Clinical trial NCT06731855: An Exploratory Physiological Study of Post-operative Recovery in Surgical Neonates and Dimethylarginine:Arginine Levels
Official title: An Exploratory Physiological Study of Post-operative Recovery in Surgical Neonates and Dimethylarginine:Arginine Levels (SuNDiAL)
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Congenital Abnormality of Gut
Gastroschisis
Congenital Diaphragmatic Hernia
Duodenal Atresia
Oesophageal Atresia with Tracheo-Oesophageal Fistula
Oesophageal Atresia
Exomphalos
Keywords: Neonatal
Abdominal Surgery
Asymmetric Dimethylarginine
ADMA
Arginine
Recovery
Neonate
Lead sponsor: Liverpool Women's NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Alder Hey Children's NHS Foundation Trust
First posted: 2024-12-12
Enrollment: 30
Sex: ALL
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population with be of 30 infants born \>35 weeks gestation and has a condition requiring major gastrointestinal surgery within 5 days (120 hours) of birth. This is expected to include predominantly congenital gut malformations: gastroschisis, gut atresias, volvulus and congenital diaphragmatic hernia (who are stable enough for surgery in this time frame).

Patient will be recruited over a 1 year period. These infants will be born at Liverpool Women's Hospital or at their local hospital in the north west of England region, and transferred to Alder Hey Children's Hospital for their operation, either directly or via Liverpool Women's Hospital Neonatal Intensive Care Unit. They will recover in Alder Hey Children's Hospital's Paediatric Intensive Care Unit or Neonatal Surgical Unit and may later be transferred back to Liverpool Women's Hospital.

Brief summary: The SuNDiAL study will measure levels of two naturally occurring amino acids: Arginine and Asymmetric Dimethylarginine (ADMA) in neonates undergoing abdominal surgery in the first 5 days of life due to congenital abdominal malformations recover from their surgery.

We hypothesise that the relationship between Arginine and ADMA may be useful in predicting recovery and complications in babies who have had abdominal surgery due to previous research published in adult patients undergoing abdominal surgery. If this relationship is found to be useful there may be options for developing treatments (such as arginine supplementation) in the future to improve recovery and reduce complications in neonates undergoing abdominal surgery.

Neonates born after 35 weeks gestation who have a congenital abdominal malformation who require abdominal surgery in the first 5 days will be eligible to participate in the SuNDiAL study.

Arginine and ADMA will be measured from blood samples that are left over from the baby's blood tests that are taken as part of their routine clinical care. We will measure Arginine and ADMA preoperatively and at least 10 points in the 30 days following their surgery, or until they fully recover from their surgery (which ever comes first). There is no intervention in the SuNDiAL study, and there will be no extra blood or blood samples taken.

We will store samples that are left over from the babies routine clinical blood tests securely in the hospitals laboratory until analysis for Arginine and ADMA.

The levels of Arginine and ADMA will be compared to the time it takes the babies to recover from surgery and any complications that may arise following surgery. During the study the study team will use the patients electronic medical record to establish when the patient became fully established on oral feeding and monitor for any complications that occurred during their recovery.

Detailed description: The study will be a prospective observational, physiological study running across the two trust that form the Liverpool Neonatal Partnership; Liverpool Women's Hospital NHS Foundation Trust and Alder Hey Children's Hospital Foundation Trust.

There is no study intervention and therefore all patients will be managed in accordance with existing local protocols and current accepted clinical practice. Participants will receive standard neonatal and surgical care as per LNP Guidelines. They will have routine blood tests taken as part of their routine care. No additional blood or blood tests will be taken for the SuNDiAL study.

The study will involve the analysis of any blood left over from samples taken routinely pre and postoperatively in infants who have undergone abdominal surgery. Residual serum samples will be analysed from the remaining blood samples taken for routine blood monitoring in the infants enrolled in the study. Biochemical samples will undergo Enzyme-linked immunosorbent assay (ELISA) analysis for ADMA and arginine.

The study period is from preoperatively until 30 days post operatively or until the baby fully recovers from surgery, marked by being fully fed with milk into their stomach. The aim is to obtain at least 1 measurement preoperatively, and a minimum of 4 measurements in the post-operative period. The expectation is that 3-5 measurements first 10 postoperative days should be achievable.

The SuNDiAL study will aim to determine if the level of ADMA and/or Arginine and/or the ARG/ADMA ratio is associated with the time taken to recover following major abdominal surgery in neonates born after 35 weeks gestation. Recovery will be measured as the time taken to no longer require intravenous nutrition following surgery as the primary objective.

