Case Discussion <Brief History> A 66-year-old woman had been diagnosed as Type 2 Diabetes for 20 years and treated with regularly insulin and metformin (500mg tid). Poor renal function was noted during outpatient clinic (OPD) follow-up (BUN /Cr: 43.6/5.93 mg/dl). Two weeks prior to the admission, she complained of poor appetite, but she still kept taking the OHA. One episode of syncope occurred about one week prior to the admission, and hypoglycemia was suspected by her family. On the day of admission, she complained of general weakness, persistent nausea and then she was sent an emergency room. <Physical Examination> Physical examination revealed an obese but well-developed woman in acute distress. Her consciousness was drowsy, heart rate was 92 bpm, temperature was 36.9 ℃, blood pressure was 160/76 mmHg, and respiration rate was 30/min. Kussmaul’s respiration pattern was noted. Breath sounds were clear. There was no other remarkable finding in heart, abdomen, and extremities. No focal neurological deficit was found. <Laboratory and Image Study> 1. CBC/DC: Date WBC K/μL RBC M/μL Hgb g/dL  Hct % MCV fL  Plt K/μL 930421 16.69 3.12 8.8 29.3 93.9 246 930422 20.34 2.89 8.1 26.3 91 282 2. Biochemistry Date BUN mg/dl Cre mg/dl Na mmol/l K mmol/l Cl mmol/l Ca mmol/l P mmol/l  Mg mmol/l 930421 74 6.86 140 6.33 99.0 2.1  2.9 0.89 930422 95.2 8.77 139 6.7 97 2.2 3.0 0.88   GOT U/l T -Bil mg/dl LDH U/l CRP mg/dl Lactic acid meq/l Sugar g/dl 930421 20 0.25 958 >12 12 150 930422 21 0.3 1037 >12 14 210 3. Urine analysis: Date Appearance Sp. gr pH Protein mg/dL Glu g/dL Ketones O.B Urobil EU/dL Bil 930421 Y;T 1.020 6.0 >300 2+ － － 0.1 － Date  Nitrite  RBC /HPF WBC /HPF EpithCell /HPF Cast /LPF Crystal Bact 930421 － 3-5 5-10 2 － － － 4. Arterial blood gas analysis: PH PCO2 mmHg PO2 mmHg HCO3 mEq/l  BaseExcess mEq/l 930421 7.224 19.7 72.0 8.2  -16.9 930422 7.25 23.1 137.1 9.7 -16.1 No obstructive uropathy was found by renal sonography. <Course and Treatment> After emergency room, high anion-gap metabolic acidosis was noted. Metformin associated lactic acidosis was suspected. Under the clinical condition of acute on chronic renal failure, severe lactic acidosis and hyperkalemia; emergent hemodialysis was arranged promptly. However, her blood pressure dropped during the dialysis session and that cursed her a loss consciousness. Immediate CPR with ventilator support was done, and she was transferred to ICU for further care. During ICU, severe lactic acidosis persisted and continuous veno-venous hemofiltration (CVVH) was used for relieving refractory metabolic acidosis. However, the lactic acidosis was poor controlled and unstable hemodynamic status developed even under strong inotropic agents. The patient passed away 5 days after admission due to refractory hemodynamic instability and metabolic acidosis. <Analysis> Lactic acidosis is a common clinical condition which can be divided into type A and type B. Type A lactic acidosis results from tissue underperfusion and/or hypoxia, such like in cardiogenic shock, hemorrhagic shock, acute hypoxia, CO intoxication and severe anemia. However, type B lactic acidosis develops in clinical condition without hypotension and hypoxia, like hereditary enzyme deficiency (G6PD), drug, toxin, some systemic diseases such as liver failure, malignancy. Drugs which were reported to induce lactic acidosis include penformin, metformin, INH and salicylate. The most flagrant drug is metformin. Clinically, both types could appear simultaneously. All tissue can metabolize glucose to lactate under certain condition, and the balance of glucose to lactate depends on the Cori cycle. When lactate > 20 meq/L (or 12 in different literature) hints higher mortality. Treatment was aimed to correct underlying disease. Metformin is a kind of biguanides with bioavailbility around 50~60%. The plasma half time is 1.5 to 4.9 hour. Kidney is the predominant organ responsible for excretion. The absolute and relative contradication for metformin is at Table 1. Metformin associated lactic acidosis (MALA) belongs to type B lactic acidosis which has an incidence around 1~9/100000 person-year (0.03%) and near 50% of mortality. Metformin increase intestinal lactate production & contributes to the hyperlactatemia seen in patients with renal or hepatic failure. The predisposing factors to MALA are renal dysfunction, liver disease, advanced cardiopulmonary disorder, surgery and intravenous contrast medium. MALA has non-specific symptoms as malaise, somnolence, abdominal discomfort, respiratory distress, ventricular fibrillation and asystole. Plasma metformin concentration correlates with the severity of MALA (> 5 ug/ml is generally seen in MALA). Treatment for MALA is supportive care mainly. Hemodialysis is recommended in refractory acidosis with impaired renal function. Bicarbonate is controversial for which may induce paradoxical intracellular acidosis, and there is no evidence of decline in mortality. Table 1. Absolute Contraindication & Precautionary Condition for Prescribing Metformin Absolute Contraindication Precautionary Conditions Renal disease or renal dysfunction(Cr > 1.5 mg/ml (Male), > 1.4 (Female)) Age > 80 y/o (unless CCr is not reduced) Congestive heart failure requiring pharmacological treatment Clinical or Lab evidence of hepatic disease Acute or chronic metabolic acidosis Concomitant cationic drug use Metformin use should be discontinued at a procedure requiring IV iodinated contrast material, for at least 48 hr after the procedure, and until renal function is deemed normal Presence of any condition associated with hypoxemia (COPD, sepsis, AMI, dehydration) Excessive alcohol intake After any surgery until oral intake is resumed and renal function is deemed normal <Reference> 1. J Am Soc Nephrol. 2001 Feb;12 Suppl 17:S15-9 2. Diabetes Obes Metab. 2000 Jun;2(3):131-7. 3. Primer on Kidney Disease. 3rd ed, 2001. National Kidney Foundation. 4. J Intern Med. 2004 Feb;255(2):179-87 5. Arch Intern Med. 2003 Nov 24;163(21):2594-602. 6. QJM. 2003 Apr;96(4):315-6 7. Ann Pharmacother. 2003 Jan;37(1):66-9 8. J Nephrol. 2002 Jul-Aug;15(4):398-402 繼續教育考題 1. (C) Lactic acidosis屬於哪一類的代謝性酸中毒？ A Non anion-gap (AG) B  Low AG C  High AG D Mixed low and high AG 2. (A) Hemorrhagic shock屬於哪一類的lactic acidosis？ A Type A B Type B C Type C D 無法分類 3. (B) Metformin associated lactic acidosis屬於哪一類的lactic acidosis？ A Type A B  Type B C Type C D 無法分類 4. (A) Metformin如何引起lactic acidosis？ A 增加腸道lactate的製造 B 減少腎臟lactate的排除 C 減少肝臟lactate的吸收 D 以上皆非 5. (E) Metformin associated lactic acidosis的主要臨床表現？ A malaise B abdominal discomfort C ventricular fibrillation and asystole D respiratory distress E all of above 6. (D) 在使用metformin的病患上，何種情況易使病患發生Metformin associated lactic acidosis？ A renal dysfunction B liver disease C IV contrast medium D all of above 7. (D) 何者不是Metformin使用上的禁忌？ A 心臟衰竭 B 慢性腎臟病 (Cr > 1.8 mg/dl) C 肝硬化 D 第一度房室阻斷 8. (D) 何種藥物會造成lactic acidosis？ A penformin B isoniazid C salicylate D all of above 9. (A) 何者不是Metformin associated lactic acidosis的主要治療方式？ A 大量的 Bicarbonate矯正 B 儘快給予血液透析 C 藥物立即停用 D 支持性療法 10. (D) 使用metformin的病患追蹤須注意何種情況? A 腎功能 B 肝功能 C 血糖狀況 D 以上皆是 答案解說 (C) (A) (B) (A)Metformin increase intestinal lactate production & contributes to the hyperlactatemia seen in patients with renal or hepatic failure. (E) (D)Renal dysfunction, Liver disease,Advanced cardiopulmonary disorder, Surgery, IV contrast medium (D)如表一 (D) (A)Treatment for MALA is supportive care mainly. Hemodialysis should be also considered. Bicarbonate is controversial for which may induce paradoxical intracellular acidosis, and there is no evidence of decline in mortality. (D)