Effects of Sodium Lactate Infusion in Two Girls with Glucose Transporter 1 Deficiency Syndrome.

BACKGROUND: Glucose is an important fuel for the brain. In glucose transporter 1 deficiency syndrome (GLUT1DS), the transport of glucose across the blood-brain barrier is limited. Most individuals with GLUT1DS present with developmental problems, epilepsy, and (paroxysmal) movement disorders, and respond favorably to the ketogenic diet. Similar to ketones, lactate is an alternative energy source for the brain. The aim of this study is to investigate whether intravenous infusion of sodium lactate in children with GLUT1DS has beneficial effects on their epilepsy. METHODS: We performed a proof of principle study with two subjects with GLUT1DS who were not on a ketogenic diet and suffered from absence epilepsy. After overnight fasting, sodium lactate (600 mmol/L) was infused during 120 minutes, under video electroencephalographic (EEG) recording and monitoring of serum lactate, glucose, electrolytes, and pH. Furthermore, the EEGs were compared with pre-/postprandial EEGs of both subjects, obtained shortly before the study. RESULTS: Fasting EEGs of both subjects showed frequent bilateral, frontocentral polyspike and wave complexes. In one subject, no more epileptic discharges were seen postprandially and after the start of lactate infusion. The EEG of the other subject did not change, neither postprandially nor after lactate infusion. Serum pH, lactate, and sodium changed temporarily during the study. CONCLUSION: This study suggests that sodium lactate infusion is possible in individuals with GLUT1DS, and may have potential therapeutic effects. Cellular abnormalities, beyond neuronal energy failure, may contribute to the underlying disease mechanisms of GLUT1DS, explaining why not all individuals respond to the supplementation of alternative energy sources.

Efecto de la infusión de lactato de sodio 0.5 molar sobre el medio interno de pacientes críticos / Effect of half-molar sodium lactate infusion on biochemical parameters in critically ill patients

Objetivo Evaluar el impacto de la infusión de lactato de sodio 0,5M sobre variables del medio interno y sobre la presión intracraneana en pacientes críticos. Diseño Estudio prospectivo experimental de cohorte única. Ámbito Unidad de cuidados intensivos de un hospital universitario. Pacientes Pacientes con shock y neurocríticos con hipertensión intracraneana. Intervenciones Se infundió una carga de 500 cc de infusión de lactato de sodio 0,5M en 15 min y se midió el nivel plasmático de sodio, potasio, magnesio, calcio, cloro, lactato, bicarbonato, PaCO2 arterial, pH, fosfato y albúmina en 3 tiempos: T0 preinfusión; T1 a los 30 min y T2 a los 60 min postinfusión. Se midieron la presión arterial media y presión intracraneana en T0 y T2. Resultados Recibieron el fluido N=41: n=19 como osmoagente y 22 como expansor. Se constató alcalosis metabólica: T0 vs. T1 (p=0,007); T1 vs. T2 (p=0,003). La natremia aumentó en los 3 tiempos (T0 vs. T1; p<0,0001; T1 vs. T2; p=0,0001). Se demostró un descenso de la presión intracraneana (T0: 24,83±5,4 vs. T2: 15,06±5,8; p <0,001). El lactato aumentó inicialmente (T1) con un rápido descenso (T2) (p <0,0001), incluso en aquellos pacientes con hiperlactatemia basal (p=0,002). Conclusiones La infusión de lactato de sodio 0,5M genera alcalosis metabólica, hipernatremia, disminución de la cloremia y un cambio bifásico del lactato, y muestra eficacia en el descenso de la presión intracraneana en pacientes con daño encefálico agudo. (AU)

