Fasting-induced hypoglycaemia in anaesthetised paediatric patients (FIGS): protocol of an opt-out approach to consent for a multicentre cohort study measuring glycaemia and ketonaemia

Abstract

Background

Hypoglycaemia is a potentially a serious complication of the iatrogenic fasting required to deliver safe anaesthesia. Children may be at a higher risk because of their metabolic immaturity.

Methods

This is a prospective multi-centre cohort study recruiting children fasting before a procedure under general anaesthesia. Children will have their blood glucose and ketones measured using point-of-care testing on venous blood drawn from a cannula inserted during i.v. or inhalation induction of general anaesthesia. The primary aim is to recruit as many children as possible across the four nations of the United Kingdom, using an opt-out approach to consent, to assess different thresholds used by anaesthetists to define hypoglycaemia and identify risk factors of this metabolic complication. The primary endpoint is the decision by anaesthetists to manage a hypoglycaemia at induction in a large paediatric population. Secondary endpoints are the actual values of glycaemia and ketonaemia and to evaluate the distributions of these parameters in a large paediatric population together with assessing potential risk factors of adverse metabolic responses to fasting (mainly hypoglycaemia, hypoketosis, and hyperketosis). The fasting-induced hypoglycaemia in anaesthetised paediatric patients (FIGS) study aims to recruit over 2000 children across the 4 nations of the United Kingdom. Trial recruitment is in progress starting May 2025 and expected to end May 2026, with analysis and results shared in 2027.

Dissemintation Plans

This study, using an opt-out approach to consent, will provide a large data set of glycaemia and ketonaemia values in a paediatric population, assessing current practice, identifying risk factors, and building new recommendations for the management of the metabolic risk in fasting children.

Clinical trial registrations

IRAS 329701 and NCT07259629.

Protocol version number and date

1.8, 14 April 2026.

Optimising patient recruitment is a critical task in clinical research to achieve study goals. In paediatric anaesthesia, this is particularly challenging given that patients are often seen in the morning of their procedure by the anaesthetist.¹ The task becomes harder in multi-centre studies, where local teams might not have the same capacity as the research team to incorporate research constraints within their clinical workflow. Children make up 20% of the population yet are involved in only approximately 2–5% of research, with only 5% of dedicated funding,² driving an imperative to improve recruitment in paediatric research.

Clinical study and trial regulations have been evolving in the UK to facilitate research implementation and recruitment. Whilst maintaining the highest standards of scrutiny for patient safety and data reliability, efforts are being made to tailor regulatory, governance, monitoring, and safety requirements to a given study/trial with specifically low risks, rather than a standard approach. In particular, it has now become the hard regulatory expectation to facilitate simplified arrangements for seeking and evidencing informed consent for sponsors of clinical studies that meet certain criteria and request these arrangements. These ‘principles of simplified arrangements for consent’ are being developed by the Health Research Authority, including considerations from patient advocacy groups.

When certain conditions are met and approved by a research ethics committee (REC), the traditional process can be replaced with other approaches.³ Deferred consents (patients at the early stage of critical management),⁴ implied consents (patients willingly engage in a survey),⁵ waived consents (patient rights and welfare are protected), or opt-out consents (research aligns with standards of care and information shared ahead of the initial visit) can be used⁶; see Fig. 1. For opt-out consent, it is recommended that multiple ways of opting out should be offered to avoid pressurising children and parents/care givers into participating. In the Fasting Induced hypoGlycemia in pedatric pateintS (FIGS) protocol trial development phase, patients and parents were engaged extensively through young patient and parent/carer advisory groups to ascertain the acceptability of the protocol. All patient-facing documents were reviewed by these groups to make sure documents were understandable to a general audience and age appropriate.

Fig 1.

Schematic describing the different forms of consent often used in clinical research. Drawings were generated using ChatGPT and Perplexity artificial intelligence tools.

Fasting is a requirement to anaesthetise patients safely through reducing the aspiration risk; however, this puts young children at a higher risk of hypoglycaemia owing to the immaturity of their endocrine system and absence of metabolic reserves.7, 8, 9, 10, 11, 12 There is no unified definition of hypoglycaemia in fasting children, with different glycaemia thresholds used by anaesthetists to diagnose and initiate treatment. From a biological perspective, ketonaemia is a normal response to fasting, whereas hypoglycaemia is abnormal. An inadequate ketotic response (hypoketosis) or an excessive or rapid-onset ketosis (hyperketosis) in response to fasting is also abnormal. In fasting children, idiopathic ketotic hypoglycaemia during fasting is considered an immature and abnormal response leading to hyperketosis and potentially hypoglycaemia if fasting continues.¹³ Here, we will assess how these biological parameters could guide anaesthetists to diagnose and treat fasting-induced metabolic complications in the perioperative context.

The Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI) recommends that most children can be given fluids without dextrose, provided that blood glucose is monitored.¹⁴ Building on these guidelines and the necessity to insert a cannula as part of the induction of general anaesthesia, we sought approval to use an opt-out approach to consent to collect drops of blood flushed back from this cannula and measure blood glucose and ketones in fasting children before a procedure under general anaesthesia. The main research question is to establish which children are considered hypoglycaemic by anaesthetists and receive treatment. Secondary outcomes will explore which thresholds anaesthetists should use to define hypoglycaemia (3.3, 3.6, or 4 mM) based on the ketotic response and risk factors of adverse metabolic response to fasting, including hypoglycaemia, hypoketosis, and hyperketosis.

Study description and intervention

Here, we designed a non-commercial, multi-centre, prospective cohort study, aiming to measure glycaemia and ketonaemia during anaesthetic induction in children fasting before a procedure under general anaesthesia, using an opt-out approach to consent. This is the only intervention with no or limited risk given that blood is drawn from the cannula inserted as part of routine care for general anaesthesia during i.v. or inhalation inductions. There are no additional research visits. The expected benefits are the identification of metabolic complications, their risk factors, and management according to local guidelines.

This study is sponsored by Guy’s and St Thomas’ NHS Foundation Trust (GSTT) and was granted ethics approval with an opt-out approach to consent by the Riverside REC, using the Integrated Research Application System identification number 329701, in January 2025. The protocol is registered on ClinicalTrials.gov (NCT07259629).

Parent/carer and age-appropriate patient leaflets will be shared via e-mails ahead of the day of the procedure or on the day (1 h will be given to parents and patients to consider the study documents and decide whether they prefer to opt out). Additional questions could be answered on the day by the anaesthetists running the list. Opting out could be verbally expressed and secured by signing an opt-out form or sending an e-mail or letter to the local principal investigator up to a month after the end of the 1-yr recruitment period of the whole study. Out of courtesy to children and parents/caregivers, we encourage centres to remind parents/carers and children in the morning of the procedure about the study and ask whether they received and read the information leaflets about the study and understood that the patient would be recruited unless they tell the local team otherwise; see Fig. 2.

Fig 2.

Flowchart of the fasting-induced hypoglycaemia in paediatric patients (FIGS) study (blue with rounded-angle boxes) and the ancillary FIGS missed recruitment audit (purple with sharp-angle box). Clinical workflow is highlighted in bold. REC, research ethics committee.

Our main objective is to identify factors, used by anaesthetists, that determine the diagnosis of hypoglycaemia and initiation of hypoglycaemia treatment. Secondary objectives include assessing whether 3.3, 3.6, or 4 mM¹¹ is a more widely used threshold in clinical practice and identifying potential risk factors of hypoglycaemia in nested cohorts. We will assess the anaesthetic management against three different thresholds: 3.6 mM is commonly referred to in clinical research,¹⁰ and 3.3 mM¹⁵ is the lowest threshold used by anaesthetists in Canada, whereas UK paediatric anaesthetists often base their decision on a 4 mM threshold.¹¹ Ketogenic response to fasting will be evaluated, with a particular interest in hyper- or hypoketosis, constituting abnormal metabolic responses alongside hypoglycaemia. These data could help us refine the definitions of biochemical hypoglycaemia, clinically actionable hypoglycaemia, or ketotic adaptation for anaesthetic management.

Recruitment centres are to start recruitment after securing capacity and capability from their local Research and Development Department, followed by a virtual site initiation visit (study presentation, training on metre use and calibration, REDCap) leading to the study green light at the recruiting centre. Equipment will be delivered between the green light and scheduled recruitment start date.

Standard Protocol Items: Recommendations for Interventional Trials–Children and Adolescents reporting items are presented in Table 1.¹⁶

Table 1.

SPIRIT-C 2026 extension reporting item table, as recently described.¹⁶ CRF, case report form; ED, emergency department; FIGS, fasting-induced hypoglycaemia in anaesthetised paediatric patients; HRA, Health Research Authority; IPD, individual participant data; PCPIE, Patient, Carer and Public Involvement and Engagement; PICU, paediatric ICU; POCT, point-of-care testing; QC, quality control; R&D, research and development; SPIRIT-C, Standard Protocol Items: Recommendations for Interventional Trials–Children and Adolescents.

