Dexmedetomidine Effect on Mitochondrial Function
- Conditions
- Complication of AnesthesiaIschaemia-reperfusion Injury
- Interventions
- Drug: 0.9% NaCl
- Registration Number
- NCT02299063
- Lead Sponsor
- The Hospital for Sick Children
- 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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 36
- aged between 3 - 36 months
- having primary corrective heart surgery
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo (0.9% Saline) 0.9% NaCl 0.9% Saline: bolus dose of 0.125mL/kg infused over 10 minutes, followed by a continuous infusion (CI) dose at 0.15mL/kg/hr for the duration of surgery. Dexmedetomidine Dexmedetomidine Dexmedetomidine: bolus dose of 0.5 mcg/kg infused over 10 minutes, followed by a continuous infusion (CI) dose at 0.6 mcg/kg/hr for the duration of surgery.
- Primary Outcome Measures
Name Time Method Mitochondrial function (use high content imaging (HCI) Intraoperative The primary outcomes for mitochondria will be grouped into mitochondrial function, morphology, content and mtDNA damage.
- Secondary Outcome Measures
Name Time Method Cardiac function (Left ventricular ejection fraction measured by trans-thoracic echocardiography) Postoperative day 1 Left ventricular ejection fraction measured by trans-thoracic echocardiography
Creatinine level (Marker of acute renal injury) Postoperative day 1 Marker of acute renal injury
Inotropes and vasopressors (Duration and dose of inotropes and vasopressors after surgery) Postoperative day 1 Duration and dose of inotropes and vasopressors after surgery
Trial Locations
- Locations (1)
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada