Elevated Lactate Concentrations Research Articles

Lactate imaging with Hadamard‐encoded slice‐selective multiple quantum coherence chemical‐shift imaging

The ability to generate in vivo maps of lactate may have significant diagnostic utility in staging and treatment planning of a wide variety of cancers. The double selective multiple quantum filter technique (SelMQC) has been shown to be effective for nonlocalized detection of lactate with little or no interference from other signals. Here the SelMQC technique has been combined with longitudinal Hadamard slice selection and chemical shift imaging (CSI) to yield slice-selective images of lactate. The technique is shown to be effective in phantoms and in WSU-DLCL2 xenografts implanted in flanks of SCID mice. Tumors exhibited an annulus of elevated lactate concentration surrounding a necrotic tumor core.

Lactate modulates gene expression in human mesenchymal stem cells

Surgical wounds are characterised by elevated tissue lactate concentrations. This accumulated lactate is capable of stimulating collagen synthesis and new vessel growth as well. Recently, it has been shown in vivo that lactate is also able to favour homing of stem cells. The aim of this investigation was to test the hypothesis that lactate has an impact on gene expression of mesenchymal stem cells (MSC). MSC were isolated from human bone marrow using the density gradient technique and incubated with alpha-methoxyethoxymethyl containing 10% fetal calf serum at 37 degrees C under 95% air and 5% CO(2). Cultured MSC were characterised by in vitro differentiation assays and fluorescence-activated cell sorting (FACS) analysis. Characterised MSC were treated with 15 mM lactate for different time periods (1, 6 and 24 h and 3 and 7 days). Gene expression analysis was performed using a custom-designed oligonucleotide microarray. A significant alteration of gene expression was defined as a two-fold stimulation or inhibition. The phenotype of MSC was investigated by FACS analysis of specific surface epitope patterns. Gene expression analysis shows 63 up- and 51 down-regulated genes after 1 h of treatment, 45 up- and 47 down-regulated genes after 6 h of treatment, 57 up- and 72 down-regulated genes after 24 h of treatment, 103 up- and 28 down-regulated genes after 3 days of treatment and 50 up- and 101 down-regulated genes after 7 days of treatment with lactate. The majority of the modulated genes are related to the expression of cytokines, transcription factors and cell-cycle- or cellular-matrix-associated proteins. In particular, lactate up-regulates the expression of interleukin-6 (3 days, 4.11-fold), of heat shock protein 70 (3 days, 2.36-fold) and of hypoxia-inducible factor-1alpha (3 days, 2.09-fold). A down-regulating effect of lactate is observed for superoxide dismutase 2 (1 h, 0.5-fold; 24 h, 0.4-fold; 7 days, 0.32-fold) and BCL2-associated X protein (24 h, 0.42-fold; 7 days, 0.4-fold). Expression of cell surface antigens clusters of differentiation 29, 44, 59, 73, 90, 105, 106 and 146 does not change over the time period of lactate treatment. Lactate modulates expression of genes involved in wound healing. However, lactate does not profoundly change the phenotype of MSC. In addition to providing new insights into the wound healing physiology, these data could also be the rationale for new treatment strategies for chronic non-healing wounds.

Factors Affecting Catch‐and‐Release Mortality of Bluefish

AbstractRecreational harvests of bluefish Pomatomus saltatrix along the U.S. coast from Maine to Florida exceed commercial harvests, and in recent years about 60–70% of angler‐captured fish are released alive. The proportion of fish that survive hooking, handling, and release back to the ocean is unknown; however, if catch‐and‐release mortality is high, it may represent a significant component of the overall bluefish mortality rate. We estimated long‐term (21‐d) hooking mortality rates of field‐captured bluefish and investigated the effects of various factors on postrelease mortality. Age, length, and the occurrence of bleeding were significant factors associated with catch‐and‐release mortality, which we estimated to be 38.8%. About 65% of the mortality was initial mortality, and the remainder was delayed mortality. We also performed a laboratory study to examine the physiological response of bluefish to two independent processes (hooking and release versus transfer in coolers to the laboratory) relevant to the field study. Laboratory‐held fish that were hooked and released exhibited elevated concentrations of potassium in their blood, suggesting that they experienced either an osmotic imbalance or cellular damage. Laboratory‐held fish exposed to the transfer treatment only exhibited osmotic imbalance (elevated plasma sodium concentration) and evidence of anaerobic metabolism (elevated plasma lactate concentration). Our findings indicate that bluefish age and size contribute to variable levels of metabolic stress and that delayed postrelease mortality is considerable.

Pyruvate Dehydrogenase Complex Deficiency Caused by Ubiquitination and Proteasome-mediated Degradation of the E1β Subunit

Congenital deficiencies of the human pyruvate dehydrogenase (PDH) complex are considered to be due to loss of function mutations in one of the component enzymes. Here we describe a case of PDH deficiency associated with the PDH E1beta subunit (PDHB) gene. The clinical phenotype of the patient was consistent with reported cases of PDH deficiency. Cultured skin fibroblasts demonstrated a 55% reduction in PDH activity and markedly decreased immunoreactivity for PDHB protein, compared with healthy controls. Surprisingly, nucleotide sequence analyses of cDNAs corresponding to the patient PDH E1alpha (PDHA1) and PDHB genes revealed no pathological mutations. Moreover, the relative expression level of PDHB mRNA and the rates of transcription and translation of the PDHB gene were normal. However, PDC activity could be restored in cells from this patient following treatment with MG132, a specific proteasome inhibitor, and normal levels of E1beta could be detected in MG132-treated cells. Similar results were obtained following treatment with Tyr-phostin 23 (Tyr23), a specific inhibitor of epidermal growth factor receptor-protein-tyrosine kinase (EGFR-PTK), which also restored E1beta protein levels to those in cells from healthy subjects or from patients with PDHA1 deficiency. The index patient's cells contained a high basal level of EGFR-PTK activity that correlated with the high level of ubiquitination of cellular proteins, although the total EGFR protein levels were similar to those in cells from Elalpha-deficient subjects and healthy subjects. These data indicate that PDH deficiency in our patient involves a post-translational modification in which EGFR-PTK-mediated tyrosine phosphorylation of the E1beta protein leads to enhanced ubiquitination followed by proteasome-mediated degradation. They also provide a novel mechanism accounting for congenital deficiency of the PDH complex and perhaps other inborn errors of metabolism.

Emergency feasibility in medical intensive care unit of extracorporeal life support for refractory cardiac arrest

To report the feasibility, complications, and outcomes of emergency extracorporeal life support (ECLS) in refractory cardiac arrests in medical intensive care unit (ICU). Prospective cohort study in the medical ICU in a university hospital in collaboration with the cardiosurgical team of a neighboring hospital. Seventeen patients (poisonings: 12/17) admitted over a 2-year period for cardiac arrest unresponsive to cardiopulmonary resuscitation (CPR) and advanced cardiac life support, without return of spontaneous circulation. ECLS femoral implantation under continuous cardiac massage, using a centrifugal pump connected to a hollow-fiber membrane oxygenator. Stable ECLS was achieved in 14 of 17 patients. Early complications included massive transfusions (n=8) and the need for surgical revision at the cannulation site for bleeding (n=1). Four patients (24%) survived at medical ICU discharge. Deaths resulted from multiorgan failure (n=8), thoracic bleeding(n=2), severe sepsis (n=2), and brain death (n=1). Massive hemorrhagic pulmonary edema during CPR (n=5) and major capillary leak syndrome (n=6) were observed. Three cardiotoxic-poisoned patients (18%, CPR duration: 30, 100, and 180 min) were alive at 1-year follow-up without sequelae. Two of these patients survived despite elevated plasma lactate concentrations before cannulation (39.0 and 20.0 mmol/l). ECLS was associated with a significantly lower ICU mortality rate than that expected from the Simplified Acute Physiology Score II (91.9%) and lower than the maximum Sequential Organ Failure Assessment score (>90%). Emergency ECLS is feasible in medical ICU and should be considered as a resuscitative tool for selected patients suffering from refractory cardiac arrest.

Perinatal palliative care or termination of pregnancy after prenatal diagnosis of lethal fetal abnormality

Moderate to severe encephalopathy developed in 28 (33%) and 10 (11.9%) infants, respectively; all with severe encephalopathy died. First postnatal blood lactate concentrations, measured at a median (IQR) age of 65 min (38–119 min), ranged from 0.5 to 42.7 mmol/l. All infants with first lactate of <12 mmol/l survived but 24% of those with values above this died. Median (IQR) first postnatal blood lactate concentration was significantly higher among infants with moderate to severe encephalopathy than among those with no or mild encephalopathy [19 (14.6–22) vs. 8.4 (5.22–12.5); p<0.0001]. Blood lactate concentration showed similar discriminating ability for prediction of moderate to severe encephalopathy as the first postnatal pH or base excess [area under ROC curve – 0.88 (S.E.=0.04), 0.78 (S.E.=0.06) and 0.82 (S.E.=0.06), respectively}. The sensitivity, specificity, positive and negative predictive values of first postnatal blood lactate concentration of ≥12 mmol/l for moderate to severe encephalopathy were 92%, 67%, 58% and 95%, respectively, the corresponding values for a composite predictor (5-min Apgar score≤5, or pH<7.0, or base excess≤−16 mmol/l) being 93%, 39%, 43% and 92%, respectively. Lactate concentration of ≥12 mmol/l correctly classified 75% of infants compared to 57% when the composite predictor was present. Conclusions: Elevated blood lactate concentration during the first 3 h after birth is a significant predictor of moderate to severe encephalopathy, similar to that reported by Shah et al. [1]. The relationship between early hyperlactatemia and long-term neurodevelopmental outcome remains to be determined. Reference [1] Shah S, et al. J Perinatol 2004;24:16–20.

Effects of tributyltin on the energy metabolism of pen shell ( Atrina pectinata japonica)

We examined the effects of tributyltin (TBT) on aerobic and anaerobic energy metabolism of pen shell ( Atrina pectinata japonica). We exposed pen shells to TBT at nominal concentrations of 0 (control) and 1.0 μg/l for 72 h under aerobic condition. At the end of the exposure, half of the pen shells in each treatment were wrapped in plastic wrap to simulate exposure to hypoxia and held at 25 °C for another 12 h. The concentrations of the products of energy metabolism, namely lactate, pyruvate, fumarate and succinate, in adductor muscle were measured. The exposure to TBT under aerobic condition significantly elevated lactate, pyruvate and fumarate concentrations ( p < 0.001). After subsequent exposure to anaerobic condition, the mean concentration of succinate in the TBT treatment group was 64% of that in the control group, but there were no significant differences. Our results suggest that the energy metabolism of pen shell is disrupted by exposure to TBT.

Fluid resuscitation with hemoglobin-vesicle solution does not increase hypoxia or inflammatory responses in moderate hemorrhagic shock

The aim of the present study was to compare the hypoxic and inflammatory effects of transfusing hemoglobin-vesicles (HbV) or lactated Ringer's (LR) solution on several organs in a hemorrhagic shock model. Hemorrhagic shock was induced in 48 anesthetized rats by withdrawing 28 mL/kg blood. The animals were resuscitated by replacing the blood with an equal volume of HbV solution or three times the volume of LR solution. The heart, lung, liver, kidney and spleen were extracted at different time points following resuscitation, and mRNA expression levels of hypoxia-induced factor 1-alpha (HIF-1alpha) and tumor necrosis factor-alpha (TNF-alpha) were determined. Blood lactate concentrations in the HbV group rapidly returned to baseline levels, whereas elevated lactate concentrations in the LR group were prolonged. There were no significant differences between the two resuscitation groups in terms of HIF-1alpha and TNF-alpha expression in the organs examined. HIF-1alpha and TNF-alpha expression in the lungs was significantly greater than in other organs. Our results suggest that resuscitation from hemorrhagic shock with HbV did not increase hypoxic or inflammatory effects in major organs, compared with resuscitation using LR solution, despite prolonged elevation of blood lactate.

