for metabolic acidosis, and dextrose for hypoglycemia, he was referred to our hospital. The patient had been previously healthy and had no past medical history of diabetes mellitus or renal disease.

On admission to intensive care unit, his vital signs were as follows: blood pressure 110/70 mm Hg, heart rate 112 beats/min, respiratory rate 20/min, and body temperature

35.4?C. laboratory investigations disclosed the following: blood glucose level 142 mg/dL, serum sodium 148 mmol/L, potassium 4.4 mmol/L, urea 63 mg/dL, creatinine 2.7 mg/dL, pH 7.1, pCO₂ 11.3 mm Hg, bicarbonate 3.6 mmol/ L, and arterial lactate level 17.0 mmol/L. The anion gap, defined as [Na⁺]-{[Cl^-]+[HCO^-]}, was 32.4 mmol/L. The diagnosis of MALA with acute renal failure was made. Passive External rewarming therapy was started for hypothermia. A bicarbonate hemodialysis was initiated using a low-flux membrane for 4 hours. Despite efficient hemodialysis, arterial lactate level increased to 17.8 mmol/L with a pH of 7.27, and HCO3 6.1 mmol/L. Thus, a second session of hemodialysis with continuous bicarbonate application was performed for 10 hours with a high-flux membrane (Gambro, Arylane H6). After hemodialysis, his arterial lactate level was 8.0 mmol/L, pH 7.46, and bicarbonate 20.6 mmol/L. No further sessions of hemodi- alysis were needed, and his lactate level fell to 3.8 within

3

48 hours. The kidney function tests declined to normal

levels, and the patient was discharged with a Complete recovery in the fourth day of his hospitalization.

Lactic acidosis is defined as a metabolic acidosis with a blood pH less than 7.35 and a serum lactate concentration greater than 5 mmol/L. Two types of lactic acidosis have been described, including type A, which occurs secondary to tissue hypoxia in conditions such as sepsis or Cardiovascular collapse, and type B secondary to increased lactat production or decreased lactat clearance [4]. Metfor- min overdose is typically associated with type B lactic acidosis because the drug can interfere with both the production and clearance of lactic acid by several mecha- nisms [5]. Because the present case did not have any risk factors that may result in tissue hypoxia, we believe that our patient developed a pure type B lactic acidosis secondary to metformin overdose.

0735-6757/$ - see front matter (C) 2011

575.e4 Case Report

The current therapeutic approach of MALA includes normalization of the acid-base imbalance, acceleration of lactate metabolism, elimination of metformin, and treatment of concomitant diseases. Sodium bicarbonate infusion is commonly used to correct metabolic acidosis in MALA. However, the use of high-dose sodium bicarbonate infusion has critical disadvantages, including a left shift of the oxyhemoglobin dissociation curve, hipervolemia owing to excess sodium load, and worsening of intracellular acidosis [1,3]. Currently, instead of sodium bicarbonate infusion alone, hemodialysis with bicarbonate as the buffer is recommended to correct metabolic acidosis in severe MALA. This modality has the possibility of both removing metformin accumulated in the body and treating metabolic acidosis without the associated risk of intravenous sodium bicarbonate infusion [3]. In patients suffering from hemo- dynamic instability, continuous Venovenous hemofiltration is the preferred Treatment modality [6]. This modality is as effective as conventional hemodialysis because metformin dialysance has appeared satisfactory even in relatively low blood flow conditions [7]. The removal of metformin by hemodialysis is limited because of the large volume of distribution due to intracellular binding [8]. The drug accumulates much higher concentrations in the intestines and erythrocytes, which contributes to the prolonged production and continuing increase of Serum lactate levels [5,9]. The rebound increase in lactate production after a short session of hemodialysis may be partly explained by this mechanism [3,6]. To overcome this rebound phenomenon, duration of the hemodialysis sessions is extended to maximize metformin removal and provide sufficient bicar- bonate to effectively treat the accompanying lactic acidosis. During such a prolonged hemodialysis session, lactate production may initially exceed its elimination by hemodi- alysis; however, with a decreased lactate production rate, hemodialysis will be able to remove lactate more efficiently. Thus, hemodialysis or hemofiltration should be continued even if lactate levels increase during the treatment of MALA [9]. In the present case, we initially performed a conventional bicarbonate hemodialysis using a low-flux dialyser, which resulted in a rebound increase in lactate levels. Subsequently, a prolonged hemodialysis performed for 10 hours using a high-flux membrane contributed a significant decrease in lactate level at the end of the procedure. High-flux membranes contain large pores that allow for enhanced permeability of larger molecules. Thus, we preferred the high-flux membrane both to augment diffusive metformin removal and to transfer large amounts of bicarbonate from the dialysate to patient.

In conclusion, the present case demonstrated that metformin intoxication may lead to a life-threatening form of lactic acidosis even in younger individuals with no other comorbid conditions. Early and intensive support- ive care together with prolonged hemodialysis for treatment of metabolic acidosis is essential for the possibility of a good outcome.

Hadim Akoglu MD

Department of Nephrology Ankara Numune Research and Education Hospital 06100 Samanpazari, Ankara, Turkey

E-mail address: [email protected]

Belgin Akan MD Department of Anesthesiology and Reanimation Ankara Numune Research and Education Hospital 06100 Samanpazari, Ankara, Turkey

Serhan Piskinpasa MD

Department of Nephrology Ankara Numune Research and Education Hospital 06100 Samanpazari, Ankara, Turkey

Omer Karaca MD Department of Anesthesiology and Reanimation Ankara Numune Research and Education Hospital 06100 Samanpazari, Ankara, Turkey

Fatih Dede MD

Department of Nephrology Ankara Numune Research and Education Hospital 06100 Samanpazari, Ankara, Turkey

Deniz Erdem MD Mahinur Demet Albayrak MD

Department of Anesthesiology and Reanimation Ankara Numune Research and Education Hospital 06100 Samanpazari, Ankara, Turkey

Ali Riza Odabas MD

Department of Nephrology Ankara Numune Research and Education Hospital 06100 Samanpazari, Ankara, Turkey

doi:10.1016/j.ajem.2010.06.005

References

1. Seidowsky A, Nseir S, Houdret N, et al. Metformin-associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med 2009;37:2191-6.
2. Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care 1999;22:925-7.
3. Heaney D, Majid A, Junor B. Bicarbonate haemodialysis as a treatment of metformin overdose. Nephrol Dial Transpl 1997;12:1046-7.
4. Turkcuer I, Erdur B, Sari I, et al. Severe metformin intoxication treated with prolonged haemodialyses and plasma exchange. Eur J Emerg Med 2009;16:11-3.
5. Spiller HA, Quadrani DA. Toxic effects from metformin exposure. Ann

Pharmacother 2004;38:776-80.

1. Panzer U, Kluge S, Kreymann G, et al. Combination of intermittent haemodialysis and high-volume continuous haemofiltration for the treatment of severe metformin-induced lactic acidosis. Nephrol Dial Transpl 2004;19:2157-8.
2. Lalau JD, Andrejak M, Moriniere P, et al. Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin: a study of metformin elimination. Int J Clin Pharmacol Ther Toxicol 1989;27:285-8.

Case Report 575.e5

1. Guo PY, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metfor- min. Semin Dialysis 2006;19:80-3.
2. Lacher M, Hermanns-Clausen M, Haeffner K, et al. Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr 2005;164:362-5.