A prospective study was conducted on 34 stable septic patients to determine whether mild hyperlactatemia is a marker of lactate overproduction or an indicator of lactate underutilization during sepsis. Plasma lactate clearance and lactate production were evaluated by modeling the lactate kinetic induced by an infusion of 1 mmol/kg L-lactate over 15 min. The patients were divided in two groups depending on their blood lactate: < or = 1.5 mmol/L (n = 20, lactate = 1.2+/-0.2 mmol/L) or > or = 2 mmol/L (n = 10, lactate = 2.6+/-0.6 mmol/L). The hyperlactatemic patients had a lower lactate clearance (473+/-102 ml/kg/h) than those with normal blood lactate (1,002+/-284 ml/kg/h, p < 0.001), whereas lactate production in the two groups was similar (1,194+/-230 and 1,181+/-325 micromol/kg/h, p = 0.90). A second analysis including all the patients confirmed that the blood lactate concentration was closely linked to the reciprocal of lactate clearance (r2 = 0.73, p < 0.001) but not to lactate production (r2 = 0.03, p = 0.29). We conclude that a mild hyperlactatemia occurring in a stable septic patient is mainly due to a defect in lactate utilization.

. Cell death during ischemia: relationship to mitochondrial depolarization and ROS generation. Am J Physiol Heart Circ Physiol 284: H549-H558, 2003. First published October 10, 2002 10.1152/ajpheart.00708.2002.-Ischemia-reperfusion injury induces cell death, but the responsible mechanisms are not understood. This study examined mitochondrial depolarization and cell death during ischemia and reperfusion. Contracting cardiomyocytes were subjected to 60-min ischemia followed by 3-h reperfusion. Mitochondrial membrane potential (⌬⌿m) was assessed with tetramethylrhodamine methyl ester. During ischemia, ⌬⌿m decreased to 24 Ϯ 5.5% of baseline, but no recovery was evident during reperfusion. Cell death assessed by Sytox Green was minimal during ischemia but averaged 66 Ϯ 7% after 3-h reperfusion. Cyclosporin A, an inhibitor of mitochondrial permeability transition, was not protective. However, pharmacological antioxidants attenuated the fall in ⌬⌿m during ischemia and cell death after reperfusion and decreased lipid peroxidation as assessed with C11-BODIPY. Cell death was also attenuated when residual O2 was scavenged from the perfusate, creating anoxic ischemia. These results suggested that reactive oxygen species (ROS) were important for the decrease in ⌬⌿m during ischemia. Finally, 143B-0 osteosarcoma cells lacking a mitochondrial electron transport chain failed to demonstrate a depletion of ⌬⌿m during ischemia and were significantly protected against cell death during reperfusion. Collectively, these studies identify a central role for mitochondrial ROS generation during ischemia in the mitochondrial depolarization and subsequent cell death induced by ischemia and reperfusion in this model. reactive oxygen species; hypoxia; oxidants REACTIVE OXYGEN SPECIES (ROS) have been implicated as participants in the myocardial damage induced by ischemia-reperfusion (I/R) (1,4,9,17,21,25). Most studies have focused on the importance of oxidant stress generated during reperfusion, when a burst of ROS is generated after oxygen is reintroduced into the system after a prolonged period of ischemia (32, 39). However, growing evidence suggests that oxidant stress begins during ischemia before reperfusion. For example, in cardiomyocytes subjected to simulated I/R, we observed (32, 33) an increase in ROS generation during ischemia followed by a large burst of oxidant production during the first few minutes after reoxygenation. In that model, antioxidants were more protective when given throughout the experiment than when given only at reperfusion, which supports the idea that oxidants generated during the ischemic phase contribute to cell injury and are important determinants of cell survival and recovery of function (2, 35).ROS generation cannot occur during ischemia unless some residual O 2 is still present. Previous studies using cardiomyocytes revealed that trace levels of O 2 are still detectable during simulated ischemia (PO 2 ϭ 5-7 mmHg). During ischemia, indexes of oxidant stress were attenuated by mitochondrial electron trans...

Death occurring in emergency departments mainly concerned elderly patients with multiple chronic diseases and was frequently preceded by a decision to withdraw and/or withhold life-support therapies. Training of future ED physicians must be aimed at improving the level of care of dying patients, with particular emphasis on collegial decision-taking and institution of palliative care.

Low lactate clearance in severely ill septic patients with normal or mildly elevated blood lactate is predictive of poor outcome independently of other known risk factors such as age and number of organ failures.

Continuous venovenous hemofiltration with dialysis cannot mask lactate overproduction, and its blood concentration remains a reliable marker of tissue oxygenation in patients receiving this renal replacement technique.