We aimed to established an interlink among the kallikrein-kinin system (KKS), endothelial dysfunction and POD in response to cardiosurgery , using clinic investigation.

This prospective, single-center observational study enrolled 287 adult patients undergoing elective cardiac surgery between October 2023 and September 2025. Plasma samples were collected at three predefined time points: preoperatively, immediately after surgery, and 24 hours post-surgery. Clinical follow-up for delirium assessments was performed for up to seven days postoperatively or until hospital discharge.

Participants In this prospective, observational cohort study, consecutive adult patients (aged ≥18 years) scheduled for elective cardiac surgery requiring CPB-including open-heart valve repair or replacement-were screened for eligibility between October 2023 and September 2025. Absolute exclusion criteria were strictly defined as follows: 1) pregnancy; 2) preoperative cognitive impairment, preexisting delirium, or a history of severe psychiatric disorders (e.g., dementia, schizophrenia, major depressive disorder) with significant psychotropic medication use; 3) major neurological disorders, including a history of stroke, severe cerebrovascular disease, or severe traumatic brain injury within the past six months; 4) emergent or salvage surgery; 5) severe hepatic or renal dysfunction requiring dialysis; 6) current systemic infection or severe immunosuppression; and 7) administration of nitrates after hospital admission.

During the screening phase, patients who met the predefined exclusion criteria, lacked incomplete perioperative plasma sampling, or declined to provide informed consent were excluded. Ultimately, a final cohort of 287 eligible patients was enrolled in the study . Based on their intraoperative clinical management, the enrolled patients were categorized into the ulinastatin treatment group (n = 123) and the untreated control group (n = 164).

Adult patients undergoing elective cardiac surgery, including open-heart valve repair, valve replacement with cardiopulmonary bypass (CPB) were consecutively screened for eligibility between October 2023 and September 2025. Patients were excluded if they were ≤18 years old, pregnant, had preexisting POD or a history of psychiatric disorders such as schizophrenia or major depressive disorder, had a significant history of psychotropic medication use, received nitrates after admission, or had major neurological disorders including severe traumatic brain injury or stroke within the past six months.

Variables and Clinical Outcomes Preoperative baseline variables, including patient demographics and comorbidities, were systematically extracted from electronic health records. To evaluate the systemic inflammatory and organ injury status, peak postoperative cTnI and lactate Lac levels were recorded as secondary clinical endpoints. Simultaneously, serial perioperative plasma KLK1 levels were quantified as the primary mechanistic and predictive biomarker. The primary clinical outcome was the incidence of POD within 7 days post-surgery. Delirium was assessed twice daily using the Confusion Assessment Method for the ICU (CAM-ICU) or the 3D-CAM by trained evaluators who were strictly blinded to the patients' clinical exposure and biomarker data.

Inclusion Criteria

1. Patients were eligible for enrollment if they met all of the following criteria:
2. Adult patients aged 18 years or older.
3. Scheduled for elective cardiac surgery requiring cardiopulmonary bypass (CPB), specifically including open-heart valve repair or replacement.
4. Provided written informed consent from the patient or a legally authorized representative.

Exclusion Criteria

Patients meeting any of the following criteria were excluded from the study:

1. Neurological and Psychiatric Factors:

   Preoperative cognitive impairment or preexisting delirium.

   History of severe psychiatric disorders (e.g., schizophrenia, major depressive disorder) requiring significant psychotropic medication use.

   Major neurological disorders, including a history of stroke, severe cerebrovascular disease, or severe traumatic brain injury within the past six months.

2. Surgical and Systemic Factors:

   Scheduled for emergent or salvage cardiac surgery.

   Severe hepatic or renal dysfunction requiring dialysis.

   Current systemic infection, sepsis, or a state of severe immunosuppression.

   Pregnant or lactating women.

3. Pharmacological Factors:

Administration of nitrates after hospital admission (due to potential confounding effects on endothelial function and nitric oxide signaling).

In this prospective, observational cohort study, consecutive adult patients (aged ≥18 years) scheduled for elective cardiac surgery requiring cardiopulmonary bypass (CPB)-including open-heart valve repair or replacement-were screened for eligibility between October 2023 and September 2025.

During the screening phase, patients who met the predefined exclusion criteria, had incomplete perioperative plasma sampling, or declined to provide informed consent were excluded. Ultimately, a final cohort of 287 eligible patients was enrolled in the study . Based on their intraoperative clinical management, the enrolled patients were categorized into the ulinastatin treatment group (n = 123) and the untreated control group (n = 164).