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PIVOTAL Clinical Training - Core v1.0 21.01.2026

ICNARC CTU

Created on January 21, 2026

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Transcript

Paediatric Intensive Care Adaptive Platform Trial

CLINICAL TRAINING:Core aspects of the PIVOTAL study

v1.1 09 March 2026

To navigate this training package, use the arrows on either side of the screen

    Use this button to view the contents of the training and move between different sections:

      Click on the three dots in the bottom right hand corner of the screen if you want to navigate to a specific page...

        www.icnarc.org

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        PIVOTAL training packs

        There are 4 separate training packs for the PIVOTAL research study. One for ‘core’ platform training and one for each domain:

        • Core platform training: Overall summary of platform, eligibility and examples of scenarios for possible randomisations
        • Fluid domain
        • Sedation domain
        • Blood transfusion thresholds domain

          It is recommended to undertake the core training first

          www.icnarc.org

          www.icnarc.org

          PIVOTAL training packs

          Core Platform
          Blood transfusion thresholds domain
          Fluid domain
          Sedation domain

          www.icnarc.org

          www.icnarc.org

          Contents

          • Aim of PIVOTAL
          • Which patients?
          • Organ support – trial definition
          • Strata
          • Domains
          • Trial design
          • Why these domains?
          • Definition of ‘days’
          • Patient flow:
            • Screening and eligibility criteria
            • Randomisation
            • Domain treatment allocations on randomisation
            • Consent
          • Review your knowledge
          • Next steps
          • Support and resources
          • Questions
          • Training confirmation form

          www.icnarc.org

          www.icnarc.org

          Aim of PIVOTAL

          • The overall aim of the PIVOTAL platform research study is to simultaneously evaluate the clinical and cost-effectiveness of multiple interventions in critically ill children
          • These interventions are all core processes in PICU and are called ‘domains’

            Platform trials allow multiple interventions to be tested simultaneously providing efficiency in trial delivery, time and cost. Importantly this also reduces burden on parents.

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            www.icnarc.org

            Which patients?

            Cardiac and non-cardiac strata (groups)
            All patients receiving organ support
            Definitions: see next slides

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            www.icnarc.org

            Organ support

            • Defined as receipt of respiratory, cardiovascular or renal support within PICU according to the Paediatric Critical Care Minimum Dataset.
            Click each type of organ support to reveal the full list...

            Renal

            Respiratory

            Cardiovascular

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            Strata

            Cardiac

            Non-cardiac

            Primary cardiac disease (structural, myocardial or arrythmia) as the main reason for PICU admission

            Non-cardiac cause as the main reason for admission to PICU

            www.icnarc.org

            www.icnarc.org

            Domains

            Fluid

            Sedation

            Transfusion

            • Intervention: Conservative fluid management and active fluid removal
            • Control:
            Usual care
            • Strata:
            Non-cardiac patients only
            • Intervention: Dexmedetomidine or Clonidine
            • Control:
            Midazolam
            • Strata:
            Non-cardiac and cardiac patients
            • Intervention: Restrictive RBC transfusion strategy
            • Control: Liberal RBC transfusion strategy
            • Strata:
            Non-cardiac and cardiac patients

            www.icnarc.org

            www.icnarc.org

            Trial design

            • Multi-centre, randomised, Bayesian adaptive, platform trial with an internal pilot phase

            www.icnarc.org

            www.icnarc.org

            Trial design

            Projected monthly recruitment: ~320 platform eligible patients per month
            Expected to open: March 2026

            A great title

            Recruitment
            Target: No fixed recruitment number (maximum 12,900 in current grant)
            Participating nations: England, Wales, Scotland and Northern Ireland

            A great title

            A great title

            www.icnarc.org

            www.icnarc.org

            Areas of treatment covered are core processes in PICU

            IV fluid use is universal in PICU After resuscitation, children continue to receive large volumes of fluid, commonly leading to fluid accumulation

            Fluid Management

            Over 50% of UK PICU patients on invasive mechanical ventilation receive continuous sedation Optimal sedation avoids both under-sedation (distress, agitation) and over-sedation (prolonged ventilation, PICU stay, delirium)

            Sedation

            Anaemia is very common in PICU – up to 74% of children RBC transfusion is the main treatment to quickly raise haemoglobin (Hb)

            Blood Transfusions

            www.icnarc.org

            www.icnarc.org

            Why these domains in PIVOTAL?

            Click below to reveal information about each domain...

            Current guidelines advise restriction but supporting evidence remains weak. Other paediatric trials of restriction alone have not achieved meaningful separation – must also combine active fluid removal (AFR).

            Systematic reviews show poor reporting of sedation outcomes – trials are small and heterogeneous. No trials in children have directly compared clonidine vs dexmedetomidine despite similar mechanisms and costs.

            Paediatric evidence largely informed by single trial with limitations. Guidelines provide only conditional recommendations for children with cardiac disease or acute brain injury due to lack of high-quality trials.

            Use this side of the card to provide more information about a topic. Focus on one concept. Make learning and communication more efficient.

            Use this side of the card to provide more information about a topic. Focus on one concept. Make learning and communication more efficient.

            Use this side of the card to provide more information about a topic. Focus on one concept. Make learning and communication more efficient.

            Blood transfusion domain

            Fluid domain

            Sedation domain

            Title

            Title

            Title

            Write a brief description here

            Write a brief description here

            Write a brief description here

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            www.icnarc.org

            Definition of ‘Days’

            To support practical application of the study, days are defined as either calendar days or chart days. This is only relevant for fluid calculation in the fluid domain and for all data collection (CRF) by the research team. You should continue to record patient care as usual in your PICU (i.e., use of patients' medical records, PICU charts, prescription charts etc).

            Day 1 = Day/date of randomisation
            Details for each domain on next slides...

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            www.icnarc.org

            Definition of ‘Days’: Fluid Domain

            ‘Days’ refer to your usual chart days.

            • Day 1 = Day of randomisation
            From date/time of randomisation until the end of your usual chart day
            • Day 2 = From the start of your next chart day until the end of that chart day

            Examples on next slide...

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            Definition of ‘Days’: Sedation Domain

            ‘Days’ refer to calendar days/dates

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            www.icnarc.org

            Definition of ‘Days’: Transfusion Thresholds Domain

            ‘Days’ refer to calendar days/dates If randomised to other domains(s) but not the transfusion domain yet, screening for eligibility is up to the end of day 4 (calendar day/date) - more detail in later slides

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            Patient flow

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            Platform eligibility

            Inclusion criteria:

            Gestational age at birth ≥37 weeks, or combined gestational age and post-birth age ≥37 weeks, and <16 years at the time of randomisation
            Receiving at least one of respiratory, cardiovascular, or renal support
            Expected to remain on organ support the following day
            Face-to-face contact with PICU or transport team

            Exclusion criteria:

            Previously recruited to a domain in PIVOTAL either in the last 30 days or during the same hospital admission

            Death perceived as imminent

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            www.icnarc.org

            Fluid eligibility

            Patients confirmed platform eligible and meet all fluid eligibility criteria at the time of randomisation.

            Click below to reveal more information about the domain...
            • Admitted with a condition that requires a specific fluid management regimen (e.g. diabetic ketoacidosis, tumour lysis syndrome, diabetes insipidus)
            • Participating in another research study that requires fluid management
            • Receiving renal replacement therapy or Extracorporeal Membrane Oxygenation support
            • Over 12 hours since meeting the platform and domain inclusion criteria

            Non-cardiac ONLY (i.e. non-cardiac cause as the main reason for admission to PICU)

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            Use this side of the card to provide more information about a topic. Focus on one concept. Make learning and communication more efficient.

            Title

            Receiving invasive mechanical ventilation

            Exclusion criteria

            Inclusion criteria

            Use this side to give more information about a topic.

            Strata

            Subtitle

            Title

            Title

            Write a brief description here

            Write a brief description here

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            www.icnarc.org

            Sedation eligibility

            Patients confirmed platform eligible and meet all sedation eligibility criteria at the time of randomisation.

