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

Pediatric ALL Clinical Trial

— EPIVA  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05936853
• Other study ID #: RHM CRI0434
• Status: Active, not recruiting
• Phase: N/A
• Start date: August 3, 2023
• Est. completion date: July 1, 2025

Study information

• Verified date: April 2024
• Source: University Hospital Southampton NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 16
• Est. completion date: July 1, 2025
• Est. primary completion date: February 23, 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 6 Months to 3 Years

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Other:
• Intravenous approach to anaesthetic maintenance
Anaesthetic agents given directly into the bloodstream via a cannula.
• Inhalational approach to anaesthetic maintenance
Volatile-based anaesthetic drugs are breathed in and then absorbed into the bloodstream through the lungs.

Locations

Country	Name	City	State
United Kingdom	University Hospital Southampton	Southampton	Hampshire

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Southampton NHS Foundation Trust	University of Southampton

Country where clinical trial is conducted

United Kingdom, 

References & Publications (15)

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. — View Citation

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. — View Citation

DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009 Oct;21(4):286-91. doi: 10.1097/ANA.0b013e3181a71f11. — View Citation

Holtkamp C, Koos B, Unterberg M, Rahmel T, Bergmann L, Bazzi Z, Bazzi M, Bukhari H, Adamzik M, Rump K. A novel understanding of postoperative complications: In vitro study of the impact of propofol on epigenetic modifications in cholinergic genes. PLoS One. 2019 May 29;14(5):e0217269. doi: 10.1371/journal.pone.0217269. eCollection 2019. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Joseph PD, Craig JC, Caldwell PH. Clinical trials in children. Br J Clin Pharmacol. 2015 Mar;79(3):357-69. doi: 10.1111/bcp.12305. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci. 2016 Oct 18;17(11):705-717. doi: 10.1038/nrn.2016.128. — View Citation

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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of eligible patients screened	Total number of patients during period that would be eligible for the trial	6 months
Primary	Recruitment rate	Number of participants randomised divided by the number screened	6 months
Primary	Retention rate	Number of participants that complete the study divided by the number who start it	6 months
Primary	Protocol compliance	Number of deviations from trial protocol for each patient	6 months
Primary	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
Primary	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	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
Secondary	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

External Links

•   FDA warning for drugs used for general anaesthesia