Elevated Lactate Concentrations Research Articles

LPS-induced monocarboxylate transporter-1 inhibition facilitates lactate accumulation triggering epithelial-mesenchymal transformation and pulmonary fibrosis

The epithelial-mesenchymal transformation (EMT) process of alveolar epithelial cells is recognized as involved in the development of pulmonary fibrosis. Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung tissue and elevated lactate concentration are associated with the pathogenesis of sepsis-associated pulmonary fibrosis. However, it is uncertain whether LPS promotes the development of sepsis-associated pulmonary fibrosis by promoting lactate accumulation in lung tissue, thereby initiating EMT process. We hypothesized that monocarboxylate transporter-1 (MCT1), as the main protein for lactate transport, may be crucial in the pathogenic process of sepsis-associated pulmonary fibrosis. We found that high concentrations of lactate induced EMT while moderate concentrations did not. Besides, we demonstrated that MCT1 inhibition enhanced EMT process in MLE-12 cells, while MCT1 upregulation could reverse lactate-induced EMT. LPS could promote EMT in MLE-12 cells through MCT1 inhibition and lactate accumulation, while this could be alleviated by upregulating the expression of MCT1. In addition, the overexpression of MCT1 prevented LPS-induced EMT and pulmonary fibrosis in vivo. Altogether, this study revealed that LPS could inhibit the expression of MCT1 in mouse alveolar epithelial cells and cause lactate transport disorder, which leads to lactate accumulation, and ultimately promotes the process of EMT and lung fibrosis.

Low methyl nutrition microenvironment as a key regulator in modulating epigenetic regulation and switching energy metabolism to stimulate hepatocellular carcinoma stemness properties

The influence of changes in dietary habits, chemical treatments, variations in the activity of one-carbon enzyme gene modifications, and liver function impairment make hepatocellular carcinoma (HCC) patients prone to marginal methyl nutrient deficiency. Hepatocellular carcinoma has consistently ranked among the top five cancer incidence rates around the world, yet the issue of methyl nutrient deficiency still lacks systematic basic scientific assessment. This study aims to investigate whether the deficiency of methyl nutrients, specifically folate, choline, and betaine, induces the stem cell-like properties of hepatocellular carcinoma cells and promotes malignant progression, as well as to clarify the potential mechanisms involved. We found that human hepatocellular carcinoma cells (HepG2) cultured in a low methyl nutrient environment exhibited the following: (1) Methyl nutrient deficiency induced self-renewal cancer stem cell characteristics in hepatocellular carcinoma cells, forming tumor spheres on the seventh day, with a greater number and larger volume observed in environments with low folate and low choline. Upon isolating the tumor spheres and re-culturing, we found that the sphere cells induced by methyl nutrient deficiency (2) showed increased intracellular NADPH, accompanied by elevated lactate concentration in the microenvironment and changes in energy-related indicators of Warburg metabolism. At the same time, the expression of post-reprogramming related proteins Sirt1 and DNMT1 was altered. In summary, methyl nutrient deficiency may promote the malignant progression of hepatocellular carcinoma through both epigenetic modifications and energy conversion. National Science and Technology Council (NSTC112-2320-B-567-001). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

An in vitro study of metformin adsorption to activated charcoal

Introduction Metformin is a biguanide used to manage patients with type 2 diabetes mellitus. However, metabolic acidosis with an elevated lactate concentration and death caused by metformin overdoses are toxicological concerns. Although activated charcoal has been widely used for gastrointestinal decontamination in cases of acute poisoning, there is no evidence regarding its efficacy in treating metformin overdoses. We therefore evaluated the adsorptive capacity of activated charcoal for metformin in vitro. Methods Activated charcoal (specific surface area: 1,080 m2/g) mixed with various concentrations of metformin solution was dissolved in simulated gastric and intestinal fluids at 37° Celsius. The suspension was then filtered and the metformin concentration in the filtrate was determined using high-performance liquid chromatography. The maximum adsorptive capacity for metformin was calculated using the Langmuir adsorption isotherm equation. Results The amount of metformin adsorbed per gram of activated charcoal ranged from 0.7 to 8.1 mg/g at pH 1.2, and from 8.4 to 48.2 mg/g at pH 6.8. The corresponding maximum adsorptive capacities were 10.6 mg/g and 55.9 mg/g respectively. Discussion The maximum adsorptive capacity of activated charcoal for metformin was similar to that of its capacity for other poorly adsorbed substances. This is likely because metformin is water-soluble and has high polarity—factors that correlate with poor adsorption on activated charcoal. Conclusions The maximum adsorption of metformin by activated charcoal was low. Therefore, activated charcoal may not be effective for treating patients with metformin overdose.

