Bacterial colonization and infection of electrophysiological cardiac devices detected with sonication and swab culture.

BACKGROUND: Electrophysiological cardiac devices are increasingly used. The frequency of subclinical infection is unknown. We investigated all explanted devices using sonication, a method for detection of microbial biofilms on foreign bodies. METHODS AND RESULTS: Consecutive patients in whom cardiac pacemakers and implantable cardioverter/defibrillators were removed at our institution between October 2007 and December 2008 were prospectively included. Devices (generator and/or leads) were aseptically removed and sonicated, and the resulting sonication fluid was cultured. In parallel, conventional swabs of the generator pouch were performed. A total of 121 removed devices (68 pacemakers, 53 implantable cardioverter/defibrillators) were included. The reasons for removal were insufficient battery charge (n=102), device upgrading (n=9), device dysfunction (n=4), or infection (n=6). In 115 episodes (95%) without clinical evidence of infection, 44 (38%) grew bacteria in sonication fluid, including Propionibacterium acnes (n=27), coagulase-negative staphylococci (n=11), Gram-positive anaerobe cocci (n=3), Gram-positive anaerobe rods (n=1), Gram-negative rods (n=1), and mixed bacteria (n=1). In 21 of 44 sonication-positive episodes, bacterial counts were significant (>or=10 colony-forming units/mL of sonication fluid). In 26 sterilized controls, sonication cultures remained negative in 25 cases (96%). In 112 cases without clinical infection, conventional swab cultures were performed: 30 cultures (27%) were positive, and 18 (60%) were concordant with sonication fluid cultures. Six devices and leads were removed because of infection, growing Staphylococcus aureus, Streptococcus mitis, and coagulase-negative staphylococci in 6 sonication fluid cultures and 4 conventional swab cultures. CONCLUSIONS: Bacteria can colonize cardiac electrophysiological devices without clinical signs of infection.

Invasion of lesion territory by regenerating fibers after spinal cord injury in adult macaque monkeys.

In adult macaque monkeys subjected to an incomplete spinal cord injury (SCI), corticospinal (CS) fibers are rarely observed to grow in the lesion territory. This situation is little affected by the application of an anti-Nogo-A antibody which otherwise fosters the growth of CS fibers rostrally and caudally to the lesion. However, when using the Sternberger monoclonal-incorporated antibody 32 (SMI-32), a marker detecting a non-phosphorylated neurofilament epitope, numerous SMI-32-positive (+) fibers were observed in the spinal lesion territory of 18 adult macaque monkeys; eight of these animals had received a control antibody infusion intrathecally for 1month after the injury, five animals an anti-Nogo-A antibody, and five animals received an anti-Nogo-A antibody together with brain-derived neurotrophic factor (BDNF). These fibers occupied the whole dorso-ventral axis of the lesion site with a tendency to accumulate on the ventral side, and their trajectories were erratic. Most of these fibers (about 87%) were larger than 1.3μm and densely SMI-32 (+) stained. In the undamaged spinal tissue, motoneurons form the only large population of SMI-32 (+) neurons which are densely stained and have large diameter axons. These data therefore suggest that a sizeable proportion of the fibers seen in the lesion territory originate from motoneurons, although fibers of other origins could also contribute. Neither the presence of the antibody neutralizing Nogo-A alone, nor the presence of the antibody neutralizing Nogo-A combined with BDNF influenced the number or the length of the SMI-32 (+) fibers in the spinal lesion area. In summary, our data show that after a spinal cord lesion in adult monkeys, the lesion site is colonized by fibers, a large portion of which presumably originate from motoneurons.

Calcium reabsorption in the distal tubule: regulation by sodium, pH, and flow.