Fecal D- and L- Lactate, Succinate, and Volatile Fatty Acid Levels in Young Dairy Calves

For evaluation of physiologically significant organic anions in the colonic environment, 87 samples of normal feces were collected from the rectum of 15 calves less than 60 days old. The calves were fed milk replacer with free access to starter diet and hay. After fecal extraction with water, pH, D- and L-lactate, succinate, and volatile fatty acid (VFA) concentrations were determined. There was wide variation in fecal pH (4.3 to 7.7). Higher lactate concentrations were observed in feces samples with lower pH, and most of these samples were collected during the first 4 weeks of life. Elevated lactate concentrations included both the D- and L-isomers, and the D-isomer comprised approximately 30-50% of total lactate. Elevated succinate concentrations were observed in only 8 fecal samples, while other samples had lower or trace amounts of succinate. Elevated fecal succinate showed no relationship with fecal pH or VFA concentrations. Fecal VFA concentrations were lower in samples collected in the early postnatal stage, but fecal VFA concentrations were not necessarily related to age. We confirmed that fecal D- and L-lactate concentrations increased with a concomitant decrease of VFA in the acidic lumen of the colon, although acidic feces were not necessarily accompanied by elevated concentrations of lactate. In contrast, succinate production was not related to fecal pH or VFA concentrations.

Fatal lactic acidosis due to leukemic transformation in a patient with non-Hodgkin’s lymphoma: Case report

Lactic acidosis (LA) associated with hematologic malignancies is uncommon, life-threatening, and generally occurs in adults. Its pathogenesis is poorly understood. This is a case report of LA due to leukemic transformation that occurred in a patient with non-Hodgkin's lymphoma (NHL). A 24-year-old man with NHL was admitted to the hospital with dyspnea. Venous blood gas analysis revealed metabolic acidosis (pH 7.05; HCO3 6 mEq/L; BE 22 mmol/L; anion gap 28 mEq/L); the patient had an elevated plasma lactate concentration (12 mmol/L) and low glucose concentration (38 mg/dL). There was no reason other than leukemia-such as infection, circulatory failure, or drug use-for the development of severe LA. This case report shows that in patients with NHL, leukemic transformation may give rise to LA.

200 Neonatal Necrotising Enterocolitis: Results of a Retrospective Study on 128 Patients Over 25 Years

Introduction: Necrotising enterocolitis (NEC) is the most common neonatal surgical emergency with a high mortality. However frequency is low and even in perinatal centers NEC is observed rarely. Thus, retrospective studies are substantial to analyse large patient cohorts.Material and methods: Over a 25 year period (1978–2003) data were available from 128 patients and entered into a database.Results: Main results were: 1 Low birth weight (BW) and gestational age (GA), severity of NEC, elevated lactate concentration and the need for intraoperative erythrocyte transfusion had influence on survival. 2 Manifestation of NEC was significantly earlier in children < 1000g birth weight (BW) than in children > 1500g BW (P<0.05). 3 Infants < 1500g BW required more postoperative medication and treatment than infants > 1500g. 4 Changes in hemoglobin concentration, CRP and leukocyte or thrombocyte count were not of diagnostic or prognostic value in NEC. 5 Gestational age (GA) (p<0.005) and BW (p=0.026) were significantly lower in infants with small bowel involvement than in infants with large bowel affections. 6 Infants with only mucosal (P=0.02) or mucosal plus submucosal involvement (P<0.001) had lower GA and BW than infants with transmural necrosis. BW and GA had more impact on prognosis than histological findings as survival was higher in infants with elevated BW and GA despite an increased rate of transmural necrosis.

