Dexmedetomidine Effect on Mitochondrial Function

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.

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.

Study Overview

• Status: Unknown
• Conditions: Complication of Anesthesia; Ischaemia-reperfusion Injury
• Intervention / Treatment: Drug: 0.9% NaCl; Drug: Dexmedetomidine

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.

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: James D O'Leary, MBBCh; Phone Number: 228845 (416) 813-1500; Email: james.oleary@sickkids.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G1X8
      • Recruiting
      • Hospital for Sick Children
      • Principal Investigator: James D O'Leary, MBBCh
      • Sub-Investigator: John Coles, MD
      • Sub-Investigator: Jason T Maynes, MD PhD
      • Sub-Investigator: Daniel Stocki

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 3 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo (0.9% Saline); 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.	Drug: 0.9% NaCl; Other Names: Normal Saline
Experimental: 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.	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.; Other Names: Precedex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Creatinine level (Marker of acute renal injury)	Marker of acute renal injury	Postoperative day 1
Cardiac function (Left ventricular ejection fraction measured by trans-thoracic echocardiography)	Left ventricular ejection fraction measured by trans-thoracic echocardiography	Postoperative day 1
Inotropes and vasopressors (Duration and dose of inotropes and vasopressors after surgery)	Duration and dose of inotropes and vasopressors after surgery	Postoperative day 1

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analgesic effects (Morphine equivalent dose of narcotics consumed)	Morphine equivalent dose of narcotics consumed	Perioperative (from induction of anesthesia for 24 hours)
Sedative effects (Duration of intubation)	Duration of intubation.	Perioperative (from induction of anesthesia for 24 hours)

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Investigators: Principal Investigator: James D O'Leary, MBBCh, The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: November 18, 2014
• First Submitted That Met QC Criteria: November 21, 2014
• First Posted (Estimate): November 24, 2014

Study Record Updates

• Last Update Posted (Actual): May 9, 2018
• Last Update Submitted That Met QC Criteria: May 8, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Heart Defects, Congenital; Dexmedetomidine; Mitochondria
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Ischemia; Reperfusion Injury; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: 1000044746

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No