Increased Lactate Clearance Research Articles

Foam Rolling Intervention Improves Lactate Clearance After High-Intensity Exercise

The acute effects of a foam rolling intervention on lactate clearance and the impaired executive function associated with fatigue after high-intensity exercise remain unclear. This study examined whether foam rolling is an effective tool for fatigue recovery. Eighteen healthy adults without consistent exercise habits participated in this study. Participants performed high-intensity exercises, and the post-exercise foam rolling intervention was compared to the control condition. Measurements included lactate, vigor/fatigue by the Profile of Mood States 2nd Edition, cognitive function (cognitive task performance), leg and body rating of perceived exertion pre- and post-exercise, and post-intervention. Blood lactate concentrations post-foam rolling intervention (−7.3 ± 3.0 mmol/L) were significantly reduced among all participants. Increased lactate clearance by foam rolling correlated with a faster recovery of executive function for those with greater lactate clearance. However, cognitive fatigue was not observed after high-intensity exercise (p = 0.086, r = 0.41). Lactate clearance was not significantly correlated with the rating of perceived exertion in the foam rolling condition. The rating of the perceived exertion decreased with increased lactate clearance for those with greater lactate clearance in the control condition (leg: r = 0.778; body: r = 0.669). In conclusion, foam rolling intervention may be effective for exhausting exercise recovery.

Association of lactate detection with in-hospital mortality in critically ill patients with acute myocardial infarction: a retrospective cohort study

ObjectivesTo assess the associations of lactate level or lactate clearance at different time points with in-hospital mortality in critically ill patients with acute myocardial infarction (AMI).DesignA cohort study.SettingThe Medical Information...

Significance of lactate clearance in septic shock patients with high bilirubin levels

Lactate clearance is affected by hepatic function. However, it is unclear whether the association between hepatic dysfunction and lactate clearance can act as a prognostic marker of clinical outcomes in patients with septic shock. We aimed to evaluate the association between lactate clearance and mortality in two cohorts of septic shock patient who had hepatic dysfunction based on their total serum bilirubin levels (TBIL). Lactate clearance at 24 h after the onset of septic shock was analyzed using two cohorts, sub-categorized into two groups based on TBIL: < 2 mg/dL and ≥ 2 mg/dL. In the derivation cohort, lactate clearance was lower in non-survivors than in survivors with TBIL ≥ 2 mg/dL, while there was no significant difference in lactate clearance between non-survivors and survivors with TBIL < 2 mg/dL. Multivariate logistic regression analysis revealed that increased lactate clearance was significantly associated with decreased 28-day mortality in the TBIL ≥ 2 mg/dL group (10% lactate clearance, adjusted odds ratio [OR]: 0.88, 95% confidence interval (CI): 0.80–0.97, P = 0.0075), Creatinine level ≥ 2 mg/dL group (adjusted OR: 0.88, 95% CI: 0.81–0.95, P = 0.00069) and APACHE II score ≥ 35 group (adjusted OR: 0.93, 95% CI: 0.87–0.98, P = 0.013). In the validation cohort, lactate clearance was lower in non-survivors than in survivors with TBIL ≥ 2 mg/dL, while no significant difference in lactate clearance was observed between non-survivors and survivors with TBIL < 2 mg/dL. Increased lactate clearance was significantly associated with decreased 28-day mortality in the TBIL ≥ 2 mg/dL group (10% lactate clearance, adjusted OR: 0.89, 95% CI: 0.83–0.96, P = 0.0038) and the association was just about significant in APACHE II score ≥ 35 group (adjusted OR: 0.86, 95% CI: 0.74–1.00, P = 0.051). In conclusion, increased lactate clearance in septic shock patients with hepatic dysfunction (TBIL ≥ 2 mg/dL) or high severity (APACHE II score ≥ 35) was associated with decreased 28-day mortality.

Quantitative Assessment of Blood Lactate in Shock: Measure of Hypoxia or Beneficial Energy Source.

