high-train low' (LHTL) altitude training increases exercise performance. Haematological and skeletal muscle adaptations have both been proposed. To test the hypotheses that (i) LHTL improves maximal oxygen uptake (VO(2)max) and (ii) this improvement is related to hypoxia-induced increases in total haemogl...

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 norepinephri...

to the editor: Garvican et al. ([3a][1]) raise several methodological concerns toward the use of the classic CO re-breathing technique ([2][2]) in our recently performed study ([8][3]). First, they suggest that sampling at 8 min may yield spuriously high Hbmass values. However, their own data ([3][4

It was investigated if athletes subjected to 4 wk of living in normobaric hypoxia (3,000 m; 16 h/day) while training at 800-1,300 m ["live high-train low" (LHTL)] increase muscular and systemic capacity for maintaining pH and K(+) homeostasis as well as intense exercise performance. The design was double-blind and placebo controlled. Mean power dur...

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. Prospective observation. One ni...

Room Confinement or Suggested Inappropriate Training is Unlikely to Explain the Absence of Performance Gains Following Normobaric LHTL TO THE EDITOR: Although we appreciate feedback on our study (6) from people within the coaching community, we are puz-zled by the comments raised by Schmitt and Millet (3), criti-cizing us for concluding that room c...

Acute hypoxia impairs aerobic exercise by reducing the capacity for maximal O2 uptake (VO2max). This is mainly the consequence of a lower arterial O2 content (caO2) and, in severe hypoxia, cardiac output during maximal exercise as the combination of these two factors attenuates convective O2 supply to the exercising muscle cells. Nevertheless, the...

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 tes...

Data on sleep at altitude are scant due to the limited availability of polysomnography. Therefore, we investigated whether actigraphy might serve as a simple tool for monitoring sleep during altitude field studies. Fourteen mountaineers participating in studies on dexamethasone prophylaxis of high altitude pulmonary edema were monitored by actigrap...

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 amo...

We have previously demonstrated that prophylactic intake of dexamethasone improves maximal oxygen uptake (Vo(2)max) in high altitude pulmonary edema (HAPE) susceptible subjects 4 to 6 h after a 2-day climb to 4559 m. However, since with this ascent protocol HAPE usually develops after the first night at 4559 m or later, we hypothesized that a conti...