Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study

Rene A. Posma,Reimar W. Thomsen,Bente Jespersen,Maarten W. Nijsten,Daan J. Touw,Iwan C. C. van der Horst,Christian F. Christiansen,Trine Frøslev

doi:10.1186/s13613-020-00652-0

Abstract

BackgroundLactate is a robust prognostic marker for the outcome of critically ill patients. Several small studies reported that metformin users have higher lactate levels at ICU admission without a concomitant increase in mortality. However, this has not been investigated in a larger cohort. We aimed to determine whether the association between lactate levels around ICU admission and mortality is different in metformin users compared to metformin nonusers.MethodsThis cohort study included patients admitted to ICUs in northern Denmark between January 2010 and August 2017 with any circulating lactate measured around ICU admission, which was defined as 12 h before until 6 h after admission. The association between the mean of the lactate levels measured during this period and 30-day mortality was determined for metformin users and nonusers by modelling restricted cubic splines obtained from a Cox regression model.ResultsOf 37,293 included patients, 3183 (9%) used metformin. The median (interquartile range) lactate level was 1.8 (1.2–3.2) in metformin users and 1.6 (1.0–2.7) mmol/L in metformin nonusers. Lactate levels were strongly associated with mortality for both metformin users and nonusers. However, the association of lactate with mortality was different for metformin users, with a lower mortality rate in metformin users than in nonusers when admitted with similar lactate levels. This was observed over the whole range of lactate levels, and consequently, the relation of lactate with mortality was shifted rightwards for metformin users.ConclusionIn this large observational cohort of critically ill patients, early lactate levels were strongly associated with mortality. Irrespective of the degree of hyperlactataemia, similar lactate levels were associated with a lower mortality rate in metformin users compared with metformin nonusers. Therefore, lactate levels around ICU admission should be interpreted according to metformin use.

Highlights

Lactate is a robust prognostic marker for the outcome of critically ill patients
To determine whether the association between early lactate level and mortality during critical illness is different in metformin users compared with metformin nonusers, we studied a large cohort of patients admitted to intensive care units (ICU) in northern Denmark
Four metformin users did not have a diagnosis of diabetes mellitus, but these patients had a diagnosis of polycystic ovarian syndrome recorded within 10 years before ICU admission

Summary

Introduction

Several small studies reported that metformin users have higher lactate levels at ICU admission without a concomitant increase in mortality. This has not been investigated in a larger cohort. Conversion of lactate into glucose in the liver, as part of the Cori cycle, plays a pivotal role in lactate metabolism during physiological stress [3, 10]. Inhibition of this cycle by metformin may result in more marked hyperlactataemia in times of critical illness [11]. Some patients with renal dysfunction accumulate metformin and develop severe lactic acidosis, which is caused by excessive systemic and hepatic mitochondrial inhibition [11, 12]

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