Objective To evaluate the impact of the infusion of sodium lactate 500ml upon different biochemical variables and intracranial pressure in patients admitted to the intensive care unit. Design A prospective experimental single cohort study was carried out. Scope Polyvalent intensive care unit of a university hospital. Patients Critical patients with shock and intracranial hypertension. Procedure A 500ml sodium lactate bolus was infused in 15min. Plasma levels of sodium, potassium, magnesium, calcium, chloride, lactate, bicarbonate, PaCO2, pH, phosphate and albumin were recorded at 3timepoints: T0 pre-infusion; T1 at 30minutes, and T2 at 60minutes post-infusion. Mean arterial pressure and intracranial pressure were measured at T0 and T2. Results Forty-one patients received sodium lactate: 19 as an osmotically active agent and 22 as a volume expander. Metabolic alkalosis was observed: T0 vs. T1 (P=0.007); T1 vs. T2 (P=0.003). Sodium increased at the 3time points (T0 vs. T1, P<0.0001; T1 vs. T2, P=0.0001). In addition, sodium lactate decreased intracranial pressure (T0: 24.83±5.4 vs. T2: 15.06±5.8; P<0.001). Likewise, plasma lactate showed a biphasic effect, with a rapid decrease at T2 (P<0.0001), including in those with previous hyperlactatemia (P=0.002). Conclusions The infusion of sodium lactate is associated to metabolic alkalosis, hypernatremia, reduced chloremia, and a biphasic change in plasma lactate levels. Moreover, a decrease in intracranial pressure was observed in patients with acute brain injury. (AU)

Lactate Stimulates a Potential for Hypertrophy and Regeneration of Mouse Skeletal Muscle.

The effects of lactate on muscle mass and regeneration were investigated using mouse skeletal muscle tissue and cultured C2C12 cells. Male C57BL/6J mice were randomly divided into (1) control, (2) lactate (1 mol/L in distilled water, 8.9 mL/g body weight)-administered, (3) cardio toxin (CTX)-injected (CX), and (4) lactate-administered after CTX-injection (LX) groups. CTX was injected into right tibialis anterior (TA) muscle before the oral administration of sodium lactate (five days/week for two weeks) to the mice. Oral lactate administration increased the muscle weight and fiber cross-sectional area, and the population of Pax7-positive nuclei in mouse TA skeletal muscle. Oral administration of lactate also facilitated the recovery process of CTX-associated injured mouse TA muscle mass accompanied with a transient increase in the population of Pax7-positive nuclei. Mouse myoblast-derived C2C12 cells were differentiated for five days to form myotubes with or without lactate administration. C2C12 myotube formation with an increase in protein content, fiber diameter, length, and myo-nuclei was stimulated by lactate. These observations suggest that lactate may be a potential molecule to stimulate muscle hypertrophy and regeneration of mouse skeletal muscle via the activation of muscle satellite cells.

Diagnostic Utility of Sodium Lactate Infusion and CO2-35% Inhalation for Panic Disorder.

Laboratory measures have played an integral role in diagnosing pathology; however, compared to traditional medicine, psychiatric medicine has lagged behind in using such measures. A growing body of literature has begun to examine the viability and development of different laboratory measures in order to diagnose psychopathologies. The present review examines the current state of development of both sodium lactate infusion and CO2-35% inhalation as potential ancillary measures to diagnose panic disorder (PD). A previously established 3-step approach to identifying laboratory-based diagnostic tests was applied to available literature assessing the ability of both sodium lactate infusion or CO2-35% inhalation to induce panic attacks in PD patients, healthy controls, and individuals with other psychiatric conditions. Results suggest that across the literature reviewed, individuals with PD were more likely to exhibit panic attacks following administration of sodium lactate or CO2-35% compared to control participants. The majority of the studies examined only compared individuals with PD to healthy controls, suggesting that these ancillary measures are underdeveloped. In order to further determine the utility of these ancillary measures, research is needed to determine if panic attacks following administration of these chemical agents are unique to PD, or if individuals with related pathologies also respond, which may be indicative of transdiagnostic characteristics found across disorders.

The comparative effects of 3% saline and 0.5M sodium lactate on cardiac function:a randomised, crossover study in volunteers.