Troponin in cardiogenic shock not caused by acute myocardial infarction, a predictor of mortality

Abstract Background Cardiogenic shock is associated with a high mortality and morbidity due to organ damage and multi-organ failure including direct damage to the myocardium. Purpose This study aimed to assess troponin as a marker of myocardial damage in patients with cardiogenic shock outside of a myocardial infarction (e.g., non-ischaemic cardiogenic shock). Methods Data from unselected patients with cardiogenic shock not caused by myocardial infarction were anonymised and combined in a multicentre cohort study from 15 centres in 5 European countries (2011-2020). Cardiogenic shock was defined by clinical signs and symptoms, elevated lactate concentrations (arterial >2.0 mmol/l, venous >2.5 mmol/l), and hypotension (systolic <90 mmHg or need for vasopressors). Patients with need for urgent coronary revascularisation, predominant right heart failure, eCPR or cardiogenic shock after cardiotomy were excluded. Baseline was defined to reflect the worst clinical status within 6 hours before/after admission (for patients not treated with mechanical circulatory support) or after device implantation (for patients treated with mechanical circulatory support). Troponin concentrations at baseline as well as after 24 hours were quantified using the Elecsys® Troponin T high-sensitive assay by Roche (99th percentile 14 ng/l). Baseline troponin (displayed per 250 ng/l) and its increase within 24 hours were associated with 30-day mortality by fitting Cox regression models adjusted for age, sex, baseline creatinine, baseline lactate, baseline pH, prior cardiac arrest, duration of CPR, acute-on-chronic or de novo heart failure, and mechanical ventilation. Results Overall, 477 patients were analysed [mean age 62 (±15) years, 144 women (30.2%), acute-on-chronic heart failure in 255 (53.6%)]. Median LVEF was 20% (IQR 15-30%), CPR was performed in 196 cases (41.1%), median lactate at baseline was 7.3 mmol/l (IQR 4.2-10.8 mmol/l) and median baseline troponin T was 164 ng/l (IQR 77-678 ng/l). Patients with a higher troponin T at baseline (e.g., ≥median) more frequently presented with de novo heart failure (54.8 vs. 37.9%, p<0.01) or after prior CPR (47.7 vs. 34.3%, p<0.01) although other parameters reflecting cardiogenic shock severity (e.g., blood pressure, baseline lactate or LVEF) were not significantly different. Finally, troponin T at baseline showed a significant association with 30-day mortality (HR 1.006, 95% CI: 1.0-1.011, p = 0.041) while the relative troponin T increase within 24 hours did not (HR 1.005, 95% CI: 0.997-1.013, p = 0.212) (Figure 1). Conclusion Cardiac organ damage in cardiogenic shock outside of a myocardial infarction (e.g., non-ischaemic cardiogenic shock) is associated with increased risk of death within 30 days. Elevated troponin levels could identify a group of patients with cardiogenic shock in need for cardioprotective therapies.Figure 1

The value of elevated cerebrospinal fluid lactate concentrations in post-neurosurgical bacterial meningitis

Bacterial meningitis is a serious complication after neurosurgery and has a high mortality rate. Early diagnosis and timely treatment are crucial or will have disastrous consequences. The classic triad of bacterial meningitis lacks sensitivity and specificity. Therefore, the diagnosis of post-neurosurgical bacterial meningitis relies on cerebrospinal fluid. But traditional cerebrospinal fluid parameters are not completely reliable in diagnosing post-neurosurgical bacterial meningitis. Previous studies have found that CSF lactate concentration is related to bacterial meningitis. But, after the craniocerebral operation, the cerebrospinal fluid of most patients is bloody. Whether red blood cells interfere with diagnosing PNBM based on lactate concentration is limited. In the current study, we further analysis on whether red blood cells interfere with diagnosing PNBM based on lactate concentration. This study aimed to investigate the value of cerebrospinal fluid lactate concentrations in post-neurosurgical bacterial meningitis. A prospective observational study was performed on 62 patients at Kunshan First People’s Hospital’s intensive care unit affiliated with Jiangsu University. We found that erythrocytes do not affect cerebrospinal fluid lactate, and elevated lactate concentrations can be used as a marker for postoperative bacterial meningitis.

