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Stress hyperlactataemia: present understanding and controversy

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Summary

An increased blood lactate concentration is common during physiological (exercise) and pathophysiological stress (stress hyperlactataemia). In disease states, there is overwhelming evidence that stress hyperlactataemia is a strong independent predictor of mortality. However, the source, biochemistry, and physiology of exercise-induced and disease-associated stress hyperlactataemia are controversial. The dominant paradigm suggests that an increased lactate concentration is secondary to anaerobic glycolysis induced by tissue hypoperfusion, hypoxia, or both. However, in the past two decades, much evidence has shown that stress hyperlactataemia is actually due to increased aerobic lactate production, with or without decreased lactate clearance. Moreover, this lactate production is associated with and is probably secondary to adrenergic stimulation. Increased lactate production seems to be an evolutionarily preserved protective mechanism, which facilitates bioenergetic efficiency in muscle and other organs and provides necessary substrate for gluconeogenesis. Finally, lactate appears to act like a hormone that modifies the expression of various proteins, which themselves increase the efficiency of energy utilisation and metabolism. Clinicians need to be aware of these advances in our understanding of stress hyperlactataemia to approach patient management according to logical principles. We discuss the new insights and controversies about stress hyperlactataemia.

Introduction

An increased blood lactate concentration (hyperlactataemia) is typical during exercise,1 critical illness,2 most notably sepsis,3 cardiogenic shock,4 and liver failure,5 and also during open heart surgery.6 In almost all severe disease-related physiological stress, a raised blood lactate concentration is an independent predictor of mortality.2, 7 However, the source, biochemistry, pathophysiology, and metabolic function of lactate remain unclear. Whether such stress hyperlactataemia represents a maladaptive or protective response is also unkown.

There are many reasons for the lack of a clear understanding of stress hyperlactataemia, but perhaps the most important is the sheer complexity of lactate, a widely produced and utilised metabolite, which, like glucose, is central to almost every energy-related pathway.8, 9 Despite this extraordinary complexity, stress hyperlactataemia has been traditionally and, in our view, irrationally simplified to represent the presence of either global tissue hypoxia or tissue hypoperfusion with anaerobic glycolysis.10 This unproven and untested basic theory has, and continues, to dominate clinical thinking and practice.11, 12

Here, we look at key aspects of stress hyperlactataemia and explain why it cannot be used as a reliable marker of tissue hypoxia, hypoperfusion, and anaerobic glycolysis. Instead, we provide findings that show that lactate is an important aerobically produced intermediate metabolite in human bioenergetics that is oxidised as a biofuel in many different tissues including skeletal muscle, brain, heart, kidney, and liver, and that regulates the hormonal and intracellular response to stress.

Section snippets

Lactate metabolism

The normal value of blood lactate concentration is less than 2 mmol/L, the consequence of a balance between production and removal. Lactate can be released by many different cells.9 Skeletal muscle,13 adipose tissue,14 and brain15 seem to have a major role in lactate release, but also lung,16 heart,17 and gut5 can contribute to net lactate production. The exact contribution of each tissue to net lactate production remains unknown.

Daily lactate production in resting human beings has been

Lactate production

Lactate formation is believed to arise from pyruvate in the cytosol as part of glycolysis. Lactate concentration is in equilibrium with pyruvate. This equilibrium is maintained by lactate dehydrogenase with a fairly constant lactate to pyruvate ratio of 10:1.26 Thus, cytosolic lactate needs to, by enzymatic equilibrium, increase under most if not all circumstances in which cytosolic pyruvate increases. Therefore, lactate accumulation might not imply a state of anaerobic glycolysis but simply a

Lactate oxidation

Gluconeogenesis via the Cori cycle is not the only metabolic pathway for lactate utilisation. Findings of studies of radiolabelled lactate have shown that oxidation (via pyruvate and the tricarboxylic acid cycle) is another major metabolic fate for lactate.29 Approximately half of available lactate is disposed of via oxidation at rest, and 75–80% during exercise.30 This oxidation pathway has been assessed in exercising human skeletal muscle, in which results of isotope studies confirm

Hyperlactataemia during the physiological stress of exercise

There is incontrovertible evidence that moderate to high intensity exercise induces stress hyperlactataemia.1, 30, 32 Many studies in which investigators used isotopes, kinetics assessment, and biopsy fluorometric assays, have shown that muscle and blood lactate accumulation increases slowly with small increments in exercise intensity. However, when a given percentage of maximum oxygen consumption (%VO2max) is reached, blood lactate accumulation accelerates. This inflection point has been

Critical illness and hyperlactataemia

There is overwhelming evidence that critical illnesses (eg, severe sepsis and septic or cardiogenic shock) are associated with hyperlactataemia. During severe sepsis and septic shock, hyperlactataemia can reach levels as high as 15·0 mmol/L.63 The higher the lactate concentrations are in blood, the greater is the risk of death.64 Even relative hyperlactataemia (blood lactate concentrations >0·75 mmol/L) is independently associated with increased hospital mortality.2

Despite these insights from

Cardiac surgery and cardiogenic shock and hyperlactataemia

Hyperlactataemia in patients who have undergone cardiac surgery is fairly common.6 Irrespective of whether hyperlactataemia is early (admission) or late (post-admission), it is strongly associated with mortality.86 Most studies refer to tissue hypoxia or organ oxygen debt as the main explanations for hyperlactataemia.87 However, when measured by microdialysis during cardiopulmonary bypass, no association was found between tissue and plasma lactate concentrations.88 Instead, other studies found

Liver failure and hyperlactataemia

Acute liver failure is strongly associated with hyperlactataemia, which has prognostic importance in this group of patients.95, 96 Liver dysfunction is believed to contribute to hyperlactataemia via decreased clearance.97 However, when isotope tracers and lactate infusion were used in patients before and after major hepatectomy, lactate clearance, oxidation, and transformation into glucose were not different to healthy controls.98 This finding suggests that decreased hepatic lactate utilisation

Conclusions

Stress hyperlactataemia is ubiquitous in human beings during exercise and pathophysiological stress and is a strong predictor of mortality in critical illness. However, the hyperlactataemia is not a consequence of anaerobic glycolysis, tissue hypoperfusion, or cellular hypoxia. In all studied settings, lactate production happens under fully aerobic conditions. Such hyperlactataemia is probably indicative of a stress response, with increased metabolic rate and sympathetic nervous system

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      The production of lactate, which serves as a substrate for gluconeogenesis and as fuel for tissues and organs such as red blood cells, heart, and brain, is increased during stress. This is thought to be due to an increase in anaerobic glycolysis attributable to tissue hypoperfusion and/or hypoxia, although aerobic lactate production may also be increased.[3,28] Stress hyperglycemia is common with changes in glucose metabolism, and is further exacerbated by elevated levels of counter-regulatory hormones and cytokines that promote insulin resistance and hepatic glucose production.[3]

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