AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

By the turn of the 20th century, it had become apparent 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.

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" (Siegel JH, 1979).

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 (De Becker D, 1998). 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 (Vary TC, 1995). 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 (Vary TC, 1998)

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. (Gunnerson KJ, 2006)

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Inborn errors of metabolism
Pyruvate dehydrogenase deficiency
Oxidative phosphorylation defects

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• In many cases, the suggestion of lactic acidosis arises because of laboratory evidence of metabolic acidosis without an obvious etiology.
• Anion gap
• • During the workup of a patient with metabolic acidosis, as indicated by low plasma bicarbonate and low pH on arterial blood gas (ABG) determinations (bicarbonate less than 22 mmol/L and pH less than 7.35), calculation of serum anion gap may provide further clues to the etiology. The anion gap is the difference between measured cations and measured anions and is calculated by the following formula:
    anion gap = sodium - (chloride + bicarbonate)

    The normal anion gap may vary depending on the laboratory, but it generally ranges from 8-12 mmol/L. Furthermore, the normal value for anion gap must be adjusted in patients with hypoalbuminemia. Reduction in serum albumin by 10 g/L reduces the normal value for anion gap by 2.5 mmol/L.

  • An elevated anion gap can be observed with renal failure and organic acidosis such as lactic acidosis, ketoacidosis, and certain poisonings. However, clinically significant hyperlactatemia may occur in the absence of an increased anion gap. Hypoalbuminemia may falsely normalize the anion gap. Albumin has a strongly negative charge and makes up a substantial portion of the clinically unmeasured anion concentration. The decrease in anion gap caused by hypoalbuminemia also may mask coexisting hyperlactatemia.
  • In many patients, neither the anion gap nor the arterial pH may reflect the presence or severity of lactic acidosis. Therefore, the most accurate assessment of the severity of lactic acidosis is direct measurement of lactic level.

• Lactate assay
• • In the past, lactate assays were difficult and tedious. Newer autoanalyzers can rapidly and accurately measure blood, serum, or plasma lactate levels within minutes.
  • Either arterial blood or a mixed venous sample is preferable because the peripheral venous specimen may reflect regional, rather than systemic, lactate concentrations. The blood specimen should be immediately transported on ice and analyzed without delay because blood cells continue to produce lactate in vitro and falsely elevate the concentration.
  • In some instances, the sample can be collected in special tubes containing glycolytic inhibitor such as sodium fluoride or iodoacetic acid.

• In patients with circulatory shock, lactate elevation above 2.5 mmol/L is associated with excessive mortality. If circulatory failure develops, serial lactate values are helpful in following the course of the hypoperfusion state and the response to therapeutic interventions.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The anaerobic metabolism of glucose produces lactate, by either increased production or decreased use. The imbalance between systemic oxygen demand and oxygen availability results in tissue hypoxia, which is the most common cause of lactic acidosis. Other etiologies of hyperlactemia are rare. Any critically ill patient should have a measurement of serum electrolytes, ABGs, and direct measurement of blood lactate. The therapy is directed towards correcting the underlying cause and optimizing tissue oxygen delivery by cardiopulmonary support. Alkali therapy has not proved to be beneficial and, in fact, may be harmful by worsening intracellular acidosis.

• General measures
• • Although patients may be tachypneic initially, ventilatory muscle fatigue may ensue rapidly and may require mechanical assistance.
  
  
  
  • Cardiovascular collapse should be treated with fluid replacement, preferably with isotonic sodium chloride preparations, avoiding solutions containing lactate.
  
  
  
  • Every effort should be made to avoid using vasoconstrictor drugs because of their potential to exacerbate ischemia in critical tissue beds.
  
  
  
  • The therapy also should be directed at administration of appropriate antibiotics, surgical drainage and debridement of a septic focus, chemotherapy of malignant disorders, discontinuation of causative drugs, and dietary modification in certain types of congenital lactate acidosis.
     
