- ICH GCP
- Yhdysvaltain kliinisten tutkimusten rekisteri
- Kliininen tutkimus NCT00607672
The RAS, Fibrinolysis and Cardiopulmonary Bypass
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.
Tutkimuksen yleiskatsaus
Tila
Ehdot
Interventio / Hoito
Opintotyyppi
Ilmoittautuminen (Todellinen)
Vaihe
- Vaihe 4
Yhteystiedot ja paikat
Opiskelupaikat
-
-
Tennessee
-
Nashville, Tennessee, Yhdysvallat, 37232
- Vanderbilt University
-
Nashville, Tennessee, Yhdysvallat, 37212
- TN Valley Healthcare System
-
-
Osallistumiskriteerit
Kelpoisuusvaatimukset
Opintokelpoiset iät
Hyväksyy terveitä vapaaehtoisia
Sukupuolet, jotka voivat opiskella
Kuvaus
Inclusion Criteria:
Inclusion Criteria
- Subjects, 18 to 80 years of age, scheduled for elective cardiac surgery requiring CPB
- 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:
- Left ventricle ejection fraction less than 30%
- History of ACE inhibitor-induced angioedema
- Hypotension (systolic blood pressure <100 mmHg and evidence of hypoperfusion)
- Hyperkalemia (baseline potassium >5.0 mEq/L)
- Inability to discontinue current ACE inhibitor or AT1 receptor antagonist.
- Emergency surgery
- Impaired renal function (serum creatinine >1.6 mg/dl)
- Pregnancy
- Breast-feeding
- 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
- History of alcohol or drug abuse
- Treatment with any investigational drug in the 1 month preceding the study
- Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
- Inability to comply with the protocol, e.g. uncooperative attitude and unlikelihood of completing the study
Opintosuunnitelma
Miten tutkimus on suunniteltu?
Suunnittelun yksityiskohdat
- Ensisijainen käyttötarkoitus: Hoito
- Jako: Satunnaistettu
- Inventiomalli: Rinnakkaistehtävä
- Naamiointi: Nelinkertaistaa
Aseet ja interventiot
Osallistujaryhmä / Arm |
Interventio / Hoito |
---|---|
Placebo Comparator: 1
Patients are randomized to placebo prior to surgery
|
Plasebo
|
Active Comparator: 2
Patients are randomized to Ramipril prior to surgery
|
Ramipril 2.5mg day 1 and 2 and then 5mg/d thereafter
|
Active Comparator: 3
Patients are randomized to Candesartan (ARB) prior to surgery
|
Candesartan 16mg/d
|
Mitä tutkimuksessa mitataan?
Ensisijaiset tulostoimenpiteet
Tulosmittaus |
Toimenpiteen kuvaus |
Aikaikkuna |
---|---|---|
Tissue-type Plasminogen Activator (t-PA) Antigen Response
Aikaikkuna: From the start of surgery until postoperative day 2
|
To compare the effects of angiotensin II type I (AT1) receptor antagonism or angiotensin-converting enzyme (ACE) inhibition versus placebo on the fibrinolytic responses to cardiopulmonary bypass (CPB) as measured by t-PA antigen response
|
From the start of surgery until postoperative day 2
|
Plasminogen Activator Inhibitor-1 (PAI-1) Response
Aikaikkuna: From the start of surgery until postoperative day 2
|
To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the fibrinolytic responses to CPB as measured by PAI-1 response
|
From the start of surgery until postoperative day 2
|
Interleukin-6 (IL-6) Response
Aikaikkuna: From the start of surgery until postoperative day 2
|
To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-6
|
From the start of surgery until postoperative day 2
|
Interleukin-8 (IL-8) Response
Aikaikkuna: From the start of surgery until postoperative day 2
|
To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-8
|
From the start of surgery until postoperative day 2
|
Interleukin-10 (IL-10) Response
Aikaikkuna: From the start of surgery until postoperative day 2
|
To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by the IL-10 response
|
From the start of surgery until postoperative day 2
|
Toissijaiset tulostoimenpiteet
Tulosmittaus |
Toimenpiteen kuvaus |
Aikaikkuna |
---|---|---|
Blood Loss