Existencia de hipoperfusión oculta sistémica en el traumatismo craneoencefálico. Estudio preliminar

To determine the correlation between blood lactic acid levels in the first 48 hours and outcome, in hemodynamically stable patients, with moderate or severe head injury (HI), and to investigate the risk factors associated with abnormal lactate levels. A prospective observational study, in 210 adults patients with moderate or severe head injury. When the patients were hemodynamically stable, blood lactate concentrations were measured once on admission, twice daily during the first 2 days and once daily until lactate levels were normalized. The whole group 210 patients were divided into 2 groups. Group 1: (LA < 2.2 mmol/L) patients without occult hypoperfussion (OH), and group 2: (LA >or= 2.2 mmol/L) patients with OH. One hundred and fifteen patients (57.76%) were categorized as group 1, and 95 patients (45.24%) as group 2. In the univariate analysis of risk factors for blood lactate >or=2.2 mmol/L the following variables showed statistical significance: severity of the head injury measured by several scales [Glasgow Coma Scale (GCS), Injury Severity Score (ISS), Revised Trauma Score (RTS) and Acute Physiology and Chronic Health Evaluation (APACHE) II], arterial hypotension, hypoxemia, anaemia, hyperglucemia, hypothermia, a greater incidence of norepinephrine infusion, and the higher percentage of type II lesions in the head computerized tomography at admission showed in the group 1 (53.91% vs. 38.94%) (p<0.03). In the multiple logistic regression analysis only two variables were risk independently associated with elevated blood lactate concentration: APACHE II in the first 24 hours: OR 1.12 (95% IC 1.06--1.196; p<0.0001) and the first 48-hours total fluid infusion volumes: OR 1.09 (95% IC 1.021,16; p < 0.0001). The infection rate (63.2% vs 47.8%, p=0.026), and length of ICU stay [mediana (percentil 25--75)] [13.29 (7.11--21.22) days vs. 8.78 (4.40--16.72) days; p<0.018] were significantly higher in patients with blood lactate >or=2.2 mmol/L (group 2). Although, the percentage of intracranial hypertension and mortality was higher in the group 2, there was no significant difference. In the multivariate analysis, the increase of blood lactate concentration, was not independently associated as a risk factor with studied complications. The presence of OH in patients with moderate or severe head injury, with postres uscitation arterial pressure, according to present recommendations, is associated with a more severe head injury, showed by APACHE II and the total fluid infusion volumes in the first 48 hours. OH in head injury increases the infection rate and length of ICU stay.

Mode of locomotion places selective pressures on Antarctic and temperate labriform swimming fish

The physiological responses to exercise and stress of the Antarctic labriform swimmer Pagothenia borchgrevinki were compared to the temperate labriform swimmers Notolabrus celidotus and Notolabrus fucicola. Basic swimming characteristics were very similar amongst the three species with P. borchgrevinki showing a reduced capacity for exercise. P. borchgrevinki showed large increases in haematocrit (Hct) following exercise that were not seen in the temperate species. Lactate dehydrogenase (LDH) activities were high in the white myotomal muscle from the Antarctic fish, with a distinct indication of metabolic cold adaptation in this enzyme. Nevertheless, although the temperate fish showed elevated muscle lactate concentrations following either exercise or electrical stimulation the Antarctic fish did not. The data suggest that poor anaerobic performance of white muscle is associated with the labriform mode of locomotion.

Mice Lacking α-Synuclein have an Attenuated Loss of Striatal Dopamine Following Prolonged Chronic MPTP Administration

