Administration Of Lactate Research Articles

Exercise-induced endothelial Mecp2 lactylation suppresses atherosclerosis via the Ereg/MAPK signalling pathway

Background and aimsLactylation, a recently identified post-translational modification (PTM), plays a central role in the regulation of multiple physiological and pathological processes. Exercise is known to provide protection against cardiovascular disease. However, whether exercise-generated lactate changes lactylation and is involved in the exercise-induced attenuation of atherosclerotic cardiovascular disease (ASCVD) remains unclear. The purpose of this study was to investigate the effects and mechanisms of exercise-induced lactylation on ASCVD. Methods and ResultsUsing the high-fat diet-induced apolipoprotein-deficient mouse model of ASCVD, we found that exercise training promoted Mecp2 lysine lactylation (Mecp2k271la); it also decreased the expression of vascular cell adhesion molecule 1 (Vcam-1), intercellular adhesion molecule 1 (Icam-1), monocyte chemoattractant protein 1 (Mcp-1), interleukin (IL)-1β, IL-6, and increased the level of endothelial nitric oxide synthase (Enos) in the aortic tissue of mice. To explore the underlying mechanisms, mouse aortic endothelial cells (MAECs) were subjected to RNA-sequencing and CHIP-qPCR, which confirmed that Mecp2k271la repressed the expression of epiregulin (Ereg) by binding to its chromatin, demonstrating Ereg as a key downstream molecule for Mecp2k271la. Furthermore, Ereg altered the mitogen-activated protein kinase (MAPK) signalling pathway through regulating the phosphorylation level of epidermal growth factor receptor, thereby affecting the expression of Vcam-1, Icam-1, Mcp-1, IL-1β, IL-6, and Enos in ECs, which in turn promoted the regression of atherosclerosis. In addition, increasing the level of Mecp2k271la by exogenous lactate administration in vivo also inhibits the expression of Ereg and the MAPK activity in ECs, resulting in repressed atherosclerotic progression. ConclusionsIn summary, this study provides a mechanistic link between exercise and lactylation modification, offering new insight into the anti-atherosclerotic effects of exercise-induced PTM.

Exogenous lactate augments exercise-induced improvement in memory but not in hippocampal neurogenesis

Adult hippocampal neurogenesis (AHN), the lifelong process of formation of new neurons in the mammalian brain, plays an important role in learning and memory. Exercise is an effective enhancer of AHN; however, the molecular mediators of exercise-induced AHN are unknown. Recently, lactate was considered as an important mediator of exercise-induced AHN. Therefore, we hypothesized that exercise with lactate intake could augment exercise-induced AHN. This study was conducted for 5 weeks with 7-week-old ICR male mice that performed mild-intensity exercise (just below lactate threshold, 55–60%VO2max) with or without oral administration of lactate 5 days/week. Cell proliferation, neuronal differentiation, neurogenesis-relevant factors, reference and retention memory, and spatial working memory were evaluated at the end of the experiment. The results showed that AHN was enhanced by lactate intake, but exercise-induced AHN was not augmented by exercise with lactate intake. Nevertheless, exercise-induced improvement in reference and retention memory was augmented by exercise with lactate intake. And spatial working memory was promoted by the co-treatment, also protein expression of hippocampal FNDC5, BDNF, PGC1α, and MCT2 were elevated by the co-treatment. Therefore, our findings suggest that lactate has a potential to be developed as a novel supplement that improves the positive effects of exercise on the hippocampus and its cognitive function.

Effects of Pyruvate Kinase M2 (PKM2) Gene Deletion on Astrocyte-Specific Glycolysis and Global Cerebral Ischemia-Induced Neuronal Death.

Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte-neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that dephosphorylates phosphoenolpyruvate to pyruvate during glycolysis in astrocytes. We hypothesized that a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death. Mice harboring a PKM2 gene deletion were established by administering tamoxifen to Aldh1l1-CreERT2; PKM2f/f mice. Upon development of global cerebral ischemia, mice were immediately injected with sodium l-lactate (250 mg/kg, i.p.). To verify our hypothesis, we compared oxidative damage, microtubule disruption, ANLS disruption, and neuronal death between the gene deletion and control subjects. We observed that PKM2 gene deletion increases the degree of neuronal damage and impairment of lactate metabolism in the hippocampal region after GCI. The lactate administration groups showed significantly reduced neuronal death and increases in neuron survival and cognitive function. We found that lactate supply via the ANLS in astrocytes plays a crucial role in maintaining energy metabolism in neurons. Lactate administration may have potential as a therapeutic tool to prevent neuronal damage following ischemic stroke.

Lactate induces the development of beige adipocytes via an increase in the level of reactive oxygen species.

Recent studies have indicated that lactate acts as a signaling molecule in various tissues. We previously demonstrated that intake of an amino acid mixture combined with exercise synergistically induced beige adipocyte formation in inguinal white adipose tissue (iWAT) in mice. Moreover, plasma lactate levels remained significantly elevated in the amino acid mixture + exercise group even 16 h after exercise, indicating that a lactate-mediated pathway may be involved in the induction of beige adipocyte formation. Against this background, we hypothesized that oral intake of lactate would induce beige adipocyte formation via the lactate signaling pathway without exercise. Furthermore, if oral intake of lactate can produce the same effect as exercise, lactate might be used as a food-derived exercise replacement-factor. Oral intake of lactate (100 mM in drinking water) for 4 weeks significantly induced beige adipocyte formation in iWAT in mice as well as a significant elevation of lactate transporter (monocarboxylic acid transporter 1; MCT1) and lactate dehydrogenase B levels. Administration of lactate to adipocytes significantly increased reactive oxygen species (ROS) and superoxide levels and the NADH/NAD+ ratio. The induction of lactate-mediated uncoupling protein 1 (UCP1) expression and ROS production were significantly suppressed by antioxidant treatment or inhibition of MCT1. However, UCP1 induction was not significantly affected by the inhibition of lactate receptor (hydroxycarboxylic acid receptor 1). These findings suggest that lactate-mediated ROS production induces beige adipocyte formation, and thus oral intake of lactate may confer some benefits of exercise without the need to perform exercise.

Abstract 14872: Lactate Promotes Endothelial-to-Mesenchymal Transition via Snail1 Lactylation After Myocardial Infarction

Introduction: High levels of lactate are positively associated with the prognosis and mortality in the patients with acute heart attack and heart failure. Endothelial-to-mesenchymal transition (EndMT) plays an important role in the progression of cardiac fibrosis in multiple cardiovascular diseases. We investigated whether lactate exerts a biological role in EndMT following myocardial infarction (MI). Methods: MI was induced in endothelial cell specific GFP labeled (TIE2GFP) mice by left anterior descending (LAD) coronary artery ligation. To suppress lactate production, 2-Deoxy-D-glucose (2-DG, 2g/kg body weight) was intraperitoneally injected daily for 7 days. Supplemental lactic acid (adjust to pH 6.8, 0.5 g/kg body weight) was administrated to mice either by i.p. injection every 7 days for 1 or 4 weeks or using osmotic mini-pumps after surgery. In vitro , endothelial cells were treated with 5 mM or 10 mM L-lactic acid followed by normoxic or hypoxic challenge in a hypoxia chamber. Results: Our data showed that inhibition of lactate production by 2-DG ameliorated MI induced EndMT, cardiac fibrosis and cardiac dysfunction. On the contrary, administration of supplemental lactate further promoted EndMT and worsened cardiac dysfunction post-MI. In vitro analysis shows that treatment of endothelial cells with lactate decreases the expression of endothelial cell markers and accelerates mesenchymal marker expression, as well as disrupts endothelial cell function and induces mesenchymal like function following hypoxic challenge via activating transforming growth factor-β (TGF-β)/Smad2 signaling pathway. Of note, lactate accelerated the lactylation of Snail1, a transcription factor of TGF-β, promoted its nuclear translocation to bind at the promoter of TGF-β, and upregulated TGF-β expression. Conclusion: In summary, we conclude that lactate acts as an important molecule that upregulates cardiac fibrosis after MI via induction of Snail1 lactylation and nuclear translocation to activate TGF-β/Smad2 pathway, resulting in EndMT.

LACTATE IMPAIRS VASCULAR PERMEABILITY BY INHIBITING HSPA12B EXPRESSION VIA GPR81-DEPENDENT SIGNALING IN SEPSIS.