            Click below to reveal more information about the domain...
            • Known hyper-sensitivity or contraindication to one of the sedative agents
            • Known pregnancy
            • Over 12 hours since meeting the platform and domain inclusion criteria
            • Receiving invasive mechanical ventilation
            • Receiving, or about to receive, a continuous intravenous sedative

            Use this side of the card to provide more information about a topic. Focus on one concept. Make learning and communication more efficient.

            Use this side of the card to provide more information about a topic. Focus on one concept. Make learning and communication more efficient.

            Title

            Exclusion criteria

            Inclusion criteria

            Use this side to give more information about a topic.

            Non-cardiac and cardiac

            Strata

            Subtitle

            Title

            Title

            Write a brief description here

            Write a brief description here

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            www.icnarc.org

            Blood transfusion thresholds eligibility

            Patients confirmed platform eligible and meet all blood transfusion thresholds eligibility criteria.

            Click below to reveal more information about the domain...
            • Latest Hb less than or equal to the relevant threshold outlined below:

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            Inclusion criteria

            Title

            Use this side to give more information about a topic.

            Non-cardiac and cardiac

            Strata

            Subtitle

            Title

            Write a brief description here

            www.icnarc.org

            www.icnarc.org

            Blood transfusion thresholds eligibility

            Click below to reveal more information about the domain...
            • Haemoglobinopathies (e.g. sickle cell disease, thalassemia) where red blood cell transfusions may be used to prevent haemolytic or aggregation crises
            • Unrepaired cyanotic congenital heart disease and/or functionally single ventricle circulation and/or palliated parallel circulation
            • Known advance decision refusing blood/blood component transfusions (e.g. Jehovah’s Witnesses)
            • Receiving Extracorporeal Membrane Oxygenation (ECMO)
            • Receipt of RBC transfusion for a reason other than bleeding or extracorporeal support (on ECMO or for priming renal replacement circuit) since meeting the platform inclusion criteria

            Exclusion criteria

            Title

            Use this side to give more information about a topic.

            Subtitle

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            www.icnarc.org

            Blood transfusion threshold - eligibility

            If first randomised into another domain(s), patients may become eligible for the transfusion domain at a later timepoint

            Patients may be randomised at the same time as the other domains

            Patients may be randomised to the transfusion domain only

            OR
            OR
            • After domain-specific eligibility is confirmed, a second randomisation will be conducted
              • Day 1 = day of first randomisation (use calendar days)
              • If Hb does not meet threshold prior to the end of Day 4, patient will not be eligible for inclusion into the transfusion domain

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            Who can confirm eligibility?

            • A qualified healthcare professional (does not need to be a doctor) responsible for the care of the patient on PICU

            Name of person confirming eligibility is recorded on the online randomisation form (Sealed Envelope)

            Trial training required to confirm eligibility
            Documented on Training Log

            Does not need to be on the Delegation Log or have GCP training

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            www.icnarc.org

            Patient flow

            www.icnarc.org

            www.icnarc.org

            Randomisation

            • Dedicated 24/7 service – “Sealed Envelope”
              • Web randomisation only
            Name of person randomising is recorded on the online randomisation form (Sealed Envelope)
            Trial training required to randomise
            Documented on Training Log
            Appropriate clinical staff may be involved solely in the screening and randomisation of patients e.g., out-of-hours staff
            GCP training not required to randomise

            www.icnarc.org

            www.icnarc.org

            Randomisation

            Patients are randomised into one of the possible groups for each domain:

            Fluid

            Sedation

            Transfusion

            • Continuous IV infusion of Dexmedetomidine
            • Continuous IV infusion of Clonidine
            • Continuous IV infusion of Midazolam
            • Conservative fluid management
            • Usual fluid management
            • Restrictive transfusion threshold
            • Liberal transfusion threshold
            • Conservative fluid management
            • Usual fluid management

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            www.icnarc.org

            Randomisation - Transfusion

            • Patients may become eligible for Transfusion domain later
              • A second randomisation can be carried out when eligible (if patient was not eligible for this domain at the first randomisation timepoint)
            • Following the first randomisation, patients have until the end of day 4 (calendar days) to be randomised to transfusion
              • Participant list tab on Sealed Envelope – will only show patients who are still within the window to be randomised to transfusion

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            Patient flow

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            Treatment allocation on randomisation

            Patients are randomised into one of the possible groups for each domain. Details are discussed in the individual domain training packs.

