Clinical and Genomic Responses to Open Heart Surgery - Full Text View

Purpose

This study will be the first large scale randomized study of remote ischemic preconditioning (RIPC) ever performed and will define the role of this novel therapy as a clinical tool. This study will also be the first to define preoperative gene expression profiles associated with poor postoperative outcomes in a control (SHAM) population of children undergoing cardiac surgery. Finally, the role of RIPC in modifying these gene expression profiles will be examined. Therefore, mechanistic insight into the proven ability of RIPC to improve markers of tissue injury, and the expected improvement in clinically relevant endpoints, will be examined.

Condition	Intervention	Phase
Ischemia-reperfusion (IR) Injury	Procedure: Remote ischemic preconditioning (RIPC) Procedure: SHAM	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Official Title:	Clinical and Genomic Responses to Open Heart Surgery: A Randomized Controlled Trial of the Effects of Remote Ischemic Preconditioning

Resource links provided by NLM:

MedlinePlus related topics: Heart Surgery

U.S. FDA Resources

Further study details as provided by The Hospital for Sick Children:

Primary Outcome Measures:

Impact of RIPC on length of hospital stay. [ Time Frame: Assessed through post-operative hospitalization. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Gene expression patterns associated with effects of RIPC. [ Time Frame: Assessed and recorded during the first 24 hours after surgery. ] [ Designated as safety issue: No ]
Patterns of baseline gene expression predictive of the clinical and physiologic impact of cardiopulmonary bypass in children (SHAM group only). [ Time Frame: Assessed and recorded during the first 24 hours after surgery. ] [ Designated as safety issue: No ]
Impact of RIPC on clinical and physiologic markers related to ischemia-reperfusion injury after cardiac surgery in children. [ Time Frame: Assessed and recorded serially during the first 48 hours after surgery. ] [ Designated as safety issue: No ]
Neurodevelopmental Outcomes (Age < 2 years old at surgery) [ Time Frame: Follow-up at 12-18 months post-surgery ] [ Designated as safety issue: No ]
Patients less than a two years of age at the time of surgery will return at 12 -18 months postoperative to be assessed using the BSID- III. During the same visit, parents will complete questionnaires pertaining to their child's behavior and adaptive behavior; the parent version of the Child Behavior Checklist and the parent version of the Vineland Adaptive Behavior Scales - II.
Neurodevelopmental Outcomes (Age 2-6 years old at surgery) [ Time Frame: Follow-up at 12-18 months post-surgery ] [ Designated as safety issue: No ]
Patients greater than two years of age at the time of surgery will be assessed using the Wechsler Preschool and Primary Scale of Intelligence-Revised, the Peabody Picture Vocabulary Test - IV and the Beery-Buktenica Developmental Test of Visual-Motor Integration, 5th Edition. Parents will complete questionnaires pertaining to their child's behavior and adaptive behavior; the parent version of the Child Behavior Checklist and the parent version of the Vineland Adaptive Behavior Scales - II.

Estimated Enrollment:	296
Study Start Date:	March 2008
Estimated Study Completion Date:	December 2012
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1	Procedure: Remote ischemic preconditioning (RIPC) The RIPC stimulus will be delivered in the OR prep room after the induction of anesthesia (while the anesthesiologist and staff are inserting vascular cannulae and preparing the patient for surgery). Whenever possible, the left lower limb will be selected for delivery of the stimulus. An appropriate sized cuff will be selected and connected to a hand aneroid sphygmomanometer. A second cuff and hand aneroid sphygmomanometer will be placed beside the one connected to the study subject. The cuff on the limb will be inflated and deflated to provide a total of four cycles of limb ischemia and reperfusion.
Active Comparator: 2	Procedure: SHAM For this group, the procedure will be identical for that described for the RIPC stimulus, with the exception that the blood pressure cuff placed on the subject will not be inflated, but the second cuff, that has been placed beside, will be inflated.

