Dexmedetomidine Effect on Mitochondrial Function

Complication of Anesthesia Clinical Trial

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02299063
• Other study ID #: 1000044746
• Status: Recruiting
• Phase: Phase 4
• Start date: November 2014
• Est. completion date: December 2019

Study information

• Verified date: May 2018
• Source: The Hospital for Sick Children
• Contact: James D O'Leary, MBBCh
• Phone: (416) 813-1500
• Email: james.oleary[@]sickkids.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: December 2019
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 36 Months

Eligibility

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

Related Conditions & MeSH terms

• Complication of Anesthesia
• Ischaemia-reperfusion Injury
• Ischemia
• Reperfusion Injury

Intervention

Drug:
• Dexmedetomidine
A bolus dose of 0.5 mcg/kg infused over 10 minutes will be administered, followed by a continuous infusion for the duration of the surgery at 0.6 mcg/kg/hr.
• 0.9% NaCl

Locations

Country	Name	City	State
Canada	Hospital for Sick Children	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
The Hospital for Sick Children

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Analgesic effects (Morphine equivalent dose of narcotics consumed)	Morphine equivalent dose of narcotics consumed	Perioperative (from induction of anesthesia for 24 hours)
Other	Sedative effects (Duration of intubation)	Duration of intubation.	Perioperative (from induction of anesthesia for 24 hours)
Primary	Mitochondrial function (use high content imaging (HCI)	The primary outcomes for mitochondria will be grouped into mitochondrial function, morphology, content and mtDNA damage.	Intraoperative
Secondary	Creatinine level (Marker of acute renal injury)	Marker of acute renal injury	Postoperative day 1
Secondary	Cardiac function (Left ventricular ejection fraction measured by trans-thoracic echocardiography)	Left ventricular ejection fraction measured by trans-thoracic echocardiography	Postoperative day 1
Secondary	Inotropes and vasopressors (Duration and dose of inotropes and vasopressors after surgery)	Duration and dose of inotropes and vasopressors after surgery	Postoperative day 1