Aikaikkuna: First 24 hours after arrival in the intensive care unit
|
Blood loss over 24 hours as measured by chest tube output
|
First 24 hours after arrival in the intensive care unit
|
Re-exploration for Bleeding
Aikaikkuna: From arrival in intensive care unit until discharge from hospital
|
The percentage of patients that were taken back to the operating room for re-exploration because of bleeding
|
From arrival in intensive care unit until discharge from hospital
|
Blood Product Transfusion Requirement
Aikaikkuna: From the start of surgery until discharge from hospital
|
Percentage of patients that received blood product transfusion
|
From the start of surgery until discharge from hospital
|
Vasopressor Drug Use
Aikaikkuna: From the end of cardiopulmonary bypass until arrival in intensive care unit
|
From the end of cardiopulmonary bypass until arrival in intensive care unit
|
|
New Onset Atrial Fibrillation
Aikaikkuna: From arrival in intensive care unit until discharge from hospital
|
New onset atrial fibrillation based on electrocardiogram (ECG) rhythm strips with a duration longer than 10 seconds
|
From arrival in intensive care unit until discharge from hospital
|
Acute Kidney Injury
Aikaikkuna: From the start of surgery until postoperative day 3
|
Acute kidney injury (AKI) was defined according to Acute Kidney Injury Network (AKIN) criteria,specifically any increase in subject serum creatinine concentration of 50% or 0.3 mg/dL (26.5 umol/L) within 72 hours of surgery.
|
From the start of surgery until postoperative day 3
|
Stroke
Aikaikkuna: From arrival in intensive care unit until discharge from hospital
|
New onset neurological deficit with a duration of longer than 24 hours
|
From arrival in intensive care unit until discharge from hospital
|
Length of Hospital Stay
Aikaikkuna: From the start of surgery until discharge from hospital
|
From the start of surgery until discharge from hospital
|
Yhteistyökumppanit ja tutkijat
Sponsori
Tutkijat
- Päätutkija: Mias Pretorius, MBChB, MSc, Vanderbilt University
Julkaisuja ja hyödyllisiä linkkejä
Yleiset julkaisut
- Gamboa JL, Pretorius M, Sprinkel KC, Brown NJ, Ikizler TA. Angiotensin converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis--a randomized cross-over study. BMC Nephrol. 2015 Oct 22;16:167. doi: 10.1186/s12882-015-0162-x.
- Billings FT 4th, Balaguer JM, C Y, Wright P, Petracek MR, Byrne JG, Brown NJ, Pretorius M. Comparative effects of angiotensin receptor blockade and ACE inhibition on the fibrinolytic and inflammatory responses to cardiopulmonary bypass. Clin Pharmacol Ther. 2012 Jun;91(6):1065-73. doi: 10.1038/clpt.2011.356.
Opintojen ennätyspäivät
Opi tärkeimmät päivämäärät
Opiskelun aloitus
Ensisijainen valmistuminen (Todellinen)
Opintojen valmistuminen (Todellinen)
Opintoihin ilmoittautumispäivät
Ensimmäinen lähetetty
Ensimmäinen toimitettu, joka täytti QC-kriteerit
Ensimmäinen Lähetetty (Arvio)
Tutkimustietojen päivitykset
Viimeisin päivitys julkaistu (Arvio)
Viimeisin lähetetty päivitys, joka täytti QC-kriteerit
Viimeksi vahvistettu
Lisää tietoa
Tähän tutkimukseen liittyvät termit
Avainsanat
Muita asiaankuuluvia MeSH-ehtoja
- Patologiset prosessit
- Sydänlihaksen iskemia
- Sydänsairaudet
- Sydän-ja verisuonitaudit
- Verisuonisairaudet
- Valtimotauti
- Valtimon tukossairaudet
- Sepelvaltimotauti
- Sepelvaltimotauti
- Tulehdus
- Farmakologisen vaikutuksen molekyylimekanismit
- Verenpainetta alentavat aineet
- Entsyymin estäjät
- Proteaasin estäjät
- Angiotensiini II tyypin 1 reseptorin salpaajat
- Angiotensiinireseptorin antagonistit
- Angiotensiiniä konvertoivan entsyymin estäjät
- Candesartan
- Ramipril
Muut tutkimustunnusnumerot
- 051170
- HL 085740-01
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