Beta-adrenergic blockade increases pulmonary vascular resistance and causes exaggerated hypoxic pulmonary vasoconstriction at high altitude: a physiological study.

BACKGROUND: An increasing number of hypertensive persons travel to high altitude while using antihypertensive medications such as betablockers. 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 animals, ß-adrenergic blockade has induced pulmonary vasoconstriction in normoxia and exaggerated hypoxic pulmonary vasoconstriction (HPV) and both effects were abolished by muscarinic blockade. We thus hypothesized that in humans propranolol (PROP) increases Ppa and PVR in normoxia and exaggerates HPV, and that these effects of PROP are abolished by glycopyrrolate (GLYC). METHODS: In seven healthy male lowlanders, pulmonary artery pressure was invasively measured without medication, with PROP and PROP+GLYC, both at sea level (SL, 488m) and after a three-week sojourn at 3454m altitude (HA). Bilateral thigh-cuff release maneuvers were performed to derive pulmonary pressure-flow relationships and pulmonary vessel distensibility. RESULTS: At SL, PROP increased Ppa and PVR from (mean±SEM) 14±1 to 17±1mmHg and from 69±8 to 108±11dyn*s*cm-5 (21 and 57% increase, p=0.01 and p<0.0001). The PVR response to PROP was amplified at HA to 76% (p<0.0001, p[interaction]=0.05). At both altitudes, PROP+GLYC abolished the effect of PROP on Ppa and PVR. Pulmonary vessel distensibility decreased from 2.9±0.5 to 1.7±0.2 at HA (p<0.0001) and to 1.2±0.2 with PROP, and further decreased to 0.9±0.2%*mmHg-1 with PROP+GLYC (p=0.01). CONCLUSIONS: Our data show that ß-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that ß-adrenergic blockade exaggerates HPV for the management of mountaineers using ß-blockers for prevention or treatment of cardiovascular conditions.

Critical care staffing ratio and outcome of COVID-19 patients requiring intensive care unit admission during the first pandemic wave: a retrospective analysis across Switzerland from the RISC-19-ICU observational cohort.

STUDY AIM: The surge of admissions due to severe COVID-19 increased the patients-to-critical care staffing ratio within the ICUs. We investigated whether the daily level of staffing was associated with an increased risk of ICU mortality (primary endpoint), length of stay (LOS), mechanical ventilation and the evolution of disease (secondary endpoints). METHODS: We employed a retrospective multicentre analysis of the international Risk Stratification in COVID-19 patients in the ICU (RISC-19-ICU) registry, limited to the period between March 1 and May 31, 2020, and to Switzerland. Hierarchical regression models were used to investigate crude and adjusted effects of the critical care staffing ratio on study endpoints. We adjusted for disease severity and weekly caseload. RESULTS: Among the 38 participating Swiss ICUs, 17 recorded staffing information. The study population included 437 patients and 2,342 daily assessments of patient-to-critical care staffing ratio. Median of daily patient-to-nurse ratio started at 1.0 [IQR 0.5-1.5; calendar week 9] and peaked at 2.4 (IQR 0.4-2.0; calendar week 16), while the median of daily patient-to-physician ratio started at 4.0 (IQR 2.1-5.0; calendar week 9) and peaked at 6.8 (IQR 6.3-7.3; calendar week 19). Neither the patient-to-nurse (adjusted OR 1.28, 95% CI 0.85-1.93; doubling of ratio) nor the patient-to-physician ratio (adjusted OR 1.07, 95% CI 0.87-1.32; doubling of ratio) were associated with ICU mortality. We found no association of daily critical care staffing on the secondary endpoints in adjusted models. CONCLUSION: We found no association of reduced availability of critical care staffing resources in Swiss ICUs with overall ICU length of stay nor mortality. Whether long-term outcome of critically ill patients with COVID-19 have been affected remains to be studied.

Effectiveness of a Brief Hypnotic Induction in Third Molar Extraction: A Randomized Controlled Trial (HypMol).