ABSTRACTIntroduction: Sepsis impaired vascular integrity results in multiple organ failure. Circulating lactate level is positively correlated with sepsis-induced mortality. We investigated whether lactate plays a role in causing endothelial barrier dysfunction in sepsis. Methods: Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). Lactic acid was injected i.p. (pH 6.8, 0.5 g/kg body weight) 6 h after CLP or sham surgery. To elucidate the role of heat shock protein A12B (HSPA12B), wild-type, HSPA12B-transgenic, and endothelial HSPA12B-deficient mice were subjected to CLP or sham surgery. To suppress lactate signaling, 3OBA (120 μM) was injected i.p. 3 h before surgery. Vascular permeability was evaluated with the Evans blue dye penetration assay. Results: We found that administration of lactate elevated CLP-induced vascular permeability. Vascular endothelial cadherin (VE-cadherin), claudin 5, and zonula occluden 1 (ZO-1) play a crucial role in the maintenance of endothelial cell junction and vascular integrity. Lactate administration significantly decreased VE-cadherin, claudin 5, and ZO-1 expression in the heart of septic mice. Our in vitro data showed that lactate (10 mM) treatment disrupted VE-cadherin, claudin 5, and ZO-1 in endothelial cells. Mechanistically, we observed that lactate promoted VE-cadherin endocytosis by reducing the expression of HSPA12B. Overexpression of HSPA12B prevented lactate-induced VE-cadherin disorganization. G protein–coupled receptor 81 (GPR81) is a specific receptor for lactate. Inhibition of GPR81 with its antagonist 3OBA attenuated vascular permeability and reversed HSPA12B expression in septic mice. Conclusions: The present study demonstrated a novel role of lactate in promoting vascular permeability by decreasing VE-cadherin junctions and tight junctions in endothelial cells. The deleterious effects of lactate in vascular hyperpermeability are mediated via HSPA12B- and GPR81-dependent signaling.

Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity

Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.

Effects of lactate administration on hypertrophy and mTOR signaling activation in mouse skeletal muscle.

Lactate is a metabolic product of glycolysis and has recently been shown to act as a signaling molecule that induces adaptations in oxidative metabolism. In this study, we investigated whether lactate administration enhanced muscle hypertrophy and protein synthesis responses during resistance exercise in animal models. We used male ICR mice (7–8 weeks old) were used for chronic (mechanical overload induced by synergist ablation: [OL]) and acute (high‐intensity muscle contraction by electrical stimulation: [ES]) resistance exercise models. The animals were intraperitoneally administrated a single dose of sodium lactate (1 g/kg of body weight) in the ES study, and once a day for 14 consecutive days in the OL study. Two weeks of mechanical overload increased plantaris muscle wet weight (main effect of OL: p < 0.05) and fiber cross‐sectional area (main effect of OL: p < 0.05), but those were not affected by lactate administration. Following the acute resistance exercise by ES, protein synthesis and phosphorylation of p70 S6 kinase and ribosomal protein S6, which are downstream molecules in the anabolic signaling cascade, were increased (main effect of ES: p < 0.05), but lactate administration had no effect. This study demonstrated that exogenous lactate administration has little effect on the muscle hypertrophic response during resistance exercise using acute ES and chronic OL models. Our results do not support the hypothesis that elevated blood lactate concentration induces protein synthesis responses in skeletal muscle.

Effects of Lactate Administration on Mitochondrial Respiratory Function in Mouse Skeletal Muscle

Recent evidence has shown that mitochondrial respiratory function contributes to exercise performance and metabolic health. Given that lactate is considered a potential signaling molecule that induces mitochondrial adaptations, we tested the hypothesis that lactate would change mitochondrial respiratory function in skeletal muscle. Male ICR mice (8 weeks old) received intraperitoneal injection of PBS or sodium lactate (1 g/kg BW) 5 days a week for 4 weeks. Mitochondria were isolated from freshly excised gastrocnemius muscle using differential centrifugation and were used for all analyses. Lactate administration significantly enhanced pyruvate + malate- and glutamate + malate-induced (complex I-driven) state 3 (maximal/ATP synthesis-coupled) respiration, but not state 2 (basal/proton conductance) respiration. In contrast, lactate administration significantly decreased succinate + rotenone-induced (complex II-driven) state 3 and 2 respiration. No significant differences were observed in malate + octanoyl-l-carnitine-induced state 3 or 2 respiration. The enzymatic activity of complex I was tended to increase and those of complexes I + III and IV were significantly increased after lactate administration. No differences were observed in the activities of complexes II or II + III. Moreover, lactate administration increased the protein content of NDUFS4, a subunit of complex I, but not those of the other components. The present findings suggest that lactate alters mitochondrial respiratory function in skeletal muscle.

