Rise In Lactate Research Articles

Impact of intensive care unit supportive care on the physiology of Ebola virus disease in a universally lethal non-human primate model

BackgroundThere are currently limited data for the use of specific antiviral therapies for the treatment of Ebola virus disease (EVD). While there is anecdotal evidence that supportive care may be effective, there is a paucity of direct experimental data to demonstrate a role for supportive care in EVD. We studied the impact of ICU-level supportive care interventions including fluid resuscitation, vasoactive medications, blood transfusion, hydrocortisone, and ventilator support on the pathophysiology of EVD in rhesus macaques infected with a universally lethal dose of Ebola virus strain Makona C07.MethodsFour NHPs were infected with a universally lethal dose Ebola virus strain Makona, in accordance with the gold standard lethal Ebola NHP challenge model. Following infection, the following therapeutic interventions were employed: continuous bedside supportive care, ventilator support, judicious fluid resuscitation, vasoactive medications, blood transfusion, and hydrocortisone as needed to treat cardiovascular compromise. A range of physiological parameters were continuously monitored to gage any response to the interventions.ResultsAll four NHPs developed EVD and demonstrated a similar clinical course. All animals reached a terminal endpoint, which occurred at an average time of 166.5 ± 14.8 h post-infection. Fluid administration may have temporarily blunted a rise in lactate, but the effect was short lived. Vasoactive medications resulted in short-lived improvements in mean arterial pressure. Blood transfusion and hydrocortisone did not appear to have a significant positive impact on the course of the disease.ConclusionsThe model employed for this study is reflective of an intramuscular infection in humans (e.g., needle stick) and is highly lethal to NHPs. Using this model, we found that the animals developed progressive severe organ dysfunction and profound shock preceding death. While the overall impact of supportive care on the observed pathophysiology was limited, we did observe some time-dependent positive responses. Since this model is highly lethal, it does not reflect the full spectrum of human EVD. Our findings support the need for continued development of animal models that replicate the spectrum of human disease as well as ongoing development of anti-Ebola therapies to complement supportive care.

Asthaxanthin Improves Aerobic Exercise Recovery Without Affecting Heat Tolerance in Humans.

Objectives: To examine the supplementation effects of the xanthophyll carotenoid Astaxanthin on physical performance and exertional heat strain in humans.Design: A randomized double blind placebo controlled trial.Methods: Twenty two male participants (Age: 23.14 ± 3.5 y, height: 175 ± 6 cm, body mass: 69.6 ± 8.7 kg, % body fat: 16.8 ± 3.8) received placebo (PLA, n = 10) or Astaxanthin (ATX, n = 12) 12 mg/day Per os (P.O), for 30 days, and were tested pre and post-supplementation with a maximal oxygen uptake (VO2 Max) test and the heat tolerance test (HTT) (2 h walk at 40°C, 40% relative humidity (RH), 5 kph, 2% incline). NIH database registration no. NCT02088242. Gas exchange, Heart rate (HR), Relative perceived exertion (RPE), and blood lactate were measured during the VO2 Max test. Heart rate (HR), rectal (Trec), and skin (Tskin) temperatures, RPE, and sweat rate (SR) were monitored in the HTT. Serum heat shock protein 72 (HSP72), Creatine phospho-kinase (CPK), C-reactive protein (CRP), and lipid profile were measured before and after the test.Results: The rise in blood lactate caused by the VO2 Max test was significantly diminished in the ATX group (9.4 ± 3.1 and 13.0 ± 3.1 mmole*l−1 in the ATX and PLA groups, respectively P < 0.02), as was the change in oxygen uptake during recovery (−2.02 ± 0.64 and 0.83 ± 0.79% of VO2 Max in the ATX and PLA group, respectively, p = 0.001). No significant differences were observed in the anaerobic threshold or VO2 Max. In the HTT, no significant physiological or biochemical differences were observed (HR <120 bpm, Trec rose by ~1°C to <38°C, no difference in SR).Conclusions: Astaxanthin supplementation improved exercise recovery. No benefit was observed for ATX over PLA in response to heat stress. Further examination of Astaxanthin in higher exertional heat strain is required.

Heart transplant complicated by metformin induced lactic acidosis

Introduction Mild lactic acidosis following heart transplant is a known laboratory finding that generally does not require treatment. However, we encountered a case in which a diabetic patient on metformin underwent a heart transplant and developed a profound rise in lactate which caused a severe anion gap metabolic acidosis and refractory vasoplegia. Methods Case Report. Results A 52 year old man with a past medical history of type 2 diabetes mellitus managed with metformin, chronic kidney disease, and coronary artery disease underwent an LVAD explant and a heart transplant utilizing bicaval anastomosis technique. Twenty minutes after separating from bypass, an arterial blood gas was notable for a lactate of 7.8 mmol/L. Over the next two hours, the patient developed vasoplegia and a severe anion gap metabolic acidosis with a lactate that peaked at 18.0 mmol/L. TEE and surgical visualization agreed that cardiac function was excellent and without evidence of tamponade. The patient's hyperdynamic cardiac function was confirmed by the cardiac output values nearing 14 L/m via Swan-Ganz thermodilution. The patient's preoperative medication history was once more analyzed and metformin induced lactic acidosis was added to our working differential diagnosis. A dialysis line was placed, and continuous veno-venous hemofiltration (CVVH) was initiated in the OR, followed by a downtrend of lactate and improvement in hemodynamics. CVVH was continued in the ICU resulting in resolution of lactemia. Discussion Metformin induced lactic acidosis is rare and a diagnosis of exclusion. We ruled out hypovolemia due to a CVP of 14-15 mmHg and ischemic bowel by benign abdominal exam and normal AST, ALT, amylase, and lipase. Sepsis was considered less likely due to lack of infectious source/fever and maintenance of scheduled antibiotic prophylaxis. We had established that the donor cardiac function was excellent. Due to the unpredictable nature of heart transplant, our patient received metformin within 48 hours of surgery. The patient's known chronic kidney disease, potentially exacerbated by cardiopulmonary bypass, likely contributed to metformin induced lactic acidosis.

Plasmapheresis Effect on Hematological and Biochemical Parameters in Athletic Horses Subjected to Exercise

To evaluate the effect of plasmapheresis on clinical, hematological, and biochemical parameters after exercise, a plasmapheresis session was realized on six jumping horses (plasmapheresis group) that underwent three consecutive days of physical graded exercise. The control group (n = 6) went through the same exercise but not subjected to the plasmapheresis session. Seventeen milliliters of plasma/kg of body weight was harvested from each horse. The procedure was well tolerated by the horses. The plasmapheresis leads to a significant increase of the hemoglobin, hematocrit, red blood cell, white blood cell, and lymphocytes counts. Plasmapheresis induced a very significant decrease (P < .001) of albumin and globulin levels and of total protein, which were reestablished 24 hours later. Plasmapheresis also generated a very significant increase (P < .001) in sodium levels and a significant decline of potassium (P < .05) and calcium (P < .01) levels. Several other biochemical variables remained unchanged. Results also showed that, after a significant rise of lactate, aspartate aminotransferase, and creatine kinase levels which are subsequent to the exercise, the plasmapheresis session induced a very significant continuous decrease (P < .001) of these parameters. The present work has demonstrated that the plasmapheresis is able to modify the physiology after exercise and to affect both the hematology and the biochemistry of the blood hematobiochemical parameters in horses subjected to physical exercise.

Metabolic alterations of uterine grafts after extended cold ischemic storage: experimental study in ewes.

Uterine transplantation from a deceased donor could become an available option for widely treating uterine infertility. However, this procedure requires more precise knowledge about the graft's tolerance to extended cold ischemia. Here, we sought to assess the uterine metabolic alterations after extended cold ischemic storage in a model of auto-transplantation in ewe. A total of 14 uterine auto-transplantations were performed, divided into 2 groups: 7 after 3h of cold ischemia time (CIT) and 7 after 24h. Venous uterine blood was collected before uterus retrieval and during reperfusion (30, 60 and 90min); thereafter, blood gases, lactate, glucose and amino acids (AAs) were analyzed. Apoptosis analyses were performed before uterus retrieval and following reperfusion in uterus biopsies. A total of 12 uterine auto-transplantations were successfully performed and 7 ewes were alive ≥8days after transplantation. After reperfusion, a decrease in pH, a rise of lactate and lactate/glucose ratio and a delayed decrease of pO2 were found in the 3h CIT group. No significant variation of these parameters was observed in the 24h CIT group. Significant decreases of AAs were observed during reperfusion and these decreases were more pronounced and concerned a larger number of compounds in the 24h CIT group than in the 3h CIT group. There was no significant uterine apoptotic signal in either group. Overall, these results suggest that extended CIT storage delayed restoration of aerobic glycolysis and induced an increase in AA requirements of the uterus after reperfusion. However, this biochemical alteration did not reduce success rate for uterine transplantation.

