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Background: This cross-sectional study investigated the relationship between genetic variations in monocarboxylate transporter genes and blood lactate production and removal after high-intensity efforts in humans. The study was conducted to explore how genetic variations in the MCT1, MCT2, and MCT4 genes influenced lactate dynamics and to advance the field of sports genetics by pinpointing critical genetic markers that can enhance athletic performance and recovery. Methods: 337 male athletes from Poland and the Czech Republic underwent two intermittent all-out Wingate tests. Before the tests, DNA samples were taken from each participant, and SNP (single nucleotide polymorphism) analysis was carried out. Two intermittent all-out tests were implemented, and lactate concentrations were assessed before and after these tests. Results: Sprinters more frequently exhibited the haplotype TAC in the MCT2 gene, which was associated with an increase in the difference between maximum lactate and final lactate concentration. Additionally, this haplotype was linked to higher maximum lactate concentration and was more frequently observed in sprinters. The genotypic interactions AG/T- and GGxT- (MCT1 rs3789592 x MCT4 rs11323780), TTxTT (MCT1 rs12028967 x MCT2 rs3763979), and MCT1 rs7556664 x MCT4 rs11323780 were all associated with an increase in the difference between maximum lactate concentration and final lactate concentration. Conversely, the AGxGG (MCT1 rs3789592 x MCT2 rs995343) interaction was linked to a decrease in this difference. The relationship between maximum lactate concentration and genotypic interactions can be observed as follows: when ATxTT (MCT2 rs3763980 x MCT4 rs11323780) or CTxCT (MCT1 rs10857983 x MCT2 rs3763979) genotypic combinations are present, it leads to a decrease in maximum lactate concentration. Similarly, the combination of CTxCT (MCT1 rs4301628 x MCT2 rs3763979), CT x TT (MCT1 rs4301628 x MCT4 rs11323780), and CTxTT (MCT1 rs4301628 x MCT2 rs3763979) results in decreased maximum lactate concentration. Conclusions: The TAC haplotype (rs3763980, rs995343, rs3763979) in the MCT2 gene is associated with altered lactate clearance in sprinters, potentially affecting performance and recovery by elevating post-exercise lactate concentrations. While MCT4 rs11323780 is also identified as a significant variant in lactate metabolism, suggesting its role as a biomarker for sprinting performance, further investigation is necessary to clarify underlying mechanisms and consider additional factors. Based on elite male athletes from Poland and the Czech Republic, the study may not generalize to all sprinters or diverse athletic populations. Although genetic variants show promise as biomarkers for sprinting success, athletic performance is influenced by a complex interplay of genetics, environment, and training extending beyond MCT genes. [ABSTRACT FROM AUTHOR]

Context Ghrelin circulates in acylated (AG) and deacylated (DAG) forms, which are known to affect appetite. Although acute exercise has been shown to modulate ghrelin levels, data on the impact of exercise intensity on AG and DAG levels and their effects on appetite are sparse and primarily limited to males. Objective To investigate the effect of exercise intensity and sex on ghrelin levels and appetite in untrained humans. Methods Eight males (age: 43.1 ± 10.9 years; body mass index [BMI]: 22.2 ± 1.7 kg/m2; peak oxygen consumption [VO2peak]: 36.3 ± 6.4 mL/kg/min) and 6 females (age: 32.2 ± 11.1 years; BMI: 22.7 ± 1.0 kg/m2; VO2peak: 29.2 ± 4.0 mL/kg/min) completed a maximal graded cycle ergometer lactate threshold (LT)/VO2peak test. These data were used to determine the exercise intensity on 3 subsequent randomized control or calorically matched cycle exercise bouts: (1) CON, no exercise; (2) MOD, the power output at LT; (3) HIGH, the power output associated with 75% of the difference between LT and VO2peak. Perception of appetite was analyzed using visual analog scales. Results Females had higher levels of total ghrelin (TG) (P =.03) and DAG (P =.01) at baseline than males. Both groups exhibited reduced DAG levels in HIGH compared with MOD and CON (P <.0001-.004); however, only females had significantly reduced AG in HIGH (P <.0001). Hunger scores were higher in MOD than in CON (P <.01). Conclusion High-intensity may be superior to moderate-intensity exercise for reducing ghrelin levels and modifying hunger, and sex may impact this response. [ABSTRACT FROM AUTHOR]

We wanted to determine the influence of total blood volume (BV) and blood lactate quantity on lactate concentrations during incremental exercise. Twenty-six healthy, nonsmoking, heterogeneously trained females (27.5 ± 5.9 ys) performed an incremental cardiopulmonary exercise test on a cycle ergometer during which maximum oxygen uptake ( V · O2max), lactate concentrations ([La−]) and hemoglobin concentrations ([Hb]) were determined. Hemoglobin mass and blood volume (BV) were determined using an optimised carbon monoxide-rebreathing method. V · O2max and maximum power (Pmax) ranged between 32 and 62 mL·min−1·kg−1 and 2.3 and 5.5 W·kg−1, respectively. BV ranged between 81 and 121 mL·kg−1 of lean body mass and decreased by 280 ± 115 mL (5.7%, p = 0.001) until Pmax. At Pmax, the [La−] was significantly correlated to the systemic lactate quantity (La−, r = 0.84, p < 0.0001) but also significantly negatively correlated to the BV (r = −0.44, p < 0.05). We calculated that the exercise-induced BV shifts significantly reduced the lactate transport capacity by 10.8% (p < 0.0001). Our results demonstrate that both the total BV and La− have a major influence on the resulting [La−] during dynamic exercise. Moreover, the blood La− transport capacity might be significantly reduced by the shift in plasma volume. We conclude, that the total BV might be another relevant factor in the interpretation of [La−] during a cardio-pulmonary exercise test. [ABSTRACT FROM AUTHOR]

