Wednesday, March 10, 2010

CONSULT ROUNDS: Metformin toxicity, Lactic Acidosis, and dialysis

What is the role of dialysis in Metformin associated Lactic acidosis?

Review of literature about metformin associated severe L lactic acidosis ( MALA):
Lactic Acidosis: Lactate is generated from pyruvate with lactate dehydrogenase as a catalyst. Lactic acidosis results when:
1) lactate production exceeds consumption This occurs when tissue hypoperfusion or hypoxia ( Type A or fast LA).
2) compromised lactate metabolism without hypoxia, which is frequently termed type B (slow) lactic acidosis. Biguanides may inhibit oxidative metabolism and thus increase the concentration of NADH, reduce gluconeogenesis, and suppress the gastrointestinal absorption of glucose.

Metformin-associated lactic acidosis is a rare but serious complication of biguanide treatment associated with high mortality. Population-based studies have estimated a rate of 0.02–0.09 cases of LA in metformin users per 1000 patient-years, but results vary. Risk is higher in patients with renal failure, heart and liver failure.

Management includes supportive care including fluid resuscitation, mantaining tissue oxygenation, IV bicarbonate therapy for severe acidosis and hemodialysis or CVVHDF.
There are mostly case reports of severe lactic acidosis due to metformin toxicity succesfully treated with CRRT. One study looked at metformin levels before and after dialysis and showed that sequential measurements of metformin levels during HD were consistent with a bicompartmental elimination pattern. A cumulative HD duration of 15 hours was associated with the return of metformin level to the therapeutic normal range. Available data suggest prolonged HD is required to correct metformin overdose.

Of interest, only initial PT activity ( measure of liver function) is independently associated with mortality and degree of lactic acidosis or metformin levels has no effect on survival.

Some Reviews:
Lactic Acidosis Update for Critical Care Clinicians FRIEDRICH C. LUFT J Am Soc Nephrol 12:S15-S19, 2001

Metformin and antihypertensive therapy with drugs blocking the renin angiotensin system, a cause of concern? Gudmundsdottir H, Aksnes H, Heldal K, Krogh A, Froyshov S, Rudberg N, Os I.Clin Nephrol. 2006 Nov;66(5):380-5.

Metformin-associated lactic acidosis: A prognostic and therapeutic study Seidowsky, Alexandre MD Critical Care Medicine: July 2009 - Volume 37 - Issue 7 - pp 2191-2196

Metformin-associated lactic acidosis treated with continuous renal replacement therapy.
Alivanis P, Giannikouris I, Paliuras C, Arvanitis A, Volanaki M, Zervos A. Clin Ther. 2006 Mar;28(3):396-400.

Sigrun Friesecke, Peter Abel, Matthias Kraft, Andreas Gerner, and Soeren RungeCombined renal replacement therapy for severe metformin-induced lactic acidosisNephrol. Dial. Transplant., July 2006; 21: 2038 - 2039.

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