Blood lactate concentration predicts mortality in critically ill patients and is clinically used in the diagnosis, grading of severity, and monitoring response to therapy of septic shock. This paper summarizes available quantitative data to provide the first comprehensive description and critique of the accepted concepts of the physiology of lactate in health and shock, with particular emphasis on the controversy of whether lactate release is simply a manifestation of tissue hypoxia versus a purposeful transfer (“shuttle”) of lactate between tissues. Basic issues discussed include (1) effect of nonproductive lactate-pyruvate exchange that artifactually enhances flux measurements obtained with labeled lactate, (2) heterogeneous tissue oxygen partial pressure (Krogh model) and potential for unrecognized hypoxia that exists in all tissues, and (3) pathophysiology that distinguishes septic from other forms of shock. Our analysis suggests that due to exchange artifacts, the turnover rate of lactate and the lactate clearance are only about 60% of the values of 1.05 mmol/min/70 kg and 1.5 L/min/70 kg, respectively, determined from the standard tracer kinetics. Lactate turnover reflects lactate release primarily from muscle, gut, adipose, and erythrocytes and uptake by the liver and kidney, primarily for the purpose of energy production (TCA cycle) while the remainder is used for gluconeogenesis (Cori cycle). The well-studied physiology of exercise-induced hyperlactatemia demonstrates massive release from the contracting muscle accompanied by an increased lactate clearance that may occur in recovering nonexercising muscle as well as the liver. The very limited data on lactate kinetics in shock patients suggests that hyperlactatemia reflects both decreased clearance and increased production, possibly primarily in the gut. Our analysis of available data in health and shock suggests that the conventional concept of tissue hypoxia can account for most blood lactate findings and there is no need to implicate a purposeful production of lactate for export to other organs.

Altered proximal tubular cell glucose metabolism during acute kidney injury is associated with mortality.

Acute kidney injury (AKI) is strongly associated with mortality, independently of its cause. The kidney contributes to up to 40% of systemic glucose production by gluconeogenesis during fasting and under stress conditions. Whether kidney gluconeogenesis is impaired during AKI and how this might influence systemic metabolism remain unknown. Here we show that glucose production and lactate clearance are impaired during human and experimental AKI by using renal arteriovenous catheterization in patients, lactate tolerance testing in mice and glucose isotope labelling in rats. Single-cell transcriptomics reveal that gluconeogenesis is impaired in proximal tubule cells during AKI. In a retrospective cohort of critically ill patients, we demonstrate that altered glucose metabolism during AKI is a major determinant of systemic glucose and lactate levels and is strongly associated with mortality. Thiamine supplementation increases lactate clearance without modifying renal function in mice with AKI, enhances glucose production by renal tubular cells ex vivo and is associated with reduced mortality and improvement of the metabolic pattern in a retrospective cohort of critically ill patients with AKI. This study highlights an unappreciated systemic role of renal glucose and lactate metabolism under stress conditions, delineates general mechanisms of AKI-associated mortality and introduces a potential intervention targeting metabolism for a highly prevalent clinical condition with limited therapeutic options.

Effect of magnesium supplementation on lactate clearance in critically ill patients with severe sepsis: a randomized clinical trial.

In this study, changes in lactate clearance following magnesium supplementation were evaluated in critically ill patients with severe sepsis. Fifty-eight patients with severe sepsis were randomly assigned to receive either magnesium (n = 30) or placebo (n = 28). Patients in the magnesium group received intravenous magnesium sulfate to maintain serum magnesium level around 3 mg/dL for 3 days. The placebo group received the same volume of normal saline. Change in lactate clearance was considered primary outcome of the study. Mean increase in the lactate clearance in the magnesium group was significantly higher than the placebo group on day 2 (27.53% vs. 23.79% respectively, p < 0.001) and day 3 (49.83% vs. 37.02% respectively, p < 0.001). Time to lactate clearance was also significantly shorter in the magnesium group than the placebo group (47.28 ± 20.59 vs. 61.20 ± 24.31 h respectively, p = 0.03). Sepsis-related mortality was not significantly different but median length of ICU stay was significantly shorter in the magnesium group than the placebo group (8 vs. 15 days respectively, p < 0.01). Magnesium supplementation increased lactate clearance in critically ill patients with severe sepsis. Optimizing serum magnesium level near the upper limit of the normal range may improve severe sepsis outcomes.

Effect of Dexmedetomidine on Lactate Clearance in Patients With Septic Shock: A Subanalysis of a Multicenter Randomized Controlled Trial.

Lactate clearance is useful to guide initial resuscitation of patients with septic shock. We conducted this study to evaluate whether dexmedetomidine increases lactate clearance in patients with septic shock. This was a randomized controlled trial that involved a post hoc subgroup analysis. Adult patients with septic shock under ventilation were randomized to receive sedation strategy with or without dexmedetomidine (60 in the dexmedetomidine and 51 in the nondexmedetomidine groups). The primary outcome was the lactate clearance at 6 h, defined as the percent decrease in lactate from randomization to 6 h after. The median Acute Physiology and Chronic Health Evaluation II score was 25 (interquartile range 19-31). The median serum lactate value at randomization was lower in the dexmedetomidine group than in the nondexmedetomidine group (4.0 mmol/L vs. 4.8 mmol/L; P = 0.053). The lactate clearance at 6 h was higher in the dexmedetomidine group, although this was not statistically significant (23.3 ± 29.8 vs. 11.1 ± 54.4, mean difference 12.2, 95% confidence interval (CI), -4.4 to 28.8). After adjusting for the lactate level at randomization, lactate clearance at 6 h was significantly higher in the dexmedetomidine group (adjusted mean difference 18.5, 95% CI, 2.2-34.9). There was no statistically significant difference in the 28-day mortality between the dexmedetomidine and the nondexmedetomidine groups (13 [22%] vs. 18 [35%] patients, P = 0.11). In conclusion, among mechanically ventilated patients with septic shock, sedation with dexmedetomidine resulted in increased lactate clearance compared with sedation without dexmedetomidine.

Endurance Training with or without Glucose-Fructose Ingestion: Effects on Lactate Metabolism Assessed in a Randomized Clinical Trial on Sedentary Men.

Glucose-fructose ingestion increases glucose and lactate oxidation during exercise. We hypothesized that training with glucose-fructose would induce key adaptations in lactate metabolism. Two groups of eight sedentary males were endurance-trained for three weeks while ingesting either glucose-fructose (GF) or water (C). Effects of glucose-fructose on lactate appearance, oxidation, and clearance were measured at rest and during exercise, pre-training, and post-training. Pre-training, resting lactate appearance was 3.6 ± 0.5 vs. 3.6 ± 0.4 mg·kg−1·min−1 in GF and C, and was increased to 11.2 ± 1.4 vs. 8.8 ± 0.7 mg·kg−1·min−1 by exercise (Exercise: p < 0.01). Lactate oxidation represented 20.6 ± 1.0% and 17.5 ± 1.7% of lactate appearance at rest, and 86.3 ± 3.8% and 86.8 ± 6.6% during exercise (Exercise: p < 0.01) in GF and C, respectively. Training with GF increased resting lactate appearance and oxidation (Training × Intervention: both p < 0.05), but not during exercise (Training × Intervention: both p > 0.05). Training with GF and C had similar effects to increase lactate clearance during exercise (+15.5 ± 9.2 and +10.1 ± 5.9 mL·kg−1·min−1; Training: p < 0.01; Training × Intervention: p = 0.97). The findings of this study show that in sedentary participants, glucose-fructose ingestion leads to high systemic lactate appearance, most of which is disposed non-oxidatively at rest and is oxidized during exercise. Training with or without glucose-fructose increases lactate clearance, without altering lactate appearance and oxidation during exercise.

Ingestion of oxygenated water enhances lactate clearance kinetics in trained runners

BackgroundDrinks with higher dissolved oxygen concentrations have in recent times gained popularity as a potential ergogenic aid, despite a lack of evidence regarding their efficacy. The aim of this study was to assess effects of ingestion of an oxygen supplement (OS) on exercise performance and post-exercise recovery in a group of trained runners.MethodsTrained male runners (n = 25, mean ± SD; age 23 ± 6 years, mass 70 ± 9 kg, BMI 21.9 ± 2.7 kg.m−2 VO2max 64 ± 6mL.kg−1.min−1), completed a randomised double blinded, crossover study to assess the effect of ingestion of OS solution on exercise performance and recovery. Trials consisted of a 30min rest period, 5min warm-up, a 5000m treadmill time-trial, and a 30min passive recovery. Participants ingested 6x15mL of either OS or a taste matched placebo during the trials (3 during the rest phase, 1 during exercise and 2 during the recovery). Muscle tissue O2 saturation was measured via near infrared spectroscopy. Blood lactate concentrations were measured prior to, mid-way and directly after the finish of the 5000m time trials and every 3-min during the post-exercise recovery.ResultsIngestion of OS did not improve exercise performance. No significant differences were observed for muscle tissue O2 saturation at any time-points. However, lactate clearance was significantly improved during recovery in the OS trials. Both AUC (109 ± 32 vs. 123 ± 38 mmol.min, P < 0.05, d = 0.40) and lactate half-life (λ) (1127 ± 272 vs. 1223 ± 334 s, P < 0.05, d = 0.32) were significantly reduced.ConclusionsDespite no evidence of improved exercise performance, ingestion of OS did enhance post-exercise recovery via increased lactate clearance.