Introduction: Sepsis and septic shock cause significant mortality worldwide, with no targeted molecular therapies available. Metformin has pleomorphic effects that may be beneficial in sepsis, but at present, the impact of metformin exposure on sepsis remains controversial. Metformin might alter lactate metabolism, but little is known about its influence on lactate kinetics. We therefore investigated the impact of preadmission metformin use on lactate kinetics, acute kidney injury (AKI) and mortality in sepsis. Materials and Methods: We retrospectively analysed all ICU admissions with sepsis and septic shock between January 2013 and September 2020, identifying 77 users and 390 nonusers (subdivided in diabetics, n = 48 and nondiabetics, n = 342). Results: (Sub)groups did not differ in illness severity or sepsis aetiology. Admission lactate levels were similar, but evolution in lactate over the first 24 h showed a larger decrease in users vs nonusers (median − 53% vs. −36%, p =.010). No difference in AKI or renal replacement therapy was found. Mortality was lower in users vs nonusers in case of septic shock (21.9% (n = 7) vs. 42.7% (n = 61) for 90d mortality, p =.029, OR 0.38 [95% CI: 0.15–0.93]), but showed no significant differences in the combined sepsis and septic shock population. Conclusions: In our data, preadmission metformin use is associated with a significantly larger decrease in lactate after admission with sepsis or septic shock and with reduced mortality in septic shock. This underscores the need for further studies investigating the interplay between metformin, lactate and sepsis, thereby exploring the potential use of metformin or its pathways in sepsis. [ABSTRACT FROM AUTHOR]

Abstract Introduction Sepsis and septic shock cause significant mortality worldwide, with no targeted molecular therapies available. Metformin has pleomorphic effects that may be beneficial in sepsis, but at present, the impact of metformin exposure on sepsis remains controversial. Metformin might alter lactate metabolism, but little is known about its influence on lactate kinetics. We therefore investigated the impact of preadmission metformin use on lactate kinetics, acute kidney injury (AKI) and mortality in sepsis. Materials and Methods We retrospectively analysed all ICU admissions with sepsis and septic shock between January 2013 and September 2020, identifying 77 users and 390 nonusers (subdivided in diabetics, n = 48 and nondiabetics, n = 342). Results (Sub)groups did not differ in illness severity or sepsis aetiology. Admission lactate levels were similar, but evolution in lactate over the first 24 h showed a larger decrease in users vs nonusers (median − 53% vs. −36%, p = .010). No difference in AKI or renal replacement therapy was found. Mortality was lower in users vs nonusers in case of septic shock (21.9% (n = 7) vs. 42.7% (n = 61) for 90d mortality, p = .029, OR 0.38 [95% CI: 0.15–0.93]), but showed no significant differences in the combined sepsis and septic shock population. Conclusions In our data, preadmission metformin use is associated with a significantly larger decrease in lactate after admission with sepsis or septic shock and with reduced mortality in septic shock. This underscores the need for further studies investigating the interplay between metformin, lactate and sepsis, thereby exploring the potential use of metformin or its pathways in sepsis.

Abstract Background To investigate the optimal target e of lactate kinetics at different time during the resuscitation, the factors that influence whether the kinetics achieve the goals, and the clinical implications of different clinical phenotypes. Methods Patients with hyperlactatemia between May 1, 2013 and December 31, 2018 were retrospectively analyzed. Demographic data, basic organ function, hemodynamic parameters at ICU admission (T0) and at 6 h, 12 h, 24 h, 48 h, and 72 h, arterial blood lactate and blood glucose levels, cumulative clinical treatment conditions at different time points and final patient outcomes were collected. Results A total of 3298 patients were enrolled, and the mortality rate was 12.2%. The cutoff values of lactate kinetics for prognosis at 6 h, 12 h, 24 h, 48 h, and 72 h were 21%, 40%, 57%, 66%, and 72%. The APACHE II score, SOFA score, heart rate (HR), and blood glucose were risk factors that correlated with whether the lactate kinetics attained the target goal. Based on the pattens of the lactate kinetics, eight clinical phenotypes were proposed. The odds ratios of death for clinical phenotypes VIII, IV, and II were 4.39, 4.2, and 5.27-fold of those of clinical phenotype I, respectively. Conclusion Stepwise recovery of lactate kinetics is an important resuscitation target for patients with hyperlactatemia. The APACHE II score, SOFA score, HR, and blood glucose were independent risk factors that influenced achievement of lactate kinetic targets. The cinical phenotypes of stepwise lactate kinetics are closely related to the prognosis.

Introduction: Sepsis is one of the leading causes of death worldwide. Serum lactate is being used in sepsis for diagnostic and prognostic purposes for years now. In this study, we shed light over a novel use of lactate in form of various clearance parameters to determine mortality in septic patients at the 28th day. Materials and method: In our study, 200 patients with sepsis were included using quick sequential organ failure assessment (qSOFA) score and their lactate levels were measured at the time of admission (0 hour) and 24 hours after admission. Lactate clearance parameters (absolute and relative lactate clearance, lactate clearance rate) were calculated. All patients were followed up for a period of 28 days to determine the outcome, and data analysis was done accordingly. Results and conclusion: Our study showed that higher SOFA score, qSOFA score, and serum lactate levels were associated with increased 28th-day mortality. Low absolute, relative lactate clearance and lactate clearance rate were also associated with poor outcomes. The best cutoffs to predict poor outcomes were serum lactate level at 24 hours ≥4 mmol/L and relative lactate clearance ≤40.3% with good sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Abstract Background Venous–arterial carbon dioxide (CO2) to arterial–venous oxygen (O2) content difference ratio (Cv-aCO2/Ca-vO2) > 1 is supposed to be both sensitive and specific for anaerobic metabolism. What regional hemodynamic and metabolic parameters determine the ratio has not been clarified. Objectives To address determinants of systemic and renal, spleen, gut and liver Cv-aCO2/Ca-vO2. Methods Post hoc analysis of original data from published experimental studies aimed to address effects of different fluid resuscitation strategies on oxygen transport, lactate metabolism and organ dysfunction in fecal peritonitis and endotoxin infusion, and from animals in cardiac tamponade or hypoxic hypoxia. Systemic and regional hemodynamics, blood flow, lactate uptake, carbon dioxide and oxygen-derived variables were determined. Generalized estimating equations (GEE) were fit to assess contributors to systemic and regional Cv-aCO2/Ca-vO2. Results Median (range) of pooled systemic Cv-aCO2/Ca-vO2 in 64 pigs was 1.02 (0.02 to 3.84). While parameters reflecting regional lactate exchange were variably associated with the respective regional Cv-aCO2/Ca-vO2 ratios, only regional ratios were independently correlated with systemic ratio: renal Cv-aCO2 /Ca-vO2 (β = 0.148, 95% CI 0.062 to 0.234; p = 0.001), spleen Cv-aCO2/Ca-vO2 (β = 0.065, 95% CI 0.002 to 0.127; p = 0.042), gut Cv-aCO2/Ca-vO2 (β = 0.117, 95% CI 0.025 to 0.209; p = 0.013), liver Cv-aCO2/Ca-vO2 (β = − 0.159, 95% CI − 0.297 to − 0.022; p = 0.023), hepatosplanchnic Cv-aCO2/Ca-vO2 (β = 0.495, 95% CI 0.205 to 0.786; p = 0.001). Conclusion In a mixed set of animals in different shock forms or during hypoxic injury, hepatosplanchnic Cv-aCO2/Ca-vO2 ratio had the strongest independent association with systemic Cv-aCO2/Ca-vO2, while no independent association was demonstrated for lactate or hemodynamic variables.

We wanted to determine the influence of total blood volume (BV) and blood lactate quantity on lactate concentrations during incremental exercise. Twenty-six healthy, nonsmoking, heterogeneously trained females (27.5 ± 5.9 ys) performed an incremental cardiopulmonary exercise test on a cycle ergometer during which maximum oxygen uptake (V·O2max), lactate concentrations ([La−]) and hemoglobin concentrations ([Hb]) were determined. Hemoglobin mass and blood volume (BV) were determined using an optimised carbon monoxide-rebreathing method. V·O2max and maximum power (Pmax) ranged between 32 and 62 mL·min−1·kg−1 and 2.3 and 5.5 W·kg−1, respectively. BV ranged between 81 and 121 mL·kg−1 of lean body mass and decreased by 280 ± 115 mL (5.7%, p = 0.001) until Pmax. At Pmax, the [La−] was significantly correlated to the systemic lactate quantity (La−, r = 0.84, p < 0.0001) but also significantly negatively correlated to the BV (r = −0.44, p < 0.05). We calculated that the exercise-induced BV shifts significantly reduced the lactate transport capacity by 10.8% (p < 0.0001). Our results demonstrate that both the total BV and La− have a major influence on the resulting [La−] during dynamic exercise. Moreover, the blood La− transport capacity might be significantly reduced by the shift in plasma volume. We conclude, that the total BV might be another relevant factor in the interpretation of [La−] during a cardio-pulmonary exercise test.

Objective: This study aimed to measure blood flow changes in the superior mesenteric artery (SMA), using Doppler ultrasound, in post-cardiac surgery patients, to evaluate the correlation between the SMA resistance index (SMA-RI) and lactate concentrations.Methods: The patients' basic hemodynamics, blood gas parameters and lactate concentration were collected at admission. Simultaneously, the SMA blood flow parameters were collected using Doppler ultrasound with the patients in the supine position. The lactate concentrations were measured again at 2, 6, and 12-h time points after the first test. The length of intensive care unit stays and prognoses continued to be monitored.Results: A total of 67 patients were included. The SMA-RI correlated with the admission (r = 0.3117, P = 0.0102), 2-h (r = 0.5091, P < 0.0001), 6-h (r = 0.5061, P < 0.0001), and 12-h (r = 0.2483, P = 0.0428) lactate concentrations. The SMA-RI could predict the 2-h 10% [area under the curve (AUC) = 0.8294, P < 0.0001] and 6-h 40% lactate kinetics (AUC = 0.7708, P = 0.0012). The cut-off value was 0.83. When the SMA-RI was 10% lactate kinetics, and 64.71 and 75.00%, respectively, for the prediction of the 6-h >40% lactate kinetics. The lactate concentrations at admission, 2 and 6-h points were higher in the high-RI group (RI ≥ 0.83) and the intensive care unit stays were significantly longer than in the low-RI group (P = 0.0005).Conclusions: The increase in SMA-RI was associated with higher lactate concentrations and worse lactate kinetics in post-cardiac surgery patients. This may be related to intestinal hypoperfusion. The SMA-RI may be one of the indicators that should be monitored to guide resuscitation in these patients.

Abstract Background Plasma lactate concentrations and their trends over time are used for clinical prognosis, and to guide treatment, in critically ill patients. Although heavily relied upon for clinical decision-making, lactate kinetics of these patients is sparsely studied. Aim To establish and validate a feasible method to study lactate kinetics in critically ill patients. Methods Healthy volunteers (n = 6) received a bolus dose of 13C-labeled lactate (20 μmol/kg body weight), and 43 blood samples were drawn over 2 h to determine the decay in labeled lactate. Data was analyzed using non-compartmental modeling calculating rates of appearance (R a) and clearance of lactate. The area under the curve (AUC) was calculated using a linear-up log-down trapezoidal approach with extrapolation beyond 120 min using the terminal slope to obtain the whole AUC. After evaluation, the same protocol was used in an unselected group of critically ill patients (n = 10). Results R a for healthy volunteers and ICU patients were 12.8 ± 3.9 vs 22.7 ± 11.1 μmol/kg/min and metabolic clearance 1.56 ± 0.39 vs 1.12 ± 0.43 L/min, respectively. ICU patients with normal lactate concentrations showed kinetics very similar to healthy volunteers. Simulations showed that reducing the number of samples from 43 to 14 gave the same results. Our protocol yielded results on lactate kinetics very similar to previously published data using other techniques. Conclusion This simple and user-friendly protocol using an isotopically labeled bolus dose of lactate was accurate and feasible for studying lactate kinetics in critically ill ICU patients. Trial registration ANZCTR, ACTRN12617000626369, registered 8 March 2017. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372507&isReview=true

