Establishing Blood Lactate Thresholds in Intensive Care Patients – with a Particular Focus on Age and Sex Scientific Question Serum lactate is an established biomarker of mortality and morbidity in sepsis. According to the current Sepsis-3 criteria, septic shock is defined as sepsis with persistent hypotension despite adequate fluid resuscitation and a serum lactate level > 2 mmol/L. This threshold was determined through a Delphi process and is based on the lowest lactate concentration independently associated with increased mortality. More recent studies indicate, however, that lactate levels within the normal reference range are also strongly and independently associated with increased in-hospital mortality. This association has been observed both at ICU admission with levels as low as 0.75 mmol/L and for elevated time-weighted mean lactate values in patients who never exceeded 2 mmol/L. The primary scientific question is whether there are age- and sex-specific lactate thresholds in sepsis, and whether these thresholds improve the prediction of mortality and morbidity compared to the current general cut-off value of 2 mmol/L. Primary objective: To identify age- and sex-specific lactate thresholds and their association with mortality and the need for advanced medical interventions, depending on underlying conditions. Secondary objectives: To investigate whether subgroups of patients (phenotypes/endotypes) can be identified using non-linear regression models or clustering algorithms. To evaluate the relationship between lactate levels, mortality, and haemodynamic parameters. Background Traditionally, sepsis-associated hyperlactataemia (SAHL) has been viewed as a marker of tissue hypoxia. More recent data suggest that elevated lactate levels may also result from adrenergic stimulation and increased aerobic glycolysis, where pyruvate exceeds the capacity of the citric acid cycle and is converted to lactate despite adequate oxygenation. Lactate metabolism is also impaired in septic shock. The liver accounts for approximately 50–60 % of lactate clearance, while the kidneys contribute up to 30 %. Both hepatic and renal clearance capacities may be significantly reduced during sepsis. Current treatment goals in septic shock focus primarily on maintaining mean arterial pressure, but this often correlates poorly with microcirculatory and global tissue perfusion. Variability in patients’ ability to produce and clear lactate — influenced by age, sex, and comorbidities — is not considered in the current definition. Project Description Design: Retrospective cohort study based on data from Akademiska sjukhuset, Uppsala. Population: All patients with serum lactate measurements during admission at Akademiska sjukhuset between 2016 and 2024. Exclusion criteria: Patients admitted without any lactate measurement and those with unknown identity. Methods: Statistical analysis of associations between lactate levels, mortality, and patient characteristics. Non-linear regression models to identify mortality thresholds. Unsupervised machine learning (e.g. k-means or hierarchical clustering) to identify phenotypes based on lactate levels, age, sex, vital parameters, and comorbidities. Sensitivity analyses to test the robustness of identified thresholds.