Clinical trial NCT00650507: Clinical and Genomic Responses to Open Heart Surgery
Official title: Clinical and Genomic Responses to Open Heart Surgery: A Randomized Controlled Trial of the Effects of Remote Ischemic Preconditioning
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ischemia-reperfusion (IR) Injury
Keywords: children
cardiac surgery
remote ischemic preconditioning
SHAM
ischemia-reperfusion
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
First posted: 2008-04-01
Enrollment: 300
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL

Brief summary: 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.

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 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.

Primary outcomes:
measure: Impact of RIPC on length of hospital stay.
timeFrame: Assessed through post-operative hospitalization.
Secondary outcomes:
measure: Gene expression patterns associated with effects of RIPC.
timeFrame: Assessed and recorded during the first 24 hours after surgery.
measure: Patterns of baseline gene expression predictive of the clinical and physiologic impact of cardiopulmonary bypass in children (SHAM group only).
timeFrame: Assessed and recorded during the first 24 hours after surgery.
measure: Impact of RIPC on clinical and physiologic markers related to ischemia-reperfusion injury after cardiac surgery in children.
timeFrame: Assessed and recorded serially during the first 48 hours after surgery.
measure: Neurodevelopmental Outcomes (Age < 2 years old at surgery)
timeFrame: Follow-up at 12-18 months post-surgery
measure: Neurodevelopmental Outcomes (Age 2-6 years old at surgery)
timeFrame: Follow-up at 12-18 months post-surgery
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Brian W. McCrindle
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Brian W. McCrindle, MD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Andrew N. Redington, MB
role: PRINCIPAL_INVESTIGATOR
References:
citation: McCrindle BW, Clarizia NA, Khaikin S, Holtby HM, Manlhiot C, Schwartz SM, Caldarone CA, Coles JG, Van Arsdell GS, Scherer SW, Redington AN. Remote ischemic preconditioning in children undergoing cardiac surgery with cardiopulmonary bypass: a single-center double-blinded randomized trial. J Am Heart Assoc. 2014 Jul 28;3(4):e000964. doi: 10.1161/JAHA.114.000964.