OBJECTIVE: To investigate the metabolic and cardiac effects of intravenous administration of two hypertonic solutions - 3% saline (SAL) and 0.5M sodium lactate (LAC). DESIGN, SETTING AND PARTICIPANTS: A randomised, doubleblind, crossover study in ten human volunteers. Intravenous bolus of either SAL or LAC at 3 mL/kg over 20 min followed by a 2 mL/kg infusion over 60 min. MAIN OUTCOME MEASURES: Acid base parameters and echocardiographic indices of cardiac function, cardiac output (CO), left ventricular ejection fraction (LVEF) and mitral annular peak systolic velocity (Sm) before and after infusion of SAL or LAC. RESULTS: Despite haemodilution, we observed an increase in sodium (139 ± 2 mmol/L to 142 ± 2 mmol/L in both groups) and respective anions, chloride (106 ± 2 mmol/L to 112 ± 3 mmol/L) and lactate (1.01 ± 0.28 mmol/L to 2.38 ± 0.38 mmol/L) with SAL and LAC, respectively. The pH (7.37 ± 0.03 to 7.45 ± 0.03; P < 0.01) and simplified strong ion difference (SID) (36.3 ± 4.6 mmol/L to 39.2 ± 3.6 mmol/L; P < 0.01) increased during the LAC infusion. The pH was unchanged, but SID decreased during SAL infusion (36.3 ± 2.5 mmol/L to 33.9 ± 3.1 mmol/L; P = 0.01). Both solutions led to an increase in preload and cardiac function, CO (4.36 ± 0.79 L/min to 4.98 ± 1.37 L/ min v 4.62 ± 1.30 L/min to 5.13 ± 1.44 L/min), LVEF (61 ± 6% to 63 ± 8% v 64 ± 6% to 68 ± 7%). The averaged Sm improved in the LAC group as compared with the SAL group (0.088 ± 0.008 to 0.096 ± 0.016 v 0.086 ± 0.012 to 0.082 ± 0.012; P = 0.032). CONCLUSIONS: The administration of SAL or LAC has opposing effects on acid base variables such as SID. Hypertonic fluid infusion lead to increased cardiac preload and performance with Sm, suggesting better left ventricular systolic function during LAC as compared with SAL. Lactated hypertonic solutions should be evaluated as resuscitation fluids.

Lactate supplementation in severe traumatic brain injured adults by primed constant infusion of sodium L-lactate.

Carbohydrate fuel augmentation following traumatic brain injury may be a viable treatment to improve recovery when cerebral oxidative metabolism of glucose is depressed. We performed a primed constant sodium L-lactate infusion in 11 moderate to severely brain injured adults. Blood was collected before and periodically during the infusion study. We quantified global cerebral uptake of glucose and lactate and other systemic metabolites associated with energy metabolism. Our hypothesis was that cerebral lactate uptake, as measured by the arteriovenous difference of lactate (AVDlac), would increase in severely injured TBI patients in the neurocritical care unit. Infusion of sodium L-lactate changed net cerebral lactate release, where the arteriovenous difference of lactate is negative, to net cerebral lactate uptake. Results from a mixed effects model of AVDlac with the fixed effects of infusion time, arterial lactate concentration, arterial glucose concentration and arteriovenous difference of glucose shows that doubling arterial lactate concentration (from .92 to 1.84 mM) results in an increase in AVDlac from -.078 mM to .090 mM. We did not detect changes in systemic glucose during the course of the infusion study and observed significant changes in alanine (30% [20 39]), glutamine (34% [24 43]), acetate (87% [60 113]), valine (40% [28 51]), and leucine (24% [16 32]) from baseline levels. Further studies are required to establish the impact of lactate supplementation on cerebral and systemic flux of lactate, on gluconeogenesis, and on the impact on cerebral energetics following injury. © 2017 Wiley Periodicals, Inc.

Plasma Intermedin Level Indicates Severity and Treatment Efficacy of Septic Shock in Sprague-Dawley (SD) Rats.

BACKGROUND The aim of this study was to investigate the value of plasma intermedin (IMD) in assessing severity and treatment efficacy of septic shock. MATERIAL AND METHODS Healthy male Sprague-Dawley (SD) rats were chosen and divided into a normal control group (n=15) and a shock model group (n=27) that received intravenous injection of lipopolysaccharide (LPS). Then, 3 specimens were taken from each group. The shock model group rats were divided into an LPS group and a treatment group with 12 rats each. The treatment group received intravenous injection of compound sodium lactate solution. Plasma IMD and IMD1-47 mRNA expressions were compared and analyzed. RESULTS Mean arterial pressure (MAP) was lower while white blood cell count and TNF-α were higher in the shock model group than in the normal control group (P<0.05). After 10 h and 20 h, the treatment group had lower plasma IMD and IMD1-47 mRNA expressions compared with the LPS group (P<0.05). Plasma IMD and IMD1-47 mRNA expressions in the LPS group after 20 h were significantly higher than after 10 h (P<0.05). IMD was positively correlated with interleukins (IL-3, IL-6, and IL-8), white blood cell count, and body temperature (all P<0.05), but were negatively correlated with systolic pressure (r=-0.8474, P=0.0040). CONCLUSIONS Plasma IMD level can effectively reflect the severity of septic shock and can be used as an important indicator of septic shock treatment effectiveness.

