Lactic Acidosis

Cohen-Woods Classification of Lactic Acidosis

  • Type A: due to decreased perfusion or oxygenation
  • Type B1: due to underlying diseases
    • However, these may cause type A lactic acidosis in some cases
  • Type B2: due to medication or intoxication
  • Type B3: due to inborn error of metabolism

Etiology

Genetic Diseases

  • Mitochondrial Encephalomyopathy + Lactic Acidosis + Stroke-Like Episodes (MELAS)
  • Diabetes Mellitus + Deafness
  • Glucose-6-Phosphatase Deficiency
  • Fructose 1,6-Diphosphatase Deficiency
  • Pyruvate Dehydrogenase Deficiency
  • Pyruvate Carboxylase Deficiency

Malignancy/Malignancy-Related

  • General Comments
    • Tumors May Benefit from Acidosis: acidic microenvironment is critical for tumorigenesis, angiogenesis, and metastasis
    • Physiology: decreased lactate clearance (with severe liver metastases)+ increased glycolytic activity of tumor (Warburg Effect) + tissue tumor hypoxia
    • Treatment: bicarbonate administration may increase lactic acid production
  • Leukemia
  • Lymphoma (see Lymphoma, [[Lymphoma]])
    • Non-Hodgkin’s Lymphoma
    • Burkitt’s Lymphoma
  • Solid Tumors
  • Tumor Lysis Syndrome (see Tumor Lysis Syndrome, [[Tumor Lysis Syndrome]])

Shock States

  • Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]])
    • Physiology: decreased oxygen delivery to tissues + epinephrine-induced β2-adrenergic receptor stimulation
  • Congestive Heart Failure (CHF)/Cardiogenic Shock (see Congestive Heart Failure, [[Congestive Heart Failure]] and Cardiogenic Shock, [[Cardiogenic Shock]]): common etiology of lactic acidosis
    • Physiology: decreased oxygen delivery to tissues + epinephrine-induced β2-adrenergic receptor stimulation
  • Hemorrhagic Shock (see Hemorrhagic Shock, [[Hemorrhagic Shock]]): common etiology of lactic acidosis
    • Physiology: decreased oxygen delivery to tissues + epinephrine-induced β2-adrenergic receptor stimulation
  • Hypovolemic Shock (see Hypovolemic Shock, [[Hypovolemic Shock]]): common etiology of lactic acidosis
    • Physiology: decreased oxygen delivery to tissues + epinephrine-induced β2-adrenergic receptor stimulation
  • Sepsis (see Sepsis, [[Sepsis]]): common etiology of lactic acidosis
    • Physiology: decreased lactate clearance (likely due to inhibition of pyruvate dehydrogenase + epinephrine-induced β2-adrenergic receptor stimulation with/without decreased oxygen delivery to tissues
  • Severe Trauma: common etiology of lactic acidosis

Liver Disease

  • End-Stage Liver Disease (see End-Stage Liver Disease, [[End-Stage Liver Disease]])
    • Physiology: decreased lactate clearance
    • Clinical: lactate is usually only mildly elevated
  • Fulminant Hepatic Failure (see Fulminant Hepatic Failure, [[Fulminant Hepatic Failure]])
    • Physiology: due to decreased lactate clearance and increased hepatic lactate production
    • Clinical: lactate levels are usually more significantly elevated than in chronic liver disease

D-Lactic Acidosis Due to Production by Enteric Microbes

  • Post-Jejunal-Ileal Bypass Surgery
    • Physiology: D-lactic acid production by enteric microbes
  • Short Bowel Syndrome (see Short Bowel Syndrome, [[Short Bowel Syndrome]])
    • Physiology: D-lactic acid production by enteric microbes