The functional role of α-synuclein in the pathogenesis of Parkinson’s disease (PD) is not fully understood. Systemic exposure of α-synuclein-deficient mice to neurotoxins provides a direct approach to evaluate how α-synuclein may mediate cell death in a common murine model of PD. To this end, wild-type and homozygous α-synuclein knock-out mice were treated with sub-chronic and prolonged, chronic exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the sub-chronic model, wild-type and α-synuclein knock-out mice were treated for five consecutive days with MPTP (1–25 mg/kg, s.c.) or vehicle, and sacrificed 3 days following the last injection. The prolonged, chronic model consisted of two injections of MPTP (1–20 mg/kg, s.c.) per week for 5 weeks, with co-administration of probenecid (250 mg/kg, i.p.), and animals were sacrificed 3 weeks following the last injection. Sub-chronic administration of MPTP caused a dramatic, dose-dependent decrease in striatal dopamine (DA) concentrations, while an attenuated response was observed in α-synuclein knock-out mice. Similarly, prolonged, chronic administration of MPTP produced a dose-dependent decrease in striatal DA concentrations, and a corresponding loss of striatal vesicular monoamine transporter (VMAT-2) protein in wild-type mice. However, mice lacking α-synuclein had an attenuated loss of striatal DA concentrations, while no loss of striatal VMAT-2 protein was observed. Both sub-chronic and prolonged, chronic administration of MPTP caused an increase in the 3,4-dihydroxyphenylacetic acid (DOPAC) to DA ratio in wild-type mice, but not in mice lacking α-synuclein. Despite attenuated toxicity, elevated lactate concentrations were observed in α-synuclein knock-out mice following prolonged, chronic MPTP administration. The results of this study provide evidence that α-synuclein null mice have an attenuated response to the toxic effects of MPTP exposure, even over prolonged periods of time and that the biochemical sequela of a protracted insult to nigrostriatal DA neurons are distinct between mice with and without α-synuclein expression.

Maternal growth hormone treatment from day 35 to 80 of gestation alters nutrient partitioning in favor of uteroplacental growth in the overnourished adolescent sheep.

Overnourishing the pregnant adolescent ewe promotes maternal tissue synthesis at the expense of placental growth and leads to a major reduction in lamb birth weight at term. Growth hormone (GH) secretion is attenuated in these overnourished dams and the maternal somatotrophic axis may play a key role in coordinating nutrient usage in the pregnant adolescent. Thus we investigated whether increasing maternal GH during the period of rapid placental proliferation alters nutrient partitioning between the maternal, placental, and fetal tissues as assessed at Day 81 of gestation. Adolescent recipient ewes were implanted with singleton embryos, derived from superovulated dams and a single sire on Day 4 postestrus. Thereafter, the ewes were offered either a high (H) or moderate intake (M) of the same complete diet. From Day 35 to 80 of gestation, ewes were either injected twice daily (s.c. at 0800 and 1800 h) with recombinant bovine GH (bGH, 0.14 mg/kg live weight/day) or remained untreated (n = 8 ewes per group). Maternal concentrations of GH, insulin, insulin-like growth factor (IGF-1), glucose, and non-esterified fatty acids (NEFAs) were higher, and leptin secretion lower, in bGH-treated dams from both nutritional groups. Maternal body weight gain was higher in H versus M groups and was independent of bGH treatment. Treatment with bGH reduced relative perirenal and carcass fat deposition and increased carcass protein content in both H and M dams. Uteroplacental mass (uterus + placentomes + fetal membranes) averaged 1099, 1069, 1112, and 1754 g in M, H, M+GH, and H+GH groups. This significant increase in uteroplacental development in the H+GH group was associated with higher fetal kidney and liver weights and elevated fetal insulin, glucose, and lactate concentrations. Treatment with bGH also induced polyhydramnios in the H group. The transplacental glucose gradient was increased twofold in the H+GH group but placental GLUT- 1 and GLUT-3 expression was unaffected. In conclusion, administration of GH during the period of rapid placental proliferation alters endocrine status and thus nutrient partitioning in the overnourished adolescent dam in favor of uteroplacental and fetal growth. It remains to be established whether these effects are due wholly to alterations in maternal metabolism or if they also reflect an effect of bGH and/or the IGF system at the level of the uteroplacenta.