Hemodynamic Resuscitation Characteristics Associated with Improved Survival and Shock Resolution After Cardiac Arrest.

To determine which strategy of early post-cardiac arrest hemodynamic resuscitation was associated with best clinical outcomes. We hypothesized that higher mean arterial pressure (MAP) achieved using IV fluids over vasopressors would yield better outcomes. Retrospective cohort study of post-cardiac arrest patients between March 2011 and June 2012. Patients successfully resuscitated from cardiac arrest, admitted to an intensive care unit and surviving at least 24 h, were included. Patients missing data for >2 h after return of spontaneous circulation were excluded. The institutional standard for post-resuscitation MAP was ≥65 mm Hg with no guidelines on how MAP was supported. We examined the association between early (6 h) average MAP, vasopressor use summarized as cumulative vasopressor index and fluid intake with outcomes including survival to discharge, favorable neurologic outcome based on Cerebral Performance Category 1 or 2, and the surrogate outcome measure of lactate clearance using Pearson correlation and multivariable regression. Of 118 patients, 55 (46%) survived to hospital discharge, 21 (18%) with favorable neurologic outcome. Higher 6-h mean cumulative vasopressor index was independently associated with worsened survival (OR 0.67; 95% CI 0.53, 0.85; P = 0.001). Resuscitation subgroups receiving higher than median vasopressors had worsened survival to hospital discharge regardless of fluid intake. In addition, higher MAP-6h correlated with increased lactate clearance (r = 0.29; P = 0.011). Early post-return of spontaneous circulation hemodynamic resuscitation achieving higher MAP using fluid preferentially over vasopressors is associated with improved survival to hospital discharge as well as better lactate clearance.

Continuous Aerobic Training in Individualized Intensity Avoids Spontaneous Physical Activity Decline and Improves MCT1 Expression in Oxidative Muscle of Swimming Rats.

Although aerobic training has been shown to affect the lactate transport of skeletal muscle, there is no information concerning the effect of continuous aerobic training on spontaneous physical activity (SPA). Because every movement in daily life (i.e., SPA) is generated by skeletal muscle, we think that it is possible that an improvement of SPA could affect the physiological properties of muscle with regard to lactate transport. The aim of this study was to evaluate the effect of 12 weeks of continuous aerobic training in individualized intensity on SPA of rats and their gene expressions of monocarboxylate transporters (MCT) 1 and 4 in soleus (oxidative) and white gastrocnemius (glycolytic) muscles. We also analyzed the effect of continuous aerobic training on aerobic and anaerobic parameters using the lactate minimum test (LMT). Sixty-day-old rats were randomly divided into three groups: a baseline group in which rats were evaluated prior to initiation of the study; a control group (Co) in which rats were kept without any treatment during 12 weeks; and a chronic exercise group (Tr) in which rats swam for 40 min/day, 5 days/week at 80% of anaerobic threshold during 12 weeks. After the experimental period, SPA of rats was measured using a gravimetric method. Rats had their expression of MCTs determined by RT-PCR analysis. In essence, aerobic training is effective in maintaining SPA, but did not prevent the decline of aerobic capacity and anaerobic performance, leading us to propose that the decline of SPA is not fully attributed to a deterioration of physical properties. Changes in SPA were concomitant with changes in MCT1 expression in the soleus muscle of trained rats, suggestive of an additional adaptive response toward increased lactate clearance. This result is in line with our observation showing a better equilibrium on lactate production-remotion during the continuous exercise (LMT). We propose an approach to combat the decline of SPA of rats in their home cages. This new finding is worth for scientists who work with animal models to study the protective effects of exercise.

New Zealand Sujon blackcurrant lowers lactate accumulation during cycling in triathletes

