We assessed the hypothesis that the epinephrine surge present during sepsis accelerates aerobic glycolysis and lactate production by increasing the activity of skeletal muscle Na,K-ATPase. Healthy volunteers received an i.v. bolus of endotoxin or placebo in randomised order on two different days. Endotoxemia induced a pronounced acute-phase response including highly significant increases in temperature, heart rate, leg blood flow, CRP, neutrophil counts, plasma TNF- and significant reductions in lymphocyte and monocyte counts as well as in blood pressure. Endotoxemia increased plasma epinephrine to a maximum at t=2 h of 0.7 ± 0.1 vs. 0.3 ± 0.1 nmol/l (p<0.05, n=6-7). Endotoxemia reduced plasma K reaching a nadir at t=5 h of 3.3 ± 0.1 vs. 3.8 ± 0.1 mmol/l (p<0.01, n=6-7) followed by an increase to placebo level at t=7-8 h. Plasma lactate increased to a maximum at t=1 h of 2.5 ± 0.5 vs. 0.9 ± 0.1 mmol/l (p<0.05, n=8) in association with an increased release of lactate from the muscles. Following endotoxin infusion a relative accumulation of K was seen reaching a maximum at t=6 h of 8.7 ± 3.8 mmol per leg (p<0.05). These changes were not associated with hypoperfusion or hypoxia. During the first 24 h after the endotoxin infusion renal K excretion was 27 ± 7 mmol, i.e. 58% higher as compared to placebo. The combination of the well-known stimulatory effect of catecholamines on skeletal muscle Na,K-ATPase activity with the present confirmation of the correspondingly expected Na,K-ATPase-induced decline in plasma K, suggests that the increase in lactate level was due to increased Na,K-ATPase activity, supporting the hypothesis. Thus, increased lactate levels should not in general be managed from the point of view that it reflects hypoxia. The observed changes in lactate and K homeostasis are not supposed to be a specific response to endotoxemia, but may be present in general in acutely and severely ill patients with a stress response. The hypokalemia may not necessarily be interpreted as K deficiency, as it may reflect temporarily increased muscle K uptake, but on the other hand it is important to compensate for an increased renal K excretion.