Intracerebral transformation of pyruvate to lactate is deleterious for the neurological function after an experimental cardiac arrest in rabbits

Cardiac arrest is a very severe public health issue associated with dramatic neurological injury after the return of spontaneous circulation. During ischemia, neurons can use lactate as an alternative source of energy by oxidazing it into pyruvate via the lactate dehydrogenase (LDH). In the context of cardiac arrest, the neurological consequences of this phenomenon are however unknown. Our aim is to decipher the role of the cerebral lactate consumption on neurological injury after a cardiac arrest. Rabbits were resuscitated after 10 min of ventricular fibrillation and randomly received an intravenous infusion of lactate or pyruvate (10 mg/kg/min, Lact and Pyr groups, n = 6 for each), or oxamate, an inhibitor of LDH (37.5 mg/kg/min, Oxa group, n = 6). In a first set of experiment, we measured the arteriojugular concentrations differences in lactate oxygen and glucose, as well as cerebral extracellular concentration in lactate, pyruvate and glucose via microdialysis catheter during 4 h after cardiac arrest. Secondarly, we evaluated the neurological recovery of additional rabbits during 48 h after cardiac arrest. In both procedures, neuronal death and astrogliosis were assessed histologically. In control animals, cardiac arrest led to an intense metabolic crisis characterised by high cerebral consumptions in oxygen, glucose and lactate. Lactate administration slightly increased neurological dysfunction and neuronal death in comparison to control. Pyruvate administration led to a significant increase in the extracellular concentration in lactate 30 min after ROSC (8.4 ± 0.5 vs. 6.8 ± 1.1 fold change from baseline in Pyr and control groups respectively), which was associated with an aggravation of the neurological dysfunction, the number of degenerative neurons and astrogliosis. Inhibition of LDH by oxamate administration mitigated dramatically this metabolic crisis and was associated with improvement of neurological function and a decrease of neuronal death and astrogliosis compared to control group (15 ± 6 vs. 60 ± 9% of neurological dysfunction in Oxa and control groups, respectively). Our results state that cerebral oxidation of lactate into pyruvate seems to be related to neurological injury after cardiac arrest.

Lactate Administration Increases Skeletal Muscle Synthesis in Mice

PurposeLactate, secreted by skeletal muscle during exercise, had been known as fatigue substance. However, several physiological roles of lactate have been revealed in the last decades, and previous studies reported that lactate treatment increased protein synthesis factors in skeletal muscle. Nevertheless, underlying molecular mechanisms of exogenous lactate on protein synthesis and degradation remain unknown, and there was no study that confirm long‐term lactate administration with exercise training. Therefore, the purpose of study is to investigate the effect of long‐term exogenous lactate administration and lactate administration with exercise training on the skeletal muscle synthesis and degradation.Methods32 mice were randomly divided into four groups: sedentary + saline (Sed/Con), sedentary + lactate (Sed/Lac), exercise training + saline (Ex/Con), and Exercise training + lactate (Ex/Lac). Exercise training (VO2max 70%) and lactate administration (3 g/kg sodium lactate) performed 5 days a week. The timing of lactate administration was immediately after every exercise training, and saline administration groups were given same volume of saline as lactate. After 5 weeks, mice were sacrificed and immediately obtained skeletal muscle and blood. To confirm the effect of lactate on protein synthesis (IGF receptor, Akt and mTOR phosphate/total) and degradation (MuRF1, MAFbx1, FOXO1), mRNA and protein expression analyzed respectively plantaris and extensor digitorum longus. Blood parameters of lactate, insulin, IGF1, and glucose were measured.ResultsSkeletal muscle weight tended to higher Sed/Lac than Sed/Con, but Sed/Lac had significantly supplement effects compared to Sed/Con in only gastrocnemius weight (p = .000). Blood IGF1 showed that Sed/Lac was significantly lower than Sed/Con (p = .039) and Ex/Lac (p = .007). mRNA of IGF receptor had only exercise effects (p = .000). mRNA of Akt and mTOR showed that Sed/Lac was significantly higher than Sed/Con (respectively, p = .000 and p = .043). Protein expression of MuRF1, Sed/Lac was significantly lower than Sed/Con (p = .046), but exercise training effects was found saline groups (Sed/Con vs Ex/Con; p = .001).ConclusionThis study showed that long‐term lactate administration had positive effects on Akt / mTOR and MuRF1. Especially, it was confirmed that long‐term lactate administration increased skeletal muscle mass in mice. Hence, we suggest that long‐term lactate administration increases skeletal muscle synthesis and that lactate administration can be used as supplement for sarcopenia. Nevertheless, this study did not confirm synergistic effects of lactate administration with exercise training. It is suggested that post‐exercise lactate administration, unlike lactate administration at rest state, affects energy metabolism rather skeletal muscle synthesis. Therefore, future study would be necessary to investigate lactate administration timing with exercise training.