Calcium Prerinse before Fluoride Rinse Reduces Enamel Demineralization: An in situ Caries Study.

A calcium (Ca) prerinse before a fluoride (F) rinse has been shown to increase oral F levels. We tested the anticaries effect of this combination in a dose-response in situ caries model. In a double-blind, crossover experiment, 10 volunteers carried enamel slabs in palatal appliances for 14 days, during which they rinsed twice/day with one of four rinse combinations: (1) a placebo prerinse (150 mM sodium lactate) followed by a distilled water rinse (negative control); (2) a placebo prerinse followed by a 250 ppm F rinse; (3) a placebo prerinse followed by a 1,000 ppm F rinse, or (4) a Ca prerinse (150 mM Ca, as calcium lactate) followed by a 250 ppm F rinse. Sucrose solution was dripped onto the slabs 8×/day to simulate a high cariogenic challenge. The percent surface hardness loss (%SHL) was significantly lower in the Ca prerinse used with the 250 ppm F rinse group (%SHL = 38.0 ± 21.0) when compared with the F rinse alone (%SHL = 59.5 ± 24.1) and similar to the 1,000 ppm F rinse group (%SHL = 42.0 ± 18.3). Compared with the 250 ppm F rinse, the Ca prerinse increased biofilm fluid F only twice (nonsignificant). However, it greatly increased F in biofilm solids (∼22×). The Ca prerinse had little effect on loosely or firmly bound enamel F. The results showed an increased level of protection against demineralization by the use of a Ca prerinse, which seems to be caused by the enhancement of F concentration in the biofilm.

Dynamics of organohalide-respiring bacteria and their genes following in-situ chemical oxidation of chlorinated ethenes and biostimulation.

Application of Fenton's reagent and enhanced reductive dechlorination are currently the most common remediation strategies resulting in removal of chlorinated ethenes. In this study, the influence of such techniques on organohalide-respiring bacteria was assessed at a site contaminated by chlorinated ethenes using a wide spectrum of molecular genetic markers, including 16S rRNA gene of the organohalide-respiring bacteria Dehaloccocoides spp., Desulfitobacterium and Dehalobacter; reductive dehalogenase genes (vcrA, bvcA) responsible for dechlorination of vinyl chloride and sulphate-reducing and denitrifying bacteria. In-situ application of hydrogen peroxide to induce a Fenton-like reaction caused an instantaneous decline in all markers below detection limit. Two weeks after application, the bvcA gene and Desulfitobacterium relative abundance increased to levels significantly higher than those prior to application. No significant decrease in the concentration of a range of chlorinated ethenes was observed due to the low hydrogen peroxide dose used. A clear increase in marker levels was also observed following in-situ application of sodium lactate, which resulted in a seven-fold increase in Desulfitobacterium and a three-fold increase in Dehaloccocoides spp. after 70 days. An increase in the vcrA gene corresponded with increase in Dehaloccocoides spp. Analysis of selected markers clearly revealed a positive response of organohalide-respiring bacteria to biostimulation and unexpectedly fast recovery after the Fenton-like reaction.

Nutritional Strategies to Modulate Intracellular and Extracellular Buffering Capacity During High-Intensity Exercise.

Intramuscular acidosis is a contributing factor to fatigue during high-intensity exercise. Many nutritional strategies aiming to increase intra- and extracellular buffering capacity have been investigated. Among these, supplementation of beta-alanine (~3-6.4 g/day for 4 weeks or longer), the rate-limiting factor to the intramuscular synthesis of carnosine (i.e. an intracellular buffer), has been shown to result in positive effects on exercise performance in which acidosis is a contributing factor to fatigue. Furthermore, sodium bicarbonate, sodium citrate and sodium/calcium lactate supplementation have been employed in an attempt to increase the extracellular buffering capacity. Although all attempts have increased blood bicarbonate concentrations, evidence indicates that sodium bicarbonate (0.3 g/kg body mass) is the most effective in improving high-intensity exercise performance. The evidence supporting the ergogenic effects of sodium citrate and lactate remain weak. These nutritional strategies are not without side effects, as gastrointestinal distress is often associated with the effective doses of sodium bicarbonate, sodium citrate and calcium lactate. Similarly, paresthesia (i.e. tingling sensation of the skin) is currently the only known side effect associated with beta-alanine supplementation, and it is caused by the acute elevation in plasma beta-alanine concentration after a single dose of beta-alanine. Finally, the co-supplementation of beta-alanine and sodium bicarbonate may result in additive ergogenic gains during high-intensity exercise, although studies are required to investigate this combination in a wide range of sports.