Background: To investigate the optimal target e of lactate kinetics at different time during the resuscitation, the factors that influence whether the kinetics achieve the goals, and the clinical implications of different clinical phenotypes. Methods: Patients with hyperlactatemia between May 1, 2013 and December 31, 2018 were retrospectively analyzed. Demographic data, basic organ function, hemodynamic parameters at ICU admission (T0) and at 6 h, 12 h, 24 h, 48 h, and 72 h, arterial blood lactate and blood glucose levels, cumulative clinical treatment conditions at different time points and final patient outcomes were collected. Results: A total of 3298 patients were enrolled, and the mortality rate was 12.2%. The cutoff values of lactate kinetics for prognosis at 6 h, 12 h, 24 h, 48 h, and 72 h were 21%, 40%, 57%, 66%, and 72%. The APACHE II score, SOFA score, heart rate (HR), and blood glucose were risk factors that correlated with whether the lactate kinetics attained the target goal. Based on the pattens of the lactate kinetics, eight clinical phenotypes were proposed. The odds ratios of death for clinical phenotypes VIII, IV, and II were 4.39, 4.2, and 5.27-fold of those of clinical phenotype I, respectively. Conclusion: Stepwise recovery of lactate kinetics is an important resuscitation target for patients with hyperlactatemia. The APACHE II score, SOFA score, HR, and blood glucose were independent risk factors that influenced achievement of lactate kinetic targets. The cinical phenotypes of stepwise lactate kinetics are closely related to the prognosis. [ABSTRACT FROM AUTHOR]

Abstract Background A decrease in blood lactate levels (Lac) >10% during the first hours of resuscitation in sepsis is associated with better outcomes, but the mechanisms are unclear. Our objective was to investigate the relationship between the time course of Lac, inflammatory response, and mitochondrial respiration during experimental sepsis. Methods Original data from two previously published studies were reanalyzed. In cohort 1, pigs were randomized to be resuscitated for 48 h starting at 6, 12, and 24 h, respectively, after fecal peritonitis induction (n = 8 each). Animals were categorized according to the decrease in Lac during the first 6 h of resuscitation (early if ≥10% [Lac ≥10%] or late if 10% during early resuscitation (6 h) after abdominal sepsis is associated with lower levels of plasma interleukin-6 and improved brain but not hepatic or muscle mitochondrial respiration. Blood flow redistribution to abdominal organs in animals with early decrease in Lac concentrations increases the potential to both deliver and extract Lac.

Background: Plasma lactate concentrations and their trends over time are used for clinical prognosis, and to guide treatment, in critically ill patients. Although heavily relied upon for clinical decision-making, lactate kinetics of these patients is sparsely studied.Aim: To establish and validate a feasible method to study lactate kinetics in critically ill patients.Methods: Healthy volunteers (n = 6) received a bolus dose of 13C-labeled lactate (20 μmol/kg body weight), and 43 blood samples were drawn over 2 h to determine the decay in labeled lactate. Data was analyzed using non-compartmental modeling calculating rates of appearance (Ra) and clearance of lactate. The area under the curve (AUC) was calculated using a linear-up log-down trapezoidal approach with extrapolation beyond 120 min using the terminal slope to obtain the whole AUC. After evaluation, the same protocol was used in an unselected group of critically ill patients (n = 10).Results: Ra for healthy volunteers and ICU patients were 12.8 ± 3.9 vs 22.7 ± 11.1 μmol/kg/min and metabolic clearance 1.56 ± 0.39 vs 1.12 ± 0.43 L/min, respectively. ICU patients with normal lactate concentrations showed kinetics very similar to healthy volunteers. Simulations showed that reducing the number of samples from 43 to 14 gave the same results. Our protocol yielded results on lactate kinetics very similar to previously published data using other techniques.Conclusion: This simple and user-friendly protocol using an isotopically labeled bolus dose of lactate was accurate and feasible for studying lactate kinetics in critically ill ICU patients.Trial Registration: ANZCTR, ACTRN12617000626369, registered 8 March 2017. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372507&isReview=true. [ABSTRACT FROM AUTHOR]

During a continuously increasing exercise workload (WL) a point will be reached at which arterial lactate accumulates rapidly. This so-called lactate threshold (LT) is associated with the maximal lactate steady state workload (MLSSW), the highest WL, at which arterial lactate concentration [LA] does not change. However, the physiological range in which the LT and the MLSSW occur has not been demonstrated directly. We used minor WL variations in the MLSSW range to assess arterial lactate kinetics in 278 treadmill and 148 bicycle ergometer exercise tests. At a certain workload, minimal further increment of running speed (0.1–0.15 m/s) or cycling power (7–10 W) caused a steep elevation of [LA] (0.9 ± 0.43 mM, maximum increase 2.4 mM), indicating LT achievement. This sharp [LA] increase was more pronounced when higher WL increments were used (0.1 vs. 0.30 m/s, P = 0.02; 0.15 vs. 0.30 m/s, P < 0.001; 7 vs. 15 W, P = 0.002; 10 vs. 15 W, P = 0.001). A subsequent workload reduction (0.1 m/s/7 W) stopped the [LA] increase indicating MLSSW realization. LT based determination of running speed (MLSSW) was highly reproducible on a day-to-day basis (r = 0.996, P < 0.001), valid in a 10 km constant velocity setting (r = 0.981, P < 0.001) and a half marathon race (r = 0.969, P < 0.001). These results demonstrate a fine-tuned regulation of exercise-related lactate metabolism, which can be reliably captured by assessing lactate kinetics at the MLSSW.

International Journal of Exercise Science 12(2): 57-68, 2019. The response of blood lactate concentration (BLC) to exercise is a commonly used approach to set training intensities and to determine the anaerobic threshold, which are important in evaluation of endurance exercise performance. The maximal lactate steady state (MLSS) is defined as the highest workload or BLC that can be maintained without continual lactate accumulation over time. The aim of this study was to investigate MLSS in the cross-country skiing sub-technique double poling and to assess the validity of a fixed blood lactate threshold (OBLA and the 45° tangent of the lactate curve). Eight well-trained cross-country skiers (age = 27.6±8.8 years [mean±SD], body mass = 73.9±6.2 kg, height = 179.3±7.0 cm) performed an incremental test to determine OBLA and Individual Anaerobic Threshold (IAnT) and several constant workload tests of 30 min to determine the MLSS. Lactate concentration at MLSS in double poling was 6.7±1.3 mmol·L-1 which was significantly higher compared to OBLA (p<0.001) and IAnT (p<0.01). Despite significant correlations in velocities between MLSS-IAnT and MLSS-OBLA (r=0.95/0.95, p<0.001), significant (p<0.01) differences between MLSS (21.4±2.8 km·h-1) versus IAnT (20.6±3.6 km·h-1) and OBLA (19.9±3.0 km·h-1) was observed. It was concluded that both OBLA and IAnT underestimate MLSS in double poling. A fixed value of 7 mmol·L-1 would be more appropriate in lactate testing of cross-country skiers using the double poling technique, yet dissuaded because of intra-individual variations. Direct determination of MLSS is the recommended approach for useful exercise thresholds, important for training interventions in elite cross-country skiers. [ABSTRACT FROM AUTHOR]

During a continuously increasing exercise workload (WL) a point will be reached at which arterial lactate accumulates rapidly. This so-called lactate threshold (LT) is associated with the maximal lactate steady state workload (MLSSW), the highest WL, at which arterial lactate concentration [LA] does not change. However, the physiological range in which the LT and the MLSSW occur has not been demonstrated directly. We used minor WL variations in the MLSSW range to assess arterial lactate kinetics in 278 treadmill and 148 bicycle ergometer exercise tests. At a certain workload, minimal further increment of running speed (0.1-0.15 m/s) or cycling power (7-10 W) caused a steep elevation of [LA] (0.9 ± 0.43mM, maximum increase 2.4mM), indicating LT achievement. This sharp [LA] increase was more pronounced when higher WL increments were used (0.1 vs. 0.30 m/s, P = 0.02; 0.15 vs. 0.30 m/s, P < 0.001; 7 vs. 15W, P = 0.002; 10 vs. 15W, P = 0.001). A subsequent workload reduction (0.1 m/s/7 W) stopped the [LA] increase indicating MLSSW realization. LT based determination of running speed (MLSSW) was highly reproducible on a day-to-day basis (r = 0.996, P < 0.001), valid in a 10 km constant velocity setting (r = 0.981, P < 0.001) and a half marathon race (r = 0.969, P < 0.001). These results demonstrate a fine-tuned regulation of exercise-related lactate metabolism, which can be reliably captured by assessing lactate kinetics at the MLSSW. [ABSTRACT FROM AUTHOR]

Background: A decrease in blood lactate levels (Lac) >10% during the first hours of resuscitation in sepsis is associated with better outcomes, but the mechanisms are unclear. Our objective was to investigate the relationship between the time course of Lac, inflammatory response, and mitochondrial respiration during experimental sepsis.Methods: Original data from two previously published studies were reanalyzed. In cohort 1, pigs were randomized to be resuscitated for 48 h starting at 6, 12, and 24 h, respectively, after fecal peritonitis induction (n = 8 each). Animals were categorized according to the decrease in Lac during the first 6 h of resuscitation (early if ≥10% [Lac ≥10%] or late if <10% or increased [Lac <10%]), and systemic hemodynamics, inflammatory parameters, and mitochondrial function were compared between groups. In a second group of animals with fecal peritonitis and 24 h of resuscitation (n = 16, cohort 2), abdominal regional Lac exchange was measured, and animals were categorized according to the decrease in Lac as in cohort 1.Results: Overall mortality was 20% (4 of 20) in the Lac ≥10% group and 60% (12 of 20) in the Lac <10% group (p = 0.022). In cohort 1, systemic hemodynamics were similar in the Lac ≥10% (n = 13) and Lac <10% (n = 11) groups. Plasma interleukin-6 levels increased during unresuscitated sepsis and decreased during resusciation in both groups, but they were lower at study end in the Lac ≥10% group (p = 0.047). Complexes I and II maximal (state 3) and resting (state 4) isolated brain mitochondrial respiration at study end was higher in the Lac ≥10% group than in the Lac <10% group, whereas hepatic, myocardial, and skeletal muscle mitochondrial respiration was similar in both groups. In cohort 2, mesenteric, total hepatic, and renal blood flow at study end was higher in the Lac ≥10% group (n = 7) than in the Lac <10% group (n = 9), despite similar cardiac output. Hepatic lactate influx and uptake in the Lac ≥10% group were approximately 1.5 and 3 times higher, respectively, than in the Lac <10% group (p = 0.066 for both).Conclusions: A decrease in Lac >10% during early resuscitation (6 h) after abdominal sepsis is associated with lower levels of plasma interleukin-6 and improved brain but not hepatic or muscle mitochondrial respiration. Blood flow redistribution to abdominal organs in animals with early decrease in Lac concentrations increases the potential to both deliver and extract Lac. [ABSTRACT FROM AUTHOR]