SPIRIT-C 2026 extension items	FIGS study
Administrative information
1a. Title stating the trial design, population, and interventions, with identification as a protocol	FIGS—protocol of an opt-out approach to consent cohort study in paediatric anaesthesia measuring glycaemia and ketonaemia
1a.1 Identify that it is a paediatric trial protocol and include age group(s)/range(s), interventions, and, if applicable, trial acronym	Age groups are not specified in the title given that we recruit children aged 1 month to 18 yr (not included).
1b. Structured summary of trial design and methods including items from the World Health Organization Trial Registration Data Set	Primary registry and trial identifying number IRAS 329701 Date of registration in the primary registry 16 May 2023 Secondary identifying numbers NCT07259629 Source(s) of monetary or material support Evelina London Children’s Charity, Association of Paediatric Anaesthetists in Great Britain and Ireland, Nova Biomedical Sponsor Guy’s and St Thomas’ NHS Foundation Trust Contact for public queries Rachel Fay, gstt.randd@nhs.net, +44 20 7188 7188, Great Maze Pond, London SE1 9RT, UK Contact for scientific queries Dr Benjamin Blaise, benjamin.blaise@nhs.net, +44 20 7188 7188, Evelina London Children’s Hospital, Department of Paediatric Anaesthesia, Westminster Bridge Road, London SE1 7EH, UK Public title The FIGS study Scientific title Fasting-induced hypoglycaemia in anaesthetised paediatric patients Countries of recruitment UK Health condition(s) or problem(s) studied Hypoglycaemia Intervention(s) Measurement of venous glycaemia and ketonaemia using point-of-care devices Key inclusion and exclusion criteria Inclusion criteria •All ASA score 1–3 children aged 1 month to 18 yr having an elective procedure involving general anaesthesia. •Planned expedited cases in ASA 1/2 children should be included, for example, nail bed repairs and simple fractures for manipulation under anaesthetics/k-wire insertion. •Imaging, interventional radiology, and dental cases are included if patients receive a general anaesthetic. Exclusion criteria •Children younger than 1 month •Procedures performed under oral sedation or local anaesthesia only •ASA status 4 and 5 •Children with any endocrine or metabolic condition or who have a fasting plan before general anaesthesia for glucose control •Emergency and oncology procedures given that these children will have different risk factors for hypoglycaemia •Anaesthetic involvement in critically ill children, e.g. airway management in the ED and PICU •Children on glucose-containing i.v. solutions or total parenteral nutrition preoperatively •Children on systemic steroid treatment (oral/i.v.). Children on inhalers/topical steroids should be included. Study type Multi-centre, prospective cohort study Date of first enrolment 12 May 2025 Sample size There was no formal sample size determination. Based on previous studies run in the UK that were not interventional, we estimated that a maximum of 6000 patients could be recruited. The expected sample size was more than 2000 patients. Recruitment status Recruiting Primary outcome Outcome name: diagnosis of and decision to treat hypoglycaemia by the anaesthetist Metric/method of measurement: POCT on venous blood Timepoint: during anaesthetic induction Key secondary outcomes Outcome name: hypoglycaemia defined as a blood glucose of <3.3 mM Metric/method of measurement: POCT on venous blood Timepoint: during anaesthetic induction Outcome name: hypoglycaemia defined as a blood glucose of <3.6 mM Metric/method of measurement: POCT on venous blood Timepoint: during anaesthetic induction Outcome name: hypoglycaemia defined as a blood glucose of <4 mM Metric/method of measurement: POCT on venous blood Timepoint: during anaesthetic induction Outcome name: ketonaemia in mM Metric/method of measurement: POCT on venous blood Timepoint: during anaesthetic induction Additional outcomes including identification of risk factors of hypoglycaemia, hypoketosis, or hyperketosis Ethics review Status: approved Date of approval: 3 January 2025 Name and contact details of ethics committee(s): London – Riverside Research Ethics Committee, 2 Redman Place, Stratford, London E20 1JQ, UK Completion date 17 May 2026 Summary results Not applicable IPD sharing statement Data sharing has not been planned so far but could be organised after the publication of the initial results.
2. Protocol version date and identifier	14 April 2026 and version 1.8
3a. Names, affiliations, and roles of protocol contributors	Hannah F. Lewis,1 Hugh Lemonde,2 Chris Gale,3 Gemma Jones,4 Kirsty Logan,4 Salma Ayis,5 Alexandra Vincent,6 Theresa McCarrick,7 Julia Parnell,7 Nikita Delgaty,8 Elizabeth Wagster,9 Stefan Favero10 and Benjamin J. Blaise1,11 Affiliations and addresses: 1Department of Paediatric Anaesthesia, Evelina London Children’s Hospital, Guy’s and St Thomas NHS Foundation Trust, London, UK 2Department of Inherited Metabolic Disease, Evelina London Children’s Hospital, Guy’s and St Thomas NHS Foundation Trust, London, UK 3Neonatal Medicine, School of Public Health and Centre for Paediatrics and Child Health, Imperial College London, Chelsea and Westminster Hospital Campus, London, UK 4King’s Health Partners Women and Children’s Health, Becket House, London, UK 5School of Life Course and Population Sciences, Faculty of Life Sciences & Medicine, King’s College London, Addison House, Guy’s Campus, London, UK 6Guy’s and St Thomas’ Data Management Services, Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital, London, UK 7Paediatric Anaesthetists in Training Research Network, Association of Paediatric Anaesthetists of Great Britain and Ireland, Sheffield, UK 8Point-of-care testing services, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 9Nova Biomedical, Runcorn, Cheshire, UK 10Nova Biomedical, Les Ulis, France 11Department for Early Life Imaging, St Thomas’ Hospital, King’s College London, London, UK Authors’ contributions Conceptualisation: HFL, HL, CG, GJ, KL Data curation: AV, BJB Formal analysis: HL, SA, BJB Funding acquisition: HFL, BJB Project administration: GJ, KL, BJB Visualisation: BJB Study roll-out: HFL, TMC, JP, ND, EW, SF, BJB Writing—original draft: HFL, BJB Review and approval of the final draft: all authors
3b. Name and contact information for the trial sponsor	Rachel Fay, gstt.randd@nhs.net, +44 20 7188 7188, Great Maze Pond, London SE1 9RT, UK
3c. Role of trial sponsor and funders in design, conduct, analysis, and reporting of trial; including any authority over these activities	Sponsor and funders were not part of the design, conduct, analysis, and reporting of the trial.
3d. Composition, roles, and responsibilities of the coordinating site, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable.	Not applicable; the study was managed by Dr Benjamin Blaise as the chief investigator.
Open science
4. Name of trial registry, identifying number (with URL), and date of registration; if not registered yet, name of intended registry	Clinical trials, NCT07259629, 20/11/2025, https://clinicaltrials.gov/study/NCT07259629
5. Where the trial protocol and statistical analysis plan can be accessed	The trial protocol and statistical analysis plan can be requested via e-mail from the study chief investigator (benjamin.blaise@nhs.net).
6. Where and how the individual de-identified participant data (including data dictionary), statistical code, and any other materials will be accessible	All data are stored on the Guy’s and St Thomas’ curated REDCap database. Access could be granted after request to the chief investigator and establishment of a data sharing agreement with Guy’s and St Thomas’ R&D department.
7a. Sources of funding and other support (e.g. supply of drugs)	Evelina London Children’s Charity, Association of Paediatric Anaesthetists in Great Britain and Ireland, and Nova Biomedical
7b. Financial and other conflicts of interest for principal investigators and steering committee members	None to report
8. Plans to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (e.g. reporting in trial registry, plain language summary, publication)	The results of the study will be published in international peer-reviewed journals and presented at conferences. A plain English summary will be published in the Evelina Bulletin.
Introduction