Third molar extraction is a painful treatment for patients, and thus, it can be used to investigate the effects of analgesics on pain. Hypnosis can help to reduce pain and to decrease the intake of postoperative systemic analgesics. In this study, the effectiveness of a brief hypnotic induction for patients undergoing third molar extractions was investigated. Data were collected from 33 patients with third molar extractions on the right and left sides. Patients received 2 different types of pain interventions in this monocentric randomized crossover trial. Third molar extraction was conducted on 1 side with reduced preoperative local anesthetics and an additional brief hypnotic induction (Dave Elman technique). The other side was conducted with regular preoperative local anesthetics without a brief hypnotic induction (standard care). Intake of postoperative systemic analgesics was allowed in both treatments. Patients' expectations about hypnosis were assessed at baseline. The primary outcome was the area under the curve with respect to ground of pain intensity after the treatment. Secondary outcomes were the amount of postoperative analgesics consumed and the preferred treatment. There was no evidence that the area under the curve with respect to ground of pain differed between the 2 interventions (controlling for gender), but the patients' expectations affected the effectiveness of the brief hypnotic induction. This means that patients with high expectations about hypnosis benefit more from treatment with reduced preoperative local anesthetics and additional brief hypnotic induction. PERSPECTIVE: Hypnosis is used as a treatment to reduce pain in general and dental settings. In this study, additional a brief hypnotic induction with reduced preoperative local anesthetic use did not generally reduce posttreatment pain after third molar extraction more than regular local anesthetics. The expectation of the patients about the effectiveness of hypnosis affected the effectiveness of the brief hypnotic induction so that patients with high expectations had a larger benefit from a brief hypnotic induction than patients with low expectations.

Effect of Briefing on Acupuncture Treatment Outcome Expectations, Pain, and Adverse Side Effects Among Patients With Chronic Low Back Pain: A Randomized Clinical Trial.

Importance: In observational studies, patients' treatment outcome expectations have been associated with better outcomes (ie, a placebo response), whereas concerns about adverse side effects have been associated with an in increase in the negative effects of treatments (ie, a nocebo response). Some randomized trials have suggested that communication from clinicians could affect the treatment outcomes by changing patients' expectations. Objective: To investigate whether treatment outcome expectations and reported adverse side effects could be affected by different briefing contents before a minimal acupuncture treatment in patients with chronic low back pain (CLBP). Design, Setting, and Participants: This randomized single-blinded clinical trial was conducted among patients with CLBP at 1 outpatient clinic in Switzerland who had a pain intensity of at least 4 on a numeric rating scale from 0 to 10. Different recruitment channels were used to enroll patients. Data were collected from May 2016 to December 2017 and were analyzed from June to November 2018. Interventions: Patients were randomized to receive either a regular expectation briefing or a high expectation briefing (effectiveness) and either a regular adverse side effect briefing or an intense adverse side effect briefing (adverse side effect) in a 2 × 2 factorial design. The intervention (briefing sessions and written materials) was standardized and delivered before the acupuncture treatment, with additional booster informative emails provided during the 4-week, 8-session acupuncture course. Main Outcomes and Measures: The primary end point was the patients' expectations regarding the effectiveness of the acupuncture treatment (Expectation for Treatment Scale [ETS]) after the briefing and the subsequent pain intensity (numeric rating scale). The primary end point for the adverse side effect briefing was the adverse side effect score at the end of the acupuncture treatment, derived from session-by-session assessments of adverse side effects. Results: A total of 152 patients with CLBP (mean [SD] age, 39.54 [12.52] years; 100 [65.8%] women) were included. The estimated group difference (regular vs high) for the ETS was -0.16 (95% CI -0.81 to 0.50, P = .64), indicating no evidence for a difference between intervention groups. There was also no evidence for a difference in pain intensity at the end of the acupuncture treatment between the groups with different expectation briefings. The adverse side effects score in the group with the intense adverse side effect briefing were estimated to be 1.31 times higher (95% CI, 0.94 to 1.82; P = .11) than after a regular adverse side effect briefing, but the finding was not statistically significant. Conclusions and Relevance: In this study, suggestions regarding treatment benefits (placebo) and adverse side effects (nocebo) did not affect treatment expectations or adverse side effects. Information regarding adverse side effects might require more research to understand nocebo responses. Trial Registration: German Clinical Trials Register Identifier: DRKS00010191.

