The EPigenetic Consequences in Children of Intravenous vs Volatile Anaesthesia for Surgery (EPIVA)

Study Overview
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Brief Summary
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More than half a million children have an anaesthetic each year in the UK. Though anaesthesia is usually thought to be safe and necessary to improve health, concerns remain the effects that the drugs used may have on brain development in children and the potential long-term consequences for health. The two techniques used to keep someone asleep during anaesthesia are either giving the appropriate drugs through a small plastic tube into a vein or introducing different drugs into the lungs in gas form. Gene expression is the process by which instructions in DNA are used to make products such as proteins. Anaesthetic drugs may change how a child's genes are expressed; a process called epigenetics. Studies have shown that different anaesthetic drugs can cause epigenetic changes in animals and affect the processing ability of their brains. This study will focus on children aged under 3 undergoing general anaesthesia for planned hypospadias surgery (a developmental condition where the look and function of the penis may not be completely normally). Participants will either receive their general anaesthetic in gas form or through directly into their veins - both techniques are commonly used. A small blood sample (between 1 and 2 teaspoons) will be collected at the start and end of the operation whilst under anaesthetic. Samples will be analysed to look for any changes in signals on DNA (epigenetic changes) and other markers. Further analysis may then look at other measures of gene expression and additional processes/markers that could be affected. There is relatively less medical research carried out in children and this work will show whether this type of study is possible in this age-group and provide information for future trials. It will help towards improving our understanding of the effects of anaesthesia ultimately help doctors and families make better informed decisions.

Detailed Description
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There remains uncertainty about the impact that general anaesthesia may have on many different processes and systems for a child. The effect on the developing brain is an area that has received growing attention over the last decade. Pre-clinical studies, including those looking at cells and animal models, have demonstrated the harmful effect that anaesthetic drugs can cause in nerve cells. Large studies of children have suggested that early age exposure to anaesthetic drugs may impact cognitive and behavioural outcomes however, although this has not been a universal finding. In 2016 the United States Food and Drug Administration (FDA) issued a warning regarding the use of anaesthetic drugs for children aged under 3 years, with the highest level of concern afforded to those who have prolonged and/or repeat exposures, showing the importance of this topic. This importance is further highlighted by the annual paediatric anaesthetic caseload - more than half a million children have an anaesthetic each year in the UK. There have been pre-clinical studies that have suggested that the way in which anaesthetic drugs can impact on neurodevelopment and cognition is through modifying the way in which genes are expressed by altering signals on DNA (epigenetics). This research aims to explore whether these changes in signals in DNA (epigenetic changes) can be seen in children undergoing anaesthesia and whether this is impacted by the type of anaesthetic given. To do this, the trial has been designed as a randomised, clinical, feasibility trial in which participants undergoing hypospadias surgery will be randomised to one of the two anaesthetic maintenance approaches that are used routinely in clinical practice: intravenous or inhalational. Baseline data, including demographics, will be collected. On the day of their surgery, participants will receive maintenance of anaesthesia either through inhalational anaesthesia or intravenous anaesthesia according to allocation at randomisation - participants and their legal representatives will be blinded to group allocation and subsequent analysis will be performed with blinding to allocation. The participant will then be anaesthetised, and a baseline blood sample will be taken from the cannula that is routinely inserted into a vein to give medication to the patient. If this is not possible, the sample will be taken from a peripheral site. After the surgical procedure is complete and before the participant wakes up from general anaesthesia, a second blood will be taken. Blood will then undergo laboratory analysis including epigenetic, biochemical, haematological, and redox. This trial has been designed as a feasibility trial to evaluate whether a larger scale trial looking at anaesthesia and surgery in relation to changes in markers on DNA (epigenetics) is both possible, and of value. Currently there have been no published studies looking at whether general anaesthesia can cause epigenetic changes in children, and whether the type of anaesthetic given has an impact on any changes present. There is significantly less published research in children as it necessitates many additional considerations; this is part of the rationale for this study being designed as a feasibility trial with the primary objective of assessing and determining the feasibility of conducting a paediatric perioperative epigenetics study in which participants are randomised to two methods of maintaining anaesthesia for surgery. Alongside measures such as recruitment and retention rate, screening numbers, protocol compliance figures, this objective will incorporate feedback on acceptability for participants and clinical staff, the success of the data management system used, and if any additional resources are required. It has also been designed to address the secondary objectives of exploring whether anaesthesia and surgery are associated with epigenetic changes in whole blood, whether the strategy used to maintain anaesthesia impacts any epigenetic changes observed, and to identify which genes, pathways, and functional biological processes, may potentially be involved. Those with day-to-day responsibility for trial conduct will either be Good Clinical Practice trained trial-team members, or members of the treating clinical team. The Sponsor will continue to have oversight of the trial throughout, and their representatives will communicate closely with the trial team. The end of the study is defined as completion of the full set of analyses of the blood samples taken from participants. The findings will be disseminated in both a timely and responsible manner amongst the relevant scientific community and shared in an appropriate fashion with the legal representatives of the children who took part after. Reporting of the findings may take the form of presentations at meetings/conferences alongside the writing of a manuscript for submission to a scientific journal.

Official Title
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The EPigenetic Consequences in Children of Intravenous vs Volatile Anaesthesia for Surgery (EPIVA) - A Randomised, Feasibility Trial

Conditions
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Hypospadias, Anesthesia; Adverse Effect, Perioperative Complication, Pediatric ALL

Intervention / Treatment
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* Other: Intravenous approach to anaesthetic maintenance
* Other: Inhalational approach to anaesthetic maintenance


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥6 months and ≤ 3 years at time of initial operation Undergoing hypospadias surgery Maintenance phase of anaesthesia for procedure has an estimated length of ≥1 hour (established through MDT discussion prior to surgery). Completed informed consent form (ICF) from legal representative (LR (this is the person who is empowered to give informed consent on behalf of a participant. For most children this will be one or both parents. This may also be a guardian or custodian with legal custody)). Exclusion Criteria: LR unable to provide completed ICF Withdrawal of consent at any stage Previous exposure to general anaesthesia at any stage of life, including in-utero (through maternal exposure at any stage until delivery) Neurodevelopmental/neurodisability diagnosis (given or under investigation) from a paediatric service including autistic specturm disorder (ASD), attention deficit disorder (ADHD), traumatic brain injury (TBI), down's syndrome, cerebral palsy, epilepsy Known contraindication to either volatile-based inhalational anaesthesia or TIVA (surgery or participant) Clinician refusal

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 3 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomised to receive maintenance of anaesthesia through either an intravenous approach (TIVA) or inhalational approach (using volatile agents). As is routine anaesthetic practice for this age-group, a gas/inhalational induction will be performed for all participants. After induction a baseline sample of blood will be taken. For participants in the inhalational maintenance group the volatile-based anaesthetic agent (in an air and oxygen mixture) will be continued after induction for the duration of the case. For participants in the TIVA maintenance group, once induction of anaesthesia has been successfully completed, at the earliest appropriate opportunity, the volatile-based anaesthetic will be switched to TIVA which will then be continued for the duration of the case. After the surgical procedure has been completed, and prior to emergence from general anaesthesia, a further blood sample will be taken for analysis.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Total intravenous anaesthesia (TIVA)<br>This arm will receive maintenance of anaesthesia through a total intravenous anaesthesia approach (TIVA) | Other: Intravenous approach to anaesthetic maintenance<br>* Anaesthetic agents given directly into the bloodstream via a cannula.<br>|
| Active Comparator: Inhalational anaesthesia<br>This arm will receive maintenance of anaesthesia through an inhalational anaesthesia approach | Other: Inhalational approach to anaesthetic maintenance<br>* Volatile-based anaesthetic drugs are breathed in and then absorbed into the bloodstream through the lungs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of eligible patients screened | Total number of patients during period that would be eligible for the trial | 6 months | 
| Recruitment rate | Number of participants randomised divided by the number screened | 6 months | 
| Retention rate | Number of participants that complete the study divided by the number who start it | 6 months | 
| Protocol compliance | Number of deviations from trial protocol for each patient | 6 months | 
| Acceptability of trial process for the legal representatives of participants | Outcome to assess whether the legal representatives of participants found the process of partaking in the trial acceptable. This will be self-reported through feedback requests. | Up to 1 month | 
| Acceptability of trial process for clinical staff | Outcome to assess whether the clinical staff involved in conducting the protocol found this acceptable. This will be self-reported through feedback requests. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Epigenetic changes in whole blood in those undergoing anaesthesia for hypospadias surgery | Changes in DNA methylation profile of whole blood (using Illumina Infinium MethylationEPIC BeadChip (850K)) between pre-surgery and post-surgery | 5 minutes after induction of anaesthesia, 5 minutes after completion of surgical procedure | 
| Epigenetic changes in whole blood; comparing the two arms of the trial | Changes in DNA methylation profile of whole blood (using Illumina Infinium MethylationEPIC BeadChip (850K)) between the two trial arms (TIVA vs inhalational anaesthesia) | 5 minutes after induction of anaesthesia and 5 minutes after completion of surgical procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Total intravenous anaesthesia, TIVA, Volatile, Epigenetics, Trial, Surgery, Pediatric, Paediatric, General Anaesthesia