American Diabetes Association. Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019;42(Suppl 1):S1-S193.
Araszkiewicz A, Bandurska-Stankiewicz E, Budzyński A, et al. 2019 Guidelines on the management of diabetic patients. A position of Diabetes Poland. Clinical Diabetology. 2019;8(1):1-95. doi: 10.5603/DK.2019.0001.
International Hypoglycaemia Study Group. Glucose Concentrations of Less Than 3.0 mmol/L (54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2017 Jan;40(1):155-157. doi: 10.2337/dc16-2215. Epub 2016 Nov 21. Review. PubMed PMID: 27872155.
Moioli A, Maresca B, Manzione A, et al. Metformin associated lactic acidosis (MALA): clinical profiling and management. J Nephrol. 2016 Dec;29(6):783-789. Epub 2016 Jan 22. Review. PubMed PMID: 26800971.
Pasquel FJ, Klein R, Adigweme A, et al. Metformin-associated lactic acidosis. Am J Med Sci. 2015 Mar;349(3):263-7. doi: 10.1097/MAJ.0b013e3182a562b7. Review. PubMed PMID: 24326619.
Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014 Dec 11;371(24):2309-19. doi: 10.1056/NEJMra1309483. Review. PubMed PMID: 25494270.
Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013 May;36(5):1384-95. doi: 10.2337/dc12-2480. Epub 2013 Apr 15. PubMed PMID: 23589542; PubMed Central PMCID: PMC3631867.
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009 Jul;32(7):1335-43. doi: 10.2337/dc09-9032. Review. PubMed PMID: 19564476; PubMed Central PMCID: PMC2699725.
Definition, Etiology, PathogenesisTop
Lactic acidosis is a metabolic acidosis with a high anion gap characterized by serum lactate levels >5 mmol/L (4 mEq/L). It is caused by increased anaerobic glucose metabolism and consequent lactate accumulation in the bloodstream. Lactic acidosis is not a disease-specific complication of diabetes mellitus; it is triggered by precipitating factors and is most frequently and nonspecifically seen in patients with shock. Metformin-associated lactic acidosis is more specific to diabetes, with an estimated incidence of 4.3 cases per 100,000 person-years in patients treated with metformin. Lactic acidosis is less frequent than other complications in patients with diabetes that may lead to coma, but when present, the mortality rate may be as high as 50%. It develops more often in patients with type 2 diabetes, especially when associated with conditions that can precipitate drug accumulation (eg, renal insufficiency or failure) and/or decrease in lactate clearance (eg, liver impairment). In patients with type 1 diabetes, advanced microangiopathy (especially in patients with renal failure) can be a risk factor for lactic acidosis.
Types of lactic acidosis associated with diabetes:
1) Type A lactic acidosis (anaerobic) develops in the case of tissue hypoxia or hyperperfusion (sepsis, shock, heart failure, respiratory failure, and severe trauma).
2) Type B lactic acidosis (aerobic) is caused by factors other than hypoxia. In patients with diabetes mellitus, it accompanies severe complications of diabetes (eg, diabetic ketoacidosis [DKA]), renal failure, liver failure, and malignancy. Type B lactic acidosis is also caused by inappropriate use of metformin (a condition known as metformin-associated lactic acidosis [MALA]), precipitated by an imbalance between lactate production, drug accumulation, and lactate clearance (contraindications: Table 5.2-5). Ingestion of high doses of salicylates, methyl alcohol, ethyl alcohol, propylene glycol, and certain drugs like antiretroviral agents and propofol that impair oxidative phosphorylation can also cause type B lactic acidosis. Malignancy, high alcohol consumption, and HIV infection have also been associated with this kind of acidosis.
Clinical Features and DiagnosisTop
Symptoms include severe weakness, nausea, vomiting, and abdominal pain. Patients may have a history of ingestion of a toxic substance, alcohol, or treatment with metformin despite contraindications.