Background Blackcurrant intake has been reported to increase peripheral blood flow in humans (Matsumoto, et al., 2005), potentially by anthocyanin-induced vasorelaxation and vasodilation (Ziberna, et al., 2013). Increased peripheral blood flow may affect the exercise intensity at lactate indicators (e.g. onset of blood lactate accumulation (OBLA) at 4 mmol∙L-1) and maximum oxygen uptake. We examined the effect of 1-week Sujon blackcurrant powder supplementation on the blood lactate curve and aerobic capacity of trained triathletes. Methods Healthy male (n=8) and female (n=5) triathletes with >3 yrs experience (age: 38±8 yrs, height: 174±5 cm, body mass: 71±9 kg, BMI: 23±2, BF%: 19±5%, mean±SD) performed cycling tests for lactate responses (4 min stages with 2 min recovery, start power 50 W with 30 W increments) and maximum oxygen uptake (start power 50 W for 4 min with 30 W∙min-1 increments) at self-selected pedal cadence (SRM ergometer, SRM International, Germany). Familiarized participants were tested following 7 days of Sujon blackcurrant powder (S, 6g/day) or placebo (P) intake. Experimental design was double-blind and randomized with a wash-out period of 4 weeks. Oxygen consumption (Douglas bag technique) and heart rate were recorded during the cycling tests. Intensity, oxygen uptake and heart rate at 4 mmol∙L-1 OBLA were calculated using lactate analysis software (Newell et al., 2007). Lactate responses were calculated at relative intensities with individual lactate curves. Paired t-tests were used for analysis with significance accepted at p<.05. Results The intensity at 4 mmol∙L-1 OBLA was 6% higher with Sujon (P: 223±57, S: 236±60 W, range -5 to 22%, 11 participants showed an increase and 1 no change) (p<.01). In both conditions at 4 mmol∙L-1 OBLA, there were no differences in heart rate (P: 159±7, S: 164±10 b∙min-1, p=.13) or oxygen uptake (P: 2.91±0.73, S: 2.96±0.71 L∙min-1, p=.31). Blood lactate was lower at 40% (P: 1.24±0.52, S: 0.91±0.46 mmol∙L-1), 50% (P: 1.58±0.78, S: 1.23±0.64 mmol∙L-1), 60% (P: 2.29±0.96, S: 1.91±0.87 mmol∙L-1) and 70% (P: 3.52±1.10, S: 3.08±1.21 mmol∙L-1) of maximum power, decreases of 27%, 22%, 17% and 13%, respectively (all p<.01). There was no effect on maximum values of oxygen uptake (P: 49.1±6.2, S: 49.7±6.1 mL∙kg-1∙min-1, p=.16), power (P: 305±68, S: 307±62 W, p=.66) or heart rate (P: 172±10, S: 172±11 b∙min-1, p=.68). However, maximum oxygen uptake with Sujon was obtained with 14% lower lactate values (measured 3-min after exhaustion; P: 7.85±1.69, S: 6.79±1.51 mmol∙L-1, range -27 to 48%, 10 participants showed a decrease and 1 no change) (p=0.02). Conclusions Intake of New Zealand Sujon blackcurrant powder is associated with 1) a substantial downward and rightward shift of the lactate curve during cycling over a wide range of intensities, and 2) lower lactate accumulation at aerobic capacity suggesting increased lactate clearance or altered substrate oxidation. These findings may have implications for training practice and aerobic performance of endurance athletes. Acknowledgement Funding for this study and conference attendance was provided by the University of Chichester, Health Currancy Ltd (UK) and Gibb Holdings (Nelson) Ltd (NZ).

Magnesium Enhances Exercise Performance via Increasing Glucose Availability in the Blood, Muscle, and Brain during Exercise

Glucose mobilization and utilization in the periphery and central nervous system are important during exercise and are responsible for exercise efficacy. Magnesium (Mg) is involved in energy production and plays a role in exercise performance. This study aimed to explore the effects of Mg on the dynamic changes in glucose and lactate levels in the muscle, blood and brain of exercising rats using a combination of auto-blood sampling and microdialysis. Sprague-Dawley rats were pretreated with saline or magnesium sulfate (MgSO4, 90 mg/kg, i.p.) 30 min before treadmill exercise (20 m/min for 60 min). Our results indicated that the muscle, blood, and brain glucose levels immediately increased during exercise, and then gradually decreased to near basal levels in the recovery periods of both groups. These glucose levels were significantly enhanced to approximately two-fold (P<0.05) in the Mg group. Lactate levels in the muscle, blood, and brain rapidly and significantly increased in both groups during exercise, and brain lactate levels in the Mg group further elevated (P<0.05) than those in the control group during exercise. Lactate levels significantly decreased after exercise in both groups. In conclusion, Mg enhanced glucose availability in the peripheral and central systems, and increased lactate clearance in the muscle during exercise.

CurraNZ blackcurrant improves cycling performance and recovery in trained endurance athletes

Background Peripheral blood flow is increased by blackcurrant intake in humans (Matsumoto, et al., 2005), potentially by anthocyanin-induced vasorelaxation and vasodilation (Ziberna, et al., 2013), which may affect substrate delivery, exercise performance and recovery. We examined the effect of 1-week CurraNZ blackcurrant on substrate oxidation during steady state cycling, 16.1 km (10 mile) time-trial performance and lactate clearance following exercise in trained endurance athletes. Methods Nine male endurance athletes (club level cyclists and triathletes with >3 yrs experience; age: 35±14 years, height: 179±3 cm, body mass: 76±9 kg, BMI: 24±2, VO2max: 54±6 mL∙kg-1∙min-1, maximum power: 366±42 W, mean±SD) visited the laboratory for 4 sessions. Cycling tests for lactate responses (4 min stages with 2 min recovery, start power 50 W with 30 W increments) and maximum oxygen uptake (start power 50 W for 4 min with 30 W∙min-1 increments) at self-selected pedal cadence (SRM ergometer, SRM International, Germany) were performed to establish power values at 45%, 55%, and 65% of VO2max. Experimental design was double-blind and randomized with a wash-out period of 2 weeks. Familiarized participants were tested following 7 days of blackcurrant extract (CurraNZ, 300mg/day) (Health Currancy Ltd, UK) or placebo (P) capsule intake. Indirect calorimetry (Douglas bag technique) was used at low (~45%) and moderate intensity (~55% and ~65%) steady-state cycling (10 min stages) with lactate sampling. Subsequently, a 16.1 km time-trial was performed with lactate sampling during recovery for 20 min. Paired t-tests were used for analysis with significance accepted at p<.05. Results There were no differences between CurraNZ and placebo at ~45%, ~55% and ~65% VO2max for fat oxidation, carbohydrate oxidation, lactate, heart rate, minute ventilation and cycling economy (P>.05). CurraNZ improved 16.1 km time-trial performance substantially by 3.6% (P: 1784±121, CurraNZ: 1718±108 sec, p=.03, 7 out of 9 participants improved, range -2.2-8.6%). Lactate was higher with CurraNZ immediately following the time-trial (P: 5.4±1.6, CurraNZ: 6.5±1.8 mmol∙L-1, p=.03, all participants). Lactate decreases were higher with CurraNZ after 20 min of passive recovery following the time-trial (P: 3.2±0.8, CurraNZ: 3.9±1.2 mmol∙L-1, p=.03, 8 out of 9 participants). Conclusions Intake of CurraNZ blackcurrant is associated with 1) normal metabolic and physiological responses at low and moderate intensity cycling, 2) improved 16.1 km (10 mile) time-trial cycling performance, 3) potentially a higher lactate tolerance during time-trial performance, and 4) increased lactate clearance after exercise indicating improved recovery. It is concluded that CurraNZ blackcurrant intake has favourable implications in endurance athletes for aerobic exercise performance, lactate tolerance, and recovery. Acknowledgement Funding for this study and conference attendance was provided by Health Currancy Ltd (UK).

Abstract 2: PTEN Inhibition Improves Cardiovascular Function and Energy Metabolism While Decreasing Inflammation After Mouse Cardiac Arrest

Introduction: The survival kinase Akt mediates therapeutic hypothermia protection after mouse cardiac arrest (CA). This central kinase affects cardiovascular function, metabolism and inflammation. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a primary phosphatase that negatively regulates Akt activity. We hypothesized that the PTEN inhibitor, VO-OHpic (VO), will mimic hypothermia protection by enhancing energy metabolism and cardiac function while reducing inflammation after CA. Methods: C57BL6 mice underwent 8 min of KCl-induced (0.08 mg/g) asystolic CA. VO (10 μg/kg) was administrated IP 30 min before CA. Neurologically intact survival at 72 h after CPR was measured and cardiac function was evaluated by Millar catheter. Blood lactate and glucose were assessed using colorimetric kits, and a cytokine panel using multiplex ELISA. Phosphorylation of Akt, GSK3β and phospholamban in heart and brain were studied by Western blot as markers of Akt activation. Heart cells isolated from 1-2-day old C57BL6 mice and exposed to 30 min ischemia and 90 min reperfusion were used to measure VO effects on contractile function in a cell model of cardiac stunning. Results: VO improved 72 hour survival (90% vs. 50%, p &lt; 0.01). At 30 min after ROSC, VO significantly increased Dp/dt max (5123.4 ± 1026.9 mmHg/s vs. 4033.5 ± 622.4 mmHg/s, p&lt;0.05), and ETCO2 (39.1 ± 2.8 vs. 35.3 ± 1.2 mmHg, p&lt;0.05) with continued benefit seen at 2 hours. VO significantly increased lactate clearance by 4 hours demonstrated by decreased plasma lactate and glucose. The anti-inflammatory cytokine IL10 was increased while VO decreased the pro-inflammatory IL-1β. VO increased the phosphorylation of Akt (Thr308 and Ser473), p-GSK3β and the Akt target phospholamban. In mouse cardiomyocytes, VO (1 μM) improved the contractile velocity (54.6 ± 2.3 % vs. 33.3 ± 3.9 %, p &lt; 0.05), increased total ATP content and the ratio of ATP/ADP during ischemia and enhanced L-type calcium channel recovery. Conclusions: PTEN inhibition improved neurologically intact survival after CA, with improved energy metabolism and cardiac function, and decreased inflammation. Use of PTEN inhibitors such as VO may be a novel strategy with or without cooling for treating the metabolic phase of cardiac arrest.