Drugs

  • β2-Adrenergic Receptor Agonists (see β2-Adrenergic Receptor Agonists, [[β2-Adrenergic Receptor Agonists]])
    • Epidemiology: most common in the setting of their β2-agonist use in acute asthma exacerbation
    • Physiology: stimulation of aerobic glycolysis
    • Clinical: may be accompanied by hypokalemia (see Hypokalemia, [[Hypokalemia]])
  • Isoniazid (INH) (see Isoniazid, [[Isoniazid]])
  • Linezolid (see Linezolid, [[Linezolid]])
  • Metformin (see Metformin, [[Metformin]])
    • Epidemiology: biguanide anti-hyperglycemic
      • Lactic Acidosis is Usually Seen in Association with High Plasma Metformin Levels
    • Physiology
      • Metformin Promotes the Conversion of Glucose to Lactate in the Small Intestinal Splanchnic Bed
      • Metformin Inhibits Mitochondrial Respiratory Chain Complex 1: impairs hepatic gluconeogenesis from lactate, pyruvate, and alanine -> results in additional lactate and substrate for lactate production
    • Treatment: hemodialysis is beneficial
  • Nucleoside Reverse Transcriptase Inhibitors (see Nucleoside Reverse Transcriptase Inhibitors, [[Nucleoside Reverse Transcriptase Inhibitors]])
    • Epidemiology: severe lactic acidosis is uncommon in the absence of other precipitating factors
    • Physiology: impair oxidative phosphorylation
  • Phenformin (see Phenformin, [[Phenformin]])
    • Epidemiology: biguanide anti-hyperglycemic
      • More Common Cause of Lactic Acidosis than Metformin
      • Most Commonly Occurs in the Setting of Renal Failure: biguanide that accumulates and inhibits oxidative phosphorylation
    • Physiology: inhibition of oxidative phosphorylation
  • Propofol Infusion Syndrome (see Propofol, [[Propofol]])
    • Epidemiology: associated with prolonged high-dose propofol infusion
    • Physiology: propofol impairs oxidative phosphorylation
  • Salicylates (see Salicylates, [[Salicylates]])
    • Physiology: impairment of oxidative phosphorylation
    • Clinical: hyperlactatemia is usually minimal

Toxins

  • Carbon Monoxide Intoxication (see Carbon Monoxide, [[Carbon Monoxide]])
    • Physiology: decreased oxygen delivery to tissues + impairment of oxidative phosphorylation
  • Cocaine Intoxication (see Cocaine, [[Cocaine]])
    • Physiology: decreased oxygen delivery to tissues + epinephrine-induced β2-adrenergic receptor stimulation
      • In Addition, Clenbuterol (Found as an Adulterant in Cocaine) Can Cause Lactic Acidosis (see Clenbuterol, [[Clenbuterol]])
    • Clinical: marked hyperlactatemia may be seen in in patients having seizures or who are restrained
  • Cyanide Intoxication (see Cyanide, [[Cyanide]])
    • Physiology: impairment of oxidative phosphorylation
    • Clinical: hyperlactatemia is an important clinical manifestation
  • Diethylene Glycol (see Diethylene Glycol, [[Diethylene Glycol]])
    • Physiology: impairment of oxidative phosphorylation
  • Ethylene Glycol (see Ethylene Glycol, [[Ethylene Glycol]])
    • Physiology: impairment of oxidative phosphorylation
  • Hydrogen Sulfide Gas Inhalation (see Hydrogen Sulfide Gas, [[Hydrogen Sulfide Gas]])
    • Physiology: impairment of cytochrome oxidase and cellular respiration -> cytoxic asphyxiant
  • Kombucha (see Kombucha, [[Kombucha]])
    • Epidemiology: case report occurring in association with acute renal failure and hyperthermia
  • Methamphetamine Intoxication (see Methamphetamine, [[Methamphetamine]])
  • Methemoglobinemia (see Methemoglobinemia, [[Methemoglobinemia]])
  • Methanol (see Methanol, [[Methanol]])
    • Physiology: impairment of oxidative phosphorylation
  • Propylene Glycol Intoxication (see Propylene Glycol, [[Propylene Glycol]])
    • Physiology: D-lactic acid and L-lactic acid are normal products of propylene glycol metabolism
    • Clinical
      • Lactic Acidosis is Variably Present
      • Elevated D-lactic Acid Levels Have Been Detected in Some Cases

