Sepsis-associated hyperlactatemia

Abstract

There is overwhelming evidence that sepsis and septic shock are associated with hyperlactatemia (sepsis-associated hyperlactatemia (SAHL)). SAHL is a strong independent predictor of mortality and its presence and progression are widely appreciated by clinicians to define a very high-risk population. Until recently, the dominant paradigm has been that SAHL is a marker of tissue hypoxia. Accordingly, SAHL has been interpreted to indicate the presence of an 'oxygen debt' or 'hypoperfusion', which leads to increased lactate generation via anaerobic glycolysis. In light of such interpretation of the meaning of SAHL, maneuvers to increase oxygen delivery have been proposed as its treatment. Moreover, lactate levels have been proposed as a method to evaluate the adequacy of resuscitation and the nature of the response to the initial treatment for sepsis. However, a large body of evidence has accumulated that strongly challenges such notions. Much evidence now supports the view that SAHL is not due only to tissue hypoxia or anaerobic glycolysis. Experimental and human studies all consistently support the view that SAHL is more logically explained by increased aerobic glycolysis secondary to activation of the stress response (adrenergic stimulation). More importantly, new evidence suggests that SAHL may actually serve to facilitate bioenergetic efficiency through an increase in lactate oxidation. In this sense, the characteristics of lactate production best fit the notion of an adaptive survival response that grows in intensity as disease severity increases. Clinicians need to be aware of these developments in our understanding of SAHL in order to approach patient management according to biological principles and to interpret lactate concentrations during sepsis resuscitation according to current best knowledge.

Figures

Figure 1

Schematic view of the intracellular lactate shuttle with the mitochondrial lactate oxidation complex and the cell-to-cell lactate shuttle (CCLS). Myocytes have a glycolytic and an oxidative compartment. The glycolytic compartment in the cytosol is close to the myofibrils and their glycogen stores. It is associated with glycogenolysis/glycolysis and lactate release into the circulation. The oxidative compartment in close proximity to the mitochondria is considered responsible for lactate oxidation. Lactate produced in the cytosol is oxidized to pyruvate via the lactate oxidation complex in the mitochondria of the same cell. Pyruvate is then transported across the inner mitochondrial membrane via a monocarboxylate transport protein (MCT1). MCT1 is found in the mitochondrial inner membrane as part of the lactate oxidation complex together with its chaperone protein CD147, cytochrome oxidase (COX) and mitochondrial lactate dehydrogenase (mLDH). mLDH is found in the outer side of the inner membrane. Once pyruvate enters the mitochondrial matrix, it is metabolized by the tricarboxylic acid cycle (TCA). The CCLS hypothesis supports the idea that lactate produced in muscle can also serve as a substrate in highly oxidative cells (heart, brain) or contribute to gluconeogenesis (liver, kidney). cLDH, cytosolic lactate dehydrogenase.

Figure 2

Relationship between arterial blood lactate levels and oxygen delivery (DO2)/mixed venous oxygen saturation (SvO2). No critical values of DO2 or SvO2 were seen to be associated with hyperlactatemia in septic patients (mean values of lactate 5.3 mmol/L). Increases in arterial lactate concentrations were present over a wide range of DO2 and SvO2 values.

Figure 3

Epinephrine-increased glycogenolysis and glycolysis is coupled to a Na+/K+-ATPase pump. Epinephrine increases cyclic AMP (cAMP) production, inducing stimulation of glycogenolysis/glycolysis and activation of the Na+/K+-ATPase pump. This activation consumes ATP, leading to the generation of ADP. ADP reactivates glycolysis and hence generates more pyruvate and, consequently, more lactate. TCA, tricarboxylic acid cycle.