Whole body hypoxia occurring during cardiac arrest or severe hypovolaemia triggers anaerobic metabolism. Lactate concentrations directly reflect cellular hypoxia.
Consequently, during in-hospital cardiac arrest and 1 h after return of spontaneous circulation, lactate concentrations are predictive of survival. During systemic inflammatory response syndrome SIRS or early sepsis, hyperlactaemia may reflect tissue hypoxia.
Early enhancement of oxygen delivery improves outcome. Stable septic patients have elevated oxygen delivery and tissue oxygen levels generally exceed those that trigger anaerobic metabolism. Impaired lactate clearance is usually more significant than increased production. Aerobic lactate production in such patients may be involved in modulation of carbohydrate metabolism under stress.
Gut hypoxia causes anaerobic metabolism. The liver receives more lactate from the portal vein. Initially, this is oxidized or converted to glucose by the periportal hepatocytes. Bacterial translocation and profound fluid shifts contribute to circulatory collapse. Global oxygen delivery falls.
Endogenous catecholamine release attempts to support the circulation but will also increase glycolysis and lactate formation. As shock develops hepatic blood flow falls and intracellular acidosis inhibits gluconeogenesis from lactate. The liver produces rather than clears lactate. Intestinal bacteria metabolize glucose and carbohydrate to d -lactate. This is only slowly metabolized by human LDH and contributes to the escalating lactic acidosis.
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Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Malignancy: tumors may cause production of glycolytic enzymes, impaired liver clearance and malnutrition leading to thiamine deficiency. Liver dysfunction: the liver is the primary organ responsible for lactate clearance; injury or failure results in decreased lactate clearance.
Genetic: inborn disorders of metabolism, particularly in the pediatric population, may cause elevated lactate levels. Drugs and Toxins that may cause increased lactate: Metformin biguanide Acetaminophen Nucleoside reverse transcriptase inhibitors NRTI Linezolid Beta-2 agonists Propofol Epinephrine Theophylline Alcohols ethanol, propylene glycol and methanol Cocaine Carbon monoxide Cyanide Treatment of elevated lactate levels should be determined by the underlying cause.
If hypoperfusion or hypoxemia is the culprit, focus on improving perfusion to the affected tissues. In shock, treatments include fluid administration, vasopressors, or inotropes. In regional ischemia, surgery may be needed to restore circulation or remove damaged tissue. References: 1. Anderson, L. Etiology and therapeutic approach to elevated lactate. Mayo Clinic Proceedings, 88 10 , This energy comes from glucose through a process called glycolysis, in which glucose is broken down or metabolized into a substance called pyruvate through a series of steps.
When the body has plenty of oxygen, pyruvate is shuttled to an aerobic pathway to be further broken down for more energy. But when oxygen is limited, the body temporarily converts pyruvate into a substance called lactate, which allows glucose breakdown—and thus energy production—to continue. The working muscle cells can continue this type of anaerobic energy production at high rates for one to three minutes, during which time lactate can accumulate to high levels.
A side effect of high lactate levels is an increase in the acidity of the muscle cells, along with disruptions of other metabolites. The same metabolic pathways that permit the breakdown of glucose to energy perform poorly in this acidic environment. On the surface, it seems counterproductive that a working muscle would produce something that would slow its capacity for more work. In reality, this is a natural defense mechanism for the body; it prevents permanent damage during extreme exertion by slowing the key systems needed to maintain muscle contraction.
Contrary to popular opinion, lactate or, as it is often called, lactic acid buildup is not responsible for the muscle soreness felt in the days following strenuous exercise. Rather, the production of lactate and other metabolites during extreme exertion results in the burning sensation often felt in active muscles, though which exact metabolites are involved remains unclear.
Lactate, the anion that results from dissociation of lactic acid, is a product of glucose metabolism; specifically it is the end product of anaerobic glycolysis. The glycolytic pathway Fig. The final step of anaerobic glycolysis is conversion of pyruvate to lactate by the enzyme lactate dehydrogenase. Production of lactate is the only means for glucose utilization and ATP production in erythrocytes which have no mitochondrion and in exercising muscle cells which have an oxygen debt.
In well-oxygenated tissue cells that contain mitochondrion, pyruvate is not preferentially converted to lactate but rather metabolized to carbon dioxide and water in mitochondria via two integrated metabolic pathways: the citric acid cycle and oxidative phosphorylation. Conversion of a molecule of glucose to lactate anaerobic glycolysis yields just two molecules of ATP, whereas conversion to carbon dioxide and water aerobic glycolysis has a much higher energy yield of 38 ATP molecules.
FIG 1: Lactate - a product of anaerobic glycolysis. Although lactate can be produced in all tissues, skeletal muscle, erythrocytes, brain and renal medulla tissues are the principal production sites in health.
Normal daily lactate production is of the order of mmol [1]. There are two main routes of lactate disposal: conversion to pyruvate or elimination in urine Fig.
Although lactate is freely filtered at the glomerulus, it is almost all reabsorbed and normally This pyruvate has two principal fates. The first is oxidation to acetyl CoA by the enzyme pyruvate dehydrogenase for ultimate metabolism to carbon dioxide and water via the citric acid cycle and oxidative phosphorylation.
