Increased ratio of P[v-a]CO 2 to C[a-v]O 2 without global hypoxia: the case of metformin-induced lactic acidosis

The ratio of venoarterial CO2 tension to arteriovenous O2 content difference (P[v-a]CO2/C[a-v]O2) increases when lactic acidosis is due to inadequate oxygen supply (hypoxia); we aimed to verify whether it also increases when lactic acidosis develops because of mitochondrial dysfunction (dysoxia) with constant oxygen delivery. Twelve anaesthetised, mechanically ventilated pigs were intoxicated with IV metformin (4.0 to 6.4 g over 2.5 to 4.0 h). Saline and norepinephrine were used to preserve oxygen delivery. Lactate and P[v-a]CO2/C[a-v]O2 were measured every one or two hours (arterial and mixed venous blood). During metformin intoxication, lactate increased from 0.8 (0.6-0.9) to 8.5 (5.0-10.9) mmol/l (p < 0.001), even if oxygen delivery remained constant (from 352 ± 78 to 343 ± 97 ml/min, p = 0.098). P[v-a]CO2/C[a-v]O2 increased from 1.6 (1.2-1.8) to 2.3 (1.9-3.2) mmHg/ml/dl (p = 0.004). The intraclass correlation coefficient between lactate and P[v-a]CO2/C[a-v]O2 was 0.72 (p < 0.001). We conclude that P[v-a]CO2/C[a-v]O2 increases when lactic acidosis is due to dysoxia. Therefore, a high P[v-a]CO2/C[a-v]O2 may not discriminate hypoxia from dysoxia as the cause of lactic acidosis.