Lactic Acidosis


Cohen-Woods Classification of Lactic Acidosis

Type A Lactic Acidosis

  • Type A Lactic Acidosis is Due to Decreased Perfusion or Oxygenation

Type B Lactic Acidosis

  • Type B Lactic Acidosis is Not Due to Decreased Systemic Perfusion
    • General Comments
      • However, Type B Lactic Acidosis May Be Due to Toxin-Mediated Impairment of Cellular Metabolism and/or Regional Tissue Ischemia)
    • Type B1 Lactic Acidosis: due to underlying diseases
      • However, These Disorders May Cause Type A Lactic Acidosis in Some Cases
    • Type B2 Lactic Acidosis: due to medication or intoxication
    • Type B3 Lactic Acidosis: 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
  • Mechanisms by Which Tumors Produce Acidosis
    • Decreased Lactate Clearance (in the Setting of Severe Liver Metastases)
    • Increased Glycolytic Activity of the Tumor (Warburg Effect)
      • Otto Warburg (a German Physiologist) First Demonstrated that Cancer Cells Can Metabolize Glucose into Lactate Even Under Normoxic Conditions (“Aerobic Glycolysis”) in 1920 [LINK]
      • This Capability Enables Cancer Cells to Divert Their Biosynthetic Machinery to Utilize Glucose (Via Upregulation of Key Glucose Transporters and Hexokinases) and Enhance the Synthesis of New Cancer Cells
      • “Warburg Phenotype” Can Be Switched On/Off, Depending on the Microenvironment Supply of Oxygen (Sci Rep, 2014) [MEDLINE]
      • The Glycolytic/Warburg Pathway Consumes Glucose and Produces Higher Levels of Lactate than the Normal Oxidative Process (J Clin Invest, 2013) [MEDLINE]
        • The Glycolytic/Warburg Phenotype Inefficiently Produces ATP, with the Generation of Only 2 ATP Molecules, as Opposed to the Generation of 36 ATP Molecules During the Normal Oxidative Process, Resulting in Excessive Lactate and Hydrogen Ion Production
        • The Resulting Local Hypoxia and Acidosis Promotes Expression of Survival Genes (Hypoxia-Inducible Factor-1α, HIF1α and Others), Invasion, Enhanced Metastatic Potential, Clonal Evolution and Radio-Resistance
    • Tumor Tissue Hypoxia
  • Treatment
    • Bicarbonate Administration May Undesirably Increase Lactate Production

Tumors

  • Leukemia
  • Lymphoma (see Lymphoma)
    • Non-Hodgkin’s Lymphoma
    • Burkitt’s Lymphoma
      • First Reported Case of Burkitt Lymphoma Associated with Hypoglycemia and Lactic Acidosis (Leuk Lymphoma, 2005) [MEDLINE]
        • Increased Lactate Production by the Tumor was the Likely Mechanism (Achieving a Peak Lactate of 15.8 mmol/L)
        • Absence of Liver Involvement in This Patient Suggested that the Decreased Lactate Clearance was Not a Contributing Mechanism
  • Multiple Myeloma
    • Multiple Myeloma Cases with Hypoglycemia and Lactic Acidosis Have Been Reported (EJHaem, 2021) [MEDLINE]
  • Solid Tumors
    • Pheochromocytoma (see Pheochromocytoma) (BMJ Case Rep, 2020) [MEDLINE]
      • Epidemiology
        • Rarely, Lactic Acidosis is the Presenting Feature of Pheochromocytoma
      • Physiology
        • Decreased Oxygen Delivery to Tissues
        • Epinephrine-Induced β2-Adrenergic Receptor Stimulation with Increased Lactate Production
    • Prostate Cancer (Metastatic) (see Prostate Cancer) (BMJ Case Rep, 2020) [MEDLINE]
    • Small Cell Carcinoma of the Liver (BMJ Case Rep, 2020) [MEDLINE]

Tumor Lysis Syndrome (see Tumor Lysis Syndrome)

  • Physiology
    • Due to Tumor Cell Death

Shock States with Impaired Oxygen Delivery to Tissues

Abdominal Compartment Syndrome (see Abdominal Compartment Syndrome)