Mechanism of dichloroacetate-induced hypolactatemia in humans with or without cirrhosis

Dichloroacetate (DCA) has been used as an experimental treatment for lactic acidosis because it lowers plasma lactic acid concentration. Three potential mechanisms could underlie the hypolactatemic action of DCA, but the dominant mechanism in vivo remains unclear. This study tested whether DCA-induced hypolactatemia occurs via decreased lactate production, increased lactate clearance, or decreased rate of glycolysis in healthy humans and in patients with end-stage cirrhosis. Cirrhosis is associated with decreased hepatic pyruvate dehydrogenase (PDH) content. Six healthy volunteers and 7 cirrhotic patients received a primed, constant infusion of 1- 13C-pyruvate and 15N-alanine for 5 hours. DCA (35 mg/kg intravenously) was administered at 2 hours. Plasma isotopic enrichment was measured by gas chromatography/mass spectrometry (GC/MS), and exhaled CO 2 enrichment by isotope ratio mass spectrometry. Pyruvate and alanine production rates (Ra) were determined by isotope dilution, and pyruvate oxidation calculated as 13CO 2 production from 13C-pyruvate. Ra lactate was calculated as the difference between Ra pyruvate and its disposal by oxidation to CO 2 and conversion to alanine. Baseline plasma lactate kinetics in cirrhotic patients did not differ from controls. DCA decreased lactate concentration in both groups by approximately 53%. DCA decreased glycolysis (Ra pyruvate) by 24%, increased the fraction of pyruvate oxidized to CO 2 by 26%, and decreased pyruvate transamination to alanine by 25%. DCA also inhibited lactate production by 85%, but decreased plasma lactate clearance by 60% in both groups. DCA reduces plasma lactic acid concentration by inhibiting production, via stimulating pyruvate oxidation and inhibiting glycolysis, rather than increasing clearance. In addition, end-stage cirrhosis does not alter either the mechanism or the magnitude of the metabolic response to DCA.

MECHANISM OF DICHLOROACETATE-INDUCED HYPOLACTATEMIA IN HUMANS WITH OR WITHOUT CIRRHOSIS

Dichloroacetate (DCA) has been used as an experimental treatment for lactic acidosis because it lowers plasma lactic acid concentration. Three potential mechanisms could underlie the hypolactatemic action of DCA, but the dominant mechanism in vivo remains unclear. This study tested whether DCA-induced hypolactatemia occurs via decreased lactate production, increased lactate clearance, or decreased rate of glycolysis in healthy humans and in patients with end-stage cirrhosis. Cirrhosis is associated with decreased hepatic pyruvate dehydrogenase (PDH) content. Six healthy volunteers and 7 cirrhotic patients received a primed, constant infusion of 1-13C-pyruvate and 15N-alanine for 5 hours. DCA (35 mg/kg intravenously) was administered at 2 hours. Plasma isotopic enrichment was measured by gas chromatography/mass spectrometry (GC/MS), and exhaled CO2 enrichment by isotope ratio mass spectrometry. Pyruvate and alanine production rates (Ra) were determined by isotope dilution, and pyruvate oxidation calculated as 13CO2 production from 13C-pyruvate. Ra lactate was calculated as the difference between Ra pyruvate and its disposal by oxidation to CO2 and conversion to alanine. Baseline plasma lactate kinetics in cirrhotic patients did not differ from controls. DCA decreased lactate concentration in both groups by approximately 53%. DCA decreased glycolysis (Ra pyruvate) by 24%, increased the fraction of pyruvate oxidized to CO2 by 26%, and decreased pyruvate transamination to alanine by 25%. DCA also inhibited lactate production by 85%, but decreased plasma lactate clearance by 60% in both groups. DCA reduces plasma lactic acid concentration by inhibiting production, via stimulating pyruvate oxidation and inhibiting glycolysis, rather than increasing clearance. In addition, end-stage cirrhosis does not alter either the mechanism or the magnitude of the metabolic response to DCA.

