MUSCLE Lactate Production in Sepsis

University Of Cincinnati, Cincinnati OH

Investigators

Linked publications & trials

Abstract

The long-term objective of this work is to understand the changes in metabolism in sepsis in order to improve the therapy of septic patients. Sepsis results in a hypermetabolic state in which many aspects of carbohydrate metabolism are abnormal: enhanced peripheral glucose uptake and utilization, hyperlactacidemia, increased gluconeogenesis, depressed glycogen synthesis, glucose intolerance and insulin resistance. Traditionally, high circulating lactate concentration has been interpreted as tissue hypoxia or mitochondrial dysfunction. However, therapy to improve tissue perfusion does not always prevent lactate accumulation. Current understanding of energy metabolism cannot explain persistent glycolysis by well-oxygenated tissues. High epinephrine levels in sepsis may cause the characteristic changes in carbohydrate metabolism through stimulation of the Na+-K+ pump in skeletal muscle. The stimulation of glycogen breakdown and lactate production in muscle by epinephrine may be closely tied to stimulation of the Na+, K+-ATPase, implying that muscle energy metabolism takes place in separate glycolytic and oxidative compartments. ATP consumption by the Na+, K+-ATPase appears to be the primary influence on ATP production in the glycolytic compartment. This proposal aims to explore these relationships in greater detail, both in septic and nonsepticrats. Studies will combine in vivo and in vitro assessments of Na+-K+ pump activity, membrane recruitment, glycolysis, glycogenolysis, ATP content and membrane permeability to Na+ and K+. The central role of epinephrine in sepsis-induced metabolic derangements will be examined in two ways (i) chronic infusion of epinephrine using implantable minipumps and (ii) chronic infusion of the beta-adrenergic blockers in sepsis. Studies in vitro will examine the persistence of epinephrine's effects on glycolysis and Na+, K+-ATPase activity after beta-blockade has occurred. Results of these studies will clarify metabolic relationships that are important both in health and disease.