Other

  • Diabetic Ketoacidosis (DKA)/Hyperosmolar Hyperglycemic State (see Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State, [[Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State]])
    • Physiology: mechanism of lactic acidosis is unclear
    • Diagnosis: elevated D-lactic acid levels have been detected in some cases
    • Clinical: presence of coexistent lactic acidosis increases the mortality rate in DKA
  • Hypoxemia (see Hypoxemia, [[Hypoxemia]])
    • Physiology: decreased oxygen delivery to tissues
  • Malaria (see Malaria, [[Malaria]])
  • Pheochromocytoma (see Pheochromocytoma, [[Pheochromocytoma]]
    • Epidemiology: rarely, lactic acidosis is the presenting feature of pheochromocytoma
    • Physiology: decreased oxygen delivery to tissues + epinephrine-induced β2-adrenergic receptor stimulation
  • Regional Ischemia
  • Seizures (see Seizures, [[Seizures]])
    • Epidemiology: post-ictal lactic acidosis is common
    • Physiology: increased oxygen consumption
    • Clinical: acidemia and hyperlactatemia are usually transient
      • Normokalemia is Usually Present
  • Severe Anemia (Hb <5 g/dL) (see Anemia, [[Anemia]])
    • Physiology: decreased oxygen delivery to tissues
  • Shivering
    • Physiology: increased oxygen consumption
    • Clinical: acidemia and hyperlactatemia are usually transient
  • Strenuous Exercise
    • Physiology: increased oxygen consumption
    • Clinical: acidemia and hyperlactatemia are usually transient
      • Lactic Acidosis Can Impair Exercise Performance
  • Thiamine Deficiency (see Thiamine, [[Thiamine]])
    • Epidemiology: most common in patients on chronic total parenteral nutrition or in those with fulminant beriberi
    • Physiology: thiamine deficiency blocks pyruvate entry into mitochondria, impairing pyruvate dehydrogenase activity

Physiology

Normal Lactate Physiology

  • Approximately 20 mmol/kg of Lactate is Produced Daily in the Human Body: this occurs predominantly by highly glycolytic tissues (such as skeletal muscle) which contain the LDHA-rich isoform of the Lactate Dehydrogenase enyzme
    • LDHA Subunit Has Higher Affinity for Pyruvate and Its Reduction Than the LDHB Subunit
    • Lactate is Produced from Glycolysis with Release of Protons: glucose + 2(ADP + inorganic phosphate) -> 2lactate + 2Hydrogen Ions + 2ATP
  • Lactate is Normally Reconverted to Pyruvate and Consumed in the Mitochondria of the Liver/Kidney/Muscle/Heart/Brain/Other Tissues (All of These Tissues Have LDHB-Rich LDH Isoforms): liver accounts for 70% of whole body lactate clearance
    • Liver/Kidney Reconversion of Lactate to Pyruvate Involves the Cori Cycle
      • Pyruvate (the First Designated Substrate of the Gluconeogenesis Pathway) is Subsequently Converted to Glucose in the Liver/Kidney, a Process Which Generates Bicarbonate
    • Liver/Kidney/Muscle/Heart/Brain/Other Tissue Reconversion of Lactate to Pyruvate Involves the Tricarboxylic Acid Cycle and Oxidative Phosphorylation
      • Pyruvate is Oxidized to Carbon Dioxide and Water

Lactate Generation and Consumption

  • In the Steady-State, Lactate Generation and Consumption are Equivalent: therefore, serum lactate concentration remains stable
  • During Seizures/Maximal Exercise, Serum Lactate Production Increases Markedly: however, it is also rapidly consumed after cessation of seizures/exerise

Diagnosis

Serum Lactate (see Serum Lactate, [[Serum Lactate]])

  • Elevated: however, lactate values at the upper limit of normal range may be associated with increased mortality in critically ill patients (Crit Care, 2009) [MEDLINE]
    • Therefore, Lactate Values Increased from Baseline (But Not Outside the Reference Range) May Be Clinically Important
    • In Addition, Hyperlactatemia Does Not Always Indicate the Presence of Tissue Hypoxia
  • Peripheral Venous Lactate and Arterial Lactate Values are Equivalent

Serum Osmolal Gap (see Serum Osmolality, [[Serum Osmolality]])

