Lactate-Protected Hypoglycemia (LPH)

Here, we provide an overview of the concept of a lactate-protected hypoglycemia ("LPH"), originally proposed as lowering glucose while simultaneously increasing lactate concentration as a method by which tumors might be targeted. Central to this hypothesis is that lactate can act as a critical salvage fuel for the central nervous system, allowing for wide perturbations in whole body and central nervous system glucose concentrations. Further, many tumors exhibit "the Warburg" effect, consuming glucose and producing and exporting lactate despite adequate oxygenation. While some recent data have provided evidence for a "reverse-Warburg," where some tumors may preferentially consume lactate, many of these experimental methods rely on a significant elevation in lactate in the tumor microenvironment. To date it remains unclear how various tumors behavein vivo, and how they might respond to perturbations in lactate and glucose concentrations or transport inhibition. By exploiting and targeting lactate transport and metabolism in tumors (with a combination of changes in lactate and glucose concentrations, transport inhibitors, etc.), we can begin developing novel methods for targeting otherwise difficult to treat pathologies in the brain and spinal cord. Here we discuss evidence both experimental and observational, and provide direction for next steps in developing therapies based on these concepts

Lactate-protechypoglycemia (LPH)

Here, we provide an overview of the concept of a lactate-protected hypoglycemia ( LPH ), originally proposed as lowering glucose while simultaneously increasing lactate concentration as a method by which tumors might be targeted. Central to this hypothesis is that lactate can act as a critical salvage fuel for the central nervous system, allowing for wide perturbations in whole body and central nervous system glucose concentrations. Further, many tumors exhibit the Warburg effect, consuming glucose and producing and exporting lactate despite adequate oxygenation. While some recent data have provided evidence for a reverse-Warburg, where some tumors may preferentially consume lactate, many of these experimental methods rely on a significant elevation in lactate in the tumor microenvironment. To date it remains unclear how various tumors behav

Introducing intravascular microdialysis for continuous lactate monitoring in patients undergoing cardiac surgery:a prospective observational study

Introduction: Lactate is a marker of hypoperfusion and may be used for risk assessment in critically ill patients. Although evidence suggests that repeated lactate measurements are of clinical interest, how and when lactate should be analyzed is controversial. Intravascular microdialysis provides a novel method for the continuous monitoring of lactate, which may be clinically beneficial in critically ill patients. Methods: Circulating lactate levels were continuously monitored in 80 patients undergoing cardiac surgery using either a separate single-lumen microdialysis catheter or a triple-lumen central venous catheter with an integrated microdialysis function. The catheter was placed with the tip positioned in the superior vena cava. Arterial blood gas samples were taken every hour to obtain reference values, and the lactate levels were analyzed in a blood gas analyzer. Results: A total of 1,601 paired microdialysis-arterial blood gas lactate samples were obtained. Bland-Altman analysis showed a bias (mean difference) +/- limits of agreement (+/- 1.96 SD) of 0.02 +/- 0.42 mmol/L. The regression coefficient was 0.98 (P = 0.0001). Conclusions: Central venous microdialysis is an accurate and reliable method for continuous blood lactate monitoring in patients undergoing cardiac surgery. The system may be useful for early lactate-guided therapy in critically ill patients

A fast and simple method for the simultaneous analysis of midazolam, 1-hydroxymidazolam, 4-hydroxymidazolam and 1-hydroxymidazolam glucuronide in human serum, plasma and urine

For the quantification of the sedative and anesthetic drug midazolam and its main (active) metabolites 1-hydroxymidazolam, 4-hydroxymidazolam and 1-hydroxymidazolam glucuronide in human serum, human EDTA plasma, human heparin plasma and human urine a single accurate method by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) has been developed. Protein precipitation as sample preparation, without the need of a time-consuming deglucuronidation step for the quantification of 1-hydroxymidazolam glucuronide, resulted in a simple and rapid assay suitable for clinical practice with a total runtime of only 1.1 min. The four components and the isotope-labeled internal standards were separated on a C18 column and detection was performed with a triple-stage quadrupole mass spectrometer operating in positive ionization mode. The method was validated based on the "Guidance for Industry Bioanalytical Method Validation" (Food and Drug Administration, FDA) and the "Guideline on bioanalytical method validation" of the European Medicines Agency (EMA). Linearity was proven over the ranges of 5-1500 μg/L for midazolam, 1-hydroxymidazolam and 4-hydroxymidazolam and 25-5000 μg/L for 1-hydroxymidazolam glucuronide, using a sample volume of 100 μL. Matrix comparison indicated that the assay is also applicable to other human matrices like EDTA and heparin plasma and urine. Stability experiments showed good results for the stability of midazolam, 1-hydroxymidazolam and 1-hydroxymidazolam glucuronide in serum, EDTA and heparin plasma and urine stored for 7 days under different conditions. At room temperature, 4-hydroxymidazo-lam is stable for 7 days in EDTA plasma, but stable for only 3 days in serum and heparin plasma and less than 24 h in urine. All four compounds were found to be stable in serum, EDTA plasma, heparin plasma and urine for 7 days after sample preparation and for 3 freeze-thaw cycles. The assay has been applied in therapeutic drug monitoring of midazolam for (pediatric) intensive care patients

Fluid balance and phase angle as assessed by bioelectrical impedance analysis in critically ill patients:a multicenter prospective cohort study

Background: Bioelectrical impedance analysis (BIA) is a validated method to assess body composition in persons with fluid homeostasis and reliable body weight. This is not the case during critical illness. The raw BIA markers resistance, reactance, phase angle, and vector length are body weight independent. Phase angle reflects cellular health and has prognostic significance. We aimed to assess the course of phase angle and vector length during intensive care unit (ICU) admission, and determine the relation between their changes (Δ) and changes in body hydration. Methods: A prospective, dual-center observational study of adult ICU patients was conducted. Univariate and multivariable regression analyses were performed, including reactance as a marker of cellular mass and integrity and total body water according to the Biasioli equation (TBWBiasioli) and fluid balance as body weight independent markers of hydration. Results: One hundred and fifty-six ICU patients (mean ± SD age 62.5 ± 14.5 years, 67% male) were included. Between days 1 and 3, there was a significant decrease in reactance/m (−2.6 ± 6.0 Ω), phase angle (−0.4 ± 1.1°), and vector length (−12.2 ± 44.3 Ω/m). Markers of hydration significantly increased. Δphase angle and Δvector length were both positively related to Δreactance/m (r2 = 0.55, p < 0.01; r2 = 0.38, p < 0.01). Adding ΔTBWBiasioli as explaining factor strongly improved the association between Δphase angle and Δreactance/m (r2 = 0.73, p < 0.01), and Δvector length and Δreactance/m (r2 = 0.77, p < 0.01). Conclusions: Our results show that during critical illness, changes in phase angle and vector length partially reflect changes in hydration

FDG-PET/CT in intensive care patients with bloodstream infection

BACKGROUND: 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) is an advanced imaging technique that can be used to examine the whole body for an infection focus in a single examination in patients with bloodstream infection (BSI) of unknown origin. However, literature on the use of this technique in intensive care patients is scarce. The purpose of this study was to evaluate the diagnostic yield of FDG-PET/CT in intensive care patients with BSI. METHODS: In this retrospective cohort study, all intensive care patients from our Dutch university medical center who had culture-proven BSI between 2010 and 2020 and underwent FDG-PET/CT to find the focus of infection were included. Diagnostic performance was calculated and logistic regression analysis was performed to evaluate the association between FDG-PET/CT outcome and C-reactive protein level (CRP), leukocyte count, duration of antibiotic treatment, duration of ICU stay, quality of FDG-PET/CT, and dependency on mechanical ventilation. In addition, the impact of FDG-PET/CT on clinical treatment was evaluated. RESULTS: 30 intensive care patients with BSI were included. In 21 patients, an infection focus was found on FDG-PET/CT which led to changes in clinical management in 14 patients. FDG-PET/CT achieved a sensitivity of 90.9% and specificity of 87.5% for identifying the focus of infection. Poor quality of the FDG-PET images significantly decreased the likelihood of finding an infection focus as compared to reasonable or good image quality (OR 0.16, P = 0.034). No other variables were significantly associated with FDG-PET/CT outcome. No adverse events during the FDG-PET/CT procedure were reported. CONCLUSION: FDG-PET/CT has a high diagnostic yield for detecting the infection focus in patients with BSI admitted to intensive care. Poor PET image quality was significantly associated with a decreased likelihood of finding the infection focus in patients with BSI. This could be improved by adequate dietary preparation and cessation of intravenous glucose and glucose-regulating drugs. Recent advances in PET/CT technology enable higher image quality with shorter imaging time and may contribute to routinely performing FDG-PET/CT in intensive care patients with BSI of unknown origin