Intensive care nurses' self-reported practice of intravenous fluid bolus therapy.

OBJECTIVE: To describe self-reported practice of fluid bolus therapy by intensive care nurses. RESEARCH METHODOLOGY: Multi-choice questionnaire of intensive care nurses conducted in July, 2014. SETTING: Major university tertiary referral centre. FINDINGS: 141 (64%) intensive care nurses responded. The majority of respondents identified 4% albumin as the commonest fluid bolus type and stated a fluid bolus was 250ml; however fluid bolus volume varied from 100ml to 1000ml. Hypotension was identified as the primary physiological trigger for a fluid bolus. In the hour following a fluid bolus for hypotension almost half of respondents expected an 'increase in mean arterial pressure of 0-10mmHg'; for oliguria, >60% expected an 'increase in urinary output of '0.5-1ml/kg/hour'; for low CVP, 50% expected 'an increase in CVP of 3-4mmHg'; and, for tachycardia, 45% expected a 'decrease in heart rate of 11-20beats/minute'. Finally, 7-10% of respondents were 'unsure' about the physiological response to a fluid bolus. CONCLUSION: Most respondents identified fluid bolus therapy to be at least 250ml of 4% albumin given as quickly as possible; however, volumes from 100 to 1000ml were also accepted. There was much uncertainty about the expected physiological response to fluid bolus therapy according to indication.

Efeito alcalinizante de soluções eletrolíticas intravenosas com concentrações elevadas de lactato de sódio infundidas em bezerros sadios / Alkalinizing effect of intravenous electrolyte solutions with high sodium lactate concentrations infused in healthy calves

Com o objetivo de investigar o potencial alcalinizante de soluções eletrolíticas com concentrações elevadas de lactato de sódio em bezerros sadios, foram idealizadas seis soluções contendo 28, 56 e 84mEq/L de lactato (L28, L56 e L84) ou de bicarbonato (B28, B56 e B84), com concentrações de sódio, de potássio e de cálcio semelhantes às da solução de Ringer com lactato (SRL). As soluções contendo bicarbonato de sódio foram utilizadas como padrão para comparação. Seis bezerros receberam, por via intravenosa, todas as seis soluções, uma a cada vez, com intervalo de quatro a cinco dias entre as infusões, em volume correspondente a 10% do peso corporal, durante cinco horas (20mL/kg/h). Amostras de sangue venoso e de urina foram coletadas antes de iniciar a infusão, na metade do volume, ao término e duas horas e meia após o término da infusão. Determinaram-se concentração de proteína plasmática total, pH sanguíneo e urinário, pCO2, HCO3 -, BE, concentração plasmática e urinária de lactato L e concentrações séricas e urinárias de Na+, K+, Cl- e creatinina. A solução L28, idêntica à SRL, provocou discreto incremento da reserva alcalina e, consequentemente, produziu efeito alcalinizante insuficiente para a correção de estados de acidose metabólica. A solução L84, além de provar-se segura, provocou o maior aumento da reserva alcalina, equivalente à B84, e, assim, produziu efeito capaz de corrigir o grau moderado de acidose metabólica.

The alkalinizing effects of electrolyte solutions with high concentration of sodium lactate were evaluated in healthy calves. Six solutions were formulated containing 28, 56 and 84mEq/L of lactate (L28, L56 and L84) or bicarbonate (B28, B56 and B84), and sodium, potassium and calcium concentrations similar to the lactated Ringer's solution (LRS). The solutions containing sodium bicarbonate were used as a standard for comparison. Six calves received all six solutions intravenously, one at a time, with an interval of four to five days between the infusions, in a volume corresponding to 10% of body weight, during five hours (20mL/kg/h). Venous blood and urine samples were taken prior to the beginning of the infusion, at a half volume, at the end and two and a half hours after the end of the infusion. Total plasma protein concentration, urinary and blood pH, blood pCO2, HCO3 - and BE, plasma and urine L lactate concentration and serum and urine Na+, K+, Cl- and creatinine concentrations were measured. The L28 solution, equal to LRS, caused a slight increase in the alkaline reserve, producing an alkalinizing effect insufficient for correction of metabolic acidosis states. The L84 solution was safe and produced the greater increase in the alkaline reserve, equivalent to B84 solution, and suitable for correcting a moderate degree of metabolic acidosis.

