Correct!
3. There is no therapy proven to improve survival in MALA
In the absence of acute overdose, Metformin-associated lactic acidosis rarely develops in patients without comorbidities such as renal or hepatic insufficiency or acute infection. A systematic review found the incidence of such lactic acidosis to be fewer than 5.1 cases per 100,000 patient years and a mortality rate >40% (3).
Supportive therapy is recommended with bicarbonate infusions to achieve pH >7.1 followed by high-flux hemodialysis for both acidosis correction and drug removal, but there is no proven therapy which has been shown to improve survival in MALA (3). The mechanism of metformin-associated lactic acidosis is complex. Metformin normally works to decrease plasma glucose levels by inhibiting gluconeogenesis in the liver, decreasing intestinal glucose absorption and promotes the conversion of glucose to lactate in the splanchnic bed, and facilitating glucose uptake into myocytes by increasing insulin sensitivity.
When metformin levels become toxic, metformin may poison (inhibit) the cytochrome chain halting electron transport and oxidative phosphorylation, with an increase in the redox potential (NADH/NAD+). When oxidative phosphorylation stops, NADH cannot regenerate NAD+ and the Kreb's cycle winds down forcing pyruvate into lactate which uses up the abundance of NAD+ to drive the reaction. The excess lactate travels to the liver in the blood, which is supposed to reform pyruvate and send it into gluconeogenesis and the Kreb's cycle, but we already said the Kreb's cycle and gluconeogenesis has been shut down, so the lactate just continues to build up in the blood.
In healthy individuals, the excess lactate is simply cleared by other mechanisms (including uptake by the kidneys, when their function is unimpaired), and no significant elevation in blood levels of lactate occurs. When there is impaired renal function, however, clearance of metformin and lactate is reduced, leading to increased levels of both, and causing lactic acidosis with a buildup of lactic acid. Hemodialysis has been performed but survival in a small series was no different between those dialyzed and those not dialyzed (3).
In our patient the very low pH caused concern. A central line was placed and 300 mEq NaHCO3 was given. A repeat venous blood gas showed a pH 7.06; pCO2 20.5 mmHg; pO2 59 mmHg; central venous O2 saturation 79%, and another bolus of 100 mEq of NaHCO3 was followed with an infusion at 50 mEq/hr. The patient’s blood pressure fell to 74/45 mmHg and an intravenous infusion of levophed was started at 10 mcg/min. High flux hemodialysis was started. Serum beta-hydroxybutyrate was 103 mg/dL (normal < 2.8 mg/dL), and serum salicylate, ethanol, methanol and ethylene glycol levels were all undetectable.
Within four hours of arrival in the ICU, the patient was more alert and reported return of normal vision. His eyes tracked normally and demonstrated normal pupillary reflexes. An arterial blood gas drawn an hour later showed pH 7.24; pCO2 16 mmHg and bicarbonate of 6 mmol/L. The consultant ophthalmologist subsequently arrived and documented a normal eye examination.
Sixteen hours after admission, hypotension and acidosis had completely resolved, and the urinary output was 100-200mL/hr. Dialysis was discontinued. Cultures of urine and blood remained negative, and antibiotics were discontinued at 48 hours. The patient was discharged on the sixth day with normal renal function and a urology follow-up for benign prostatic hypertrophy. His metformin level eventually returned 9.4 (therapeutic range 1-2 and toxic levels producing lactic acidosis when >5).
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