eMedicine Specialties > Emergency Medicine > Endocrine & Metabolic

Lactic Acidosis

Author: Bret A Nicks, MD, Assistant Professor, Assistant Medical Director, Department of Emergency Medicine, Wake Forest University Health Sciences
Coauthor(s): Henderson D McGinnis, MD, Assistant Medical Director, AirCare Critical Care Transport Services; Clinical Instructor, Department of Emergency Medicine, Wake Forest University Baptist Medical Center; Stephen W Borron, MD, MS, FACEP, FACMT, Professor of Emergency Medicine and Medical Toxicology, Division of Medical Toxicology, Department of Emergency Medicine, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center; Associate Medical Director, West Texas Regional Poison Center; Bruno Mégarbane, MD, Fellow, Medical and Toxicological Intensive Care Unit, Lariboisière University Hospital
Contributor Information and Disclosures

Updated: May 8, 2009

Introduction

Metabolic acidosis is defined as a state of decreased systemic pH resulting from either a primary increase in hydrogen ion (H⁺) or a reduction in bicarbonate (HCO_3-) concentrations. In the acute state, respiratory compensation of acidosis occurs by hyperventilation resulting in a relative reduction in PaCO₂. Chronically, renal compensation occurs by means of reabsorption of HCO₃.

Acidosis arises from an increased production of acids, a loss of alkali, or a decreased renal excretion of acids (see Metabolic Acidosis). The underlying etiology of metabolic acidosis is classically categorized into those that cause an elevated anion gap (AG) and those that do not. Lactic acidosis, identified by a state of acidosis and an elevated plasma lactate concentration is one type of anion gap metabolic acidosis and may result from numerous conditions.  

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 persistent increase in blood lactate concentration (2-5 mmol/L) without metabolic acidosis, whereas lactic acidosis is characterized by persistently increased blood lactate levels (usually >4-5 mmol/L) in association with metabolic acidosis.

Pathophysiology

Lactate, a product of anaerobic glucose metabolism, is generated from pyruvate with lactate dehydrogenase as a catalyst. Pyruvate is normally aerobically metabolized to CO₂ and H₂ O in the mitochondrion in the process of gluconeogenesis. Additionally, pyruvate is in a state of equilibrium with lactate that, under certain conditions, can shift toward the overproduction of lactate. Lactic acidosis results from an increase in blood lactate levels when lactate production exceeds consumption and body buffer systems become overburdened. This occurs when tissue oxygenation is inadequate to meet metabolic requirements as a result of either hypoperfusion or hypoxia.

Lactate is cleared from blood, primarily by the liver, with the kidneys (10-20%) and skeletal muscles to a lesser degree. Cardiopulmonary failure, sepsis, trauma, thiamine deficiency, side effects of drugs and toxins, oncologic pathology, and various acquired and congenital diseases can lead to lactic acidosis.

Types of lactic acidosis

Classically, lactic acidosis was described and classified by Cohen and Woods into 2 categories¹ :

• Type A lactic acidosis occurs with decreased tissue ATP in the setting of poor tissue perfusion or oxygenation.  
  • Overproduction: Circulatory, pulmonary, or hemoglobin transfer disorders are commonly responsible.
  • Underutilization: Liver disease, gluconeogenesis inhibition, thiamine deficiency, and uncoupled oxidative phosphorylation
• Type B lactic acidosis is classically defined as when evidence of poor tissue perfusion or oxygenation is absent. However, in many cases of type B lactic acidosis, occult tissue hypoperfusion is now recognized to accompany the primary etiology. Type B is divided into 3 subtypes based on underlying etiology. 
  • Type B1 occurs in association with systemic disease such as renal and hepatic failure, diabetes, and malignancy.
  • Type B2 is caused by several classes of drugs and toxins including biguanides, alcohols, iron, isoniazid, and salicylates.
  • Type B3 is due to inborn errors of metabolism.
• Lactic acid exists in 2 forms, the L-lactate and D-lactate.  
  • L-lactate is the most commonly measured level, as it is the only form produced in human metabolism. Its excess represents increased anaerobic metabolism due to tissue hypoperfusion.
  • D-lactate is a byproduct of bacterial metabolism and may accumulate in patients with short-gut syndrome or in those with a history of gastric bypass or small-bowel resection.

In basic terms, lactic acid is the normal endpoint of the anaerobic breakdown of glucose in the tissues. The lactate exits the cells and is transported to the liver where it is oxidized back to glucose. In the setting of decreased tissue oxygenation, lactic acid is produced as the anaerobic cycle is utilized for energy production. With a persistent oxygen debt and overwhelming of the body's buffering abilities (whether from chronic dysfunction or excessive production), lactic acidosis ensues.

See Media file 1 for a classification table of lactic acidosis types.

Aberrant lactate metabolism is frequently encountered among critically ill patients. Those with predisposing underlying disease states and medications portend an increased occurrence. The overall incidence of lactic acidosis in critically ill patients is unknown; however, increasing acid-base evaluations of critically ill patients indicate its persistence increases associated morbidity and mortality. 

The use of lactate as an index of tissue perfusion has several limitations as briefly identified above. Chronic underutilization states, such as liver disease, can cause a decreased ability to clear lactate during periods of increased production whether acidemic or not. Various causes of type B lactate acidosis may produce hyperlactemia and lactate acidosis in the absence of tissue hypoperfusion. Regional hypoperfusion of tissues may be present despite a normal lactate if metabolism remains intact and reperfusion has not occurred.

Further tests are ongoing at this time to better delineate the value of lactate measurements in this patient population and how it interrelates to other markers of resuscitation and acid-base abnormalities.

Mortality/morbidity

Patients exhibiting a disorder of lactate metabolism are typically significantly ill and are at risk for developing multiple organ failure. Patients suffer a hospital mortality rate that increases nearly linearly with the concentration of serum lactate. Several studies have shown that vigilant correction of hyperlactemia is associated with decreased morbidity and mortality. The mortality rate of patients with a serum lactate level greater than 2 mmol/L persisting after 24 hours with an associated acidemia approaches 70%.

Clinical

History

No single historical feature itself is indicative of the presence of lactic acidosis, as symptoms are dependent on the underlying etiology. Nevertheless, a careful history is vital to determine the underlying pathology. The onset of acidosis may be rapid (ie, within minutes to hours) or progressive (ie, over a period of several days).  

Historical features such as recent or chronic illnesses, change in medications (eg, biguanides, antiretrovirals), or potential toxicologic interactions should be solicited.

Physical findings

The physical examination also depends on the underlying cause of lactic acidosis. Signs of cardiovascular compromise frequently include cyanosis , cool extremities, tachycardia, hypotension, dry mucous membranes, dyspnea, confusion, lethargy, stupor, or coma. Hyperventilation is common as a compensatory mechanism causing respiratory alkalosis.

Systemic effects of acidosis

• Respiratory  
  • Dyspnea, tachypnea, Kussmaul respirations
  • Increased minute ventilation
  • Decreased diaphragm contractility
• Cardiac
  • Decreased catecholamine responsiveness
  • Decreased fibrillation threshold
  • Decreased contractility at pH <7.1
  • Increased heart rate and contractility at pH >7.2
• Neurologic  
  • Increased cerebral blood flow
  • Decreased cerebral metabolism
  • Altered mental status
  • Increase sympathetic catecholamine discharge
• Other  
  • Decreased renal and hepatic perfusion
  • Increased metabolic rate
  • Increased protein catabolism

Etiology

Classification of lactic acidosis

The most frequent cause of lactic acidosis is poor tissue perfusion, which is induced by various shock states causing tissue hypoxia. In ischemic tissues of the skeletal muscle (and less significantly intestine, erythrocytes, and brain), production of lactate is accelerated with a concomitant fall in lactate consumption by the liver, kidney, and myocardium. The accumulation of a normally balanced level of serum lactate overwhelms the body's buffering capacity and results in acidosis.

Lactic acidosis occurring from associated underlying diseases, known as type B1, has been identified with diabetes mellitus, bowel ischemia, severe iron-deficiency anemia, liver disease, alcoholic ketoacidosis, pancreatitis, malignancy (leukemia, lymphoma, lung cancer), infection, renal failure, seizures, heat stroke, pheochromocytoma, thiamine deficiency, short gut syndrome, and other carbohydrate malabsorption syndromes.

Medicinal and toxic causes of lactic acidosis, known as type B2, are numerous, including acetaminophen, alcohols and glycols (ethanol, ethylene glycol, methanol, propylene glycol), antiretroviral nucleoside analogs (zidovudine, didanosine, lamivudine), beta-adrenergic agents (epinephrine, ritodrine, terbutaline), biguanides (phenformin, metformin), cocaine, cyanogenic compounds (cyanide, aliphatic nitriles, nitroprusside), diethyl ether, 5-fluorouracil, halothane, iron, isoniazid, propofol, sugars and sugar alcohols (fructose, sorbitol, and xylitol), salicylates, strychnine, sulfasalazine, and valproic acid.

Type B3 lactic acidosis may result in those with inborn errors of metabolism. These include glucose-6-phosphatase deficiency (von Gierke disease), fructose-1,6-diphosphatase deficiency, pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, oxidative phosphorylation deficiency, and methylmalonic aciduria.

Lactic acidosis rarely may present in the MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes), which appears to be caused by a point mutation in mitochondrial DNA tRNALeu (UUR) gene. This syndrome is characterized by migrainelike headaches, dementia, hearing loss, ataxia, and episodic vomiting.

Workup

Laboratory studies

Biochemical markers of impaired tissue perfusion may be useful because they are indicative of end-organ failure, whereas hemodynamic patterns can vary in different patient groups.

• Anion gap (AG): Calculation from serum electrolytes (AG = sodium - [CO₂ + chloride]).
• Arterial blood gas (ABG) analysis: The base deficit, derived from blood gas analysis, gives an approximation of tissue acidosis, an indirect evaluation tissue perfusion. However, several studies have been conducted finding poor correlation between serum lactate and base deficit levels. However, the presence of an acidemia is required for the diagnosis.
• Serum lactate level
  • No significant differences in lactate levels are noted in arterial and venous blood samples. The concentration of serum lactate must be measured as quickly as possible (within 4 h of collection) in a sample transported on ice. The advent of bedside point-of-care testing has allowed for more rapid evaluation and management of resuscitation. The normal serum lactate level is approximately 1 mmol/L with a range up to 2 mmol/L. Values above 4-5 mmol/L in the setting of acidemia are indicative of lactic acidosis.  
  • In hypoperfused states, persistent lactate elevation 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.

New devices (near-infrared spectroscopy) that look noninvasively at the correlation between tissue perfusion and lactate levels are currently being studied.

Other tests

Additional laboratory tests may be selected on the basis of the suspected underlying etiology of lactic acidosis.

Treatment

Prehospital care

Initial treatment predicates an understanding of basic resuscitation. Airway assessment and stabilization is essential for all patients. Supplemental oxygen may be required, and the airway must be repeatedly reassessed, especially if the patient's mental status or vital signs decline.

An intravenous (IV) line should be established, and fluid repletion with normal saline may be initiated if the patient exhibits tachycardia, hypotension, or other signs of poor tissue perfusion (eg, poor capillary refill, cool extremities). Vital signs and cardiac rhythm must be monitored closely because acidosis predisposes to dysrhythmias including tachydysrhythmias and fibrillation.

Established prehospital treatment protocols should be followed, and nonprotocol medications, such as sodium bicarbonate, should be administered only in conjunction with medical control. Transport all patients to the appropriate emergency facility for further management.

Emergency department care

Lactic acidosis is typically associated with tissue hypoperfusion and states of acute circulatory failure. Treatment of lactic acidosis requires identification of the primary illness and directed therapy.

Restoration of tissue oxygen delivery, thereby causing cessation of acid production, remains the primary therapeutic focus. Goal-directed therapy for sepsis is well described and is associated with improved outcomes. Appropriate measures include treatment of shock, restoration of circulating fluid volume, improved cardiac function, identification of sepsis source and appropriate therapy, and resection of any potential ischemic regions.

Continuing care

In addition to general supportive measures, treatments must be directed at correction of the underlying disorder and may include the administration of appropriate antibiotics, surgical drainage or debridement, chemotherapy for malignancy, discontinuation of potentially causative medications, and dietary modification in inborn errors of metabolism.

Procedures

Aside from resuscitation measures including adequate intravenous access and airway stabilization in all potentially ill patients, hemoperfusion or hemodialysis may be indicated in association with ethylene glycol and methanol poisoning. Dialysis may also be useful when severe lactic acidosis exists in the setting of renal failure or congestive heart failure and additionally with metformin intoxication.

Medications

One of the primary goals in treating critically ill patients is maximizing systemic oxygen delivery. Much debate has surrounded the potential use of buffering agents (specifically bicarbonate) to reverse the potentially negative effects of acidosis, but their use is generally advocated in the setting of severe acidosis.

It seems somewhat intuitive that acidosis should be corrected and homeostasis maintained for physiologic functions to return. However, large studies have been conducted that do not necessarily support this approach. Prior to the initiation of pharmacologic therapy, consultation with a critical care specialist and/or nephrologist is recommended to determine the optimal course of action.