Signs include hyperpnea (Kussmaul respiration), altered mental status with hallucinations and coma, moderate dehydration, oliguria, hypothermia, hypotension, and shock.
Diagnosis is based on lactate levels ≥5 mmol/L (4 mEq/L), even in the absence of overt acidemia. Minor hyperglycemia (or sometimes normal glucose levels), serum lactate levels usually >7 mmol/L (increasing with deteriorating renal function and resulting in elevated mortality with higher levels), low blood pH <7.35, serum bicarbonate levels <10 mmol/L, anion gap >16 mEq/L, usually hyperkalemia (except in grand mal seizures, which present with normokalemia), and normal serum sodium levels (these may be low in patients abusing alcohol) are also typically found.
Measurement of metformin plasma concentration is important to confirm involvement of this drug in patients with suspected MALA. The mean plasma concentrations of metformin in healthy patients fluctuate between about 0.5 and 1 mg/L while fasting and 1 to 2 mg/L after a meal.
Differential diagnosis includes DKA (higher levels of glucose and ketone bodies without signs and symptoms of shock, lactate usually not as high), hyperglycemic hyperosmolar state (HHS) (significant hyperosmolality; serum lactate levels and blood pH within reference ranges), alcohol poisoning (no significant decrease in blood pH, normal blood glucose levels, no features of shock, serum lactate levels <5 mmol/L), other types of coma (hepatic, uremic), and other causes of shock.
1. Prevention and treatment of shock:
1) Use fluid resuscitation to increase intravascular volume as in DKA or HHS. Crystalloid and colloid solutions are both effective.
2) In patients with hypotension, IV administration of catecholamines may be ineffective (as in other instances of severe acidosis).
3) High doses of catecholamines can aggravate hyperlactatemia by reducing tissue perfusion or overstimulating beta2-adrenergic receptors; therefore, the dose should be adjusted carefully.
2. Improvement of blood oxygenation and treatment of hypoxia: Administer oxygen as needed. Invasive ventilation may also be required to prevent hypercapnia, particularly if acidemia persists or worsens (note that achieving levels of hyperventilation required to mimic spontaneous hyperventilation may be difficult or impossible).
3. Reduction of hyperglycemia:
1) Administer insulin infusion as in the treatment of HHS.
2) When blood glucose levels decrease <11.1 mmol/L (200 mg/dL), administer a 5% glucose (dextrose) infusion. Once blood glucose levels have normalized, administer a 10% glucose infusion and continue the insulin infusion.
4. Treatment of acidosis: Administer IV sodium bicarbonate (this remains a controversial intervention; it is usually done with a pH <7.2; associated with some benefits in other instances of lactic acidosis)Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Jaber S, Paugam C, Futier E, et al; BICAR-ICU Study Group. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet. 2018 Jul 7;392(10141):31-40. doi: 10.1016/S0140-6736(18)31080-8. Epub 2018 Jun 14. Erratum in: Lancet. 2018 Dec 8;392(10163):2440. PubMed PMID: 29910040. (see Metabolic Acidosis).
5. Hemodialysis: Renal replacement therapy may be needed.
6. Treatment of the underlying condition.
7. Measurement of the blood lactate level remains the cornerstone of monitoring for lactic acidosis. Lactate can be measured in arterial or venous blood. Although a single elevated blood lactate level often predicts an adverse outcome, sustained hyperlactatemia is associated with even worse prognoses. An interval of 2 to 6 hours has been suggested for repeat lactate measurements.
Consider risk factors. MALA develops when there is an imbalance between increased lactate production and impaired metabolism/reduced clearance. This is observed in individuals with poor renal function (reduced metformin clearance), impaired hepatic metabolism (reduced lactate clearance), and/or in the presence of increased lactate production (eg, sepsis, reduced tissue perfusion, anoxia). Other conditions that may increase the risk of lactic acidosis include severe dehydration, shock, alcohol use, and advanced age.