Near real-time observation reveals increased prevalence of young patients in the ICU during the emerging third SARS-CoV-2 wave in Switzerland.

AIMS OF THE STUDY: During the ongoing COVID-19 pandemic, the launch of a large-scale vaccination campaign and virus mutations have hinted at possible changes in transmissibility and the virulence affecting disease progression up to critical illness, and carry potential for future vaccination failure. To monitor disease development over time with respect to critically ill COVID-19 patients, we report near real-time prospective observational data from the RISC-19-ICU registry that indicate changed characteristics of critically ill patients admitted to Swiss intensive care units (ICUs) at the onset of a third pandemic wave. METHODS: 1829 of 3344 critically ill COVID-19 patients enrolled in the international RISC-19-ICU registry as of 31 May 2021 were treated in Switzerland and were included in the present study. Of these, 1690 patients were admitted to the ICU before 1 February 2021 and were compared with 139 patients admitted during the emerging third pandemic wave RESULTS: Third wave patients were a mean of 5.2 years (95% confidence interval [CI] 3.2–7.1) younger (median 66.0 years, interquartile range [IQR] 57.0–73.0 vs 62.0 years, IQR 54.5–68.0; p <0.0001) and had a higher body mass index than patients admitted in the previous pandemic period. They presented with lower SAPS II and APACHE II scores, less need for circulatory support and lower white blood cell counts at ICU admission. P/F ratio was similar, but a 14% increase in ventilatory ratio was observed over time (p = 0.03) CONCLUSION: Near real-time registry data show that the latest COVID-19 patients admitted to ICUs in Switzerland at the onset of the third wave were on average 5 years younger, had a higher body mass index, and presented with lower physiological risk scores but a trend towards more severe lung failure. These differences may primarily be related to the ongoing nationwide vaccination campaign, but the possibility that changes in virus-host interactions may be a co-factor in the age shift and change in disease characteristics is cause for concern, and should be taken into account in the public health and vaccination strategy during the ongoing pandemic. (ClinicalTrials.gov Identifier: NCT04357275).

Determinants of maximal whole-body fat oxidation in elite cross-country skiers: Role of skeletal muscle mitochondria.

Elite endurance athletes possess a high capacity for whole-body maximal fat oxidation (MFO). The aim was to investigate the determinants of a high MFO in endurance athletes. The hypotheses were that augmented MFO in endurance athletes is related to concomitantly increments of skeletal muscle mitochondrial volume density (MitoVD ) and mitochondrial fatty acid oxidation (FAOp ), that is, quantitative mitochondrial adaptations as well as intrinsic FAOp per mitochondria, that is, qualitative adaptations. Eight competitive male cross-country skiers and eight untrained controls were compared in the study. A graded exercise test was performed to determine MFO, the intensity where MFO occurs (FatMax ), and V ˙ O 2 Max . Skeletal muscle biopsies were obtained to determine MitoVD (electron microscopy), FAOp , and OXPHOSp (high-resolution respirometry). The following were higher (P < 0.05) in endurance athletes compared to controls: MFO (mean [95% confidence intervals]) (0.60 g/min [0.50-0.70] vs 0.32 [0.24-0.39]), FatMax (46% V ˙ O 2 Max [44-47] vs 35 [34-37]), V ˙ O 2 Max (71 mL/min/kg [69-72] vs 48 [47-49]), MitoVD (7.8% [7.2-8.5] vs 6.0 [5.3-6.8]), FAOp (34 pmol/s/mg muscle ww [27-40] vs 21 [17-25]), and OXPHOSp (108 pmol/s/mg muscle ww [104-112] vs 69 [68-71]). Intrinsic FAOp (4.0 pmol/s/mg muscle w.w/MitoVD [2.7-5.3] vs 3.3 [2.7-3.9]) and OXPHOSp (14 pmol/s/mg muscle ww/MitoVD [13-15] vs 11 [10-13]) were, however, similar in the endurance athletes and untrained controls. MFO and MitoVD correlated (r2  = 0.504, P < 0.05) in the endurance athletes. A strong correlation between MitoVD and MFO suggests that expansion of MitoVD might be rate-limiting for MFO in the endurance athletes. In contrast, intrinsic mitochondrial changes were not associated with augmented MFO.

Four days of bed rest increases intrinsic mitochondrial respiratory capacity in young healthy males.

Bed rest leads to impaired glucose tolerance. Whether this is linked to maladaptation's in skeletal muscle mitochondrial function and in particular to the level of reactive oxygen species (ROS) is at present unknown. The aim of this longitudinal study was to quantify skeletal muscle mitochondrial function (respiratory capacity and ROS production) together with glucose tolerance after 4 days of strict bed rest in healthy young male subjects (n = 14). Mitochondrial function was determined in permeabilized muscle fibers using high-resolution respirometry and fluorometry, mitochondrial content (citrate synthase [CS] activity) and antioxidant protein expression levels were assessed in parallel to this. Glucose tolerance was determined by means of oral glucose tolerance tests. Intrinsic mitochondrial respiratory capacity was augmented after the bed rest period (CI + IIP : 0.43 ± 0.12 vs. 0.55 ± 0.14 [pmol/sec/mg]/CS activity), due to a decreased CS activity (158 ± 39 vs. 129 ± 25 mU/mg dw.). No differences were observed in ROS production (per mg of tissue or when normalized to CS activity). Furthermore, the protein content for catalase was increased while superoxide dismutase and glutathione peroxidase remained unaffected. These findings were accompanied by an impaired glucose tolerance after the bed rest period (Matsuda index: 12 ± 6 vs. 9 ± 5). The change in intrinsic mitochondrial respiratory capacity could be an early indication in the development of impaired glucose tolerance. The increased catalase protein content might explain that no change was seen in ROS production after 4 days of bed rest. Whether these findings can be extrapolated to lifestyle-dependent decrements in physical activity and the development of type-2-diabetes remains unknown.

CORP: The assessment of total hemoglobin mass by carbon monoxide rebreathing.

In this Cores of Reproducibility in Physiology (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. The dilution principle then allows calculation of the total number of circulating hemoglobin molecules based on the number of absorbed CO molecules and the resulting changes in the fraction of carboxyhemoglobin in blood. Total hemoglobin mass is derived by multiplication with the molar weight of hemoglobin. CO rebreathing has been used for >100 yr and has undergone steady improvement so that today excellent values in terms of accuracy and precision can be achieved if the methodological precautions are carefully followed.

Combined effects of physical inactivity and acute hyperglycemia on arterial distensibility.

Arterial distensibility, an independent predictor of cardiovascular events, is transiently increased with acute hyperglycemia (AHG) in healthy individuals. Whether this response interacts with physical inactivity remains unknown. We examined the effects of short-term bed rest (BR) on the response of carotid artery distensibility (CD) to AHG, and the influence of underlying changes in insulin resistance and blood volume. CD was assessed with ultrasonography before as well as 30 and 120 minutes following ingestion of 75 g of glucose prior to and after 3 days of BR in 15 healthy male volunteers. Plasma insulin/glucose concentrations and blood volumes were concomitantly determined. On day 4 of BR, blood volume was re-established to pre-BR levels by albumin infusion and CD and insulin/glucose concentrations were determined as in the previous experimental days. Basal CD was not affected by BR. AHG increased CD before and after BR but reached a higher peak increment after BR (12% vs 60% at 30 min OGTT, p=0.028). BR also increased the plasma insulin concentration during AHG ( p=0.007). In regression analyses, plasma insulin and glucose concentrations were positively correlated to CD, particularly after BR ( r=0.31, p<0.05). Restoration of the BR-induced loss (5%) in blood volume did not affect the response of CD to AHG. In conclusion, short-term physical inactivity strongly accentuates the initial increase in CD in response to AHG in healthy individuals. This effect is associated with concomitant increases in circulating insulin concentration attributable to early insulin resistance.