9a. Scientific background and rationale, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention	There is no harm expected from a blood sample taken from a cannula inserted as part of the routine care for general anaesthesia. The benefits include the identification of a hypoglycaemia or a risk of ketotic hypoglycaemia that will benefit from standard glucose management as per local guidelines.
9a.1. Describe the prevalence or incidence of the disease condition in children/adolescents	An audit run at the Evelina London Children’s Hospital identified the prevalence of hypoglycaemia in patients younger than 1 yr as 11.1% and 7.6% in those aged between 1 and 2 yr.
9a.2. Describe the potential for extrapolation from other paediatric populations or adult data or why extrapolation is not considered appropriate	Extrapolation was not considered appropriate given the metabolic variations with age. We recruited a cohort covering the entire childhood range.
9a.3. Include a description of the research question or aim with a justification for undertaking the trial in children/adolescents	Assess factors leading to the diagnosis and treatment of hypoglycaemia and different thresholds used by anaesthetists to define hypoglycaemia and identify risk factors of this metabolic complication. Fasting children, compared with adults, are at a higher risk of becoming hypoglycaemic (difference in metabolism), justifying the reason to undertake this research in children.
9b. Explanation of choice of comparator	Not applicable
10. Specific objectives related to benefits and harms	Identification of hypoglycaemia and immediate management; no harm is expected.
Methods: patient and public involvement and trial design
11. Details of, or plans for, patient and public involvement in the design, conduct, and reporting of the trial	Young patients’, parents’, and carers’ involvement and peer review by anaesthetists were organised in the design of the study.
12. Description of the trial design including type of trials (e.g. parallel group, crossover), allocation ratio, and framework (e.g. superiority, equivalence, non-inferiority, exploratory)	Multi-centre, prospective cohort study
Methods: participants, interventions, and outcomes
13. Settings (e.g. community, hospital) and locations (e.g. countries, sites) where the trial will be conducted	Hospital, four devolved nations of the United Kingdom
13.1 Describe any adaptations put in place to support inclusion and participation of children/adolescents	Specific poster and age-appropriate information leaflets were designed with a young patient advisory group and a parent and carer advisory group (Great Ormond Street Hospital, Mrs Deirdre Leyden)
14a. Eligibility criteria for participants	Children aged 1 month to 17 yr referred for a procedure under general anaesthesia
14a.1. Provide a justification for including multiple age groups or children/adolescents at different developmental stages, and address potential age- or development-related differences in treatment effects.	Metabolic variations are observed in different age groups, justifying the inclusion of children aged 1 month to 17 yr.
14b. If applicable, eligibility criteria for sites and for individuals who will deliver the interventions (e.g. surgeons, physiotherapists)	Anaesthetists will deliver the intervention. It will be left at the discretion of the local R&D department to decide whether all anaesthetists involved would need Good Clinical Practice training in place, or this could be covered by delegation by the local principal investigator.
15a. Intervention and comparator with sufficient details to allow replication including how, when, and by whom they will be administered; if relevant, where additional materials describing the intervention and comparator (e.g. intervention manual) can be accessed	Measurement of venous glycaemia and ketonaemia using POCT with blood collected from the cannula inserted during the induction of general anaesthesia
15a.1 Describe whether there is an intervention dose and/or formulation appropriate for the trial population and whether there are any adjustments made based on age, weight, or body surface area.	Not applicable
15a.2 Give rationale for adapting interventions used in other paediatric populations or adults for the present trial.	Not applicable
15a.3 Describe whether the trial interventions will be delivered with the help of a support person.	Operating department practitioner might support anaesthetists for the measurements as per standard practice in anaesthesia in the UK.
15.b Criteria for discontinuing or modifying allocated intervention/comparator for a trial participant (e.g. drug dose change in response to harms, participant requests, or improving/worsening disease)	Not applicable
15.c Strategies to improve adherence to intervention/comparator protocols, if applicable, and any procedures for monitoring adherence (e.g. drug tablet return, sessions attended)	Not applicable
15.d Concomitant care that is permitted or prohibited during the trial	Patients will receive anaesthetic care, the procedure they have been referred for, and perioperative care. Patients could be included in other studies.
16. Primary and secondary outcomes, including the specific measurement variable (e.g. systolic blood pressure), analysis metric (e.g. change from baseline, final value, time to event), method of aggregation (e.g. median, proportion), and timepoint for each outcome	Primary outcome Outcome name: hypoglycaemia defined as the decision by an anaesthetist to diagnose and treat a change in blood glucose Metric/method of measurement: POCT on venous blood Timepoint: during anaesthetic induction Key secondary outcomes Outcome name: hypoglycaemia defined as a blood glucose of <3.3 mM Metric/method of measurement: POCT on venous blood Timepoint: during anaesthetic induction Outcome name: hypoglycaemia defined as a blood glucose of <3.6 mM Metric/method of measurement: POCT on venous blood Timepoint: during anaesthetic induction Outcome name: hypoglycaemia defined as a blood glucose of <4 mM Metric/method of measurement: POCT on venous blood Timepoint: during anaesthetic induction Outcome name: ketonaemia in mM Metric/method of measurement: POCT on venous blood Timepoint: during anaesthetic induction
16.1 Explanation of the validity, reliability, and responsiveness of the outcome measurement instruments for the prespecified age groups	POCT is the gold standard test for the measurement of glycaemia and identification of hypoglycaemia in the perioperative period.
17. How harms are defined and will be assessed (e.g. systematically, non-systematically)	No harm was expected.
17.1 Describe whether the trial interventions and/or procedures will induce fear, pain, or distress or are invasive and what measures are taken to mitigate this.	No, the blood will be taken from the cannula inserted for the safe delivery of anaesthesia as part as routine care. A large proportion is expected to have this done after inhalation induction. The children undergoing an i.v. induction will be shielded using traditional distraction technologies such as books or videos. Information will be shared with them during the insertion of the cannula and short extra squeeze they might feel to bleed the cannula and collect the 0.2 ml of blood.
17.2 Describe all efforts to reduce the child/adolescent’s risk associated with trial participation.	Open information was shared with child/adolescent about the procedure and how it should happen. This is also described in the information leaflets shared with them.
18. Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants; a schematic diagram is highly recommended.	Information will be sent ahead of the procedure to the parents for them to share and discuss with their children if age appropriate. Study documents could also be shared on the day. All study procedure should happen on the day of their procedure (anaesthetic assessment, courtesy check regarding opt-out, blood sampling). There are no further enrolment interventions, assessments, or visits (see Fig. 2).
19. How sample size was determined, including all assumptions supporting the sample size calculation	There was no formal sample size determination for this cohort.
20. Strategies for achieving adequate participant enrolment to reach target sample size	The Paediatric Anaesthetists in Training Research Network will provide support to share study information with hospitals managing children and facilitate study roll-out.
20.1 Describe the anticipated impact of trial participation on the child/adolescent’s daily life.	No impact on the child/adolescent’s daily life expected given that the intervention is limited to the day of their procedure under general anaesthesia
