Epigenetics in PostOperative Pediatric Emergence Delirium (EPOPED)

January 19, 2022 updated by: Maria José Carvalho Carmona, University of Sao Paulo

Investigation of the DNA Methylation Profile in Children Who Presented Emergence Delirium

Emergence delirium (ED) infers the occurrence of behavior and cognition changes during the early postoperative period. Main signs and symptoms of ED are the disturbances of consciousness and awareness of the environment, with disorientation and perceptual alterations, including hypersensitivity to external stimuli and hyperactive motor behaviors. The incidence may be higher than 80%. Risk factors include pre-school age, use of sevoflurane, ophthalmologic and otorhinolaryngologic surgeries, child anxiety, parental or caregiver anxiety. The recurrence of ED is controversial. The only validated scale for diagnosis of ED is the PAED (Pediatric Anesthesia Emergence Delirium). Prevention is the best approach, as well as the use of alpha-2 agonists, propofol and total intravenous anesthesia. There are still no clear markers for postoperative delirium, especially ED. Cognitive alterations may be related to epigenetic modifications. Anesthesia-induced epigenetic changes may be the key to understanding perioperative complications and outcomes and is a field of future research in anesthesia. The study aims to analyze the DNA methylation profile in children with ED. A prospective, randomized study will be carried out in up to 322 children undergoing general anesthesia (inhalation group or intravenous group) to perform endoscopic procedures at the Instituto da Criança, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil. Patients will have blood samples drawn, and analysis of the DNA methylation profile through the array technique will be performed in 40 children (20 of each group ) who presented ED as well as in 08 control cases. Also, the occurrence of ED will be correlated with the degree of anxiety of the child, parents and during anesthetic induction, in addition to comparing the two anesthetic techniques with the occurrence of ED and late postoperative cognitive alterations.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

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Intervention / Treatment

Intervention / Treatment

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Detailed Description

BACKGROUND: The risks of neurotoxicity and late cognitive impairment supported the recent US Food and Drug Administration (FDA) recommendation on caution in the indication of anesthesia in children up to 3 years of age. Among the cognitive alterations related to pediatric anesthesia, emergence delirium (ED) is frequent in pre-school children. There is no consensus on the risk factors and forms of ED prevention, which occurs more frequently after inhalation anesthesia. On the other hand, anesthesia-induced epigenetic changes may be the key to understanding various complications and perioperative outcomes. There are no specific biomarkers for ED. Such biomarkers would be used to measure the risk of ED and would contribute to prevention and treatment. It has been hypothesized that behavioral changes in ED may be related to epigenetic modifications, analyzed through the DNA methylation profile. OBJECTIVES: The primary aim of the study is to investigate the DNA methylation profile in children with ED. The secondary objectives are to evaluate the correlation between the DNA methylation profile with the anesthetic technique and the degree of preoperative anxiety. METHODS: Children (N=322) from 1 to 12 years old, candidates to digestive endoscopy under general anesthesia will be recruited in an outpatient clinic from a tertiary university hospital. After informed consent, the child and parents' preoperative anxiety will be assessed through the modified Yale Preoperative Anxiety Scale (mYPAS) and VAS-Anx (Anxiety Visual Analogic Scale), respectively. The quality of anesthetic induction will be evaluated through Pediatric Anesthesia Behavior (PAB) scale and Perioperative Adult Child Behavior Interaction Scale (PACBIS). After inhaled induction with sevoflurane, blood sample collection will be performed to evaluate DNA methylation, followed by randomization in two groups to maintain anesthesia using the venous technique, with propofol or inhaled anesthesia with sevoflurane. Upon awakening, the ED will be evaluated through PAED (Pediatric Anesthesia Emergence Delirium) scale. Twenty children from each group presenting ED as well as 08 control cases will have their venous blood samples sent for DNA methylation analysis using the array technique. After hospital discharge, the postoperative behavioral changes will be observed through the PHBQ (Post Hospitalization Behavior Questionnaire) questionnaire.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
175

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Brazil
      • São Paulo, Brazil
        • Instituto da Crianca do Hospital das Clinicas da FMUSP

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

1 year to 12 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • children with ASA physical status 1, 2 or 3

Exclusion Criteria:

  • children under psychiatric medication
  • developmental delays
  • genetics syndromes that course with developmental delays
  • contraindication to randomization

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Screening
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Sevoflurane
All children will receive inhalation anesthesia with sevoflurane through facial mask in concentrations between 3-8% for anesthesia induction . After induction and peripheral vein puncture, the anesthesia will be maintained only with sevoflurane 3% until completion of the procedure.
Drug: Sevoflurane
All children will receive inhalation anesthesia with sevoflurane through facial mask in concentrations between 3-8% for anesthesia induction. After induction and peripheral vein puncture, the anesthesia will be maintained only with sevoflurane 3% until completion of the procedure.
Other Names:
  • Inhalation Anesthesia
Active Comparator: Propofol
All children will receive inhalation anesthesia with sevoflurane through facial mask in concentrations between 3-8% until lost of conscience and peripheral vein puncture. After that, sevoflurane will be turned off and its clearance will be analyzed through gas analyzer monitor. From here, anesthesia will be maintained as total venous with continuous propofol infusion 100 mcg.kg.min-1 until completion of the procedure.
Drug: Propofol
All children will receive inhalation anesthesia with sevoflurane through facial mask in concentrations between 3-8% until lost of conscience and peripheral vein puncture. After that, sevoflurane will be turned off and its clearance will be analyzed through gas analyzer monitor. From here, anesthesia will be maintained as total venous with continuous propofol infusion 100 mcg.kg.min-1 until completion of the procedure.
Other Names:
  • Intravenous Anesthesia

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
DNA methylation profile of children who presented emergence delirium
Time Frame: An average of one month after discharge from outpatient clinic.
DNA methylation profile will be measured through an array experiment in the Illumina iScanSQ (Illumina®) platform using the BeadChip Infinium MethylationEPIC and BeadChip HumanCytoSNP850K kits, following the protocol and manufacturer's instructions. The extracted samples will be initially treated with bisulfite using the EZ DNA Methylation Kit (Zymo Research®). The methylation profile is measured by the Beta value. This value ranges from 0 to 1. Closer to zero, more hypomethylated is the DNA and closer to 1, more hypermethylated is the DNA. To compare the profile, the average Beta value of each patient with emergence delirium and their controls will be used. All raw data obtained will be analyzed by bioinformatics methods to compose the DNA methylation profile of each patient.
An average of one month after discharge from outpatient clinic.

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Emergence delirium
Time Frame: First, 5th, 10th and 15th minutes after anesthesia awakening
Emergence delirium will be measured through Pediatric Anesthesia Emergence Delirium (PAED) scale. This scale measures 5 items regarding child's awakening: eye contact with the caregiver, purposefulness of child's action, awareness of child's surroundings, child's restlessness and if the child is inconsolable. The first three items are scored from 4 to 1 as follow: 4 not at all, 3 just a little, 2 quite a bit, 1 very much, 0 extremely. Items 4 and 5 are scored as follow: 0 not at all, 1 just a little, 2 quite a bit, 3 very much, 4 extremely. The scores of each item were summed to obtain a total Pediatric Anesthesia Emergence Delirium (PAED) scale score. The degree of emergence delirium increased directly with the total score. We considered a score of ≥ 10 as a cutoff of emergence delirium.
First, 5th, 10th and 15th minutes after anesthesia awakening
Children's preoperative anxiety
Time Frame: 10 minutes before induction of anesthesia
This outcome will be measured through modified Yale Preoperative Anxiety Scale (mYPAS). This scale analysis 5 items regarding child's behavior right before induction of anesthesia. A. Activity 1 Looking around. 2 Not exploring. 3 Moving from toy to parent in unfocused manner. 4 Actively trying to get away. B. Vocalizations 1 Reading or asking questions. 2 Responding to adults but whispers. 3 Quiet or no sounds. 4 Whimpering or silently crying. 5 Crying. 6 Crying or screaming loudly. C. Emotional expressivity 1 Manifestly happy. 2 Neutral. 3 Worried to frightened. 4 Distressed. D. State of apparent arousal 1 Alert. 2 Child sitting still and quiet. 3 Vigilant. 4 Panicked. E. Use of parents 1 Busy playing. 2 Reaches out to parent. 3 Looks to parents quietly. 4 Keeps parent. To calculate the final score, we divide each item rating by the highest possible, add all of the produced values, divide by 5, and multiply by 100. Score of ≥ 30 indicates high anxiety before anesthesia.
10 minutes before induction of anesthesia
Caregiver's anxiety before anesthesia
Time Frame: 10 minutes before induction of anesthesia
This outcome will be measured through a Visual Analogic Scale (VAS) validated for anxiety. This is a 100-mm scale, which will be applied to caregivers right before induction of anesthesia. Score higher than or equal to 70 mm will be considered as high caregiver's anxiety.
10 minutes before induction of anesthesia
Children's behavior and adult interaction during anesthesia induction
Time Frame: First minute during monitoring and anesthesia induction
This outcome will be measured through Perioperative Adult Child Behavior Interaction Scale (PACBIS). The PACBIS consists of four domains (Child Coping, Child Distress, Parent Positive, and Parent Negative), each of which is assigned one of three possible scores (0, 1 or 2). Scores for each domain are assigned based upon the observer's impression of the most typical expression of the subject's behavior within that domain during the observation period. By identifying the specific area leading to maladaptive behavioral responses, we will be able to correlate with occurrence of emergence delirium.
First minute during monitoring and anesthesia induction
Children's behavior during anesthesia induction
Time Frame: First minute during anesthesia induction
This outcome will be measured through Pediatric Anesthesia Behavior (PAB) score. The Pediatric Anesthesia Behavior (PAB) score is scored from one to three based upon the criteria: Group 1 happy calm and controlled, compliant with induction, Group 2 (sad) tearful and/or withdrawn but compliant with induction or Group 3 (mad) loud vocal resistance (screaming or shouting) and/or physical resistance to induction requiring physical restraint by staff and/or parents. Higher scores (2 or 3) could be associated with emergence delirium, and the development of posthospitalization behavior changes.
First minute during anesthesia induction
Post hospitalization behavior changes
Time Frame: First, 7th and 14th day after discharge from outpatient clinic
This outcome will be measured through Post Hospital Behavior Questionnaire. This questionnaire is composed by the following questions: Does your child make a fuss about eating? Does your child spend time just sitting or lying? Is your child uninterested in what goes on around him/her? Does your child get upset when you leave him/her alone for a few minutes? Does your child need a lot of help doing things? Is it difficult to get your child interested in doing things? Does your child have temper tantrums? Is it difficult to get your child to talk to you? Does your child have bad dreams or wake up and cry? Does your child have trouble getting to sleep? Does your child have a poor appetite? For each item, parents are asked to compare their child's behavior before hospitalization to their current behavior as follows: much less than before (1), less than before (2), same as before (3), more than before (4), and much more than before (5). Score ≥ 3 will be considered positive.
First, 7th and 14th day after discharge from outpatient clinic

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Sao Paulo

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Maria JC Carmona, PHD, Associate professor

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 24, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 7, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 18, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 21, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 26, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 20, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 19, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • EPOPED-USP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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