The Effects of Exercise Training with Oral Intake of Lactate on Hippocampal Neurogenesis and Neurotrophic Factors in Mice

Hippocampal neurogenesis plays an important role in learning and memory. Healthy hippocampal environment is also necessary for improvement of its cognitive function. Therefore, enhancing of both hippocampal neurogenesis and environment is required to prevent or ameliorate neurodegenerative statements.Exercise is powerful enhancer of both, and it is considered that the exercise effects are resulted from alterations in brain (central mechanism), also in soma, i.e., skeletal muscle, (somatic mechanism). Yet the exact mechanism is unclear.Lactate, known as just byproduct of glycolysis and primary factor of fatigue when exercise, is highlighting as a promising signaling molecule that mediates the exercise effects on hippocampus. In this perspective, exercise training with intake of lactate can be remarkable strategy for strengthening the exercise effects on hippocampus.Therefore, the purpose of the current study is to investigate whether combination of exercise and lactate intake can additively enhance exercise‐induced hippocampal neurogenesis and neurotrophic factors.The study was conducted for 5 weeks using 4 groups of mice: CON (vehicle group), LAC (oral administration of 3g/kg lactate 5days/week), EXE (mid‐intensity exercise 5days/week), and EXE+LAC (lactate administration immediately after every exercise). At the last week of experiment, cognitive function was evaluated by Y‐maze spontaneous alternation test. After the experiment ended, hippocampal neurogenesis (Ki67, neural stem cell proliferation marker; DCX, marker of differentiation to immature neurons) and neurotrophic factors (PGC1α, FNDC5, VEGFA, and BDNF) were evaluated respectively by immunohistochemistry (IHC) and by Western blot (WB) on hippocampus.From the IHC results, exercise training significantly increased the number of Ki67 and DCX positive cells (p= 0.001 and p = 0.004 respectively) which were also increased in LAC than CON (p = 0.064 and p = 0.03 respectively). There was no difference in Ki67 and DCX positive cells between EXE and EXE+LAC. From the WB results, however, FNDC5 of EXE+LAC was significantly higher than that of EXE (p = 0.005). BDNF and PGC1α of EXE+LAC was higher than that of EXE respectively by 20% and 9% (but not significant). There was no difference in VEGFA between EXE and EXE+LAC. From the Y‐maze test results, interestingly, while there was no difference in the performance between CON and LAC, the performance of EXE+LAC was significantly enhanced than that of EXE (p = 0.006).In conclusion, combination of exercise training and lactate intake additively promoted the performance of spontaneous alternation test and tended to additively enhance exercise‐induced neurotrophic factors, but not hippocampal neurogenesis. Therefore, the study revealed the potential that exercise training with oral intake of lactate can be remarkable strategy for strengthening the exercise effects on hippocampus.

Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance.

Endothelial cells differ from other cell types responsible for the formation of the vascular wall in their unusual reliance on glycolysis for most energy needs, which results in extensive production of lactate. We find that endothelium-derived lactate is taken up by pericytes, and contributes substantially to pericyte metabolism including energy generation and amino acid biosynthesis. Endothelial-pericyte proximity is required to facilitate the transport of endothelium-derived lactate into pericytes. Inhibition of lactate production in the endothelium by deletion of the glucose transporter-1 (GLUT1) in mice results in loss of pericyte coverage in the retina and brain vasculatures, leading to the blood-brain barrier breakdown and increased permeability. These abnormalities can be largely restored by oral lactate administration. Our studies demonstrate an unexpected link between endothelial and pericyte metabolisms and the role of endothelial lactate production in the maintenance of the blood-brain barrier integrity. In addition, our observations indicate that lactate supplementation could be a useful therapeutic approach for GLUT1 deficiency metabolic syndrome patients.

Effect of lactate administration on cerebral blood flow during hypoglycemia in people with type 1 diabetes

IntroductionImpaired awareness of hypoglycemia, clinically reflected by the inability to timely detect hypoglycemia, affects approximately 25% of the people with type 1 diabetes. Both altered brain lactate handling and increased...

