Severe Metformin Associated Lactic Acidosis: a Case Series of an Intensive Care Unit
Keywords:Metformin, Lactic acidosis, continuous renal replacement therapy
Background: Severe metformin-associated lactic acidosis (MALA) is a rare but potentially fatal side effect of metformin. The clinical presentation is often unspecific, thus hindering early recognition. We aimed to assess the prevalence of MALA in an intensive care unit (ICU) and describe the demographic and clinical characteristics according to patient outcome.
Methods: We conducted a 13-year single-center retrospective study, including all patients admitted in ICU with a high anion-gap metabolic acidosis and hyperlactatemia secondary to therapeutic use of metformin, after excluding other medical causes of acidosis.
Results: Twenty one patients were admitted in ICU due to severe MALA (less than 1% of all admissions) with an ICU mortality rate of 23.8% (N=5). The baseline clinical characteristics were similar in survivors and nonsurvivors, both with a high prevalence of cardiovascular comorbidities as well as frequent concomitant therapy with angiotensin-converting-enzyme inhibitors and diuretics. All patients were treated with continuous renal replacement therapy (CRRT) and other organ failure support. Normal acid-base balance was achieved in all survivors in the first 24 hours. At baseline, the clinical and laboratory features of nonsurvivors were undistinguishable from survivors.
Conclusions: Severe MALA is a rare cause of admission in the ICU. Although early institution of supportive therapy, MALA can progress to severe multiple-organ failure, especially when diagnosis and CRRT are delayed. Clinicians should suspect of MALA in all diabetic patients taking metformin with unexplained high anion-gap metabolic acidosis and hyperlactatemia.Â
Turner R. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854â€“865.
Peters N, Jay N, Barraud D, Cravoisy A, Nace L, Bollaert P-E, Gibot S. Metformin-associated lactic acidosis in an intensive care unit. Crit Care. 2008;12(6):R149.
Silvestre J, Carvalho S, Mendes V, Coelho L, Tapadinhas C, Ferreira P, Povoa P, Ceia F. Metformin-induced lactic acidosis: a case series. J Med Case Rep. 2007;1(1):126.
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(9):550â€“554.
Wollen N, Bailey CJ. Inhibition of hepatic gluconeogenesis by metformin. Synergism with insulin. Biochem Pharmacol. 1988;37(22):4353â€“4358.
Minot A, Dodd K, Saunders J. THE ACIDOSIS OF GUANIDINE INTOXICATION 1. J Clin Invest. 1934;13(6):917-932.
Almirall J, Briculle M, Gonzalez-Clemente J. Metformin-associated lactic acidosis in type 2 diabetes mellitus: incidence and presentation in common clinical practice. Nephrol Dial Transplant. 2008;23(7):2436â€“2438.
Protti A, Russo R, Tagliabue P, Vecchio S, Singer M, Rudiger A, Foti G, Rossi A, Mistraletti G, Gattinoni L. Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication. Crit Care. 2010;14(1):R22.
Misbin RI, Green L, Stadel B V., Gueriguian JL, Gubbi A, G. Alexander Fleming. Lactic Acidosis in Patients with Diabetes Treated with Metformin. N Engl J Med. 1998;338(4):265â€“266.
Lalau JD, Westeel PF, Debussche X, Dkissi H, Tolani M, Coevoet B, Temperville B, Fournier A, Quichaud J. Bicarbonate haemodialysis: an adequate treatment for lactic acidosis in diabetics treated by metformin. Intensive Care Med. 1987;13(6):383â€“387.
Salpeter SR, Greyber E, Th, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Arch Intern Med. 2003;163(21):2594.
Lalau JD, Race JM. Metformin and lactic acidosis in diabetic humans. Diabetes, Obes Metab. 2000;2(3):131â€“137.
Lalau J, Mourlhon C, Bergeret A, Lacroix C. Consequences of metformin intoxication. Diabetes Care. 1998;21(11):2036â€“2037.
Florez H, Luo J, Castillo-Florez S, Mitsi G, Hanna J, Tamariz L, Palacio A, Nagendran S, Hagan M. Impact of metformin-induced gastrointestinal symptoms on quality of life and adherence in patients with type 2 diabetes. Postgrad Med. 2010;122(2):112â€“120.
Gudmundsdottir H, Aksnes H, Heldal K, Krogh A, Froyshov S, Rudberg N, Os I. Metformin and antihypertensive therapy with drugs blocking the renin angiotensin system, a cause of concern? Clin Nephrol. 2006;66(11):380â€“385.
Pertek J, Vidal S, Mariot J, Galy-Flocâ€™h M, Azoulay E. Acidose lactique toxique Ã la metformine provoquÃ©e par une insuffisance rÃ©nale aiguÃ«. Ann Fr Anesth Reanim. 2003;22(5):457â€“460.
Sabatini S, Kurtzman NA. Bicarbonate therapy in severe metabolic acidosis. J Am Soc Nephrol. 2009;20(4):692â€“695.
Jagia M, Taqi S, Hanafi M. Metformin poisoning: A complex presentation. Indian J Anaesth. 2011;55(2):190â€“192.
Lam N, Sekhon G, House AA. Metformin-Associated Lactic Acidosis following Intentional Overdose Successfully Treated with Tris-Hydroxymethyl Aminomethane and Renal Replacement Therapy. Case Reports in Nephrology. 2012;2012:1â€“5.
Cooper DJ, Walley KR, Wiggs BR, Russell JA. Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study. Ann Intern Med. 1990;112(7):492â€“498.
Schoolwerth AC, Kaneko TM, Sedlacek M, Block CA, Remillard BD. Acid-base disturbances in the intensive care unit: Metabolic acidosis. Seminars in Dialysis. 2006;19(6):492â€“495.
Finkle SN. Should dialysis be offered in all cases of metformin-associated lactic acidosis? Crit care. 2009;13(1):110.
Wooten EW. Calculation of physiological acid-base parameters in multicompartment systems with application to human blood. J Appl Physiol. 2003;95(6):2333â€“2344.
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