Hyperlactatemia and Lactic Acidosis

Objectives

This chapter will:

1.
Review the major factors that modulate physiologic lactate production and utilization.
2.
Discuss the mechanisms that modulate lactate during critical illness.
3.
Review acid-base aspects of lactic acidosis.
4.
Review causes of lactic acidosis that have particular relevance to critical care practitioners.
5.
Provide a framework for the approach to patients with lactic acidosis of unknown cause.

Hyperlactatemia, clinically defined as an increase in plasma lactate concentration above 2 mmol/L, is one of the most frequently encountered metabolic alterations in the critically ill patient. Two important paradigms have framed current understanding of hyperlactatemia in this setting. The first is that lactate is a marker of tissue hypoperfusion and thus of oxygen debt. The trail of evidence supporting this notion can be traced to the work of Hill, Long, and Lupton, who in the early 1920s published a series of papers suggesting the association between “lactic acid and the supply and utilization of oxygen.” Huckabee further supported this notion with his studies in the 1950s and 1960s by demonstrating an association between oxygen deficit and excess lactate (Excess lactate = ([Lt − Lo]−[Pt − Po] × Lo/Po) in humans during exercise. Weil and Afifi demonstrated a significant correlation between lactate and oxygen debt in hemorrhaged rats (r = 0.5, p < .0005), and between lactate and survival in 142 patients with clinical manifestations of circulatory shock.

The second concept is that hyperlactatemia is an ominous sign. This is a conception that has been ingrained rightfully in the psyche of clinicians based on data that originated in Weil's seminal work but that has stood the test of time in demonstrating a clear association between elevated lactate levels and worse outcome. The wide embrace of these two concepts has reduced the understanding of lactate to that of being an “evil” molecule, and a marker of tissue hypoxia and anaerobic metabolism. This chapter provides the reader with a different perspective, providing evidence that lactate is not just a waste product of anaerobiosis, but rather a key player in intermediary metabolism and energy homeostasis. Lactate is crucial for intercellular and interorgan cooperation, substrate distribution, and perhaps adaptation to injury, and thus hyperlactatemia cannot be an exclusive reflection of tissue hypoxia.

Normal Metabolism of Lactate and Physiologic Hyperlactatemia During Exercise

Given the reasons stated above, and as a framework to understanding hyperlactatemia during critical illness, it is important to provide the reader with evidence that supports what it is known about physiologic lactate production and utilization.

Lactate Production

The resting basal rate of lactate production in humans has been quantified by using either isotropic dilution of 14C L-lactate or infusion of unlabeled L-lactate; it has been estimated to be 0.84 mmol/kg/hr with a range of 0.77 to 1.0 mmol/kg/hr, for a total daily production of 1290 to 1500 mmol. Although many cells in the body contribute to this basal lactate production, the largest contributors during normal conditions are skeletal muscle (17%), skin (27%), brain (18%), and red blood cells (23%).

Lactate is produced from the reduction of pyruvate by action of the enzyme lactate dehydrogenase (LDH). LDH is expressed in the cytosol and exists in several isoforms with diverse tissue specific distributions. Lactate concentrations are maintained in equilibrium with pyruvate by LDH at a ratio of about 10 : 1. The equilibrium is represented by the following equation:

Pyruvate + NADH + H^{+} \leftrightarrow Lactate + N A D^{+}

$Pyruvate + NADH + H^{+} \leftrightarrow Lactate + N A D^{+}$

where NADH is reduced nicotinamide adenine dinucleotide and NAD is oxidized nicotinamide adenine dinucleotide. From this, three important conclusions about lactate production can be drawn. First, any condition increasing glycolytic flux will increase pyruvate and lactate production by the law of mass action, that is, without altering the kinetic rates between substrates. Second, lactate accumulation can occur in fully oxygenated tissue (i.e., aerobic glycolysis) as the consequence of stimuli (i.e., cytokines, epinephrine) that increase glycolytic flux. Third, transferring electrons from NADH to pyruvate to form lactate is an efficient and necessary cytosolic mechanism to recycle NAD ⁺ , because without the presence of sufficient NAD ⁺ as an electron acceptor, glycolysis cannot occur. It is therefore evident that lactate production is much more complex than commonly regarded, and interpreting hyperlactatemia as indicative of the presence of tissue dysoxia is a major oversimplification.