Background: Setting lactate kinetics at >30% might improve the clinical outcomes of patients with sepsis-associated hyperlactatemia. The aim of this study was to explore the outcome benefits of stepwise lactate kinetics vs central venous oxygen saturation (ScvO2)-oriented hemodynamic therapy at 6 h as the protocol goal during early resuscitation.Methods: The relevant parameters and adverse events after different targets in 360 randomly assigned patients with sepsis-associated hyperlactatemia were recorded and compared.Results: Heart rate (HR) at 48 h in the ScvO2 group was higher than in the lactate kinetics group (105 ± 19 bpm vs 99 ± 20 bpm, P = 0.040). The liquid balance at 4 h, 12 h, and 24 h in the lactate kinetics group was larger than in the ScvO2 group (1535 (1271-1778) ml vs 826 (631-1219) ml, P < 0.001; 1688 (1173-1923) ml vs 1277 (962 - 1588) ml, P <0.001; and 1510 (904-2087) ml vs 1236 (740-1808) ml, P = 0.005), respectively. Mortality was higher in the ScvO2 group (27.9% vs 18.3%, P = 0.033), but there was no significant difference between the two groups in the length of stay in the ICU or mechanical ventilation. In terms of new onset organ dysfunction, there was a significant difference between the two groups in total bilirubin at 48 h and 72 h. Based on the 60-day survival curves, there was significantly more mortality in the ScvO2 group than in the lactate kinetics group (X 2 = 4.133, P = 0.042). In addition, fewer adverse events occurred in the lactate kinetics group.Conclusions: Stepwise lactate kinetics-oriented hemodynamic therapy can reduce mortality in patients with sepsis-associated hyperlactatemia compared with ScvO2-oriented therapy.Trial Registration: National Institutes of Health Clinical Trials Registry, NCT02566460 . Registered on 26 September 2015. [ABSTRACT FROM AUTHOR]

The purpose of this study was to test if the lactate exchange (γ1) and removal (γ2) abilities during recovery following short all-out supramaximal exercise correlate with the muscle content of MCT1 and MCT4, the two isoforms of the monocarboxylate transporters family involved in lactate and H+ co-transport in skeletal muscle. Eighteen lightweight rowers completed a 3-min all-out exercise on rowing ergometer. Blood lactate samples were collected during the subsequent passive recovery to assess an individual blood lactate curve (IBLC). IBLC were fitted to the bi-exponential time function: La(t) = [La](0) + ...) where [La](0) is the blood lactate concentration at exercise completion and the velocity constants γ1 and γ2 denote the lactate exchange and removal abilities, respectively. An application of the bi-compartmental model of lactate distribution space allowed estimation of the lactate removal rate at exercise completion [LRR(0)]. Biopsy of the right vastus lateralis was taken at rest to measure muscle MCT1 and MCT4 content. Fiber type distribution, activity of key enzymes and capillary density (CD) were also assessed. γ1 was correlated with [La](0) (r = -0.54, P < 0.05) but not with MCT1, MCT4 or CD. γ2 and LRR(0) were correlated with MCT4 (r = 0.63, P < 0.01 and r = 0.73, P < 0.001, respectively) but not with MCT1 or cytochrome c oxidase activity. These findings suggest that the lactate exchange ability is highly dependent on the milieu so that the importance of the muscle MCT1 and MCT4 content in γ1 was hidden in the present study. Our results also suggest that during recovery following all-out supramaximal exercise in well-trained rowers, MCT4 might play a significant role in the distribution and delivery of lactate for its subsequent removal. [ABSTRACT FROM AUTHOR]

To examine the influence of aerobic and anaerobic indices on repeated sprint (RS) performance and ability (RSA), 8 sprinters (SPR), 8 endurance runners (END), and 8 active participants (ACT) performed the following tests: ( i) incremental test; ( ii) 1-min test to determine first decay time constant of pulmonary oxygen uptake off-kinetics and parameters related to anaerobic energy supply, lactate exchange, and removal abilities from blood lactate kinetics; and ( iii) RS test (ten 35-m sprints, departing every 20 s) to determine best (RSbest) and mean (RSmean) sprint times and percentage of sprint decrement (%Dec). While SPR had a 98%-100% likelihood of having the fastest RSbest (Cohen's d of 1.8 and 1.4 for ACT and END, respectively) and RSmean (2.1 and 0.9 for ACT and END, respectively), END presented a 97%-100% likelihood of having the lowest %Dec (0.9 and 2.2 for ACT and SPR, respectively). RSmean was very largely correlated with RSbest ( r = 0.85) and moderately correlated with estimates of anaerobic energy supply ( r = -0.40 to -0.49). RSmean adjusted for RSbest (which indirectly reflects RSA) was largely correlated with lactate exchange ability ( r = 0.55). Our results confirm the importance of locomotor- and anaerobic-related variables to RS performance, and highlight the importance of disposal of selected metabolic by-products to RSA. [ABSTRACT FROM AUTHOR]

To verify the effects of training status and blood lactate concentration (BLC) responses on the early excess postexercise oxygen consumption (EPOC), 8 sprinters, 7 endurance runners, and 7 untrained subjects performed an incremental test to determine maximal oxygen uptake and a 1-min all-out test to determine BLC and oxygen uptake recovery curves. BLC kinetics was evaluated to assess the quantity of lactate accumulated during exercise ( QlaA), lactate removal ability ( k2), and quantity of lactate removed from 0 to 10 min postexercise ( QlaR). Oxygen uptake off-kinetics was evaluated to assess the decay time constants (τ1 and τ2); moreover, EPOC was measured during the first 10 min after exercise. While sprinters had 98%-100% and 94%-100% likelihood of having the highest EPOC and decay time constants, endurance runners had 98%-100% and 95%-100% likelihood of having the lowest EPOC and decay time constants. EPOC was correlated with QlaA ( r = 0.74) and QlaR ( r = 0.61). τ1 and τ2 were correlated with maximal oxygen uptake ( r > -0.57), k2 ( r > -0.48), and QlaR relative to QlaA ( r > -0.60). Our findings indicate that oxygen uptake recovery is associated with fast lactate removal and aerobic training. Furthermore, the metabolites derived from anaerobic energy production seem to induce a greater EPOC after all-out exercise. [ABSTRACT FROM AUTHOR]