Late onset of stroke-like episode associated with a 3256C→T point mutation of mitochondrial DNA

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) are usually associated with the common 3243A→G mutation of mtDNA. Onset of stroke-like episodes usually occurs before age 30. We report a patient with late onset MELAS harboring a rare 3256C→T mutation in the tRNA Leu(UUR) gene of mtDNA. The patient presented with a stroke-like episode at age 36. MRI showed a stroke-like lesion in the right parietooccipital brain region. Proton MR spectroscopy showed elevated lactate concentrations in the lesion (8.4 mmol/l), and in the mid-occipital region (2.3–3.2 mmol/l) that appeared normal on MRI. Further tests revealed evidence of a severe oxidative defect of muscle metabolism as well.

Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients.

To evaluate the prognostic value of lactate clearance and lactate production in severely ill septic patients with normal or mildly elevated blood lactate concentration. DESIGN Prospective, observational study. Nineteen-bed mixed medicosurgical intensive care unit. Fifty-six patients with severe sepsis and blood lactate concentration <3 mmol/L. Lactate metabolism was evaluated in all patients. Lactate clearance was measured by modeling the change in arterial blood lactate over time induced by an infusion of 1 mmol/kg sodium lactate for 15 mins. Lactate production was calculated as the product of lactate clearance times the blood lactate concentration before the infusion. Outcome was taken to be mortality at 28 days after the beginning of the septic episode. A logistic regression model taking into account different risk factors was constructed. Among the 56 patients, 17 (30.3%) died before the 28th day. Basal blood lactate concentration was not different between survivors and nonsurvivors, whereas lactate clearance and production were higher in survivors (0.86 +/- 0.32 vs. 0.58 +/- 0.18 L/hr/kg, p < .005, and 1.19 +/- 0.63 vs. 0.89 +/- 0.24 mmol/hr/kg, p = .055, respectively). An increase in blood lactate 45 mins after the end of the lactate infusion (Deltalact-T60) > or = 0.6 mmol/L was predictive of 28-day mortality with 53% sensitivity and 90% specificity. Multivariate analysis showed that only three factors were independently and significantly correlated with 28-day mortality: presence of more than two organ failures (odds ratio, 27; p = .04), age >70 yrs (odds ratio, 5.7; p = .032), and Deltalact-T60 > or =0.6 mmol/L (odds ratio, 14.2; p = .042). Low lactate clearance in severely ill septic patients with normal or mildly elevated blood lactate is predictive of poor outcome independently of other known risk factors such as age and number of organ failures.

Lactate metabolism in resting and contracting canine skeletal muscle with elevated lactate concentration.

This study was undertaken to quantitatively account for the metabolic disposal of lactate in skeletal muscle exposed to an elevated lactate concentration during rest and mild-intensity contractions. The gastrocnemius plantaris muscle group (GP) was isolated in situ in seven anesthetized dogs. In two experiments, the muscles were perfused with an artificial perfusate with a blood lactate concentration of ~9 mM while normal blood gas/pH status was maintained with [U-(14)C]lactate included to follow lactate metabolism. Lactate uptake and metabolic disposal were measured during two consecutive 40-min periods, during which the muscles rested or contracted at 1.25 Hz. Oxygen consumption averaged 10.1 +/- 2.0 micromol. 100 g(-1). min(-1) (2.26 +/- 0.45 ml. kg(-1). min(-1)) at rest and 143.3 +/- 16.2 micromol. 100 g(-1). min(-1) (32.1 +/- 3.63 ml. kg(-1). min(-1)) during contractions. Lactate uptake was positive during both conditions, increasing from 10.5 micromol. 100 g(-1). min(-1) at rest to 25.0 micromol. 100 g(-1). min(-1) during contractions. Oxidation and glycogen synthesis represented minor pathways for lactate disposal during rest at only 6 and 15%, respectively, of the [(14)C]lactate removed by the muscle. The majority of the [(14)C]lactate removed by the muscle at rest was recovered in the muscle extracts, suggesting that quiescent muscle serves as a site of passive storage for lactate carbon during high-lactate conditions. During contractions, oxidation was the dominant means for lactate disposal at >80% of the [(14)C]lactate removed by the muscle. These results suggest that oxidation is a limited means for lactate disposal in resting canine GP exposed to elevated lactate concentrations due to the muscle's low resting metabolic rate.