Metformin Preconditioning Improves Hepatobiliary Function and Reduces Injury in a Rat Model of Normothermic Machine Perfusion and Orthotopic Transplantation

Background. Preconditioning of donor livers before organ retrieval may improve organ quality after transplantation. We investigated whether preconditioning with metformin reduces preservation injury and improves hepatobiliary function in rat donor livers during ex situ normothermic machine perfusion (NMP) and after orthotopic liver transplantation. Methods. Lewis rats were administered metformin via oral gavage, after which a donor hepatectomy was performed followed by a standardized cold storage period of 4 hours. Graft assessment was performed using NMP via double perfusion of the hepatic artery and portal vein. In an additional experiment, rat donor livers preconditioned with metformin were stored on ice for 4 hours and transplanted to confirm postoperative liver function and survival. Data were analyzed and compared with sham-fed controls. Results. Graft assessment using NMP confirmed that preconditioning significantly improved ATP production, markers for hepatobiliary function (total bile production, biliary bilirubin, and bicarbonate), and significantly lowered levels of lactate, glucose, and apoptosis. After orthotopic liver transplantation, metformin preconditioning significantly reduced transaminase levels. Conclusions. Preconditioning with metformin lowers hepatobiliary injury and improves hepatobiliary function in an in situ and ex situ model of rat donor liver transplantation

Effect of high-dose dexamethasone on perioperative lactate levels and glucose control:a randomized controlled trial

INTRODUCTION: Blood lactate levels are increasingly used to monitor patients. Steroids are frequently administered to critically ill patients. However, the effect of steroids on lactate levels has not been adequately investigated. We studied the effect of a single intraoperative high dose of dexamethasone on lactate and glucose levels in patients undergoing cardiac surgery. METHODS: The Dexamethasone for Cardiac Surgery (DECS) trial was a multicenter randomized trial on the effect of dexamethasone 1 mg/kg versus placebo on clinical outcomes after cardiac surgery in adults. Here we report a pre-planned secondary analysis of data from DECS trial participants included at the University Medical Center Groningen. The use of a computer-assisted glucose regulation protocol--Glucose Regulation for Intensive care Patients (GRIP)--was part of routine postoperative care. GRIP aimed at glucose levels of 4 to 8 mmol/L. Primary outcome parameters were area under the lactate and glucose curves over the first 15 hours of ICU stay (AUC₁₅). ICU length of stay and mortality were observed as well. RESULTS: The primary outcome could be determined in 497 patients of the 500 included patients. During the first 15 hours of ICU stay, lactate and glucose levels were significantly higher in the dexamethasone group than in the placebo group: lactate AUC₁₅ 25.8 (13.1) versus 19.9 (11.2) mmol/L × hour, P <0.001 and glucose AUC₁₅ 126.5 (13.0) versus 114.4 (13.9) mmol/L × hour, P <0.001. In this period, patients in the dexamethasone group required twice as much insulin compared with patients who had received placebo. Multivariate and cross-correlation analyses suggest that the effect of dexamethasone on lactate levels is related to preceding increased glucose levels. Patients in the placebo group were more likely to stay in the ICU for more than 24 hours (39.2%) compared with patients in the dexamethasone group (25.0%, P = 0.001), and 30-day mortality rates were 1.6% and 2.4%, respectively (P = 0.759). CONCLUSIONS: Intraoperative high-dose dexamethasone increased postoperative lactate and glucose levels in the first 15 hours of ICU stay. Still, patients in the dexamethasone group had a shorter ICU length of stay and similar mortality compared with controls. TRIAL REGISTRATION: ClinicalTrials.gov NCT00293592 . Registered 16 February 2006