Expanding the phenotypic and biochemical spectrum of NDUFAF3-related mitochondrial disease

Recessive variants in NDUFAF3 are a known cause of complex I (CI)-related mitochondrial disorders (MDs). The seven patients reported to date exhibited severe neurologic symptoms and lactic acidosis, followed by a fatal course and death during infancy in most cases.We present a 10-year-old patient with a neurodevelopmental disorder, progressive exercise intolerance, dystonia, basal ganglia abnormalities, and elevated lactate concentration in blood. Trio-exome sequencing revealed compound-heterozygosity for a pathogenic splice-site and a likely pathogenic missense variant in NDUFAF3. Spectrophotometric analysis of fibroblast-derived mitochondria demonstrated a relatively mild reduction of CI activity. Complexome analyses revealed severely reduced NDUFAF3 as well as CI in patient fibroblasts. Accumulation of early sub-assemblies of the membrane arm of CI associated with mitochondrial complex I intermediate assembly (MCIA) complex was observed. The most striking additional findings were both the unusual occurrence of free monomeric CI holding MCIA and other assembly factors.Here we discuss our patient in context of genotype, phenotype and metabolite data from previously reported NDUFAF3 cases. With the atypical presentation of our patient, we provide further insight into the phenotypic spectrum of NDUFAF3-related MDs. Complexome analysis in our patient confirms the previously defined role of NDUFAF3 within CI biogenesis, yet adds new aspects regarding the correct timing of both the association of soluble and membrane arm modules and CI-maturation as well as respiratory supercomplex formation.

Royal jelly acid suppresses hepatocellular carcinoma tumorigenicity by inhibiting H3 histone lactylation at H3K9la and H3K14la sites

Background and purposeHuman hepatocellular carcinoma (HCC) features include enhanced glycolysis and elevated lactate concentrations. Accumulation of lactate during metabolism provides a precursor for histone lysine modification. This study was designed to determine whether royal jelly acid (RJA) acts against HCC through the lactate modification pathway. Experimental approachThe effects of RJA on Hep3B and HCCLM3 cell invasion, migration, proliferation, and apoptosis were investigated using cell scratching, colony formation assay, flow cytometry, western blotting, and real-time qPCR, gas chromatography, and RNA sequencing to determine the pathways and molecular targets involved. Tumor xenografts were used to evaluate the anti-HCC effects of RJA in vivo. In-cell Western blotting and expression correlation analysis were applied to confirm the associations between H3 histone lactylation and the antitumor effects of RJA. Key resultsRJA has good antitumor effects in vivo and in vitro. Multi-omics analysis with metabolome and transcriptome determined that the glycolytic metabolic pathway provided the principle antitumor effect of RJA. Further mechanistic studies showed that RJA inhibited HCC development by interfering with lactate production and inhibiting H3 histone lactylation at H3K9la and H3K14la sites. Conclusions and implicationsThis study first demonstrated that RJA exerts antitumor effects by affecting the glycolytic pathway. RJA could regulate the lactylation of H3K9la and H3K14la sites on H3 histone using lactate as a clue in the glycolytic pathway. Therefore, the lactylation of H3 histone is vital in exerting the antitumor effect of RJA, providing new evidence for screening and exploring antitumor drug mechanisms in the later stage.

Population variability in thermal performance of pre-spawning adult Chinook salmon.