The shuttling of intermediary metabolites such as lactate through the vasculature contributes to the dynamic energy and biosynthetic needs of tissues. Tracer kinetic studies offer a powerful tool to measure the metabolism of substrates like lactate that are simultaneously taken up from and released into the circulation by organs, but in each circulatory passage, the entire cardiac output traverses the pulmonary parenchyma. To determine whether transpulmonary lactate shuttling affects whole-body lactate kinetics in vivo, we examined the effects of a lactate load (via lactate clamp, LC) and epinephrine (Epi) stimulation on transpulmonary lactate kinetics in an anesthetized rat model using a primedcontinuous infusion of [U-13C]lactate. Under all conditions studied, control 1.2 (SD 0.7) (Con), LC 1.9 (SD 2.5), and Epi 1.9 (SD 3.5) mg/min net transpulmonary lactate uptake occurred. Compared with Con, a lactate load via LC significantly increased mixed central venous ([...]) [1.9 mM (SD 0.5) vs. 4.7 (SD 0.4)] and arterial ([a]) [1.6 mM (SD 0.4) vs. 4.1 (SD 0.6)] lactate concentrations (P < 0.05). Transpulmonary lactate gradient ([...] - [a]) was highest during the lactate clamp condition [0.6 mM (SD 0.7)] and lowest during Epi [0.2 mM (SD 0.5)] stimulation (P < 0.05). Tracer measured lactate fractional extractions were similar for control, 16.6% (SD 15.3), and lactate clamp, 8.2% (SD 15.3) conditions, but negative during Epi stimulation, -25.3% (SD 45.5) when there occurred a transpulmonary production, the conversion of mixed central venous pyruvate to arterial lactate. Further, isotopic equilibration between L and P occurred following tracer lactate infusion, but depending on compartment (... or a) and physiological stimulus, [L]/[P] concentration and isotopic enrichment ratios ranged widely. We conclude that pulmonary arterial-vein concentration difference measurements across the lungs provide an incomplete, and perhaps misleading picture of parenchymal lactate metabolism, especially during epinephrine stimulation. [ABSTRACT FROM AUTHOR]

Current understanding of lactate metabolism in fish is based almost entirely on the interpretation of concentration measurements that cannot be used to infer changes in flux. The goals of this investigation were: (1) to quantify baseline lactate fluxes in rainbow trout (Oncorhynchus mykiss) under normoxic conditions; (2) to establish how changes in rates of lactate appearance (Ra) and disposal (Rd) account for the increase in blood lactate elicited by hypoxia; and (3) to identify the tissues responsible for lactate production. Ra and Rd lactate of rainbow trout were measured in vivo by continuous infusion of [U-14C]lactate in trout exposed to 25% O2 saturation or maintained in normoxia for 90mm. In normoxic fish, Ra lactate decreased from 18.2 to 13.1 μmol kg-1 min-1 and Rd lactate from 19.0 to 12.8. Ra and Rd were always matched, thereby maintaining a steady baseline blood lactate concentration of ∼0.8 mmol l-1. By contrast, the hypoxic fish increased blood lactate to 8.9mmol l-1 and Ra lactate from 18.4 to 36.5 μmol kg-1 min-1. This stimulation of anaerobic glycolysis was unexpectedly accompanied by a 52% increase in Rd lactate from 19.9 to 30.3μmol kg-1 min-1. White muscle was the main producer of lactate, which accumulated to 19.2 μmol g-1 in this tissue. This first study of non-steady-state lactate kinetics in fish shows that the increase in lactate disposal elicited by hypoxia plays a strategic role in reducing the lactate load on the circulation. Without this crucial response, blood lactate accumulation would double. [ABSTRACT FROM AUTHOR]

The effects of a 7 d high-fructose diet (HFrD) or control diet on lipid metabolism were studied in a group of six healthy lean males. Plasma NEFA and β-hydroxybutyrate concentrations, net lipid oxidation (indirect calorimetry) and exogenous lipid oxidation (13CO2 production) were monitored in basal conditions, after lipid loading (olive oil labelled with [13C]triolein) and during a standardised mental stress. Lactate clearance and the metabolic effects of an exogenous lactate infusion were also monitored. The HFrD lowered plasma concentrations of NEFA and β-hydroxybutyrate as well as lipid oxidation in both basal and after lipid-loading conditions. In addition, the HFrD blunted the increase in plasma NEFA and exogenous lipid oxidation during mental stress. The HFrD also increased basal lactate concentrations by 31·8 %, and lactate production by 53·8 %, while lactate clearance remained unchanged. Lactate infusion lowered plasma NEFA with the control diet, and net lipid oxidation with both the HFrD and control diet. These results indicate that a 7 d HFrD markedly inhibits lipolysis and lipid oxidation. The HFrD also increases lactate production, and the ensuing increased lactate utilisation may contribute to suppress lipid oxidation. [ABSTRACT FROM PUBLISHER]

The present study investigated whether muscular monocarboxylate transporter (MCT) 1 and 4 contents are related to the blood lactate removal after supramaximal exercise, fatigue indexes measured during different supramaximal exercises, and muscle oxidative parameters in 15 humans with different training status. Lactate recovery curves were obtained after a 1-min all-out exercise. A biexponential time function was then used to determine the velocity constant of the slow phase (γ2), which denoted the blood lactate removal ability. Fatigue indexes were calculated during 1-min all-out (FIAO) and repeated 10-s (FISprint) cycling sprints. Biopsies were taken from the vastus lateralis muscle. MCT1 and MCT4 contents were quantified by Western blots, and maximal muscle oxidative capacity (Vmax) was evaluated with pyruvate + malate and glutamate + malate as substrates. The results showed that the blood lactate removal ability (i.e., γ2) after a l-min all-out test was significantly related to MCT1 content (r = 0.70, P < 0.01) but not to MCT4 (r = 0.50, P > 0.05). However, greater MCT1 and MCT4 contents were negatively related with a reduction of blood lactate concentration at the end of l-min all-out exercise (r = -0.56, and r = -0.61, P < 0.05, respectively). Among skeletal muscle oxidative indexes, we only found a relationship between MCT1 and glutamate + malate Vmax (r = 0.63, P < 0.05). Furthermore, MCT1 content, but not MCT4, was inversely related to FIAO (r = -0.54, P < 0.05) and FISprint (r = -0.58, P < 0.05). We concluded that skeletal muscle MCT1 expression was associated with the velocity constant of net blood lactate removal after a 1-min all-out test and with the fatigue indexes. It is proposed that MCT1 expression may be important for blood lactate removal after supramaximal exercise based on the existence of lactate shuttles and, in turn, in favor of a better tolerance to muscle fatigue. [ABSTRACT FROM AUTHOR]