The starting dose is one third to one half of the calculated extracellular bicarbonate deficit:

HCO₃ deficit (in mEq) = 0.5 X (Wt in kg) X (Desired HCO₃ - Measured HCO₃)

Toxic etiologies of lactic acidosis, such as methanol, ethylene glycol, and cyanide poisoning may justify administration of bicarbonate (see articles on Toxicity, Cyanide, Toxicity, Ethylene Glycol, and Toxicity, Alcohols).

Tris-[hydroxymethyl] aminomethane

Tris-[hydroxymethyl] aminomethane (THAM) has theoretical advantages over bicarbonate because CO₂ is not generated. It has been studied in animals and humans but has not been proven to be more effective than bicarbonate.

Carbicarb

Carbicarb is a combination of sodium carbonate and sodium bicarbonate that buffers comparably to bicarbonate but does not generate CO₂. While this theoretical advantage should favor its use over bicarbonate, there is no evidence in humans to support improved outcomes.

Dichloroacetate

This agent is not a buffer, but it stimulates the oxidation of pyruvate. This has resulted in improved lactate utilization and increased tissue levels of ATP. Prospective studies have failed to demonstrate its efficacy.

Thiamine

Thiamine deficiency may be associated with cardiovascular compromise and lactic acidosis. The response to thiamine repletion (given as 50-100 mg IV followed by 50 mg/d PO for 1-2 wk) may be dramatic and potentially life saving.

Miscellaneous agents

Coenzyme Q, l-carnitine, and riboflavin have been used to treat lactic acidosis due to antiretroviral therapy, without definitive demonstration of efficacy.

Prognosis

Lactate levels have been well described to correlate with the presence of tissue hypoperfusion in shock. Elevated levels have been shown to be correlated with increased mortality. Serum lactate levels above 4 mmol/L were associated with a survival of only 11% in critically ill ICU patients if persistent after 24 hours. Further studies have demonstrated an association between a 12-hour rise in lactate concentration above 2.5 mmol/L and multisystem organ failure.

The duration and degree of increased serum lactic acid appear to predict morbidity and mortality. Abramson et al identified 100% survival with normalization of serum lactate concentration (<2 mmol/L) within the first 24 hours following multiple trauma, 78% survival if normalization occurred in 24-48 hours, and only 14% survival if after 48 hours.²

With the onset of bedside serum lactate analyzers, measurements can be obtained in minutes with excellent correlation with traditional measurements. Studies have been performed to predict required hospital admission and mortality, but they were unable to define a lactate level below which a patient could be safely discharged from the ED. The lactate level should be used only as a single tool in combination with clinical findings and other measures of circulatory failure rather than as a decisive indicator of disease severity.

Summary

Lactic acidosis is characterized by an excess of serum lactate due to lactate production that exceeds systemic consumption. Numerous etiologies may be responsible for its presence, most commonly circulatory failure and hypoxia. Evidence suggests increased morbidity and mortality for patients with persistently elevated or increasing lactate levels. Identification and discontinuation of any offending agents and treatment of known pathology should occur promptly. Although treatment with buffering agents remains controversial, their use should be considered in certain instances with the assistance of critical care consultation.

Elevated lactate levels as a marker for inadequate tissue perfusion should be considered within the confines of each patient individually because it alone cannot provide definitive confirmation of disease presence, severity, or prognosis.

Multimedia

(Enlarge Image)

Media file 1: Pathophysiologic classification of lactic acidosis.

Keywords

lactic acidosis, symptoms, treatment, causes, metabolic acidosis, arterial blood pH less than 7.35, plasma bicarbonate concentration less than 22 mmol/L, hyperlactatemia, hypoperfusion, hypoxia, cardiopulmonary failure, inborn errors of metabolism, multiple organ failure, cyanosis, cold extremities, tachycardia

hypotension, hyperventilation, dyspnea, lethargy, stupor, coma, diabetes mellitus, liver diseases, alcoholic ketoacidosis, leukemias, lymphomas, lung cancer, alkalosis, renal failure, pheochromocytoma

thiamine deficiency, short gut syndrome, carbohydrate malabsorption syndromes, d-lactic acidosis, glucose-6-phosphatase deficiency, vonGierke disease, fructose-1, 6-diphosphatase deficiency, pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, oxidativephosphorylationdeficiency, methylmalonic aciduria, MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes), tRNALeu (UUR) gene

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