Role of the Kallikrein-kinin System in Septic Cardiomyopathy

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

The purpose of this study is to investigate whether there are differential expressions of molecules in the kallikrein-kinin system (KKS) pathway in septic cardiomyopathy, and to analyze their regulatory mechanisms and gene expression changes.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: Ulinastatin

Detailed Description

This prospective observational study enrolled 567 critically ill adults within 24 hours of their intensive care unit (ICU) admission across three medical centers in Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology (Wuhan, China)Wuhan, China. Recruitment occurred during two distinct periods: June 2017 to September 2018 and September 2023 to October 2024. Patients were categorized according to Sepsis-3.0 criteria into non-sepsis and sepsis groups. The non-sepsis control group comprised individuals without evidence of infection whose Sequential Organ Failure Assessment (SOFA) scores remained below 2 points. Exclusion criteria included: 1) paraquat poisoning; 2) age under 18 years at diagnosis; 3) acute cardiovascular and cerebrovascular diseases unrelated to inflammation; 4) history of cardiac surgery; 5) pregnancy or breastfeeding; and 6) intellectual or psychological disorders precluding suitable study participation. Within the sepsis cohort, patients meeting the Sepsis-3 criteria who concurrently developed new-onset myocardial injury (troponin elevation exceeding the upper limit of normal, e.g., > 0.05 ng/mL) and/or echocardiographic evidence of myocardial dysfunction (ejection fraction < 50%) or B-type natriuretic peptide (BNP) > 500 pg/mL directly attributable to sepsis. All echocardiographic assessments were performed by accredited sonographers from the Tongji Clinic Echo Lab, with subsequent interpretations conducted by board-certified cardiologists from the same institution.

During the study periods, a total of 652 ICU patients were initially assessed for eligibility. Based on our predefined criteria, 85 patients were excluded: meeting absolute exclusion criteria (n = 18), failing to meet specific strict group definitions (n = 14), declining to participate or missing informed consent (n = 19), lacking baseline plasma samples within 24 hours (n = 16), and having incomplete echocardiographic or core clinical data (n = 18). Ultimately, 567 critically ill patients were enrolled, comprising 417 septic patients (including 104 who developed SIC) and 150 non-septic controls.

• Study Type: Observational
• Enrollment (Actual): 567

Contacts and Locations

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Critical ill patients without sepsis; Patients with sepsis and patients diagnosed with septic cardiomyopathy.

Description

Inclusion Criteria:

1. Age >= 18 years old.
2. Admitted to the Intensive Care Unit (ICU) with an anticipated length of stay exceeding 24 hours.
3. Patient or legally authorized representative provides written informed consent prior to enrollment.

4. Categorized into one of the following three mutually exclusive cohorts within 24 hours of ICU admission:

   • Cohort 1 (Non-sepsis Controls): Admitted for definitive non-infectious etiologies (e.g., severe trauma, major non-cardiac surgery) with no clinical or microbiological evidence of infection throughout the ICU stay.
   • Cohort 2 (Sepsis without SIC): Diagnosed with sepsis according to the Sepsis-3 criteria (acute change in SOFA score >= 2 points driven by infection), but with normal cardiac troponin levels and preserved cardiac function.
   • Cohort 3 (Sepsis-Induced Cardiomyopathy, SIC): Diagnosed with sepsis according to the Sepsis-3 criteria, accompanied by new-onset myocardial injury (elevated cardiac troponin above the upper limit of normal) and/or echocardiographic evidence of myocardial dysfunction directly attributable to sepsis.

Exclusion Criteria:

1. Pre-existing severe chronic cardiac conditions, including history of cardiac surgery, severe pre-existing heart failure (NYHA Class III or IV), persistent severe arrhythmias, or known primary cardiomyopathy (e.g., hypertrophic or dilated cardiomyopathy).
2. Acute non-infectious cardiovascular or cerebrovascular events prior to or upon ICU admission, such as acute myocardial infarction (Type 1), acute ischemic/hemorrhagic stroke, or cardiac arrest.
3. Severe end-stage comorbidities, including end-stage renal disease (ESRD) requiring chronic maintenance dialysis prior to this illness, Child-Pugh Class C hepatic cirrhosis, or advanced malignant tumors with a life expectancy < 3 months.
4. History of paraquat poisoning or other toxic ingestions known to directly cause profound myocardial or pulmonary toxicity.
5. Pregnant or breastfeeding women.
6. Indeterminate or ambiguous infectious status (e.g., cases treated with empiric antibiotics for suspected infection but where infection could neither be confirmed nor ruled out), excluded to prevent misclassification bias.
7. Intellectual, psychological, or neurological disorders that preclude necessary clinical examinations or compliance with study procedures.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Sepsis; Critically ill patients diagnosed with sepsis. In this observational cohort, a subset of these patients received Ulinastatin based solely on the attending physicians' clinical experience and standard routine care, rather than a predefined study protocol. For those who received the treatment, the typical regimen was Ulinastatin (intravenous), 500,000 U, once daily (qd) during their ICU stay.	Drug: Ulinastatin; Observational exposure. Ulinastatin was administered intravenously based solely on the attending physicians' clinical judgment during routine care, typically at a dosage of 500,000 U, once daily (qd). It was not assigned by a predefined study protocol.
Controls; Critically ill patients without sepsis admitted to the ICU. These patients received standard intensive care appropriate for their primary diagnoses and did not receive Ulinastatin treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Sepsis-Induced Cardiomyopathy (SIC)	Number of participants who develop sepsis-induced cardiomyopathy during their ICU stay	During ICU stay (assessed up to day 28)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Levels of KKS Pathway Proteins (KLK1/B1R/Bradykinin/iNOS)	Concentrations of KLK1, B1R, bradykinin, and iNOS measured in plasma to investigate the mechanistic pathway through which Ulinastatin suppresses sepsis-induced cardiomyopathy.	Baseline (within 24 hours of admission)
28-Day All-Cause Mortality	Overall survival status evaluated at 28 days following ICU admission.	28 days
Echocardiographic Parameters of Cardiac Function	Quantitative assessment of Echocardiographic Parameters of Cardiac Function, such as Left Ventricular Ejection Fraction (LVEF) used for SIC diagnosis.	Baseline (within 24 hours of admission)

Collaborators and Investigators

• Sponsor: Qin Zhang
• Investigators: Principal Investigator: QIN Zhang, phd, Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2017
• Primary Completion (Actual): October 14, 2024
• Study Completion (Actual): October 14, 2024

Study Registration Dates

• First Submitted: October 6, 2023
• First Submitted That Met QC Criteria: October 6, 2023
• First Posted (Actual): October 12, 2023

Study Record Updates

• Last Update Posted (Actual): July 28, 2026
• Last Update Submitted That Met QC Criteria: July 24, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: sepsis; Septic cardiomyopathy; KKS
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathological Conditions, Signs and Symptoms; Sepsis; urinastatin
• Other Study ID Numbers: TJ-IRB202308109

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No