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Lactate, as a normal end product of glucose metabolism, is produced from pyruvate. When pyruvate concentration exceeds the capacity of the slow metabolic Krebs cycle pathway, the fast metabolic pathway to lactate production is preferred resulting in the net production of 2 mol ATP per mol glucose metabolized. Although this amount of ATP is small compared to the additional 34 mol ATP produced in the Krebs cycle, the lactate pathway is fast and can thus produce large amounts of energy.29 The increased levels of lactate in these conditions thus do not reflect the pathologic condition where pyruvate accumulates due to hypoxia. Lactate at the level of the organism also acts as an intermediate fuel that can be exchanged between various tissues.30 In clinical practice, it is frequently difficult to separate these 2 states that clearly have significantly different impact on survival.
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Lactate and Tissue Hypoxia
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Decreasing oxygen delivery to the cells will ultimately result in decreasing oxygen consumption and increasing lactate levels.31,32 It is important to realize that lactate levels do not necessarily represent the adequacy of oxygenation in different regional circulations as these have different levels of critical oxygen delivery.33,34
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When oxygen delivery decreases below a critical level, oxygen consumption starts to decrease and lactate levels increase. This supply-dependent oxygen consumption in relation to increased lactate levels is a key characteristic of shock. Whereas this relationship is easily shown in experimental conditions, clinical circumstances, and ethical considerations limit the possibility to study this in humans. However, a few studies have identified the presence of supply-dependent oxygen consumption in relation to increased lactate levels also in patients with septic shock.35,36,37
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In a model of tamponade, Zhang et al32 recently showed that decreasing oxygen delivery beyond the critical value resulted in a rapid increase in lactate levels. Subsequent resolution of the tamponade resulted in supply-independent oxygen consumption and normalization of lactate levels (Figure 73–2). In the same model, van Genderen et al38 showed that increasing tamponade was associated with decreased microvascular perfusion and increased lactate levels. In this model, resolving tamponade was associated with a normalization of microvascular perfusion and rapidly decreasing lactate levels. In patients with septic shock, Friedman et al showed similar findings.35 Supply-dependent oxygen consumption was a characteristic of patients early in septic shock with hyperlactatemia, whereas supply-independent oxygen consumption was found following resuscitation and normalization of lactate levels. In addition, improving microvascular perfusion in septic-shock patients with increased lactate levels has been associated with decreasing lactate levels.39
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Lactate and Aerobic Metabolism
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These important observations as mentioned earlier underscore the importance of evaluating increased lactate levels to diagnose and treat supply-dependent oxygen consumption in critically ill patients. However, as lactate is a normal end product of glucose metabolism, increased aerobic glucose metabolism has been shown to increase lactate levels in the presence of adequate tissue oxygenation. Increases in pyruvate either by increasing glycolysis by means of hyperventilation or by infusing pyruvate result in increased lactate levels.40,41 Similarly, the administration of epinephrine and corticosteroids, known to increase glycolysis, results in dose-dependent increase in lactate.42,43 Very high lactate levels found in patients suspected of malignant lymphoma may have aerobic lactate production due to what is called the Warburg effect.44 Treatment of the lymphoma is associated with a decrease in lactate levels, whereas subsequent tumor load leads to rapid increases in lactate levels.29 In patients with septic shock, the increased activity of the cellular sodium/potassium pump has been associated with increased lactate levels not related to tissue hypoxia.45 In addition, sepsis is also characterized by increased glycolysis due to cytokine-mediated glucose uptake.46 Finally, mitochondrial dysfunction, not related to tissue hypoxia, can increase pyruvate levels and thus lactate levels.47,48 In clinical practice, infusion of Ringer’s lactate does not interfere with lactate measurements,49 whereas high-volume hemofiltration using lactate-buffered solutions do result in transiently increased lactate levels.50,51 Many other causes of increased lactate levels, not related to the presence of tissue hypoxia, have been identified.52,53,54,55,56 In the presence of ethylene glycol intoxication, a high lactate level measured with a point-of-care device may be confounded by the adverse reaction to the lactate electrode in the machine.57 A subsequent normal lactate in the central laboratory can even be used as a diagnostic tool in these circumstances.58
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The body is able to clear large lactate loads rapidly as demonstrated by the decrease in lactate levels following exercise, cessation of seizures, or return of circulation in cardiac arrest. However, in specific circumstances, the clearance of lactate maybe limited that could result in prolonged increased lactate levels following resuscitation or in limited increased lactate levels in the case of normal production. Impaired liver function is known to decrease the clearance of lactate by the liver.36,59 Also in patients following cardiac surgery, clearance is impaired following a bolus infusion of lactate.60 The dysfunction of pyruvate dehydrogenase in septic conditions, which can be alleviated by the administration of dichloroacetate, also limits lactate metabolism and results in increased lactate levels, where adequate oxygenation maybe present.61,62