The RAS, Fibrinolysis and Cardiopulmonary Bypass
Information source: Vanderbilt University
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Coronary Artery Disease; Angiotensin Converting Enzyme; Angiotensin Receptor Blockers; Cardiopulmonary Bypass; Fibrinolysis; Inflammation
Intervention: Placebo (Drug); Ramipril (Drug); Candesartan (Drug)
Phase: Phase 4
Status: Completed
Sponsored by: Vanderbilt University Official(s) and/or principal investigator(s): Mias Pretorius, MBChB, MSc, Principal Investigator, Affiliation: Vanderbilt University
Summary
Each year over a million patients worldwide undergo cardiac surgery requiring
cardiopulmonary bypass (CPB).1 CPB is associated with significant morbidity including
hemodynamic instability, the transfusion of allogenic blood products, and inflammation.
Blood product transfusion increases mortality after cardiac surgery. Enhanced fibrinolysis
contributes to increased blood product transfusion requirements in the perioperative period.
CPB activates the kallikrein-kinin system (KKS), leading to increased bradykinin
concentrations. Bradykinin, acting through its B2 receptor, stimulates the release of nitric
oxide, inflammatory cytokines and tissue-type plasminogen activator (t-PA). Based on data
indicating that angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients
with coronary artery disease, many patients undergoing CPB are taking ACE inhibitors. While
interruption of the renin-angiotensin system (RAS) reduces inflammation in response to CPB,
ACE inhibitors also potentiate the effects of bradykinin and may augment B2-mediated change
in fibrinolytic balance and inflammation. In contrast, angiotensin II type 1 receptor
antagonism does not potentiate bradykinin and does not inhibit bradykinin metabolism.
Studies in animals suggest that bradykinin receptor antagonism inhibits reperfusion-induced
increases in vascular permeability and neutrophil recruitment. A randomized, placebo
controlled clinical trial of a bradykinin B2 receptor antagonist demonstrated some effect on
survival in patients with systemic inflammatory response syndrome and gram-negative sepsis.
In addition, we and others have shown bradykinin B2 receptor antagonism reduces vascular
t-PA release during ACE inhibition. The current proposal derives from data from our
laboratory and others elucidating the role of the KKS in the inflammatory, hypotensive and
fibrinolytic response to CPB. Specifically, we have found that CPB activates the KKS and
that ACE inhibition and smoking further increases bradykinin concentrations. During CPB,
bradykinin concentrations correlate inversely with mean arterial pressure and directly with
t-PA. Moreover, we have found that bradykinin receptor antagonism attenuates
protamine-related hypotension following CPB. The current proposal tests the central
hypothesis that the fibrinolytic and inflammatory response to cardiopulmonary bypass differ
during angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor
antagonism.
Clinical Details
Official title: The RAS, Fibrinolysis and Cardiopulmonary Bypass
Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Tissue-type Plasminogen Activator (t-PA) Antigen ResponsePlasminogen Activator Inhibitor-1 (PAI-1) Response Interleukin-6 (IL-6) Response Interleukin-8 (IL-8) Response Interleukin-10 (IL-10) Response
Secondary outcome: Blood LossRe-exploration for Bleeding Blood Product Transfusion Requirement Vasopressor Drug Use New Onset Atrial Fibrillation Acute Kidney Injury Stroke Length of Hospital Stay
Eligibility
Minimum age: 18 Years.
Maximum age: 80 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
Inclusion Criteria
1. Subjects, 18 to 80 years of age, scheduled for elective cardiac surgery requiring CPB
2. For female subjects, the following conditions must be met:
postmenopausal for at least 1 year, or status-post surgical sterilization, or if of
childbearing potential, utilizing adequate birth control and willing to undergo urine
beta-hcg testing prior to drug treatment and on every study day
Exclusion Criteria:
1. Left ventricle ejection fraction less than 30%
2. History of ACE inhibitor-induced angioedema
3. Hypotension (systolic blood pressure <100 mmHg and evidence of hypoperfusion)
4. Hyperkalemia (baseline potassium >5. 0 mEq/L)
5. Inability to discontinue current ACE inhibitor or AT1 receptor antagonist.
6. Emergency surgery
7. Impaired renal function (serum creatinine >1. 6 mg/dl)
8. Pregnancy
9. Breast-feeding
10. Any underlying or acute disease requiring regular medication which could possibly
pose a threat to the subject or make implementation of the protocol or interpretation
of the study results difficult
11. History of alcohol or drug abuse
12. Treatment with any investigational drug in the 1 month preceding the study
13. Mental conditions rendering the subject unable to understand the nature, scope and
possible consequences of the study
14. Inability to comply with the protocol, e. g. uncooperative attitude and unlikelihood
of completing the study
Locations and Contacts
TN Valley Healthcare System, Nashville, Tennessee 37212, United States
Vanderbilt University, Nashville, Tennessee 37232, United States
Additional Information
Starting date: August 2006
Last updated: September 7, 2012
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