Safety and efficacy of beta-blockers to improve oxygenation in patients on veno-venous ECMO

PurposeBeta-blockers (BB) may improve oxygenation in patients on veno-venous extracorporeal membrane oxygenation (V-V ECMO). This study analyzed safety and efficacy of BB in hypoxemic patients on V-V ECMO. Materials and methodsRetrospective analysis of patients who were treated with BB during V-V ECMO in two centers. The primary safety outcome was a composite of occurrence of bradycardia or hypotension with need for intervention, resuscitation, unexplained rise in serum lactate, and discontinuation of beta-blockers for other reasons than inefficacy or resolution on hypoxemia during the first 5 days of therapy. The main efficacy outcome was increase in oxygen saturation (SaO2) within 12 h after start of BB. Results33 patients received BB for 4 [3–7] days while on V-V ECMO. Fifteen episodes of adverse events occurred in 13 patients (39%); BB had to be discontinued in only one patient for sustained hypotension. In two other patients, doses were reduced or temporarily withheld due to bradycardia. There was an increase in SaO2 from 92 [90–96]% to 96 [94–97]% at 12 h, with unchanged mean arterial pressure and norepinephrine doses. ConclusionsIn this study, use of BB in hypoxemic patients on V-V ECMO was safe and associated with a moderate increase in SaO2.

Sex Differences in Heart Failure With Preserved Ejection Fraction Pathophysiology: A Detailed Invasive Hemodynamic and Echocardiographic Analysis

ObjectivesThis study sought to identify sex differences in central and peripheral factors that contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF) by using complementary invasive hemodynamic and echocardiographic approaches. BackgroundWomen are overrepresented among patients with HFpEF, and there are established sex differences in myocardial structure and function. Exercise intolerance is a fundamental feature of HFpEF; however, sex differences in the physiological determinants of exercise capacity in HFpEF are yet to be established. MethodsPatients with exertional intolerance with confirmed HFpEF were included in this study. Evaluation of the subjects included resting and exercise hemodynamics, echocardiography, and mixed venous blood gas sampling. ResultsA total of 161 subjects included 114 females (71%). Compared to males, females had a higher pulmonary capillary wedge pressure (PCWP) indexed to peak exercise workload (0.8 [0.5 to 1.2] mm Hg/W vs. 0.6 [0.4 to 1] mm Hg/W, respectively; p = 0.001) and lower systemic (1.1 [0.9 to 1.5] ml/mm Hg vs. 1 [0.7 to 1.2] ml/mm Hg, respectively; p = 0.019) and pulmonary (2.9 [2.2 to 4.2] ml/mm Hg vs. 2.4 [1.9 to 3] ml/mm Hg, respectively; p = 0.032) arterial compliance at exercise. Mixed venous blood gas analysis demonstrated a greater rise in lactate indexed to peak workload (0.05 [0.04 to 0.09] mmol/l/W vs. 0.04 [0.03 to 0.06] mmol/l/W, respectively; p = 0.007) in women compared to men. Women had higher mitral inflow velocity to diastolic mitral annular velocity at early filling (E/e′) ratios at rest and peak exercise, along with a higher ejection fraction and smaller ventricular dimensions. ConclusionsWomen with HFpEF demonstrate poorer diastolic reserve with higher echocardiographic and invasive measurements of left ventricular filling pressures at exercise, accompanied by lower systemic and pulmonary arterial compliance and poorer peripheral oxygen kinetics.

Cerebrovascular Reactivity during Prolonged Breath-Hold in Experienced Freedivers.