Lactate Utilization (Removal): Gluconeogenesis and Oxidation

Clearance of lactate after maximal exercise depends on recovery intensity, with faster clearance occurring with active than with passive recovery. In critically ill patients, lactate clearance (i.e., volume of plasma that is cleared off of lactate per unit of time) has been estimated by quantifying the disposal of infused sodium L-lactate and was found to be approximately 800 to 1800 mL/minute. Although many organs consume lactate, the liver and the kidney represent the major sites of lactate uptake and clearance as they metabolize approximately 53% and 30% of daily lactate production, respectively. Lactate is metabolized by two main mechanisms: First, lactate can be used as a substrate to regenerate glucose by gluconeogenesis, a process that is exclusive to liver and the kidney. Second, at least 50% of circulating lactate is removed and metabolized by means of oxidation during resting conditions. Unlike gluconeogenesis, which is restricted to liver and kidney, oxidation can take place in many organs, including the heart, brain, and skeletal muscle.

Gluconeogenesis and the Cori Cycle

During normal conditions, at least half of the lactate released into the circulation by the muscle is taken up by the liver and the renal cortex and converted into glucose in the Cori cycle. Glucose generated by gluconeogenesis then is released to the circulation to maintain sufficient availability of energy substrates to organs that are dependent on glucose utilization such as brain, erythrocytes, and leukocytes ( Fig. 67.1 ).

FIGURE 67.1, Schematic representation of the interorgan (Cori cycle), intercellular, and intracellular lactate shuttling systems. The right panel also represents the theory of cellular compartmentalization of carbohydrate metabolism into cytosolic glycolytic and mitochondrial oxidative compartments. COX, Cytochrome oxidase; MCT1, monocarboxylate transporter 1; mLDH, mitochondrial lactate dehydrogenase; mLOC, mitochondrial lactate oxidation complex.

Gluconeogenesis is thus an evolutionarily conserved, fundamental cellular process by which glucose is generated from noncarbohydrate gluconeogenic substrates such as lactate, glutamate, alanine, and glycerol to maintain blood glucose levels during fasting. More importantly to lactate kinetics, gluconeogenesis is a fundamental mechanism of lactate removal and metabolism because in terms of substrate utilization, lactate is the most important contributor to gluconeogenesis, accounting for approximately 53% of total renal glucose release. Gluconeogenesis is exclusive to the liver and kidney (renal cortex), because they alone contain glucose-6-phosphatase, the enzyme that catalyzes the formation of free glucose that is released into the circulation via glucose transporter membrane proteins. A human study performed during the anhepatic phase of liver transplantation demonstrated the importance of the kidney in maintenance of lactate homeostasis by showing that the steady-state concentration of lactate in blood increased by only 1 mmol/L after the liver was removed. Indeed, the kidney contributes with approximately 40% of all gluconeogenesis, with 50% of the total conversion of lactate to glucose, and with about 30% of total lactate metabolism.

The differential utilization of substrates in the renal cortex and medulla is the result of a particular enzymatic distribution. Although the cortex relies on fatty acid oxidation for its high levels of oxidative enzymes, the medulla depends on glycolysis because of its very low oxidative capacity. This particular enzymatic distribution and differential utilization of substrates in the renal cortex and medulla insinuate the presence of a corticomedullary recycling system and suggest this cooperative substrate utilization, reminiscent of the Cori cycle, as a general (within organ and between organs) metabolic adaptive strategy.

Oxidation of Lactate

Hochachka has described lactate as an efficient energetic currency that can be distributed rapidly to other cells to be used as a carbon source and bioenergetic substrate. Indeed, at least 50% of circulating lactate is taken up by many cells and metabolized by oxidation via the Krebs cycle to generate adenosine triphosphate (ATP). This process has been studied extensively in human skeletal muscle; myocytes have been shown to be simultaneously capable of producing, releasing, and oxidizing lactate. Importantly, exercise increases skeletal muscle uptake of lactate in humans, changing myocyte lactate metabolism from net production and release, to uptake and oxidation. This provides evidence that lactate is indeed a valuable energy substrate, and that depending on the physiologic condition organs and tissues can resort to lactate to supplement their energetic requirements. This capacity for a dual, adaptive function (lactate release vs. uptake) in skeletal muscle is best explained by the presence of compartmentalization of cytosolic carbohydrate metabolism, and by the cell-cell and intracellular lactate shuttle theories, which are discussed later ( Fig. 67.1 ).

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