Oral lactate slows gastric emptying and suppresses appetite in young males

Lactate serves as an alternative energy fuel but is also an important signaling metabolite. We aimed to investigate whether oral lactate administration affects appetite-regulating hormones, slows gastric emptying rate, and dampens appetite. Ten healthy male volunteers were investigated on two separate occasions: 1) following oral ingestion of D/L-Na-lactate and 2) following oral ingestion of isotonic iso-voluminous NaCl and intravenous iso-lactemic D/L-Na-lactate infusions. Appetite was evaluated by questionnaires and ad libitum meal tests were performed at the end of each study day. Gastric emptying rate was evaluated using the acetaminophen test. Plasma concentrations of growth differential factor 15 (GDF15, primary outcome) increased following oral and iv administration of lactate (p<0.001) with no detectable difference between interventions (p=0.15). Oral lactate administration lowered plasma concentrations of acylated ghrelin (p=0.02) and elevated glucagon like peptide-1 (GLP-1, p=0.045), insulin (p<0.001), and glucagon (p<0.001) compared with iv administration. Oral lactate administration slowed gastric emptying (p<0.001), increased the feeling of being "full" (p=0.008) and lowered the "anticipated future food intake" (p=0.007) compared with iv administration. Food intake during the ad libitum meal test did not differ between the two study days. Oral lactate administration has a direct effect on the upper gastrointestinal tract, affecting gut hormone secretion, motility and appetite sensations which cannot be mediated through lactate in the systemic circulation alone. These data suggest that compounds rich in lactate may be useful in the treatment of metabolic disease. NCT0429981, https://clinicaltrials.gov/ct2/show/NCT04299815.

135. Association Between Implementation of the Centers for Medicare &amp; Medicaid Services Sepsis Performance Measure (SEP-1) and Outcomes in U.S. Hospitals

BackgroundIn October 2015, CMS began requiring U.S. hospitals to report compliance with the Severe Sepsis/Septic Shock Early Management Bundle (SEP-1). We evaluated the impact of SEP-1 implementation on sepsis treatment patterns and outcomes using detailed clinical data from diverse hospitals.MethodsWe conducted a quasi-experimental interrupted time-series analysis of adults admitted to 114 hospitals in the Cerner HealthFacts dataset from October 2013-December 2017 with suspected sepsis (defined by blood culture orders, SIRS criteria, and acute organ dysfunction) within 24 hours of hospital arrival. The primary outcome was quarterly short-term mortality rates (in-hospital death or discharge to hospice). Secondary outcomes included lactate testing and administration of anti-MRSA or anti-Pseudomonal beta-lactam antibiotics within 24 hours of hospital arrival. Generalized estimating equations with robust sandwich variances were used to fit logistic regression models to assess for immediate SEP-1 impact and changes in quarterly trends after October 2015, adjusting for baseline characteristics and severity-of-illness. ResultsThe cohort included 117,510 patients with suspected sepsis on admission. Lactate testing rates increased over the study period (61.9% pre-SEP-1 vs 77.9% post-SEP-1) with a significant immediate increase in risk-adjusted testing rates after SEP-1 (OR 1.34, 95% CI 1.04-1.74) (Figure 1). There was also an increase in utilization of anti-MRSA (20.6% pre vs 23.2% post-SEP-1) and anti-Pseudomonal antibiotics (30.1% vs 39.8%), %), but these trends began before SEP-1 implementation. Unadjusted short-term mortality was similar in the pre vs post-SEP-1 periods (20.3% vs 20.4%). SEP-1 was not associated with either an immediate change (OR 0.94, 95% CI 0.68-1.29] or quarterly trend change (OR 1.00, 95% CI 0.97-1.04] in risk-adjusted short-term mortality (Figure 2). Figure 1. Quarterly risk-adjusted rates of A) lactate testing, B) anti-MRSA antibiotic administration, and C) anti-Pseudomonal beta-lactam antibiotic administration within 24 hours of hospital presentation for patients with suspected sepsis before and after SEP-1 implementation in Q4 2015. All models included time (in quarters), an indicator of the post-SEP-1 implementation period (starting Q12016, to allow for evaluation of an immediate policy effect), and a two-way interaction term to assess whether SEP-1 implementation resulted in a change in trend. When data suggested no change in trend, models were also fit without this interaction term; this yielded a significant association for an immediate level change in lactate testing (OR 1.34 [95% CI 1.04-1.74]) but not antibiotic utilization. All analyses were adjusted for patient severity of illness and baseline characteristics including age, sex, race, initial vital signs (systolic blood pressure, temperature, respiratory rate, heart rate), and initial laboratory results (creatinine, platelet count, bilirubin, white blood cell count) if done within 24 hours.Figure 2. Quarterly risk-adjusted outcomes of patients with suspected sepsis before and after SEP-1 implementation in Q4 2015: A) In-hospital death or discharge to hospice, and B) In-hospital death alone. Models included time (in quarters), an indicator of the post-SEP-1 implementation period (starting Q12016, to allow for evaluation of an immediate policy effect), and a two-way interaction term to assess whether SEP-1 implementation resulted in a change in trend. Analyses were adjusted for patient severity of illness and baseline characteristics including age, sex, race, initial vital signs (systolic blood pressure, temperature, respiratory rate, heart rate), and initial laboratory results (creatinine, platelet count, bilirubin, white blood cell count) if done within 24 hours.ConclusionSEP-1 implementation was associated with an immediate increase in lactate testing rates, no significant change in already-rising rates of broad-spectrum antibiotic use, and no change in short-term mortality rates for patients with suspected sepsis in a large cohort of hospitals. Other approaches to decrease sepsis mortality may be warranted. Disclosures Chanu Rhee, MD, MPH, UpToDate (Other Financial or Material Support, Chapter Author) Sameer S. Kadri, MD, MS, FIDSA, Nothing to disclose Michael Klompas, MD, MPH, UpToDate (Other Financial or Material Support, Chapter Author)