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            www.icnarc.org

            Patient flow

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            Research Without Prior Consent

            • Due to the emergency and time-sensitive nature of the clinical situation, PIVOTAL will use a research without prior consent model
              • This means that patients may be recruited into the trial before consent
            • After randomisation and once patient’s medical situation is no longer considered an emergency, the research team will begin consent procedures
            • Parents/legal guardians may consent to all or some of the domains
            • Family Room Poster and Information Leaflets (general and cardiac) available

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            www.icnarc.org

            Planned admissions

            • E.g., following elective cardiac surgery
            • Parents may be given an information leaflet in advance e.g. at pre-op clinic or appointments
              • Information leaflet explains that their child may become eligible for PIVOTAL if admitted to PICU
            • Parents are not consented prospectively

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            Review your knowledge

            www.icnarc.org

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            Review knowledge: Scenario 1

            Harry, 10 day old 3.8kg baby admitted to PICU 2 hours ago with possible sepsis. He is sedated and ventilated.

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            Review knowledge: Scenario 1

            Harry, 10 day old 3.8kg baby admitted to PICU 2 hours ago with possible sepsis. He is sedated and ventilated.

            www.icnarc.org

            www.icnarc.org

            Review knowledge: Scenario 1

            Answer: Harry is eligible for both Fluid and Sedation but his eligibility for Transfusion depends on his Hb...

            He would be eligible for the Transfusion domain if his Hb is less than or equal to 85g/L, now or within 4 days of randomisation into the other domains of PIVOTAL. This is because he is non-cardiac, non-ABI.

            • Latest Hb less than or equal to the relevant threshold outline below:

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            Review knowledge: Scenario 1

            Harry’s Hb is 100g/L.

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            Review knowledge: Scenario 1

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            Review knowledge: Scenario 1

            Harry was entered into the Fluid and Sedation domains two days ago. He was allocated to:

            • Fluid domain: Conservative fluid management
            • Sedation domain: Clonidine
            Today his Hb is 80g/L.

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            www.icnarc.org

            Review knowledge: Scenario 2

            Joe, 4 year old boy admitted post cardiac surgery today. Sedated and ventilated.

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            Review knowledge: Scenario 3

            Jasmine, a 7 year old, 22kg, girl admitted with pneumonia two days ago. She remains sedated and ventilated. She was entered into the Fluid and Sedation domains on the day of admission and randomised to:

            • Fluid domain: Usual care
            • Sedation domain: Midazolam

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              Next steps

              Other PIVOTAL training packs available

              • Domains:
                • Fluid
                • Sedation
                • Blood transfusion thresholds

              www.icnarc.org

              www.icnarc.org

              Support and resources

              Click here

              • Website:
                • Domain training packs
                • Administration guides (one per domain)
                • Trial summary for bedside teaching
                • Bedside notices
                • Stickers for charts
                • AFR assessment form

              www.icnarc.org

              www.icnarc.org

              Questions

              If you have any questions on this domain or any part of the PIVOTAL trial, please ask your PICU research team first or contact the clinical trials unit at PIVOTAL@icnarc.org

                www.icnarc.org

                www.icnarc.org

                Training confirmation form

                Once you have completed this training pack, complete the online form via this link:

                  Click here

                  www.icnarc.org

                  www.icnarc.org

                  Renal support:

                  • Peritoneal dialysis
                  • Hemofiltration
                  • Haemodialysis

                  Cardiovascular support:

                  • Continuous infusion of inotrope or vasodilator
                  • Mechanical – ECMO
                  • Mechanical – ventricular assist device (VAD)

                  Respiratory support:

                  • Invasive ventilation via endotracheal tube
                  • Invasive ventilation via tracheostomy tube
                  • Non-invasive ventilatory support
                  • Heated humidified high flow therapy (HHHFT)