  • While Usually Normal, an Elevated Osmolal Gap Has Been Reported in Some Cases of Lactic Acidosis (Ann Intern Med, 1990)[MEDLINE]
    • Typically Osmolal Gap in Lactic Acidosis: small osmolal gap (<15-20 mOsm/L)
    • However, the Presence of an Osmolal Gap Indicates Mandates that Other Potential Etiologies (Ethylene Glycol, etc) Be Ruled Out
  • Mechanisms Contributing to Development of the Osmolal Gap in Lactic Acidosis: the mechanism by which lactate contributes to an osmolal gap is not clear, since lactate is completely ionized at physiologic pH (lactic acid requires an accompanying sodium cation) and does not contribute directly to the osmolal gap
    • May Be Caused by Tissue Release of Smaller Glycogen Breakdown Products

Serum Anion Gap (see Serum Anion Gap, [[Serum Anion Gap]])

  • Anion Gap is Usually Elevated in Lactic Acidosis: AG is usually >20
    • However, a Normal Anion Gap Does Not Rule Out Lactic Acidosis: in one study, 50% of patients with a serum lactate 5-10 mmol/L had a normal anion gap (Crit Care Med 1990) [MEDLINE]

Delta Gap/Delta Bicarbonate Ratio

  • General Comments: in simple acid-base disturbances, there is a significant variability in the delta gap/delta bicarb ratio between patients [MEDLINE]
    • Recommendation: the delta gap/delta bicarb ratio should be used with caution in diagnosing a mixed acid-base disturbance in any individual patient
  • L-Lactic Acidosis -> Delta Anion Gap/Delta Bicarbonate Ratio is Typically Around 1.6 (see Lactic Acidosis, [[Lactic Acidosis]])
    • Mechanisms
      • Most of the Lactate Anions Which Enter the Extracellular Space Remain in that Space
      • Urinary Lactate Excretion is Decreased Due to Associated Renal Hypoperfusion/Dysfunction
      • Lactate Does Not Usually Enter the Intracellular Fluid Space
      • Over 50% of Hydrogen Ions are Buffered in the Cells and Bone (Even More So When the Acidosis is Severe): when hydrogen ions are buffered in cells/bone, the serum bicarbonate does not decrease -> therefore, anion gap increases more than the serum bicarbonate decreases
    • Clinical Time Course: since hydrogen ion buffering in cells and bone may take several hours to equilibrate, the ratio may initially be 1.1 and increase over time toward the ratio of 1.6
  • Exercise-Induced Lactic Acidosis -> Delta Anion Gap/Delta Bicarbonate Ratio Varies Based on Serum Lactate and pH (see Lactic Acidosis, [[Lactic Acidosis]])
    • Mechanism: may be due to better buffering by nonbicarbonate buffers (such as hemoglobin) at lower pH values
    • Clinical
      • Serum Lactate <15 mEq/L: delta gap/delta bicarb ratio is around 1
      • Serum Lactate >15 mEq/L (with pH <7/15): delta gap/delta bicarb ratio increases to >1
  • D-Lactic Acidosis -> Delta Anion Gap/Delta Bicarbonate Ratio is Typically Around 1 (or <1) (see Lactic Acidosis, [[Lactic Acidosis]])
    • Mechanism: proximal tubule sodium/L-lactate co-transporter is stereospecific and does not transport D-lactate -> therefore, filtered D-lactate is rapidly excreted in the urine
    • Clinical
      • Normal Renal Function: delta gap/delta bicarb ratio may be 0 (i.e. NAGMA) to <1 (i.e. mild AGMA)
      • Impaired Renal Function: delta gap/delta bicarb ratio is around 1 (i.e. typical AGMA)

Clinical Manifestations

Physiologic Effects of Acute Metabolic Acidosis

  • Blunted Response to Catecholamines (Nat Rev Nephrol, 2012) [MEDLINE]: due to acidemia
  • Cardiac Arrhythmias
  • Decreased Affinity of Hemoglobin for Oxygen with Increased Tissue Oxygen Delivery
  • Decreased Cardiac Contractility and Cardiac Output
  • Hypotension (see Hypotension, [[Hypotension]])
  • Decreased Tissue Oxygen Delivery
  • Decreased ATP Generation
  • Increased Apoptosis
  • Impaired Glucose Regulation
  • Impaired Immune Response
  • Impaired Phagocytosis
  • Increased Ionized Calcium: which may augment cardiac contractility
  • Peripheral Vasodilatation with Increased Blood Flow to Tissues
  • Stimulation of Inflammatory Mediators