Detection of blood volumes and haemoglobin mass by means of CO re-breathing and indocyanine green and sodium fluorescein injections.

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 is higher than venous haematocrit such an approach might comprise certain errors. To test this experimentally, four different methods for detecting blood volumes and haemoglobin mass (Hbmass) were compared, namely the carbon monoxide (CO) re-breathing (for Hbmass), the indocyanine green (ICG; for plasma volume [PV]) and the sodium fluorescein (SoF; for red blood cell volume [RBCV]) methods. No difference between ICG and CO re-breathing derived PV could be established when a whole body/venous haematocrit correction factor of 0.91 was applied (p = 0.11, r = 0.43, mean difference -340 ± 612 mL). In contrast, when comparing RBCV derived by the CO re-breathing and the SoF method, the SoF method revealed lower RBCV values as compared to the CO re-breathing method (p < 0.05, r = 0.95, mean difference -728 ± 184 mL). However, compared to the ICG and the SoF methods, the typical error (%TE) and hence reliability of the CO re-breathing method was lower for all measured parameters. Therefore, estimating blood volume compartments by the direct assessment of another compartment can be considered a suitable approach. The CO re-breathing method proved accurate in determining the induced phlebotomy and is at the same time judged easier to perform than any of the other methods.

Parasympathetic withdrawal increases heart rate after 2 weeks at 3454 m altitude.

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 inhibition of sympathetic and/or parasympathetic control of the heart. Inhibition of parasympathetic control of the heart alone or in combination with inhibition of sympathetic control abolished the high altitude-induced increase in heart rate. Inhibition of sympathetic control of the heart alone did not prevent the high altitude-induced increase in heart rate. These results indicate that a reduced parasympathetic nervous activity is the main mechanism underlying the elevated heart rate in chronic hypoxia. ABSTRACT: Chronic hypoxia increases resting heart rate (HR), but the underlying mechanism remains incompletely understood. We investigated the relative contributions of the sympathetic and parasympathetic nervous systems, along with potential non-autonomic mechanisms, by individual and combined pharmacological inhibition of muscarinic and/or ß-adrenergic receptors. In seven healthy lowlanders, resting HR was determined at sea level (SL) and after 15-18 days of exposure to 3454 m high altitude (HA) without drug intervention (control, CONT) as well as after intravenous administration of either propranolol (PROP), or glycopyrrolate (GLYC), or PROP and GLYC in combination (PROP+GLYC). Circulating noradrenaline concentration increased from 0.9 ± 0.4 nmol l-1 at SL to 2.7 ± 1.5 nmol l-1 at HA (P = 0.03). The effect of HA on HR depended on the type of autonomic inhibition (P = 0.006). Specifically, HR was increased at HA from 64 ± 10 to 74 ± 12 beats min-1 during the CONT treatment (P = 0.007) and from 52 ± 4 to 59 ± 5 beats min-1 during the PROP treatment (P < 0.001). In contrast, HR was similar between SL and HA during the GLYC treatment (110 ± 7 and 112 ± 5 beats min-1 , P = 0.28) and PROP+GLYC treatment (83 ± 5 and 85 ± 5 beats min-1 , P = 0.25). Our results identify a reduction in cardiac parasympathetic activity as the primary mechanism underlying the elevated HR associated with 2 weeks of exposure to hypoxia. Unexpectedly, the sympathoactivation at HA that was evidenced by increased circulating noradrenaline concentration had little effect on HR, potentially reflecting down-regulation of cardiac ß-adrenergic receptor function in chronic hypoxia. These effects of chronic hypoxia on autonomic control of the heart may concern not only HA dwellers, but also patients with disorders that are associated with hypoxaemia.