Sodium lactate for fluid resuscitation: the preferred solution for the coming decades?

In a recent issue of Critical Care, 0.5 M sodium lactate infusion for 24 hours was reported to increase cardiac output in patients with acute heart failure. This effect was associated with a concomitant metabolic alkalosis and a negative water balance. Growing data strongly support the role of lactate as a preferential oxidizable substrate to supply energy metabolism leading to improved organ function (heart and brain especially) in ischemic conditions. Due to its sodium/chloride imbalance, this solution prevents hyperchloremic acidosis and limits fluid overload despite the obligatory high sodium load. Sodium lactate solution therefore shows many advantages and appears a very promising means for resuscitation of critically ill patients. Further studies are needed to establish the most appropriate dose and indications for sodium lactate infusion in order to prevent the occurrence of severe hypernatremia and metabolic alkalosis.

Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomised controlled clinical trial.

INTRODUCTION: Acute heart failure (AHF) is characterized by inadequate cardiac output (CO), congestive symptoms, poor peripheral perfusion and end-organ dysfunction. Treatment often includes a combination of diuretics, oxygen, positive pressure ventilation, inotropes and vasodilators or vasopressors. Lactate is a marker of illness severity but is also an important metabolic substrate for the myocardium at rest and during stress. We tested the effects of half-molar sodium lactate infusion on cardiac performance in AHF. METHODS: We conducted a prospective, randomised, controlled, open-label, pilot clinical trial in 40 patients fulfilling two of the following three criteria for AHF: (1) left ventricular ejection fraction <40%, (2) acute pulmonary oedema or respiratory failure of predominantly cardiac origin requiring mechanical ventilation and (3) currently receiving vasopressor and/or inotropic support. Patients in the intervention group received a 3 ml/kg bolus of half-molar sodium lactate over the course of 15 minutes followed by 1 ml/kg/h continuous infusion for 24 hours. The control group received only a 3 ml/kg bolus of Hartmann's solution without continuous infusion. The primary outcome was CO assessed by transthoracic echocardiography 24 hours after randomisation. Secondary outcomes included a measure of right ventricular systolic function (tricuspid annular plane systolic excursion (TAPSE)), acid-base balance, electrolyte and organ function parameters, along with length of stay and mortality. RESULTS: The infusion of half-molar sodium lactate increased (mean ± SD) CO from 4.05 ± 1.37 L/min to 5.49 ± 1.9 L/min (P < 0.01) and TAPSE from 14.7 ± 5.5 mm to 18.3 ± 7 mm (P = 0.02). Plasma sodium and pH increased (136 ± 4 to 146 ± 6 and 7.40 ± 0.06 to 7.53 ± 0.03, respectively; both P < 0.01), but potassium, chloride and phosphate levels decreased. There were no significant differences in the need for vasoactive therapy, respiratory support, renal or liver function tests, duration of ICU and hospital stay or 28- and 90-day mortality. CONCLUSIONS: Infusion of half-molar sodium lactate improved cardiac performance and led to metabolic alkalosis in AHF patients without any detrimental effects on organ function. TRIAL REGISTRATION: Clinicaltrials.gov NCT01981655. Registered 13 August 2013.

Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity.