• Sodium bicarbonate

• Controversy continues to surround the use of alkali in treating lactic acidosis. As sodium bicarbonate (NaHCO₃) breaks down into carbon dioxide and water in the tissues, patients must have effective ventilation to eliminate carbon dioxide and should be able to handle additional sodium and volume load.

• The animal models of lactic acidosis have shown that intravenous administration of NaHCO₃ may increase lactate production (particularly by splanchnic bed), decrease portal vein flow, lower intracellular pH in muscle and liver, lower arterial pH, and worsen the cardiac output.

• In a double-blind, placebo-controlled trial of intravenous NaHCO₃ administration, no improvement in cardiac hemodynamics occurred, although significant improvement in PaCO₂ was observed.

• The current evidence is strongly against the routine use of intravenous NaHCO₃ in the treatment of acquired forms of lactic acidosis, regardless of the arterial pH or serum bicarbonate level. Although several anecdotal reports have suggested the use of bicarbonate dialysate as therapy for lactic acidosis, this approach has not been evaluated vigorously. The improvement noted in hemodynamic status when bicarbonate is administrated during acidosis may be caused by other mechanisms than correction of acidosis (eg, increased preload, effect of tonicity). The arterial pH could always be corrected by lowering the PaCO₂ by increasing the rate of ventilation. This may correct both the extracellular and intracellular acidosis. The use of bicarbonate in patients with severe metabolic acidosis and arterial pH less than 7.15 should be reserved to maintain the pH above 7.15 until the underlying process is corrected.

• The amount of NaHCO₃ can be calculated by the following formula: NaHCO₃ required = (bicarbonate desired - bicarbonate observed) x 0.4 x body weight (kg)

• Dichloroacetate

• Dichloroacetate is the most potent stimulus of pyruvate dehydrogenase, the rate-limiting enzyme for the aerobic oxidation of glucose, pyruvate, and lactate. Dichloroacetate may inhibit glycolysis and, thereby, lactate production. Dichloroacetate also exerts a positive inotropic effect that has been attributed to improvement in myocardial glucose use and high-energy phosphate production.



• The data from animal studies and one placebo-controlled double-blind clinical trial have shown that dichloroacetate was superior to placebo in improving the acid-base status of the patients; however, the magnitude of change was small and did not alter hemodynamics or survival.

• Carbicarb

• Carbicarb is a new buffering agent with potential use in metabolic acidosis. Carbicarb is an equimolecular mixture of sodium bicarbonate and sodium carbonate. Carbicarb has a buffering capacity similar to sodium bicarbonate but does not generate carbon dioxide.



• In animal models of hypoxic lactic acidosis, Carbicarb reduced circulating lactate and improved tissue and blood acid-base status compared to sodium bicarbonate.



• Controlled studies with Carbicarb in patients with metabolic studies are lacking presently.

• Omega-3 fatty acids

• Omega-3 polyunsaturated fatty acids have been administered as dietary lipids or as components of parenteral nutrition solutions to experimental animals with endotoxin-induced lactic acidosis.



• The animals receiving omega-3 fatty acids developed less severe hyperlactatemia and pulmonary toxicity and had better microvascular blood flow in muscles.



• These are interesting preliminary studies, but their benefit in humans is unproven.

• Dialysis

• Dialysis may be a useful mode of therapy when severe lactic acidosis exists in conjunction with renal failure or congestive heart failure. Dialysis would allow bicarbonate infusion without precipitating or worsening fluid overload. Therefore, dialysis corrects acidosis by restoring the buffer pool.



• Hemodialysis or continuous hemofiltration used in conjunction with alkali infusion may be tolerated in a patient with cardiovascular instability. However, the overall benefit of such therapy to a patient's outcome is not known. Metformin-induced lactic acidosis has been reported to improve after prolonged hemodialysis (Py, 2006).

• Other therapies

• A number of other therapies have been advocated at one time or another for lactate acidosis, including methylene blue, glucose and insulin, tris-hydroxymethyl aminomethane (THAM or tris buffer), thiamine, and nitroprusside. The oxidizing agent methylene blue was proposed as a means of pharmacologically altering intracellular redox potential but has proved to be ineffective. THAM has been advocated for its alkalizing properties and more rapid cellular permeability, but the effect on patient outcome is uncertain.



• Theoretical reasons and some clinical evidence exist for thiamine treatment to improve lactic acidosis associated with thiamine deficiency. Thiamine is indicated in patients with beriberi and generally is indicated in patients hospitalized for alcoholism because of their increased tendency for developing thiamine deficiency. Similarly, thiamine can be administered safely to patients with lactic acidosis, particularly in absence of an obvious alternate etiology. Thiamine is administered intravenously as 50-100 mg followed by 50 mg/d orally for 1-2 weeks.

Consultations

• Consultation with a critical care medicine specialist for further diagnostic procedures and supportive therapy is a must for patients who are critically ill.
• Patients with chronic mild hyperlactemia should be referred to an endocrinologist for elucidation of the underlying pathology and appropriate management.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Definite treatment for lactic acidosis is correction of the underlying cause for type A and removal of offending drug or toxin in type B lactic acidosis.

Drug Category: Alkalinizing agents

NaHCO₃ may be used as a temporizing measure in very severe acidosis and in patients who become hemodynamically unstable because of the acidosis. Other therapies (eg, THAM or Carbicarb) are not available in the United States at present and have not been shown to be clinically effective.

Drug Category: Vitamins

Thiamine deficiency may rarely cause lactic acidosis.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients who are critically ill should be admitted to the intensive care unit.

Complications

• Severe metabolic acidosis with arterial pH of less than 7.2 is associated with impaired cardiac contractility and suboptimal response to exogenous catecholamines. Elevation of serum lactate concentration may have negative inotropic effects independent of serum pH. Furthermore, bicarbonate therapy may lead to electrolyte disturbances, such as hypokalemia and hypocalcemia, primarily a decrease in ionized calcium.

Prognosis

• Although the etiology of shock influences the probability of survival, blood lactate concentration has prognostic value. Serum lactate levels of greater than 2.5 mmol/L have been associated with an increase in mortality rate.
• Antiretroviral-associated hyperlactemia rarely causes death, but, generally, the outcome for patients was favorable after antiretroviral therapy was stopped and supportive treatment with vitamins and antioxidants was initiated.

  Early diagnosis, vigilance, and routine measurements of the anion gap are crucial.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Because the mortality rate of patients who develop lactic acidosis is high, prompt recognition and treatment of the underlying cause remain the only realistic hope for improving survival.
• The clinical significance of mild hyperlactatemia greater than 3 mmol/L but less than 5 mmol/L is uncertain.
• The benefit of alkali administration in hypoxia-induced lactic acidosis remains controversial. The judicious use of bicarbonate in patients with severe metabolic acidosis and hemodynamic instability is recommended.

Special Concerns

• Lactic acidosis is observed frequently in patients who are critically ill. Despite a large number of potential etiologies, tissue hyperfusion is by far the most common etiology.
• • Aggressive cardiorespiratory resuscitation designed to restore tissue perfusion is the fundamental approach to these patients.
  • Titrating therapies to traditional endpoints may not ensure that the microvascular bed is reperfused. Monitoring blood lactate concentration not only allows for prognostication but also serves as an indicator of when supportive therapies are restoring tissue perfusion.

• D-lactic acidosis
• • A unique form of lactic acidosis can occur in patients with jejunoileal bypass or small bowel resection causing short bowel syndrome. In these settings, the glucose and carbohydrates are metabolized in the colon into D-lactic acid, which is absorbed into systemic circulation.
  • The overgrowth of gram-positive anaerobes such as lactobacilli is able to produce lactate from carbohydrates. These patients develop confusion, ataxia, slurred speech, and altered mental status. The treatment is NaHCO₃ to correct acidemia and antibiotics to decrease the number of organisms producing D-lactate.