Experienced freedivers can endure prolonged breath-holds despite severe hypoxemia and are therefore ideal subjects to study apnea-induced cerebrovascular reactivity. This multiparametric study investigated CBF, the spatial coefficient of variation as a correlate of arterial transit time and brain metabolism, dynamics during prolonged apnea. Fifteen male freedivers (age range, 20-64 years; cumulative previous prolonged breath-holds >2 minutes and 30 seconds: 4-79,200) underwent repetitive 3T pseudocontinuous arterial spin-labeling and 31P-/1H-MR spectroscopy before, during, and after a 5-minute breath-hold (split into early and late phases) and gave temporally matching venous blood gas samples. Correlation of temporal and regional cerebrovascular reactivity to blood gases and cumulative previous breath-holds of >2 minutes and 30 seconds in a lifetime was assessed. The spatial coefficient of variation of CBF (by arterial spin-labeling) decreased during the early breath-hold phase (-30.0%, P = .002), whereas CBF remained almost stable during this phase and increased in the late phase (+51.8%, P = .001). CBF differed between the anterior and the posterior circulation during all phases (eg, during late breath-hold: MCA, 57.3 ± 14.2 versus posterior cerebral artery, 42.7 ± 10.8 mL/100 g/min; P = .001). There was an association between breath-hold experience and lower CBF (1000 previous breath-holds reduced WM CBF by 0.6 mL/100 g/min; 95% CI, 0.15-1.1 mL/100 g/min; P = .01). While breath-hold caused peripheral lactate rise (+18.5%) and hypoxemia (oxygen saturation, -24.0%), cerebral lactate and adenosine diphosphate remained within physiologic ranges despite early signs of oxidative stress [-6.4% phosphocreatine / (adenosine triphosphate + adenosine diphosphate); P = .02]. This study revealed that the cerebral energy metabolism of trained freedivers withstands severe hypoxic hypercarbia in prolonged breath-hold due to a complex cerebrovascular hemodynamic response.

Amino acid profile in women with gestational diabetes mellitus treated with metformin or insulin

AimsWe compared the effects of metformin and insulin treatments of gestational diabetes mellitus (GDM) on amino acid metabolism. Methods217 pregnant women diagnosed with GDM were randomized to receive either metformin or insulin. 1H nuclear magnetic spectroscopy was used to determine serum concentrations of alanine, glutamine, glycine, isoleucine, leucine, valine, histidine, phenylalanine, tyrosine, glucose and lactate at the time of diagnosis and at 36 gestational weeks (gw). ResultsMajority of the amino acid concentrations increased from 30 to 36 gw. The rise in alanine (16% vs. 8%, p < 0.0001), isoleucine (11% vs. 5%, p = 0.035) and lactate (29% vs. 14% p = 0.015) was larger in the metformin group compared to insulin group. Baseline alanine, glycine, isoleucine, leucine, valine and tyrosine were positively related to slightly earlier delivery. Alanine at 36 gw was positively associated with birth weight and glutamine with gestational hypertension or preeclampsia. Lactate at 36 gw was not associated with any adverse outcome. ConclusionsCompared to insulin metformin caused a greater increase in serum alanine, isoleucine and lactate concentrations. Although the observed differences in the metabolic variables were relatively small and not outright concerning, additional studies and follow-up data are required to ensure the safety of metformin use in pregnancy.The trial was registered in Clinicaltrials.gov, NCT01240785; http://clinicaltrials.gov/ct2/show/NCT01240785.

Does Intravenous Lactated Ringer’s Solution Raise Serum Lactate?

BackgroundSerum lactate increases in states of severe sepsis and shock, but its interpretation may be subject to confounders. Lactated Ringer's solution (LR) is used in the resuscitation of septic patients and contains 28 mmol/L of sodium lactate. ObjectivesWe sought to determine if a bolus of 30 mL/kg of LR increases serum lactate levels. MethodsIn this double-blind, randomized controlled trial, 30 volunteers were assigned to receive either 30 mL/kg of intravenous LR or normal saline (NS). Serum lactate was measured before and after the fluid bolus. The primary outcome was the difference in the change in lactate between the LR and NS groups. Secondarily, we assessed the change in pH, bicarbonate, sodium, and chloride in each group. ResultsAfter 30 mL/kg of intravenous LR, the mean serum lactate level increased by 0.93 mmol/L (95% confidence interval 0.42–1.44 mmol/L). However, there was also a small increase in the mean serum lactate level in the NS group of 0.37 mmol/L (95% confidence interval −0.26 mmol/L to 1.00 mmol/L), such that there was not a statistically significant difference in the change in lactate when comparing the LR group to the NS group (p = 0.2). The NS group saw larger declines in pH and bicarbonate and greater increases in chloride compared with the LR group. ConclusionIn healthy individuals, a modest but significant rise in mean serum lactate was seen after a 30 cc/kg LR bolus. There was no difference in mean serum lactate when comparing a 30 mL/kg bolus of NS to LR.