Climate change is causing large declines in many Pacific salmon populations. In particular, warm rivers are associated with high levels of premature mortality in migrating adults. The Fraser River watershed in British Columbia, Canada, supports some of the largest Chinook salmon (Oncorhynchus tshawytscha) runs in the world. However, the Fraser River is warming at a rate that threatens these populations at critical freshwater life stages. A growing body of literature suggests salmonids are locally adapted to their thermal migratory experience, and thus, population-specific thermal performance information can aid in management decisions. We compared the thermal performance of pre-spawning adult Chinook salmon from two populations, a coastal fall-run from the Chilliwack River (125km cooler migration) and an interior summer-run from the Shuswap River (565km warmer migration). We acutely exposed fish to temperatures reflecting current (12°C, 18°C) and future projected temperatures (21°C, 24°C) in the Fraser River and assessed survival, aerobic capacity (resting and maximum metabolic rates, absolute aerobic scope (AAS), muscle and ventricle citrate synthase), anaerobic capacity (muscle and ventricle lactate dehydrogenase) and recovery capacity (post-exercise metabolism, blood physiology, tissue lactate). Chilliwack Chinook salmon performed worse at high temperatures, indicated by elevated mortality, reduced breadth in AAS, enhanced plasma lactate and potassium levels and elevated tissue lactate concentrations compared with Shuswap Chinook salmon. At water temperatures exceeding the upper pejus temperatures (Tpejus, defined here as 80% of maximum AAS) of Chilliwack (18.7°C) and Shuswap (20.2°C) Chinook salmon populations, physiological performance will decline and affect migration and survival to spawn. Our results reveal population differences in pre-spawning Chinook salmon performance across scales of biological organization at ecologically relevant temperatures. Given the rapid warming of rivers, we show that it is critical to consider the intra-specific variation in thermal physiology to assist in the conservation and management of Pacific salmon.

Mitochondrial DNA m.3243A>G mutation in ethambutol-induced optic neuropathy: A case report

A 35-year-old man with maternally inherited diabetes presented with blurring of vision in both eyes for 6 months. He previously received antituberculous therapy including ethambutol (EMB) for 2 years. Temporal disc pallor and central scotomas were noticed in both eyes. P100 latency was delayed in visual evoked potential bilaterally. In addition, an elevated blood lactate concentration was observed. Interestingly, although EMB's potential optic neuropathy toxicity was our first consideration, a m.3243A>G mutation of mitochondrial DNA was found in the blood. Herein, we reported a young patient carrying a novel Leber's hereditary optic neuropathy mutation who developed EMB-induced optic neuropathy.

565 UNUSUAL LIFE-THREATENING FLECAINIDE TOXICITY: A CASE REPORT

Abstract Background Anti-arrhythmic drug therapy has often a narrow therapeutic index and could be responsible of toxic side effects including malignant arrhythmias and life-threatening hemodynamic deterioration. Flecainide toxicity can occur even at normal serum levels in the setting of electrolyte disturbances such as hyponatremia. We report a case of flecainide toxicity, likely due to dual mechanism: reduced excretion and potentiation of the toxic effects due to concomitant hyponatremia. Case description A 82-year-old woman was admitted to our hospital for syncope. The ECG at admission showed atrial fibrillation, complete atrio-ventricular (AV) block and a wide QRS escape rhythm. She has a history of hypertension, COPD and atrial fibrillation. She was currently taking flecainide at a dosage of 150 mg per die. Laboratory tests reported an elevated lactate concentration (4.6 mmol/L), hyponatremia (128 mmol/L), severe reduction of renal function (eGFR 19 ml/min), and NT-proB-type Natriuretic Peptide 17563 pg/ml, (ULN<450). Echocardiography showed a reduced left ventricular ejection fraction (EF=35%). Suspecting flecainide poisoning, we started intravenous sodium bicarbonate and temporary pacing for severe bradycardia and pauses. However, despite numerous attempts of lead reposition and the use of maximum output, we failed to document ventricular capture in the immediate post-operative. Half hour later, dopamine infusion was started for sustained severe hypotension. The day after we were able to obtain ventricular capture. At serial ECG examination, she also developed progressive QRS narrowing with concomitant clinical improvement. Discussion Flecainide toxicity is a rare but potentially life-threatening condition. The excess of sodium channel blockade causes in fact delayed conduction through the AV node, His-Purkinje system, and ventricles with possible AV block, ventricular tachycardia, ventricular fibrillation, and asystole. In addition, hemodynamic instability can develop rapidly in flecainide intoxication due to chronotropic and inotropic incompetence. The majority of flecainide intoxication reported cases are due to a drug overdose. However, flecainide toxicity can occur with serum levels within the range of normality. Particularly, this can occur in the setting of hyponatremia. The observed pacemaker malfunction was also due to flecainide intoxication. In our case, the patient was taking therapeutic doses of this drug. The toxic effect was probably due to the reduced excretion (secondary to kidney failure) and the simultaneous presence of hyponatremia. The main treatment for flecainide intoxication is sodium bicarbonate and supportive care. However, there is currently no recommended standardized protocol for flecainide toxicity. The inotropic agents could be helpful in case of cardiogenic shock, but their use may be limited by the rate-dependent effect of flecainide and the increased risk ventricular arrhythmias. Left ventricular assist devices have been also used to support hemodynamic through flecainide-induced cardiogenic shock.

Extracorporeal life support in cardiotoxicant poisoning-A narrative review.

Extracorporeal life support (ECLS) improves circulation in life-threatening cardiac dysfunction or arrest patients. Its benefits in drug-induced cardiovascular complications are debated. Indications and outcomes are poorly established. We performed a narrative review discussing ECLS indications, timing and results in cardiotoxicant-poisoned patients. The review was focused on antiarrhythmic drugs and aluminium phosphide. Literature analysis was limited to the past 30 years in adults. Most reports were single cases and retrospective except one prospective case series of limited size, two of them controlled. ECLS indications and timing were at the discretion of physicians in charge but mostly included persistent cardiovascular failure despite elevated doses of inotropic/vasopressor support associated with elevated blood lactate concentrations (usually, >5mmol/L) and collapsed left ventricular ejection fraction (LVEF; usually, ≤40%). Survival improved using ECLS versus standard care in one study. Survival was ~80% if ECLS was implemented in refractory cardiovascular failure and 25%-66% if implemented in cardiac arrest. In two controlled studies, survival of ECLS-treated aluminium phosphide-poisoned patients was improved versus standard care, if implemented in the presence of systolic blood pressure ≤80 mmHg despite inotropic/vasopressor treatment, arterial pH ≤ 7.0 and LVEF ≤ 40%. Despite low-to-moderate level of evidence, ECLS seems effective to improve survival in selected cardiotoxicant-poisoned patients. Selection criteria need clarification.

S2793 Adrenal Crisis in a Patient With Crohn’s Disease: A Legacy of the Corticosteroid Treatment Era

Introduction: Before the era of biologic agents, corticosteroids were the most effective therapy available for inflammatory bowel disease (IBD) as well as other inflammatory and immune-mediated disorders, and treatment often was prolonged. As a result, many patients developed secondary adrenal insufficiency, in which the normal circadian rhythm of cortisol secretion was maintained but a defect in the cortisol response to stress persisted, as was the risk of adrenal crisis in response to severe physiologic stress. As corticosteroids are no longer used chronically in IBD, adrenal crisis has become a rare complication, and many gastroenterologists have no personal experience with it. We recently saw such a case which we are presenting as a reminder of its continued existence. Case Description/Methods: A 73-year-old female with Crohn’s disease diagnosed at the age of 18, complicated by short bowel syndrome and esophageal involvement, who had been steroid dependent for 15 years though stable on ustekinumab and no steroids for more than 8 years, presented to the emergency department with an acute onset of abdominal pain, diarrhea with incontinence, profound weakness, disorientation, and possible syncope, one hour after IV iron sucrose therapy. Initial physical exam was notable for pallor and edema of hands and feet. Laboratory exams showed hemoconcentration, leukocytosis, hyponatremia, plus elevated serum lactate concentration and anion gap. Because of the severity of this response, the possibility of adrenal crisis was raised: serum cortisol was 15.5 ug/dL (nl 6.2-29) despite the stressful situation and the patient responded clinically to 100 mg of hydrocortisone IV. She was discharged within 24 hours and all laboratory abnormalities reversed within 72 hours. Discussion: Adrenal crisis can present with a wide variety of nonspecific symptoms and should be in the differential diagnosis when a patient presents after a significant physiologic stress and has a history of chronic oral corticosteroid use. Electrolyte disturbances are less common in secondary adrenal insufficiency as the zona glomerulosa of the adrenal gland is not affected. Secondary adrenal insufficiency may persist for many years after chronic steroid use and may be permanent. In patients with secondary adrenal insufficiency. Important hints are the patient’s age and GI history, which includes extent of exposure to corticosteroids. Effective diagnosis requires maintaining a high index of suspicion.

Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.

Pathogenic biallelic variants in PCK1 coding for the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) cause PEPCK-C deficiency, a rare disorder of gluconeogenesis presenting with hypoglycemia, lactic acidosis, and hepatopathy. To date, there has been no systematic analysis of its phenotypic, biochemical, and genetic spectrum. All currently published individuals and a novel patient with genetically confirmed PEPCK-C deficiency were included. Clinical, biochemical, and genetic findings were analyzed. Protein and in-silico prediction score modeling was applied to analyze potential variant effects. Thirty-two individuals from 25 families were found, including one previously unreported patient. The typical biochemical pattern was hypoglycemia triggered by catabolic situations, elevated urinary concentrations of tricarboxylic acid cycle metabolites, mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum. Plasma glutamine concentrations were elevated in some patients and may be a suitable marker for newborn screening. With adequate treatment, biochemical abnormalities usually normalized following a hypoglycemic episode. Symptom onset usually occurred in infancy with a broad range from neonatal age to adulthood. Regardless of the genotype, different phenotypes with a broad clinical spectrum were found. To date, eight genotypes with nine different PCK1 variants were identified, of which alleles with the recurrent variant c.925G > A; p.(Gly309Arg) are predominant and appear to be endemic in the Finnish population. Protein modeling suggests altered manganese- and substrate-binding as superordinate pathomechanisms. Environmental factors appear to be the main determinant for the phenotype in patients with biallelic variants in PCK1. Based on the biochemical pattern, PEPCK-C deficiency is a recognizable cause of childhood hypoglycemia. It is a treatable disease and early diagnosis is important to prevent metabolic derailment and morbidity. Newborn screening can identify at least a sub-cohort of affected individuals through elevated glutamine concentrations in dry blood.

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.

54-Year-Old Woman With Altered Mental Status and Abdominal Pain

54-Year-Old Woman With Altered Mental Status and Abdominal Pain

227-LB: Elevated Plasma Lactate and the Risk for Metabolic Syndrome—Is Skeletal Muscle a Producer or Consumer?

Background: The incidence of metabolic diseases is rising and there is a dire need for early detection to implement prevention. Fasting plasma lactate concentrations have been shown to be elevated in individuals with obesity and predictive of type 2 diabetes. An elevated fasting lactate concentration could possibly be the product of a reduction in muscle oxidative capacity and increased muscle lactate output. However, it is unknown how early this is evident, as are the mechanisms involved. Aim: The aim of this study was to determine if fasting lactate concentrations were linked with a reduction in skeletal muscle oxidative capacity in a cohort without metabolic disease. Methods: Young (age 28 ± 7; N=21) overweight (BMI (27.1 ± 0.4 kg/m2) men (n=12) and women (n=9) were recruited for this study. Blood biomarkers were measured in the fasted state and body composition was determined by DXA. Muscle oxidative capacity was measured in skeletal muscle homogenates (vastus lateralis biopsy) using 14C-labeled labeled palmitate and pyruvate. Muscle lactate output was determined by microdialysis during a hyperinsulinemic euglycemic clamp procedure. Results: Elevated lactate was associated with elevated visceral adiposity (R2=.40, p=.003) , elevated triglycerides (R2=.56, p=.0001) , as well as elevations in systolic blood pressure (R2=.39, p=.003) . Subjects with higher lactate had lower ratio of fatty acid oxidation to pyruvate oxidation (ratio R2=.49, p=.002) . Muscle lactate uptake in the basal state of the clamp positively associated with plasma lactate (R2=.92, p=&amp;lt;.0001) ; however, in the insulin phase net lactate output was near zero. Conclusion: Individuals who are overweight but otherwise healthy have elevated plasma lactate that associates with parameters of the metabolic syndrome. Lactate was associated with a shift from lipid to carbohydrate oxidation. Muscle is a consumer of lactate in the fasted state, whereas adipose tissue may be the source of production postprandially. Disclosure N. T. Broskey: None. E. J. Demaria: None. W. J. Pories: None. J. A. Houmard: None. L. Dohm: None. T. E. Jones: None. C. J. Tanner: None. D. Zheng: None. F. Jevtovic: None. P. Krassovskaia: None. L. E. Matarese: None. R. N. Cortright: None. R. Hickner: None. Funding NIH (R01DK120296)

