Clinical trial NCT02299063: Dexmedetomidine Effect on Mitochondrial Function
Official title: The Protective Effect of the α2-agonist Dexmedetomidine on Mitochondrial Structure and Function for Children With Non-cyanotic Congenital Heart Defects Having Cardiac Surgery: A Randomized Controlled Trial.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Complication of Anesthesia
Ischaemia-reperfusion Injury
Keywords: Mitochondria
Dexmedetomidine
Heart Defects, Congenital
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
First posted: 2014-11-24
Enrollment: 36
Sex: ALL
Minimum age (years): 3
Maximum age (years): 36
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The investigators hypothesize that in addition to a known sympatholytic effect, intraoperative dexmedetomidine reduces adverse changes in mitochondrial function and structure attenuating ischaemia-reperfusion and end-organ injury for children with non cyanotic congenital heart defects having corrective heart surgery.

Detailed description: PICO: For children with non cyanotic congenital heart defects having corrective heart surgery (P) does intraoperative dexmedetomidine (I) reduce real-time changes in mitochondrial function and content (O) compared with children not receiving dexmedetomidine (C).

The study drug (dexmedetomidine or placebo) will be mixed in a standardized syringe of 4mcg/mL for active syringes or 50mL 0.9% sodium chloride for placebo. Blinded syringes will be prepared by the Research Support Pharmacy.

Administration is via the existing central venous line. A bolus dose of 0.125mL/kg (0.5 mcg/kg dexmedetomidine) infused over 10 minutes will be administered, followed by a continuous infusion for the duration of the surgery. The dexmedetomidine/placebo continuous infusion (CI) dose will run at 0.15mL/kg/hr (0.6 mcg/kg/hr dexmedetomidine).

Blood samples will be obtained from each child at three points in the operating room: 1) after the induction of anesthesia, 2) at the first separation from CPB (prior to administration of blood products), and 3) at the end of the surgery.

Samples obtained will be analyzed for mitochondrial function and morphology, total cellular mitochondrial biomass, and mitochondrial deoxyribonucleic acid (mtDNA) damage:

1. After isolating lymphocytes, we will use high content imaging (HCI) to assess mitochondrial function and morphology. The lymphocytes will be stained with tetramethylrhodamine methyl ester (TMRM), which stains mitochondria in proportion to mitochondrial membrane potential, giving a metric for mitochondrial function. In addition, the cells will be stained with MitoTracker Green®, which can be used to assess mitochondrial morphology. Mitochondrial morphology will be quantified in a non-biased fashion using a mathematical image analysis algorithm.
2. After extraction of genomic DNA, total cellular mitochondrial biomass and mitochondrial DNA damage will be measured using traditional and long-patch quantitative polymerase chain reaction (PCR).

Myocardial tissue will be also collected prior to closure of the atriotomy. Samples will be placed into 3% buffered glutaraldehyde at the time of biopsy, and imaging of mitochondrial structure using electron microscopy will be performed.

Eligibility criteria: Inclusion Criteria:

* aged between 3 - 36 months
* having primary corrective heart surgery

Exclusion Criteria:

* recent surgery (\< 3 months)
* previous chemotherapy
* previous transfusion of blood products
* neurodevelopmental disorders (including Trisomy 21)
* supplemental oxygen requirement (\< 3 months)
* asthma requiring regular therapy
* obstructive sleep apnea
* the presence of concurrent infection or inflammation
* a known allergy to dexmedetomidine hydrochloride

Primary outcomes:
measure: Mitochondrial function (use high content imaging (HCI)
timeFrame: Intraoperative
Secondary outcomes:
measure: Creatinine level (Marker of acute renal injury)
timeFrame: Postoperative day 1
measure: Cardiac function (Left ventricular ejection fraction measured by trans-thoracic echocardiography)
timeFrame: Postoperative day 1
measure: Inotropes and vasopressors (Duration and dose of inotropes and vasopressors after surgery)
timeFrame: Postoperative day 1
Other outcomes:
measure: Analgesic effects (Morphine equivalent dose of narcotics consumed)
timeFrame: Perioperative (from induction of anesthesia for 24 hours)
measure: Sedative effects (Duration of intubation)
timeFrame: Perioperative (from induction of anesthesia for 24 hours)
Locations:
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: James D O'Leary, MBBCh
role: PRINCIPAL_INVESTIGATOR
References: