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BANTAO Journal 2009; 7 (2): 44-46 BJ
Case Report

Lactic Acidosis due to Metformin Overdose. What treatment should be?
A Case Report and Review of the Literature.

Taner Basturk 1, Bedih Balkan 2, Mehmet Aytekin 2, Abdulkadır Unsal 3 and Aysın Alagol 2
1Departman of Nephrology, 2Anaesthesiology, Bagcılar Research and Education Hospıtal, Istanbul/Turkey. 3Departman of Nephrology Sıslı Etfal Research and Education Istanbul/Turkey
Abstract
This relatively noninvasive method is an effective treat- Background. Metformin is one of several oral biguani-
des that are used for the treatment of diabetes mellitus Keywords: metformin, lactic asidosis, bicarbonate treatment
Lactic acidosis in metformin use is awidely recognised ___________________________________________ with rare side effect. Patients with previously normal re- nal function and younger patients with no other comor- Introduction
bid conditions at all might develop metformin induced Metformin is an oral hypoglycemic drug that in the pre- Case presentation. A 25-year-old healthy woman in-
sence of insulin suppresses hepatic gluconeogenesis and gested 100 g of metformin in a suicide attempt. After 3 improves insulin’s action. Its association with lactic aci- hours; she, was admitted to hospital with nause, vomi- dosis is rare with an estimated incidence of 6.3 per ting, abdominal discomfort complaints. At admission, 100.000 patient years. Intentional metformin overdose is she was anxious and agitated, with following finding; also rare, especially metformin associated lactic acidosis Total Glasgow Coma Scale score of 15 out of 15, pulse in diabetic patients who have renal or hepatic insuffici- rate of 84 beats/min, blood pressure of 80/50 mmHg, ency. Most cases have been described in therpeutic use, and respiratory rate of 20breaths/min. Analysis of arte- and very few of them have been described in over dose. rial blood gases revealed a high anion gap, 16.2 mEq/L It is reported that overdose with metformin might result metabolic acidosis with pH 7.16, pCO2. 35.4 mm Hg, in lactic acidosis in healty patients, a condition that is pO2 of 119.5 mmHg on oxygen (2L/min), Lactate 6.55 associated with a high mortality of 50-80% [1,11]. Regarding the drug history, clinical and laboratory fin- Case report
dings, the patients was admited to intensive care unit (ICU) with the suspicion of metformin-associated lactic A 25-year-old healthy woman ingested 100 g (1.94 g/kg body weight) of metformin in a suicide attempt. After 3 The patient was treated on an emergency basis and rece- hours; she, was admitted to hospital with nause, vomi- ived fluid management, intravenous sodium bicarbonate ting, abdominal discomfort complaints. The patients had and activated charcoal, 100 g orally in first four hours no comorbid conditions (diabetes mellitus, renal dysfun- after admission, The patient follow-up, reversibl acut re- nal failure was developed (maximum creatinine: 1.66 At admission, she was anxious and agitated, with follo- mg/dl). The bicarbonate ampoules were added to 5% wing finding; Total Glasgow Coma Scale score of 15 dextrose, so, the patient’s glucose level was not low Ini- out of 15, pulse rate of 84 beats/min, blood pressure of tially, the decrease in bicarbonate level and pH, lactate 80/50 mmHg, and respiratory rate of 20 breaths/min. levels increased. After the treatment, acid-base balance Other clinical examinations unremarkable. Preliminary improved. Two days later, she was transfered to a gene- laboratory studies WBC: 14.560 mm3 Hb: 12.5g/dl, PLT: ral medical ward, ICU follow-up was not necessary. She 270.000 mm3, Na 142,mEq/L, K 4,35 meq/L, CI:115 mEq/ was discharged in good clinical condition 5 days Add- L, urea: 17 mg/dL, creatinine: 0.83 mg/dL, glucose: 110 mg/dL. Analysis of arterial blood gases (ABG) revealed Conclusion. High anion gap metabolic acidosis and in-
a high anion gap, 16.2 mEq/L (8 -16 mEq/L) metabolic creased serum lactate level in patients should be a rea- acidosis with pH 7.16 (7.35-7.45) pCO2. 35.4 mmHg son for metformin associated lactic acidosis suspicion. (35-45 mmHg), pO2 of 119.5 mmHg on oxygen (2L/min ) We present a case of successful management of metfor- (80-100 mmHg), Lactate 6.55mEq/L (0.44-2.22) and Bi- min-associated lactic acidosis, treated simply, with in- carbonate: 15.7 mEq/L (21-28 mEq/L). Liver function travenous sodium bicarbonate and intensive monitoring. ________________________ Correspondence to: Basturk Taner, Departman of Nephrplogy, Bagcılar Research and Education Hospıtal, 80650 Istanbul, Turkey; Phone: +902124404000; E-mail: [email protected] tests and amylase were within normal ranges, and keto- four hours after admission, Early hemodialysis was not nes we was not detected in either serum or urine. applied because of her renal function was not markedly Regarding the drug history, clinical and laboratory fin- impaired and a life-threatening metabolic acidosis, was dings, the patients was admited to intensive care unit (ICU) with the suspicion of metformin-associated lactic The patient follow-up, reversibl acut renal failure was developed (maximum creatinine: 1.66 mg/dl). The bi- The physician at the Poison Control Center was reco- carbonate ampoules were added to 5% dextrose, so, the mmended standart gastrointestinal decontamination, se- patient’s glucose level was not low Initially, the dec- rial ABG with aggressive correction of the metabolic rease in bicarbonate level and pH, lactate levels increa- acidosis with bicarbonat drip and consideration of early sed. After the treatment, acid-base balance improved. Two days later, she was transfered to a general medical The patient was treated on an emergency basis and rece- ward, ICU follow-up was not necessary. She was dis- ived fluid management, intravenous sodium bicarbonate charged in good clinical condition 5 days later (Table 1). (1 mEq/kg) and activated charcoal, 100 g orally in first Table 1. Arterial blood gases and creatinine results of patient
12.hours
Emergency
Second day
externed
1. Intensive care unit or in service hospitalizations of patients as a routine consent form is signed; 2. The patient does not want to write name, including shortening; 3. Permission for publication was taken from the patient
Discussion
on, lactic acidosis is predominantely due to a lack of lactate's clearance than to an increased production [3]. Metformin is one of several oral biguanides that are Lactic acidosis was defined according to the criteria of used for the treatment of diabetes mellitus. Biguanides Luft: arterial lactate>5 mmol/l and blood pH<7,35. Cli- act to lower serum glucose levels by inducing decre- nically, disorders of lactate metabolism have been divi- asing gastrointestinal absorption carbohydrates, inhibi- ded into either anaerobic (type A) or aerobic (type B). ting hepatic gluconeogenesis, and increasing cellular The hallmark of type A lactic acidosis is tissue hypoxia up take of glucose. Metformin is absorbed relatively resulting in anaerobic lactic acid production. The most quickly at the intestinal level, is not metabolized, and 90 common causes of type A lactic acidosis are cardiopul- % of the drug is eliminated by glomerulofiltration and monary arrest and other states characterized by impaired tubular secretion. Protein binding of metformin is negli- cardiac performance, reduced tissue perfusion, and arte- gible. The mean volume of distribution is 63 to 276 lit- rial hypoxemia. In type B lactic acidosis, on the other res. These two properties of metformin mean that ha- hand, it appears that tissue hypoxia is not present, and, emodialysis or haemofiltration can effectively remove instead, lactic acid production is enhanced metabolically metformin from serum. Its half life is around 6.5 hours for other reasons in an otherwise aerobic state. Exam- in patients with a normal renal function [2]. ples of type B lactic acidosis include diabetes mellitus, MALA is rare with an estimated incidence of 6.3 per certain malignancies, and congenital diseases of the li- 100,000 patients years, mostly in patients with predispo- ver that impair lactic acid metabolism. Of the two forms sing factors. Significant renal and hepatic disease, alco- of lactic acidosis, type A is by far the more important holism and conditions associated with hypoxia (eg. Car- diac and pulmonary disease, surgery) are contraindica- Signs and symptoms of biguanide-induced lactic acido- tions to the use of metformin. Other risk factors for met- sis are nonspecific and include anorexia, nausea, vomi- formin-induced lactic acidosis are sepsis, dehydration, ting, altered level of consciousness, hyperpnoea, abdo- minal pain and thirst. Hypotension, hypotermia, hypo- The physiopathology of MALA is complex and mostly glycemia and respiratory failure have been described [5]. unclear. However, this side effect seems to be closely Salpeter et al. reviewedall studies of metformin treat- related to the anti-hyperglycaemic effect of metformin. ment 1966 up to 2005.Their data revealed no cases of It is also known that metformin impairs lactate clearan- fatal or nonfatal lactic acidosis. Also,there was no diffe- ce of the liver through the inhibition of complex I of the rence in lactate levels between metformin and placebo or other treatment groups.They concluded that there is Although increased lactic acid production may be indu- no evidence that metformin is associated with an incre- ced by haemodynamic instability and/or tissue hypoxia ased risk of increased lactate levels or lactic acidosis. associated with severe metformin overdose or any un- Nevertheless, over the last years, several case reports derlying unstable cardiovascular or respiratory conditi- have been published on association between metformin and lactic acidosis [1]. In cases of metformin induced severe refractory lactic Here we present the case a woman, who attempted to acidosis, Early haemodialysis or hemodiafiltration sho- commit suicide by ingesting an 100g massive metfor- uld be considered to –correct acidosis and eliminate min overdose associated with lactic acidosis, in the ab- metformin.This approach is very effective and can be li- sence of other causes of lactic acidosis. The patients had