We developed a mathematical model of Ca transport along the late distal convoluted tubule (DCT2) and the connecting tubule (CNT) to investigate the mechanisms that regulate Ca reabsorption in the DCT2-CNT. The model accounts for apical Ca influx across transient receptor potential vanilloid 5 (TRPV5) channels and basolateral Ca efflux via plasma membrane Ca-ATPase pumps and type 1 Na/Ca exchangers (NCX1). Model simulations reproduce experimentally observed variations in Ca uptake as a function of extracellular pH, Na, and Mg concentration. Our results indicate that amiloride enhances Ca reabsorption in the DCT2-CNT predominantly by increasing the driving force across NCX1, thereby stimulating Ca efflux. They also suggest that because aldosterone upregulates both apical and basolateral Na transport pathways, it has a lesser impact on Ca reabsorption than amiloride. Conversely, the model predicts that full NCX1 inhibition and parathyroidectomy each augment the Ca load delivered to the collecting duct severalfold. In addition, our results suggest that regulation of TRPV5 activity by luminal pH has a small impact, per se, on transepithelial Ca fluxes; the reduction in Ca reabsorption induced by metabolic acidosis likely stems from decreases in TRPV5 expression. In contrast, elevations in luminal Ca are predicted to significantly decrease TRPV5 activity via the Ca-sensing receptor. Nevertheless, following the administration of furosemide, the calcium-sensing receptor-mediated increase in Ca reabsorption in the DCT2-CNT is calculated to be insufficient to prevent hypercalciuria. Altogether, our model predicts complex interactions between calcium and sodium reabsorption in the DCT2-CNT.

Rise in plasma lactate concentrations with psychosocial stress: a possible sign of cerebral energy demand.

OBJECTIVE: It is known that exogenous lactate given as an i.v. energy infusion is able to counteract a neuroglycopenic state that developed during psychosocial stress. It is unknown, however, whether the brain under stressful conditions can induce a rise in plasma lactate to satisfy its increased needs during stress. Since lactate is i) an alternative cerebral energy substrate to glucose and ii) its plasmatic concentration is influenced by the sympathetic nervous system, the present study aimed at investigating whether plasma lactate concentrations increase with psychosocial stress in humans. METHODS: 30 healthy young men participated in two sessions (stress induced by the Trier Social Stress Test and a non-stress control session). Blood samples were frequently taken to assess plasma lactate concentrations and stress hormone profiles. RESULTS: Plasma lactate increased 47% during psychosocial stress (from 0.9 ± 0.05 to 1.4 ± 0.1 mmol/l; interaction time × stress intervention: F = 19.7, p < 0.001). This increase in lactate concentrations during stress was associated with an increase in epinephrine (R(2) = 0.221, p = 0.02) and ACTH concentrations (R(2) = 0.460, p < 0.001). CONCLUSION: Plasma lactate concentrations increase during acute psychosocial stress in humans. This finding suggests the existence of a demand mechanism that functions to allocate an additional source of energy from the body towards the brain, which we refer to as 'cerebral lactate demand'.

Effects of neuropeptide Y on the blood pressure response to various vasoconstrictor agents.

Neuropeptide Y (NPY) is known to potentiate the pressor effect of norepinephrine. In the present work, we evaluated in unanesthetized normotensive rats the effect of NPY on blood pressure responsiveness not only to norepinephrine, but also to tyramine, a sympathomimetic agent acting indirectly to B-HT933, a selective alpha-2 adrenoceptor stimulant, to angiotensin II and vasopressin. Dose-response curves to the various pressor agents were established starting at the 45th min of an i.v. infusion with either NPY (0.025 and 0.1 microgram/min) or its vehicle. The two doses of NPY increased blood pressure by an average of approximately 6 mm Hg, which was not significantly different from the vehicle-induced blood pressure changes. NPY significantly enhanced the pressor effect of norepinephrine, tyramine and angiotensin II, but not that of B-HT933 and vasopressin. We also tested whether NPY inhibits the enzyme activity of Na, K-adenosine triphosphatase using a purified toad kidney preparation. Concentrations of NPY from 10(-14) M up to 10(-6) M had no effect on the enzyme activity. It appears therefore that the blood pressure potentiating effect of NPY is not restricted to alpha adrenoceptor stimulation with norepinephrine, but involves also the vasoconstrictor hormone angiotensin II. This NPY-induced potentiation does not seem to depend upon stimulation of alpha-2 adrenoceptors or inhibition of Na,K-adenosine triphosphatase.

Effects of fructose on hepatic glucose metabolism in humans.

Hepatic and extrahepatic insulin sensitivity was assessed in six healthy humans from the insulin infusion required to maintain an 8 mmol/l glucose concentration during hyperglycemic pancreatic clamp with or without infusion of 16.7 micromol. kg(-1). min(-1) fructose. Glucose rate of disappearance (GR(d)), net endogenous glucose production (NEGP), total glucose output (TGO), and glucose cycling (GC) were measured with [6,6-(2)H(2)]- and [2-(2)H(1)]glucose. Hepatic glycogen synthesis was estimated from uridine diphosphoglucose (UDPG) kinetics as assessed with [1-(13)C]galactose and acetaminophen. Fructose infusion increased insulin requirements 2.3-fold to maintain blood glucose. Fructose infusion doubled UDPG turnover, but there was no effect on TGO, GC, NEGP, or GR(d) under hyperglycemic pancreatic clamp protocol conditions. When insulin concentrations were matched during a second hyperglycemic pancreatic clamp protocol, fructose administration was associated with an 11.1 micromol. kg(-1). min(-1) increase in TGO, a 7.8 micromol. kg(-1). min(-1) increase in NEGP, a 2.2 micromol. kg(-1). min(-1) increase in GC, and a 7.2 micromol. kg(-1). min(-1) decrease in GR(d) (P < 0. 05). These results indicate that fructose infusion induces hepatic and extrahepatic insulin resistance in humans.

Panobacumab adjunctive immuno-therapy for Pseudomonas aeruginosa hospital-acquired pneumonia versus a cohort group

Objectives: To assess the efficacy of Panobacumab, a fully human IgM monoclonal antibody against P. aeruginosa serotype O11, by comparing a phase IIa trial with a standard care cohort trial both in hospital acquired pneumonia (HAP) caused by P. aeruginosa O11. Methods: Demographics, outcome and survival of HAP including Ventilator Associated Pneumonia (VAP) in patients either treated with standard antimicrobial therapy in a retrospective cohort trial (CT) or with adjunctive Panobacumab therapy during an open phase IIa trial were compared. Both trials applied the same inclusion exclusion criteria and the same trial period of 30 days. Results: 17 patients with VAP/HAP (14 / 3) caused by P. aeruginosa O11 were enrolled in a phase IIa trial (ITT population) and treated with Panobacumab, 13 of them received the full treatment course of 3 infusions (PP population, 12 VAP, 1 HAP) and 4 patients received only one infusion. In the cohort trial 14 patients (VAP/HAP: 12 / 2) treated with standard antibiotic therapy were included. The mean age and weight were 65.8 y (years) (SD 17.2) and 78.0 kg (SD 22.1) in the PP, 67.8 y (SD 15.4) and 77.1 kg (SD 20.2) in the ITT population and 51.8 y (SD 22.3) and 67.1 kg (SD 13.0) in the CT. At the time of suspicion of pneumonia a mean APACHE II and CPIS of 19.4 (13 - 33) and 8.7 (7 - 11) in the PP, 18.9 (13-33) and 8.5 (7 -11) in the ITT and 14.5 (2 - 24) and 7.5 (3 -12) in the CT population were observed. Tracheostomy was present in 53.8% and 52.9% in the PP and ITT populations and 38.4% in the CT. The pneumonia was polymicrobial in 69.2%, 70.6% and 85.7% in the PP, ITT and CT respectively. Stay at ICU and hospital before diagnosis of pneumonia were similar in the 3 groups. All 13 patients that received 3 doses of Panobacumab achieved resolution of pneumonia with only two relapsing during the study. Hence 85% achieved resolution and 15% recurrence at day 30. In the ITT group 64.7% of the pneumonia resolved 11.8% recurred and 23.5% continued while in the CT 57% resolved, 7% recurred and 34% continued. Resolution of pneumonia occurred markedly earlier in the Panobacumab trial (8.9 days, SD: 3.3) than in the cohort trial (15.3 days, SD: 9.5). The expected mortality derived from APACHE II score was 31% and 32% in the PP and ITT population and 22% in the cohort group. All patients who received 3 doses of Panobacumab survived, 18% died in the ITT group while in the CT 21% mortality matched the predicted mortality. Conclusions: Treatment of VAP/HAP caused by P. aeruginosa O11 with 3 doses of Panobacumab resulted in 100% survival, with highest pneumonia resolution (85%), and in a shorter time when compared with patients under standard therapy. The results indicate that Panobacumab may be effective in such life-threatening indication and warrants larger controlled trials.

Hyponatrémie: une histoire en deux temps... [Hyponatremia: an unusual case report]

Hyponatremia is a frequent finding and asks for a rapid diagnostic evaluation. We report a case of recurrent hyponatremia secondary to an adrenal insufficiency of medicamentous and tuberculous origin. This case illustrates the importance of a rapid etiologic diagnosis of hyponatremia and allows us to review adrenal insufficiency of tuberculous origin. It also stresses the danger of potential drug interactions in case of corticosteroid substitution.

Effect of computerisation on the quality and safety of chemotherapy prescription.

BACKGROUND: Chemotherapy is prescribed according to protocols of several cycles. These protocols include not only therapeutic agents but also adjuvant solvents and inherent supportive care measures. Multiple errors can occur during the prescription, the transmission of documents and the drug delivery processes, and lead to potentially serious consequences. OBJECTIVE: To assess the effect of a computerised physician order entry (CPOE) system on the number of errors in prescription recorded by the centralised chemotherapy unit of a pharmacy service in a university hospital. PATIENTS AND METHODS: Existing chemotherapy protocols were standardised by a multidisciplinary team (composed of a doctor, a pharmacist and a nurse) and a CPOE system was developed from a File Maker Pro database. Chemotherapy protocols were progressively introduced into the CPOE system. The effect of the system on prescribing errors was measured over 15 months before and 21 months after starting computerised protocol prescription. Errors were classified as major (dosage and drug name) and minor (volume or type of infusion solution). RESULTS: Before computerisation, 141 errors were recorded for 940 prescribed chemotherapy regimens (15%). After introduction of the CPOE system, 75 errors were recorded for 1505 prescribed chemotherapy regimens (5%). Of these errors, 69 (92%) were recorded in prescriptions that did not use a computerised protocol. A dramatic decrease in the number of errors was noticeable when 50% of the chemotherapy protocols were prescribed through the CPOE system. CONCLUSION: Errors in chemotherapy prescription nearly disappeared after implementation of CPOE. The safety of chemotherapy prescription was markedly improved.

Effect of bicarbonate and lactate buffer on glucose and lactate metabolism during hemodiafiltration in patients with multiple organ failure.

OBJECTIVE: To compare the effects of sodium bicarbonate and lactate for continuous veno-venous hemodiafiltration (CVVHDF) in critically ill patients. DESIGN AND SETTINGS: Prospective crossed-over controlled trial in the surgical and medical ICUs of a university hospital. PATIENTS: Eight patients with multiple organ dysfunction syndrome (MODS) requiring CVVHDF. INTERVENTION: Each patient received the two buffers in a randomized sequence over two consecutive days. MEASUREMENTS AND RESULTS: The following variables were determined: acid-base parameters, lactate production and utilization ((13)C lactate infusion), glucose turnover (6,6(2)H(2)-glucose), gas exchange (indirect calorimetry). No side effect was observed during lactate administration. Baseline arterial acid-base variables were equal with the two buffers. Arterial lactate (2.9 versus 1.5 mmol/l), glycemia (+18%) and glucose turnover (+23%) were higher in the lactate period. Bicarbonate and glucose losses in CVVHDF were substantial, but not lactate elimination. Infusing (13)C lactate increased plasma lactate levels equally with the two buffers. Lactate clearance (7.8+/-0.8 vs 7.5+/-0.8 ml/kg per min in the bicarbonate and lactate periods) and endogenous production rates (14.0+/-2.6 vs 13.6+/-2.6 mmol/kg per min) were similar. (13)C lactate was used as a metabolic substrate, as shown by (13)CO(2) excretion. Glycemia and metabolic rate increased significantly and similarly during the two periods during lactate infusion. CONCLUSION: Lactate was rapidly cleared from the blood of critically ill patients without acute liver failure requiring CVVHDF, being transformed into glucose or oxidized. Lactate did not exert undesirable effects, except moderate hyperglycemia, and achieved comparable effects on acid-base balance to bicarbonate.

