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Etiology and Therapeutic Approach to Elevated Lactate Levels

      Abstract

      Lactate levels are commonly evaluated in acutely ill patients. Although most often used in the context of evaluating shock, lactate levels can be elevated for many reasons. While tissue hypoperfusion may be the most common cause of elevation, many other etiologies or contributing factors exist. Clinicians need to be aware of the many potential causes of lactate level elevation as the clinical and prognostic importance of an elevated lactate level varies widely by disease state. Moreover, specific therapy may need to be tailored to the underlying cause of elevation. The present review is based on a comprehensive PubMed search between the dates of January 1, 1960, to April 30, 2013, using the search term lactate or lactic acidosis combined with known associations, such as shock, sepsis, cardiac arrest, trauma, seizure, ischemia, diabetic ketoacidosis, thiamine, malignancy, liver, toxins, overdose, and medication. We provide an overview of the pathogenesis of lactate level elevation followed by an in-depth look at the varied etiologies, including medication-related causes. The strengths and weaknesses of lactate as a diagnostic/prognostic tool and its potential use as a clinical end point of resuscitation are discussed. The review ends with some general recommendations on the management of patients with elevated lactate levels.

      Abbreviations and Acronyms:

      DKA (diabetic ketoacidosis), ScvO2 (central venous oxygen saturation)
      Article Highlights
      • Elevated lactate levels can be caused by a variety of conditions, including shock, sepsis, cardiac arrest, trauma, seizure, ischemia, diabetic ketoacidosis, thiamine deficiency, malignancy, liver dysfunction, genetic disorders, toxins, and medications
      • Elevated lactate levels have been associated with increased mortality rates in a variety of diseases, such as sepsis, trauma, and cardiac arrest
      • Decreased lactate clearance has been found to be associated with increased mortality rates in sepsis, post–cardiac arrest, trauma, burns, and other conditions
      • The use of lactate clearance as an end point of resuscitation might prove beneficial, but further research is warranted
      • When approaching the patient with an elevated lactate level, the possibility of a multifactorial etiology must be considered
      • Despite its imperfect sensitivity and specificity, the lactate assay remains a clinically useful test that can alert a clinician to underlying hypoperfusion in need of immediate treatment or an etiology not readily apparent on initial evaluation
      Lactate levels in clinical practice are often used as a surrogate for illness severity and to gauge response to therapeutic interventions. The use of lactate as a clinical prognostic tool was first suggested in 1964 by Broder and Weil
      • Broder G.
      • Weil M.H.
      Excess lactate: an index of reversibility of shock in human patients.
      when they observed that a lactate level of more than 4 mmol/L was associated with poor outcomes in patients with undifferentiated shock. Since then, much has been published on the use of lactate in a variety of patient populations. Moreover, causes of elevated lactate levels apart from tissue hypoperfusion have been recognized and should be considered in the appropriate clinical context.
      This review focuses on the use and interpretation of lactate levels across various disease states and clinical scenarios. First, we describe the physiologic features and pathogenesis of lactate production. We then discuss the different etiologies of elevated lactate levels, focusing first on states of tissue hypoxia/hypoperfusion (type A) and then on other causes not related to tissue hypoxia (type B).
      • Woods H.F.
      • Cohen R.D.
      Clinical and Biochemical Aspects of Lactic Acidosis.
      Last, a clinical checklist for the differential diagnosis and approach to treatment of elevated lactate levels is proposed, and limitations are discussed.
      For the present review, we searched PubMed between the dates January 1, 1960, to April 30, 2013, using the search term lactate or lactic acidosis combined with known associations, such as shock, sepsis, cardiac arrest, trauma, seizure, ischemia, diabetic ketoacidosis, thiamine, malignancy, liver, toxins, overdose, and medication. No formal inclusion criteria were used, but the primary search was restricted to human studies in English, and preference was given to newer studies. Additional references found in these articles were used as appropriate, and articles familiar to the authors were reviewed for broader coverage.

      Physiology and Pathogenesis

      Lactate is produced by most tissues in the human body, with the highest level of production found in muscle.
      • Consoli A.
      • Nurjhan N.
      • Reilly Jr., J.J.
      • Bier D.M.
      • Gerich J.E.
      Contribution of liver and skeletal muscle to alanine and lactate metabolism in humans.
      • van Hall G.
      Lactate kinetics in human tissues at rest and during exercise.
      Under normal conditions, lactate is rapidly cleared by the liver, with a small amount of additional clearance by the kidneys.
      • Consoli A.
      • Nurjhan N.
      • Reilly Jr., J.J.
      • Bier D.M.
      • Gerich J.E.
      Contribution of liver and skeletal muscle to alanine and lactate metabolism in humans.
      • Connor H.
      • Woods H.F.
      • Ledingham J.G.
      • Murray J.D.
      A model of L(+)-lactate metabolism in normal man.
      In aerobic conditions, pyruvate is produced via glycolysis and then enters the Krebs cycle, largely bypassing the production of lactate. Under anaerobic conditions, lactate is an end product of glycolysis and feeds into the Cori cycle as a substrate for gluconeogenesis (Figure 1). Lactate exists in 2 isomers: l-lactate and d-lactate. Current lactate measurements include only l-lactate (the primary isomer produced in humans), which is the focus of the present review. d-Lactate is produced by bacteria in the human colon on exposure to large amounts of unabsorbed carbohydrates. In the setting of alteration in the intestinal flora and a high carbohydrate load (such as in short bowel syndrome), there will be an excess production of d-lactate, which can cross into the bloodstream and potentially cause neurologic symptoms. The role of d-lactate has been described elsewhere
      • Petersen C.
      D-lactic acidosis.
      and will not be considered further in the present review.
      Figure thumbnail gr1
      Figure 1Aerobic and anaerobic metabolism. ATP = adenosine triphosphate; CoA = coenzyme A; PDH = pyruvate dehydrogenase.
      Elevated lactate levels are not clearly and universally defined, but most studies use cutoff values of 2.0 to 2.5 mmol/L,
      • Kruse O.
      • Grunnet N.
      • Barfod C.
      Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review.
      whereas “high” lactate levels have been defined as greater than 4.0 mmol/L in several studies.
      • Howell M.D.
      • Donnino M.
      • Clardy P.
      • Talmor D.
      • Shapiro N.I.
      Occult hypoperfusion and mortality in patients with suspected infection.
      • Cox K.
      • Cocchi M.N.
      • Salciccioli J.D.
      • Carney E.
      • Howell M.
      • Donnino M.W.
      Prevalence and significance of lactic acidosis in diabetic ketoacidosis.
      • Shapiro N.I.
      • Howell M.D.
      • Talmor D.
      • et al.
      Serum lactate as a predictor of mortality in emergency department patients with infection.
      • Callaway D.W.
      • Shapiro N.I.
      • Donnino M.W.
      • Baker C.
      • Rosen C.L.
      Serum lactate and base deficit as predictors of mortality in normotensive elderly blunt trauma patients.
      Furthermore, the “normal value” may vary depending on the assay used. The terms lactate and lactic acid are often used interchangeably, but lactate (the component measured in blood) is strictly a weak base, whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate levels, but it should be reserved for cases in which there is a corresponding acidosis (pH <7.35).
      • Luft D.
      • Deichsel G.
      • Schmulling R.M.
      • Stein W.
      • Eggstein M.
      Definition of clinically relevant lactic acidosis in patients with internal diseases.
      The exact pathogenesis of elevated lactate levels in various conditions is likely multifactorial, patient specific, and disease specific. In general, lactate level elevation may be caused by increased production, decreased clearance, or a combination of both. The etiology of elevated lactate levels is perhaps best studied in shock states. Contributing factors seem to include hypoperfusion due to macrocirculatory or microcirculatory dysfunction, mitochondrial dysfunction (including a potential lack of key enzymatic cofactors), and the presence of a hypermetabolic state, among others.
      • Gore D.C.
      • Jahoor F.
      • Hibbert J.M.
      • DeMaria E.J.
      Lactic acidosis during sepsis is related to increased pyruvate production, not deficits in tissue oxygen availability.
      • James J.H.
      • Luchette F.A.
      • McCarter F.D.
      • Fischer J.E.
      Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis.
      • Jones A.E.
      • Puskarich M.A.
      Sepsis-induced tissue hypoperfusion.
      • Rady M.Y.
      The role of central venous oximetry, lactic acid concentration and shock index in the evaluation of clinical shock: a review.
      • Trzeciak S.
      • Dellinger R.P.
      • Parrillo J.E.
      • et al.
      Microcirculatory Alterations in Resuscitation and Shock Investigators
      Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival.
      • Donnino M.W.
      • Carney E.
      • Cocchi M.N.
      • et al.
      Thiamine deficiency in critically ill patients with sepsis.
      Liver dysfunction may contribute to increased production and decreased clearance, which becomes even more important in states of hypoperfusion.