  • Physiology
    • Hepatic Ability to Remove Lactic Acid is Impaired by an Increase in Intra-Abdominal Pressure by as Little as 10 mm Hg (Gastroenterology, 1993)[MEDLINE] (J Trauma, 1998) [MEDLINE]
      • This Occurs Even in the Presence of a Normal Cardiac Output and Normal Mean Arterial Blood Pressure
  • Clinical
    • In This Setting, Lactic Acidosis May Clear More Slowly than Expected, Despite Adequate Resuscitation

Acute Limb Ischemia (see Acute Limb Ischemia and Extremity Compartment Syndrome)

  • Physiology
    • Regional Tissue Hypoperfusion with Increased Lactate Production

Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism)

  • Physiology
    • Obstructive Shock-Associated Decreased Oxygen Delivery to Tissues
  • Clinical
    • Study of Serum Venous Lactate in the Prediction of In-Hospital Adverse Outcomes in Normotensive Acute Pulmonary Embolism (Eur J Intern Med, 2021) [MEDLINE]
      • An Optimized Venous Lactate Cutoff Value of 3.3 mmol/L Predicted Both In-Hospital Adverse Outcome (Odds Ratio 11.0; 95% CI 4.6-26.3) and All-Cause Mortality (Odds Ratio 3.8; 95%CI 1.3-11.3)
      • The Established Cutoff Value for Arterial Lactate (2.0 mmol/L) and the Upper Limit of Normal for Venous Lactate (2.3 mmol/l) Had Lower Prognostic Value for Adverse Outcomes (Odds Ratio 3.6; 95% CI 1.5-8.7 and Odds Ratio 5.7; 95% CI 2.4-13.6, Respectively) and Did Not Predict Mortality
      • If Added to the 2019 European Society of Cardiology Algorithm, Venous Lactate <2.3 mmol/L was Associated with a High Negative Predictive Value (0.99 [95% CI 0.97-1.00]) for Adverse Outcomes in Intermediate-Low Risk Patients, Whereas Lactate Levels ≥3.3 mmol/L Predicted Adverse Outcomes in the Intermediate-High Risk Group (Odds Ratio 5.2; 95% CI 1.8-15.0)

Anaphylaxis (see Anaphylaxis)

  • Physiology
    • Distributive Shock-Associated Decreased Oxygen Delivery to Tissues
    • Epinephrine-Induced β2-Adrenergic Receptor Stimulation

Asthma Exacerbation (see Asthma)

  • Multiple Potential Mechanisms
    • Due to Increased Work of Breathing, Resulting in Increased Lactate Production (Chest, 2014) [MEDLINE]
      • Likely Results in Type A Lactic Acidosis
    • Due to Hypoxemia (Respir Care, 2012) [MEDLINE]
      • Likely Results in Type A Lactic Acidosis
    • Due to Pulsus Paradoxus and Auto-PEEP, Resulting in a Decrease in Venous Return to the Right Side of the Heart and a Consequent Decrease in Cardiac Output (Respir Care, 2012) [MEDLINE]
      • Likely Results in Type A Lactic Acidosis
    • Due to Use of β2-Adrenergic Receptor Agonists (see β2-Adrenergic Receptor Agonists) (Chest, 2014) [MEDLINE]
      • Likely Results in Type B Lactic Acidosis
    • Due to Respiratory Alkalosis During Asthma Exacerbation Which Stimulates Phosphofructokinase (Rate-Limiting Step in Glycolysis), Enhancing Glycolysis, Increasing Pyruvate, and Increasing Lactate Production (at Least in Animal Studies) (Respir Care, 2012) [MEDLINE]
      • In Humans, This Likely Only Occurs with Extreme Alkalosis (pH >7.6 and pCO2 <20 mm Hg)
      • Likely Results in Type B Lactic Acidosis

Congestive Heart Failure (CHF)/Cardiogenic Shock (see Congestive Heart Failure and Cardiogenic Shock)

  • Epidemiology
    • Cardiogenic Shock is a Common Etiology of Lactic Acidosis
  • Physiology
    • Cardiogenic Shock-AssociatedDecreased Oxygen Delivery to Tissues
      • Note that Oxygen Delivery is a Function of Hemoglobin (“Number of Boxcars”), Oxygen Saturation (“How Full the Boxcars are”), and Cardiac Output (“How Fast the Train is Moving”)
    • Epinephrine-Induced β2-Adrenergic Receptor Stimulation

Hemorrhagic Shock (see Hemorrhagic Shock)

  • Epidemiology
    • Hemorrhagic Shock is a Common Etiology of Lactic Acidosis
  • Physiology
    • Hemorrhagic Shock-Associated Decreased Oxygen Delivery to Tissues
    • Epinephrine-Induced β2-Adrenergic Receptor Stimulation

Hypovolemic Shock (see Hypovolemic Shock)

  • Epidemiology
    • Hypovolemic Shock is a Common Etiology of Lactic Acidosis
  • Physiology
    • Hypovolemia-Associated Decreased Oxygen Delivery to Tissues
    • Epinephrine-Induced β2-Adrenergic Receptor Stimulation

Hypoxemia (see Hypoxemia)

  • Epidemiology
    • Hypoxemia is a Common Etiology of Lactic Acidosis (Especially in the Setting of Decreased Cardiac Output, Where Oxygen Delivery is Even Further Impaired)
  • Physiology
    • Decreased Oxygen Delivery to Tissues
      • Note that Oxygen Delivery is a Function of Hemoglobin (“Number of Boxcars”), Oxygen Saturation (“How Full the Boxcars are”), and Cardiac Output (“How Fast the Train is Moving”)

Intestinal Ischemia/Infarction (see Acute Mesenteric Ischemia)

  • Physiology
    • Regional Tissue Hypoperfusion with Increased Lactate Production

Sepsis (see Sepsis)

  • Epidemiology
    • Sepsis is a 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 Anemia (Hb <5 g/dL) (see Anemia)

  • Physiology
    • Decreased Oxygen Delivery to Tissues
      • Note that Oxygen Delivery is a Function of Hemoglobin (“Number of Boxcars”), Oxygen Saturation (“How Full the Boxcars are”), and Cardiac Output (“How Fast the Train is Moving”)

Severe Trauma

  • Epidemiology
    • Severe Trauma is a Common Etiology of Lactic Acidosis
  • Physiology
    • Hypovolemia/Hemorrhagic Shock-Associated Decreased Oxygen Delivery to Tissues

Liver Disease

Cirrhosis/End-Stage Liver Disease (see Cirrhosis)

  • Physiology
    • Decreased Hepatic Lactate Clearance
  • Clinical
    • Lactate is Usually Only Mildly Elevated

Acute Liver Failure (see Acute Liver Failure)

  • Physiology
    • Decreased Hepatic Lactate Clearance
    • Increased Hepatic Lactate Production
  • Clinical
    • Lactate Levels are Usually More Significantly Elevated in Acute Liver Failure 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)

  • Physiology
    • D-Lactic Acid Production by Enteric Microbes

Drugs

β2-Adrenergic Receptor Agonists (see β2-Adrenergic Receptor Agonists)

  • Epidemiology
    • β2-Agonist-Associated Lactic Acidosis is Most Commonly Observed in the Setting of High-Dose β2-Agonist Administration in the Treatment of Acute Asthma Exacerbation or During Use as Tocolytic for Preterm Labor (see Asthma)
  • Physiology
    • Stimulation of Aerobic Glycolysis with Increased Lactate Production
  • Clinical

Catecholamines

  • Agents
  • Physiology
    • Increased Glycolysis and Pyruvate Production
    • Increased Lipolysis with Resultant Inhibition of Pyruvate Dehydrogenase: this prevents pyruvate from going through the Krebs cycle, resulting in pyruvate reduction to lactate

Isoniazid (INH) (see Isoniazid)

  • Epidemiology
    • Cases Have Been Reported (Most in the Setting of Overdose) (Chest, 1971) [MEDLINE] (Am J Emerg Med, 1987) [MEDLINE] (BMC Res Notes, 2017) [MEDLINE]

Linezolid (Zyvox) (see Linezolid)

  • Epidemiology
    • Cases Have Been Reported Both Soon After the Initiation of Linezolid and After Prolonged Linezolid Courses (Nat Rev Nephrol, 2010) [MEDLINE] (Mitochondrion, 2011) [MEDLINE]
  • Pharmacology
    • Linezolid is an Oxazolidinone Antibiotic Which Inhibits a Subunit of Bacterial Ribosomes, Impairing Bacterial Protein Synthesis
      • It Can Also Affect Human Mitochondrial Ribosomes and Protein Synthesis
  • Physiology
    • Due to Impairment of Mitochondrial Function

