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Metformin Associated Lactic Acidosis and of glucose (increased production of lactate) in the
Iodinated Contrast Media
intestinal wall and decreased conversion of lactate Definition
Usage of metformin in NIDDM patients does not Metformin associated lactic acidosis is referred to cause MALA. However, if these patients have the development of lactic acidosis due to the use of concomitant illness such as acute cardiorespiratory metformin in patients with type II diabetes mellitus1,2. dysfunction, sepsis, renal dysfunction, or liver failure, these will increase the risk of developing Epidemiology
Metformin associated lactic acidosis (MALA) is rare but once it has developed, it could result in Contrast Medium Nephrotoxicity
severe consequences. Research was conducted in Contrast medium nephrotoxicity (CMN) is Saskatchewan, Canada, on the incidence of MALA. defined as an acute decline in renal function after Data between 1980 and 1995 was collected and administration of ICM11. Reduction in renal function analyzed. The results indicated the incidence of usually occurs within 72 hours post ICM injection12. MALA is approximate 9 cases per 100,000 person- Iodinated contrast media has demonstrated years (adding number of days of each prescription) several mechanisms that cause renal tubular epithelial cell toxicity and renal medullary ischemia that result in decreasing renal function11. ICM Pathophysiology
Metformin associated lactic acidosis can occur in vasoconstrictors such as endothelin and adenosine patients with normal renal function. It can also result and reduces the release of vasodilators such as after diagnostic examinations or procedures with nitric oxide and prostacyclin12. The imbalance of parenteral injection of radiographic iodinated contrast vasoconstrictors and vasodilators causes decreases in renal blood flow, which leads to a decrease in renal function. ICM also activates the oxygen free Metformin
radicals and damages the renal tubules. Most CMN The two major groups of oral hypoglycemic are self-limiting and resolve within 1 – 2 weeks, agents are sulphonylureas such as glyburide and however, permanent renal damages have also been biguanides such as metformin and buformin4. Metformin is the first line oral antihyperglycemic agent for patients with non-insulin dependent Metformin associated Lactic Acidosis Resulted
diabetes mellitus (NIDDM or type II DM)1,3. It is called from the use of Iodinated Contrast Media
an antihyperglycemic agent as it does not stimulate Metformin is not nephrotoxic and does not the production of insulin and will not cause interact with iodinate contrast media5. However, if hypoglycemia5. Metformin is hydrophilic and not CMN occurs, metformin excretion will be decreased. bound with plasma protein; it is mainly absorbed in Excessive accumulation of metformin may result in the small intestine. Metformin is not metabolized in metformin associated lactate acidosis13. The risk of the body and is excreted unchanged via the renal MALA is very low (0.005%), however, mortality rate Prevention measures of MALA post ICM injection gluconeogenesis in liver, decreasing intestinal include intravascular volume expansion. Some glucose absorption, increasing insulin sensitivity, researchers suggest intravenous infusion of NaCl promoting peripheral cellular glucose uptake, and 0.9% 100mL/h starting 4 hours before the procedure increasing glucose oxidation1,7. Plasma half-life of with ICM and continuing with the infusion for 24 metformin is about 2-5 hours for patients with normal hours post procedure12 if not contraindicated. Avoid renal function8. Metformin blocks the conversion of concomitant uses of nephrotoxic medications14. lactate in liver, which can result in lactate Acetylcysteine is an antioxidant that inhibits production of hydrogen peroxide in renal epithelial Metformin associated lactic acidosis could be the cells11. Use of acetylcysteine as prophylaxis for combined result of increased anaerobic metabolism patient with decreased renal function is also suggested12. Diagnostic test
Reference
Metformin associated lactic acidosis is a high Tonolini, M. (2012). Iodine-based radiographic contrast medium anion gap metabolic acidosis15. Arterial blood gas may precipitate metformin-associated lactate acidosis in diabetic patients. A case report, literature review and practice approach. results with pH < 7.35 and serum lactate > Clinical Therapeutics, 163, 59-62. 5.0mmol/L with no other causes can be diagnosed Vecchio, S., & Protti, A. (2011). Metformin-induced lactic acidosis: No one left behind. Critical Care, 15, 107. Stang, M.R., Wysowski, D.K., & Butler-Jones, D. (1999).
Treatment Options