Effect of Increased Blood Flow on Pulmonary Circulation Before and During High Altitude Acclimatization.

Matthias Peter Hilty, Andrea Mueller, Daniela Flück, Christoph Siebenmann, Peter Rasmussen, Stefanie Keiser, Katja Auinger, Carsten Lundby, and Marco Maggiorini. Effect of increased blood flow on the pulmonary circulation before and during high altitude acclimatization. High Alt Med Biol. 17:305-314, 2016.-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 in seven healthy male subjects, echocardiography was performed at sea level (SL; 488 m) weekly during a 4-week sojourn at 3454 m (HA1-HA4) and upon return (SL2). Pulmonary artery catheterization and bilateral thigh cuff release maneuver were performed at SL and HA3 to study the properties of pulmonary circulation after 3 weeks of acclimatization. RESULTS: Pulmonary artery catheter determined that systolic Ppa (mean ± SEM) was increased from 20 ± 1 at SL to 27 ± 2 mmHg at HA3 (p < 0.01). Echocardiography assessed that systolic Ppa remained equally increased throughout acclimatization (26 ± 2, 25 ± 2, 25 ± 2, and 24 ± 2 mmHg at HA1-HA4; p = 0.93) and returned to baseline upon return (17 ± 2, 18 ± 1 mmHg at SL, SL2; p = 0.3). The same was shown for PVR. Right heart function remained unaffected. Thigh cuff release maneuvers at SL and HA3 resulted in similar increase in cardiac output (2.5 ± 0.5 and 2.2 ± 0.4 L/min; p = 0.61) without affecting mean Ppa. CONCLUSIONS: Prolonged altitude exposure leads to a persistent increase in Ppa and PVR without affecting right heart function and is fully reversible within 1 week after return to SL. The thigh cuff release maneuver-induced increase in cardiac output suggests a preserved ability of pulmonary circulation to cope with sudden remarkable increase in pulmonary blood flow throughout acclimatization.

Arterial stiffness is strongly and negatively associated with the total volume of red blood cells.

BACKGROUND: Erythropoiesis is partly regulated through classic feedback pathways that govern blood volume (BV) as sensed by veno-atrial but also arterial stretch receptors. Hence, the total volume of red blood cells (RBCV) could be associated with arterial stiffness (AS), although such hypothesis has not yet been tested. Therefore, we sought to investigate the association of AS with hematological variables including RBCV. METHODS: Fourteen healthy physically active individuals volunteered for the study (age=23±2). RBCV, plasma volume (PV), and BV were calculated from measures of hematocrit and total hemoglobin mass (Hbmass) determined by CO-rebreathing. Carotid compliance with ultrasonography and carotid-ankle pulse wave velocity (PWV) were determined at rest and immediately after a maximal exercise test. The rationale for assessment of AS after exercise derives from the potential marked role of AS in the regulation of erythropoiesis in the setting of reduced central venous pressure. RESULTS: At rest, carotid compliance was positively associated with Hbmass, RBCV, BV, but not PV, with coefficients of determination (R(2)) ranging from 0.39 to 0.57. Following exercise, closer positive associations were observed between carotid compliance and Hbmass, RBCV, or BV. Moreover, carotid-ankle PWV was negatively associated with all hematological variables after exercise except for PV, with R(2) ranging from 0.49 to 0.75. Similar results were observed when adjusted by body weight. CONCLUSIONS: AS is strongly and inversely associated with RBCV in healthy individuals. These findings suggest that AS may adversely intercede in the regulation of erythropoiesis through the alteration of mechanisms that control BV.

Haematological rather than skeletal muscle adaptations contribute to the increase in peak oxygen uptake induced by moderate endurance training.