Concomitant administration of intravenous drugs in the ICU: evaluation of physico-chemical compatibilities

Background and objective: Patients in the ICU often get many intravenous (iv) drugs at the same time. Even with three-lumen central venous catheters, the administration of more than one drug in the same iv line (IVL) is frequently necessary. The objective of this study was to observe how nurses managed to administer these many medications and to evaluate the proportion of two-drugs associations (TDA) that are compatible or not, based on known compatibility data. Design: Observational prospective study over 4 consecutive months. All patients receiving simultaneously more than one drugs in the same IVL (Y-site injection or mixed in the same container) were included. For each patient, all iv drugs were recorded, as well as concentration, infusion solution, location on the IVL system, time, rate and duration of administration. For each association of two or more drugs, compatibility of each drug was checked with each other. Compatibilities between these pairs of drugs were assessed using published data (mainly Trissel LA. Handbook on Injectable Drugs and Trissel's Tables of Physical Compatibility) and visual tests performed in our quality control laboratory. Setting: 34 beds university hospital adult ICU. Main outcome measures: Percentage of compatibilities and incompatibilities between drugs administered in the same IVL. Results: We observed 1,913 associations of drugs administered together in the same IVL, 783 implying only two drugs. The average number of drugs per IVL was 3.1 ± 0.8 (range: 2-9). 83.2% of the drugs were given by continuous infusion, 14.3% by intermittent infusion and 2.5% in bolus. The associations observed allowed to form 8,421 pairs of drugs (71.7% drug-drug and 28.3% drug-solute). According to literature data, 80.2% of the association were considered as compatible and 4.4% incompatible. 15.4% were not interpretable because of different conditions between local practices and those described in the literature (drug concentration, solute, etc.) or because of a lack of data. After laboratory tests performed on the most used drugs (furosemide, KH2PO4, morphine HCl, etc.), the proportion of compatible TDA raised to 85.7%, the incompatible stayed at 4.6% and only 9.7% remain unknown or not interpretable. Conclusions: Nurses managed the administration of iv medications quite well, as only less than 5% of observed TDA were considered as incompatible. But the 10% of TDA with unavailable compatibility data should have been avoided too, since the consequences of their concomitant administration cannot be predictable. For practical reasons, drugs were analysed only by pairs, which constitutes the main limit of this work. The average number of drugs in the same association being three, laboratory tests are currently performed to evaluate some of the most observed three-drugs associations.

Glutamine synthesis rate in the hyperammonaemic rat brain using simultaneous localized in vivo H-1 and N-15 MRS

Objectives: Glutamine synthetase is a critical step in the glutamate-glutamine cycle, the major mechanism of glutamate neurotransmission and is implicated in the mechanism of ammonia toxicity. 15N MRS is an alternative approach to 13C MRS in studying glutamate- glutamine metabolism. 15N MRS studies allow to measure an apparent glutamine synthesis rate (Vsyn) which reflects a combination of the glutamate- glutamine cycle activity (Vnt) and net glutamine accumulation. The net glutamine synthesis (Vsyn-Vnt) can be directly measured from 1H NMR. Therefore, the aim of this study was to perform in vivo localized 1H MRS interleaved with 15N MRS to directly measure the net glutamine synthesis rate and the apparent glutamine synthesis rate under 15N labeled ammonia infusion in the rat brain, respectively. Methods: 1H and 15N MRS data were acquired interleaved on a 9.4T system (Varian/Magnex Scientific) using 5 rats. 15NH4Cl solution was infused continuously into the femoral vein for up to 10 h (4.5 mmol/h/kg).1 The plasma ammonia concentration was increased to 0.95±0.08 mmol/L (Analox GM7 analyzer). 1H spectra were acquired and quantified as described previously.2 15N unlocalized and localized spectra were acquired using the sequence;3 and quantified using AMARES and an external reference method.4 The metabolic model used to analyze the total Gln and 5-15N labeled Gln time courses is shown on Figure 1A. Results: Glutamine concentration increased from 2.5±0.3 to 15±3.3 mmol/kg whereas the total glutamate concentrations remained unchanged (Figure 1B). The linear fit of the time-evolution of the total Gln from the 1H spectra gave the net synthesis flux (Vsyn-Vnt), which was 0.021± 0.006 mmol/min per g (Figure 1D). The 5-15N Gln peak (_271 ppm) was visible in the first and all subsequent scans, whereas the 2-15N Gln/Glu peak (_342 ppm) appeared after B1.5 h (Figure 1C). From the in vivo 5-15N Gln time course, Vsyn = 0.29±0.1 mmol/min per g and a plasma NH3 fractional enrichment of 71%±6% were calculated. Vnt was 0.26±0.1 mmol/min/g, obtained assuming a negligible Gln efflux.5 Vsyn and Vnt were within the range of 13C NMR measurements.6 Conclusion: The combination of 1H and 15N NMR allowed for the first time a direct and localized measurement of Vnt and apparent glutamine synthesis rate. Vnt is approximately one order of magnitude faster than the net glutamine accumulation.