Metformin (Glucophage) (see Metformin): biguanide anti-hyperglycemic

  • Epidemiology
    • There are Approximately 9 Cases of Lactic Acidosis Per 100,000 Person-Years of Metformin Exposure (Compared to 40-64 Lactic Acidosis Cases Per 100,000 Person-Years of Phenformin Exposure) (see Phenformin)
    • Systematic Reviews Suggest that the Incidence of Metformin-Induced Lactic Acidosis is Very Low (Cochrane Database Syst Rev, 2010) [MEDLINE]: however, it is not clear from the trial data as to how many patients had contraindications to metformin use (such as significant chronic kidney disease)
  • Risk Factors
    • Administration of Intravenous Iodinated Contrast (see Radiographic Contrast)
    • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease)
      • Lactic Acidosis Usually Occurs in the Setting of Baseline Chronic Kidney Disease (Although it May Occur in Patients with Normal Renal and Hepatic Function in the Setting of an Overdose)
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure)
    • Dehydration
    • Hypoxemia (see Hypoxemia)
    • Maternally-Inherited Diabetes and Deafness (MIDD) Syndrome
    • Sepsis (see Sepsis)
  • Mechanisms
    • Metformin is a Biguanide Anti-Hyperglycemic
    • In the Setting of Renal Failure, Excess Lactate Cannot Be Adequately Cleared by the Kidneys
      • Metformin-Induced Lactic Acidosis Usually Occurs in the Setting of High Plasma Metformin Levels
    • Metformin Inhibits Mitochondrial Respiratory Chain Complex 1, Impairing Hepatic Gluconeogenesis from Lactate, Pyruvate, and Alanine
      • This Results in Additional Lactate and Substrate for Lactate Production
    • Metformin Promotes the Conversion of Glucose to Lactate in the Small Intestinal Splanchnic Bed
  • Diagnosis
    • Lactate Levels are Usually <2 mmol/L (But May Be Higher in Patients with Other Risk Factors for Lactic Acidosis)
  • Treatment
    • Bicarbonate Hemodialysis Can Correct the Acidosis and Remove Metformin
  • Prognosis
    • Metformin-Induced Lactic Acidosis has a High Case-Fatality Rate (Approximately 45%)
    • Neither Arterial Lactate Nor Plasma Metformin Concentrations Predict Mortality

Nucleoside Reverse Transcriptase Inhibitors (see Nucleoside Reverse Transcriptase Inhibitors)

  • Epidemiology
    • Severe Lactic Acidosis is Uncommon in the Absence of Other Precipitating Factors
  • Agents
  • Physiology
    • Drug-Induced Mitochondrial Dysfunction (Type B Lactic Acidosis)

Phenformin (see Phenformin)

  • Epidemiology
    • Phenformin is a More Common Cause of Lactic Acidosis than Metformin
    • Most Commonly Occurs in the Setting of Renal Failure
      • Biguanide Accumulates and Inhibits Oxidative Phosphorylation
  • Physiology
    • Phenformin is a Biguanide Anti-Hyperglycemic
    • Impairment of Oxidative Phosphorylation

Propofol Infusion Syndrome (see Propofol)

  • Epidemiology
    • Associated with Prolonged High-Dose Propofol Infusion (Anaesthesia, 2007) [MEDLINE]
  • Physiology
    • Impairment of Oxidative Phosphorylation

Salicylate Intoxication (see Salicylates)

  • Physiology
    • Impairment of Oxidative Phosphorylation
  • Clinical
    • Hyperlactatemia is Usually Minimal

Toxins

Carboxyhemoglobinemia (Carbon Monoxide Intoxication) (see Carboxyhemoglobinemia)

  • Physiology
    • Decreased Oxygen Delivery to Tissues
    • Impairment of Oxidative Phosphorylation

Cocaine Intoxication (see 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)
  • Clinical
    • Marked Hyperlactatemia May Be Seen in Patients Having Seizures or Who are Restrained

Cyanide Intoxication (see Cyanide)