20.2 Describe how participating children/adolescents will be given recognition for trial participation.	Patients will be orally thanked for taking part in the study.
Methods: assignment of interventions
21a Who will generate the random allocation sequence and the method used	Not applicable
21b Type of randomisation (simple or restricted) and details of any factors for stratification. To reduce predictability of a random sequence, other details of any planned restriction (e.g. blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions.	Not applicable
22. Mechanism used to implement random allocation sequence (e.g. central computer/telephone, sequentially numbered, opaque, sealed containers), describing any steps to conceal the sequence until interventions are assigned	Not applicable
23. Whether the personnel who will enrol and those who will assign participants to the interventions will have access to the random allocation sequence	Not applicable
24a Who will be blinded after assignment to interventions (e.g. participants, care providers, outcome assessors, data analysts)	Not applicable
24b If blinded, how blinding will be achieved and description of the similarity of interventions	Not applicable
24c If blinded, circumstances under which unblinding is permissible and procedure for revealing a participant’s allocated intervention during the trial	Not applicable
Methods: data collection, management, and analysis
25a Plans for assessment and collection of data trial, including any related process to promote data quality (e.g. duplicate measurements, training of assessors) and a description of trial instruments (e.g. questionnaires, laboratory tests) along with their reliability and validity, if known; reference to where data collection forms can be accessed, if not in protocol	As part of the site initiation visit, training will be provided for device use and QC testing. Video and e-learning presentation will be shared, including the aforementioned points. QC should be done every 24 h and results documented in a logbook.
16.1 Explanation of the validity, reliability, and responsiveness of the outcome measurement instruments for the prespecified age groups	Glycaemia and ketonaemia measurements should be done on venous samples. This is the usual practice in anaesthesia, to avoid multiple capillary tests.
25b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols	Not applicable Patient involvement is limited to the immediate perioperative period.
26 Plans for data entry, coding, security, and storage, including any related processes to promote data quality (e.g. double data entry, range checks for data values); reference to where details of data management procedures can be accessed, if not in the protocol	CRFs are automatised to avoid miscalculations in fasting times. Local teams will be invited to upload their data directly onto REDCap to avoid any reporting issues. If not possible, paper CRF will be made available. A double identification system is created to avoid any data entry errors.
27a Statistical methods used to compare groups for primary and secondary outcomes, including harms	For continuous variables, summary statistics such as means and standard deviations (for normal distributions) or medians and interquartile ranges (for non-normal distributions) will be provided. Categorical variables will be presented as frequencies and percentages. Comparisons between the hypoglycaemic groups will be performed using a χ2 test or Fisher’s exact test where appropriate for categorical variables. For continuous measures, a t-test or Mann–Whitney U-test will be performed. Mixed-effects logistic regressions will be used to account for unbalanced and clustered data. Random-effects models will be used to account for the multi-centre nature of the cohort. We expect some repeat measurements, but they should be limited in the cohort. Multiple imputations will be used to handle missing values, unless both glycaemia and ketonaemia values are missing. In this case, the whole raw data will be excluded. If the glycaemia or ketonaemia value is missing, then missing-at-random imputation will be used.
27b Definition of who will be included in each analysis (e.g. all randomised participants) and in which group	All participants should be included in the analyses.
27c How missing data will be handled in the analysis	Patients missing both glucose and ketone values will be excluded from the analysis; absence of specific metadata will lead to exclusion if the metadata are considered in the subgroup analysis.
27d Methods for any additional analyses (e.g. subgroup and sensitivity analyses)	To evaluate the prognostic factors associated with hypoglycaemia, a logistic regression model adjusting for potential baseline prognostic patient and clinical characteristics will be used. A post hoc sensitivity analysis will be undertaken to evaluate variability among hospital sites. Several sensitivity analyses of the definition of hypoglycaemia threshold will be examined: •Hypoglycaemia: any blood glucose concentration of less than 3.3 mM •Hypoglycaemia: any blood glucose concentration of less than 3.6 mM •Hypoglycaemia: any blood glucose concentration of less than 4.0 mM
Methods: monitoring
28a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and funder; and conflicts of interest and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed	Given the short recruitment window in each centre (2–3 weeks), it was deemed unnecessary to have a monitoring plan. Local investigators will be trained to do QC testing. Local principal investigators are asked to do QC testing every 24 h on metres, using testing solutions provided by Nova Biomedical. These QC tests should be documented in a logbook provided as part of the study documents.
28b Explanation of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial	No interim analysis planned
29. Frequency and procedures for monitoring trial conduct; if there is no monitoring, give explanation.	Given that cannulation and POCT are part of routine anaesthetic care, it was deemed that hospital mandatory training should be sufficient.
Ethics
30. Plans for seeking research ethics committee/institutional review board approval	HRA approval was given by the London – Riverside Research Ethics Committee on 3 January 2025.
31. Plans for communicating important protocol modifications to relevant parties	Substantive and non-substantive amendments were shared by the chief investigator with relevant parties after approval.
32a Who will obtain informed consent or assent from potential trial participants or authorised proxies and how	Not applicable The study uses an opt-out approach to consent; study documents are shared with patients and families ahead of the procedure. Decision to opt out could be expressed to the anaesthetist running the list or using one of the opt-out approaches (dedicated form, phone call, or e-mail mentioning the preference sent to the local principal investigator).
32a.1 Provide information on whether developmentally appropriate materials with understandable information on the trial process will be provided to participants in obtaining informed consent or assent, and state where materials can be found or if available on request.	Yes, age-appropriate leaflets were designed for different age groups (5–7, 8–11, 12–15, and 16–17 yr) with the support of the young patient advisory group, the parent and carer advisory group at Great Ormond Street Hospital in London and the PCPIE group at the Royal College of Anaesthetists.
32b Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable	None
33. How personal information about potential and enrolled participants will be collected, shared, and maintained to protect confidentiality before, during, and after the trial	Data are pseudo-anonymised and stored on the Guy’s and St Thomas’ NHS Foundation Trust curated REDCap database. Local centres will keep code break sheet and patient data. These documents should be archived as per local hospital and R7D guidance.
34 Provisions, if any, for ancillary and post-trial care and for compensation to those who experience harm from trial participation	No harm is expected from the protocol, and there have been no such provisions for such compensation.
34.1 Describe plans for assessing outcomes and harms beyond the formal study completion date.	No harm is expected.

Patient and public inclusion

Patients and the public were involved in the design of the study through the parent/carer and young patient advisory groups at Great Ormond Street Hospital NHS Foundation Trust. They helped us ascertain the acceptability and feasibility of the study and draft the information leaflets and opt-out forms.

Review

The protocol was critically appraised by the National Institute of Academic Anaesthesia’s Health Services Research Centre Patient, Carer and Public Involvement and Engagement group. Expert anaesthetists and lay members provided positive feedback and will support the study. The project was also evaluated by the Evelina London Charity, the APAGBI, and Nova Biomedical respective scientific committees, providing financial, equipment, and scientific support. The Paediatric Anaesthetists in Training Research Network appraised the protocol and will support the study roll-out in the UK.

Participant selection

Participants will be recruited from the lists of patients scheduled for procedures under general anaesthesia in paediatric theatres in the participating centres. All eligible children and their caregivers should be approached.

Inclusion criteria

• •All ASA score 1–3 children aged 1 month to 18 yr having an elective procedure involving general anaesthesia.
• •Planned expedited cases in ASA 1/2 children should be included, for example, nail bed repairs and simple fractures for manipulation under anaesthetics/k-wire insertion.
• •Imaging, interventional radiology, and dental cases are included if patients receive a general anaesthetic.

Exclusion criteria

• •Children younger than 1 month
• •Procedures performed under oral sedation or local anaesthesia only
• •ASA status 4 and 5
• •Children with any endocrine or metabolic condition or who have a fasting plan before general anaesthesia for glucose control
• •Emergency and oncology procedures given that these children will have different risk factors for hypoglycaemia
• •Anaesthetic involvement in critically ill children, for example, airway management in the emergency department and paediatric ICU
• •Children on glucose-containing i.v. solutions or total parenteral nutrition preoperatively
• •Children on systemic steroid treatment (oral/i.v.). Children on inhalers/topical steroids should be included.

Point-of-care testing and quality control testing

Nova Biomedical (Medical Affairs, Nova Biomedical, Waltham, Massachussetts, USA) is critical in the success of the study. They will provide StatStrip® Xpress2™ metres, a point-of-care testing (POCT) in vitro diagnostic device for quantitative measurement of glucose (sample size 1.2 μL) and β-ketone concentrations (sample size 0.8 μL) in various whole blood specimens across all hospital and professional healthcare settings, including intensive care, with a turnaround time of 6 and 10 s, respectively.¹⁷ Two devices will be placed in each anaesthetic area, allowing simultaneous glycaemia and ketonaemia measurements. This will facilitate POCT measurements, whilst not distracting anaesthetists from their clinical duties during the challenging induction period. It will be emphasised, during the site initiation visits, that patient safety is our priority and that if POCT measurements could not be done immediately, anaesthetic management should be prioritised, with the possibility to collect samples after patient stabilisation. A specific section of the case report form (CRF) is available to report deviations from protocols, including the injection of i.v. medicines.

Nova Biomedical will also provide technical support to troubleshoot any issues with the equipment, including metre replacement. All equipment dispatches and collections will be organised and covered by Nova Biomedical. Centres will be advised to approach their local technical team as part of the study assessment. Disposable strips will be provided by the sponsor.

