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Metformin overdose, but not lactic acidosis per se, inhibits oxygen consumption in pigs

Alessandro Protti1*, Francesco Fortunato2, Massimo Monti1, Sarah Vecchio3, Stefano Gatti4, Giacomo P Comi2, Rachele De Giuseppe5 and Luciano Gattinoni1

Author Affiliations

1 Dipartimento di Anestesia, Rianimazione (Intensiva e Sub-Intensiva) e Terapia del Dolore, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via Francesco Sforza 35, Milano 20122, Italy

2 Centro Dino Ferrari - Dipartimento di Scienze Neurologiche, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via Francesco Sforza 35, Milano 20122, Italy

3 Centro Nazionale di Informazione Tossicologica - Centro Antiveleni, Fondazione IRCCS Salvatore Maugeri, Via Salvatore Maugeri 10, Pavia 27100, Italy

4 Centro di Ricerche Chirurgiche Precliniche, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via Francesco Sforza 35, Milano 20122, Italy

5 Fondazione Fratelli Confalonieri, Dipartimento di Scienze Mediche, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milano 20122, Italy

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Critical Care 2012, 16:R75  doi:10.1186/cc11332

Published: 8 May 2012

Abstract

Introduction

Hepatic mitochondrial dysfunction may play a critical role in the pathogenesis of metformin-induced lactic acidosis. However, patients with severe metformin intoxication may have a 30 to 60% decrease in their global oxygen consumption, as for generalized inhibition of mitochondrial respiration. We developed a pig model of severe metformin intoxication to validate this clinical finding and assess mitochondrial function in liver and other tissues.

Methods

Twenty healthy pigs were sedated and mechanically ventilated. Ten were infused with a large dose of metformin (4 to 8 g) and five were not (sham controls). Five others were infused with lactic acid to clarify whether lactic acidosis per se diminishes global oxygen use. Arterial pH, lactatemia, global oxygen consumption (VO2) (metabolic module) and delivery (DO2) (cardiac output by thermodilution) were monitored for nine hours. Oxygen extraction was computed as VO2/DO2. Activities of the main components of the mitochondrial respiratory chain (complex I, II and III, and IV) were measured with spectrophotometry (and expressed relative to citrate synthase activity) in heart, kidney, liver, skeletal muscle and platelets taken at the end of the study.

Results

Pigs infused with metformin (6 ± 2 g; final serum drug level 77 ± 45 mg/L) progressively developed lactic acidosis (final arterial pH 6.93 ± 0.24 and lactate 18 ± 7 mmol/L, P < 0.001 for both). Their VO2 declined over time (from 115 ± 34 to 71 ± 30 ml/min, P < 0.001) despite grossly preserved DO2 (from 269 ± 68 to 239 ± 51 ml/min, P = 0.58). Oxygen extraction accordingly fell from 43 ± 10 to 30 ± 10% (P = 0.008). None of these changes occurred in either sham controls or pigs infused with lactic acid (final arterial pH 6.86 ± 0.16 and lactate 22 ± 3 mmol/L). Metformin intoxication was associated with inhibition of complex I in the liver (P < 0.001), heart (P < 0.001), kidney (P = 0.003), skeletal muscle (P = 0.012) and platelets (P = 0.053). The activity of complex II and III diminished in the liver (P < 0.001), heart (P < 0.001) and kidney (P < 0.005) while that of complex IV declined in the heart (P < 0.001).

Conclusions

Metformin intoxication induces lactic acidosis, inhibits global oxygen consumption and causes mitochondrial dysfunction in liver and other tissues. Lactic acidosis per se does not decrease whole-body respiration.