      Measurement

      Lactate levels can be rapidly and easily measured in most clinical settings. A recent review by Kruse et al
      • Kruse O.
      • Grunnet N.
      • Barfod C.
      Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review.
      on the measurement of lactate levels concluded that peripheral venous lactate levels are highly correlated with arterial blood lactate levels, thus establishing that either method can be used. Tourniquet use during blood collection and the routine use of ice for transportation do not affect lactic acid levels provided the samples are measured within 15 minutes using a point-of-care device.
      • Jones A.E.
      • Leonard M.M.
      • Hernandez-Nino J.
      • Kline J.A.
      Determination of the effect of in vitro time, temperature, and tourniquet use on whole blood venous point-of-care lactate concentrations.
      Generally, samples should be processed within 15 to 30 minutes to avoid falsely elevated levels of lactate and should be kept on ice if processed later.
      • Burnett R.W.
      • Covington A.K.
      • Fogh-Andersen N.
      • et al.
      International Federation of Clinical Chemistry (IFCC): Scientific Division: Committee on pH, Blood Gases and Electrolytes: approved IFCC recommendations on whole blood sampling, transport and storage for simultaneous determination of pH, blood gases and electrolytes.
      • Andersen O.
      • Haugaard S.B.
      • Jorgensen L.T.
      • et al.
      Preanalytical handling of samples for measurement of plasma lactate in HIV patients.
      Studies have reported that although anion gap and base excess are associated with lactate, they do not necessarily predict elevated lactate levels accurately.
      • Adams B.D.
      • Bonzani T.A.
      • Hunter C.J.
      The anion gap does not accurately screen for lactic acidosis in emergency department patients.
      • Chawla L.S.
      • Jagasia D.
      • Abell L.M.
      • et al.
      Anion gap, anion gap corrected for albumin, and base deficit fail to accurately diagnose clinically significant hyperlactatemia in critically ill patients.

      Etiologies of Elevated Lactate Levels

      There are a multitude of causes for elevated lactate levels (Table 1). Recently, most of the medical literature on the importance of lactate levels has focused on septic shock, and this literature-based selection bias may lead clinicians to associate elevated lactate levels with sepsis alone. However, any form of shock or tissue hypoperfusion will result in elevated lactate levels, and a variety of causes of elevated lactate levels exist independent of shock states. The following subsections address the various causes of and conditions associated with elevated lactate levels.
      Table 1Causes of Elevated Lactate Levels
      Shock
       Distributive
       Cardiogenic
       Hypovolemic
       Obstructive
      Post–cardiac arrest
      Regional tissue ischemia
       Mesenteric ischemia
       Limb ischemia
       Burns
       Trauma
       Compartment syndrome
       Necrotizing soft-tissue infections
      Diabetic ketoacidosis
      Drugs/toxins
       Alcohols
       Cocaine
       Carbon monoxide
       Cyanide
      Pharmacological agents
       Linezolid
       Nucleoside reverse transcriptase inhibitors
       Metformin
       Epinephrine
       Propofol
       Acetaminophen
       β2-Agonists
       Theophylline
      Anaerobic muscle activity
       Seizures
       Heavy exercise
       Excessive work of breathing
      Thiamine deficiency
      Malignancy
      Liver failure
      Mitochondrial disease

      Sepsis and Septic Shock

      Septic shock is often associated with macrocirculatory dysfunction (causing arterial hypotension), microcirculatory dysfunction, and decreased oxygen and nutrient extraction by peripheral tissues. Lactate levels have become a useful marker for tissue hypoperfusion and may also serve as an end point for resuscitation in patients with sepsis and septic shock.
      • Puskarich M.A.
      • Trzeciak S.
      • Shapiro N.I.
      • et al.
      Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation.
      • Nguyen H.B.
      • Kuan W.S.
      • Batech M.
      • et al.
      ATLAS (Asia Network to Regulate Sepsis care) Investigators
      Outcome effectiveness of the severe sepsis resuscitation bundle with addition of lactate clearance as a bundle item: a multi-national evaluation.
      The prognostic value of isolated lactate measurements and serial measurements has been investigated in various settings.
      • Howell M.D.
      • Donnino M.
      • Clardy P.
      • Talmor D.
      • Shapiro N.I.
      Occult hypoperfusion and mortality in patients with suspected infection.
      • Jansen T.C.
      • van Bommel J.
      • Mulder P.G.
      • Rommes J.H.
      • Schieveld S.J.
      • Bakker J.
      The prognostic value of blood lactate levels relative to that of vital signs in the pre-hospital setting: a pilot study.
      • Bakker J.
      • de Lima A.P.
      Increased blood lacate levels: an important warning signal in surgical practice.
      In a study of 1278 patients being admitted to the hospital with infection, Shapiro et al
      • Shapiro N.I.
      • Howell M.D.
      • Talmor D.
      • et al.
      Serum lactate as a predictor of mortality in emergency department patients with infection.
      found that lactate levels could correctly stratify patients according to mortality. Lactate levels of 0 to 2.4, 2.5 to 3.9, and 4.0 mmol/L or higher were associated with mortalities of 4.9% (95% CI, 3.5%-6.3%), 9.0% (95% CI, 5.6%-12.4%), and 28.4% (95% CI, 21%-36%), respectively.
      • Shapiro N.I.
      • Howell M.D.
      • Talmor D.
      • et al.
      Serum lactate as a predictor of mortality in emergency department patients with infection.
      Furthermore, evaluation of lactate clearance through serial measurements has been shown to be a useful predictor of morbidity and mortality. Patients who clear an initially elevated lactate level to less than 2.5 mmol/L or less than 4.0 mmol/L (depending on study design) within 24 hours have significantly better outcomes than patients whose elevated lactate levels persist.
      • Bakker J.
      • Coffernils M.
      • Leon M.
      • Gris P.
      • Vincent J.L.
      Blood lactate levels are superior to oxygen-derived variables in predicting outcome in human septic shock.
      • Bakker J.
      • Gris P.
      • Coffernils M.
      • Kahn R.J.
      • Vincent J.L.
      Serial blood lactate levels can predict the development of multiple organ failure following septic shock.
      • Nguyen H.B.
      • Rivers E.P.
      • Knoblich B.P.
      • et al.
      Early lactate clearance is associated with improved outcome in severe sepsis and septic shock.
      • Arnold R.C.
      • Shapiro N.I.
      • Jones A.E.
      • et al.
      Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis.
      • Nguyen H.B.
      • Loomba M.
      • Yang J.J.
      • et al.
      Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock.
      Serial lactate level measurements may be useful in documenting treatment response to various therapeutic interventions (see below).
      Lactate may also be useful in identifying an otherwise unrecognized population of critically ill patients with normal blood pressure. Howell et al
      • Howell M.D.
      • Donnino M.
      • Clardy P.
      • Talmor D.
      • Shapiro N.I.
      Occult hypoperfusion and mortality in patients with suspected infection.
      (largely using the same patient population as Shapiro et al
      • Shapiro N.I.
      • Howell M.D.
      • Talmor D.
      • et al.
      Serum lactate as a predictor of mortality in emergency department patients with infection.
      ) enrolled patients admitted from the emergency department with clinically suspected infection, and Mikkelsen et al
      • Mikkelsen M.E.
      • Miltiades A.N.
      • Gaieski D.F.
      • et al.
      Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock.
      included patients with severe sepsis. Both studies found that elevated lactate levels were associated with mortality independent of shock, a phenomenon called occult or cryptic shock.

