Lactic Acidosis and Hyperlactatemia

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1 Lactic Acidosis and Hyperlactatemia B. Levy z Introduction Traditionally, hyperlactatemia in critically ill patients and particularly those in shock was interpreted as a marker of secondary anaerobic metabolism due to inadequate oxygen supply inducing cellular distress [1]. Many arguments have since refuted this view [2]. With lactate metabolism being extensively described in classical biochemistry manuals, this chapter will focus only on those aspects as they relate to critically ill patients. Distinction between lactic acidosis, metabolic acidosis with hyperlactatemia, and isolated hyperlactatemia will also be addressed. z Lactate Metabolism [3] Arterial lactate concentration is dependent on the balance between its production and consumption. In general, it is less than 2 mmol/l, although daily production of lactate is actually 1500 mmol/l. In physiological conditions, lactate is produced by muscles (25%), skin (25%), brain (20%), intestine (10%) and red blood cells (20%) which are devoid of mitochondria. Lactate is essentially metabolized by liver and kidney. Lactate is produced in the cytoplasm according to the following reaction (Fig. 1): Pyruvate NADH H, lactate NAD This reaction favors lactate formation yielding a 10-fold lactate/pyruvate ratio. Lactate therefore increases when production of pyruvate exceeds its utilization by the mitochondria. Pyruvate is essentially produced via glycolysis; hence any increase in glycolysis, regardless of its origin, can increase lactatemia. Pyruvate is essentially metabolized by the mitochondrial aerobic oxidation pathway via the Krebs cycle. Pyruvate coenzyme A NAD ) acetyl CoA NADH H CO 2 This reaction leads to the production of large quantities of ATP (36). Generated lactate can be transformed into oxaloacetate or alanine via the pyruvate pathway or can be utilized directly by periportal hepatocytes (60%) to produce glycogen and glucose (neoglycogenesis and neoglucogenesis) (Cori cycle). The kidney also participates in the metabolism (30%) of lactate with the cortex classically

2 Lactic Acidosis and Hyperlactatemia 89 Fig. 1. Overview of carbohydrate metabolism acting as the `metabolizer' by neoglucogenesis and the medulla as a producer of lactate. The threshold of renal excretion is 5±6 mmol/l meaning that, physiologically-speaking, lactate is not excreted in urine. Hence, lactatemia reflects a balance between production and utilization of lactate. Consequently, for the same etiological mechanism producing an increase in lactate, one can either observe a hyperlactatemia (if its metabolism decreases) or a normolactatemia. Understanding this concept is vital, notably to avoid treating solely a numerical value of lactate. z Formation of Lactate in Cases of Tissue Hypoxia By definition, hypoxia blocks mitochondrial oxidative phosphorylation [4], thereby inhibiting ATP synthesis and reoxidation of NADH. This leads to a decrease in ATP/ADP ratio and an increase of NADH/NAD ratio. A decrease in the ATP/ADP ratio induces both an accumulation of pyruvate which cannot be utilized by way of

3 90 B. Levy phosphofructokinase (PFK) stimulation and a decrease in pyruvate utilization by inhibiting pyruvate carboxylase, which converts pyruvate into oxaloacetate. An increased NADH/NAD ratio also increases pyruvate by inhibiting pyruvate dehydrogenase (PDH) and hence its conversion into acetyl coenzyme A. Consequently, the increase in lactate production in an anaerobic setting is the result of an accumulation of pyruvate, which is converted into lactate stemming from alterations in the redox potential. This conversion allows for the regeneration of some NAD +, enabling the production of ATP by anaerobic glycolysis, although clearly less efficient from an energy standpoint (2 ATP produced versus 36). It is important to consider that the modification of the redox potential induced by an increase in NADH/NAD ratio activates the transformation of pyruvate into lactate and consequently increases the lactate/pyruvate ratio. All in all, anaerobic energy metabolism is characterized by hyperlactatemia associated with an elevated lactate/pyruvate ratio, greater glucose utilization and low energy production. z Lactate/Pyruvate Ratio Lactate/pyruvate interconversion can be described by the following equation: Pyruvate NADH H, lactate NAD and, at equilibrium Lactate=pyruvate ˆ K NADH=NAD H where K represents the dissociation constant. Therefore, an increase in the NADH/NAD ratio or a dropin cytosolic ph triggers an increase in the lactate/pyruvate ratio. The use of this ratio has been advocated for differentiating hypoxia-related hyperlactatemia from hyperlactatemia resulting from an increase in glycolytic flux without hypoxic stress. However, the above equation clearly demonstrates that this NADH/NAD ratio can be altered by factors other than the inability to transfer electrons to oxygen. Furthermore, in order for the plasma lactate/pyruvate ratio to properly reflect the redox potential, one would need to demonstrate that this ratio is identical to both cytosolic and mitochondrial ratios and that the rate of cell efflux of pyruvate and lactate are also identical [5]. Lastly, use of a pyruvate assay is precarious since the latter is quickly degraded and can therefore lead to falsely elevated lactate/pyruvate levels. We have nonetheless demonstrated [6] that this ratio is very high (40Ô6) in cardiogenic shock patients with low cardiac output compared to controls (8 Ô 2), these patients representing a clinical model of tissue hypoxia (we will see further that this notion can in fact be debated). We also found a definite increase of this ratio in patients with refractory septic shock characterized by elevated catecholamine dosages, low blood-pressure, metabolic acidosis and normokinetic state. On the other hand, in stabilized septic shock patients, this ratio was slightly increased (14 Ô 1) or otherwise normal when corrected for ph. Interestingly, for equal concentrations of lactate, septic patients, with the exception of refractory septic shock patients, have

4 Lactic Acidosis and Hyperlactatemia 91 higher pyruvate levels, thus implying a mechanism other than hypoxia. In the end, the prognostic value of the lactate/pyruvate ratio was no better than that of lactate and failed to provide any additional information. z Classification of Hyperlactatemia For instructional purposes, the classification of Cohen and Woods remains the tool of reference (Table 1). It differentiates hyperlactatemia associated with signs of tissue hypoperfusion (type A) from hyperlactatemia without tissue hypoperfusion (type B). z Lactate and Shock States Classically, hyperlactatemia in shock is considered as secondary to tissue hypoxia induced by a decrease in tissue perfusion. This notion is potentially true in certain clinical situations. Situations where Hyperlactatemia is Predominantly a Reflection of Tissue Hypoperfusion Shock states induced by low cardiac output should theoretically be accompanied by a hypoxic hyperlactatemia. Cardiogenic shock, as demonstrated previously, is associated with hyperlactatemia with a very high lactate/pyruvate ratio. In theory, hemorrhagic shock should behave in an identical fashion. The problem encountered with sepsis is more complex; although at least two situations are usually accompanied by hypoxia-associated hyperlactatemia. The first is Table 1. Causes of hyperlactatemia adapted from Cohen and Woods. Type A: Imbalance between oxygen demand and supply Type B: Metabolic derangements z Shock z Severe hypoxemia, carbon monoxide poisoning z Severe anemia, excessive increase in oxygen demand (seizure, hyperpyrexia, shivering, strenuous exercise) z Cancer (tumor production or liver metastasis) z Liver failure z Cyanide poisoning z Alkalosis z Sepsis z Beta-2 agonist z Ketoacidosis z Vitamin deficiency: thiamine, biotine z Ethanol intoxication (increases in hepatic NADH and decreases in the conversion of lactate to pyruvate) z Metformin z Inborn error of metabolism

5 92 B. Levy septic shock with catecholamine-resistant cardio-circulatory failure, especially in situations of low cardiac output. The second circumstance is septic shock pre-emptively observed prior to volumetric expansion as illustrated in the study by Rivers et al. [7] in which hyperlactatemia was associated with signs of poor oxygen delivery. These two situations are nonetheless close to low output states. Situations where Hyperlactatemia Reflects a Metabolic Adjustment, such as Sepsis Indeed, many arguments argue against tissue hypoxia as the major cause of hyperlactatemia in septic shock. Theoretically, if septic shock hyperlactatemia was indeed induced by tissue hypoxia caused by hypoperfusion, then: z hyperlactatemic septic patients should display collapsed oxygen delivery, which should be corrected with increased oxygen transport, which is not the case [8] z tissue PO 2 should be low; however, and in contrast to cardiogenic shock, muscle PO 2 measured in septic shock patients is actually elevated [9] z ATP levels should be decreased. Yet these levels were found to be normal when measured in human muscle, as in many animal models [10] z dichloroacetate, a PDH activator, should not lower lactatemia in septic patients or animals since it increases the conversion of pyruvate into acetyl CoA used in the respiratory chain. However, numerous animal models and several human studies have shown that dichloroacetate significantly decreases lactatemia in septic states [11] z Finally, it has been postulated that lactate may originate from a regional source. Splanchnic circulation was initially targeted but De Backer et al. [12] demonstrated that the splanchnic area in general consumed lactate and that splanchnic production was uncommon and in any case not quantitatively sufficient to explain systemic hyperlactatemia. The lungs can also produce lactate, essentially in acute respiratory distress syndrome (ARDS), although this production is mostly explained by the presence of infiltrating inflammatory cells [13] and not by hypoxia. Aerobic Production of Lactate Aerobic is defined as any situation involving oxygen. Lactate formation occurring during the first part of glycolysis is termed anaerobic, as it does not require the presence of oxygen. A sepsis-associated inflammatory state induces an increase in pyruvate production combined with accrued synthesis of glucose transporter-1 (GLUT-1) mrna [14]. This state, called accelerated aerobic glycolysis, occurs when the rate of carbohydrate metabolism exceeds the oxidative capacity of the mitochondria. Pyruvate is produced by an increased influx of glucose [15] but also via muscle protein catabolism, releasing amino acids subsequently transformed into pyruvate and, thereafter, lactate. Moreover, PDH dysfunction has been described in sepsis and thus may participate in the accumulation of pyruvate [16]. Compartmentalization of Glycolysis, Epinephrine, Muscle and Na + K + ATPase Pump. Cytosolic glycolytic flux is functionally divided into two distinct compartments. There are two distinctive glycolytic pathways utilizing separate glycolytic enzyme pools. The first pathway participates in oxidative metabolism via the Krebs cycle. The sec-

6 Lactic Acidosis and Hyperlactatemia 93 ond pathway is linked to activity of the Na + K + ATPase pump (Fig. 2). Indeed, ATP produced by this pathway is used to fuel this membrane pump [17, 18]. Numerous studies [19, 20] have demonstrated that epinephrine, via b 2 -adrenoceptor stimulation, increases camp production inducing the stimulation of glycogenolysis and glycolysis (ATP production) as well as activation of the Na + K + ATPase pump, which in turn will consume this ATP, thereby producing ADP. This generated ADP via PFK stimulation, will re-activate glycolysis and hence generate more pyruvate and, thereafter, lactate. Muscle tissue, which represents approximately 40% of total cell mass in the body is particularly implicated in this mechanism, not to mention that over 99% of muscle adrenergic receptors are b 2 receptors [21]. In order to confirm this hypothesis, we utilized muscle microdialysis in hyperlactatemic septic shock patients under catecholamine treatment. This technique consists of inserting into the quadriceps muscle a very fine catheter perfused with a liquid similar to the extracellular medium but lactate-free. The catheter is comprised of a membrane similar to a dialysis membrane, therefore enabling the retrieval, following an equilibrium period, of a fluid whose composition is in equilibrium with the interstitial fluid. When the liquid is perfused very slowly (0.3 ll/min), the composition of the collected fluid is equal to the composition of the interstitial fluid. Furthermore, it is possible to add a biologically active substance to the perfusate whose effect will be strictly limited to cells surrounding the catheter. Finally, by measuring the arterial concentration of the compound of interest, one can establish an interstitial muscular-arterial gradient which, if positive, indicates muscle production. Our working hypothesis stipulated that epinephrine, secreted in response to a shock state, boosted production of muscle lactate by activating the Na + K + ATPase pump. We, therefore, introduced two microdialysis catheters; the first perfused with lactate-free Ringer's and the second perfused with the same solution in combination with ouabain, a selective inhibitor of the Na + K + ATPase pump. A key finding Fig. 2. Epinephrine-increased glycolysis is coupled to Na + K + ATPase activity. The ATP furnished by the glycolysis under epinephrine stimulation is used to fuel Na + K + ATPase activity