The secondary objectives include:

1. To develop a mathematical model of postoperative ADMA and/or ARG/ADMA ratio. This will allow future randomised controlled trial designs investigating postoperative recovery time to include ADMA and ARG/ADMA in the study protocol. This modelling has the potential to develop future arginine supplementation protocols to target and/or refine arginine dosage and duration based on the trajectory of the ADMA levels or arginine:ADMA ratio. This approach includes specific post operative complications following surgery that may delay recovery (such as mortality, wound healing, sepsis, parenteral nutrition cholestasis)
2. To compare ADMA and/or ARG/ADMA ratio in specific gastrointestinal conditions that require major abdominal surgery.
3. To assess ADMA and the ARG/ADMA ratio in specific gastrointestinal conditions that require major abdominal surgery, pre and postoperatively.
4. To identify whether amino acid (protein) and/or arginine intake affect plasma ADMA levels in the post-operative period and to incorporate this outcome in future randomised controlled trials investigation arginine supplementation and other nutritional interventions.

Parents of potential participants will be approached preoperatively or up to 5 days postoperatively to complete the informed consent process.

Once the parents have had sufficient time to read and process the information regarding the study (minimum 2 hours), and sufficient time to ask questions regarding the study, written consent will be obtained.

Blood samples will be taken by the clinical team routinely as part of their clinical care. Patients will be managed as per accepted clinical practice and local clinical guidelines by the clinical team. There will be no changes from routine practice due to the SuNDiAL study. No extra blood tests will be taken for the SuNDiAL study.

If an infant is eligible and has consented to participate in the SuNDiAL study, at the time of ordering routine clinical blood tests the clinical team will order an additional dummy blood test 'SUNDIAL store sample'.

If there is any remaining serum following routine clinical blood tests, the 'SUNDIAL store sample' will alert the lab to store the blood sample for the SuNDiAL study. The sample will frozen and be stored in the SuNDiAL area of the research laboratory freezer in Alder Hey Children's Hospital. All samples with serum remaining will be stored. Samples will stop being stored once the patient is fully recovered or after 30 days post operatively which ever occurs first. The sample will be available for the clinical team to do further tests if these are required and this will take priority over testing the blood for research purposes.

Once there is sufficient samples to run an analysis the samples with be transported to the research laboratory. They will then be analysed by the ELISA technique, to measure Arginine and ADMA. Samples will be anonymised by the research team prior to being transported to the Research Laboratory in the Institute in the park at Alder Hey Children hospital.

The data will be anonymised prior to analysis. Data will be analysed for both the primary and secondary outcomes outlined above by the University of Liverpool Computational Biological Facility.

Eligibility criteria: Inclusion Criteria:

1. Infants born \>35 weeks gestation
2. Have a condition requiring major gastrointestinal surgery
3. Surgery within the first 5 days (120 hours) following birth (including congenital diaphragmatic hernia who are stable enough for surgery in this time frame).
4. Parent(s)/guardian(s) must have a comprehensive understanding of written and spoken English, sufficient to provide informed using the translation services available to the research team.
5. Must be willing and able to provide informed consent in order to take part in the study

Exclusion Criteria:

1. Infants who are unlikely to survive because of poor immediate postoperative condition.
2. Infants known (or suspected to have) a diagnosis of inborn error of metabolism or serious liver dysfunction.
3. Parent(s)/guardian(s) who are unable to give informed consent.
4. Infants who it is not possible to obtain the minimum required residual serum samples from routine biochemical blood testing as outlined in the study schedule

Primary outcomes:
measure: The relationship between Arginine, ADMA and the Arginine to ADMA ratio in comparison to the time taken to recover from abdominal surgery.
timeFrame: From Enrolment to 30 days following surgery
Secondary outcomes:
measure: Develop a mathematical model to describe the entire postoperative (30 days) trajectory of Arginine, ADMA and the ARG/ADMA ratio in relation to PN dependency.
timeFrame: From enrolment until day 30 post operatively.
measure: To study the relationship over time between nutritional intake and arginine, ADMA and the ARG/ADMA ratio.
timeFrame: From enrolment until day 30 postoperatively.
measure: The relationship over time between clinically monitored postoperative inflammatory and biochemical markers and arginine, ADMA and the ARG/ADMA ratio
timeFrame: From Enrolment to 30 days post operatively
measure: Impact of individual episodes (including duration) of any recognised postoperative complication (eg wound complications, bowel complications, sepsis) on the recovery time and the mathematical model described above.
timeFrame: From enrolment to 30 days post operation
measure: Weight Gain/head growth over the study period in relationship to Arginine, ADMA and Arginine to ADMA ratio.
timeFrame: Enrolment to 30 days post operation.
measure: Level of care and major treatments (eg ventilation, inotropic support, antibiotics for sepsis) during the study period in relation to Arginine, ADMA and the Arginine to ADMA ratio.
timeFrame: From enrolment to 30 days postoperatively.
Other outcomes:
Locations:
city: Liverpool
country: United Kingdom
facility: Alder Hey Childrens Hospital NSH Foundation Trust
state: Merseyside
city: Liverpool
country: United Kingdom
facility: Liverpool Womens Hospital NHS Foundation Trust
state: Merseyside
Study officials:
References: