The pathogenesis of lactic acidosis in sepsis

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Abstract
Lactic acidosis is a common finding in critically ill patients during severe sepsis/septic shock, and a powerful predictor of mortality. Because of the knowledge that lactate is the end product of anaerobic glycolysis, the presence of hyperlactatemia in sepsis has been taken to indicate the development of anaerobic glycolysis within tissues. Such anaerobic glycolysis is understood to result from oxygen “debt” at cellular level. The metabolic acidosis frequently associated with hyperlactatemia has thus been ascribed to hydrogen ions released from adenosine triphosphate hydrolysis. This simplistic view of the pathogenesis and meaning of hyperlactatemia, however, is not supported by available data. Systemic oxygen transport is usually increased rather than decreased in septic patients. Whenever studied, tissue oxygenation is either preserved or increased in septic animals and humans. In addition, lactate levels may fluctuate in response to inotropic drugs and do not consistently decrease when tissue oxygen delivery is increased. Furthermore, there is strong evidence that large amounts of lactate can be produced and released under aerobic conditions and that the pathogenesis of hyperlactatemia in septic states is complex. Such pathogenesis may involve accelerated glycolytic fluxes, the inhibition of pyruvate dehydrogenase activity, and changes in intermediary metabolism. It may also involve the need to modulate the rate and efficiency of glycolytic flux by controlling the redox state of cytoplasm and mitochondria through lactate accumulation. Furthermore, recent investigations have attempted to establish which organs are responsible for lactate production in septic humans and endotoxemic animals. These studies suggest that the lung may be a major source of much of the excess lactate produced under these circumstances. They also suggest that decreased lactate elimination is also an important component of the pathogenesis of hyperlactatemia. Finally, the pathogenesis of the metabolic acidosis associated with hyperlactatemia is most likely to be related to the effect of the lactate ion on the strong ion difference and subsequently on the dissociation of plasma water into hydrogen ions. A great deal remains to be understood about the pathogenesis of lactic acidosis in sepsis. It is important, however, to understand that the concepts of “anaerobic glycolysis” and “unfettered adenosine triphosphate hydrolysis” are not convincingly supported by available evidence and probably represent an inaccurate and simplistic explanation of this complex phenomenon.