      Cardiogenic, Obstructive, and Hemorrhagic Shock

      The utility of lactate in cardiogenic shock has not been evaluated extensively, but studies in patients with myocardial dysfunction resulting in shock after cardiac surgery found elevated lactate levels in this setting. Investigators found that the elevation was primarily related to increased tissue lactate production and not to decreased clearance.
      • Chiolero R.L.
      • Revelly J.P.
      • Leverve X.
      • et al.
      Effects of cardiogenic shock on lactate and glucose metabolism after heart surgery.
      In patients with cardiogenic shock requiring extracorporeal membrane oxygenation, lactate has been found to be a useful variable for predicting mortality.
      • Formica F.
      • Avalli L.
      • Colagrande L.
      • et al.
      Extracorporeal membrane oxygenation to support adult patients with cardiac failure: predictive factors of 30-day mortality.
      In cardiogenic shock after ST-elevation myocardial infarction, patients with ineffective lactate clearance (<10%) had a lower survival rate.
      • Attana P.
      • Lazzeri C.
      • Chiostri M.
      • Picariello C.
      • Gensini G.F.
      • Valente S.
      Lactate clearance in cardiogenic shock following ST elevation myocardial infarction: a pilot study.
      Elevated lactate levels can also be seen in the setting of pulmonary embolism. Vanni et al
      • Vanni S.
      • Viviani G.
      • Baioni M.
      • et al.
      Prognostic value of plasma lactate levels among patients with acute pulmonary embolism: the thrombo-embolism lactate outcome study.
      found that elevated lactate levels (>2 mmol/L) were associated with increased mortality rates independent of hemodynamic status and right ventricular dysfunction.
      Hemorrhagic shock is another potential cause of elevated lactate levels. Akkose et al
      • Akkose S.
      • Ozgurer A.
      • Bulut M.
      • Koksal O.
      • Ozdemir F.
      • Ozguc H.
      Relationships between markers of inflammation, severity of injury, and clinical outcomes in hemorrhagic shock.
      measured lactate levels in 60 patients presenting to an emergency department and found that lactate levels were significantly elevated in traumatic and nontraumatic hemorrhagic shock compared with controls, with the traumatic group having the highest value. The study was not adequately powered to detect differences in mortality rates.
      • Akkose S.
      • Ozgurer A.
      • Bulut M.
      • Koksal O.
      • Ozdemir F.
      • Ozguc H.
      Relationships between markers of inflammation, severity of injury, and clinical outcomes in hemorrhagic shock.

      Cardiac Arrest

      The role of lactate in the post–cardiac arrest population has also been explored. The ischemia that occurs due to lack of blood flow during arrest, as well as the inflammation resulting from ischemia-reperfusion injury, is the likely cause of the initial increase in lactate levels. Etiologies of persistently elevated lactate levels in the postarrest period may include systemic inflammatory response and ongoing tissue hypoxia, myocardial stunning causing cardiogenic shock, an uncorrected underlying etiology of the original arrest, microcirculatory dysfunction, and mitochondrial injury and dysfunction.
      • Nolan J.P.
      • Neumar R.W.
      • Adrie C.
      • et al.
      Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication: a Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke.
      • Cocchi M.N.
      • Miller J.
      • Hunziker S.
      • et al.
      The association of lactate and vasopressor need for mortality prediction in survivors of cardiac arrest.
      • Donnino M.W.
      • Miller J.
      • Goyal N.
      • et al.
      Effective lactate clearance is associated with improved outcome in post-cardiac arrest patients.
      In a retrospective cohort of patients after cardiac arrest, the combination of initial lactate level and the need for vasopressor support in the immediate postarrest period could stratify patients and accurately predict outcome. Post-cardiac arrest patients with an initial lactate level less than 5 mmol/L had a mortality of 39%, whereas mortality increased to 92% with an initial lactate level greater than 10 mmol/L.
      • Cocchi M.N.
      • Miller J.
      • Hunziker S.
      • et al.
      The association of lactate and vasopressor need for mortality prediction in survivors of cardiac arrest.
      Furthermore, the ability to clear lactate in the postarrest period was a predictor of increased survival in 2 studies of patients after cardiac arrest.
      • Donnino M.W.
      • Miller J.
      • Goyal N.
      • et al.
      Effective lactate clearance is associated with improved outcome in post-cardiac arrest patients.
      • Kliegel A.
      • Losert H.
      • Sterz F.
      • et al.
      Serial lactate determinations for prediction of outcome after cardiac arrest.

      Trauma

      Hypoperfusion, most often related to blood loss, is common in patients with traumatic injury.
      • Kaplan L.J.
      • Kellum J.A.
      Initial pH, base deficit, lactate, anion gap, strong ion difference, and strong ion gap predict outcome from major vascular injury.
      Although the presence of vital sign abnormalities may help identify shock, their absence does not definitively exclude occult hypoperfusion.
      • Blow O.
      • Magliore L.
      • Claridge J.A.
      • Butler K.
      • Young J.S.
      The golden hour and the silver day: detection and correction of occult hypoperfusion within 24 hours improves outcome from major trauma.
      Lactate level elevation may help identify a patient whose initially normal vital signs may mask ongoing tissue hypoperfusion.
      • Wo C.C.
      • Shoemaker W.C.
      • Appel P.L.
      • Bishop M.H.
      • Kram H.B.
      • Hardin E.
      Unreliability of blood pressure and heart rate to evaluate cardiac output in emergency resuscitation and critical illness.
      As in sepsis and cardiac arrest, initial lactate levels have been found to be significantly higher in nonsurvivors compared with survivors of trauma.
      • Kaplan L.J.
      • Kellum J.A.
      Initial pH, base deficit, lactate, anion gap, strong ion difference, and strong ion gap predict outcome from major vascular injury.
      • Tisherman S.A.
      • Barie P.
      • Bokhari F.
      • et al.
      Clinical practice guideline: endpoints of resuscitation.
      • Martin M.
      • Murray J.
      • Berne T.
      • Demetriades D.
      • Belzberg H.
      Diagnosis of acid-base derangements and mortality prediction in the trauma intensive care unit: the physiochemical approach.
      • Cerovic O.
      • Golubovic V.
      • Spec-Marn A.
      • Kremzar B.
      • Vidmar G.
      Relationship between injury severity and lactate levels in severely injured patients.
      • Durham R.M.
      • Moran J.J.
      • Mazuski J.E.
      • Shapiro M.J.
      • Baue A.E.
      • Flint L.M.
      Multiple organ failure in trauma patients.
      • Aslar A.K.
      • Kuzu M.A.
      • Elhan A.H.
      • Tanik A.
      • Hengirmen S.
      Admission lactate level and the APACHE II score are the most useful predictors of prognosis following torso trauma.
      • Lavery R.F.
      • Livingston D.H.
      • Tortella B.J.
      • Sambol J.T.
      • Slomovitz B.M.
      • Siegel J.H.
      The utility of venous lactate to triage injured patients in the trauma center.
      One study reported calculated sensitivity of 84% and specificity of 86% for death in patients with torso trauma and a lactate level greater than 4 mmol/L.
      • Aslar A.K.
      • Kuzu M.A.
      • Elhan A.H.
      • Tanik A.
      • Hengirmen S.
      Admission lactate level and the APACHE II score are the most useful predictors of prognosis following torso trauma.
      The degree of elevated lactate levels and the rate of lactate clearance strongly correlate with the risk of multiorgan dysfunction and survival after traumatic injury, and lactate clearance could potentially serve as an end point to guide resuscitation.
      • Manikis P.
      • Jankowski S.
      • Zhang H.
      • Kahn R.J.
      • Vincent J.L.
      Correlation of serial blood lactate levels to organ failure and mortality after trauma.
      • Abramson D.
      • Scalea T.M.
      • Hitchcock R.
      • Trooskin S.Z.
      • Henry S.M.
      • Greenspan J.
      Lactate clearance and survival following injury.
      • Odom S.R.
      • Howell M.D.
      • Silva G.S.
      • et al.
      Lactate clearance as a predictor of mortality in trauma patients.

      Seizure

      Seizures, depending on the type, can result in a profound elevation of lactate levels. Elevated lactate levels in this setting are transient, which is important for the clinician to recognize. Once the seizure has resolved, the production of lactate ceases, and lactate is rapidly cleared. Persistently elevated lactate levels beyond the expected 1 to 2 hours after a seizure may suggest a different or concomitant underlying etiology and warrant further consideration.
      • Lipka K.
      • Bulow H.H.
      Lactic acidosis following convulsions.
      • Orringer C.E.
      • Eustace J.C.
      • Wunsch C.D.
      • Gardner L.B.
      Natural history of lactic acidosis after grand-mal seizures: a model for the study of an anion-gap acidosis not associated with hyperkalemia.

      Excessive Muscle Activity

      Lactate levels increase with heavy exercise, mainly due to anaerobic metabolism.
      • Cerretelli P.
      • Samaja M.
      Acid-base balance at exercise in normoxia and in chronic hypoxia: revisiting the “lactate paradox”.
      Siegel et al
      • Siegel A.J.
      • Januzzi J.
      • Sluss P.
      • et al.
      Cardiac biomarkers, electrolytes, and other analytes in collapsed marathon runners: implications for the evaluation of runners following competition.
      found that lactate levels were elevated in 95% of collapsed marathon runners, with levels of 1.1 to 11.2 mmol/L.
      Elevated lactate levels in the setting of acute severe asthma may be caused, at least in part, by excessive muscle work.
      • Appel D.
      • Rubenstein R.
      • Schrager K.
      • Williams Jr., M.H.
      Lactic acidosis in severe asthma.
      Rabbat et al
      • Rabbat A.
      • Laaban J.P.
      • Boussairi A.
      • Rochemaure J.
      Hyperlactatemia during acute severe asthma.
      found that elevated lactate levels are common in acute severe asthma and that lactate levels increase in the first 6 hours after hospital admission. They found no association with mortality or progression to respiratory failure. β-Agonists used in asthma treatment may also play a role owing to excessive adrenergic stimulation, but the exact pathogenesis of elevated lactate levels in asthma warrants further research.
      • Prakash S.
      • Mehta S.
      Lactic acidosis in asthma: report of two cases and review of the literature.
      Furthermore, excessive muscle work and respiratory muscle fatigue independent of the underlying etiology have been suggested to cause elevated lactate levels, but further research is necessary to clarify this relationship.
      • Roussos C.
      Respiratory muscle fatigue and ventilatory failure.
      Elevated lactate levels due to excessive muscle activity have also been associated with the use of restraints. A delirious or intoxicated patient may struggle against restraints and produce lactate due to muscle activity and tissue hypoxia. Sudden death has been reported in this population, although whether that is a result of acidosis remains unknown. Proper sedation or alternative methods for restraint may be required for patient safety in this scenario.
      • Alshayeb H.
      • Showkat A.
      • Wall B.M.
      Lactic acidosis in restrained cocaine intoxicated patients.

      Regional Ischemia

      Early recognition of mesenteric ischemia can be challenging. Lange and Toivola
      • Lange H.
      • Toivola A.
      Warning signals in acute abdominal disorders: lactate is the best marker of mesenteric ischemia.
      found elevated lactate levels to be 96% sensitive and 38% specific for mesenteric ischemia; however, other investigators report much lower sensitivity.
      • Acosta S.
      • Block T.
      • Bjornsson S.
      • Resch T.
      • Bjorck M.
      • Nilsson T.
      Diagnostic pitfalls at admission in patients with acute superior mesenteric artery occlusion.
      Furthermore, elevated lactate levels in the setting of mesenteric ischemia have been associated with increased mortality rates.
      • Meyer T.
      • Klein P.
      • Schweiger H.
      • Lang W.
      How can the prognosis of acute mesenteric artery ischemia be improved? results of a retrospective analysis.
      • Newman T.S.
      • Magnuson T.H.
      • Ahrendt S.A.
      • Smith-Meek M.A.
      • Bender J.S.
      The changing face of mesenteric infarction.
      In cases of abdominal pain in which mesenteric ischemia is considered, lactate level measurements may be a useful way to guide and expedite further diagnostic workup because lactate has been found in animal models to increase within 1 hour of induced bowel ischemia.
      • Liao X.P.
      • She Y.X.
      • Shi C.R.
      • Li M.
      Changes in body fluid markers in intestinal ischemia.
      • Jonas J.
      • Schwarz S.
      • Alebrahim-Dehkordy A.
      Behavior of the lactate level in occlusion and reperfusion of the right superior mesenteric artery: an animal experiment study.
      However, as noted, lactate levels are not always elevated in patients with mesenteric ischemia, and larger studies are required to determine the true sensitivity and specificity.
      • Demir I.E.
      • Ceyhan G.O.
      • Friess H.
      Beyond lactate: is there a role for serum lactate measurement in diagnosing acute mesenteric ischemia?.
      Aside from mesenteric ischemia, other acute abdominal diseases, such as bacterial peritonitis and acute pancreatitis, can cause elevated lactate levels.
      • Lange H.
      • Jackel R.
      Usefulness of plasma lactate concentration in the diagnosis of acute abdominal disease.
      In a study of severely injured trauma patients, lactate levels were significantly higher in those with acute lower extremity compartment syndrome.
      • Kosir R.
      • Moore F.A.
      • Selby J.H.
      • et al.
      Acute lower extremity compartment syndrome (ALECS) screening protocol in critically ill trauma patients.
      In Fournier gangrene and other types of necrotizing soft-tissue infections, lactate has been associated with mortality.
      • Elliott D.C.
      • Kufera J.A.
      • Myers R.A.
      Necrotizing soft tissue infections: risk factors for mortality and strategies for management.
      • Yaghoubian A.
      • de Virgilio C.
      • Dauphine C.
      • Lewis R.J.
      • Lin M.
      Use of admission serum lactate and sodium levels to predict mortality in necrotizing soft-tissue infections.
      • Martinschek A.
      • Evers B.
      • Lampl L.
      • Gerngross H.
      • Schmidt R.
      • Sparwasser C.
      Prognostic aspects, survival rate, and predisposing risk factors in patients with Fournier's gangrene and necrotizing soft tissue infections: evaluation of clinical outcome of 55 patients.

      Burns and Smoke Inhalation

      In severe burns, lactate has been found to be a strong predictor of outcome. Jeng et al
      • Jeng J.C.
      • Jablonski K.
      • Bridgeman A.
      • Jordan M.H.
      Serum lactate, not base deficit, rapidly predicts survival after major burns.
      found that the initial lactate level was a useful variable to separate survivors from nonsurvivors. Another prospective study by Kamolz et al
      • Kamolz L.P.
      • Andel H.
      • Schramm W.
      • Meissl G.
      • Herndon D.N.
      • Frey M.
      Lactate: early predictor of morbidity and mortality in patients with severe burns.
      found similar results with a cutoff level for initial lactate of 2 mmol/L. Moreover, they showed that rapid lactate clearance was associated with decreased mortality rates. Furthermore, because sepsis with multisystem organ failure is a major cause of morbidity and mortality in burns, lactate values should be obtained and taken into consideration when dealing with patients with burns, although the role of lactate as a resuscitation end point is questionable.
      • Pham T.N.
      • Cancio L.C.
      • Gibran N.S.
      American Burn Association practice guidelines burn shock resuscitation.
      Smoke inhalation victims are at particular risk for elevated lactate levels due to potential inhalation of cyanide or carbon monoxide.

      Diabetic Ketoacidosis

      Although not traditionally appreciated, elevated lactate levels may occur in diabetic ketoacidosis (DKA), but they do not seem to be associated with worse outcomes, in contrast to other disease states.
      • Cox K.
      • Cocchi M.N.
      • Salciccioli J.D.
      • Carney E.
      • Howell M.
      • Donnino M.W.
      Prevalence and significance of lactic acidosis in diabetic ketoacidosis.
      Cox et al
      • Cox K.
      • Cocchi M.N.
      • Salciccioli J.D.
      • Carney E.
      • Howell M.
      • Donnino M.W.
      Prevalence and significance of lactic acidosis in diabetic ketoacidosis.
      conducted a retrospective study of 68 patients with DKA and found that 40% had a lactate level greater than 4 mmol/L. In this cohort, there was no correlation between lactate and intensive care unit length of stay or mortality. A positive correlation of lactate with glucose and a negative correlation between lactate and thiamine levels raises the possibility that elevated lactate levels in DKA may be due not only to hypoperfusion but also to an altered metabolic profile, but further investigation is warranted.
      • Cox K.
      • Cocchi M.N.
      • Salciccioli J.D.
      • Carney E.
      • Howell M.
      • Donnino M.W.
      Prevalence and significance of lactic acidosis in diabetic ketoacidosis.
      • Moskowitz A.
      • Berg K.
      • Giberson T.
      • Graver A.
      • Donnino M.
      The relationship between lactic acid and thiamine levels in patients with diabetic ketoacidosis.

      Thiamine Deficiency

      Thiamine serves as a cofactor for multiple cellular enzymes, including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, components essential to the tricarboxylic acid cycle and aerobic carbohydrate metabolism (Figure 1). In the absence of thiamine, anaerobic metabolism predominates, and lactate production increases.
      • Butterworth R.F.
      Thiamine deficiency-related brain dysfunction in chronic liver failure.
      The development of elevated lactate levels in serum and cerebrospinal fluid secondary to thiamine deficiency has been well described.
      • Kountchev J.
      • Bijuklic K.
      • Bellmann R.
      • Joannidis M.
      A patient with severe lactic acidosis and rapidly evolving multiple organ failure: a case of shoshin beri-beri.
      • Fattal-Valevski A.
      • Kesler A.
      • Sela B.A.
      • et al.
      Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-based formula.
      • Donnino M.
      Gastrointestinal beriberi: a previously unrecognized syndrome.
      • Klein M.
      • Weksler N.
      • Gurman G.M.
      Fatal metabolic acidosis caused by thiamine deficiency.
      Risk factors for thiamine deficiency include states of nutritional deficiency, such as alcoholism, chronic wasting diseases, hyperemesis gravidarum, anorexia nervosa, and gastric bypass surgery.
      • Donnino M.W.
      • Vega J.
      • Miller J.
      • Walsh M.
      Myths and misconceptions of Wernicke's encephalopathy: what every emergency physician should know.
      • Munir A.
      • Hussain S.A.
      • Sondhi D.
      • Ameh J.
      • Rosner F.
      Wernicke's encephalopathy in a non-alcoholic man: case report and brief review.
      • Rossouw J.E.
      • Labadarios D.
      • Krasner N.
      • Davis M.
      • Williams R.
      Red blood cell transketolase activity and the effect of thiamine supplementation in patients with chronic liver disease.
      • Toth C.
      • Voll C.
      Wernicke's encephalopathy following gastroplasty for morbid obesity.
      • Saad L.
      • Silva L.F.
      • Banzato C.E.
      • Dantas C.R.
      • Garcia Jr., C.
      Anorexia nervosa and Wernicke-Korsakoff syndrome: a case report.
      An elevated lactate level resulting from thiamine deficiency is an often overlooked but easily treated condition that should be considered in cases of otherwise unexplained elevated lactate levels.
      • Thomas L.
      • Fay D.
      • Moraillon X.
      • Delubac G.
      • Berthet P.
      • Demingeon G.
      Lactic acidosis treated with thiamine: 3 cases.
      • Campbell C.H.
      The severe lacticacidosis of thiamine deficiency: acute pernicious or fulminating beriberi.
      • Wrenn K.D.
      • Murphy F.
      • Slovis C.M.
      A toxicity study of parenteral thiamine hydrochloride.
      • Shivalkar B.
      • Engelmann I.
      • Carp L.
      • De Raedt H.
      • Daelemans R.
      Shoshin syndrome: two case reports representing opposite ends of the same disease spectrum.

      Malignancy

      Most patients with cancer who present with cancer-related elevated lactate levels are adults with rapidly progressive leukemia or lymphoma, often with liver involvement. The pathogenesis is poorly understood but is likely related to tumor overexpression of certain glycolytic enzymes, mitochondrial dysfunction, impaired hepatic clearance, and, perhaps, malnutrition, leading to thiamine deficiency.
      • Sillos E.M.
      • Shenep J.L.
      • Burghen G.A.
      • Pui C.H.
      • Behm F.G.
      • Sandlund J.T.
      Lactic acidosis: a metabolic complication of hematologic malignancies: case report and review of the literature.
      • Friedenberg A.S.
      • Brandoff D.E.
      • Schiffman F.J.
      Type B lactic acidosis as a severe metabolic complication in lymphoma and leukemia: a case series from a single institution and literature review.

      Liver Dysfunction

      The liver is the organ primarily responsible for lactate clearance, and in the presence of severe liver dysfunction, lactate clearance may be impaired.
      • Record C.O.
      • Chase R.A.
      • Williams R.
      • Appleton D.
      Disturbances of lactate metabolism in patients with liver damage due to paracetamol overdose.
      • Almenoff P.L.
      • Leavy J.
      • Weil M.H.
      • Goldberg N.B.
      • Vega D.
      • Rackow E.C.
      Prolongation of the half-life of lactate after maximal exercise in patients with hepatic dysfunction.
      Additionally, studies have shown that the acutely injured liver may itself act as a source of lactate.
      • Clemmesen J.O.
      • Hoy C.E.
      • Kondrup J.
      • Ott P.
      Splanchnic metabolism of fuel substrates in acute liver failure.
      • Pastor C.M.
      • Billiar T.R.
      • Losser M.R.
      • Payen D.M.
      Liver injury during sepsis.
      • Mizock B.A.
      The hepatosplanchnic area and hyperlactatemia: a tale of two lactates.
      • Murphy N.D.
      • Kodakat S.K.
      • Wendon J.A.
      • et al.
      Liver and intestinal lactate metabolism in patients with acute hepatic failure undergoing liver transplantation.
      Clinicians should be cautioned against attributing a high lactate level to liver disease alone without adequately investigating or treating for other causes of elevated lactate levels.
      • Kruse J.A.
      • Zaidi S.A.
      • Carlson R.W.
      Significance of blood lactate levels in critically ill patients with liver disease.
      Moreover, in shock states, accompanying liver failure likely accentuates lactic acid level elevation secondary to poor clearance but is not the proximate cause of the initially increased production.

      Inborn Errors of Metabolism

      In rare cases, especially in the pediatric population, elevated lactate levels can be caused by inborn errors of metabolism. The genetic disorders involved can cause dysfunction in a variety of metabolic steps, including gluconeogenesis, pyruvate dehydrogenase, the tricarboxylic acid cycle, and the respiratory chain.
      • Goldberg G.R.
      • Greene C.L.
      Update on inborn errors of metabolism: primary lactic acidemia.

      Pharmacologic Agents and Toxins Associated With Elevated Lactate Levels

      A variety of medications and toxins associated with elevated lactate levels are listed in Table 2.
      • Prakash S.
      • Mehta S.
      Lactic acidosis in asthma: report of two cases and review of the literature.
      • Misbin R.I.
      • Green L.
      • Stadel B.V.
      • Gueriguian J.L.
      • Gubbi A.
      • Fleming G.A.
      Lactic acidosis in patients with diabetes treated with metformin.
      • Lalau J.D.
      Lactic acidosis induced by metformin: incidence, management and prevention.
      • Dragovic G.
      • Jevtovic D.
      The role of nucleoside reverse transcriptase inhibitors usage in the incidence of hyperlactatemia and lactic acidosis in HIV/AIDS patients.
      • Leung L.
      • Wilson D.
      • Manini A.F.
      Fatal toxicity from symptomatic hyperlactataemia: a retrospective cohort study of factors implicated with long-term nucleoside reverse transcriptase inhibitor use in a South African hospital.
      • Bolhaar M.G.
      • Karstaedt A.S.
      A high incidence of lactic acidosis and symptomatic hyperlactatemia in women receiving highly active antiretroviral therapy in Soweto, South Africa.
      • Wiener M.
      • Guo Y.
      • Patel G.
      • Fries B.C.
      Lactic acidosis after treatment with linezolid.
      • Garrabou G.
      • Soriano A.
      • Lopez S.
      • et al.
      Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia.
      • Soriano A.
      • Miro O.
      • Mensa J.
      Mitochondrial toxicity associated with linezolid.
      • Meert K.L.
      • McCaulley L.
      • Sarnaik A.P.
      Mechanism of lactic acidosis in children with acute severe asthma.
      • Meert K.L.
      • Clark J.
      • Sarnaik A.P.
      Metabolic acidosis as an underlying mechanism of respiratory distress in children with severe acute asthma.
      • Vasile B.
      • Rasulo F.
      • Candiani A.
      • Latronico N.
      The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome.
      • Wolf A.
      • Weir P.
      • Segar P.
      • Stone J.
      • Shield J.
      Impaired fatty acid oxidation in propofol infusion syndrome.
      • Karakitsos D.
      • Poularas J.
      • Kalogeromitros A.
      • Karabinis A.
      The propofol infusion syndrome treated with haemofiltration: is there a time for genetic screening?.
      • Kam P.C.
      • Cardone D.
      Propofol infusion syndrome.
      • Totaro R.J.
      • Raper R.F.
      Epinephrine-induced lactic acidosis following cardiopulmonary bypass.
      • Levy B.
      • Perez P.
      • Perny J.
      • Thivilier C.
      • Gerard A.
      Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock: a prospective, randomized pilot study.
      • Charytan D.
      • Jansen K.
      Severe metabolic complications from theophylline intoxication.
      • Leventhal L.J.
      • Kochar G.
      • Feldman N.H.
      • Podolsky S.M.
      • Stanek M.S.
      Lactic acidosis in theophylline overdose.
      • MacDonald L.
      • Kruse J.A.
      • Levy D.B.
      • Marulendra S.
      • Sweeny P.J.
      Lactic acidosis and acute ethanol intoxication.
      • Zehtabchi S.
      • Sinert R.
      • Baron B.J.
      • Paladino L.
      • Yadav K.
      Does ethanol explain the acidosis commonly seen in ethanol-intoxicated patients?.
      • Halperin M.L.
      • Hammeke M.
      • Josse R.G.
      • Jungas R.L.
      Metabolic acidosis in the alcoholic: a pathophysiologic approach.
      • Boghdadi M.S.
      • Henning R.J.
      Cocaine: pathophysiology and clinical toxicology.
      • Bethke R.A.
      • Gratton M.
      • Watson W.A.
      Severe hyperlactemia and metabolic acidosis following cocaine use and exertion.
      • Moon J.M.
      • Shin M.H.
      • Chun B.J.
      The value of initial lactate in patients with carbon monoxide intoxication: in the emergency department.
      • Hampson N.B.
      • Piantadosi C.A.
      • Thom S.R.
      • Weaver L.K.
      Practice recommendations in the diagnosis, management, and prevention of carbon monoxide poisoning.
      • Baud F.J.
      • Borron S.W.
      • Megarbane B.
      • et al.
      Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning.
      • Reade M.C.
      • Davies S.R.
      • Morley P.T.
      • Dennett J.
      • Jacobs I.C.
      Australian Resuscitation Council
      Review article: management of cyanide poisoning.
      • Shah A.D.
      • Wood D.M.
      • Dargan P.I.
      Understanding lactic acidosis in paracetamol (acetaminophen) poisoning.
      Owing to the rarity of most of these clinical scenarios, there is a lack of research on treatment options, and some of the associations are highly suspected but not fully proved. Treatment choice should be based on the specific clinical scenario, and current recommendations as noted in Table 2 are often based on case reports and expert opinion. Moreover, many medications and toxins not listed in Table 2 might cause elevated lactate levels but are beyond the scope of the present review, particularly overdoses. Special attention is given in the following subsections to metformin and alcohols owing to the high prevalence of exposure to these agents.
      Table 2Common Drugs and Toxins Associated With Elevated Lactate Levels
      NADH = nicotinamide adenine dinucleotide; NRTI = nucleoside reverse transcriptase inhibitor, PDH = pyruvate dehydrogenase.
      Drug/toxinRisk factorsProposed mechanismSuggested treatment in addition to cessation of the offending agent
      Metformin
      • Misbin R.I.
      • Green L.
      • Stadel B.V.
      • Gueriguian J.L.
      • Gubbi A.
      • Fleming G.A.
      Lactic acidosis in patients with diabetes treated with metformin.
      • Lalau J.D.
      Lactic acidosis induced by metformin: incidence, management and prevention.
      See the text for more details.
      Congestive heart failure, kidney failure, liver failure, or overdoseInhibition of gluconeogenesis and mitochondrial impairment, inhibition of lactate eliminationConsider hemodialysis
      Acetaminophen
      • Shah A.D.
      • Wood D.M.
      • Dargan P.I.
      Understanding lactic acidosis in paracetamol (acetaminophen) poisoning.
      OverdoseImpairment of the mitochondrial electron transport chain; later hepatotoxicity and systemic effectsEnteral activated charcoal and N-acetylcysteine
      NRTI
      • Dragovic G.
      • Jevtovic D.
      The role of nucleoside reverse transcriptase inhibitors usage in the incidence of hyperlactatemia and lactic acidosis in HIV/AIDS patients.
      • Leung L.
      • Wilson D.
      • Manini A.F.
      Fatal toxicity from symptomatic hyperlactataemia: a retrospective cohort study of factors implicated with long-term nucleoside reverse transcriptase inhibitor use in a South African hospital.
      • Bolhaar M.G.
      • Karstaedt A.S.
      A high incidence of lactic acidosis and symptomatic hyperlactatemia in women receiving highly active antiretroviral therapy in Soweto, South Africa.
      Female sexDirect mitochondrial toxicityNo specific treatment
      Linezolid
      • Wiener M.
      • Guo Y.
      • Patel G.
      • Fries B.C.
      Lactic acidosis after treatment with linezolid.
      • Garrabou G.
      • Soriano A.
      • Lopez S.
      • et al.
      Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia.
      • Soriano A.
      • Miro O.
      • Mensa J.
      Mitochondrial toxicity associated with linezolid.
      Possibly prolonged use in elderly patientsDirect mitochondrial toxicityNo specific treatment
      β2-Agonists
      • Prakash S.
      • Mehta S.
      Lactic acidosis in asthma: report of two cases and review of the literature.
      • Meert K.L.
      • McCaulley L.
      • Sarnaik A.P.
      Mechanism of lactic acidosis in children with acute severe asthma.
      • Meert K.L.
      • Clark J.
      • Sarnaik A.P.
      Metabolic acidosis as an underlying mechanism of respiratory distress in children with severe acute asthma.
      Not applicableβ2-Adrenergic stimulation causing increased glycogenolysis, glycolysis, and lipolysis; free fatty acids released by lipolysis may inhibit PDHDepending on the clinical situation, the β2-agonist may/should be continued
      Propofol
      • Vasile B.
      • Rasulo F.
      • Candiani A.
      • Latronico N.
      The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome.
      • Wolf A.
      • Weir P.
      • Segar P.
      • Stone J.
      • Shield J.
      Impaired fatty acid oxidation in propofol infusion syndrome.
      • Karakitsos D.
      • Poularas J.
      • Kalogeromitros A.
      • Karabinis A.
      The propofol infusion syndrome treated with haemofiltration: is there a time for genetic screening?.
      • Kam P.C.
      • Cardone D.
      Propofol infusion syndrome.
      Prolonged high-dose use (propofol infusion syndrome
      The propofol infusion syndrome is characterized by cardiac failure, rhabdomyolysis, metabolic acidosis, and renal failure.
      )
      Impairment of the mitochondrial electron transport chain and fatty acid oxidationSupportive treatment and potentially hemodialysis should be considered
      Epinephrine
      • Totaro R.J.
      • Raper R.F.
      Epinephrine-induced lactic acidosis following cardiopulmonary bypass.
      • Levy B.
      • Perez P.
      • Perny J.
      • Thivilier C.
      • Gerard A.
      Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock: a prospective, randomized pilot study.
      Not applicableLikely due to β2-adrenergic stimulation (see β2-agonists)Depending on the clinical situation, epinephrine may be continued
      Theophylline
      • Charytan D.
      • Jansen K.
      Severe metabolic complications from theophylline intoxication.
      • Leventhal L.J.
      • Kochar G.
      • Feldman N.H.
      • Podolsky S.M.
      • Stanek M.S.
      Lactic acidosis in theophylline overdose.
      Overdose, although reported in standard dosesIncreased levels of catecholamines (see β2-agonists)Enteral activated charcoal; hemodialysis in severe cases
      Alcohols (ethanol, methanol, propylene glycol)
      • MacDonald L.
      • Kruse J.A.
      • Levy D.B.
      • Marulendra S.
      • Sweeny P.J.
      Lactic acidosis and acute ethanol intoxication.
      • Zehtabchi S.
      • Sinert R.
      • Baron B.J.
      • Paladino L.
      • Yadav K.
      Does ethanol explain the acidosis commonly seen in ethanol-intoxicated patients?.
      • Halperin M.L.
      • Hammeke M.
      • Josse R.G.
      • Jungas R.L.
      Metabolic acidosis in the alcoholic: a pathophysiologic approach.
      See the text for more details.
      Ethylene glycol may cause falsely elevated lactate levels.
      Clinical relevance controversial and may be confounded by comorbidities (thiamine deficiency, seizures, sepsis, and other toxins)Increased NADH levels due to ethanol metabolism may inhibit PDH and the use of lactate; contributions from underlying comorbidities or possibly ketoacidosis may play a roleIdentification and treatment of underlying disorders, including administration of thiamine
      Cocaine
      • Boghdadi M.S.
      • Henning R.J.
      Cocaine: pathophysiology and clinical toxicology.
      • Bethke R.A.
      • Gratton M.
      • Watson W.A.
      Severe hyperlactemia and metabolic acidosis following cocaine use and exertion.
      Not applicableβ2-Adrenergic stimulation (see β2-agonists); vasoconstriction causing ischemiaSupportive care and benzodiazepine
      Carbon monoxide
      • Moon J.M.
      • Shin M.H.
      • Chun B.J.
      The value of initial lactate in patients with carbon monoxide intoxication: in the emergency department.
      • Hampson N.B.
      • Piantadosi C.A.
      • Thom S.R.
      • Weaver L.K.
      Practice recommendations in the diagnosis, management, and prevention of carbon monoxide poisoning.
      Not applicableDecreased oxygen-carrying capacity of the bloodHigh-flow/hyperbaric oxygen; consider co-exposure to cyanide
      Cyanide
      • Baud F.J.
      • Borron S.W.
      • Megarbane B.
      • et al.
      Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning.
      • Reade M.C.
      • Davies S.R.
      • Morley P.T.
      • Dennett J.
      • Jacobs I.C.
      Australian Resuscitation Council
      Review article: management of cyanide poisoning.
      Not applicableNoncompetitive inhibition of cytochrome c oxidase causing mitochondrial dysfunction and inability to use oxygenHydroxocobalamin or other cyanide antidote kit (sodium nitrite, amyl nitrite, sodium thiosulfate); consider co-exposure to carbon monoxide
      a NADH = nicotinamide adenine dinucleotide; NRTI = nucleoside reverse transcriptase inhibitor, PDH = pyruvate dehydrogenase.
      b See the text for more details.
      c The propofol infusion syndrome is characterized by cardiac failure, rhabdomyolysis, metabolic acidosis, and renal failure.
      d Ethylene glycol may cause falsely elevated lactate levels.