Incorporating estuarine-angler behaviour and delayed blood sampling into the rapid assessment of catch-and release angling on the iconic dusky kob Argyrosomus japonicus

Argyrosomus japonicus is arguably South Africa’s most important estuarine recreational and small-scale fishery species. Although juvenile A. japonicus predominate in estuarine environments, where catch-and-release angling is common, limited C&R studies have taken place. The aim of this study was to use angler-behaviour to robustly examine the physiological stress response, reflex impairment and short-term (12–36-hour) survival of A. japonicus following C&R angling. Observations of estuarine recreational angling informed three air exposure treatments based on minimum (10 s), mean (75 s) and maximum (240 s) observed times, for use in a controlled angling experiment. Based on a prior laboratory study, blood sampling was delayed 30–40 min post-capture to allow for peak accumulations of lactate and glucose. Long air exposure (240 s) predicted significantly higher blood glucose concentrations (ANOVA, p = 0.03) than short (10 s) exposure. Similarly, both long (p = 0.01) and moderate (75 s; p = 0.01) air exposure significantly predicted elevated blood lactate concentrations, when compared with short exposure. In terms of physical impairment, long air exposure (240 s) had a significant negative influence on the reflex response (cumulative link model, p = 0.01) of A. japonicus. An observed short-term mortality of 7.7% was primarily attributed to hooking injury. To reduce significant physiological and physical stress, it is proposed that anglers should aim to reduce air exposure times to below the observed mean of 75 s, and ideally to 10 s. For relevant and meaningful future C&R studies, we propound the incorporation of angler behavioural assessments, and the investigation of physiological stress responses, prior to designing field studies.

Predictors of response to intra-arterial vasodilatory therapy of non-occlusive mesenteric ischemia in patients with severe shock: results from a prospective observational study

BackgroundNon-occlusive mesenteric ischemia (NOMI) is a life-threatening condition occurring in patients with shock and is characterized by vasoconstriction of the mesenteric arteries leading to intestinal ischemia and multi-organ failure. Although minimal invasive local intra-arterial infusion of vasodilators into the mesenteric circulation has been suggested as a therapeutic option in NOMI, current knowledge is based on retrospective case series and it remains unclear which patients might benefit. Here, we prospectively analyzed predictors of response to intra-arterial therapy in patients with NOMI.MethodsThis is a prospective single-center observational study to analyze improvement of ischemia (indicated by reduction of blood lactate > 2 mmol/l from baseline after 24 h, primary endpoint) and 28-day mortality (key secondary endpoint) in patients with NOMI undergoing intra-arterial vasodilatory therapy. Predictors of response to therapy concerning primary and key secondary endpoint were identified using a) clinical parameters as well as b) data from 2D-perfusion angiography and c) experimental biomarkers of intestinal injury.ResultsA total of 42 patients were included into this study. At inclusion patients had severe shock, indicated by high doses of norepinephrine (NE) (median (interquartile range (IQR)) 0.37 (0.21–0.60) μg/kg/min), elevated lactate concentrations (9.2 (5.2–13) mmol/l) and multi-organ failure. Patients showed a continuous reduction of lactate following intra-arterial prostaglandin infusion (baseline: (9.2 (5.2–13) mmol/l vs. 24 h: 4.4 (2.5–9.1) mmol/l, p < 0.001) with 22 patients (52.4%) reaching a lactate reduction > 2 mmol/l at 24 h following intervention. Initial higher lactate concentrations and lower NE doses at baseline were independent predictors of an improvement of ischemia. 28-day mortality was 59% in patients with a reduction of lactate > 2 mmol/l 24 h after inclusion, while it was 85% in all other patients (hazard ratio 0.409; 95% CI, 0.14–0.631, p = 0.005).ConclusionsA reduction of lactate concentrations was observed following implementation of intra-arterial therapy, and lactate reduction was associated with better survival. Our findings concerning outcome predictors in NOMI patients undergoing intra-arterial prostaglandin therapy might help designing a randomized controlled trial to further investigate this therapeutic approach.Trial registration Retrospectively registered on January 22, 2020, at clinicaltrials.gov (REPERFUSE, NCT04235634), https://clinicaltrials.gov/ct2/show/NCT04235634?cond=NOMI&draw=2&rank=1.

