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

NCT05936853 | Active Not Recruiting

• 1 other identifier: RHM CRI0434
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Keywords

Total intravenous anaesthesia; TIVA; Volatile; Epigenetics; Trial; Surgery; Pediatric; Paediatric; General Anaesthesia

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (2)

• Epigenetic changes in whole blood in those undergoing anaesthesia for hypospadias 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

  5 minutes after induction of anaesthesia and 5 minutes after completion of surgical procedure

Study Arms (2)

Total intravenous anaesthesia (TIVA)

ACTIVE COMPARATOR

This arm will receive maintenance of anaesthesia through a total intravenous anaesthesia approach (TIVA)

Other: Intravenous approach to anaesthetic maintenance

Inhalational anaesthesia

ACTIVE COMPARATOR

This arm will receive maintenance of anaesthesia through an inhalational anaesthesia approach

Other: Inhalational approach to anaesthetic maintenance

Interventions

Intravenous approach to anaesthetic maintenance OTHER

Anaesthetic agents given directly into the bloodstream via a cannula.

Total intravenous anaesthesia (TIVA)

Inhalational approach to anaesthetic maintenance OTHER

Volatile-based anaesthetic drugs are breathed in and then absorbed into the bloodstream through the lungs.

Inhalational anaesthesia

Eligibility Criteria

• Age: 6 Months - 3 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)).

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital Southampton NHS Foundation Trust: lead
• University of Southampton: collaborator

Study Sites (1)

University Hospital Southampton

Southampton, Hampshire, SO16 6YD, United Kingdom

Location

Related Publications (15)

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• Vutskits L, Davidson A. Update on developmental anesthesia neurotoxicity. Curr Opin Anaesthesiol. 2017 Jun;30(3):337-342. doi: 10.1097/ACO.0000000000000461.

  PMID: 28277380 BACKGROUND

• Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003 Feb 1;23(3):876-82. doi: 10.1523/JNEUROSCI.23-03-00876.2003.

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• Brambrink AM, Back SA, Riddle A, Gong X, Moravec MD, Dissen GA, Creeley CE, Dikranian KT, Olney JW. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol. 2012 Oct;72(4):525-35. doi: 10.1002/ana.23652.

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  PMID: 19955889 BACKGROUND

• Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS, Davidson A, Wood AJ, Li G, Sun LS. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012 Sep;130(3):e476-85. doi: 10.1542/peds.2011-3822. Epub 2012 Aug 20.

  PMID: 22908104 BACKGROUND

• Hu D, Flick RP, Zaccariello MJ, Colligan RC, Katusic SK, Schroeder DR, Hanson AC, Buenvenida SL, Gleich SJ, Wilder RT, Sprung J, Warner DO. Association between Exposure of Young Children to Procedures Requiring General Anesthesia and Learning and Behavioral Outcomes in a Population-based Birth Cohort. Anesthesiology. 2017 Aug;127(2):227-240. doi: 10.1097/ALN.0000000000001735.

  PMID: 28609302 BACKGROUND

• Warner DO, Zaccariello MJ, Katusic SK, Schroeder DR, Hanson AC, Schulte PJ, Buenvenida SL, Gleich SJ, Wilder RT, Sprung J, Hu D, Voigt RG, Paule MG, Chelonis JJ, Flick RP. Neuropsychological and Behavioral Outcomes after Exposure of Young Children to Procedures Requiring General Anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study. Anesthesiology. 2018 Jul;129(1):89-105. doi: 10.1097/ALN.0000000000002232.

  PMID: 29672337 BACKGROUND

• Ko WR, Huang JY, Chiang YC, Nfor ON, Ko PC, Jan SR, Lung CC, Chang HC, Lin LY, Liaw YP. Risk of autistic disorder after exposure to general anaesthesia and surgery: a nationwide, retrospective matched cohort study. Eur J Anaesthesiol. 2015 May;32(5):303-10. doi: 10.1097/EJA.0000000000000130.

  PMID: 25101714 BACKGROUND

• Sun LS, Li G, Miller TL, Salorio C, Byrne MW, Bellinger DC, Ing C, Park R, Radcliffe J, Hays SR, DiMaggio CJ, Cooper TJ, Rauh V, Maxwell LG, Youn A, McGowan FX. Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA. 2016 Jun 7;315(21):2312-20. doi: 10.1001/jama.2016.6967.

  PMID: 27272582 BACKGROUND

• Sury MR, Palmer JH, Cook TM, Pandit JJ. The state of UK anaesthesia: a survey of National Health Service activity in 2013. Br J Anaesth. 2014 Oct;113(4):575-84. doi: 10.1093/bja/aeu292. Epub 2014 Aug 7.

  PMID: 25236896 BACKGROUND

• Milanovic D, Pesic V, Loncarevic-Vasiljkovic N, Avramovic V, Tesic V, Jevtovic-Todorovic V, Kanazir S, Ruzdijic S. Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats. Neurotox Res. 2017 Aug;32(2):247-263. doi: 10.1007/s12640-017-9730-0. Epub 2017 Apr 24.

  PMID: 28435999 BACKGROUND

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  PMID: 31141559 BACKGROUND

• Bourgeois FT, Murthy S, Pinto C, Olson KL, Ioannidis JP, Mandl KD. Pediatric versus adult drug trials for conditions with high pediatric disease burden. Pediatrics. 2012 Aug;130(2):285-92. doi: 10.1542/peds.2012-0139. Epub 2012 Jul 23.

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Related Links

• FDA warning for drugs used for general anaesthesia

MeSH Terms

Conditions

Hypospadias; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Condition Hierarchy (Ancestors)

Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Penile Diseases; Genital Diseases, Male; Genital Diseases; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Joseph Larvin, BMBCH

  University Hospital Southampton and University of Southampton

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: It will not be possible to mask the participant's anaesthetist for the case, or the member of the research team. The participant, their Legal Representatives, and the members of the investigation team that are not present for the case, will all remain blinded for the duration of the trial. To ensure blinding to arm allocation at the time of outcome analysis/assessment, each participant will also be given a separate 'unique sample identifier code' directly linked to their 'unique participant ID'. This link will not be known by members of the research team.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 20, 2023
• First Posted: July 10, 2023
• Study Start: August 3, 2023
• Primary Completion: February 23, 2024
• Study Completion (Estimated): September 30, 2026
• Last Updated: June 15, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: This data will be made available on request from the point of first publication of the results, or 2 years after recruitment is closed.
• Access Criteria: Requests for access to the datasets will be discussed by the study's trial management group before any sharing.

Locations

GB (1)