Neurobiological and Cognitive Changes Following Exposure to Either Sevoflurane- or Propofol-based Anesthesia in Children

Neurobiological, Cognitive-affective and Behavioral Changes Following Exposure to Either Sevoflurane- or Propofol-based Anesthesia in Children Undergoing MRI

The demand for magnetic resonance imaging (MRI) in pediatric patients is increasing due to its use in medical diagnosis and surveillance. Pediatric patients often require general anesthesia (GA) for MRI due to the need for prolonged immobility during the scanning process to obtain high quality images. Two widely used anesthetic techniques for pediatric MRIs are volatile-based anesthesia using sevoflurane and total intravenous anesthesia (TIVA) using propofol. Concerns have been raised regarding the potential neurotoxic effects of anesthetics on the developing brain. Within the animal literature, there is emerging evidence to suggest that both sevoflurane and propofol may cause inflammation, impacting brain cell survival and connections, thereby contributing to possible cognitive dysfunction. However, given the challenges in extrapolating the animal data to humans, and the relatively limited human cohort studies examining the long-term effects of anesthesia exposure, there is inadequate information available to make informed clinical decisions regarding the choice of optimal anesthetic agents for MRI in children. Therefore, this study will uniquely examine the mechanisms of two widely used anesthetics and their short and long-term impact on developmental outcomes in healthy children.

Study Overview

• Status: Completed
• Conditions: Cognitive Change; Behavior
• Intervention / Treatment: Drug: Sevoflurane; Drug: Ametop; Drug: Ondansetron; Drug: Propofol

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 1N4
      • University of Calgary

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 5 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Those between the ages 2 to 5 years who require general anesthesia for MRI Brain and have an American Society of Anesthesiologists' physical status of I to II

Exclusion Criteria:

• Emergency cases
• Intubated prior to MRI
• Allergies/contraindication to anesthetics
• Requirement of a painful procedure with MRI
• Significant developmental delay
• Autism or suspected autism
• History of extreme prematurity <28 wks gestational age
• Sedation or general anesthesia in the last 14 days
• Receiving chemotherapy or radiation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Inhalational Technique; All patients will receive Ametop local anesthetic to the dorsum of both hands 30-45 minutes prior to induction. After inhalation induction of anesthesia with sevoflurane (in 100% O2), an IV will be obtained. Anesthesia will be maintained with sevoflurane (in a mixture of air:oxygen) with a minimum alveolar concentration of 1.0-1.3, titrated to effect. No long acting opioids or nitrous oxide will be used. Airway management will be at the discretion of the anesthesiologist. Each patient will receive the antiemetic ondansetron 0.1mg/kg IV.	Drug: Sevoflurane; The child will be randomized via a block design to receive either a volatile anesthetic (induction: sevoflurane), or total intravenous anesthetic technique (induction: propofol); Drug: Ametop; Each patient will receive Ametop local anesthetic to the dorsum of both hands 30-45 minutes prior to induction.; Drug: Ondansetron; Each patient will receive the antiemetic ondansetron 0.1mg/kg IV.
EXPERIMENTAL: Total Intravenous Anesthetic Technique; All patients will receive Ametop local anesthetic to the dorsum of both hands 30-45 minutes prior to IV insertion. Once an IV is established, patients will receive an IV bolus of propofol (2-6mg/kg). Anesthesia will be maintained with a propofol infusion starting at 250 mcg/kg/min and titrated to effect. Airway management will be at the discretion of the anesthesiologist. Each patient will receive the antiemetic ondansetron 0.1mg/kg IV.	Drug: Ametop; Each patient will receive Ametop local anesthetic to the dorsum of both hands 30-45 minutes prior to induction.; Drug: Ondansetron; Each patient will receive the antiemetic ondansetron 0.1mg/kg IV.; Drug: Propofol; The child will be randomized via a block design to receive either a volatile anesthetic (induction: sevoflurane), or total intravenous anesthetic technique (induction: propofol)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV)	The WPPSI - IV is designed for children aged 2.5 to 7.5 years, and is used to assess general intelligence.	12-15 weeks from date of randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Child Behavior Checklist (CBCL) 1.5 to 5 years	The CBCL is widely used for identifying problem behaviors in children ages 1.5 to 5 years	Change from baseline at 12-13 weeks after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P)	The BRIEF-P is the first standardized rating scale designed to specifically measure executive function in preschool-aged children (ages 2-5).	Change from baseline within 1 week after randomization
The Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P)	The BRIEF-P is the first standardized rating scale designed to specifically measure executive function in preschool-aged children (ages 2-5).	Change from baseline within 2-3 weeks after randomization
The Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P)	The BRIEF-P is the first standardized rating scale designed to specifically measure executive function in preschool-aged children (ages 2-5).	Change from baseline within 12-13 weeks after randomization
The Post Hospital Behavior Questionnaire (PHBQ)	The PHBQ asks parents to rate their child's behavior on 27 items concerning sleep, eating, internalizing and externalizing behaviors. For each item parents must compare their child's current behavior with their behavior one week prior to hospitalization.	Within 1 week after randomization
The Post Hospital Behavior Questionnaire (PHBQ)	The PHBQ asks parents to rate their child's behavior on 27 items concerning sleep, eating, internalizing and externalizing behaviors. For each item parents must compare their child's current behavior with their behavior one week prior to hospitalization.	Within 2-3 weeks after randomization
The Modified Yale Preoperative Anxiety Scale (mYPAS)	The mYPAS is the current "gold standard" for assessing anxiety during induction of anesthesia for children ages 2-16 years.	On the day of randomization, obtained just prior to the intervention
Pediatric Anesthesia Emergence Delirium (PAED) Scale	Validated tool to measure emergence delirium in children.	On the day or randomization, obtained immediately after the intervention
Nuclear Magnetic Resonance Spectroscopy (NMRS)	Glucose, lactate, choline and NAA values will be obtained from the parietal cortex	On the day of randomization, obtained during the intervention
Resting State Functional Magnetic Resonance Imaging (rfMRI)	Resting functional brain networks will be identified and compared between groups	On the day of randomization, obtained during the intervention
Inflammatory Markers	Concentrations of plasma IL-1b, TNF-a, IL-6, IL-10 will be quantified	On the day of randomization, change from baseline, obtained immediately after the intervention
Blood metabolites	Concentrations of plasma proteins, peptides and metabolites will be quantified	On the day of randomization, change from baseline, obtained immediately after the intervention

Collaborators and Investigators

• Sponsor: University of Calgary
• Investigators: Principal Investigator: Tiffany Rice, PhD, MD, University of Calgary

Study record dates

Study Major Dates

• Study Start: January 1, 2017
• Primary Completion (ACTUAL): September 1, 2019
• Study Completion (ACTUAL): September 1, 2019

Study Registration Dates

• First Submitted: December 21, 2016
• First Submitted That Met QC Criteria: January 11, 2017
• First Posted (ESTIMATE): January 16, 2017

Study Record Updates

• Last Update Posted (ACTUAL): March 26, 2020
• Last Update Submitted That Met QC Criteria: March 24, 2020
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Platelet Aggregation Inhibitors; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Antagonists; Hypnotics and Sedatives; Anti-Anxiety Agents; Anesthetics, Inhalation; Antipruritics; Propofol; Sevoflurane; Ondansetron
• Other Study ID Numbers: REB16-0104

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED