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

Background Lactate 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. Methods This 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. Results Of 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. Conclusion In 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.


Additional Figures
-  Figure S2 -Tukey's boxplot of mean lactate levels and mortality rate for patients in the total cohort, among patients with diabetes mellitus, undergoing elective surgery, or with a normal renal function or chronic kidney disease one year before ICU admission. . 3 Figure Figure S9 -Association of lactate level with estimated 30-day mortality and its corresponding adjusted hazard ratio for metformin users and nonusers among patients with a normal renal function or chronic kidney disease one year before ICU admission. ........ 10 Additional Tables  Table S1 - Table S4 -Thirty-day mortality, hazard ratios, and the relative excess risk due to interaction by lactate category for metformin nonusers and users when restricting to complete cases ..  Table S9 -Thirty-day mortality, hazard ratios, and the relative excess risk due to interaction by lactate category for metformin nonusers and users among patients with diabetes mellitus ..   Additional file 1 -Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study 3 Figure S2 -Tukey's boxplot of mean lactate levels and mortality rate for patients in the total cohort, among patients with diabetes mellitus, undergoing elective surgery, or with a normal renal function (eGFR ≥60 ml/min/1.72m 2 ) or chronic kidney disease (eGFR <60 ml/min/1.72m 2 ) one year before ICU admission.
Additional file 1 -Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study 4 Figure S3 -Distribution of metformin users and nonusers based on mean or maximum lactate level Both for mean lactate level and maximum lactate level around ICU admission, metformin users more often have higher lactate levels than nonusers, illustrated by the rightward shift of the curve. Therefore, more metformin users have a maximum lactate ≥2 mmol/L (dashed line), which is often used to identify severe critical illness, such as septic shock. The x-axis is logarithmically transformed because of the skewed data distribution.
Additional file 1 -Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study Figure S4 -Association of lactate level with estimated 30-day mortality for metformin users and nonusers when restricted to complete cases Data were fit by a multivariable-adjusted Cox regression model based on restricted cubic splines constructed with four evenly spaced knots. A dataset restricted to complete cases was used for this analysis. The grey area represents the 95% confidence interval.
Figure S5 -Association of mean lactate level with adjusted odds ratio for 30-day mortality for metformin users and nonusers in the total cohort. Data were fit by a multivariable-adjusted logistic regression model based on restricted cubic splines constructed with four evenly spaced knots. A multiple imputed dataset was used for this analysis. The grey area represents the 95% confidence interval.
Additional file 1 -Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study Figure S6 -Association of first and maximum lactate level, respectively, measured within 12 hours before until 6 hours after ICU admission with estimated 30-day mortality and its corresponding adjusted hazard ratio for metformin users and nonusers in the total cohort. Data were fit by a multivariable-adjusted Cox regression model based on restricted cubic splines constructed with four evenly spaced knots. A multiple imputed dataset was used for this analysis. The grey area represents the 95% confidence interval.
Additional file 1 -Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study Figure S7 -Association of lactate level with estimated 30-day mortality and its corresponding adjusted hazard ratio for metformin users and nonusers when including patients with diabetes mellitus. Data were fit by a multivariable-adjusted Cox regression model based on restricted cubic splines constructed with four evenly spaced knots. A multiple imputed dataset was used for this analysis. The grey area represents the 95% confidence interval.
Additional file 1 -Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study Figure S8 -Association of lactate level with estimated 30-day mortality and its corresponding adjusted hazard ratio for metformin users and nonusers when only including patients undergoing elective surgery. Data were fit by a multivariable-adjusted Cox regression model based on restricted cubic splines constructed with four evenly spaced knots. A multiple imputed dataset was used for this analysis. The grey area represents the 95% confidence interval.
Additional file 1 -Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study Figure S9 -Association of lactate level with estimated 30-day mortality and its corresponding adjusted hazard ratio for metformin users and nonusers among patients with a normal renal function (eGFR ≥60 ml/min/1.72m 2 ) or chronic kidney disease (eGFR <60 ml/min/1.72m 2 ) one year before ICU admission. Data were fit by a multivariable-adjusted Cox regression model based on restricted cubic splines constructed with four evenly spaced knots. A multiple imputed dataset was used for this analysis. The grey area represents the 95% confidence interval.
a Adjusted for age, gender, mean of all creatinine measurements 1 year before ICU admission, and previous diagnosis of myocardial infarction, congestive heart failure, peripheral artery disease, cerebrovascular disease, dementia, connective tissue disease, peptic ulcer disease, chronic pulmonary disease, mild to severe liver disease, any tumor, metastatic solid tumor, leukemia, and lymphoma, respectively, 10 years before ICU admission. Codes used for each variable are stated in Appendix 1. Hazard ratio (HR) with 95% confidence interval (95% CI) was computed using Cox proportional regression analysis based on a dataset restricted to complete cases.
a Adjusted for age, gender, last HbA1c measurement within 4 weeks before ICU admission, mean of all creatinine measurements 1 year before ICU admission, number of lactate measurements, and previous diagnosis of myocardial infarction, congestive heart failure, peripheral artery disease, cerebrovascular disease, dementia, connective tissue disease, peptic ulcer disease, chronic pulmonary disease, mild to severe liver disease, any tumor, metastatic solid tumor, leukemia, and lymphoma, respectively, 10 years before ICU admission. Codes used for each variable are stated in Appendix 1. Odds ratio (OR) with 95% confidence interval (95% CI) was computed using logistic regression analysis based on a multiple imputed dataset.
a Adjusted for age, gender, last HbA1c measurement within 4 weeks before ICU admission, mean of all creatinine measurements 1 year before ICU admission, and previous diagnosis of myocardial infarction, congestive heart failure, peripheral artery disease, cerebrovascular disease, dementia, connective tissue disease, peptic ulcer disease, chronic pulmonary disease, mild to severe liver disease, any tumor, metastatic solid tumor, leukemia, and lymphoma, respectively, 10 years before ICU admission. Codes used for each variable are stated in Appendix 1.
b Relative excess risk due to interaction (RERI) quantifies interaction on an additive scale, which approaches zero in the absence of interaction.
a Adjusted for age, gender, last HbA1c measurement within 4 weeks before ICU admission, mean of all creatinine measurements 1 year before ICU admission, concomitant use of insulin, sulfonylurea derivates, or other antihyperglycemic drugs 90 days before ICU admission, and previous diagnosis of myocardial infarction, congestive heart failure, peripheral artery disease, cerebrovascular disease, dementia, connective tissue disease, peptic ulcer disease, chronic pulmonary disease, mild to severe liver disease, any tumor, metastatic solid tumor, leukemia, and lymphoma, respectively, 10 years before ICU admission. Codes used for each variable are stated in Appendix 1.
b Relative excess risk due to interaction (RERI) quantifies interaction on an additive scale, which approaches zero in the absence of interaction.
Additional file 1 -Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study Additional file 1 -Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study b Relative excess risk due to interaction (RERI) quantifies interaction on an additive scale, which approaches zero in the absence of interaction.