Does a Normal Peripheral Lactate Value Always Indicate an Aerobic Tissue Metabolism?

This article refers to ‘Prevalence of lactic acidaemia in patients with advanced heart failure and depressed cardiac output’ by L. Adamo et al., published in this issue on pages 1027–1033. Heart failure (HF) has been classically defined as a condition in which the heart is unable to deliver sufficient oxygen to match the needs of the metabolizing tissues. Dr Paul Wood was the first to state that ‘heart failure can be defined as a state in which the heart fails to maintain an adequate circulation for the needs of the body despite a satisfactory venous filling pressure’ in his classic textbook Diseases of the Heart and Circulation, published in 1956.1 Dr Eugene Braunwald later modified this definition to ‘a pathophysiological state in which the heart is unable to pump blood at a rate commensurate with the requirements of the metabolizing tissues or can do so only from an elevated filling pressure’.2 In the present issue of this journal, Adamo et al. publish a retrospective analysis designed to determine the prevalence of elevated lactate levels in stable patients with advanced HF.3 The authors used a single peripheral lactate measurement as a surrogate for the balance between oxygen supply and metabolic demand. The study included 96 HF patients who underwent evaluation for a left ventricular assist device (LVAD) with right heart catheterization. Lactate was measured within 24 h of LVAD placement in a single sample of peripheral venous blood collected on ice. The arterio–venous oxygen (a–vO2) difference was above the upper limit of normal (>5 mL/100 mL) in 93% of these patients. Lactate levels were normal (<2.1 mmol/L) in ∼75% of the patients. There was no correlation between cardiac index and peripheral lactate level. The authors conclude: ‘Lactate levels were normal in ∼75% of the patients with advanced HF and a widened a–vO2 difference, suggesting that the cardiac output was sufficient to meet the metabolic needs of the peripheral metabolizing tissues. Given that ∼4% of HF patients are in NYHA class IV, these findings suggest that the classic definition of HF pertains to ∼1% of patients with HF.’3 Few studies have assessed resting lactate levels in patients with severe HF. The data from the present study3 are therefore welcomed. However, there are some pitfalls related to the interpretation of peripheral lactate values that should be considered when reading the analysis by Adamo et al.3 Lactate is produced from pyruvate by lactate dehydrogenase (LDH). When pyruvate concentration increases, a shift in the LDH equilibrium causes an increase in lactate production. Lactate formation regenerates cytosolic NAD+ from the glycolytic formed NADH. This regeneration of NAD+ enables a high glycolytic rate when NADH mitochondrial transport and oxidation are limited, such as in an oxygen-deficient state. In the presence of hypoperfusion there is insufficient oxygen delivery to the tissues and lactate is produced if energy demands exceed the capacity of adenosine triphosphate (ATP) delivery by oxidative phosphorylation. Assessment of circulating lactate has therefore been considered a marker of tissue hypoperfusion in clinical conditions such as septic shock.4 In line with the classic definition of HF, one may therefore anticipate that circulating lactate levels are elevated in patients with severe HF. The major methodological limitation of the analysis by Adamo et al.3 refers to the availability of only a single measurement of peripheral venous lactate in each patient. When assessing peripheral lactate levels, it is important to appreciate that peripheral lactate is the sum of lactate production and clearance. In a steady state situation, lactate production and clearance are in balance. There is no direct relationship between lactate production and peripheral lactate level when the rate of lactate production is below that of lactate clearance. Peripheral lactate levels may therefore be normal despite increased lactate production as a result of a concomitant increase in clearance. Under normal, steady state, post-absorptive resting conditions, there is a net lactate production by skeletal muscle, adipose tissue and brain.5 This production is balanced by a net lactate clearance by the liver, kidney and heart. The liver and kidneys are the primary organs involved in lactate clearance. The liver accounts for approximately 50% of lactate uptake,6 whereas the kidneys account for 20–30% of lactate clearance.5 An increase in lactate production will increase lactate clearance by the liver, kidneys, muscle and brain.5 Lactate is an important energy substrate in most tissues during stress. In the heart, increased availability of lactate is associated with increased cardiac output in patients with acute HF.7 Conversely, a decrease in available lactate is associated with decreased cardiac function in animal models.8 Both lactate production and clearance are closely influenced by changes in perfusion, hormones, availability of glucose, tissue energy requirement and medication. In the liver, lactate is metabolized by oxidation or used as a substrate for gluconeogenesis. Total hepatic blood flow is a major determinant of hepatic lactate metabolism. There is a large hepatic metabolic reserve that maintains lactate clearance despite significant reductions in blood flow.9 However, when blood flow falls below a critical level, hepatic lactate uptake and oxidation are severely reduced.10 In a rat model, the critical reduction in hepatic blood flow occurs when blood flow is reduced to below 25% of the normal level.11 The critical blood flow for lactate metabolism in humans is most likely organ-specific and remains to be identified for most organs. There is no simple relationship between systemic lactate and anaerobic metabolism. In non-steady state conditions such as septic shock, systemic lactate levels may be normal despite significant organ ischaemia12, 13 and in systemic hypoperfusion.14 In a study of patients in vasopressor-dependent septic shock, 45% of subjects were found to have initially normal (<2.4 mmol/L) lactate levels despite high mortality.13 However, the relevance of these studies to lactate kinetics in chronic HF is unclear. In the context of long-term systemic hypoperfusion, such as in HF, multiple mechanisms may contribute to an apparently normal systemic steady state lactate despite chronic tissue hypoperfusion. Firstly, long-lasting hypoperfusion may be compensated by increased oxygen extraction from circulating blood. Secondly, redistribution of blood flow to and within central organs, such as the liver and kidneys, may be sufficient to maintain an oxygen delivery that will support an adequate lactate clearance in resting conditions despite reduced cardiac output. These observations may explain the normal lactate levels observed by Adamo et al.3 The findings of the study by Adamo et al.3 are important in that they demonstrate that normal peripheral lactate levels may be present in patients with advanced HF despite reduced cardiac output and a widened a–vO2 difference. However, the analysis did not have access to data on lactate gradients across organs, or to lactate kinetics such as provided by lactate tracer dilution methodology.5 The metabolic needs of peripheral metabolizing tissues therefore cannot be adequately evaluated. Until we have more data on the determinants of lactate metabolism, we must be cautious in interpreting normal peripheral lactate levels in these patients. Despite these considerations, Adamo et al.3 are to be congratulated for initiating an important discussion on the validity of the classic definition of HF. Conflict of interest: None to declare.