BACKGROUND & AIMS: The NACHT, LRR, and pyrin domain-containing protein 3 (NLRP3) inflammasome induces inflammation in response to organ injury, but little is known about its regulation. Toll-like receptors (TLRs) provide the first signal required for activation of the inflammasome and stimulate aerobic glycolysis to generate lactate. We examined whether lactate and the lactate receptor, Gi-protein-coupled receptor 81 (GPR81), regulate TLR induction of signal 1 and limit inflammasome activation and organ injury. METHODS: Primary mouse macrophages and human monocytes were incubated with TLR4 agonists and lactate and assayed for levels of pro-interleukin (IL)1ß, NLRP3, and caspase-1 (CASP1); release of IL1ß; and activation of nuclear factor-κB (NF-κB) and caspase-1. Small interfering RNAs were used to reduce levels of GPR81 and arrestin ß-2 (ARRB2), and an NF-κB luciferase reporter transgene was transfected in RAW 264.7 cells. Cell lysates were analyzed by immunoprecipitation with an antibody against GPR81. Acute hepatitis was induced in C56BL/6N mice by administration of lipopolysaccharide and D-galactosamine. Acute pancreatitis was induced by administration of lipopolysaccharide and cerulein. Some mice were given intraperitoneal injections of sodium lactate or small interfering RNA against Gpr81. Activation of NF-κB in tissue macrophages was assessed in mice that expressed a reporter transgene. RESULTS: In macrophages and monocytes, increasing concentrations of lactate reduced TLR4-mediated induction of Il1B, Nlrp3, and Casp1; activation of NF-κB; release of IL1ß; and cleavage of CASP1. GPR81 and ARRB2 physically interacted and were required for these effects. The administration of lactate reduced inflammation and organ injury in mice with immune hepatitis; this reduction required Gpr81 dependence in vivo. Lactate also prevented activation of NF-κB in macrophages of mice, and, when given after injury, reduced the severity of acute pancreatitis and acute liver injury. CONCLUSIONS: Lactate negatively regulates TLR induction of the NLRP3 inflammasome and production of IL1ß, via ARRB2 and GPR81. Lactate could be a promising immunomodulatory therapy for patients with acute organ injury.

Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain.

PURPOSE: Experimental evidence suggests that lactate is neuroprotective after acute brain injury; however, data in humans are lacking. We examined whether exogenous lactate supplementation improves cerebral energy metabolism in humans with traumatic brain injury (TBI). METHODS: We prospectively studied 15 consecutive patients with severe TBI monitored with cerebral microdialysis (CMD), brain tissue PO2 (PbtO2), and intracranial pressure (ICP). Intervention consisted of a 3-h intravenous infusion of hypertonic sodium lactate (aiming to increase systemic lactate to ca. 5 mmol/L), administered in the early phase following TBI. We examined the effect of sodium lactate on neurochemistry (CMD lactate, pyruvate, glucose, and glutamate), PbtO2, and ICP. RESULTS: Treatment was started on average 33 ± 16 h after TBI. A mixed-effects multilevel regression model revealed that sodium lactate therapy was associated with a significant increase in CMD concentrations of lactate [coefficient 0.47 mmol/L, 95% confidence interval (CI) 0.31-0.63 mmol/L], pyruvate [13.1 (8.78-17.4) µmol/L], and glucose [0.1 (0.04-0.16) mmol/L; all p < 0.01]. A concomitant reduction of CMD glutamate [-0.95 (-1.94 to 0.06) mmol/L, p = 0.06] and ICP [-0.86 (-1.47 to -0.24) mmHg, p < 0.01] was also observed. CONCLUSIONS: Exogenous supplemental lactate can be utilized aerobically as a preferential energy substrate by the injured human brain, with sparing of cerebral glucose. Increased availability of cerebral extracellular pyruvate and glucose, coupled with a reduction of brain glutamate and ICP, suggests that hypertonic lactate therapy has beneficial cerebral metabolic and hemodynamic effects after TBI.

Half-molar sodium lactate infusion to prevent intracranial hypertensive episodes in severe traumatic brain injured patients: a randomized controlled trial.

PURPOSE: Preventive treatments of traumatic intracranial hypertension are not yet established. We aimed to compare the efficiency of half-molar sodium lactate (SL) versus saline serum solutions in preventing episodes of raised intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI). METHODS: This was a double-blind, randomized controlled trial including 60 patients with severe TBI requiring ICP monitoring. Patients were randomly allocated to receive a 48-h continuous infusion at 0.5 ml/kg/h of either SL (SL group) or isotonic saline solution (control group) within the first 12 h post-trauma. Serial measurements of ICP, as well as fluid, sodium, and chloride balance were performed over the 48-h study period. The primary outcome was the number of raised ICP (≥20 mmHg) requiring a specific treatment. RESULTS: Raised ICP episodes were reduced in the SL group as compared to the control group within the 48-h study period: 23 versus 53 episodes, respectively (p < 0.05). The proportion of patients presenting raised ICP episodes was smaller in the SL group than in the saline group: 11 (36 %) versus 20 patients (66 %) (p < 0.05). Cumulative 48-h fluid and chloride balances were reduced in the SL group compared to the control group (both p < 0.01). CONCLUSION: A 48-h infusion of SL decreased the occurrence of raised ICP episodes in patients with severe TBI, while reducing fluid and chloride balances. These findings suggest that SL solution could be considered as an alternative treatment to prevent raised ICP following severe TBI.