Percutaneous delivery of self-propelling hemostatic powder for managing non-compressible abdominal hemorrhage: a proof-of-concept study in swine

IntroductionNon-compressible intra-abdominal hemorrhage (NCIAH) is a major cause of preventable death on the battlefield and in civilian trauma. Currently, it can only be definitively managed with surgery, as there are limited strategies for controlling ongoing NCIAH in the prehospital environment. We hypothesized that a self-propelling thrombin-containing powder (SPTP) could increase survival in a swine model of NCIAH when delivered percutaneously into the closed abdomen using an engineered spray system. Materials and MethodsNineteen swine underwent surgical laparotomy followed by a Grade V liver injury that created massive hemorrhage, before closing the abdomen with sutures. Animals either received treatment with standard of care fluid resuscitation (n=9) or the SPTP spray system (n=10), which consisted of a spray device and a 14 Fr catheter. Using the spray system, SPTP was delivered into a hemoperitoneum identified using a focused assessment with sonography in trauma (FAST) exam. Lactated Ringer's solution was administered to all animals to maintain a mean arterial pressure (MAP) of >50 mmHg. The primary outcome was percentage of animals surviving at three hours following injury. ResultsIn the swine model of NCIAH, a greater percentage of animals receiving SPTP survived to three hours, although differences were not significant. The SPTP spray system increased the median survival of animals from 1.6 hr in the fluid resuscitation group to 4.3 hr. The SPTP spray system delivered a total mass of 18.5 ± 1.0 g of SPTP. The mean change in intra-abdominal pressure following SPTP delivery was 5.2 ± 1.8 mmHg (mean ± SEM). The intervention time was 6.7 ± 1.7 min. No adverse effects related to the SPTP formulation or the spray system were observed. SPTP was especially beneficial in animals that had either severely elevated lactate concentrations or low mean arterial pressure of <35 mmHg shortly after injury. ConclusionsThis demonstrates proof-of-concept for use of a new minimally invasive procedure for managing NCIAH, which could extend survival time to enable patients to reach definitive surgical care.

Outcomes and factors associated with occult septic shock in emergency department patients with soft tissue Infection

Patients who develop occult septic shock (OSS) are associated with worse outcomes than those with early septic shock (ESS). Patients with skin and soft tissue infection (SSTI) may have underlying organ dysfunction due to OSS, yet the prevalence and the outcomes of patients with SSTI and early versus occult shock have not been described. This study compared the clinical characteristics of SSTI patients and the prevalence of having no septic shock (NSS), ESS, or OSS. We retrospectively analyzed charts of adult patients who were transferred from any emergency department to our academic center between January 1, 2014, and December 31, 2016. Outcomes of interest were the development of OSS and acute kidney injury (AKI). We performed logistic regressions to measure the association between clinical factors with the outcomes and created probability plots to show the relationship between key clinical variables and outcomes of OSS or AKI. Among 269 patients, 218 (81%) patients had NSS, 16 (6%) patients had ESS, and 35 (13%) patients had OSS. Patients with OSS had higher mean serum lactate concentrations than patients with NSS (3.5 vs. 2.1 mmol/L, P < 0.01). Higher sequential organ failure assessment (SOFA) score was associated with higher likelihood of developing OSS (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.23-1.62, P < 0.001). NSS was associated with very low odds of developing AKI (OR 0.16, 95% CI 0.08-0.33, P < 0.001). 13% of the patients with SSTI developed OSS. Patients with OSS had elevated serum lactate concentration and higher SOFA score than those with NSS. Increased SOFA score is a predictor for the development of OSS.