Arms

Assigned Interventions

Experimental: 1

Procedure: Remote ischemic preconditioning (RIPC)

The RIPC stimulus will be delivered in the OR prep room after the induction of anesthesia (while the anesthesiologist and staff are inserting vascular cannulae and preparing the patient for surgery). Whenever possible, the left lower limb will be selected for delivery of the stimulus. An appropriate sized cuff will be selected and connected to a hand aneroid sphygmomanometer. A second cuff and hand aneroid sphygmomanometer will be placed beside the one connected to the study subject. The cuff on the limb will be inflated and deflated to provide a total of four cycles of limb ischemia and reperfusion.

Active Comparator: 2

Procedure: SHAM

For this group, the procedure will be identical for that described for the RIPC stimulus, with the exception that the blood pressure cuff placed on the subject will not be inflated, but the second cuff, that has been placed beside, will be inflated.

Detailed Description:

Remote ischemic preconditioning (RIPC) is a powerful, innate mechanism of protection against ischemia-reperfusion (IR) injury. During the course of previous investigations, it was shown in animal models that transient limb ischemia (our stimulus for generating remote ischemic preconditioning) leads to induction of a portfolio of myocardial genomic responses concerned with stress-response and repair mechanisms, reduces myocardial infarction after prolonged coronary occlusion, protects against cardiopulmonary bypass-induced neural, pulmonary and myocardial damage, and when administered to the recipient, reduces IR injury in the transplanted heart.

In humans, it has been have shown that RIPC downregulates genes responsible for pro-inflammatory pathways concerned with TNFα-signaling, apoptosis and exocytosis in circulating leukocytes, reduces ischemia-induced endothelial dysfunction, and decreases markers of myocardial and lung injury in a pilot study of children undergoing open heart surgery. However, the latter study was not powered to demonstrate differences in anatomic and age-related subgroups, or clinically relevant 'hard' end-points such as ventilation time, intensive care, and length of hospital stay.

Thus, we are now proposing a large-scale clinical study examining genetic predictors of clinically relevant postoperative outcomes, and how they are modified by remote preconditioning.

Eligibility

Ages Eligible for Study:	up to 17 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Subject age birth (>36 weeks gestation) to 17 years.
Underlying cardiac anatomy and planned primary repair with no anticipated residual shunting. Repair must necessitate use of cardiopulmonary bypass.
Informed consent/assent of subject, parent(s) or legal guardian as appropriate.

Exclusion Criteria:

Current or recent ischemic insult, defined as vascular occlusion or episode of cardiorespiratory collapse requiring medical intervention occurring within 7 days of enrollment.
Evidence in any system for organ dysfunction that requires medical intervention.
Current treatment with systemic anticoagulation therapy or the presence of a bleeding diathesis.
Presence of important pulmonary or airway disease requiring medical intervention.
Current or previous (within 10 days of screening) use of systemic corticosteroids.
Recent (within 7 days of screening) or current documented systemic infection or sepsis.
Anticipated unavailability of an uninstrumented limb with no anatomic or physiologic abnormality precluding administration of RIPC stimulus using a standard blood pressure cuff.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00650507

Contacts

Contact: Brian W. McCrindle, MD

(416)813-7610

brian.mccrindle@sickkids.ca

Locations

Canada, Ontario
Brian W. McCrindle	Recruiting
Toronto, Ontario, Canada
Contact: Brian W. McCrindle, MD (416)813-7610 brian.mccrindle@sickkids.ca

Sponsors and Collaborators

The Hospital for Sick Children

Investigators

Principal Investigator:	Brian W. McCrindle, MD MPH	The Hospital for Sick Children
Principal Investigator:	Andrew N. Redington, MB	The Hospital for Sick Children

More Information

No publications provided

Responsible Party:	Brian McCrindle/Principal Investigator, The Hospital for Sick Children
ClinicalTrials.gov Identifier:	NCT00650507 History of Changes
Other Study ID Numbers:	1000011898
Study First Received:	March 27, 2008
Last Updated:	January 26, 2011
Health Authority:	Canada: Ethics Review Committee

Keywords provided by The Hospital for Sick Children:

children
cardiac surgery
remote ischemic preconditioning
SHAM
ischemia-reperfusion

Additional relevant MeSH terms:

Ischemia
Pathologic Processes

ClinicalTrials.gov processed this record on May 19, 2013