fe saving [8,12]. But here we present a case of success- been suffering from gastrointestinal symptoms prior to ful management of metformin-associated lactic acidosis, admission. These symtoms could have been side effects treated simply, with intravenous sodium bicarbonate of metformin or first signs of a developing lactic and intensive monitoring. This relatively noninvasive method is an effective treatment option. However, he- The management of MALA is controversial. Treatment modialysis still has a valuable role in the management may include supportive care, activated charcoal, bicar- of acidosis which proves refractory to conservative bonate infusion, hemodialysis, or continuous venove- nous hemofiltration. Activated charcoal can absorb met- formin and prevent absorption by the intestines so it is Conflict of interest statement. None declared. recommended in treating metformin overdose. The ad- ministration of agents such as methylene blue and sodi- References
um dichloroacetate has gained attention, but their clini- cal significance and efficacy are controversial and have Salpeter SR, Greyber E, Pasternak GA, Salpeter Posthumous EE.Risk of fatal and nonfatal lactic acidosis Bicarbonate therapy for severe lactic acidosis remains a with metformin use in type 2 diabetes mellitus. controversial therapy. The most recent Surviving Sepsis Cochrane Database Syst Rev 2010; 20(1): CD002967. Guidelines of 2008 strongly recommend against the use Davidson MB, Peter AL. An overview of metformin in the treatment of type 2 diabetes me-llitus. of bicarbonate in patients with pH at least 7.15, while deferring judgment in more severe acidemia. Cooper et Cusi K, Consoli A, DeFronzo RA. Metabolic effects of al. Monitored fourteen patients who had metabolic aci- metforminon glucose and lactate meta-bolism in dosis (bicarbonate <17 mmol/L and base excess <-10) noninsulin-dependent diabetes mellitus. J Clin and increased arterial lactate (mean, 7.8 mmol/L), Each Endocrinol Metab 1996; 81: 4059-4067. patient sequentially received sodium bicarbonate (2 mmol/kg Luft D, Deichsel G, Schmülling RM, Stein W, body weight). Correction of acidemia using sodium bi- Eggstein M. Definition of clinically relevant lactic carbonate did not improve hemodynamics in critically ill acidosis in patients with internal disease. Am J Clin patients who had metabolic acidosis and increased blood Chang C, Chen YC, Fang JT, Huang CC. Metformin- asociated lactic acidosis:case reports and literature Hemodialysis has been shown to facilitate clearance of rewiew. J Nephrol 2000; 15: 398-402. lactate and ketones from the circulation in patients with Cooper DJ, Walley KR, Wiggs BR, Russell JA. biguanide-induced metabolic acidosis. However, the Bicarbonate Does Not Improve Hemodynamics in effectiveness of haemodialysis in the treatment of bigu- Critically III Patients Who Have Lactic Acidosis: A anideinduced lactic acidosis is a function of the quantity Prospective, Controlled Clinical Study. Ann Intern Med of biguanide that has been ingested. Multiple haemodi- alysis treatments may successfully remove the majority Lalau JD, Andrejak M, Morinière P, Coevoet B, of metformin and buformin from the tissues [7]. Ha- Debussche X, Westeel PF, Fournier A, Quichaud J. Hemodialysis in the treatment of lactic acidosis in emodialysis is appealing as it can buffer acidosis and diabetics treated by metformin. A study of metformin theoretically extract metformin from blood. Unfortuna- elimination. Int J Clin Pharmacol Ther Toxicol 1989; tely, this technique has not gained widespread acceptan- ce due to the lack of well-conducted studies. Indeed, on- Panzer U, Kluge S, Kreymann G, Wolf G. Combination ly case reports have dealt with this subject [8,9]. of intermittent haemodialysis and the high-volume Peters and et. systematically evaluated outcomes in continous haemofiltration for the treatment of severe MALA patients admitted to their intensive care unit. metformin-induced lactic acidosis. Nephrol Dial The mortality rate of patients who received dialysis was similar to that of patients who were not dialyzed. Ho- Heaney D, Majid A, Junor B. Bicarbonate haemodialysis as treatment of metformin overdose. wever, it was the more acutely and chronically ill pati- ents who actually received dialysis [10]. 10. Peters N, Jay N, Barraud D, Cravoisy A, Nace L, Bollaert PE, Gibot S. Metformin-associated lactic acidosis in an Conclusıon
intensive care unit. Crit Care 2009; 13(1): 110. 11. Khaled Al-khasawneh, Peter White, Jr. Lactıc Acıdosıs Secon- Metformin induced lactic acidosis may occur in patients dary to Metformin Overdose. Chest Suppl 2006; 130(4): 336. with previously normal renal function, a condition that 12. Alivanis P, Giannikouris I, Paliuras C, Arvanitis A, is a associated with a high mortality of 50-80% [11]. Volanaki M, Zervos A. Metformin - associated lactic High anion gap metabolic acidosis and increased serum acidosis treated with continuous renal replacement therapy. lactate level in patients should be a reason for metfor- min associated lactic acidosis suspicion.

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