Paediatric Applications

Scale of Problem Brain injury kills five times more children than cancer Nearly 25% PICU adm: risk of acute neurological injury High incidence of traumatic brain injury (TBI) In US: 35,000 severe TBI and 7440 deaths/yr (CDC) Apprx 50% poor neurological outcomes at 6 mo Mean age ~ 9 yrs, productive life-years 1.3 million/yr PCCM 2011;12:601-2 Neurotherapeutics 2012;9:3-16

Cerebrovascular Dynamics in Children Age/gender related differences: ICP, CBF, CA LLA may not be lower in lower age groups Association of autoregulation with outcome Age-related changes in mean flow velocity of middle cerebral artery (VMCA) in both genders, cerebral blood flow (CBF), cerebral metabolic rate of glucose (CMRglu) (Adult values: VMCA ∼ 50 cm/sec, CBF 50 ml/100g/min, CMRglu 19-33 μmol/100g/min) Pediatr Neurol 2008;38:225-34

Secondary Brain Injury Cerebral Blood Flow Impaired autoregulation Brain oedema Increased ICP Energy Flow Glucose utilization Glucose availability Mitochondrial failure Secondary Brain Injury Oxygen Hypoxia/Ischaemia Impaired O2 Regulation Impaired microcirculation Excitotoxicity Excessive neurotramitter release Spreading cortical depolarisations Seizures

N=12 (8 survivors)

N=36 (23 favourable outcome, 7 unfavourable outcome)

Sample Size Mean (± SD) PRx of 0.03 ± 0.13 for favourable outcome and mean (± SD) PRx of 0.10 ± 0.17 (SD) for unfavourable outcome One sided analysis, favourable: unfavourable ratio of 0.77 (80% power and alpha error of 5% & allowance for losses (protocol violations, withdrawal of consent, or loss of FU) Total: 135 patients.

IRAS: 242229 REC: 18/SW/0053 Funded by AMRC and ACT Sponsored by Cambridge University Hospitals

Current Status Multicentre UK study: 10 sites Funded by Action Medical Research and ACT 135 patients over 3 years with one year follow-up Consent waiver for acute data collection Objectives: Primary: Optimal PRx with 12 mo outcome (GOSE peds) Secondary: Optimal CPP

shruti.agrawal@addenbrookes.nhs.uk, sa882@cam.ac.uk, mc916@cam.ac.uk 16 years or younger admitted to PICU TBI confirmed on CT or MRI Clinical requirement for monitoring ICP &ABP No exclusion criteria Consent for Follow-up before hospital discharge shruti.agrawal@addenbrookes.nhs.uk, sa882@cam.ac.uk, mc916@cam.ac.uk

Birmingham Children’s Hospital: Cambridge University Hospitals Great Ormond Street Hospital King’s College Hospital Leeds Children’s Hospital Manchester Children’s Hospital Nottingham Children’s Hospital Royal London Hospital Sheffield Children’s Hospital Southampton Children’s Hospital

Data Collection Schedule: Acute Data Data Elements Acute data (PICU stay) ICM + data collection (till ICP monitoring stops)   As soon as possible after ICP bolt and arterial line insertion CRF- Once per admission Demographics √ Pre-PICU events Neuro-monitoring Severity scores (PIM 2 and AIS) Discharge CRF- Daily (till ICP monitoring stops) Laboratory Values TBI: Medical interventions TBI: Surgical interventions PICU complications/events (as required)

Data Collection Schedule: Follow-up CRF for Outcomes Assessment 6 Months 12 months Parents Teachers GOSE- Peds   √ (telephone) X BRIEF √ (questionnaire) SDQ PedsQL CASP CCC RCADS x

STARSHIP: CUH Team PICU: Shruti Agrawal (chief Investigator) & Ricardo Branco (co-investigator) Deborah White & Esther Daubney (PICU research nurses) Phil Castle (ODP for technical support) Paediatric Neurology: Dr Anna Maw Dr Suzanna Watson (Neuropsychologist) Brain Physics: Manuel Cabeleira (Research Assistant) Dr Peter Smielewski & Prof Marek Czosnyka Neurosurgery Prof Peter Hutchison Ms Helen Fernandes & Mr Matthew Garnett Mr Adam Young

shruti.agrawal@addenbrookes.nhs.uk, sa882@cam.ac.uk, mc916@cam.ac.uk Progress (10th September 2018) 8 site initiation completed, 6 sites live. Recruited: 3 Collaboration with KidsBrainIT: BIR, NOT, MAN Future Directions Ongoing national and international collaboration Database to study age/gender related differences shruti.agrawal@addenbrookes.nhs.uk, sa882@cam.ac.uk, mc916@cam.ac.uk

???? Brain Physics Group members Acknowledgments: Brain Physics Department: Professor Marek Czosynka Dr Peter Smielewski Mr Manuel Cabeleira Dr Joseph Donnelly PhD students & research staff Academic Neurosciences Professor Peter Hutchison Mr Matthew Garnett Mrs Helen Fernandez Mr Adam Young ????