7 94 B. Levy Fig. 3. Lactate concentrations in 14 patients with septic shock in 24 h of study. From [22] with permission revealed that muscle lactate was consistently greater than arterial lactate thus indicating muscle production (Fig. 3) and that this production was totally inhibited by ouabain confirming a Na + K + ATPase±dependent mechanism, but independent of tissue hypoxia [22]. Significance. Muscle lactate, produced under the effect of epinephrine and released into the bloodstream is utilized by the liver to produce glucose through neoglucogenesis (Cori cycle) (Fig. 4) or by other cells for oxidative purposes. Neoglucogenesis is associated with a lower energetic efficiency since 2 ATP are produced per molecule of glucose to generate lactate, while 6 ATP are consumed for every molecule of glucose generated from lactate. This process nonetheless allows the liver to use the ATP generated by fatty acid b oxidation to produce glucose. Hence, fatty acids which supply large quantities of available energy, albeit in a slow process, are used to produce limited stocks of glucose. This mechanism underscores the pivotal role of lactate during aerobic energy metabolism. The `lactate shuttle' theory suggests that aerobic production of lactate represents an important mechanism by which various tissues share a common source of carbons for oxidation and other biochemical processes such as neoglucogenesis. Hyperlactatemia in shock states may, therefore, constitute an adaptive protective mechanism by favoring the oxidation of lactate rather than that of glucose in tissues where oxygen is available, thus preserving glucose in tissues where oxygen content is rare. Thus, an elevated lactate/pyruvate ratio is an indicator of a cytoplasmic accumulation of reduced equivalents (NADH) from which NADH can be used to regenerate ATP (ADP +NADH +H + )ATP+NAD). Henceforth, the combination of lactate/pyruvate could be considered as an adaptive energetic substrate, able to navigate from cell to cell or from organ to organ [23]. This hypothesis is largely supported by several experimental studies demonstrating, for example, that the brain [24] or heart can utilize lactate as a preferred

8 Lactic Acidosis and Hyperlactatemia 95 Fig. 4. Cori cycle: Lactate is produced by muscle and released in the blood. It reaches the liver where it enters the Cori cycle and becomes glucose. The energy for such gluconeogenesis is supplied by beta-oxidation of fatty acids. The glucose is either used locally or recycled to supply fast energy to cells. These pathways ensure conversion of slow energy stored as fat into fast energy that is readily available as glucose. The energy cost is ±4 moles of ATP [32] source of energy in certain situations of stress. It was also demonstrated that lactate depletion in the myocardium resulting from hemorrhagic shock reduced myocardial performance [25]. Other Etiologies of Non-hypoxic Hyperlactatemia Reduction in lactate clearance: Levraut et al. [26] have elegantly demonstrated through the use of labeled lactate that persistent hyperlactatemia in hemodynamically-stable septic shock patients was due to a reduction in lactate clearance and not an increase in lactate production. Pyruvate Dehydrogenase dysfunction: PDH converts pyruvate into acetyl CoA allowing pyruvate to enter the mitochondria. PDH activity was found to be lower in septic muscle and restored by dichloroacetate. Dichloroacetate lowers lactatemia in septic patients. It is, therefore, likely that there is a certain degree of dysfunction or saturation of PDH activity in septic states [27], although this phenomenon remains secondary. Protein degradation: Protein catabolism generates the release of amino-acids which are converted into pyruvate and thereafter into lactate. z Accelerated Glycolysis is a Universal Mechanism in Shock States Indeed, the initial reaction to a state of shock or to aggression, regardless of etiology, is catecholamine secretion. It, therefore, appears logical that at least a portion of the hyperlactatemia observed in low cardiac output states, such as that observed during hypovolemia, hemorrhagic or cardiogenic shock, would be due to a Na + K + ATPase pump-dependent mechanism. McCarter et al. [28] demonstrated in a rat

9 96 B. Levy model of hemorrhagic shock that muscle lactate was produced under the stimulatory effect of the epinephrine-induced Na + K + ATPase pump. Using muscle microdialysis, we have demonstrated that non-selective beta blockers, ouabain as well as a selective b 2 blocker, considerably decreased muscle lactate production in hemorrhagic shock, although not suppressing it completely (unpublished data); the conclusion of this study being that hyperlactatemia is in large part secondary to the stimulation of muscle b 2 receptors, including low output shock states. Lactate and Metabolic Acidosis Lactic acidosis is generally defined by a build-upof lactic acid (lactatemia > 5 mmol/l) and metabolic acidosis (ph < 7.25). Classically, it is considered that during tissue hypoxia, acidosis is induced by the hydrolysis of ATP, from which the resulting release of H + ion is accumulated in the cytoplasm. On the other hand, in the absence of hypoxia, ATP hydrolysis also leads to the release of H + ions which will ultimately be recycled during glucose metabolism, thereby explaining the absence of acidosis. This concept has been questioned by Stewart [29], who demonstrated that the acid-base balance is dependent on PCO 2, the presence of weak acids (phosphates and proteins) and a `strong ion gap [SIG]' defined by (Na + +K + +Ca ++ +Mg ++ )± (Cl ± + lactate). Lactate, as does chloride or citrate for example, reduces the gap between positive ions and negative ions. This reduction in [SIG] alters the dissociation of plasmatic water. Water, which is normally partially dissociated into H + and OH ±, becomes more dissociated, thus generating more H + ions measured by a reduction in ph. While it appears evident that lactate is a significant component of [SID] by increasing the concentration of H + ions, it is not solely responsible for the variations in ph. This explains why a certain number of hyperlactatemias are not accompanied by acidosis or exhibit lesser acidosis relative to the actual concentration of lactate. z Prognostic Value of Lactate Regardless of the mechanism of production, hyperlactatemia and especially the persistence of hyperlactatemia, remains a major prognostic factor in diseases with etiologies as varied as polytrauma or shock, whether it be septic, hemorrhagic or cardiogenic [30, 31]. Persistence of an elevated lactate level can be due to an incessant overproduction related to a persistence of the initiator mechanism but also to a lowering of lactate clearance notably due to hepatic dysfunction. z Line of Conduct when Facing Hyperlactatemia Lactate must be assayed in all situations predisposing to its formation and particularly in the diagnosis and follow-upof shock states, including all cases of severe sepsis. Rivers et al. [7] demonstrated, for example, that a large proportion of patients with severe sepsis without hypotension exhibited hyperlactatemia and low central venous oxygen saturation (ScvO 2 ), and that this hyperlactatemia was corrected during ensuing management.

10 Lactic Acidosis and Hyperlactatemia 97 Initiated treatment should be based on alleged mechanisms of formation but mostly on observed physiopathological disorders as they relate to objective parameters warranted by the situation: cardiac output, blood-pressure, echocardiography, mixed venous oxygen saturation (SvO 2 ), abdominal pressure. Lactate can be used to monitor the efficiency of initiated therapy insofar as confounding factors such as catecholamines, particularly epinephrine, and hepatic function are taken into account. The major concern of the treating critical care specialist when facing hyperlactatemia and, even more so, when it is accompanied by metabolic acidosis, is cardiovascular dysfunction, regardless of its origin. Once this diagnosis is eliminated, when warranted, by treatment aimed at increasing oxygen delivery the etiological diagnosis will rest on a knowledge of the various etiologies involved (Table 1). To date, there is no specific treatment available; furthermore, several pathophysiological components cited above actually suggest that hyperlactatemia could even be beneficial. z Conclusion Measurement of plasma lactate remains a primordial component for a sound diagnostic and therapeutic line of conduct in critical care. The concept of lactate as merely a metabolic waste product (bad lactate) has now evolved towards lactate being viewed as an energy shuttle (good lactate). In most clinical critical care situations, hyperlactatemia must be perceived as an adaptive response to an aggressive state and not as a marker of tissue hypoxia. Nevertheless, irrespective of its mechanism of formation, hyperlactatemia remains an excellent prognostic marker. References 1. Mizock BA, Falk JL (1992) Lactic acidosis in critical illness. Crit Care Med 20:80±93 2. Gladden LB (2004) Lactate metabolism ± a new paradigm for the third millennium. J Physiol 558:5±30 3. Cohen RD, Simpson R (1975) Lactate metabolism. Anesthesiology 43:661± Alberti KG (1977) The biochemical consequences of hypoxia. J Clin Pathol Suppl (R Coll Pathol) 11:14±20 5. Leverve XM (1999) From tissue perfusion to metabolic marker: assessing organ competition and co-operation in critically ill patients? Intensive Care Med 25:890± Levy B, Sadoune LO, Gelot AM, Bollaert PE, Nabet P, Larcan A (2000) Evolution of lactate/ pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock. Crit Care Med 28:114± Rivers E, Nguyen B, Havstad S, et al (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368± Gilbert EM, Haupt MT, Mandanas RY, Huaringa AJ, Carlson RW (1986) The effect of fluid loading, blood transfusion, and catecholamine infusion on oxygen delivery and consumption in patients with sepsis. Am Rev Respir Dis 134:873± Boekstegers P, Weidenhofer S, Kapsner T, Werdan K (1994) Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit Care Med 22:640± Hotchkiss RS, Karl IE (1992) Reevaluation of the role of cellular hypoxia and bioenergetic failure in sepsis. JAMA 267:1503± Stacpoole PW, Harman EM, Curry SH, Baumgartner TG, Misbin RI (1983) Treatment of lactic acidosis with dichloroacetate. N Engl J Med 309:390± De Backer D, Creteur J, Silva E, Vincent JL (2001) The hepatosplanchnic area is not a common source of lactate in patients with severe sepsis. Crit Care Med 29:256± Iscra F, Gullo A, Biolo G (2002) Bench-to-bedside review: lactate and the lung. Crit Care 6:327±329

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