The second is conversion to glucose, a process called gluconeogenesis. Oxidation of pyruvate via the citric acid cycle can potentially occur in all cells with mitochondrion, but gluconeogenesis is confined to liver and kidney cortex cells. Overall, the body has immense capacity for lactate disposal, which can, if necessary e. FIG 2: Principal mechanisms of lactate disposal. Lactate produced within erythrocytes cannot be metabolized further and is released to the circulation.
In some tissues e. In health, blood lactate concentration is maintained within the approximate range of 0. This reflects a balance between the rate of lactate release to blood from erythrocytes and other tissue cells and rate of lactate clearance from blood, principally by the liver and kidney.
Exercise represents a physiological process in which this balance is temporarily upset due to the rapid increase in lactate production by muscle cells in temporary oxygen debt. In the presence of oxygen, hydrogen ions produced during ATP hydrolysis are utilized in the mitochondrial process of oxidative phosphorylation, but this is often not possible in the context of anaerobic glycolysis associated with hyperlactate production.
Instead, hydrogen ions accumulate in blood, eventually overwhelming the bicarbonate and other buffering systems that maintain blood pH within normal limits 7. From a biochemical viewpoint the central problem is usually decreased utilization of pyruvate in oxidative or gluconeogenic pathways.
Under these circumstances pyruvate can only be converted to lactate. For example, since oxygen is essential for pyruvate oxidation, any condition that deprives tissues of oxygen can lead to increased production of lactate, which then accumulates in blood at a faster rate than it can be removed by liver and kidneys. The problem is compounded by acidosis because the capacity of the liver to remove lactate from the circulation is pH dependent and severely impaired by reduced blood pH.
In fact, experimental evidence suggests that at blood pH of 7. There is some renal compensation because acidosis enhances kidney uptake of lactate [5].
Traditionally, lactic acidosis has been divided into two broad etiological categories; Type A and Type B. Type A is lactic acidosis resulting from tissue hypoxia biochemical mechanism outlined above and Type B is lactic acidosis occurring in the context of normal tissue perfusion and adequate global tissue oxygenation. Tissue hypoxia and Type A lactic acidosis arise as a result of inadequate perfusion of tissues in hemorrhagic, cardiogenic and septic shock. Type A lactic acidosis then is a feature of acute, life-threatening critical illness.
The conventionally held view that lactic acidosis occurring in the context of sepsis and septic shock is the sole result of tissue hypoxia is now challenged see below and for critically ill patients, whose condition is caused or complicated by infection, the distinction between Type A and Type B lactic acidosis is blurred and inappropriate. Perfusion is not the sole determinant of tissue oxygenation, which also depends on an adequate amount of oxygen in blood.
Tissue hypoxia and consequent Type A lactic acidosis can thus occur despite adequate perfusion if the oxygen content of blood or the oxygen-carrying capacity of blood is sufficiently reduced. This is the mechanism of the Type A lactic acidosis that can occur in patients with severe anemia [10], severe hypoxemia e.
In practice, anemia and hypoxemia are rarely the sole causes of Type A lactic acidosis. More commonly they are contributory factors in the development of Type A lactic acidosis among patients already predisposed because of inadequate perfusion. The massive increase in muscular activity that occurs during seizures can cause Type A lactic acidosis due to local muscle tissue hypoxia consequent on a temporary mismatch between oxygen demand and oxygen supply very similar to the physiological lactic acidosis that occurs during exercise.
In common with exercise-induced lactic acidosis, seizure-induced lactic acidosis is self-limiting, spontaneously resolving within a few hours of seizure cessation [13]. If lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics i.
The vital role of the liver and kidneys for lactate uptake from circulation and subsequent metabolism via the citric acid cycle and gluconeogenesis determines that hepatic and renal disease, whatever its cause, predisposes to mild hyperlactatemia and rarely Type B lactic acidosis.
Malignant disease may be associated with lactic acidosis, most cases of Type B lactic acidosis occurring in hematological malignancy leukemia, lymphoma [14]. Type B lactic acidosis is a feature of several individually very rare inherited disorders that are characterized by deficiency of specific enzymes involved in lactate metabolism either gluconeogenesis or pyruvate oxidation.
These include pyruvate carboxylase deficiency [15], glucosephosphate dehydrogenase G6PD deficiency, fructose-1,6-diphosphatase deficiency [16] and pyruvate dehydrogenase deficiency, the most common [17].
These conditions are collectively referred to as congenital lactic acidosis. A long list of drugs and toxins can cause lactic acidosis Table I , and taken together these represent by far the most common cause of Type B lactic acidosis. Biguanides are a class of blood glucose-lowering drugs used in the treatment of diabetes; metformin, the most widely prescribed, has been linked to lactic acidosis [18]. However, in most cases of metformin-associated lactic acidosis, there is some evidence of liver or renal impairment that predisposes to hyperlactatemia.
Biguanides e. Gluconeogenesis is also inhibited so that the combination of moderate hyperlactatemia and hypoglycemia is a not infrequent finding in patients suffering acute effects of alcohol abuse.
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