Abstract 10941: Cerebral Consumption of Lactate Increases Neurological Injury After Experimental Cardiac Arrest in Rabbits

Introduction: Neuronal consumption of lactate is known to be protective after long duration of brain ischaemia. However, its consequences on neurological function after shorter duration of ischemia like after cardiac arrest are unknown. Hypothesis: We hypothesized that cerebral lactate consumption is deleterious for neurological outcome, whereas lactate dehydrogenase inhibition by oxamate could improve recovery. Methods: Male New-Zealand rabbits were anesthetized and surgically instrumented to assess lactate, glucose and O 2 cerebral consumption by measurement of the arterio-jugular differences. After 10 min of ventricular fibrillation, animals were resuscitated and randomly received a 30-min infusion of either saline (Control, n=6), lactate (Lact, 5 mg/kg/min, n=6) or oxamate (Oxa, 37.5 mg/kg/min, n=6). They were followed during 4 h. Additional animals were submitted to the same procedure without surgical instrumentation to allow recovery and assessment of neurological function during 48 h after cardiac arrest. In both experiments, neuronal death was assessed histologically by fluorojade C staining. Results: In Control group, a strong increase of the cerebral consumption of O 2 , glucose and lactate was observed during the 4 hours following resuscitation. In Lact group, lactate consumption was increased as compared to Control, whereas it was almost abolished in Oxa group (17.13±3.59, 32.60±6.24 and 4.04±1.58 mmol/L/min in Control, Lact and Oxa, respectively). Additionally, Oxa group presented a reduced consumption of glucose and O 2 after cardiac arrest as compared to other groups. Interestingly, administration of oxamate was highly neuroprotective whereas lactate administration worsened the neurological outcome after cardiac arrest (38±4, 64±10 and 15±6 % of neurological dysfunction score at 48h in Control, Lact and Oxa, respectively). Oxamate infusion was also associated with a significant reduction in the number of degenerative neurons at 4 h and 48 h of follow-up. Conclusions: The cerebral consumption of lactate appeared to be detrimental in rabbits after cardiac arrest. Its inhibition by oxamate is potently neuroprotective.