It remains unclear whether improvements in peak oxygen uptake (V̇(O2peak)) following endurance training (ET) are primarily determined by central and/or peripheral adaptations. Herein, we tested the hypothesis that the improvement in V̇(O2peak) following 6 weeks of ET is mainly determined by haematological rather than skeletal muscle adaptations. Sixteen untrained healthy male volunteers (age = 25 ± 4 years, V̇(O2peak) = 3.5 ± 0.5 l min(-1)) underwent supervised ET (6 weeks, 3-4 sessions per week). V̇(O2peak), peak cardiac output (Q̇(peak)), haemoglobin mass (Hb(mass)) and blood volumes were assessed prior to and following ET. Skeletal muscle biopsies were analysed for mitochondrial volume density (Mito(VD)), capillarity, fibre types and respiratory capacity (OXPHOS). After the post-ET assessment, red blood cell volume (RBCV) was re-established at the pre-ET level by phlebotomy and V̇(O2peak) and Q̇(peak) were measured again. We speculated that the contribution of skeletal muscle adaptations to the ET-induced increase in V̇(O2peak) would be revealed when controlling for haematological adaptations. V̇(O2peak) and Q̇(peak) were increased (P < 0.05) following ET (9 ± 8 and 7 ± 6%, respectively) and decreased (P < 0.05) after phlebotomy (-7 ± 7 and -10 ± 7%). RBCV, plasma volume and Hb(mass) all increased (P < 0.05) after ET (8 ± 4, 4 ± 6 and 6 ± 5%). As for skeletal muscle adaptations, capillary-to-fibre ratio and total Mito(VD) increased (P < 0.05) following ET (18 ± 16 and 43 ± 30%), but OXPHOS remained unaltered. Through stepwise multiple regression analysis, Q̇(peak), RBCV and Hb(mass) were found to be independent predictors of V̇(O2peak). In conclusion, the improvement in V̇(O2peak) following 6 weeks of ET is primarily attributed to increases in Q̇(peak) and oxygen-carrying capacity of blood in untrained healthy young subjects.

Heat training increases exercise capacity in hot but not in temperate conditions: a mechanistic counter-balanced cross-over study.

The aim was to determine the mechanisms facilitating exercise performance in hot conditions following heat training. In a counter-balanced order, seven males (V̇o2max 61.2 ± 4.4 ml·min(-1)·kg(-1)) were assigned to either 10 days of 90-min exercise training in 18 or 38°C ambient temperature (30% relative humidity) applying a cross-over design. Participants were tested for V̇o2max and 30-min time trial performance in 18 (T18) and 38°C (T38) before and after training. Blood volume parameters, sweat output, cardiac output (Q̇), cerebral perfusion (i.e., middle cerebral artery velocity [MCAvmean]), and other variables were determined. Before one set of exercise tests in T38, blood volume was acutely expanded by 538 ± 16 ml with an albumin solution (T38A) to determine the role of acclimatization induced hypervolemia on exercise performance. We furthermore hypothesized that heat training would restore MCAvmean and thereby limit centrally mediated fatigue. V̇o2max and time trial performance were equally reduced in T38 and T38A (7.2 ± 1.6 and 9.3 ± 2.5% for V̇o2max; 12.8 ± 2.8 and 12.9 ± 2.8% for time trial). Following heat training both were increased in T38 (9.6 ± 2.1 and 10.4 ± 3.1%, respectively), whereas both V̇o2max and time trial performance remained unchanged in T18. As expected, heat training augmented plasma volume (6 ± 2%) and mean sweat output (26 ± 6%), whereas sweat [Na(+)] became reduced by 19 ± 7%. In T38 Q̇max remained unchanged before (21.3 ± 0.6 l/min) to after (21.7 ± 0.5 l/min) training, whereas MCAvmean was increased by 13 ± 10%. However, none of the observed adaptations correlated with the concomitant observed changes in exercise performance.

Cerebrovascular reactivity is increased with acclimatization to 3,454 m altitude.

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 study was to determine CVR throughout acclimatization to high altitude when controlling for these. Middle cerebral artery mean velocity (MCAv mean) CVR was assessed during hyperventilation (hypocapnia) and CO2 administration (hypercapnia) with background normoxia (sea level (SL)) and hypoxia (3,454 m) in nine healthy volunteers (26 ± 4 years (mean ± s.d.)) at SL, and after 30 minutes (HA0), 3 (HA3) and 22 (HA22) days of high-altitude (3,454 m) exposure. At altitude, ventilation was increased whereas MCAv mean was not altered. Hypercapnic CVR was decreased at HA0 (1.16% ± 0.16%/mm Hg, mean ± s.e.m.), whereas both hyper- and hypocapnic CVR were increased at HA3 (3.13% ± 0.18% and 2.96% ± 0.10%/mm Hg) and HA22 (3.32% ± 0.12% and 3.24% ± 0.14%/mm Hg) compared with SL (1.98% ± 0.22% and 2.38% ± 0.10%/mm Hg; P < 0.01) regardless of background oxygenation. Cerebrovascular conductance (MCAv mean/mean arterial pressure) CVR was determined to account for blood pressure changes and revealed an attenuated response. Collectively our results show that hypocapnic and hypercapnic CVR are both elevated with acclimatization to high altitude.

Age, aerobic fitness, and cerebral perfusion during exercise: role of carbon dioxide.

Middle cerebral artery mean velocity (MCAvmean) is attenuated with increasing age both at rest and during exercise. The aim of this study was to determine the influence of the age-dependent reduction in arterial Pco2 (PaCO2) and physical fitness herein. We administered supplemental CO2 (CO2 trial) or no additional gas (control trial) to the inspired air in a blinded and randomized manner, and assessed middle cerebral artery mean flow velocity during graded exercise in 1) 21 young [Y; age 24 ± 3 yr (±SD)] volunteers of whom 11 were trained (YT) and 10 considered untrained (YUT), and 2) 17 old (O; 66 ± 4 yr) volunteers of whom 8 and 9 were considered trained (OT) and untrained (OUT), respectively. A resting hypercapnic reactivity test was also performed. MCAvmean and PaCO2 were lower in O [44.9 ± 3.1 cm/s and 30 ± 1 mmHg (±SE)] compared with Y (59.3 ± 2.3 cm/s and 34 ± 1 mmHg, P < 0.01) at rest, independent of aerobic fitness level. The age-related decreases in MCAvmean and PaCO2 persisted during exercise. Supplemental CO2 reduced the age-associated decline in MCAvmean by 50%, suggesting that PaCO2 is a major component in the decline. On the other hand, relative hypercapnic reactivity was neither influenced by age (P = 0.46) nor aerobic fitness (P = 0.36). Although supplemental CO2 attenuated exercise-induced reduction in cerebral oxygenation (near-infrared spectroscopy), this did not influence exercise performance. In conclusion, PaCO2 contributes to the age-associated decline in MCAvmean at rest and during exercise; however exercise capacity did not diminish this age effect.

Kidney-synthesized erythropoietin is the main source for the hypoxia-induced increase in plasma erythropoietin in adult humans.

PURPOSE: 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. METHODS: We aimed to quantify this by assessing the distribution of EPO glycoforms which are characterized by posttranslational glycosylation patterns specific to the synthesizing cell. The analysis was performed on samples obtained in seven healthy volunteers before, during and after 1 month of sojourn at 3,454 m altitude. RESULTS: Umbilical cord (UC) plasma served as control. As expected a peak (p < 0.05) in urine (2.3 ± 0.5-fold) and plasma (3.3 ± 0.5-fold) EPO was observed on day 1 of high-altitude exposure, and thereafter the concentration decreased for the urine sample obtained after 26 days at altitude, but remained elevated (p < 0.05) by 1.5 ± 0.2-fold above the initial sea level value for the plasma sample. The EPO glycoform heterogeneity, in the urine samples collected at altitude, did not differ from values at sea level, but were markedly lower (p < 0.05) than the mean percent migrated isoform (PMI) for the umbilical cord samples. CONCLUSION: Our studies demonstrate (1) UC samples express a different glycoform distribution as compared to adult humans and hence illustrates the ability to synthesis EPO in non-kidney cells during fetal development (2) as expected hypoxia augments circulating EPO in adults and the predominant source here for remains being kidney derived.

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.