Thermogenesis and fructose metabolism in humans.

Resting metabolic rate was measured in 10 healthy volunteers (25 yr, 73 kg, 182 cm) for 1 h before and 4 h during intravenous (iv) fructose administration (20% at 50 mumol.kg-1.min-1) with (+P) or without (-P) propranolol (100 micrograms/kg, 1 microgram.kg-1.min-1) during the last 2 h. Some subjects were studied a further 2 h with fructose infusion and +P or -P in hyperinsulinemic (2.9 pmol.kg-1.min-1) euglycemic conditions. Glucose turnover ([3-3H]glucose, 20 muCi bolus and 0.2 muCi/min) was calculated over 30 min at 0, 2, 4, and 6 h. The thermic effect of iv fructose was approximately 7.5% and decreased to 4.9 +/- 0.4% (P less than 0.01) +P. During the euglycemic clamp the thermic effect was 6.2 +/- 0.9% (-P) and 5.3 +/- 0.9% (+P). Hepatic glucose production (HGP) was 11.7 mumol.kg-1.min-1 (0 h) and did not change after 2 h iv fructose (11.8 +/- 0.5 and 9.8 +/- 0.6 mumol.kg-1.min-1 -P and +P, respectively) but increased to 13.8 +/- 0.9 (-P) and 12.9 +/- 0.8 mumol.kg-1.min-1 (+P) (P less than 0.01) after 4 h. HGP was suppressed to varying degrees during the euglycemic clamp. It is concluded that 1) the greater thermic effect of fructose compared with glucose is probably due to continued gluconeogenesis (which is suppressed by glucose or glucose-insulin) and the energy cost of fructose metabolism to glucose in the liver. 2) There is a sympathetically mediated component to the thermic effect of fructose (approximately 30%) that is not mediated by elevated plasma insulin concentrations similar to those observed with iv glucose.

Intrathecal administration of Ziconotide: does single-shot injection predict efficacy?

Introduction: Though a trial of intrathecal (IT) therapy should always be performed before implantation of a definitive intrathecal pump, there is no agreement as to how this test should be performed. Ziconotide is trialed in most of cases with continuous IT administration using implanted catheters. Unlike other intrathecal drugs, there is little experience with single bolus IT injections of ziconotide. The aim of the study is to assess the feasibility of single-shot IT trialing with ziconotide. Patients and methods: Eleven consecutive patients with chronic neuropathic intractable pain were trialed with a single IT bolus of 2.5 mcg of ziconotide. Pain and side effects are monitored for at least 72 hours after the injection. Depending on the response, a second injection is given a week later, with either the same dose (if VAS decreased ≥50% without side effects), a higher dose of 3.75 mcg (if VAS decreased <50% without side effects) or a lower dose of 1.25 mcg (if VAS decreased ≥50% but with side effects). If VAS decreased less than 50% and side effects occurred, no further injection was performed. When VAS decreased >50% without side effects after the first or the second dose, the result is confirmed by one more injection of the same dose one week later. The trial is considered positive if two successive injections provide a VAS decreased more than 50% without side effects. Results: Eleven patients (6 females and 5 males) were included. Nine patients experienced modest or no pain relief. Four of these had significant side effects (dizziness, nausea, vomiting or abdominal pain) and had no further injection. In the others 5, one patient retired from study and four received a second injection of 3.75 mcg. The trial was negative in all 5 cases because of side effects (dizziness, drowsiness, weakness, muscle cramps), the pain decreased in only 2 patients. Two patients experienced profound pain relief with an IT injection of 2.5 mcg. One patient had no side effects and the other had dizziness and drowsiness that disappeared with an injection of 1.25 mcg. Pain relief without adverse effects was confirmed with the second injection. The trial was considered positive for those two patients. Discussion and conclusion: The response rate of 18% (2/11) is consistent with the success rate of a continuous infusion trialing with an implanted catheter. Single-shot injection of ziconotide may therefore predict efficacy.

Effects of endotoxin on lactate metabolism in humans.

ABSTRACT: 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.