Prehospital Lactate is Associated with the Need for Blood in Trauma

Background: Traumatic hemorrhage is the leading cause of preventable death, and its effects are often evident within the first 24 hours of hospital admission. We investigated the relationship between prehospital lactate measurement and administration of hospital blood products and life-saving interventions (LSIs) within 24 hours of hospital admission. Methods: We included trauma patients with recorded prehospital venous lactate transported by a single critical care transport service to a Level I trauma center between 2012 and 2019. We abstracted vital signs, mission type, anatomic location of injury, prehospital administration of crystalloid and blood products, and hospital LSIs started within 24 hours of admission. We used logistic regression to determine the association of prehospital lactate and in-hospital administration of blood products in groups with or without hypotensive patients. We investigated the effect of prehospital lactate concentration on secondary outcomes such as LSIs and mortality. Results: We included 2,170 patients transported from the scene or emergency department (ED), of whom 1,821 (84%) were normotensive. The median concentration of prehospital lactate was 2.10 mmol/L for the main population (IQR = 1.40–3.30) and 2.00 mmol/L for the normotensive subgroup (IQR = 1.30–2.90). A higher prehospital lactate concentration was associated with higher odds of needing early hospital blood products in the whole study population (OR = 1.12, (95% CI 1.06–1.20), p < 0.01) and in the normotensive subgroup (OR = 1.13, (95% CI 1.03–1.22), p = 0.01). These positive associations were also observed with the secondary outcome of hospital LSIs, and higher prehospital lactate was also associated with higher odds of mortality (OR = 1.32, (95% CI 1.20–1.45), p < 0.01). Conclusions: Higher concentrations of prehospital lactate were associated with the need for in-hospital blood transfusion within 24 hours of admission. The relationship between lactate and blood transfusion persisted among normotensive patients. Further work is needed to incorporate prehospital lactate into decision support tools for prehospital blood administration.

Lactate administration does not affect denervation-induced loss of mitochondrial content and muscle mass in mice.

Lactate is considered to be a signaling molecule that induces mitochondrial adaptation and muscle hypertrophy. The purpose of this study was to examine whether lactate administration attenuates denervation‐induced loss of mitochondrial content and muscle mass. Eight‐week‐old male Institute of Cancer Research mice underwent unilateral sciatic nerve transection surgery. The contralateral hindlimb served as a sham‐operated control. From the day of surgery, mice were injected intraperitoneally with PBS or sodium lactate (equivalent to 1 g·kg−1 body weight) once daily for 9 days. After 10 days of denervation, gastrocnemius muscle weight decreased to a similar extent in both the PBS‐ and lactate‐injected groups. Denervation significantly decreased mitochondrial enzyme activity, protein content, and MCT4 protein content in the gastrocnemius muscle. However, lactate administration did not have any significant effects. The current observations suggest that daily lactate administration for 9 days does not affect denervation‐induced loss of mitochondrial content and muscle mass.

Exercise-Induced Lactate Release Mediates Mitochondrial Biogenesis in the Hippocampus of Mice via Monocarboxylate Transporters.

Regular exercise training induces mitochondrial biogenesis in the brain via activation of peroxisome proliferator-activated receptor gamma-coactivator 1α (PGC-1α). However, it remains unclear whether a single bout of exercise would increase mitochondrial biogenesis in the brain. Therefore, we first investigated whether mitochondrial biogenesis in the hippocampus is affected by a single bout of exercise in mice. A single bout of high-intensity exercise, but not low- or moderate-intensity, increased hippocampal PGC-1α mRNA and mitochondrial DNA (mtDNA) copy number at 12 and 48h. These results depended on exercise intensity, and blood lactate levels observed immediately after exercise. As lactate induces mitochondrial biogenesis in the brain, we examined the effects of acute lactate administration on blood and hippocampal extracellular lactate concentration by in vivo microdialysis. Intraperitoneal (I.P.) lactate injection increased hippocampal extracellular lactate concentration to the same as blood lactate level, promoting PGC-1α mRNA expression in the hippocampus. However, this was suppressed by administering UK5099, a lactate transporter inhibitor, before lactate injection. I.P. UK5099 administration did not affect running performance and blood lactate concentration immediately after exercise but attenuated exercise-induced hippocampal PGC-1α mRNA and mtDNA copy number. In addition, hippocampal monocarboxylate transporters (MCT)1, MCT2, and brain-derived neurotrophic factor (BDNF) mRNA expression, except MCT4, also increased after high-intensity exercise, which was abolished by UK5099 administration. Further, injection of 1,4-dideoxy-1,4-imino-D-arabinitol (glycogen phosphorylase inhibitor) into the hippocampus before high-intensity exercise suppressed glycogen consumption during exercise, but hippocampal lactate, PGC-1α, MCT1, and MCT2 mRNA concentrations were not altered after exercise. These results indicate that the increased blood lactate released from skeletal muscle may induce hippocampal mitochondrial biogenesis and BDNF expression by inducing MCT expression in mice, especially during short-term high-intensity exercise. Thus, a single bout of exercise above the lactate threshold could provide an effective strategy for increasing mitochondrial biogenesis in the hippocampus.