Incidence of lactic acidosis in metformin users. Diabetes Care, 22, 925-927. The goals of treatments for MALA include earlier recognition of the problem, supportive care, correct antihyperglycaemic agents in patients with renal insufficiency. acid-base imbalance, volume expansion, and Clinical Pharmacokinetics, 31, 111-119. Rasuli, P., & Hammond, I. (1998). Metformin and contrast elimination of metformin by hemodialysis or media: Where is the conflict? Canadian Association of continuous hemofiltration1,9. Using bicarbonate to Radiologists Journal, 49, 161-166. correct acidosis should be used with caution Graham, G.G., Punt, J., Arora, M., Day, R.O., Doogue, M.P., Duong, J.K., Furlong, T.J., Greenfield!, J.R., Greenup, L.C., because of its side effects such as excessive sodium Kirkpatrick, C.M., Ray, J.E., Timmins, P., & and Williams, K.M. (2011). Clinical Pharmacokinetics of Metformin. Clinical Hemodialysis or continuous hemofiltration has demonstrated good effects in metformin and lactic Di Grande, A., Vancheri, F., Gisustolisi, V., Giuffrida, C., Narbone, G., Licata, M., Le Moli, C., Riccobene, S., Burgio, A., Bartolotta, S., Nigro, F., & Cannone, V. (2008). Metformin- induced lactic acidosis in a type 2 diabetic patient with acute Nursing Implication
renal failure. Clinical Therapeutics, 159, 87-89. It is important to assess the patients’ renal Laforest, C., Saint-Marcoux, F., Amiel, J-B., Pichon, N., & function before any diagnostic tests that involve Merle, L. (2013). Monitoring of metformin-induced lactic acidosis in a diabetic patient with acute kidney failure and effect injection of ICM. If the patient’s renal function is of hemodialysis. International Journal of Clinical Pharmacology compromised, the physician should be notified before the procedure. Many health care institutions have Lalau, J.D. (2010). Lactic acidosis induced by metformin: Incidence, management and prevention. Drug Safety, 33, 727- developed policies for pre-diagnostic test screening, which include assessing the patient’s renal function. 10) Safadi, R., Dranitzki-Ethalel, M., Popovtzer, M., & Ben-Yehuda, Monitor for any signs of lactic acidosis such as A. (1996). Metformin-induced lactic acidosis associated with tachycardia, hypotension, stupor, and coma5 post acute renal failure. American Journal of Nephrology, 16, 520-522. 11) Tepel, M., & Zidek, W. (2001). Acetylcysteine for radiocontrast Monitor for any signs of allergic reaction from the nephropathy. Current Opinion in Critical Care, 7, 390-392. ICM such as flushing, nausea and vomiting, pruritus, 12) Morcos, S.K., & Thomsen, H.S. (2001). Adverse reactions to iodinated contrasr media. European Radiology, 11, 1267-1275. headache, and urticaria. In severe cases, patients 13) Goergen, S.K., Rumbold, G., Compton, G., & Harris, C. (2010). may develop hypotension and bronchospasm12. Systemic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology, 254, 261-269. suggested metformin should be held 48 hours before 14) Jain, V., Sharma, D., Prabbaker, H., & Dash, H.H. (2007). and 48 hours after a patient’s angiogram or any tests Metformin associated lactic acidosis following contrast media- required ICM. However, in emergency situations, if induced nephrotoxicity. European Journal of Anaesthesiology, the diagnostic test with ICM is required, metformin 15) Silvestre, J., Carvalho, S., Mendes, V., Coelho, L., Tapadinhas, should be held 48 hours after the test1. The patient C., Ferrerira, P., Povoa, P., & Ceia, F. (2007). Metformin- should receive alternate medication such as insulin to induced lactic acidosis: A case series. Journal of Medical Case control their blood sugar during the time metformin is http://www.jmedicalcasereports.com/content/1/1/126 on hold. If renal function is normal at 48 hours, Currently, there is no consensus from the international guidelines about withholding metformin before and/or after the administration of ICM13. However, diabetes patients who take metformin can develop MALA even if they have normal renal function post administration of ICM14. Individual institutions should develop their own policy and guideline carefully to avoid the occurrence of CMN Disclaimer: The author of this article neither represents nor guarantees that
the practices described herein, if followed, ensure safe and effective patient
care. The author further assumes no responsibility or liability in connection with any information or recommendations contained in this article. The recommendations and instructions in this article are based on the knowledge and practice in neuroscience as of the date of publication. These Pharmacy Clinical Practice Leader, Critical Care, South recommendation and instructions are subject to change based on the availability of new scientific information. Iodinated Contrast Medium
Intra-renal Vasoconstriction
Intra-renal vasodilation
Metformin
Renal Blood Flow
Decrease
Metformin

Renal Hypoxia
excretion
Oxygen Free Radicals
Lactic
Acidosis

Contrast Medium Nephrotoxicity
Diagram Showing the Interaction of Iodinated Contrast Medium and Metformin

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