Introduction: Continuous renal replacement therapy (CRRT) is one of the most critical interventions in the intensive care unit, and anticoagulation is essential to ensure its efficacy. Regional citrate anticoagulation (RCA) has been widely adopted in clinical practice due to its reduced risk of bleeding complications. However, the suitability of RCA for CRRT in patients with hyperlactatemia remains controversial. Methods: This study aimed to evaluate the efficacy and safety of different anticoagulation strategies (heparin systemic anticoagulation, RCA, and no anticoagulation) during CRRT in critically ill patients with hyperlactatemia. Using a retrospective cohort design, we analyzed clinical data from the MIMIC-IV v3.0 database, employing propensity score matching and multivariable Cox regression models to adjust for confounding factors. Results: Our findings demonstrated that compared to the no-anticoagulation group, the citrate group exhibited significantly lower 28-day, 60-day, and 90-day mortality risks, with hazard ratios (HRs) of 0.623, 0.650, and 0.657, respectively. In contrast, the heparin group showed a significant reduction only in 28-day mortality risk (HR = 0.625). These results were further validated in the matched cohort, indicating that RCA significantly improves clinical outcomes and reduces mortality in hyperlactatemia patients requiring CRRT. Conclusion: In summary, our study indicates that citrate anticoagulation significantly improves the prognosis of CRRT in patients with hyperlactatemia, suggesting its potential as a preferred anticoagulation strategy in this clinical setting.

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