      Metformin (Biguanide)

      One of the first biguanides, phenformin, was withdrawn from the US market in 1976 because of the common occurrence of elevated lactate levels.
      • Williams R.H.
      • Palmer J.P.
      Farewell to phenformin for treating diabetes mellitus.
      Today, metformin is the only biguanide used clinically for the management of diabetes mellitus. Metformin is thought to increase the risk of elevated lactate levels, but the correlation remains controversial. The proposed mechanism includes inhibition of gluconeogenesis and mitochondrial impairment.
      • Lalau J.D.
      Lactic acidosis induced by metformin: incidence, management and prevention.
      Recently, a major Cochrane meta-analysis concluded that there was no increased risk of elevated lactate levels for metformin compared with nonmetformin treatment; however, this may reflect use in selected study populations and not necessarily those with overdoses or use in renal insufficiency, for example.
      • Salpeter S.R.
      • Greyber E.
      • Pasternak G.A.
      • Salpeter E.E.
      Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.
      The estimated rate of confirmed elevated lactate levels (lactate level >5 mmol/L) was reported to be approximately 5 cases per 100,000 patients based on numbers from the Food and Drug Administration from 1996.
      • Misbin R.I.
      • Green L.
      • Stadel B.V.
      • Gueriguian J.L.
      • Gubbi A.
      • Fleming G.A.
      Lactic acidosis in patients with diabetes treated with metformin.
      Patients with diabetes who develop this complication are often ill and have numerous comorbid issues, such as renal insufficiency and congestive heart failure. The elevated lactate levels observed in metformin users may be related to an exacerbation of their chronic disease or another acute insult and are not necessarily related to metformin use.
      • Lalau J.D.
      Lactic acidosis induced by metformin: incidence, management and prevention.
      • Price G.
      Metformin lactic acidosis, acute renal failure and rofecoxib.
      Pure metformin-associated elevated lactate levels are often seen with accumulation due to kidney failure, liver failure, or overdose. In patients with renal failure, the suggested treatment is hemodialysis, which will correct the metabolic acidosis and remove metformin.
      • Lalau J.D.
      Lactic acidosis induced by metformin: incidence, management and prevention.

      Alcohols

      The association between elevated lactate levels and ethanol remains controversial, and studies show varying results. Although ethanol may increase lactate levels in an experimental setting, clinically significant elevated lactate levels are rare in patients with no other concerns or comorbidities.
      • MacDonald L.
      • Kruse J.A.
      • Levy D.B.
      • Marulendra S.
      • Sweeny P.J.
      Lactic acidosis and acute ethanol intoxication.
      • Zehtabchi S.
      • Sinert R.
      • Baron B.J.
      • Paladino L.
      • Yadav K.
      Does ethanol explain the acidosis commonly seen in ethanol-intoxicated patients?.
      • Halperin M.L.
      • Hammeke M.
      • Josse R.G.
      • Jungas R.L.
      Metabolic acidosis in the alcoholic: a pathophysiologic approach.
      Ruling out and treating other causes of severely elevated lactate levels in these patients are, therefore, important, and lactate level elevation should not solely be attributed to the potential effects of ethanol. Ethanol-intoxicated patients might be at increased risk for other causes of elevated lactate levels, such as thiamine deficiency, seizures, sepsis, and other toxins. Other alcohols (propylene glycol and methanol) have been implicated in elevated lactate levels, and lactate levels can be falsely elevated in ethylene glycol poisoning.
      • Sandberg Y.
      • Rood P.P.
      • Russcher H.
      • Zwaans J.J.
      • Weige J.D.
      • van Daele P.L.
      Falsely elevated lactate in severe ethylene glycol intoxication.
      • Soliman H.M.
      • Vincent J.L.
      Prognostic value of admission serum lactate concentrations in intensive care unit patients.
      • Zosel A.
      • Egelhoff E.
      • Heard K.
      Severe lactic acidosis after an iatrogenic propylene glycol overdose.
      • Kruse J.A.
      Methanol poisoning.
      • Shahangian S.
      • Ash K.O.
      Formic and lactic acidosis in a fatal case of methanol intoxication.

      Approach to the Patient With an Elevated Lactate Level

      In broad terms, elevated lactate levels can be divided into 2 categories: cases in which it is driven by hypoperfusion/hypoxemia and cases in which it is not. The hypoperfusion-driven cases include all forms of shock, the post–cardiac arrest state, and regional ischemia. In all of these clinical scenarios, lactate levels that remain elevated are often important prognostically, and treatment is aimed at improving perfusion to the affected tissues. In shock, treatment can involve volume resuscitation, vasopressors, or inotropes, depending on the etiology of the shock. In regional ischemia, treatment can involve surgery to restore circulation or remove damaged tissue.
      The second general category includes cases not driven by hypoperfusion. This group includes drug effects, seizures, malignancy, and thiamine deficiency. In these cases, the elevated lactate levels stem from dysfunction of cellular metabolism or overproduction from increases in metabolism or muscle work. The treatments are, therefore, quite different from those used for hypoperfusion, focusing on stopping or reversing offending agents (possibly requiring dialysis in cases such as metformin or salicylate toxicity), remedying the deficit in metabolism (as in correction of DKA or thiamine replacement), or targeting the underlying organ dysfunction.
      Differentiating among all these causes can be difficult during a patient’s initial presentation. The clinical importance, however, is clear. Lactate in the undifferentiated patient has been associated with mortality,
      • del Portal D.A.
      • Shofer F.
      • Mikkelsen M.E.
      • et al.
      Emergency department lactate is associated with mortality in older adults admitted with and without infections.
      • Juneja D.
      • Singh O.
      • Dang R.
      Admission hyperlactatemia: causes, incidence, and impact on outcome of patients admitted in a general medical intensive care unit.
      • Soliman H.M.
      • Vincent J.L.
      Prognostic value of admission serum lactate concentrations in intensive care unit patients.
      but the association varies widely when patients are stratified according to disease (Figure 2). With the same cutoff value (lactate level >4 mmol/L), in-hospital mortality approaches zero in uncomplicated DKA but reaches more than 75% in the post–cardiac arrest population. This highlights the importance of using lactate levels in the appropriate clinical context. Thus, lactate elevation is likely irrelevant for prognosis of an asthma exacerbation or DKA but more concerning for a patient with sepsis or after cardiac arrest.
      Figure thumbnail gr2
      Figure 2Elevated lactate levels (>4 mmol/L) in different diseases and its association with in-hospital mortality.
      • Cox K.
      • Cocchi M.N.
      • Salciccioli J.D.
      • Carney E.
      • Howell M.
      • Donnino M.W.
      Prevalence and significance of lactic acidosis in diabetic ketoacidosis.
      • Shapiro N.I.
      • Howell M.D.
      • Talmor D.
      • et al.
      Serum lactate as a predictor of mortality in emergency department patients with infection.
      • Callaway D.W.
      • Shapiro N.I.
      • Donnino M.W.
      • Baker C.
      • Rosen C.L.
      Serum lactate and base deficit as predictors of mortality in normotensive elderly blunt trauma patients.
      • Cocchi M.N.
      • Miller J.
      • Hunziker S.
      • et al.
      The association of lactate and vasopressor need for mortality prediction in survivors of cardiac arrest.
      The mortality in post–cardiac arrest shown here is calculated based on data from Cocchi et al
      • Cocchi M.N.
      • Miller J.
      • Hunziker S.
      • et al.
      The association of lactate and vasopressor need for mortality prediction in survivors of cardiac arrest.
      and not specified in the original article. ED = emergency department.
      The evaluation of elevated lactate levels must include the consideration of a multifactorial etiology. Many patients are at increased risk for multiple potential causes, such as thiamine deficiency and liver dysfunction in septic shock,
      • Donnino M.W.
      • Carney E.
      • Cocchi M.N.
      • et al.
      Thiamine deficiency in critically ill patients with sepsis.
      seizures in the setting of alcohol intoxication or drug abuse,
      • Hughes J.R.
      Alcohol withdrawal seizures.
      • Alldredge B.K.
      • Lowenstein D.H.
      • Simon R.P.
      Seizures associated with recreational drug abuse.
      and cyanide/carbon monoxide poisoning in the setting of burns with concurrent smoke inhalation.
      • Lawson-Smith P.
      • Jansen E.C.
      • Hyldegaard O.
      Cyanide intoxication as part of smoke inhalation: a review on diagnosis and treatment from the emergency perspective.
      Given the complexities mentioned previously, a systematic approach to the patient with an elevated lactate level may be helpful for clinicians evaluating and treating such a patient. Although individual clinical judgment is crucial, a “checklist” tool may help avoid missed opportunities for diagnostic investigations and therapeutic interventions (Table 3).
      Table 3Clinical Checklist: Evaluation of Elevated Lactate Levels
      Evaluate for tissue hypoperfusion and restore adequate perfusion
       Shock (distributive, cardiogenic, hypovolemic, and obstructive), post–cardiac arrest syndrome
       Tissue hypoperfusion should be initially assumed/considered until proved otherwise
       Treatment is variable based on shock etiology
      Evaluate for local tissue ischemia and treat accordingly
       Mesenteric ischemia, limb ischemia, burns, trauma, compartment syndrome, necrotizing soft-tissue infections
       Consider early surgical consultation as appropriate
      Stop/reverse potential offending agents
       Pharmacological agents: linezolid, nucleoside reverse transcriptase inhibitors, metformin, valproate, theophylline, epinephrine, propofol, isoniazid, and salicylates
       Drugs and toxins: cocaine, alcohols, carbon monoxide, and cyanide poisoning
       Consider a toxicology consultation or poison control involvement
       Cessation of exposure and removal of agent (ie, dialysis) when appropriate (Table 2)
      Consider thiamine deficiency and treat if suspected
       Patient with malnutrition of any cause, often (but not exclusively) alcoholics
       Intravenous thiamine should be given
      Consider current or recent anaerobic muscle activity as etiology
       Heavy exercise, seizures, excessive work of breathing
       Consider other etiologies, especially if rapid clearance is not seen when the inciting problem is treated (ie, should rapidly clear after cessation of seizure activity)
      Consider other metabolic derangements
       Diabetic ketoacidosis
       Mitochondrial disease
       Liver dysfunction

