Dexmedetomidine Effect on Mitochondrial Function

The Hospital for Sick Children

Status and phase: Unknown; Phase 4

Conditions: Ischaemia-reperfusion Injury; Complication of Anesthesia

Treatments: Drug: Dexmedetomidine; Drug: 0.9% NaCl

Study type: Interventional

Funder types: Other

Identifiers

NCT02299063

1000044746

Details and patient eligibility

About

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.

Full 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.

Enrollment: 36 estimated patients

Sex: All

Ages: 3 to 36 months old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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36 participants in 2 patient groups, including a placebo group

Placebo (0.9% Saline)

Placebo Comparator group

Description:

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.

Treatment:

Drug: 0.9% NaCl

Dexmedetomidine

Experimental group

Description:

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.

Treatment:

Drug: Dexmedetomidine