Clinical and Genomic Responses to Open Heart Surgery

The Hospital for Sick Children

Status and phase: Completed; Phase 3

Conditions: Ischemia-reperfusion (IR) Injury

Treatments: Procedure: SHAM; Procedure: Remote ischemic preconditioning (RIPC)

Study type: Interventional

Funder types: Other

Identifiers

NCT00650507

1000011898

Details and patient eligibility

About

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.

Full 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.

Enrollment: 300 patients

Sex: All

Ages: 1 day to 17 years old

Volunteers: No Healthy Volunteers

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.

Trial design

300 participants in 2 patient groups

1

Experimental group

Treatment:

Procedure: Remote ischemic preconditioning (RIPC)

2

Active Comparator group

Treatment:

Procedure: SHAM