An e-learning and a user video have been developed in collaboration with Nova Biomedical and the POCT team at GSTT to provide adequate training in the maintenance and use of the StatStrip® Xpress2™ glucose/ketone devices. Device calibration will be discussed during the site initiation visit. Training should be recorded on a study log and daily records documented on a calibration log.

It was not deemed necessary to organise further site monitoring considering that recruitment would last between 2 and 3 weeks at each centre.

Data collection, protection, and storage

Metadata will be collected (age, sex, weight, height, medical history, ongoing treatment, type of procedure, planned anaesthetic protocol, premedication, fasting time for solids and liquids, time of induction), along with blood sugar and ketone measurements. Clinicians are asked to report whether the child is considered hypoglycaemic based on their usual practice (clinician interpretation) and the subsequent management (including treatment initiated and further glycaemic checks). Blood ketones will be measured to identify hypo- or hyperketosis, which can indicate an abnormal response to fasting. All data will be reported on an electronic CRF by the anaesthetist managing the patient.

This study adheres to the Data Protection Act 2018. This is not limited to, but includes, being responsible for and able to demonstrate compliance with the principles relating to the processing of personal data. Data storage and protection will be done according to GSTT standards. Pseudo-anonymised data will be retained for 25 yr as per paediatric research requirements. Patient data will be kept by local recruitment centres for a duration of 5 yr.

Statistical considerations

This is a non-randomised, observational study given that there is no intervention. There was no formal sample size calculation. Based on previous UK-wide studies using the Paediatric Anaesthetists in Training Research Network, we estimated that a maximum sample size of 6000 patients could be recruited. However, these studies were retrospective cohorts using an audit methodology. With a prospective cohort design using consent, we target a sample size of more than 2000 patients. Overall, an expected proportion of 5% of hypoglycaemia is expected, leading to a precision of ±1.0 if we recruit more than 2000 patients. Specific subgroups will be considered, where proportions could be higher (young age, low weight) and precision different.

In this analysis, the primary outcome is the diagnosis of hypoglycaemia (yes/no answer provided by the anaesthetist) and its treatment.⁷

Many variable interactions could occur in our data set. For instance, anaesthetists and ward staff are more likely to try to reduce fasting duration in a young/low weight patient than a teenager. Some centres have implemented reduced fasting times for clear fluids and milks, whereas others might still be using the traditional 6-/4-/2-h fasting regimen. Colonoscopy requires bowel preparation and consequently a longer fasting duration from food. The presence of non-specific clinical signs of hypoglycaemia could also trigger an intervention to give sugary clear fluids. These interactions will be examined and suitable approaches adopted to accommodate them (including dropping one variable at a time or generating a meaningful composite variable). Variable selection will use regularisation approaches (elastic net).

For continuous variables, summary statistics such as means and standard deviations (for normal distributions) or medians and interquartile ranges (for non-normal distributions) will be provided. Categorical variables will be presented as frequencies and percentages. The variance inflation factor will be used to assess the severity of multicollinearity.

Comparisons between the hypoglycaemic grouping will be performed using a χ² test or Fisher’s exact test where appropriate for categorical variables. For continuous measures, a t-test or Mann–Whitney U-test will be performed. These will be used for the anaesthetic induction glycaemia and ketonaemia measurement timepoint. Mixed-effects logistic regressions will be used to account for unbalanced and clustered data. Random-effects models will be used to account for the multi-centre nature of the cohort. We expect some repeat measurements, but they should be limited in the cohort. Candidate fixed effects should include patient characteristics (age, weight, height, ethnicity), clinical status (ASA score and comorbidities), fasting regimen (fasting duration from food, clear sugar containing drinks, and clear non-sugary drinks), anaesthesia and procedural factors (procedure done under general anaesthesia, type of induction, and premedication used), and clinical markers and interventions (clinical signs of hypoglycaemia, treatment initiated, and blood sugar after the treatment).

Multiple imputations will be used to handle missing values, unless both glycaemia and ketonaemia values are missing. In this case, the whole raw data will be excluded. If the glycaemia or ketonaemia value is missing, then missing-at-random imputation will be used.^18,19

Statistical tests and confidence intervals will be two sided. The statistical significance level will be at the 5% level, and the Benjamini-Yekutieli correction will be used to account for multiple hypothesis testing.

To evaluate the prognostic factors associated with hypoglycaemia, a logistic regression model adjusting for potential baseline prognostic patient and clinical characteristics will be used. The results will be reported as odds ratios, associated 95% confidence intervals, and q-values.

A post hoc sensitivity analysis will be undertaken to evaluate variability among hospital sites. Several sensitivity analyses of the definition of hypoglycaemia threshold will be examined:

• •Hypoglycaemia: any blood glucose concentration of less than 3.3 mM
• •Hypoglycaemia: any blood glucose concentration of less than 3.6 mM
• •Hypoglycaemia: any blood glucose concentration of less than 4 mM

A detailed statistical analysis plan has been developed, and will be conducted by King’s College London.

Protocol strengths and limitations

Fasting-induced hypoglycaemia in anaesthetised paediatric patients (FIGS) protocol balances strengths and limitations to maximise patient recruitment data capture and minimise missing data. Participating centres are located in the four devolved nations of the United Kingdom. The recruitment period will stretch from May 25 to 26. This roll-out is supported by the Paediatric Anaesthetists in Training Research Network.