Cardiovascular Manifestations

Gastrointestinal Manifestations

Renal Manifestations

Anion Gap Metabolic Acidosis (AGMA) (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]])

  • Associated Clinical Scenarios
    • Observed in L-Lactic Acidosis
    • Observed in D-Lactic Acidosis with Impaired Renal Function
  • Physiology: proximal tubule sodium/L-lactate co-transporter is stereospecific and does not transport D-lactate
    • Therefore, filtered D-lactic acid is rapidly excreted in the urine (assuming normal renal function)

Non-Anion Gap Metabolic Acidosis (NAGMA) (see Metabolic Acidosis-Normal Anion Gap, [[Metabolic Acidosis-Normal Anion Gap]])

  • Associated Clinical Scenarios
    • Observed in D-Lactic Acidosis with Normal Renal Function
  • Physiology: proximal tubule sodium/L-lactate co-transporter is stereospecific and does not transport D-lactate
    • Therefore, filtered D-lactic acid is rapidly excreted in the urine (assuming normal renal function)
  • Diagnosis
    • Delta Anion Gap/Delta Bicarbonate Ratio in D-Lactic Acidosis (see Lactic Acidosis, [[Lactic Acidosis]]): delta anion gap/delta bicarbonate ratio is around 1 (or <1)

Other Manifestations

  • Altered Mental Status/Encephalopathy
  • Hyperventilation
  • Severe Anemia (see Anemia, [[Anemia]])

Treatment

Supportive Care

Restoration of Tissue Perfusion

  • Intravenous Fluid Resuscitation: the optimal intravenous fluid to use for resuscitation in this setting is unclear
    • Normal Saline (see Normal Saline, [[Normal Saline]])
    • Lactated Ringers (see Lactated Ringers, [[Lactated Ringers]]): incremental increase in serum lactate is usually small in the absence of an abnormality in lactate clearance (Crit Care Med, 1997) [MEDLINE]
  • Vasopressors/Inotropes
    • Acidemia Blunts the Response to Catecholamines (Nat Rev Nephrol, 2012) [MEDLINE]
    • High Vasopressor Doses May Exacerbate Hyperlactatemia by Decreasing Tissue Perfusion or Overstimulating the β2-Adrenergic Receptor

Packed Red Blood Cells (PRBC) (see Packed Red Blood Cells, [[Packed Red Blood Cells]])

  • Indicated for Hemorrhage

Oxygen/Mechanical Ventilation (see Oxygen, [[Oxygen]] and General Ventilator Management, [[General Ventilator Management]]))

  • As Required

Specific Treatment of Underlying Disorder

  • Treatment of Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
  • Treatment of Sepsis (see Sepsis, [[Sepsis]])

Improvement of the Microcirculation

  • Some Studies Suggest that Vasoactive Agents Such as Dobutamine/Acetylcholine/Nitroglycerin May Improve Microvascular Perfusion Independently of Their Effects on Systemic Hemodynamics, Decrease Hyperlactatemia, and Even Improve Outcome

Sodium Bicarbonate (see Sodium Bicarbonate, [[Sodium Bicarbonate]])

  • Indications
    • pH <7.2: however, evidence for this is lacking
  • Adverse Effects
    • Hyperosmolality
    • Increased Net Lactic Acid Production: due to alkalinization (N Engl J Med, 1998) [MEDLINE]
    • Intracellular Acidification Due to the Accumulation of Carbon Dioxide: this may be more significant when large quantities of bicarbonate are administered quickly to patient with circulatory failure (impairing tissue clearance of carbon dioxide and pulmonary excretion of carbon dioxide)
    • pH-Dependent Decrease in Ionized Calcium Levels: ionized calcium levels modulate cardiac contractility
    • Sodium Load/Volume Overload

Hemodialysis (see Hemodialysis, [[Hemodialysis]])