The present study investigated whether blood lactate removal after supramaximal exercise and fatigue indexes measured during continuous and intermittent supramaximal exercises are related to the maximal muscle oxidative capacity in humans with different training status. Lactate recovery curves were obtained after a 1-min all-out exercise. A biexponential time function was then used to determine the velocity constant of the slow phase (γ2), which denoted the blood lactate removal ability. Fatigue indexes were calculated during all-out (FIAO) and repeated 10-s cycling sprints (FISprint). Biopsies were taken from the vastus lateralis muscle, and maximal ADP-stimulated mitochondrial respiration (Vmax) was evaluated in an oxygraph cell on saponin-permeabilized muscle fibers with pyruvate + malate and glutamate + malate as substrates. Significant relationships were found between γ2 and pyruvate + malate Vmax (r = 0.60, P < 0.05), γ2 and glutamate + malate Vmax (r = 0.66, P < 0.01), and γ2 and citrate synthase activity (r = 0.76, P < 0.01). In addition, γ2, glutamate + malate Vmax, and pyruvate + malate Vmax were related to FIAO (γ2 - FIAO: r = 0.85; P < 0.01; glutamate + malate Vmax - FIAO: r = 0.70, P < 0.01; and pyruvate + malate Vmax - FIAO: r = 0.63, P < 0.01)and FISprint (γ2 - FISprint: r = 0.74, P < 0.01; glutamate + malate Vmax - FISprint: r= 0.64, P < 0.01; and pyruvate + malate Vmax - FISprint: r = 0.46, P < 0.01). In conclusion, these results suggested that the maximal muscle oxidative capacity was related to blood lactate removal ability after a 1-min all-out test. Moreover, maximal muscle oxidative capacity and blood lactate removal ability were associated with the delay in the fatigue observed during continuous and intermittent supramaximal exercises in well-trained subjects. [ABSTRACT FROM AUTHOR]

Background: While ECLS is a highly invasive procedure, the identification of patients with a potentially good prognosis is of high importance. The aim of this study was to analyse changes in the acid-base balance parameters and lactate kinetics during the early stages of ECLS rewarming to determine predictors of clinical outcome., Methods: This single-centre retrospective study was conducted at the Severe Hypothermia Treatment Centre at John Paul II Hospital in Krakow, Poland. Patients ≥18 years old who had a core temperature (Tc) < 30 °C and were rewarmed with ECLS between December 2013 and August 2018 were included. Acid-base balance parameters were measured at ECLS implantation, at Tc 30 °C, and at 2 and 4 h after Tc 30 °C. The alteration in blood lactate kinetics was calculated as the percent change in serum lactate concentration relative to the baseline., Results: We included 50 patients, of which 36 (72%) were in cardiac arrest. The mean age was 56 ± 15 years old, and the mean Tc was 24.5 ± 12.6 °C. Twenty-one patients (42%) died. Lactate concentrations in the survivors group were significantly lower than in the non-survivors at all time points. In the survivors group, the mean lactate concentration decreased -2.42 ± 4.49 mmol/L from time of ECLS implantation until 4 h after reaching Tc 30 °C, while in the non-survivors' group ( p = 0.024), it increased 1.44 ± 6.41 mmol/L., Conclusions: Our results indicate that high lactate concentration is associated with a poor prognosis for hypothermic patients undergoing ECLS rewarming. A decreased value of lactate kinetics at 4 h after reaching 30 °C is also associated with a poor prognosis.

Background: Venous–arterial carbon dioxide (CO2) to arterial–venous oxygen (O2) content difference ratio (Cv-aCO2/Ca-vO2) > 1 is supposed to be both sensitive and specific for anaerobic metabolism. What regional hemodynamic and metabolic parameters determine the ratio has not been clarified. Objectives: To address determinants of systemic and renal, spleen, gut and liver Cv-aCO2/Ca-vO2. Methods: Post hoc analysis of original data from published experimental studies aimed to address effects of different fluid resuscitation strategies on oxygen transport, lactate metabolism and organ dysfunction in fecal peritonitis and endotoxin infusion, and from animals in cardiac tamponade or hypoxic hypoxia. Systemic and regional hemodynamics, blood flow, lactate uptake, carbon dioxide and oxygen-derived variables were determined. Generalized estimating equations (GEE) were fit to assess contributors to systemic and regional Cv-aCO2/Ca-vO2. Results: Median (range) of pooled systemic Cv-aCO2/Ca-vO2 in 64 pigs was 1.02 (0.02 to 3.84). While parameters reflecting regional lactate exchange were variably associated with the respective regional Cv-aCO2/Ca-vO2 ratios, only regional ratios were independently correlated with systemic ratio: renal Cv-aCO2 /Ca-vO2 (β = 0.148, 95% CI 0.062 to 0.234; p = 0.001), spleen Cv-aCO2/Ca-vO2 (β = 0.065, 95% CI 0.002 to 0.127; p = 0.042), gut Cv-aCO2/Ca-vO2 (β = 0.117, 95% CI 0.025 to 0.209; p = 0.013), liver Cv-aCO2/Ca-vO2 (β = − 0.159, 95% CI − 0.297 to − 0.022; p = 0.023), hepatosplanchnic Cv-aCO2/Ca-vO2 (β = 0.495, 95% CI 0.205 to 0.786; p = 0.001). Conclusion: In a mixed set of animals in different shock forms or during hypoxic injury, hepatosplanchnic Cv-aCO2/Ca-vO2 ratio had the strongest independent association with systemic Cv-aCO2/Ca-vO2, while no independent association was demonstrated for lactate or hemodynamic variables. [ABSTRACT FROM AUTHOR]