Association between time-weighted average lactate during cardiopulmonary bypass and postoperative infection in patients undergoing cardiac surgery: single-center, prospective cohort study protocol

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  Figure 1. Proposed mechanism by which TWA lactate during cardiopulmonary bypass induces immunosuppression leading to postoperative infection. During cardiopulmonary bypass, non-pulsatile perfusion, organ hypoperfusion, ischemia–reperfusion injury, and systemic inflammatory activation may promote serum lactate accumulation. Elevated lactate may subsequently contribute to perioperative immune dysregulation through several mechanisms, including AARS1/2-mediated lactate sensing and cGAS lactylation, suppression of T-cell migration and cytotoxic function, promotion of CD4⁺ T-cell differentiation toward the Th17 subset, impairment of mast-cell function in a pH-dependent microenvironment, and mitochondrial dysfunction with reduced oxygen consumption in immune cells. Collectively, these lactate-related immunosuppressive effects may create a favorable environment for pathogen colonization and dissemination, thereby increasing the risk of postoperative infectious complications, including pneumonia, surgical site infection, mediastinitis, infective endocarditis, and sepsis. TWA, time-weighted average; CPB, cardiopulmonary bypass; AARS1/2, alanyl-tRNA synthetase 1/2; CD4⁺ T-cell, cluster of…

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  Figure 2. Study flow diagram.

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  Figure 3. Temporal sequence of variables included in the causal framework.

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  Figure 4. Directed acyclic graph (DAG) illustrating the assumed causal structure between intraoperative TWA lactate (exposure) and postoperative infection (outcome). The exposure is represented by a green node with a triangle symbol. The outcome, postoperative infection, is shown as a blue node with a thick black vertical line. Other variables are represented as follows: blue nodes depict ancestors of the outcome, namely mediators; red nodes represent ancestors of both the exposure and outcome; pale grey nodes signify unobserved or latent variables; and darker grey nodes represent colliders. The definitions of TWA lactate and postoperative infection have been elaborated in the Methods section. Mediators located on the causal pathway between exposure and outcome, as well as colliders jointly caused by both exposure and outcome, will not be adjusted for to avoid overadjustment bias. The minimal adjustment set for this model is age, sex, BMI, lifestyle, comorbidities, preoperative lactate, anesthesia factors, and surgery and CPB factors.