CRFs were designed to incorporate usual information collected by anaesthetists (including a more thorough history of fasting times) and be completed in a short amount of time (5 min). Equipment will be procured to ensure the availability of glucose and ketone metres in each anaesthetic area. Staggered 2-week data collection periods will be organised with individual sites recruiting at different timepoints within the 1-yr study period, to ensure equipment and team availability. We encourage live data entry on REDCap (Nashville, Tennessee, USA) to avoid any reporting bias or errors.

An ancillary audit was also approved by the REC to investigate patients who will be missed to recruitment in centres willing to conducted this extra data collection duty (opt-out, absence of equipment, error/issue with equipment/absence of blood collection, anaesthetist not participating or unable to recruit). This aims to identify bias of recruitment induced by the opt-out approach and guarantee the generalisability of our results.

Fasting

Protocol limitations

Centres will be expected to fast their patients according to their local guidelines. Although this will introduce variability in the regimen, it will allow us to explore the impact of reduced fasting times (breast milk 3 h, formula milk 4 h, and ‘Sip Til Send’) compared with the more traditional regimen (6/4/2 h).

Equipment

We expect some potential issues with equipment delivery (delays, lost parcels) that could impact the initial schedule established for the FIGS study. As equipment will rotate between recruiting centres, Nova Biomedical has agreed to have up to 100 devices available for the study.

Shipment will be done by a third party contracted by Nova Biomedical.

Quality control testing

Metres require quality control testing every 24 h to ensure data quality across space and time.

This requires additional work by the local research teams, with the necessity to establish an efficient quality control testing protocol by the research team before the start of the list in each anaesthetic location. It has an impact in terms of time, but also troubleshooting potential issues. Additional meters will be provided to swap out any meters with quality control issues.

Data collection

Limiting prospective metadata collection allows better recruitment but reduces potential associations. Further retrospective data collection could be organised to explore other impacts of fasting in children if centres are willing to explore specific associations of interest to them.

Opt-out approach

The use of an opt-out approach to consent relies on efficient sharing of understandable information with families. As such, it is expected that differences will exist among centres (typically centres able to e-mail study information ahead of the day of the procedure and those sharing it on the day). Provisions have been made in the protocol to facilitate information sharing, crucial to decision making, with the parents and give them sufficient time to process the information. It will be left at the discretion of the anaesthetist to assess whether the level of understanding is sufficient and the risk of language or cultural barriers (families that cannot understand/read English without an interpreter on the ward would not be recruited). In addition, anaesthetists will double check with the families whether they received the information and are happy to support the study, answering additional questions if needed. It cannot be excluded that this approach would lead to potential passive inclusion without true understanding. This is why respecting standard anaesthetic care is crucial in this study.

Research procedure

To secure an opt-out approach to consent, it is critical not to deviate from standard practice. As such, no additional prick test or cannula insertion should be done for the sole purpose of the research. This could lead to failure to recruit if the cannula is not bleeding back.

Measurement bias

In the case of potential hypoglycaemia detected using the study equipment, centres will be asked to retest glycaemia using their Trust-approved devices and to revert to their local guidelines. This could potentially introduce a measurement bias for the post-treatment measures, using local Trust-approved devices. Centres are asked to report the post-treatment measurements on the study CRF.

Recruitment bias

Recruitment completeness will be monitored using an ancillary audit approved by the ethics committee. However, this additional work will be left at the discretion of the recruiting centres, if they have the capacity to collect these data. It will be possible, among these participating centres, to calculate the expected denominator and then to extrapolate it to the whole study. This ancillary audit will also collect patient characteristics, scheduled procedure, and reasons for not being recruited (including opt-out, hospital, clinical, or study constraints).

This protocol facilitates recruitment in a fast-paced clinical environment with limited impact or delay on NHS theatre schedules.

Breach of protocol and safety

Investigators are required to share any breach of protocol or adverse event with the chief investigator as soon as possible. It is expected that there should not be adverse events associated with the protocol.

Dissemination

Dissemination will include publication in high-impact peer-reviewed international journals and communications at international conferences. It is foreseen that the study might have far-reaching impact in paediatrics. Anonymised data will be kept on REDCap, and data sharing agreements will be evaluated on a case-by-case basis.

Amendments

The main amendments to the protocol approved the introduction of an ancillary audit (FIGS missed recruitment, to assess the characteristics of the patients that we would fail to recruit despite the opt-out approach to consent; see Fig. 2), the introduction of a patient-facing document in Welsh, and a 1.5-month extension of the recruitment window to complete recruitment in all centres who expressed interest in FIGS.

Conclusions

The opt-out approach to consent should allow the recruitment of a wide prospective cohort in paediatric anaesthesia with a target of more than 2000 children recruited eventually. The results of the FIGS study may guide perioperative metabolic management and lead to further research in this specific domain that will probably rely on a more traditional consenting approach in a smaller population and with fewer centres involved.

Authors’ contributions

Conceptualisation: HFL, HL, CG, GJ, KL

Data curation: AV, BJB

Formal analysis: HL, SA, BJB

Funding acquisition: HFL, BJB

Project administration: GJ, KL, BJB

Visualisation: BJB

Study roll-out: HFL, TMC, JP, ND, EW, SF, BJB

Writing—original draft: HFL, BJB

Review and approval of the final draft: all authors

Funding

The Evelina London Children’s Charity (grant X240103); the Association of Paediatric Anaesthetists in Great Britain and Ireland; Nova Biomedical.

Declaration of generative AI and AI-assisted technologies in the manuscript preparation process

During the preparation of this work, the authors used Perplexity AI and ChatGPT in order to create illustration in Figure 1. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Declarations of interest

The authors have no conflicts of interest to declare.

Handling Editor: Susan M Goobie