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Objective To examine the levels of systemic inflammatory response index (SIRI) and serum lipoprotein-associated phospholipase A2 (Lp-PLA2) in patients with acute carbon monoxide poisoning (ACOP), and to explore the predictive value of SIRI, Lp - PLA2 and their combination for delayed encephalopathy after acute carbon monoxide poisoning (DEACMP). Methods Total 265 patients with ACOP diagnosed and treated in Harrison International Peace Hospital of Hebei Medical University, The Second People's Hospital of Hengshui and The No.4 People's Hospital of Hengshui from March 2020 to March 2023 were included. SIRI and serum Lp-PLA2 levels were measured. According to the occurrence of DEACMP, they were divided into DEACMP group (n = 32) and non -DEACMP group (n = 233), while according to the degree of poisoning, they were divided into mild poisoning group (n = 20), moderate poisoning group (n = 107) and severe poisoning group (n = 138). Univariate and multivariate Logistic regression analyses were used to screen the risk factors of DEACMP in patients with ACOP, and the receiver operating characteristic (ROC) curve was drawn to evaluate the predictive efficacy of SIRI, Lp - PLA2 and their combination for DEACMP. Results The levels of SIRI (t = 13.068, P = 0.000) and serum Lp-PLA2 (t = 8.208, P = 0.000) in DEACMP group were higher than those in non-DEACMP group, and their levels gradually increased with the severity of poisoning, the levels of SIRI (t = 8.764, P = 0.000; t = 4.586, P = 0.000) and Lp-PLA2 (t = 3.726, P = 0.000; t = 2.038, P = 0.044) in the severe poisoning group and moderate poisoning group were higher than those in the mild poisoning group, and the levels of SIRI and serum Lp-PLA2 in the severe poisoning group were also higher than those in the moderate poisoning group (t = 10.294, P = 0.000; t = 2.700, P = 0.007). Logistic regression analysis showed the severe poisoning (OR = 11.695, 95%CI: 4.893-39.994; P = 0.000), SIRI increased (OR = 1.600, 95%CI: 1.033-2.476; P = 0.001) and Lp - PLA2 increased (OR = 11.302, 95%CI: 1.486-38.933; P = 0.000) were risk factors of DEACMP in patients with ACOP. ROC curve showed that area under the curve (AUC) predicted by Lp-PLA2, SIRI and their combination were 0.82 (95%CI: 0.754-0.894, P = 0.000), 0.82 (95%CI: 0.739-0.895, P = 0.000) and 0.87 (95%CI: 0.805-0.934, P = 0.000), sensitivity were 0.66, 0.72 and 0.84, specificity were 0.85, 0.88 and 0.90, respectively. The prediction efficiency of Lp-PLA2 combined with SIRI was better than that of Lp- PLA2 (t = 2.198, P = 0.027) or SIRI (t = 2.268, P = 0.023) alone. Conclusions DEACMP is easy to occur when SIRI and serum Lp-PLA2 were high in patients with ACOP. The combined detection of Lp-PLA2 and SIRI can be used for early screening of DEACMP.