Acute metabolic effects of metformin during critical illness

Metformin is widely used to treat type 2 diabetes mellitus. Some patients with renal dysfunction can develop metformin-associated lactic acidosis (MALA). This thesis aims to improve understanding of metformin’s pharmacokinetic and pharmacodynamic properties during critical illness.During normothermic machine perfusion of rat and porcine kidneys, an increasing metformin concentration was associated with a decreasing metformin clearance, explained by saturation of metformin transporters rather than a self-inhibitory effect. Furthermore, metformin had minor effects on renal function and injury within the same model. In patients who underwent primary percutaneous coronary intervention for myocardial infarction, metformin use was also not associated with changes in renal function. Among 37,293 patients admitted to ICUs in Northern Denmark, a similar lactate level was associated with a lower mortality rate for metformin users than nonusers. Metformin users had 0.61 mmol/L higher lactate levels than nonusers in the early phase of critical illness. Also, this difference was more pronounced in case of acute kidney injury. Lactate levels should thus be interpreted according to metformin use.Based on the autopsy of a patient with accidental metformin intoxication, sequestration of metformin within the kidney was observed. In another patient with MALA, we found that only a daily metformin dose (1769 mg) was eliminated during recovery. This small amount of metformin indicates an accordingly low volume of distribution when developing MALA. We hypothesize that acidosis might decrease metformin’s active transport and with that it’s volume of distribution. Therefore, initial treatment of MALA should be focused on correcting acidosis by bicarbonate administration