Effects of Remote Ischemic PreConditioning in Off-pump Versus On-pump Coronary Artery Bypass Grafting(RIPCON) (RIPCON)

Effects of Remote Ischemic PreConditioning in Off-pump Versus On-pump Coronary

Purpose Remote ischemic preconditioning (RIPC) with transient upper limb ischemia reduces myocardial injury in patients undergoing On-pump coronary artery bypass (CABG) surgery with cross-clamp fibrillation or blood cardioplegia for myocardial protection. The molecular mechanisms leading to these effects are yet not fully understood. The purpose of the present study is to validate previous studies and gather further evidence for RIPC during CABG with blood cardioplegia, furthermore to determine, whether or not RIPC is still operative during Off-pump coronary artery bypass surgery (OPCAB), finally to elucidate intra-cellular mechanisms involved in myocardial protection by RIPC and their possible systemic mediators.

Study Overview

• Status: Unknown
• Conditions: Myocardial Injury
• Intervention / Treatment: Procedure: Remote ischemic preconditioning (RIPC); Procedure: Coronary artery bypass grafting (CABG) without remote ischemic preconditioning protocol; Procedure: Off-pump Coronary artery bypass surgery without remote ischemic preconditioning

Detailed Description

Remote ischemic preconditioning (RIPC) protocol before CABG (study arm A) or OPCAB (study arm B) consists of 3 cycles of 5 minutes left upper arm ischemia by inflation of a blood pressure cuff to 200 mmHg and 5 minutes of reperfusion after induction of anesthesia before coronary artery bypass surgery. For myocardial molecular analyses, left ventricular biopsies are taken before induction of cardioplegic cardiac arrest (A) or first coronary incision (B), and 5 to 10 minutes after aortic unclamping during reperfusion of the myocardium (A) or 5 to 10 minutes after the completion of the last anastomosis (B). Blood samples are taken prior to RIPC and during the first three postoperative days.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Payam Akhyari, MD; Phone Number: +492118118331; Email: payam.akhyari@med.uni-duesseldorf.de
• Study Contact Backup: Name: Artur Lichtenberg, MD; Phone Number: +492118118331; Email: artur.lichtenberg@med.uni-duesseldorf.de

Study Locations

• Germany
  • Duesseldorf, Germany, 40225
    • Recruiting
    • Dept. Cardiovascular Surgery, University Hospital, Heinrich Heine University
    • Contact: Payam Akhyari, MD; Phone Number: +492118118331; Email: payam.akhyari@med.uni-duesseldorf.de
    • Contact: Alexander Albert, MD; Phone Number: +492118118331; Email: alexander.albert@med.uni-duesseldorf.de
    • Principal Investigator: Alexander Albert, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed triple vessel coronary artery disease
• Indication for surgical coronary revascularisation
• Written informed consent
• Age ≥ 18 years

Exclusion Criteria:

• Age > 80 years
• Instable angina/acute coronary syndrome
• Emergency surgery
• Recent myocardial infarction within 7 days prior to surgery
• Recent major infection/sepsis within 7 days prior to surgery
• Significant hepatic, renal oder pulmonary disease
• Other concomitant surgical procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: RIPC-CABG; Remote ischemic preconditioning (RIPC) protocol before coronary artery bypass surgery with blood cardioplegia for cardiac arrest (CABG) consists of 3 cycles of 5 minutes left upper arm ischemia by inflation of a blood pressure cuff to 200 mmHg and 5 minutes of reperfusion after induction of anesthesia before coronary artery bypass surgery. For myocardial molecular analyses, left ventricular biopsies are taken before induction of cardioplegic cardiac arrest and 5 to 10 Minutes after aortic unclamping during reperfusion of the myocardium. Blood samples are taken up to 72 hours postoperatively.	Procedure: Remote ischemic preconditioning (RIPC); 3 cycles of 5 min left upper arm ischemia by inflation of a blood pressure cuff to 200 mmHg and 5 min reperfusion. The applied anesthesia protocol avoids the use of propofol. Drugs: isoflurane+sufentanil anesthesia Anaesthesia is maintained by inhaled isoflurane in concentrations 0.7-0.8 % end-tidal with additional sufentanil injected during surgery, as required. In the CABG-arms, during extracorporal circulation patients receive isoflurane via a vaporizer incorporated in the extracorporeal gas supply in the same concentrations.; Other Names: RIPC: remote ischemic preconditioning; CABG: coronary artery bypass grafting; OPCAB: Off-pump coronary artery bypass surgery; Isoflurane: 2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane, Forane; Sufentanil, Sufenta, (R-30730)
PLACEBO_COMPARATOR: Control-CABG; Control group: Coronary artery bypass grafting without RIPC protocol	Procedure: Coronary artery bypass grafting (CABG) without remote ischemic preconditioning protocol; The applied anesthesia protocol avoids the use of propofol. Drugs: isoflurane+sufentanil anesthesia Anaesthesia is maintained by inhaled isoflurane in concentrations 0.7-0.8 % end-tidal with additional sufentanil injected during surgery, as required. During extracorporal circulation patients receive isoflurane via a vaporizer incorporated in the extracorporeal gas supply in the same concentrations.
ACTIVE_COMPARATOR: RIPC-OPCAB; Remote ischemic preconditioning (RIPC) protocol before Off-pump coronary artery bypass surgery (OPCAB) consists of 3 cycles of 5 minutes left upper arm ischemia by inflation of a blood pressure cuff to 200 mmHg and 5 minutes of reperfusion after induction of anesthesia before coronary artery bypass surgery. For myocardial molecular analyses, left ventricular biopsies are taken before first coronary artery incision and 5 to 10 Minutes after completion of the coronary anastomoses. Blood samples are taken up to 72 hours postoperatively.	Procedure: Remote ischemic preconditioning (RIPC); 3 cycles of 5 min left upper arm ischemia by inflation of a blood pressure cuff to 200 mmHg and 5 min reperfusion. The applied anesthesia protocol avoids the use of propofol. Drugs: isoflurane+sufentanil anesthesia Anaesthesia is maintained by inhaled isoflurane in concentrations 0.7-0.8 % end-tidal with additional sufentanil injected during surgery, as required. In the CABG-arms, during extracorporal circulation patients receive isoflurane via a vaporizer incorporated in the extracorporeal gas supply in the same concentrations.; Other Names: RIPC: remote ischemic preconditioning; CABG: coronary artery bypass grafting; OPCAB: Off-pump coronary artery bypass surgery; Isoflurane: 2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane, Forane; Sufentanil, Sufenta, (R-30730)
PLACEBO_COMPARATOR: Control-OPCAB; Control group: Off-pump Coronary artery bypass surgery without RIPC protocol	Procedure: Off-pump Coronary artery bypass surgery without remote ischemic preconditioning; The applied anesthesia protocol avoids the use of propofol. Drugs: isoflurane+sufentanil anesthesia Anaesthesia is maintained by inhaled isoflurane in concentrations 0.7-0.8 % end-tidal with additional sufentanil injected during surgery, as required.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Perioperative extent of myocardial injury as measured by cardiac troponin T serum release over 72 hours after coronary bypass surgery and its area under the curve (AUC).	72 hours postoperatively after CABG surgery

Secondary Outcome Measures

Outcome Measure	Time Frame
All-cause mortality	30 days and 1 year after coronary bypass surgery
Major adverse cardiac and cerebrovascular events (MACCE)	30 days and 1 year after coronary bypass surgery
Myocardial infarction	30 days and 1 year after coronary bypass surgery
Renal function	30 days and 1 year after coronary bypass surgery
circulating microparticles after coronary bypass surgery	perioperatively, 3 months and 1 year after coronary bypass surgery

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf
• Collaborators: University Hospital, Essen
• Investigators: Principal Investigator: Payam Akhyari, MD, Dept. of Cardiovascular Surgery, University Hospital, Heinrich Heine University, Duesseldorf, Germany; Principal Investigator: Alexander Albert, MD, Dept. of Cardiovascular Surgery, University Hospital, Heinrich Heine University, Duesseldorf, Germany; Principal Investigator: Artur Lichtenberg, MD, Dept. of Cardiovascular Surgery, University Hospital, Heinrich Heine University, Duesseldorf, Germany; Principal Investigator: Gerd Heusch, MD, PhD, nst. of Pathophysiology, University Duisburg-Essen, University Hospital Essen, Essen, Germany

Publications and helpful links

General Publications

• Hausenloy DJ, Erik Botker H, Condorelli G, Ferdinandy P, Garcia-Dorado D, Heusch G, Lecour S, van Laake LW, Madonna R, Ruiz-Meana M, Schulz R, Sluijter JP, Yellon DM, Ovize M. Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res. 2013 Apr 1;98(1):7-27. doi: 10.1093/cvr/cvt004. Epub 2013 Jan 19.
• Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M. STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ Res. 2012 Jan 6;110(1):111-5. doi: 10.1161/CIRCRESAHA.111.259556. Epub 2011 Nov 23.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (ANTICIPATED): June 1, 2015
• Study Completion (ANTICIPATED): December 1, 2015

Study Registration Dates

• First Submitted: May 29, 2012
• First Submitted That Met QC Criteria: May 30, 2012
• First Posted (ESTIMATE): May 31, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): July 16, 2013
• Last Update Submitted That Met QC Criteria: July 15, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: myocardial injury; remote ischemic preconditioning; coronary artery bypass grafting
• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Anesthetics, Inhalation; Isoflurane; Sufentanil
• Other Study ID Numbers: RIPCON-12