      Lactate Clearance as an End Point of Resuscitation

      As described previously, effective lactate clearance has been associated with decreased mortality in a variety of settings and conditions. Conversely, failure to clear lactate portends a worse outcome. In patients with presumed tissue hypoperfusion (eg, septic shock), failure to clear lactate should prompt reassessment of the resuscitation effort. As discussed throughout this article, lactate level elevation may derive from any of a variety of sources. Persistent lactate level elevation may indicate an unrecognized ischemic bowel, an uncontrolled source of infection, inadequate flow (either from inadequate intravascular volume or inadequate cardiac contractility), concomitant pharmacologic insult (eg, associated metformin-induced mitochondrial injury in a septic patient with renal failure), unrecognized thiamine deficiency, irreversible mitochondrial injury, or other problems. Continual reassessment for unrecognized causes is, therefore, warranted in cases of persistent elevation, because treatment may have to be tailored accordingly.
      Previous studies have attempted to use lactate clearance in a more specific manner using a protocol-driven response to persistent elevation.
      • Jones A.E.
      • Shapiro N.I.
      • Trzeciak S.
      • Arnold R.C.
      • Claremont H.A.
      • Kline J.A.
      Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.
      • Jansen T.C.
      • van Bommel J.
      • Schoonderbeek F.J.
      • et al.
      Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial.
      Jansen et al
      • Jansen T.C.
      • van Bommel J.
      • Schoonderbeek F.J.
      • et al.
      Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial.
      studied intensive care unit patients with presumed anaerobic causes of lactate levels of 3 mmol/L or greater and randomized them to either standard therapy or standard therapy and a complex treatment algorithm guided (in part) by lactate clearance. Patients in the lactate clearance group had shorter time in the intensive care unit and were weaned faster from mechanical ventilation and inotropes. There was no difference in actual lactate clearance between the groups and no difference in mortality before adjusting for risk factors. When adjusting for predefined risk factors, there was a significant decrease in hospital mortality (hazard ratio, 0.61; 95% CI, 0.43-0.87).
      • Jansen T.C.
      • van Bommel J.
      • Schoonderbeek F.J.
      • et al.
      Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial.
      Jones et al
      • Jones A.E.
      • Shapiro N.I.
      • Trzeciak S.
      • Arnold R.C.
      • Claremont H.A.
      • Kline J.A.
      Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.
      performed a randomized trial in patients with severe sepsis or septic shock to determine whether impaired lactate clearance could serve as an indicator for use of inotropic support or blood transfusion. Specifically, they compared the early goal-directed therapy
      • Rivers E.
      • Nguyen B.
      • Havstad S.
      • et al.
      Early goal-directed therapy in the treatment of severe sepsis and septic shock.
      algorithm of goal central venous pressure of 8 to 12 mm Hg, goal mean arterial pressure of at least 65 mm Hg, and use of blood or dobutamine to achieve goal central venous oxygen saturation (ScvO2) of at least 70% with a modified algorithm replacing ScvO2 with a goal lactate clearance of at least 10%. However, only 10% of patients required an intervention at the third step of blood or dobutamine for persistent ScvO2 of 70% or less or lactate clearance of 10% or less within the first 6 hours. Given that only 10% of patients required an intervention at this last step, the study was underpowered to assess this specific use of lactate clearance compared with ScvO2. Given the nonspecific nature of lactate level elevation, as described throughout this review, the physiologic rationale of providing “blind” use of dobutamine without measuring some form of cardiac output to help determine whether contractility is the likely cause remains unclear. For example, this algorithm could lead to the inappropriate provision of dobutamine to a patient with high/normal cardiac output when the cause of persistent lactate level elevation may be unrecognized ischemic bowel, concomitant fulminant hepatic failure, or inadequate volume resuscitation. Because the study was underpowered to detect change and the physiologic rationale remains unclear, we do not necessarily recommend dobutamine in this scenario but rather a careful reassessment of the patient to attempt to identify and subsequently treat the reason for persistently elevated lactate levels (one of which could turn out to be decompensated myocardial function requiring dobutamine).

      Limitations and Pitfalls of Interpreting Elevated Lactate Levels in Clinical Practice

      As reviewed herein, the etiologies of lactate level elevation are varied (Table 1). The clinical importance of elevated lactate levels also varies widely (Figure 2). This difference highlights the importance of considering all potential etiologies in the initial evaluation and using the test result in context with the overall clinical picture. In addition, multiple reasons for lactate level elevation can be present in a given patient, making interpretation challenging. Given the variety of etiologies of lactate elevation and the varied clinical importance (depending on etiology), lactate is not necessarily specific for either diagnosis or prognosis unless thoughtfully coupled with the overall clinical picture.
      In addition to being a nonspecific test, lactate may not be as sensitive a test as is commonly thought. In mesenteric ischemia and sepsis, a normal lactate level is often interpreted as reassuring, but studies suggest that this may be a false reassurance. For example, in a study of superior mesenteric artery occlusion, 13 of 27 patients had a normal lactate level.
      • Acosta S.
      • Block T.
      • Bjornsson S.
      • Resch T.
      • Bjorck M.
      • Nilsson T.
      Diagnostic pitfalls at admission in patients with acute superior mesenteric artery occlusion.
      In a study by Dugas et al,
      • Dugas A.F.
      • Mackenhauer J.
      • Salciccioli J.D.
      • Cocchi M.N.
      • Gautam S.
      • Donnino M.W.
      Prevalence and characteristics of nonlactate and lactate expressors in septic shock.
      45% of patients with vasopressor-dependent septic shock did not have a lactic acid level greater than 2.4 mmol/L initially, but their mortality rate remained high. The reason some patients express lactate more than others in these scenarios is not well understood. Dugas et al
      • Dugas A.F.
      • Mackenhauer J.
      • Salciccioli J.D.
      • Cocchi M.N.
      • Gautam S.
      • Donnino M.W.
      Prevalence and characteristics of nonlactate and lactate expressors in septic shock.
      found an association between elevated lactate levels and liver disease and bacteremia in their study of patients with vasopressor-dependent shock. The association between lactate level elevation and liver injury in the study by Dugas et al
      • Dugas A.F.
      • Mackenhauer J.
      • Salciccioli J.D.
      • Cocchi M.N.
      • Gautam S.
      • Donnino M.W.
      Prevalence and characteristics of nonlactate and lactate expressors in septic shock.
      illustrates a potential confounder that may occur in patients with sepsis given the high frequency of concurrent liver involvement.

      Conclusion

      Elevated lactate levels are encountered in a multitude of clinical presentations and disease states. Patients with elevated lactate levels may be at risk for considerable morbidity and mortality and require a prompt, thoughtful, and systematic approach to diagnosis and treatment. Despite the limitations and complexities discussed, a lactate level is an easily measured laboratory variable that can provide useful bedside information for the clinician when incorporated into the appropriate clinical context.

      Acknowledgments

      We thank Francesca Montillo for her editorial assistance in preparing the submitted manuscript and Amy Uber and Michael Ganetsky, MD, for their contributions to the manuscript content.

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