Effect of High-Dose Ulinastatin on the Cardiopulmonary Bypass-Induced Inflammatory Response in Patients Undergoing Open-Heart Surgery
Cardiopulmonary bypass (CPB) is a critical component of open-heart surgery, but it is known to induce a systemic inflammatory response. This inflammatory response can lead to postoperative complications, including organ dysfunction and prolonged recovery. Ulinastatin (UTI), a broad-spectrum elastase inhibitor, has been recognized for its ability to stabilize lysosomal membranes and inhibit the activation and release of various inflammatory cytokines caused by CPB. Despite its widespread use in clinical settings, the optimal dose of UTI for mitigating CPB-induced inflammation has not been clearly defined. This study aimed to evaluate the anti-inflammatory efficacy of high-dose UTI and explore the optimum dose in patients undergoing open-heart surgery with CPB.
The study was conducted as a prospective, randomized, controlled trial involving 60 patients with cardiac diseases, including congenital heart diseases and valvular heart diseases, who were scheduled for elective cardiac surgery under CPB. The patients were randomly divided into four groups: U1, U2, U3, and a control group, with 15 patients in each group. The U1, U2, and U3 groups received 20,000 IU/kg, 40,000 IU/kg, and 60,000 IU/kg of UTI, respectively, which was diluted in 20 mL of saline and added to the pre-filling liquid after the initiation of anesthesia. The control group received 100,000 IU of UTI added to the pre-filling liquid, followed by 100,000 IU of UTI intravenously every 8 hours for 2 days postoperatively.
The primary outcome measures were the serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) at various time points: the day before surgery (T0), 30 minutes after aortic occlusion (T1), 1 hour after aortic occlusion (T2), the moment of weaning from CPB (T3), and 6 hours (T4), 12 hours (T5), 24 hours (T6), and 48 hours (T7) after weaning from CPB. These inflammatory markers were measured using ELISA kits.
The results showed that the serum levels of TNF-α, IL-6, and IL-8 increased postoperatively in all groups, indicating that the surgical procedure activated inflammatory cytokines. However, the levels of these cytokines were significantly lower in the U3 group compared to the other groups, suggesting that high-dose UTI effectively reduced inflammation in a dose-dependent manner. Specifically, TNF-α levels peaked at T4 in the control, U1, and U2 groups, and at T5 in the U3 group. IL-6 levels peaked at T3 in the control group, at T4 in the U1 and U3 groups, and at T5 in the U2 group. IL-8 levels peaked at T3 in the U1 group, at T4 in the control and U3 groups, and at T5 in the U2 group.
The study also revealed that the effect of high-dose UTI was substantially superior to the clinical dose routinely used. Interestingly, the U1 group, which received a higher total dose of UTI intraoperatively, exhibited higher inflammatory cytokine levels compared to the control group. This discrepancy may be attributed to the different routes of administration; patients in the control group received UTI both intraoperatively and postoperatively, while those in the U1 group received the entire dose intraoperatively. The blood concentration of UTI was observed to decline rapidly within 3 hours of administration, likely due to its short half-life. This suggests that the timing and route of UTI administration are critical factors in its efficacy.
The findings of this study have important clinical implications. High-dose UTI, particularly at 60,000 IU/kg, was shown to be more effective in reducing CPB-induced inflammation compared to lower doses. This suggests that optimizing the dose and administration regimen of UTI could improve postoperative outcomes in patients undergoing open-heart surgery. However, further studies are needed to determine the most effective route and timing of UTI administration to maximize its anti-inflammatory effects.
In conclusion, this study demonstrates that high-dose Ulinastatin significantly reduces the inflammatory response induced by cardiopulmonary bypass in patients undergoing open-heart surgery. The results indicate that UTI exerts its anti-inflammatory effects in a dose-dependent manner, with the highest dose (60,000 IU/kg) providing the most substantial reduction in inflammatory cytokines. These findings underscore the potential of high-dose UTI as a therapeutic strategy to mitigate CPB-induced inflammation and improve postoperative recovery in cardiac surgery patients.
doi.org/10.1097/CM9.0000000000000832
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