Effects of endotoxin on lactate metabolism in humans.

INTRODUCTION: Hyperlactatemia represents one prominent component of the metabolic response to sepsis. In critically ill patients, hyperlactatemia is related to the severity of the underlying condition. Both an increased production and a decreased utilization and clearance might be involved in this process, but their relative contribution remains unknown. The present study aimed at assessing systemic and muscle lactate production and systemic lactate clearance in healthy human volunteers, using intravenous endotoxin (LPS) challenge. METHODS: Fourteen healthy male volunteers were enrolled in 2 consecutive studies (n = 6 in trial 1 and n = 8 in trial 2). Each subject took part in one of two investigation days (LPS-day with endotoxin injection and placebo-day with saline injection) separated by one week at least and in a random order. In trial 1, their muscle lactate metabolism was monitored using microdialysis. In trial 2, their systemic lactate metabolism was monitored by means of a constant infusion of exogenous lactate. Energy metabolism was monitored by indirect calorimetry and glucose kinetics was measured with 6,6-H2 glucose. RESULTS: In both trials, LPS increased energy expenditure (p = 0.011), lipid oxidation (p<0.0001), and plasma lactate concentration (p = 0.016). In trial 1, lactate concentration in the muscle microdialysate was higher than in blood, indicating lactate production by muscles. This was, however, similar with and without LPS. In trial 2, calculated systemic lactate production increased after LPS (p = 0.031), while lactate clearance remained unchanged. CONCLUSIONS: LPS administration increases lactatemia by increasing lactate production rather than by decreasing lactate clearance. Muscle is, however, unlikely to be a major contributor to this increase in lactate production. TRIAL REGISTRATION: ClinicalTrials.gov NCT01647997.

Intravenous fish oil blunts the physiological response to endotoxin in healthy subjects.

OBJECTIVE: To assess the effects of intravenous fish oil fat emulsion on the metabolic alterations induced by lipopolysaccharide (LPS) challenge in healthy volunteers. DESIGN: Two groups of eight healthy subjects were randomized to receive either two pharmacological doses of intravenous FO fat emulsion or no treatment. The FO group received twice 0.5 g/kg 10% emulsion (Omegaven) 48 and 24h before investigation. LPS (2 ng/kg) was injected as a bolus on the investigation day. Systemic parameters, indirect calorimetry, heart rate variability, and platelet membrane phospholipid composition were measured. RESULTS: Basal EPA and DHA content in platelet phospholipids was low (0.28% and 2.54%, respectively) and increased significantly after FO to 1.68% and 3.32%. LPS induced reproducible effects in all subjects. Fever was higher in the control [corrected] group than in FO group [corrected] the difference was significant from t (120) until t (360). FO blunted the neuroendocrine response: the rise in plasma norepinephrine was sevenfold lower at t (120) while the ACTH peak was fourfold lower. Tumor necrosis factor alpha was significantly lower between t (360) and t (180) in the FO group. CONCLUSIONS: Two doses of intravenous FO fat emulsion modified the phospholipid composition of platelets in healthy subjects. FO blunted fever and increased the neuroendocrine and the inflammatory responses to LPS.

Effects of fish oil on the neuro-endocrine responses to an endotoxin challenge in healthy volunteers.

BACKGROUND & AIMS: Fish oil (FO) has been shown to modulate the acute and chronic inflammatory responses. Endotoxin (LPS) has been shown to mimic several aspects of sepsis. The study aimed at testing the effects of oral FO supplements in healthy subjects submitted to intravenous LPS on systemic and endocrine response. SUBJECTS AND METHODS: Fifteen healthy men (aged 26.0+/-3.1 years, BMI 23.8+/-1.9 kg/m2), were enrolled. Subjects were randomised to 3-4 weeks of oral FO supplementation (7.2 g/day, providing 1.1 g/day of 20:5 (n-3) and 0.7 g/day of 22:6 (n-3) fatty acids) or no supplementation and then submitted to endotoxin challenge: 2 ng/kg of LPS. All subjects were studied twice (placebo and LPS). MEASUREMENTS: vital signs, energy expenditure (EE), glucose and lipid metabolism ((2)H2-glucose), plasma cytokines and stress hormones for 6 h after LPS or placebo. RESULTS: LPS caused cytokine release, fever, increases in heart rate, resting EE and substrate oxidation, plasma glucagon and glucose concentrations; the neuro-endocrine response was characterised by increased plasma stress hormones. FO significantly blunted fever, ACTH and cortisol plasma levels (no effect on cytokine release). FO blunted the peak norepinephrine after LPS. CONCLUSION: FO supplements blunted the endocrine stress response and the increase in body temperature, but had no impact on cytokine production after LPS. These findings conflict with the postulated anti-inflammatory effects of FO on arachidonic acid metabolism and cytokine release. These results suggest that FO may exert beneficial effects in sepsis though non-inflammatory which require further investigations.

[Autologous blood pre-donation and perioperative use of erythropoietin]. / Prédonation autologue et place de l'érythropoïétine en phase périopératoire.

The general concept of blood saving covers a number of technical and pharmacological actions which all aim to maintain the erythrocyte mass of the patient, and of which blood transfusion is only one. Severe anemia (Hb <60-80 g/l) increases postoperative mortality and morbidity. However, its correction by blood transfusion tends to worsen the prognosis. It is therefore imperative to conserve the patient's blood by any means possible. Detecting anemia is of primary importance. Whenever possible, its cause should be identified and treated. Depending on the detected anemia, as well as the blood loss expected during surgery, the patient should receive EPO (anemia with foreseeable moderate blood loss), or autologous pre-donation associated with EPO (anemia with foreseeable large blood loss).

The influence of the suppression of gastrooesophageal reflux on the gene expression pattern in Barrett's oesophagus.

About 10% of Barrett's patients develop an adenocarcinoma in the course of life. There is increasing evidence that persistent gastrooesophageal reflux is involved in carcinogenesis. We investigated whether the gene expression pattern of Barrett's epithelium cells changes upon suppression of gastrooesophageal reflux compared to unsuppressed reflux. Biopsies from various regions of Barrett's segments and, further, during and without proton pump inhibitor therapy were collected in 5 patients. The reflux profile was assessed by simultaneous 24-h oesophageal pH and bile reflux testing. m-RNA was extracted from the specimens, and integrity and absence of DNA proven by gel electrophoresis and ALU-PCR. Using the micro array technique 1,176 genes were analysed and assigned an expression level. The number of genes detected in each experiment varied from 86 to 136. There was a 91% concordance of the gene expression pattern in distal and proximal biopsies from an individual Barrett's segment. Concordance was much less (68%) between biopsies of the same patient taken during and without proton pump inhibitor therapy. The gene expression pattern in a Barrett's oesophagus varies dependent upon different reflux situations. Other factors like the location of biopsy are of minor importance. The micro array technique allows for selection of candidate genes important in carcinogenesis.