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Lactic Acidosis

Author: Kyle J Gunnerson, MD, Associate Professor, Departments of Anesthesiology/CCM and Emergency Medicine, Virginia Commonwealth University; Director of Critical Care Anesthesiology, Co-Director of Cardiac Surgery ICU, Virginia Commonwealth University Health System
Coauthor(s): Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital
Contributor Information and Disclosures

Updated: Jul 22, 2009

Introduction

Background

By the turn of the 20th century, many physicians recognized that that patients who are critically ill could exhibit metabolic acidosis unaccompanied by elevation of ketones or other measurable anions. In 1925, Clausen identified the accumulation of lactic acid in blood as a cause of acid-base disorder. Several decades later, Huckabee's seminal work firmly established that lactic acidosis frequently accompanies severe illnesses and that tissue hypoperfusion underlies the pathogenesis. In their classic 1976 monograph, Cohen and Woods classified the causes of lactic acidosis according to the presence or absence of adequate tissue oxygenation.¹

The normal blood lactate concentration in unstressed patients is 1-0.5 mmol/L. Patients with critical illness can be considered to have normal lactate concentrations of less than 2 mmol/L. Hyperlactatemia is defined as a mild-to-moderate (2-5 mmol/L) persistent increase in blood lactate concentration without metabolic acidosis, whereas lactic acidosis is characterized by persistently increased blood lactate levels (usually > 5 mmol/L) in association with metabolic acidosis.

Hyperlactatemia generally occurs in the settings of adequate tissue perfusion, intact buffering systems, and adequate tissue oxygenation. Lactic acidosis is associated with major metabolic dysregulation, tissue hypoperfusion, effects of certain drugs or toxins, or congenital abnormalities in carbohydrate metabolism. Cohen and Woods divided lactic acidosis into 2 categories, type A and type B. Type A is lactic acidosis occurring in association with clinical evidence of poor tissue perfusion or oxygenation of blood (eg, hypotension, cyanosis, cool and clammy extremities). Type B is lactic acidosis occurring when no clinical evidence of poor tissue perfusion or oxygenation exists.

Congenital lactic acidosis is secondary to inborn errors of metabolism, such as defects in gluconeogenesis, pyruvate dehydrogenase, the tricarboxylic acid (TCA) cycle, or the respiratory chain. These disorders generally reflect situations in which the disposal of pyruvate by biosynthetic or oxidative routes is impaired.

Lactic acidosis may not necessarily produce acidemia in a patient. The development of lactic acidosis depends on the magnitude of hyperlactatemia, the buffering capacity of the body, and the coexistence of other conditions that produce tachypnea and alkalosis (eg, liver disease, sepsis). Thus, hyperlactatemia or lactic acidosis may be associated with acidemia, a normal pH, or alkalemia.

Pathophysiology

The anaerobic metabolic pathway known as glycolysis is the first step of glucose metabolism and occurs in the cytoplasm of virtually all cells. The end-product of this pathway is pyruvate, which can then diffuse into the mitochondria and be metabolized to carbon dioxide by another, more energy-efficient metabolic pathway, the Krebs cycle. The metabolism of glucose to pyruvate also results in the chemical reduction of the enzyme cofactor oxidized form nicotinic acid dehydrogenase (NAD⁺) to nicotinic acid dehydrogenase (NADH) (reduced form).

Erythrocytes are capable of carrying out glycolysis; however, these cells do not have mitochondria and cannot use oxygen to produce adenosine triphosphate (ATP). The pyruvate formed during glycolysis is metabolized by the enzyme lactate dehydrogenase to lactate. The anaerobic pathway is very inefficient, and only 2 moles of ATP are produced for each molecule of glucose that is converted to lactate. The lactate diffuses out of the cells and is converted to pyruvate and then is aerobically metabolized to carbon dioxide and ATP. The heart, liver, and kidneys use lactate in this manner. Alternatively, hepatic and renal tissues can use lactate to produce glucose via another pathway referred to as gluconeogenesis.

The metabolism of glucose to lactate by one tissue, such as red blood cells, and conversion of lactate to glucose by another tissue, such as the liver, is termed the Cori cycle. The ability of the liver to consume lactate is concentration-dependent and progressively decreases as the level of blood lactate increases. Lactate uptake by the liver also is impaired by several other factors, including acidosis, hypoperfusion, and hypoxia.

Metabolic aspects of lactate production

The arterial concentration of lactate depends on the rates of its production and use by various organs. Blood lactate concentration normally is maintained below 2 mmol/L, although lactate turnover in healthy resting humans is approximately 1300 mmol every 24 hours. Lactate producers are skeletal muscle, the brain, the gut, and the erythrocytes. Lactate metabolizers are the liver, the kidneys, and the heart. When lactate blood levels exceed 4 mmol/L, the skeletal muscle becomes a net consumer of lactate.

Lactate is a byproduct of glycolysis and is formed in the cytosol catalyzed by enzyme lactate dehydrogenase as shown below:

This is a reversible reaction that favors lactate synthesis with the lactate-to-pyruvate ratio that is normally at 25:1. Lactate synthesis increases when the rate of pyruvate formation in the cytosol exceeds its rate of use by the mitochondria. This occurs when a rapid increase in metabolic rate occurs or when oxygen delivery to the mitochondria declines, such as in tissue hypoxia. Lactate synthesis also may occur when the rate of glucose metabolism exceeds the oxidative capacity of the mitochondria, as observed with administration of catecholamines or errors of metabolism.

Cellular energy metabolism and lactate production

Cells require a continuous supply of energy for protein synthesis. This energy is stored in the phosphate bonds of the ATP molecule. The hydrolysis of ATP results in the following reaction, where ADP is adenosine diphosphate and Pi is inorganic phosphate:

With an adequate supply of oxygen, the cells use ADP, Pi, and H⁺ in the mitochondria to reconstitute ATP. During cellular hypoxia, the hydrolysis of ATP leads to accumulation of H and Pi in the cytosol. Therefore, ATP hydrolysis is the source of cellular acidosis during hypoxia and not the formation of lactate from glucose, which neither consumes nor generates H⁺. The glycolytic process may be viewed as the following:

The hydrolysis of 2 ATP molecules formed from the metabolism of glucose produces H⁺, ADP, and Pi.

If the oxygen supply is adequate, the metabolites of ATP are recycled in the mitochondria and the cytosolic lactate concentration rises without acidosis. On the other hand, with cellular hypoxia, the equation of anaerobic glycolysis becomes the following:

A second cellular source of anaerobic ATP is the adenylate kinase reaction, also called the myokinase reaction, where 2 molecules of ADP join to form ATP and adenosine monophosphate (AMP).

This reaction leads to increased intracellular levels of AMP, Pi, and H⁺. Thus, H⁺ is able to increase during hypoxemia without the notable increase in cellular lactate concentration.

Cellular transport of lactate

Intracellular accumulation of lactate creates a concentration gradient favoring its release from the cell. Lactate leaves the cell in exchange for a hydroxyl anion (OH-), a membrane-associated, pH-dependent, antiport system. The source of extracellular OH- is the dissociation of water into OH- and H⁺. Extracellular H⁺ combines with lactate leaving the cell, forming lactic acid, while intracellular OH- binds to H⁺ generated during the hydrolysis of ATP to form water. Therefore, cellular transport of lactate helps to moderate increases in cytosolic H⁺ resulting from hydrolysis of anaerobically generated ATP.

Cellular response to hypoxia

Declines in cellular oxygen delivery lead to more oxygen extraction from the capillary blood. This action redistributes the cardiac output to organs according to their ability to recruit capillaries and also decreases the distance from the capillaries to the cells. With severe decreases in oxygen transport, compensatory increase in the oxygen extraction ratio is insufficient to sustain aerobic metabolism. Therefore, the cell must employ anaerobic sources of energy to produce ATP, resulting in the generation of lactate and H⁺.

Lactate acidosis as a metabolic monitor of shock

Shock currently is conceptualized as a clinical syndrome resulting from an imbalance between tissue oxygen demands and tissue oxygen supply. Impaired oxygen delivery is the primary problem in hypovolemic, cardiogenic, distributive (septic), and obstructive (pericardial tamponade, tension pneumothorax) forms of shock. When tissue hypoxia is present, pyruvate oxidation decreases, lactate production increases, and ATP formation continues via glycolysis. The amount of lactate produced is believed to correlate with the total oxygen debt, the magnitude of hypoperfusion, and the severity of shock. Serial lactate determinations may be helpful in patients resuscitated from shock to assess the adequacy of therapies.

Hyperlactemia and lactic acidosis in sepsis

Patients who develop severe sepsis or septic shock commonly demonstrate hyperlactemia and lactic acidosis. The pathophysiology of sepsis associated lactic acidosis has not been well understood. Increased lactate production during anaerobic and aerobic metabolism and decreased lactate clearance are likely contributors to hyperlactemia. Patients with septic shock have lactate levels of more than 5 mmol/L, a lactate-to-pyruvate ratio greater than 10-15:1, and arterial pH of less than 7.35. Following resuscitation from septic shock, some patients continue to demonstrate hyperlactemia (lactate 2-5 mmol/L), whereas blood pH is normal or alkalemic. These patients manifest increased oxygen consumption, insulin resistance, urea nitrogen excretion in urine, and a normal lactate-to-pyruvate ratio. Hyperlactemia likely occurs from increased production of pyruvate and equilibration with lactate, this has been termed "stress hyperlactemia."²

The mechanism of lactic acidosis in septic shock is continuing to be debated. Several studies have shown an elevated lactate-to-pyruvate ratio in septic shock, suggesting tissue hypoxia as the cause of lactic acidosis. However, other investigators have documented hyperlactemia in the absence of hypoxia.

The additional possible mechanisms for hyperlactemia include activation of glycolysis and inhibition of pyruvate dehydrogenase. Some investigators have observed that patients with sepsis have decreased lactate clearance rather than increased lactate production. Skeletal muscle and lung tissue have been shown to produce lactate during sepsis. Therefore, hyperlactemia may be secondary to increased lactate production in the gut, liver, lungs, and skeletal muscles; decreased lactate clearance in the liver; or a combination of both. Still, other investigators have suggested that hyperlactemia may occur secondary to inflammatory mediators down-regulating pyruvate dehydrogenase in skeletal muscles, rather than tissue hypoxia.³ Hyperlactemia was prevented by administration of tumor necrosis factor (TNF) binding protein in a rat model of sepsis. However, this finding has not been consistently observed in other animal and clinical studies.⁴

Despite the conflicting results from these studies, hyperlactemia in patients with sepsis is a marker of the severity of stress response. Hyperlactemia may possibly develop as a byproduct of overall acceleration in glycolysis in severe sepsis. This may well be an adaptive host mechanism designed to provide for efficient generation of energy in response to severe stress.

Limitations of lactic acidosis as a monitor

The use of lactate as an index of tissue perfusion has several limitations. The presence of liver disease causes a decreased ability to clear lactate during periods of increased production. Various causes of type B lactate acidosis may produce hyperlactemia and lactate acidosis in the absence of tissue perfusion. For significant increase in blood lactate to occur, lactate must be released into the systemic circulation and the rate of production must exceed hepatic, renal, and skeletal muscle uptake. Therefore, regional hypoperfusion of tissues may be present despite normal blood lactate concentrations.

Frequency

United States

Prevalence of lactic acidosis is not known and is difficult to investigate; however, abnormal lactate metabolism is frequently encountered in patients who are critically ill.

Symptomatic hyperlactatemia is associated with antiretroviral therapy. In a large cohort of adults infected with HIV, hyperlactatemia was diagnosed in 64 patients. Incidences were 18.3 per 1000 person-years with antiretroviral therapy and 35.8 per 1000 person-years for stavudine (d4T) regimens.

Mortality/Morbidity

• Patients who have an arterial lactate level of more than 5 mmol/L and a pH of less than 7.35 are critically ill and have a very poor prognosis. The multicenter trials have shown a mortality rate of 75% in these patients.
• In another study, the median survival for patients with lactic acidosis and shock was 28 hours. Of these patients, 56% survived 24 hours and only 17% of the patients were discharged from the hospital. Nearly half of these patients showed evidence of multiorgan failure, and survival also correlated with the level of systolic blood pressure. Patients with a systolic blood pressure of less than 90 mm Hg had a 12.5% survival rate compared to patients with systolic pressures more than 90 mm Hg, who had a 55% survival rate at 72 hours.
• In a recent observational study of intensive care patients, mortality rate was highest for patients with lactic acidosis (56%) compared to anion gap acidosis (39%). A stepwise logistic regression model identified serum lactate, anion gap acidosis, phosphate, and age as independent predictors of mortality. Overall, patients with metabolic acidosis were nearly twice as likely to die as patients without metabolic acidosis.⁵

Clinical

History

Lactic acidosis frequently occurs during strenuous exercise in healthy people, bearing no consequence. However, development of lactic acidosis in disease states is ominous, often indicating a critical illness of recent onset. Therefore, a careful history should be obtained to evaluate the underlying pathophysiologic cause of shock that contributed to lactic acidosis. Furthermore, a detailed history of ingestion of various prescription drugs or toxins from the patient or a collateral history from the patient's family should be obtained.

• The clinical signs and symptoms associated with lactic acidosis are highly dependent on the underlying etiology. No distinctive features are specific for hyperlactatemia.
• Lactate acidosis is present in patients who are critically ill from hypovolemic, septic, or cardiogenic shock.
• Lactate acidosis always should be suspected in the presence of elevated anion gap metabolic acidosis.
• Lactic acidosis is a serious complication of antiretroviral therapy. A history of antiretroviral treatment should be obtained.

Physical

The clinical signs usually indicate tissue hypoperfusion. Severe hypotension, oliguria or aneuria, deteriorating mental status, and tachypnea always are present when the cause of lactic acidosis is tissue hypoxemia.

• Clinical signs of impaired tissue perfusion include the following:
  • Hypotension
  • Alteration in sensorium
  • Peripheral vasoconstriction
  • Oliguria
• The following findings may be late manifestations of shock and are relatively insensitive indicators of hypoperfusion. Patients also demonstrate the following:
  • Tachypnea
  • Hypotension
  • Deteriorating mental status
• Kussmaul hyperventilation (deep sighing respiration) may be observed if the severity of the acidosis is sufficient to elicit a degree of respiratory compensation.
• Because sepsis accounts for most cases of lactic acidosis, fever (>38.5°C) or hypothermia (35°C) commonly is present in addition to symptoms and signs indicating the organ where the sepsis originated.

Causes

Classification of acquired causes of lactic acidosis is as follows:

• Type A - Due to tissue hypoxia
  • Tissue hypoperfusion - Abnormal vascular tone or permeability, left ventricular failure, decreased cardiac output
  • Reduced arterial oxygen content - Asphyxia, hypoxemia (PaO₂ <35 mm Hg), carbon monoxide poisoning, life-threatening anemia
• Type B - Not due to tissue hypoxia
  • B1 (common disorders) - Sepsis, hepatic failure, renal failure, diabetes mellitus, cancer, malaria, cholera
  • B2 (drugs or toxins) - Biguanides, acetaminophen, ethanol, nalidixic acid, salicylates, isoniazid, methanol, streptozotocin, ethylene glycol, sorbitol, cyanide, parenteral nutrition, nitroprusside, lactulose, niacin, theophylline, catecholamines, cocaine, diethyl ether, vitamin deficiency, papaverine, paraldehyde
  • B3 (other conditions) - Strenuous muscular exercise, grand mal seizures, D-lactic acidosis

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