  • Epidemiology
    • Cyanide Ingestion
    • Smoke Inhalation of Vapors Derived from Thermal Decomposition of Nitrogen-Containing Materials (Polyurethane, Silk, Wool)
  • Physiology
    • Impairment of Oxidative Phosphorylation
  • Clinical
    • Hyperlactatemia is an Important Clinical Manifestation

Diethylene Glycol Intoxication (see Diethylene Glycol)

  • Physiology
    • Impairment of Oxidative Phosphorylation

Ethylene Glycol Intoxication (see Ethylene Glycol)

  • Physiology
    • Impairment of Oxidative Phosphorylation
  • Diagnosis
    • In Addition to Lactic Acidosis, a Pseudolactic Acidosis May Also Be Present in the Setting of Ethylene Glycol Intoxication Because the Ethylene Glycol Metabolite Glycolate (Which is Structurally Similar to Lactate) is Measured as Lactate in Several Quantitative Lactate Assays

Hydrogen Sulfide Gas Inhalation (see Hydrogen Sulfide Gas)

  • Physiology
    • Impairment of Cytochrome Oxidase and Cellular Respiration
      • Hydrogen Sulfide Gas is a Cytotoxic Asphyxiant

Kombucha (see Kombucha)

  • Epidemiology
    • Case Report Occurring in Association with Acute Renal Failure and Hyperthermia

Large Fructose Loads

  • Epidemiology
    • Cases of Lactic Acidosis Associated with Large Fructose Loads Have Been Reported (Lancet, 1971) [MEDLINE]

Methamphetamine Intoxication (see Methamphetamine)

  • Physiology
    • Due to Epinephrine-Induced β2-Adrenergic Receptor Stimulation
    • Due to Muscle Contractions/Seizures

Methemoglobinemia (see Methemoglobinemia)

  • Epidemiology
    • Lactic Acidosis May Occur in Cases of Acquired Methemoglobinemia (J Pediatr, 1982) [MEDLINE]
  • Physiology
    • Oxidation of Iron in Hemoglobin from the Ferrous (Fe2+) to the Ferric (Fe3+) State
      • Ferric Hemes of Methemoglobin are Unable to Bind Oxygen and Therefore, Result in a “Functional Anemia” with Decreased Oxygen Delivery to Tissues
      • Left-Shifting of the Hemoglobin Dissociation Curve (see Hypoxemia)
        • While the Ferric Heme is Unable to Bind Oxygen, the Remaining Three Ferrous Hemes in the Hemoglobin Tetramer Have Increased Avidity for Oxygen, Resulting in Impaired Oxygen Unloading at the Tissues (Exacerbating Tissue Hypoxia)

Methanol Intoxication (see Methanol)

  • Physiology
    • Impairment of Oxidative Phosphorylation

Propylene Glycol Intoxication (see 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)

  • Physiology
    • Mechanism of Lactic Acidosis is Unclear
      • May Involve Hypovolemia
  • Diagnosis
    • Elevated D-Lactate Levels Have Been Detected in Some Cases (Clin Chim Acta, 2011) [MEDLINE]
      • D-Lactate is Derived from Methylglyoxal, a Metabolite of Both Acetone and Dihydroxyacetone Phosphate (Which are Intermediates Which Accumulate in Diabetic Ketoacidosis)
    • Hyperlactatemia Has Also Been Reported in Diabetes Mellitus Independent of Diabetic Ketoacidosis, Possibly Due to Decreased Activity of Pyruvate Dehydrogenase (Clin Endocrinol-Oxf, 2011) [MEDLINE]
  • Clinical
    • Presence of Coexistent Lactic Acidosis Increases the Mortality Rate in Diabetic Ketoacidosis

Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) (see Human Immunodeficiency Virus)

  • Physiology
    • Unclear Mechanism

Hypoglycemia (see Hypoglycemia)

  • Physiology
    • Unclear Mechanism

Malaria (see Malaria)

  • Mechanisms
    • Decreased Hepatic/Renal Lactate Clearance
    • Hypovolemia (see Hypovolemic Shock)
    • Increased Anaerobic Glycolysis (Due to Parasite Impairment of Micro-Circulatory Flow)
    • Lactate Production by Parasite

Seizures (see Seizures)

  • Epidemiology
    • Post-Ictal Lactic Acidosis is Common
  • Physiology
    • Increased Oxygen Consumption
    • Altered Redox State Favoring Pyruvate Conversion to Lactate
  • Clinical
    • Acidemia and Hyperlactatemia are Usually Transient
    • Normokalemia is Usually Present

