U se of Lac t at e i n Smal l A n i m a l Clinical Practice Leslie C. Sharkey,
DVM, PhD
a,
*, Maxey L. Wellman,
DVM, MS, PhD
b
KEYWORDS Lactate L-Lactate D-Lactate Lactic acidosis Hypoxia Hypoperfusion Metabolic acidosis KEY POINTS Lactate concentration is used as an indicator of tissue hypoperfusion and hypoxia, particularly in critical care or perioperative settings. Lactate concentration is used to determine the severity of an underlying disorder, assess response to therapy, and predict outcome, especially if serial lactate levels are measured. Decreasing levels of lactate suggest improvement, whereas prolonged increases in lactate concentration imply deterioration with a poor prognosis. Repeated lactate concentrations should be determined on the same instrument with close attention to sample collection and processing and adherence to recommendations for instrument quality control.
INTRODUCTION
Lactate is formed primarily as the end product of anaerobic glycolysis, although small amounts are produced during aerobic metabolism. Hyperlactatemia refers to mildly increased lactate concentration without concurrent metabolic acidosis. Lactic acidosis occurs when hyperlactatemia is more severe and is accompanied by a decrease in blood pH.1–3 Lactic acidosis occurs most commonly with tissue hypoperfusion and hypoxia, often as a consequence of systemic or regional hypoperfusion, severe anemia, or hypermetabolic states. Liver disease, kidney disease, diabetes mellitus, sepsis, drugs and toxins, and uncommon mitochondrial defects can cause lactic acidosis from various mechanisms including decreased aerobic metabolism and lactate consumption.4 In healthy adult dogs, serum lactate measures 0.3 to 2.5 mmol/L.5 Puppies have higher lactate concentrations that decrease to adult values by 2 to 3 months of age.6
Disclosures: Dr M.L. Wellman is a paid consultant for IDEXX Laboratories and Marshfield Labs. a Veterinary Clinical Sciences Department, University of Minnesota College of Veterinary Medicine, 1352 Boyd Avenue, St Paul, MN 55108, USA; b Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA * Corresponding author. E-mail address: [email protected] Vet Clin Small Anim 43 (2013) 1287–1297 http://dx.doi.org/10.1016/j.cvsm.2013.07.012 vetsmall.theclinics.com 0195-5616/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
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Serum lactate in healthy adult cats is 0.5 to 2.0 mmol/L.7 Indications for measuring serum lactate include assessment of tissue perfusion and oxygenation, predicting outcome or response to therapy in critically ill patients, and evaluation of metabolic acidosis. In people, serum lactate concentration has been used as a risk stratification biomarker.8 Several studies in veterinary medicine indicate that lactate concentration may have similar implications for prognosis.4,9–11 In dogs, 3 to 5 mmol/L is considered a mild increase; 5 to 8 mmol/L is considered a moderate increase, and greater than 8 mmol/L is considered a marked increase in blood lactate concentration.12 LACTATE PHYSIOLOGY AND METABOLISM
Under aerobic conditions, glucose is metabolized to pyruvic acid, which diffuses into mitochondria to enter the Krebs cycle and undergo oxidative phosphorylation for energy production or transformation in glucose via gluconeogenesis (Fig. 1). However, in red blood cells (RBC) and other cells that lack mitochondria, and in other tissues during periods of hypoxia, glucose is metabolized to pyruvic acid by anaerobic glycolysis. In the final step of anaerobic glycolysis, lactic acid dehydrogenase catalyzes the conversion of pyruvic acid to lactic acid, a reaction that favors lactic acid formation by a ratio of 10:1 during normal metabolism (Fig. 2).8
Fig. 1. Glucose metabolism. Glucose enters the cell via the GLUT family of membrane proteins. Glucose is metabolized through several steps (only some of which are shown in the diagram) to pyruvate. Pyruvate can be oxidized via the Kreb’s cycle in the mitochondrion or transformed to glucose via the gluconeogenesis pathway. Pyruvate also can be converted to lactate via the enzyme lactate dehydrogenase (LDH), which generates nicotine adenine dinucleotide (NAD). This reaction occurs more readily when there is tissue hypoxia. Lactate in the cytoplasm crosses the cell membrane into the blood via a monocarboxylate-proton cotransporter (MCT), an anion exchange system, and simple diffusion.
Use of Lactate in Small Animal Clinical Practice
Fig. 2. The final step of anaerobic glycolysis.
Lactic acid (C3H6O3) is a nonvolatile (fixed) acid that readily dissociates into a lactate ion [C3CH(OH)COO ] and a hydrogen ion (H1) in body fluids at physiologic pH. Lactate ion most often is referred to simply as lactate. A monocarboxylate-proton cotransporter, an anion exchange system, and simple diffusion allow lactate to cross the cell membrane into the blood. The H1 ions are titrated by various body buffers, but when lactate production is increased, the buffers are depleted and acidemia develops. Lactate and H1 are metabolized to glucose or oxidized to H2O and CO2 when aerobic conditions are restored.4 The concentration of lactate in blood depends on the balance between formation and clearance. Daily lactate production is generated primarily by skeletal muscle, skin, brain, heart, intestine, renal medulla, and RBC, but lactate production occurs in many other tissues during illness.1,4,8 For example, large amounts of lactate are produced by the lungs during acute lung injury and by leukocytes during phagocytosis or from leukocyte activation associated with sepsis. Lactate is metabolized primarily by the liver (60%–70%) and kidney (20%–30%) via the Cori cycle, in which lactate produced in other tissues is converted back to pyruvate and then to glucose through gluconeogenesis.8,13 Lactate is freely filtered by the glomerulus and most is reabsorbed in the proximal tubules, with only minimal amounts being excreted in urine.1,8,14 In chronic liver disease like cirrhosis, lactate clearance is maintained, but in acute liver disease and impaired renal function can contribute to increased blood levels of lactate due to decreased clearance. Acidosis decreases hepatic clearance and may cause increased hepatic lactate production, whereas renal clearance is increased with acidosis.4,15 In marked hypoperfusion associated with shock, the liver and kidney may switch from lactate consumption to lactate production, emphasizing the importance of reinstating adequate perfusion and oxygen delivery.1 Lactate has 2 optical isomers, L-lactate, and its mirror image, D-lactate. L-Lactate is produced almost exclusively in healthy monogastric animals. D-Lactate can come from bacterial fermentation of carbohydrates in the intestinal tract or from alternate metabolic pathways that occur with some toxins or in certain diseases. Increases in D-lactate have been reported in diabetes mellitus and propylene glycol toxicity, or from intestinal bacterial overgrowth (small intestinal dysbiosis).4,16,17 Routine testing measures only L-lactate concentration. D-Lactic acidosis is sometimes suspected when there is unexplained metabolic acidosis with an increased anion gap and normal L-lactate concentration. D-Lactate can be measured by high-pressure liquid chromatography or mass spectrometry in select laboratories.17 CLASSIFICATION OF LACTIC ACIDOSIS
There are 3 types of lactic acidosis. Type A lactic acidosis is more common and occurs when there is tissue hypoperfusion and hypoxia from either decreased oxygen delivery or increased oxygen demand. Shock is an example of hypoperfusion; anemia is an example of decreased oxygen delivery, and seizures are an example of increased oxygen demand (Box 1). Type B lactic acidosis occurs when oxygen delivery
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Box 1 Causes of lactic acidosis Type A lactic acidosis Decreased oxygen delivery Hypovolemic, cardiogenic, or septic shock Severe anemia (PCV
DVM, PhD
a,
*, Maxey L. Wellman,
DVM, MS, PhD
b
KEYWORDS Lactate L-Lactate D-Lactate Lactic acidosis Hypoxia Hypoperfusion Metabolic acidosis KEY POINTS Lactate concentration is used as an indicator of tissue hypoperfusion and hypoxia, particularly in critical care or perioperative settings. Lactate concentration is used to determine the severity of an underlying disorder, assess response to therapy, and predict outcome, especially if serial lactate levels are measured. Decreasing levels of lactate suggest improvement, whereas prolonged increases in lactate concentration imply deterioration with a poor prognosis. Repeated lactate concentrations should be determined on the same instrument with close attention to sample collection and processing and adherence to recommendations for instrument quality control.
INTRODUCTION
Lactate is formed primarily as the end product of anaerobic glycolysis, although small amounts are produced during aerobic metabolism. Hyperlactatemia refers to mildly increased lactate concentration without concurrent metabolic acidosis. Lactic acidosis occurs when hyperlactatemia is more severe and is accompanied by a decrease in blood pH.1–3 Lactic acidosis occurs most commonly with tissue hypoperfusion and hypoxia, often as a consequence of systemic or regional hypoperfusion, severe anemia, or hypermetabolic states. Liver disease, kidney disease, diabetes mellitus, sepsis, drugs and toxins, and uncommon mitochondrial defects can cause lactic acidosis from various mechanisms including decreased aerobic metabolism and lactate consumption.4 In healthy adult dogs, serum lactate measures 0.3 to 2.5 mmol/L.5 Puppies have higher lactate concentrations that decrease to adult values by 2 to 3 months of age.6
Disclosures: Dr M.L. Wellman is a paid consultant for IDEXX Laboratories and Marshfield Labs. a Veterinary Clinical Sciences Department, University of Minnesota College of Veterinary Medicine, 1352 Boyd Avenue, St Paul, MN 55108, USA; b Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA * Corresponding author. E-mail address: [email protected] Vet Clin Small Anim 43 (2013) 1287–1297 http://dx.doi.org/10.1016/j.cvsm.2013.07.012 vetsmall.theclinics.com 0195-5616/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
1288
Sharkey & Wellman
Serum lactate in healthy adult cats is 0.5 to 2.0 mmol/L.7 Indications for measuring serum lactate include assessment of tissue perfusion and oxygenation, predicting outcome or response to therapy in critically ill patients, and evaluation of metabolic acidosis. In people, serum lactate concentration has been used as a risk stratification biomarker.8 Several studies in veterinary medicine indicate that lactate concentration may have similar implications for prognosis.4,9–11 In dogs, 3 to 5 mmol/L is considered a mild increase; 5 to 8 mmol/L is considered a moderate increase, and greater than 8 mmol/L is considered a marked increase in blood lactate concentration.12 LACTATE PHYSIOLOGY AND METABOLISM
Under aerobic conditions, glucose is metabolized to pyruvic acid, which diffuses into mitochondria to enter the Krebs cycle and undergo oxidative phosphorylation for energy production or transformation in glucose via gluconeogenesis (Fig. 1). However, in red blood cells (RBC) and other cells that lack mitochondria, and in other tissues during periods of hypoxia, glucose is metabolized to pyruvic acid by anaerobic glycolysis. In the final step of anaerobic glycolysis, lactic acid dehydrogenase catalyzes the conversion of pyruvic acid to lactic acid, a reaction that favors lactic acid formation by a ratio of 10:1 during normal metabolism (Fig. 2).8
Fig. 1. Glucose metabolism. Glucose enters the cell via the GLUT family of membrane proteins. Glucose is metabolized through several steps (only some of which are shown in the diagram) to pyruvate. Pyruvate can be oxidized via the Kreb’s cycle in the mitochondrion or transformed to glucose via the gluconeogenesis pathway. Pyruvate also can be converted to lactate via the enzyme lactate dehydrogenase (LDH), which generates nicotine adenine dinucleotide (NAD). This reaction occurs more readily when there is tissue hypoxia. Lactate in the cytoplasm crosses the cell membrane into the blood via a monocarboxylate-proton cotransporter (MCT), an anion exchange system, and simple diffusion.
Use of Lactate in Small Animal Clinical Practice
Fig. 2. The final step of anaerobic glycolysis.
Lactic acid (C3H6O3) is a nonvolatile (fixed) acid that readily dissociates into a lactate ion [C3CH(OH)COO ] and a hydrogen ion (H1) in body fluids at physiologic pH. Lactate ion most often is referred to simply as lactate. A monocarboxylate-proton cotransporter, an anion exchange system, and simple diffusion allow lactate to cross the cell membrane into the blood. The H1 ions are titrated by various body buffers, but when lactate production is increased, the buffers are depleted and acidemia develops. Lactate and H1 are metabolized to glucose or oxidized to H2O and CO2 when aerobic conditions are restored.4 The concentration of lactate in blood depends on the balance between formation and clearance. Daily lactate production is generated primarily by skeletal muscle, skin, brain, heart, intestine, renal medulla, and RBC, but lactate production occurs in many other tissues during illness.1,4,8 For example, large amounts of lactate are produced by the lungs during acute lung injury and by leukocytes during phagocytosis or from leukocyte activation associated with sepsis. Lactate is metabolized primarily by the liver (60%–70%) and kidney (20%–30%) via the Cori cycle, in which lactate produced in other tissues is converted back to pyruvate and then to glucose through gluconeogenesis.8,13 Lactate is freely filtered by the glomerulus and most is reabsorbed in the proximal tubules, with only minimal amounts being excreted in urine.1,8,14 In chronic liver disease like cirrhosis, lactate clearance is maintained, but in acute liver disease and impaired renal function can contribute to increased blood levels of lactate due to decreased clearance. Acidosis decreases hepatic clearance and may cause increased hepatic lactate production, whereas renal clearance is increased with acidosis.4,15 In marked hypoperfusion associated with shock, the liver and kidney may switch from lactate consumption to lactate production, emphasizing the importance of reinstating adequate perfusion and oxygen delivery.1 Lactate has 2 optical isomers, L-lactate, and its mirror image, D-lactate. L-Lactate is produced almost exclusively in healthy monogastric animals. D-Lactate can come from bacterial fermentation of carbohydrates in the intestinal tract or from alternate metabolic pathways that occur with some toxins or in certain diseases. Increases in D-lactate have been reported in diabetes mellitus and propylene glycol toxicity, or from intestinal bacterial overgrowth (small intestinal dysbiosis).4,16,17 Routine testing measures only L-lactate concentration. D-Lactic acidosis is sometimes suspected when there is unexplained metabolic acidosis with an increased anion gap and normal L-lactate concentration. D-Lactate can be measured by high-pressure liquid chromatography or mass spectrometry in select laboratories.17 CLASSIFICATION OF LACTIC ACIDOSIS
There are 3 types of lactic acidosis. Type A lactic acidosis is more common and occurs when there is tissue hypoperfusion and hypoxia from either decreased oxygen delivery or increased oxygen demand. Shock is an example of hypoperfusion; anemia is an example of decreased oxygen delivery, and seizures are an example of increased oxygen demand (Box 1). Type B lactic acidosis occurs when oxygen delivery
1289
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Box 1 Causes of lactic acidosis Type A lactic acidosis Decreased oxygen delivery Hypovolemic, cardiogenic, or septic shock Severe anemia (PCV