Intensive Supportive Care Alone Does Not Impact Survival in a Lethal Non-Human Primate Model of Ebola Virus Disease

Introduction: There are currently no licensed treatments for Ebola Virus Disease, making supportive care the only viable option. While there is anecdotal evidence that this is effective, the paucity of experimental data to demonstrate the role of supportive care in EVD has limited its use. We hypothesized that supportive care would enhance survival in a non-human primate (NHP) model of EVD. Methods: Three NHPs were infected with Ebola virus strain Makona and provided continuous bedside supportive care, including ventilatory support, fluid resuscitation, vasoactive medications, blood transfusion and hydrocortisone as needed to treat cardiovascular compromise. Findings: All three NHPs developed EVD and demonstrated a very similar clinical course and ultimately reached a terminal endpoint at an average time of 160 ± 8·7 hours post infection, which is similar to caged animals (144-192 hours). Fluid administration may have temporarily blunted a rise in lactate but the effect was short lived. Vasoactive medications, blood transfusion and hydrocortisone did not appear to have an impact. Interpretation: Supportive care did not impact survival length in a high stringency NHP EVD disease model. Our findings help support the need for the development and use of specific anti-Ebola therapies. Funding Statement: Funding was provided by the Canadian Institutes of Health Research and the Government of Canada. Declaration of Interests: None of the authors had a conflict of interest with regard to this study. Ethics Approval Statement: The study protocol was reviewed and approved by the institutional Animal Care Committee, in accordance with Canadian Council on Animal Care (CCAC) guidelines.

Age related rise in lactate and its correlation with lactate dehydrogenase (LDH) status in post-mitochondrial fractions isolated from different regions of brain in mice

Rise in brain lactate is the hallmark of ageing. Separate studies report that ageing is associated with elevation of lactate level and alterations of lactate dehydrogenase (LDH)-A/B mRNA-expression-ratio in cerebral cortex and hippocampus. However, age related lactate rise in brain and its association with LDH status and their brain regional variations are still elusive. In the present study, level of lactate, LDH (A and B) activity and LDH-A expression were evaluated in post-mitochondrial fraction of tissues isolated from four different brain regions (cerebral cortex, hippocampus, substantia nigra and cerebellum) of young and aged mice. Lactate levels elevated in four brain regions with maximum rise in substantia nigra of aged mice. LDH-A protein expression and its activity decreased in cerebral cortex, hippocampus and substantia nigra without any changes of these parameters in cerebellum of aged mice. LDH-B activity decreased in hippocampus, substantia nigra and cerebellum whereas its activity remains unaltered in cerebral cortex of aged mice. Accordingly, the ratio of LDH-A/LDH-B-activity remains unaltered in hippocampus and substantia nigra, decreased in cerebral cortex and increased in cerebellum. Therefore, rise of lactate in three brain regions (cerebral cortex, hippocampus, substantia nigra) appeared to be not correlated with the alterations of its regulatory enzymes activities in these three brain regions, rather it supports the fact of involvement of other mechanisms, like lactate transport and/or aerobic/anaerobic metabolism as the possible cause(s) of lactate rise in these three brain regions. The increase in LDH-A/LDH-B-activity-ratio appeared to be positively correlated with elevated lactate level in cerebellum of aged mice. Overall, the present study indicates that the mechanism of rise in lactate in brain varies with brain regions where LDH status plays an important role during ageing.

Neurometabolic and electrophysiological changes during cortical spreading depolarization: multimodal approach based on a lactate-glucose dual microbiosensor arrays

Spreading depolarization (SD) is a slow propagating wave of strong depolarization of neural cells, implicated in several neuropathological conditions. The breakdown of brain homeostasis promotes significant hemodynamic and metabolic alterations, which impacts on neuronal function. In this work we aimed to develop an innovative multimodal approach, encompassing metabolic, electric and hemodynamic measurements, tailored but not limited to study SD. This was based on a novel dual-biosensor based on microelectrode arrays designed to simultaneously monitor lactate and glucose fluctuations and ongoing neuronal activity with high spatial and temporal resolution. In vitro evaluation of dual lactate-glucose microbiosensor revealed an extended linear range, high sensitivity and selectivity, fast response time and low oxygen-, temperature- and pH- dependencies. In anesthetized rats, we measured with the same array a significant drop in glucose concentration matched to a rise in lactate and concurrently with pronounced changes in the spectral profile of LFP-related currents during episodes of mechanically-evoked SD. This occurred along with the stereotypical hemodynamic response of the SD wave. Overall, this multimodal approach successfully demonstrates the capability to monitor metabolic alterations and ongoing electrical activity, thus contributing to a better understanding of the metabolic changes occurring in the brain following SD.

