Dialysis therapy for lactic acidosis caused by metformin intoxication: presentation of two cases

Abstract

Metformin is an oral antidiabetic, which is frequently used in the treatment of type II diabetes mellitus. Serious side effects may be seen during the administration of high doses of metformin. Two cases of lactic acidosis due to ingestion of high dose metformin for suicidal purposes have been presented here; in both cases, clinical improvement was seen with bicarbonate hemodialysis.

Introduction

Metformin is an oral antidiabetic, which is frequently used in the treatment of type II diabetes mellitus. ¹ It acts by decreasing gluconeogenesis in the liver and absorbtion of glucose from the gastrointestinal system, in addition to increasing the peripheral utilization of glucose. ² Metformin is excreted unchanged through the renal route. It is recommended that the therapeutic dose should not exceed 2500 mg/day. Serious side effects may be seen during the administration more than 5000 mg doses. ³ Among these, the most serious adverse effect is lactic acidosis, which is especially seen in individuals with liver and renal insufficiency. ⁴ Two cases of lactic acidosis due to ingestion of high dose metformin for suicidal purposes have been presented here; in both cases, clinical improvement was seen with bicarbonate hemodialysis.

Case 1: A 17-year-old male patient presented to emergency department of our hospital following ingestion of 80 metformin 1000 mg tablets in a suicide attempt. Emergency treatment was provided in another hospital. A nasogastric catheter was inserted and gastric lavage was performed, in addition to activated charcoal treatment. The initial evaluation of the patient upon referral to our hospital revealed a state of confusion; laboratory evaluation findings were as follows: blood glucose level 90 mg/dl, urea: 31 mg/dL, creatinine: 1.2 mg/dL, sodium: 136 mmol/L, potassium: 4.6 mmol/L, chloride: 99 mmol/L and blood gases; pH: 7.29, HCO₃: 14.6 mmol/L and lactate: 11.5 mmol/L. The anion gap, defined as [(Na⁺) + (K⁺)] − [(Cl⁻) + (HCO₃⁻)] was 27 mmol/L. An emergency dialysis was planned for the patient based on the severe lactic acidosis and confusion due to ingestion of metformin. A femoral catheter was inserted and bicarbonate hemodialysis treatment was administered for 4 hours using a dialysis filter high-flux. (In the Fresenius 4008B machine, flow rate of dialysate: 500 ml/min, blood flow: 300 mL/min and Fresenius F7 1.7 m² dialyzer was used.) During the dialysis, the blood glucose level (between 75 and 100 mg/dL) was monitored due to the risk of hypoglycemia. In total, 800 cc of 20% dextrose fluid was administered to protect from hypoglycemia.

Case 2: A 34-year-old female patient ingested 50 metformin 1000 mg and 10 sertralin 50 mg tablets with the intention of suicide. The patient was admitted to our emergency department approximately 1 hour after ingesting the drugs. The general medical condition of patient was moderate; she was conscious, cooperative and orientated. Gastric lavage was performed following the insertion of a nasogastric catheter and activated charcoal treatment was initiated.

Laboratory findings were as follows: blood glucose level: 87 mg/dl, urea: 28 mg/dl, creatinine: 0.9 mg/dL, sodium: 131 mmol/L, potassium: 4.2 mmol/L, chloride: 101 mmol/L and blood gases; pH: 7.26, HCO₃: 16.2 mmol/L and lactate: 4.2 mmol/L. The anion gap was 18 mmol/L. For this patient who had ingested metformin at fatal dose and who had presented with lactic acidosis, it was decided that the patient should undergo emergency hemodialysis. A jugular catheter was inserted and hemodialysis with bicarbonate through a high flux dialysis filter was performed for 4 hours with same dialyser and machine as for other patient. Due to the risk of hypoglycemia during dialysis, 2000 cc of 10% dextrose solution was administered. Blood glucose levels (between 70 and 95 mg/dL) were monitored during and after the dialysis.

After dialysis lactate levels were 7 and 2.6 mmol/L, respectively. Lactate levels returned to normal values and no further dialysis treatment was required. Hydration therapy, mostly with dextrose solutions, was administered. Blood gases and glucose levels were monitored four times daily. Improvement in the vital and laboratory findings were observed in the follow-up visits.

The patients were discharged from the hospital upon improvement of the clinical condition and psychiatric outpatient follow-up and control were recommended.

Discussion

Metformin is an oral antidiabetic which is frequently used as a first-step agent together with life style changes. ⁵ Lactic acidosis is defined as a blood pH less than 7.35 and a serum lactate more than 2 mmol/L. Two types of lactic acidosis, type A and type B, have been described. Type B is secondary to increased lactate production or decreased lactate clearance. ⁶ Metformin 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 mechanisms. ⁷

In lactic acidosis associated with metformin, non-specific symptoms like mild somnolence, anorexia, nausea, vomiting and abdominal pain may be observed, in addition to serious symptoms like hypotension, hypothermia, respiratory failure and cardiac arrhythmia. ⁸ Metformin-associated lactic acidosis is strictly a dose-dependent phenomenon, but there are other host predispositions that remain unknown. ⁹

The most appropriate method for this purpose is hemodialysis. Besides, since metformin binds to proteins, though with a low rate, plasmapheresis used in certain intoxication cases may also be beneficial. ¹⁰ In spite of the fact that sodium bicarbonate infusion is unsatisfactory in reversing the acidosis seen in metformin overdose, it may also cause serious side effects, such as left shift of the oxyhemoglobin dissociation curve, hipervolemia owing to excess sodium load and worsening of intracellular acidosis. ¹¹

For these patients, no data related to definite duration of dialysis is available. In two cases presented previously, hemodialysis therapy was administered for 21 and 30 hours. ¹² In our cases, hemodialysis for 4 hours was found to be sufficient. The rebound increase in lactate production after a short session of hemodialysis may be partly explained by this mechanism. ⁶ In our case, the shorter dialysis' period was thought to be related early dialysis by using high-flux membrane.

In conclusion, hemodialysis is an effective and life-saving method in treatment of metformin intoxications.