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Dexmedetomidine Effect on Mitochondrial Function

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ClinicalTrials.gov Identifier: NCT02299063
Recruitment Status : Unknown
Verified May 2018 by James O'Leary, The Hospital for Sick Children.
Recruitment status was:  Recruiting
First Posted : November 24, 2014
Last Update Posted : May 9, 2018
Sponsor:
Information provided by (Responsible Party):
James O'Leary, 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.

Condition or disease Intervention/treatment Phase
Complication of Anesthesia Ischaemia-reperfusion Injury Drug: Dexmedetomidine Drug: 0.9% NaCl Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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 Start Date : November 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


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 Name: 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 Name: Precedex




Primary Outcome Measures :
  1. Mitochondrial function (use high content imaging (HCI) [ Time Frame: Intraoperative ]
    The primary outcomes for mitochondria will be grouped into mitochondrial function, morphology, content and mtDNA damage.


Secondary Outcome Measures :
  1. Creatinine level (Marker of acute renal injury) [ Time Frame: Postoperative day 1 ]
    Marker of acute renal injury

  2. Cardiac function (Left ventricular ejection fraction measured by trans-thoracic echocardiography) [ Time Frame: Postoperative day 1 ]
    Left ventricular ejection fraction measured by trans-thoracic echocardiography

  3. Inotropes and vasopressors (Duration and dose of inotropes and vasopressors after surgery) [ Time Frame: Postoperative day 1 ]
    Duration and dose of inotropes and vasopressors after surgery


Other Outcome Measures:
  1. Analgesic effects (Morphine equivalent dose of narcotics consumed) [ Time Frame: Perioperative (from induction of anesthesia for 24 hours) ]
    Morphine equivalent dose of narcotics consumed

  2. Sedative effects (Duration of intubation) [ Time Frame: Perioperative (from induction of anesthesia for 24 hours) ]
    Duration of intubation.



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Ages Eligible for Study:   3 Months to 36 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02299063


Contacts
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Contact: James D O'Leary, MBBCh (416) 813-1500 ext 228845 james.oleary@sickkids.ca

Locations
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Canada, Ontario
Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G1X8
Principal Investigator: James D O'Leary, MBBCh         
Sub-Investigator: John Coles, MD         
Sub-Investigator: Jason T Maynes, MD PhD         
Sub-Investigator: Daniel Stocki         
Sponsors and Collaborators
The Hospital for Sick Children
Investigators
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Principal Investigator: James D O'Leary, MBBCh The Hospital for Sick Children
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Responsible Party: James O'Leary, Staff Anesthesiologist, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT02299063    
Other Study ID Numbers: 1000044746
First Posted: November 24, 2014    Key Record Dates
Last Update Posted: May 9, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by James O'Leary, The Hospital for Sick Children:
Mitochondria
Dexmedetomidine
Heart Defects, Congenital
Additional relevant MeSH terms:
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Reperfusion Injury
Ischemia
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Dexmedetomidine
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action