Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication

Abstract

IntroductionLactic acidosis can develop during biguanide (metformin and phenformin) intoxication, possibly as a consequence of mitochondrial dysfunction. To verify this hypothesis, we investigated whether body oxygen consumption (VO2), that primarily depends on mitochondrial respiration, is depressed in patients with biguanide intoxication.MethodsMulticentre retrospective analysis of data collected from 24 patients with lactic acidosis (pH 6.93 ± 0.20; lactate 18 ± 6 mM at hospital admission) due to metformin (n = 23) or phenformin (n = 1) intoxication. In 11 patients, VO2 was computed as the product of simultaneously recorded arterio-venous difference in O2 content [C(a-v)O2] and cardiac index (CI). In 13 additional cases, C(a-v)O2, but not CI, was available.ResultsOn day 1, VO2 was markedly depressed (67 ± 28 ml/min/m2) despite a normal CI (3.4 ± 1.2 L/min/m2). C(a-v)O2 was abnormally low in both patients either with (2.0 ± 1.0 ml O2/100 ml) or without (2.5 ± 1.1 ml O2/100 ml) CI (and VO2) monitoring. Clearance of the accumulated drug was associated with the resolution of lactic acidosis and a parallel increase in VO2 (P < 0.001) and C(a-v)O2 (P < 0.05). Plasma lactate and VO2 were inversely correlated (R2 0.43; P < 0.001, n = 32).ConclusionsVO2 is abnormally low in patients with lactic acidosis due to biguanide intoxication. This finding is in line with the hypothesis of inhibited mitochondrial respiration and consequent hyperlactatemia.

Lactic Acidosis in a Man with Diabetes: Is Metformin the Culprit?

“…Principle mechanism of MALA is thought to be inhibition of mitochondrial function in hepatocytes resulting in inhibition of aerobic oxidation and accumulation of lactate [13]. This explains why haemodiafiltration is effective in treatment as it removes metformin and lactate to negate acidosis.…”

“…Infact in some case series survivors have had higher lactate levels [30]. This is probably due to the fact that mitochondrial inhibition by metformin is easily reversed by haemodialysis irrespective of the pH or lactate level which are rapidly reversible [13]. Furthermore, reviewing recent literature Renda et al postulate that associated co-morbid risk factors are stronger predictors of mortality than the dose of metformin or degree of impairment of its elimination, in metformin intoxication [5].…”

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“…The prognosis is partially affected by host factors and comorbidities such as renal failure, hypoxia, and hypotension. 6 Since MALA is associated with high mortality, early recognition and stoppage of drug is crucial.…”

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“…We consider that lactate clearance determination may be a better prognostic factor of organic failure and mortality, because patients with high lactate clearance have less mortality rate than those with low lactate clearance. The best lactate clearance rate is correlated as well with decreased in some biomarker such as interleukins 1,6,8,10, tumor necrosis factor alpha, caspase 3. On the other hand, some studies have demonstrated that normal lactate rates can be found on cardiogenic shock, acute renal failure, and that lactate clearance are altered on these, probably because of multiorgan failure (9,(10)(11)(12)(13)(14)(15)(16).…”

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