• Children who have a relatively mild form of congenital lactic acidosis may develop firmament metabolic acidosis during an acute illness such as respiratory infection. These patients have a deficiency in the activity of pyruvate dehydrogenase, and the stress-induced increases in the glycolytic rate may result in severe metabolic acidosis.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ahlborg G, Wahren J, Felig P. Splanchnic and peripheral glucose and lactate metabolism during and after prolonged arm exercise. J Clin Invest. Mar 1986;77(3):690-9. [Medline].
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• Blackshear PJ, Fang LS, Axelrod L. Treatment of severe lactic acidosis with dichloroacetate. Diabetes Care. Jul-Aug 1982;5(4):391-4. [Medline].
• Cohen RD, Woods HF. Lactic acidosis revisited. Diabetes. Feb 1983;32(2):181-91. [Medline].
• Cooper DJ, Walley KR, Wiggs BR, Russell JA. Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study. Ann Intern Med. Apr 1 1990;112(7):492-8. [Medline].
• Frommer JP. Lactic acidosis. Med Clin North Am. Jul 1983;67(4):815-29. [Medline].
• Gerard Y, Maulin L, Yazdanpanah Y, et al. Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy. AIDS. Dec 1 2000;14(17):2723-30. [Medline].
• Gunnerson KJ, Saul M, He S, Kellum JA. Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill patients. Crit Care. Feb 10 2006;10(1):R22. [Medline].
• Guo PY, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial. Jan-Feb 2006;19(1):80-3. [Medline].
• Hindman BJ. Sodium bicarbonate in the treatment of subtypes of acute lactic acidosis: physiologic considerations. Anesthesiology. Jun 1990;72(6):1064-76. [Medline].
• Medalle R, Webb R, Waterhouse C. Lactic acidosis and associated hypoglycemia. Arch Intern Med. Aug 1971;128(2):273-8. [Medline].
• Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med. Jan 1992;20(1):80-93. [Medline].
• Oh MS, Carroll HJ. The anion gap. N Engl J Med. Oct 13 1977;297(15):814-7. [Medline].
• Oriot D, Wood C, Gottesman R, Huault G. Severe lactic acidosis related to acute thiamine deficiency. JPEN J Parenter Enteral Nutr. Jan-Feb 1991;15(1):105-9. [Medline].
• Siegel JH, Cerra FB, Coleman B, et al. Physiological and metabolic correlations in human sepsis. Invited commentary. Surgery. Aug 1979;86(2):163-93. [Medline].
• Silva E, DeBacker D, Creteur J, Vincent JL. Effects of vasoactive drugs on gastric intramucosal pH. Crit Care Med. Oct 1998;26(10):1749-58. [Medline].
• Stacpoole PW. Lactic acidosis: the case against bicarbonate therapy. Ann Intern Med. Aug 1986;105(2):276-9. [Medline].
• Stacpoole PW, Wright EC, Baumgartner TG, et al. A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group. N Engl J Med. Nov 26 1992;327(22):1564-9. [Medline].
• Uribarri J, Oh MS, Carroll HJ. D-lactic acidosis. A review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Medicine (Baltimore). Mar 1998;77(2):73-82. [Medline].
• Vary TC, Hazen SA, Maish G, Cooney RN. TNF binding protein prevents hyperlactatemia and inactivation of PDH complex in skeletal muscle during sepsis. J Surg Res. Nov 1998;80(1):44-51. [Medline].
• Vary TC, Drnevich D, Jurasinski C, Brennan WA Jr. Mechanisms regulating skeletal muscle glucose metabolism in sepsis. Shock. Jun 1995;3(6):403-10. [Medline].

Article Last Updated: Mar 27, 2007