Shivering

  • Physiology
    • Increased Oxygen Consumption
    • Altered Redox State Favoring Pyruvate Conversion to Lactate
  • Clinical
    • Acidemia and Hyperlactatemia are Usually Transient

Strenuous Exercise

  • Physiology
    • Increased Oxygen Consumption
    • Altered Redox State Favoring Pyruvate Conversion to Lactate
  • Clinical
    • Acidemia and Hyperlactatemia are Usually Transient
    • Lactic Acidosis Can Impair Exercise Performance

Thiamine Deficiency (Vitamin B1 Deficiency) (see Thiamine Deficiency)

  • Epidemiology
    • Lactic Acidosis in the Setting of Thiamine Deficiency is Most Common with the Administration of Chronic Total Parenteral Nutrition or in Patients 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)

Technique

  • Measurement of Arterial vs Venous Lactate
    • Agreement Between Arterial and Venous Lactate is Poor at Abnormal Values, But if the Venous Lactate is Normal, the Arterial Lactate is Generally Also Normal (Eur J Emerg Med, 2014) [MEDLINE]
    • Venous Lactate is Approximately 0.25 mmol/L Higher Than the Arterial Lactate (95% Confidence Interval: 0.15-0.35) (Eur J Emerg Med, 2014) [MEDLINE]

Interpretation

  • Hyperlactatemia
    • Normal Serum Lactate: 0.5-2.2 mmol/L (4.5-19.8 mg/dL)
    • However, Serum 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 Still Inside the Reference Range) May Be Clinically Important
    • In Addition, Hyperlactatemia Does Not Always Indicate the Presence of Tissue Hypoxia

Serum Osmolal Gap (see Serum Osmolality)

Physiology

  • 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

Interpretation

  • While Usually Normal, an Elevated Osmolal Gap Has Been Reported in Some Cases of Lactic Acidosis (Ann Intern Med, 1990) [MEDLINE]
    • If Present, Osmolal Gap is Typically Small in Lactic Acidosis (<15-20 mOsm/L)
    • However, the Presence of an Osmolal Gap Mandates that Other Potential Etiologies (Ethylene Glycol, etc) of Acidosis Be Excluded

Serum Anion Gap (see Serum Anion Gap)

Interpretation

  • Anion Gap is Usually Elevated in Lactic Acidosis (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
    • Calculation of the Delta Gap (Amount of Increase in the Anion Gap Above Normal) and the Delta Bicarbonate (Decrease in the Serum Bicarbonate Below Normal) Has Been Classically Used to Determine the Presence of a Mixed Acid-Base Disturbance (i.e. if a Metabolic Acidosis is an Isolated Anion Gap Metabolic Acidosis or Not)
      • For Example, a Decrease in Serum Bicarbonate Greater than the Increase in Anion Gap Has Been Classically Interpreted to Represent a Concomitant Non-Anion Gap Metabolic Acidosis (One Which is Further Decreasing the Serum Bicarbonate)
      • For Example, a Decrease in Serum Bicarbonate Less than the Increase in Anion Gap Has Been Classically Interpreted to Represent a Concomitant Metabolic Alkalosis (One Which is Increasing the Serum Bicarbonate)
    • However, in Simple Acid-Base Disturbances, There is Significant Variability in the Delta Gap/Delta Bicarb Ratio Between Patients (Am J Med, 1986) [MEDLINE]
    • For this Reason, the Delta Gap/Gelta Bicarb Ratio Should Be Used with Caution in Diagnosing a Mixed Acid-Base Disturbance in Any Individual Patient
  • In L-Lactic Acidosis, the Delta Anion Gap/Delta Bicarbonate Ratio is Typically Around 1.6
    • 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
  • In Exercise-Induced Lactic Acidosis, the Delta Anion Gap/Delta Bicarbonate Ratio Varies Based on Serum Lactate and pH
    • 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
  • In D-Lactic Acidosis, the Delta Anion Gap/Delta Bicarbonate Ratio is Typically Around 1 (or <1)
    • Mechanism
      • Proximal Tubule Sodium/L-Lactate Co-Transporter is Stereospecific and Does Not Transport D-Lactate, Resulting in Filtered D-Lactate Being 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)
  • 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)

