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Duplicate measure of hemoglobin mass by carbon monoxide (CO)-rebreathing is a logistical challenge as recommendations prompt several hours between measures to minimize CO-accumulation. This study investigated the feasibility and reliability of performing duplicate CO-rebreathing procedures immediately following one another. Additionally, it was evaluated whether the obtained hemoglobin mass from three different CO-rebreathing devices is comparable. Fifty-five healthy participants (22 males, 23 females) performed 222 duplicate CO-rebreathing procedures in total. Additionally, in a randomized cross-over design 10 participants completed three experimental trials, each including three CO-rebreathing procedures, with the first and second separated by 24 h and the second and third separated by 5–10 min. Each trial was separated by >48 h and conducted using either a glass-spirometer, a semi-automated electromechanical device, or a standard three-way plastic valve designed for pulmonary measurements. Hemoglobin mass was 3 ± 22 g lower (p < 0.05) at the second measure when performed immediately after the first with a typical error of 1.1%. Carboxyhemoglobin levels reached 10.9 ± 1.3%. In the randomized trial, hemoglobin mass was similar between the glass-spirometer and three-way valve, but ∼6% (∼50 g) higher for the semi-automated device. Notably, differences in hemoglobin mass were up to ∼13% (∼100 g) when device-specific recommendations for correction of CO loss to myoglobin and exhalation was followed. In conclusion, it is feasible and reliable to perform two immediate CO-rebreathing procedures. Hemoglobin mass is comparable between the glass-spirometer and the three-way plastic valve, but higher for the semi-automated device. The differences are amplified if the device-specific recommendations of CO-loss corrections are followed.

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, body mass index: 14–41 kg/m2) and 107 athletes who underwent assessment of BV and hemoglobin mass (Hbmass), body composition, and cardiorespiratory fitness. BV/BM was 25% lower (70.3 ± 11.3 and 80.3 ± 10.8 mL/kgBM) in women than men, respectively, whereas BV/LBM was 6% higher in women (110.9 ± 12.5 and 105.3 ± 11.2 mL/kgLBM). Hbmass/BM was 34% lower (8.9 ± 1.4 and 11.5 ± 11.2 g/kgBM) in women than in men, respectively, but only 6% lower (14.0 ± 1.5 and 14.9 ± 1.5 g/kgLBM)/LBM. Age did not affect BV. Athlete's BV/BM was 17.2% higher than non-athletes, but decreased to only 2.5% when normalized to LBM. Of the variables analyzed, LBM was the strongest predictor for BV (R2 =.72, p <.001) and Hbmass (R2 =.81, p <.001). These data may only be valid for BV/Hbmass when assessed by CO re-breathing. Hbmass/LBM could be considered a valuable clinical matrix in medical care aiming to normalize blood homeostasis.

Blood doping is prohibited for athletes but has been a well-described practice within endurance sports throughout the years. With improved direct and indirect detection methods, the practice has allegedly moved towards micro-dosing, i.e., reducing the blood doping regime amplitude. This narrative review evaluates whether blood doping, specifically recombinant human erythropoietin (rhEpo) treatment and blood transfusions are performance-enhancing, the responsible mechanism as well as detection possibilities with a special emphasis on micro-dosing. In general, studies evaluating micro-doses of blood doping are limited. However, in randomized, double-blinded, placebo-controlled trials, three studies find that infusing as little as 130 ml red blood cells or injecting 9 IU × kg bw-1 rhEpo three times per week for four weeks improve endurance performance ~4-6 %. The responsible mechanism for a performance-enhancing effect following rhEpo or blood transfusions appear to be increased O2 -carrying capacity, which is accompanied by an increased muscular oxygen extraction and likely increased blood flow to the working muscles, enabling the ability to sustain a higher exercise intensity for a given period. Blood doping in micro-doses challenges indirect detection by the Athlete Biological Passport, albeit it can identify ~20-60% of the individuals depending on the sample timing. However, novel biomarkers are emerging, and some may provide additive value for detection of micro blood doping such as the immature reticulocytes or the iron regulatory hormones hepcidin and erythroferrone. Future studies should attempt to validate these biomarkers for implementation in real-world anti-doping efforts and continue the biomarker discovery.

Introduction: Determination of blood volume (BV) using the dual-isotope (e.g., 99mTc-labeled red blood cells [99mTc-RBC] and 125I-labeled human serum albumin [125I-HSA]) injection method is limited in medicine due to the long isotope half-life. However, BV has been determined in laboratory settings for 100 years using the carbon monoxide (CO)-rebreathing-based procedure, which allows frequent BV measurements.Methods: We investigated the reliability and accuracy of a semi-automated CO-rebreathing device by comparing it against the dual-isotope methodology and its ability to detect a known blood removal. In study A, BV was determined three times in ~2 h; twice using the device with rebreathing protocols lasting 2 (CO2min) and 10 min (CO10min) and once with the dual-isotope technique. In study B, the accuracy of the device was assessed by its ability to detect a 2% removal of BV.Results: A good correlation was observed between both the CO-rebreathing protocols (r2 = 0.89-0.98; p < 0.001) and the dual-isotope approach (r2 = 0.89-0.95; p < 0.001). In absolute terms BV was 425 ± 263 mL and 491 ± 388 mL lower (p < 0.001) when quantified with the dual-isotope compared to the CO-rebreathing protocols. When reducing BV by 132 ± 25 mL (2%), the device quantified a lower (p < 0.001) BV of 150 ± 45 mL.Conclusion: This study emphasizes that the semi-automated device accurately determines small changes (i.e., 2%) in BV and that a high correlation with the dual-isotope methodology exists. The findings are clinically relevant owing to the method's simple and fast nature (the absence of radioactive tracers and reduced time requirements, i.e., ~15 min vs. ~180 min) and the possibility for repeated measurements within a single day.

Purpose: The World Anti-Doping Agency prohibit glucocorticoid administration in-competition but not in periods out-of-competition. Glucocorticoid usage is controversial as it may improve performance, albeit debated. A hitherto undescribed but performance relevant effect of glucocorticoids in healthy humans is accelerated erythropoiesis. We investigated whether a glucocorticoid injection accelerate erythropoiesis, increase total hemoglobin mass, and improve exercise performance.Methods: In a counterbalanced, randomized, double-blinded, placebo-controlled crossover design (3-months washout), ten well-trained males (peak oxygen uptake: 60 ± 3 mL O2·min-1·kg-1) were injected with 40 mg triamcinolone acetonide (glucocorticoid group) or saline (placebo group) in the gluteal muscles. Venous blood samples collected before and 7-10 h, 1, 3, 7, 14 and 21 days after treatment were analyzed for hemoglobin concentration and reticulocyte percentage. Hemoglobin mass and mean power output in a 450-kcal time trial was measured before as well as one and three weeks after treatment.Results: A higher reticulocyte percentage was evident three (19 ± 30 %, P < 0.05) and seven (48 ± 38 %, P < 0.001) days after glucocorticoid administration, compared with placebo, whereas hemoglobin concentration was similar between groups. Additionally, hemoglobin mass was higher (P < 0.05) seven (glucocorticoid: 886 ± 104 g, placebo: 872 ± 103 g) and 21 days (glucocorticoid: 879 ± 111 g, placebo: 866 ± 103 g) after glucocorticoid administration compared with placebo. Mean power output was similar between groups seven (glucocorticoid: 278 ± 64 W, placebo: 275 ± 62 W) and 21 days (glucocorticoid: 274 ± 62 W, placebo: 275 ± 60 W) after treatment.Conclusions: Intramuscular injection of 40 mg triamcinolone acetonide accelerates erythropoiesis and increase hemoglobin mass but does not improve aerobic exercise performan

Dried blood spot (DBS) testing allows fast, easy, and minimally invasive collection of microvolumes of blood. In an anti-doping context, DBS testing has particular relevance for substances prohibited in-competition only such as ephedrine, which is currently detected by urine analysis, since DBS can add information about the blood drug concentrations during the in-competition period. Several collection methods and devices exist for DBS collection from different anatomical sites. Thus, agreements between concentrations of target analytes in DBS samples from different sampling sites, along with between DBS and those in conventional venous plasma samples, need to be evaluated. Herein, we collected matched upper-arm DBS, fingerprick DBS and venous plasma samples from 8 healthy, male subjects in an 8-hour period following oral administrations of 20 mg ('low dose') and 60 mg ('high dose') of ephedrine. We show that the use of alternative sampling sites and matrices are feasible possibilities for ephedrine analysis in doping control. We observed very good agreement between collection sites and that specificity and sensitivity can be upheld despite use of an alternative collection site. However, potential concentration differences between DBS and venous plasma should be considered, and distinct threshold might be necessary if implementing both blood matrices in ephedrine analysis.

Sports officials around the world are facing incredible challenges due to the unfair means of practices performed by the athletes to improve their performance in the game. It includes the intake of hormonal based drugs or transfusion of blood to increase their strength and the result of their training. However, the current direct test of detection of these cases includes the laboratory-based method, which is limited because of the cost factors, availability of medical experts, etc. This leads us to seek for indirect tests. With the growing interest of Artificial Intelligence in healthcare, it is important to propose an algorithm based on blood parameters to improve decision making. In this paper, we proposed a statistical and machine learning-based approach to identify the presence of doping substance rhEPO in blood samples.

Objectives: To investigate whether recombinant human erythropoietin (rHuEPO) injections during an altitude training camp impact heart function.Methods: Thirty (12 women) moderately trained subjects stayed at 2320 m altitude for 4 weeks while training. Subjects were randomized to placebo (isotonic saline) or rHuEPO (20 IU/kg body weight) i.v. injections. Transthoracic echocardiography imaging was acquired 3 days after arrival to altitude and prior to the first placebo or rHuEPO injection as well as one day after the last rHuEPO injection three weeks later.Results: rHuEPO did not alter cardiovascular morphology parameters, systolic or diastolic function. In the placebo group, altitude exposure improved left ventricle (LV) systolic function due to an increased twist angle but rHuEPO had no additional effects. Pulmonary arterial systolic pressure was unaffected in either group. Notably, rHuEPO hampered LV untwist rate without affecting LV early filling.Conclusion: rHuEPO provided during mild altitude exposure does not cause any major effects on heart function. The observed alteration in LV untwist induced by rHuEPO is unlikely to have a meaningful clinical effect. Trial registration: Registered on www.clinicaltrials.gov (NCT04227665).

Angiotensin-converting enzyme (ACE) activity may be one determinant of adaptability to exercise training, but well-controlled studies in humans without confounding conditions are lacking. Thus, the purpose of the present study was to investigate whether ACE inhibition affects cardiovascular adaptations to exercise training in healthy humans. Healthy participants of both genders (40 ± 7 years) completed a randomized, double-blind, placebo-controlled trial. Eight weeks of exercise training combined with placebo (PLA, n = 25) or ACE inhibitor (ACEi, n = 23) treatment was carried out. Before and after the intervention, cardiovascular characteristics were investigated. Mean arterial blood pressure was reduced (p < 0.001) by -5.5 [-8.4; -2.6] mmHg in ACEi , whereas the 0.7 [-2.0; 3.5] mmHg fluctuation in PLA was non-significant. Maximal oxygen uptake increased (p < 0.001) irrespective of ACE inhibitor treatment by 13 [8; 17] % in ACEi and 13 [9; 17] % in PLA. In addition, skeletal muscle endurance increased (p < 0.001) to a similar extent in both groups, with magnitudes of 82 [55; 113] % in ACEi and 74 [48; 105] % in PLA. In contrast, left atrial volume decreased (p < 0.05) by -9 [-16; -2] % in ACEi , but increased (p < 0.01) by 14 [5; 23] % in PLA. Total hemoglobin mass was reduced (p < 0.01) by -3 [-6; -1] % in ACEi , while a non-significant numeric increase of 2 [-0.4; 4] % existed in PLA. The lean mass remained constant in ACEi but increased (p < 0.001) by 3 [2; 4] % in PLA. In healthy middle-aged adults, 8 weeks of high-intensity exercise training increases maximal oxygen uptake and skeletal muscle endurance irrespective of ACE inhibitor treatment. However, ACE inhibitor treatment counteracts exercise training-induced increases in lean mass and left atrial volume. ACE inhibitor treatment compromises total

The World Anti-Doping Agency prohibit glucocorticoid (GC) administration during competition but allow administration in periods out of competition. However, GC administration may accelerate erythropoiesis and resemble blood volume manipulation methods, which are prohibited at all times. Here, we investigated whether a single GC injection accelerate erythropoiesis, increase total hemoglobin mass (Hbmass ) and improve exercise performance. In a randomized, double-blinded, placebo-controlled crossover design (3-month washout), eight trained males (maximal oxygen uptake 60±5 ml O2 ·min-1 ·kg-1 ) were injected with 40 mg triamcinolone acetonide (GC group) or saline (PLA group) in the gluteal muscles. Venous blood samples collected before and 7-10h, 1, 3, 7, 14 and 21 days after treatment were analyzed for [Hb] and reticulocyte percentage (ret%). Hbmass and mean power output in a 450-kCal time trial was measured before as well as one and three weeks after treatment. A 27±28% and 54±41% higher ret% was evident three (P<0.01) and seven (P<0.001) days after the GC administration, respectively, compared with PLA, whereas [Hb] was similar between groups. Additionally, Hbmass was 20±28g higher (P<0.05) one week after GC administration compared with PLA, but similar after three weeks. The mean power output was similar between groups one (GC: 285±70 W, PLA: 279±69 W) and three (GC: 279±72 W, PLA: 276±71 W) weeks after treatment. In conclusion, a single intramuscular injection of triamcinolone acetonide was sufficient to accelerate erythropoiesis and increase Hbmass, but did not translate into improved aerobic exercise performance in the present study. Future research should confirm whether anti-doping authorities should consider glucocorticoid injections as a method of blood volume manipulation.