Lactate production and clearance in exercise. Effects of training. A mini-review.

Lactate accumulates if pyruvate formation exceeds pyruvate oxidation. Accelerated glycogenolysis is essential for lactate production. Glycogen and epinephrine enhance glycogen phosphorylase activity and this is higher in type II b than in type I fibers. Pyruvate oxidation is enhanced by exercise-induced increase in pyruvate dehydrogenase activity and is relatively impaired by low oxygen availability and low mitochondrial oxidative capacity. During exercise lactate is eliminated in liver, heart, and resting and working muscle. In muscle, elimination depends on plasma concentration, fiber type, and fiber conditions. Due to influence on hormonal response, mitochondrial oxidative capacity and fiber recruitment, training diminishes glycogenolysis and lactate production. Training also increases lactate clearance. This reflects increased hepatic capacity for gluconeogenesis as well as increased lactate transport capacity and oxidative capacity and reduced glycogenolysis in muscle. The fact that endurance performance can be predicted from the plasma lactate versus exercise intensity relationship illustrates that the plasma lactate level is a finely balanced result of the interplay between many factors of importance for endurance exercise.

Endurance training increases skeletal muscle lactate transport.

Lactate accumulation in skeletal muscle is reduced after a period of endurance training. Explanations for this phenomena include the increased oxidative capacity of the muscle, a reduction in lactate production, and increased lactate clearance. Muscle membrane transport of lactate can be seen to be a fundamental aspect of such clearance, and transmembrane lactate flux may well be an important aspect of the training response in skeletal muscle. Therefore, the lactate transport capacity in skeletal muscle sarcolemmal membranes in endurance-trained and sedentary rats was investigated. Training consisted of 6 weeks of progressively increased treadmill exercise. Twenty-four hours before being killed, both the trained and sedentary animals completed a brief exercise bout. Studies of lactate transport (zero-trans) were conducted using highly purified sarcolemmal vesicles. When low concentrations of L-lactate (1 mM) were used a 59.4% increase in lactate transport was observed (P < 0.05). However, when a high concentration of lactate (50 mM) was used no change in lactate transport was found (P > 0.05). Several interpretations are possible for these observations: (1) that there is an alteration in the Km but not the Vmax of the lactate transport system in skeletal muscle membranes; and (2) that specific changes occur in selected isoforms of the lactate transport protein which may co-exist in muscle.

Influence of ω-3 fatty acids on splanchnic blood flow and lactate metabolism in an endotoxemic rat model

Alteration in regional blood flow is important in the pathogenesis of organ failure during endotoxemia and sepsis. In particular, intestinal ischemia is thought to enhance the translocation of bacteria into the systemic circulation. We used radioactive microspheres to measure the influence of two intravenous (IV) dietary fats (vegetable oil containing high levels of ω-6 fatty acids, and fish oil containing high levels of ω-3 fatty acids) on regional blood flow during low-dose Escherichia coli endotoxin infusion ( 0.1 mg 100 g body weight [BW] ) in a rat model. Despite absence of changes in the cardiac output, blood flow rates to the small and large intestines, stomach, and pancreas, and also to the skin and skeletal muscle were significantly reduced after 18 hours of endotoxin infusion in the rats fed standard vegetable oil. Short-term IV feeding during a period of 40 hours with an isonitrogenous, isocaloric nutrient solution containing fish oil as the only lipid source normalized intestinal perfusion and increased blood flow to the liver and spleen. Low-dose endotoxin infusion also resulted in significant increases in glucose, lactate, and pyruvate concentrations. In comparison to standard vegetable fat emulsion, fish oil significantly reduced these parameters. A second experiment was conducted to measure lactate kinetics. Based on the dilution of U- 14C-lactate, fish oil feeding was associated with higher lactate clearance than standard vegetable oil feeding during the endotoxin infusion. We conclude that short-term IV feeding with oil improves intestinal perfusion and portal blood flow, improves glucose tolerance, and increases lactate clearance in a low-dose endotoxin rat model.