  • 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)

  • 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): delta anion gap/delta bicarbonate ratio is around 1 (or <1)

Other Manifestations


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)
    • Lactated Ringers *(LR) (see 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)

  • Indicated for Hemorrhage

Oxygen/Mechanical Ventilation (see Oxygen and Mechanical Ventilation-General )

  • As Required

Specific Treatment of Underlying Disorder

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)

  • Indications: pH <7.1
    • While Evidence for This Recommendation is Lacking, the Recommendation is Made Due to the Fact that at pH <7.1, Small Changes in pCO2 and Serum Bicarbonate Result in Large Changes in the Serum pH
  • Clinical Efficacy
    • Neither of the Following Trials Demonstrated Clinical Benefit of Bicarbonate Administration in Patients with pH >7.1
    • Trial of Sodium Bicarbonate in Critically Ill Patients with Lactic Acidosis (Ann Intern Med, 1990) [MEDLINE]
      • Sodium Bicarbonate Did Not Improve Hemodynamics in Critically Ill Patients with Metabolic Acidosis and Hyperlactatemia
      • Sodium Bicarbonate Did Not Increase the Cardiovascular Response to Infused Catecholamines in in Critically Ill Patients with Metabolic Acidosis and Hyperlactatemia
      • Sodium Bicarbonate Decreased Plasma Ionized Calcium and Increased the pCO2
    • Trial of Sodium Bicarbonate in Lactic Acidosis (Crit Care Med, 1991) [MEDLINE]
      • Administration of sodium bicarbonate did not improve hemodynamic variables in patients with lactic acidosis, but did not worsen tissue oxygenation
  • Potential Adverse Effects
    • Extracellular Volume Expansion
      • Single 50 mL Ampule of Sodium Bicarbonate (Containing 50 mEq of Sodium Bicarbonate) Expands the Extracellular Fluid Volume by Approximately 250 mL
    • Hypercapnia (see Hypercapnia)
      • Due to Formation of Carbon Dioxide from Bicarbonate
      • Results in Free Diffusion of Carbon Dioxide Across the Cell Membrane, Resulting in Paradoxical Intracellular Acidification*: 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
    • Hypernatremia (see Hypernatremia)
      • Single 50 mL Ampule of Sodium Bicarbonate (Containing 50 mEq of Sodium Bicarbonate) Increases the Serum Sodium of a 70 kg Patient Approximately 1 mEq/L
    • Hyperosmolality (see Increased Serum Osmolality)
      • Sodium Bicarbonate is a Hypertonic Solution
    • Increased Net Lactic Acid Production
      • Acidosis Normally Inhibits Phosphofructokinase, Inhibiting Glycolysis and Resulting in Decreased Lactate Formation
      • Alkalinization Due to Bicarb Administration May Actually Allow Glycolysis to Continue, Increasing the Formation of Lactate (NEJM, 1998) [MEDLINE]
    • Increased Tissue Capillary pCO2
    • Leftward Shift of the Hemoglobin-Oxygen Dissociation Curve (see Hypoxemia)
      • Alkalosis Results in a Leftward Shift of the Hemoglobin-Oxygen Dissociation Curve, Increasing Hemoglobin Affinity for Oxygen and Decreasing Oxygen Delivery to Tissues
    • pH-Dependent Decrease in Ionized Calcium (see Hypocalcemia)
      • Results in Decreased Myocardial Contractility
    • Sodium Load/Volume Overload
      • Single 50 mL Ampule of Sodium Bicarbonate (Containing 50 mEq of Sodium Bicarbonate) Expands the Extracellular Fluid Volume by Approximately 250 mL

Hemodialysis (see 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)

  • 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

General

Etiology

Acute Pulmonary Embolism (see Acute Pulmonary Embolism)

Abdominal Compartment Syndrome (see Abdominal Compartment Syndrome)

β2-Adrenergic Receptor Agonists (see β2-Adrenergic Receptor Agonists)

Diabetes Mellitus (see Diabetes Mellitus)

Isoniazid (see Isoniazid)

Linezolid (see Linezolid)

Metformin (see Metformin)

Methemoglobinemia (see Methemoglobinemia)

Neoplasm

Propofol (see Propofol)

Other

Treatment