Intravenous L-lactate application in minipigs partially protects acetylcholinesteratic but not butyrylcholinesteratic activity in plasma from inhibition by paraoxon.

Intoxications with organophosphorous compounds such as paraoxon, an inhibitor of serine hydrolases, mainly butyrylcholinesterase and acetylcholinesterase, are frequent. Oximes are the only enzyme reactivators clinically available. In vitro studies have shown that L(+)-lactate reduces the inhibition of acetylcholinesteratic (AChEA) and butyrylcholinesteratic activity of plasma (BChEA) by paraoxon. The purpose of this in vivo study was to determine whether intravenous L(+)-lactate application under normoxic/normocapnic/normohydrogenemic conditions is able to protect AChEA and BChEA from paraoxon inhibition. University research institute. Eighteen female minipigs. Animals were anesthetized, intubated, and mechanically ventilated. Every animal received 1 mg of paraoxon per kilogram of body weight in 50 mL of saline over 50 mins. In addition to receiving paraoxon, six pigs of 18 received 2.5 g (0.125 g kg-1 of body weight) of intravenous L(+)-lactate in 50 mL of saline over 50 mins, and six other pigs received 10 g of L(+)-lactate (0.5 g kg-1 of body weight), whereas the six remaining served as controls. In central venous blood, plasma acetylcholinesteratic and butyrylcholinesteratic activity were measured before paraoxon (baseline, 0 mins), immediately after paraoxon (50 mins after start), and 110, 170, 230, 290, 530, and 1010 mins after the start of infusion. Although 10 g of intravenous L(+)-lactate application had a statistically significant protective effect in vivo on AChEA, 2.5 g did not. No significant protective effect on BChEA was achieved with either 2.5 g or 10 g of L(+)-lactate. Ten grams of L(+)-lactate can increase AChEA when administered simultaneously with paraoxon. Further study of the in vivo effects of L(+)-lactate after paraoxon intoxication and a formal comparison with standard oxime therapy seem warranted. Also, methods for achieving a prolonged elevated lactate concentration in vivo should be investigated.

CD8(+)-T-cell depletion ameliorates circulatory shock in Plasmodium berghei-infected mice.

The Plasmodium berghei-infected mouse model is a well-recognized model for human cerebral malaria. Mice infected with P. berghei exhibit (i) metabolic acidosis (pH < 7.3) associated with elevated plasma lactate concentrations, (ii) significant (P < 0.05) vascular leakage in their lungs, hearts, kidneys, and brains, (ii) significantly (P < 0.05) higher cell and serum glutamate concentrations, and (iv) significantly (P < 0.05) lower mean arterial blood pressures. Because these complications are similar to those of septic shock, the simplest interpretation of these findings is that the mice develop shock brought on by the P. berghei infection. To determine whether the immune system and specifically CD8(+) T cells mediate the key features of shock during P. berghei malaria, we depleted CD8(+) T cells by monoclonal antibody (mAb) treatment and assessed the complications of malarial shock. P. berghei-infected mice depleted of CD8(+) T cells by mAb treatment had significantly reduced vascular leakage in their hearts, brains, lungs, and kidneys compared with infected controls treated with rat immunoglobulin G. CD8-depleted mice were significantly (P < 0.05) protected from lactic acidosis, glutamate buildup, and diminished HCO(3)(-) levels. Although the blood pressure decreased in anti-CD8 mAb-treated mice infected with P. berghei, the cardiac output, as assessed by echocardiography, was similar to that of uninfected control mice. Collectively, our results indicate that (i) pathogenesis similar to septic shock occurs during experimental P. berghei malaria, (ii) respiratory distress with lactic acidosis occurs during P. berghei malaria, and (iii) most components of circulatory shock are ameliorated by depletion of CD8(+) T cells.