Exogenous L-lactate clearance in adult horses.

OBJECTIVE: To determine endogenous production of L-lactate and the clearance of exogenous sodium L-lactate (ExLC) in healthy adult horses. DESIGN: A sodium L-lactate solution (1 mmol/kg body weight qs to 500 mL final volume in 0.9% NaCl) was adminstered IV over 15 minutes. Blood samples for L-lactate concentration [LAC] measurement were collected immediately prior to infusion, at 5, 10, and 15 minutes during infusion and at 1 minute intervals for 15 minutes, at 30, 45, 60, 120, and 180 minutes postinfusion. Disposition modeling and pharmacokinetic analysis was performed using proprietary software. SETTING: University Teaching Hospital. ANIMALS: Six clinically healthy adult horses. MEASUREMENTS AND MAIN RESULTS: Median (range) baseline [LAC] was 0.43 (0.20-0.72) mmol/L for samples obtained every 3 hours over the 24 hours prior to ExLC and demonstrated variability primarily associated with horse. Median [LAC] immediately prior to ExLC was 0.43 (0.35-0.52) mmol/L. A 2-compartment model was used to specify the pharmacokinetic parameters. Median (range) ExLC was 1.05 (0.073-1.75) L·h(-1) ·kg(-1) and t(1/2) ß was 29.54 (20.8-38.6) min. Median lactate production based on basal [LAC] immediately prior to ExLC was was 0.49 (0.31-0.93) mmol·h(-1) ·kg(-1) . CONCLUSIONS: ExLC in healthy adult horses is greater than that of hyperlactemic human patients but similar to normolactemic-sick human patients examined using the same model, supporting development of species, and disease specific ExLC parameters.

Safety and efficacy of two potassium cocktail formulations for treatment of neonatal hyperkalemia.

BACKGROUND: A consensus has not been established for the standard treatment of hyperkalemia in the neonatal population. Most treatment regimens include a dextrose/insulin infusion. Additional agents used include calcium, sodium bicarbonate, polystyrene sulfonate, and albuterol. This study assessed the safety and efficacy of a potassium cocktail (k-cocktail) containing dextrose, insulin, calcium gluconate, and sodium lactate for treatment of neonatal hyperkalemia. OBJECTIVE: To determine whether modifications to a potassium cocktail formulation, based on a prior quality improvement project, resulted in a decrease in the incidence of hyperglycemia and acidosis associated with its use, and to evaluate the effectiveness of the k-cocktail in lowering serum potassium levels and the incidence of adverse effects. METHODS: We conducted a retrospective cohort study of neonates with hyper-kalemia who received 2 k-cocktail formulations (group 1 [n = 13], original formulation, dextrose:insulin 5:1; group 2 [n = 26], modified formulation, dextrose: insulin 3.3:1). Group 2 subjects were matched 2:1 by gestational age and birth weight with those in group 1. Variables related to safety and effectiveness of therapy were assessed by medical record review. The following tests were used to assess group differences: χ(2), Fisher exact, 2-tailed t-tests, and mixed linear models. RESULTS: The incidence of hyperglycemia during the modified k-cocktail infusion in group 2 decreased from 76.9% to 21.7% (p = 0.001). Serum blood glucose concentrations increased during the infusion, on average, for group 1 infants and were unchanged during the infusion for those in group 2. The incidence of acidosis during the infusion was similar between groups (group 1 [76.9%] vs group 2 [68.2%]; p = 0.58). No significant adverse events were observed. Serum potassium concentrations decreased similarly in both groups. CONCLUSIONS: An intravenous infusion including a dextrose:insulin ratio of 3.3:1, compared with a higher ratio, results in less hyperglycemia and appears to be as effective in decreasing potassium concentrations in newborns.