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
TumorTissue Hypoxia
Treatment
Bicarbonate Administration May Undesirably Increase Lactate Production
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
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)
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]
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)
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”)
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”)
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
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
Increased Lipolysis with Resultant Inhibition of Pyruvate Dehydrogenase: this prevents pyruvate from going through the Krebs cycle, resulting in pyruvate reduction to lactate
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)
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)
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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]
Lactic acidosis. N Engl J Med. 2014 Dec 11;371(24):2309-19. doi: 10.1056/NEJMra1309483 [MEDLINE]
Physiological approach to assessment of acid-base disturbances. N Engl J Med. 2014 Oct 9;371(15):1434-45. doi: 10.1056/NEJMra1003327 [MEDLINE]
The role of venous blood gas in the emergency department: a systematic review and meta-analysis. Eur J Emerg Med. 2014 Apr;21(2):81-8. doi: 10.1097/MEJ.0b013e32836437cf [MEDLINE]
Comprehensive review on lactate metabolism in human health. Mitochondrion. 2014 Jul;17:76-100. doi: 10.1016/j.mito.2014.05.007 [MEDLINE]
A paradoxical effect of bronchodilators. Chest. 1997 Jun;111(6):1766-7 [MEDLINE]
Lactic acidosis in asthma: report of two cases and review of the literature. Can Respir J. 2002 May-Jun;9(3):203-8 [MEDLINE]
Elevated plasma lactate level associated with high dose inhaled albuterol therapy in acute severe asthma. Emerg Med J. 2005 Jun;22(6):404-8 [MEDLINE]
An under-recognized complication of treatment of acute severe asthma. Am J Emerg Med. 2008 May;26(4):514.e1-3. doi: 10.1016/j.ajem.2007.07.035 [MEDLINE]
Take my breath away: a case of lactic acidosis in an asthma exacerbation. CJEM. 2011 Jul;13(4):284-8 [MEDLINE]
Can albuterol be blamed for lactic acidosis? Respir Care. 2012 Dec;57(12):2115-8. doi: 10.4187/respcare.01810 [MEDLINE]
Inhaled β-agonist therapy and respiratory muscle fatigue as under-recognised causes of lactic acidosis. BMJ Case Rep. 2013 Oct 14;2013. pii: bcr2013201015. doi: 10.1136/bcr-2013-201015 [MEDLINE]
Albuterol administration is commonly associated with increases in serum lactate in patients with asthma treated for acute exacerbation of asthma. Chest. 2014 Jan;145(1):53-9 [MEDLINE]
Conundrum in an asthma exacerbation. BMJ Case Rep. 2016 May 10;2016. pii: bcr2016214360. doi: 10.1136/bcr-2016-214360 [MEDLINE]
Isoniazid toxicity: reports of lactic acidosis and keratitis. Chest. 1971 Mar;59(3):245-8. doi: 10.1378/chest.59.3.245 [MEDLINE]
Profound acidosis caused by isoniazid ingestion. Am J Emerg Med. 1987 Mar;5(2):165-6. doi: 10.1016/0735-6757(87)90098-2 [MEDLINE]
Oral pyridoxine can substitute for intravenous pyridoxine in managing patients with severe poisoning with isoniazid and rifampicin fixed dose combination tablets: a case report. BMC Res Notes. 2017 Aug 8;10(1):370. doi: 10.1186/s13104-017-2678-6 [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]
Transient methemoglobinemia with acidosis in infants. J Pediatr. 1982;100(3):415 [MEDLINE]
Neoplasm
Burkitt’s lymphoma presenting with lactic acidosis and hypoglycemia – a case presentation. Leuk Lymphoma. 2005 Feb;46(2):281-3. doi: 10.1080/10428190400016723 [MEDLINE]
Targeting lactate metabolism for cancer therapeutics. J Clin Invest 2013; 123: 3685-92 [MEDLINE]
Beyond Warburg effect – dual metabolic nature of cancer cells. Sci Rep 2014; 4: 4927 [MEDLINE]
The Warburg Effect and the Hallmarks of Cancer. Anticancer Agents Med Chem. 2017;17(2):164-170. doi: 10.2174/1871520616666161031143301 [MEDLINE]
Type B lactic acidosis: a rare oncological emergency. BMJ Case Rep. 2020 Mar 31;13(3):e233068. doi: 10.1136/bcr-2019-233068 [MEDLINE]
Lactic acidosis and hypoglycemia as markers of disease progression of multiple myeloma: A case report. EJHaem. 2021 May 5;2(3):539-544. doi: 10.1002/jha2.176. eCollection 2021 Aug [MEDLINE]
Effects of fructose infusion on lactate and uric acid metabolism. Lancet. 1971 Feb 20;1(7695):366-9 [MEDLINE]
Treatment
Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis: a prospective, controlled clinical study. Ann Intern Med 1990, 112:492-498 [MEDLINE]
Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study. Crit Care Med 1991, 19:1352-1356 [MEDLINE]
Bicarbonate therapy in severe metabolic acidosis. J Am Soc Nephrol. 2009;20:692-695 [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]