  • Advantages: allows bicarbonate administration, but avoids a number of potential complications
    • Clearance of Lactate: although the quantity cleared is much lower than that being produced in the setting of severe lactic acidosis
    • Does Not Contribute to Volume Overload
    • Does Not Induce Hyperosmolality
    • May Allow Removal of Metformin: in relevant cases
    • Prevents a Decrease in Serum Calcium
  • Technique
    • Continuous Renal Replacement Therapy (CRRT)/Continuous Venovenous Hemodialysis (CVVHD) is Usually Preferred Over Intermittent Hemodialysis: due to delivery of bicarbonate at a lower rate and better hemodynamic tolerance
  • Adverse Effects
    • Increased Net Lactic Acid Production: due to alkalinization (N Engl J Med, 1998) [MEDLINE]

Other Unproven Therapies

  • THAM (Tris-Hydroxymethyl Aminomethane): available for clinical use
    • Advantages
      • Buffers Protons without Generating Carbon Dioxide
    • Disadavantages
      • Hyperkalemia/Hypercapnia/Liver Necrosis in Neonates
      • Requires Intact Renal Function or Hemodialysis
    • Administration: 0.3 M solution via central vein -> monitor pCO2 and serum potassium
  • Carbicarb: 1:1 mixture of sodium carbonate and sodium bicarbonate
    • Use: investigational
    • Advantages
      • Buffers Intracellular/Extracellular pH without Generating Significant Quantity of Carbon Dioxide
      • Preserves Cardiac Contactility in Animal Studies
  • Sodium–Hydrogen (Na+–H+) Exchanger (NHE1) Inhibitors
    • Use: investigational

Monitoring of Serum Lactate (see Serum Lactate, [[Serum Lactate]])

  • While Lactate-Guided Therapy Has Been Beneficial in Some Studies, the Use of Serum Lactate in this Setting Requires Further Study
    • One Study Demonstrated that a Decrease in Serum Lactate by 20% Every 2 hrs for the First 8 hrs was Associated with a Decrease in Morbidity/Mortality in ICU Patients (Am J Respir Crit Care Med, 2010) [MEDLINE]
  • Serial Lactate Measurements: q2-6 hrs has been suggested as an appropriate interval

References

  • Woods, Hubert Frank; Cohen, Robert (1976). Clinical and biochemical aspects of lactic acidosis. Oxford: Blackwell Scientific. ISBN 0-632-09460-5
  • Low sensitivity of the anion gap as a screen to detect hyperlactatemia in critically ill patients. Crit Care Med 1990;18:275-7 [MEDLINE]
  • Increased osmolal gap in alcoholic ketoacidosis and lactic acidosis. Ann Intern Med 1990;113:580-2 [MEDLINE]
  • Effect of intravenous lactated Ringer’s solution infusion on the circulating lactate concentration: Part 3. Results of a prospective, randomized, double-blind, placebo-controlled trial. Crit Care Med 1997;25:1851-4 [MEDLINE]
  • Protection of acid–base balance by pH regulation of acid production. N Engl J Med 1998;339: 819-26 [MEDLINE]
  • Don’t take vitals, take a lactate. Intensive Care Med 2007; 33:1863-5 [MEDLINE]
  • Occurrence and adverse effect on outcome of hyperlactatemia in the critically ill. Crit Care 2009;13:R90 [MEDLINE]
  • Emergency department lactate is associated with mortality in older adults admitted with and without infections. Acad Emerg Med 2010;17:260-8 [MEDLINE]
  • Systematic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology Jan 2010; 254:261-269 [MEDLINE]
  • Early lactate-guided therapy in intensive care unit patients: a multi-center, open-label, randomized controlled trial. Am J Respir Crit Care Med 2010;182: 752-61 [MEDLINE]
  • Treatment of acute metabolic acidosis: a pathophysiologic approach. Nat Rev Nephrol. 2012 Oct;8(10):589-601. doi: 10.1038/nrneph.2012.186. Epub 2012 Sep 4 [MEDLINE]
  • Lactic acidosis. N Engl J Med. 2014 Dec 11;371(24):2309-19. doi: 10.1056/NEJMra1309483 [MEDLINE]