Dose-Dependent Prebiotic Effect of Lactulose in a Computer-Controlled In Vitro Model of the Human Large Intestine.

Lactulose, a disaccharide of galactose and fructose, used as a laxative or ammonia-lowering drug and as a functional food ingredient, enhances growth of Bifidobacterium and Lactobacillus at clinically relevant dosages. The prebiotic effect of subclinical dosages of Lactulose, however, remains to be elucidated. This study analyses changes in the microbiota and their metabolites after a 5 days Lactulose treatment using the TIM-2 system, a computer-controlled model of the proximal large intestine representing a complex, high density, metabolically active, anaerobic microbiota of human origin. Subclinical dosages of 2–5 g Lactulose were used. While 2 g Lactulose already increased the short-chain fatty acid levels of the intestinal content, 5 g Lactulose were required daily for 5 days in this study to exert the full beneficial prebiotic effect consisting of higher bacterial counts of Bifidobacterium, Lactobacillus, and Anaerostipes, a rise in acetate, butyrate and lactate, as well as a decrease in branched-chain fatty acids, pH (suggested by an increase in NaOH usage), and ammonia.

Abstract 5913: The impact of daily exercise on tumor perfusion

Abstract Aberrant blood vessel networks in solid tumors lead to impaired tissue perfusion and areas of hypoxia (pO2 &amp;lt; 10 mmHg). Tumor hypoxia is associated with aggressive progression, dissemination, and therapeutic resistance. It is found in 40% of breast cancers, and can constitute a major obstacle to anticancer therapy. Exercise is associated with improvements in cardiovascular and respiratory function, aerobic capacity and overall health. In cancer patients undergoing therapy, exercise has been shown to decrease treatment related side effects and general fatigue. The goal of the present investigation was to determine whether aerobic exercise could be applied to improve tumor perfusion and oxygenation in a breast cancer model. Such modulation of the tumor physiology and host environment would be expected to lead to enhanced antitumor efficacy when combined with radiotherapy or chemotherapy. The effects of a single and daily bouts of moderate intensity treadmill running were studied in mice bearing the syngeneic murine mammary carcinoma 4T1. The exercise intensity was determined by measuring the anaerobic threshold, which was assessed by measuring the steady rise in blood lactate during exercise. Initial studies examined the effect of a single moderate bout of exercise (18 m/min) in mice bearing ~500 mm3 orthotopic tumors. In subsequent experiments mice were exercised at 18 m/min, 5 days a week, for 8 weeks prior to orthotopic injection of tumor cells and continued exercise (5 days a week) for 2 weeks during tumor growth. Controls for each treatment consisted of sedentary mice exposed to a stationary treadmill for the equivalent amount of time. At the end of each of the exercise regimen, tumors were harvested, sectioned, stained, and tile mapped to assess physiological changes by immunofluorescence. The detection of open blood vessels (Hoechst-33342) was used as an indirect indicator of perfusion. Tumor hypoxia was determined using the 2-nitroimidazole (EF5). Blood vessels were stained using the endothelial cell marker CD-31. All markers were quantified using Photoshop and ImageJ NIH software. Our results indicate that in the 4T1 breast cancer model moderate intensity exercise did not significantly alter tumor growth, oxygenation or blood vessel number. However, daily bouts of exercise did significantly increase the number of open tumor vessels indicating improved tumor perfusion. These results suggest that a daily exercise regimen may have the potential to improve drug delivery to mammary tumors Citation Format: Jennifer M. Wiggins, Sharon Lepler, Christine Pampo, Lori Rice, Jennifer A. Lee, Dietmar Siemann. The impact of daily exercise on tumor perfusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5913. doi:10.1158/1538-7445.AM2017-5913

Limited Resuscitation With Fresh or Stored Whole Blood Corrects Cardiovascular and Metabolic Function in a Rat Model of Polytrauma and Hemorrhage.

We have recently shown that human whole blood stored at 4°C maintains hemostatic and platelet function. In this study, we compared restoration of hemodynamic, metabolic and hemostatic function after limited resuscitation with rat fresh whole blood, rat stored whole blood, or Lactated Ringers in traumatized rats. Rat whole blood was stored for 10 days at 4°C for evaluation of hemostatic function. Polytrauma was performed on isoflurane-anesthetized Sprague-Dawley rats (350-450 g) by damage to the intestines, liver, right leg skeletal muscle, and right femur fracture, followed by 40% hemorrhage. At 1 h, rats were resuscitated (20%) with either fresh whole blood (FWB), stored whole blood, 4°C for 7 days (SWB), Lactated Ringers (LR), or nothing. Blood samples were taken before and 2 h after trauma and hemorrhage to evaluate metabolic and hemostatic function. Whole blood stored for 10 days showed a significant prolongation in prothrombin time (PT) and activated partial thromboplastin time (aPTT), and fall in fibrinogen concentration, but no change in Maximum Clot Firmness or speed of clot formation. Platelet function was maintained until day 7 in storage, than fell significantly. Polytrauma and hemorrhage in rats led to a fall in arterial pressure, plasma bicarbonate, fibrinogen, and platelet function, and a rise in plasma lactate, PT, aPTT, and creatinine. Resuscitation with either FWB or 7 day SWB, but not LR, returned arterial pressure, plasma lactate and plasma bicarbonate to levels similar to control, but had no effect on the fall in fibrinogen or platelet function, or the rise in PT, aPTT, or creatinine. Hemostatic and platelet function of rat whole blood stored at 4°C is preserved for at least 7 days in vitro. Low volume resuscitation with SWB or FWB, but not LR, restores hemodynamic and metabolic function, but not the coagulopathy after severe trauma and hemorrhage.

Agreement of Bioreactance Cardiac Output Monitoring With Thermodilution During Hemorrhagic Shock and Resuscitation in Adult Swine.

The study tests the hypothesis that noninvasive cardiac output monitoring based upon bioreactance (Cheetah Medical, Portland, OR) has acceptable agreement with intermittent bolus thermodilution over a wide range of cardiac output in an adult porcine model of hemorrhagic shock and resuscitation. Prospective laboratory animal investigation. Preclinical university laboratory. Eight ~ 50 kg Yorkshire swine with a femoral artery catheter for blood pressure measurement and a pulmonary artery catheter for bolus thermodilution. With the pigs anesthetized and mechanically ventilated, 40 mL/kg of blood was removed yielding marked hypotension and a rise in plasma lactate. After 60 minutes, pigs were resuscitated with shed blood and crystalloid. Noninvasive cardiac output monitoring and intermittent thermodilution cardiac output were simultaneously measured at nine time points spanning baseline, hemorrhage, and resuscitation. Simultaneous noninvasive cardiac output monitoring and thermodilution measurements of cardiac output were compared by Bland-Altman analysis. A plot was constructed using the difference of each paired measurement expressed as a percentage of the mean of the pair plotted against the mean of the pair. Percent bias was used to scale the differences in the measurements for the magnitude of the cardiac output. Method concordance was assessed from a four-quadrant plot with a 15% zone of exclusion. Overall, noninvasive cardiac output monitoring percent bias was 1.47% (95% CI, -2.5 to 5.4) with limits of agreement of upper equal to 33.4% (95% CI, 26.5-40.2) and lower equal to -30.4% (95% CI, -37.3 to -23.6). Trending analysis demonstrated a 97% concordance between noninvasive cardiac output monitoring and thermodilution cardiac output. Over the wide range of cardiac output produced by hemorrhage and resuscitation in large pigs, noninvasive cardiac output monitoring has acceptable agreement with thermodilution cardiac output.

Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse.

Classic neuroenergetic research has emphasized the role of glucose, its transport and its metabolism in sustaining normal neural function leading to the textbook statement that it is the necessary and sole metabolic fuel of the mammalian brain. New evidence, including the Astrocyte-to-Neuron Lactate Shuttle hypothesis, suggests that the brain can use other metabolic substrates. To further study that possibility, we examined the effect of intraperitoneally administered metabolic fuels (glucose, fructose, lactate, pyruvate, ß-hydroxybutyrate, and galactose), and insulin, on blood, and extracellular brain levels of glucose and lactate in the adult male CD1 mouse. Primary motor cortex extracellular levels of glucose and lactate were monitored in freely moving mice with the use of electrochemical electrodes. Blood concentration of these same metabolites were obtained by tail vein sampling and measured with glucose and lactate meters. Blood and extracellular fluctuations of glucose and lactate were monitored for a 2-h period. We found that the systemic injections of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate increased blood lactate levels. Apart for a small transitory rise in brain extracellular lactate levels, the main effect of the systemic injection of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate was an increase in brain extracellular glucose levels. Systemic galactose injections produced a small rise in blood glucose and lactate but almost no change in brain extracellular lactate and glucose. Systemic insulin injections led to a decrease in blood glucose and a small rise in blood lactate; however brain extracellular glucose and lactate monotonically decreased at the same rate. Our results support the concept that the brain is able to use alternative fuels and the current experiments suggest some of the mechanisms involved.

Pathophysiological Trends During Withdrawal of Life Support: Implications for Organ Donation After Circulatory Death.

Donation after circulatory death (DCD) provides an alternative pathway to deceased organ transplantation. Although clinical DCD lung, liver, and kidney transplantation are well established, transplantation of hearts retrieved from DCD donors has reached clinical translation only recently. Progress has been limited by concern regarding the viability of DCD hearts. The aim of this study was to document the pathophysiological changes that occur in the heart and circulation during withdrawal of life (WLS) support. In a porcine asphyxia model, we characterized the hemodynamic, volumetric, metabolic, biochemical, and endocrine changes after WLS for up to 40 minutes. Times to circulatory arrest and electrical asystole were recorded. After WLS, there was rapid onset of profound hypoxemia resulting in acute pulmonary hypertension and right ventricular distension. Concurrently, progressive systemic hypotension occurred with a fall in left atrial pressure and little change in left ventricular volume. Mean times to circulatory arrest and electrical asystole were 8 ± 1 and 16 ± 2 minutes, respectively. Hemodynamic changes were accompanied by a rapid fall in pH, and rise in blood lactate, troponin-T, and potassium. Plasma noradrenaline and adrenaline levels rose rapidly with dramatic increases in coronary sinus levels indicative of myocardial release. These findings provide insight into the nature and tempo of the damaging events that occur in the heart and in particular the right ventricle during WLS, and give an indication of the limited timeframe for the implementation of potential postmortem interventions that could be applied to improve organ viability.

Advances in understanding the mechanisms of mercury toxicity in wild golden grey mullet (Liza aurata) by 1H NMR-based metabolomics

Mercury (Hg) is recognized as a dangerous contaminant due to its bioaccumulation and biomagnification within trophic levels, leading to serious health risks to aquatic biota. Therefore, there is an urgent need to unravel the mechanisms underlying the toxicity of Hg. To this aim, a metabolomics approach based on protonic nuclear magnetic resonance (1H NMR), coupled with chemometrics, was performed on the gills of wild golden grey mullets L. aurata living in an Hg-polluted area in Ria de Aveiro (Portugal). Gills were selected as target organ due to their direct and continuous interaction with the surrounding environment. As a consequence of accumulated inorganic Hg and methylmercury, severe changes in the gill metabolome were observed, indicating a compromised health status of mullets. Numerous metabolites, i.e. amino acids, osmolytes, carbohydrates, and nucleotides, were identified as potential biomarkers of Hg toxicity in fish gills. Specifically, decrease of taurine and glycerophosphocholine, along with increased creatine level, suggested Hg interference with the ion-osmoregulatory processes. The rise of lactate indicated anaerobic metabolism enhancement. Moreover, the increased levels of amino acids suggested the occurrence of protein catabolism, further supported by the augmented alanine, involved in nitrogenous waste excretion. Increased level of isobutyrate, a marker of anoxia, was suggestive of onset of hypoxic stress at the Hg contaminated site. Moreover, the concomitant reduction in glycerophosphocholine and phosphocholine reflected the occurrence of membrane repair processes. Finally, perturbation in antioxidant defence system was revealed by the depletion in glutathione and its constituent amino acids. All these data were also compared to the differential Hg-induced metabolic responses previously observed in liver of the same mullets (Brandão et al., 2015). Overall, the environmental metabolomics approach demonstrated its effectiveness in the evaluation of Hg toxicity mechanisms in wild fish under realistic environmental conditions, uncovering tissue-specificities regarding Hg toxic effects namely in gills and liver.