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www.RESCUEicp.com
– progress and hurdles!
Peter Hutchinson
Academic Neurosurgery
University of Cambridge
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Head Injury
• 1 000 000 A&E attendances per annum
• Majority minor
• Severe head injury is the commonest cause
of death under the age of 40
• Survivors often severe disability
• Approx 10-15% of patients with severe head
injury develop major brain swelling and
uncontrollable elevation of intra-cranial
pressure
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The escalating cycle of brain swelling
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NCCU – Head injury management
ICP<25 mmHg
• Stage I
– Sedation and ventilation
– Nurse, head up
– Control arterial CO2 4.5 kPa
• Stage II
– External ventricular drain
• Stage III
– Inotropes / hypertonic saline / mannitol
• Stage IV
– Hypothermia
• Stage V
– Barbiturates -Thiopentone
– Decompressive craniectomy
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Indications for surgeryEstablished Unknown
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Decompressive Craniectomy‘If there is no CSF pressure, but brain pressure exists, then pressure relief
must be achieved by opening the skull’
Kocher 1901
Does decompressive
craniectomy work?
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• DC may be a useful option
when maximal medical
treatment has failed to
control ICP
• Bifrontal decompressive
craniectomy within 48
hours of injury is a
treatment option for
patients with diffuse,
medically refractory
posttraumatic cerebral
edema and resultant
intracranial hypertension
Brain Trauma
Foundationwww.braintrauma.org
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Proposal for a Clinical Trial of Decompressive Craniectomy in TBI
The RESCUEicp study
Academic Neurosurgery University of Cambridge
European Brain Injury Consortium
Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of ICP
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Principal hypothesis
• The application of
decompressive
craniectomy to head-
injured patients with
raised and refractory
ICP results in
improvement in
outcome compared to
optimal medical
management
+ ICP > 25
mmHg
?
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Prospective randomised study
Target study group n=400
Ventilated patients with refractory intracranial hypertension
Advanced medical management (inc barbiturates)
V
Surgical management (decompressive craniectomy)
Outcome assessed at 6 months, 1 year and 2 years using extended Glasgow Outcome Score and SF-36
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Progress
• Research Team
• Protocol
• Ethics
• R&D
• Randomisation
• Flow chart
• Case report form
• Data monitoring
• Funding - £1.15m
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The Team
• Research Fellow
– Ivan Timofeev
– Angelos Kolias
• Research Nurse
– Liz Corteen
• Academic FY2
– Lucia Li
• University of Cambridge
• Research Services
• Addenbrooke’s Hospital
• NHS R&D
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The Protocol
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Approval, consent and randomisation
• Approval– Ethics – information sheet
– National ethical approval in the UK
– R and D approval
– Contracts
• Consent / Assent
– next of kin on admission avoid delays in randomisation or
independent consultant
• Randomisation– 24 hour international telephone number - switchboard
– stratified by centre
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Study centres• 47 centres are currently contributing patients
• 10 initiating / ready to start recruitment
• Aim ≈ 70 centres worldwide
• > 100 interested centres,
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Data collection and follow-up
CRF paper based
Postal questionnaire and
telephone follow up
Nomadic, cognitive issues
>94% 6 months follow up
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Hurdles
• Administration
• Ethics
• R&D
• Contracts
• The Budget
• NHS support costs
• Protocol insurance
• Clinical
• Recruitment rate
• Trial fatigue
• Lack of equipoise
• Crossover
• Results from other
studies
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Protocol insurance
• Became an issue in
2009
• No new contracts / new
centres without
insurance
• Cost worldwide
insurance £250 000
• Solution
– Blanket country policy
£42000
– UK
– Canada
– Australia
– Singapore
– Malaysia
– USA
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Recruitment by centre
n=317 / 400
47 centres
0
10
20
30
40
50
60
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UKn= 219
69%
Italyn= 155%
Spainn= 124%
Braziln= 113%
Canadan= 103%
Perun= 103%
Singaporen= 93%
Saudi Arabian= 93%
Chinan= 62%
Other n= 165%
Recruitment by countryUK Italy Spain Brazil Canada Peru Singapore Saudi Arabia China Other
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Current recruitment forecast for April 2012
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Recruitment curve
RESCUEicp recruitment curve
0
2
4
6
8
10
12
14
16
18
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
1st
3rd
2004 2005 2006 2007 2008 2009 2010
Tot
al patient
s
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0
10
20
30
40
50
60
2004 2005 2006 2007 2008 2009 2010
Rate
Hospitals (cumulative)
Recruitment v
number of centres recruiting
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Crossover – a problem for surgical trials total
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0
1721
27
16
24 23
0
5
10
15
20
25
30
2004 2005 2006 2007 2008 2009 2010
Crossover as % of annual recruitment
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What happens to recruitment
when a similar study is
published!!!
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Randomised trials of decompressive craniectomy for TBI
• RESCUEicp
• Cambridge UK
• 400 patients
• Recruitment on-going
• 10-65 years
• Raised ICP refractory to protocol-
based medical management
• ICP threshold 25mmHg
• DECRA
• Melbourne Australia
• 155 patients randomised
• Completed
• 15-60 years
• Severe diffuse brain injury within
72 hours injury
• ICP threshold 20mmHg
Li et al, Anaesth Analg, 2010
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DECRA – results – decompressive
craniectomy resulted in worse outcome
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Screening log
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Summary - project timeline• 2004: start of recruitment
• 2007: MRC/NIHR Clinical Trials Grant awarded (2nd attempt)
• 2011: applying for grant extension
• December 2012: end of recruitment
• June 2013: 6 months follow-up completed (primary endpoint)
• October 2013: trial results (6 month follow-up) published
• December 2013: 1 year follow-up completed
• April 2014: 1 year follow-up results published
• December 2014: 2 year follow-up completed (end of trial)
• April 2015: 2 year follow-up results published
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RESCUEicp – study - conclusion
• A long journey 2004-
2014
• Ups and downs
• Travelling
• Visiting different units
• Hurdles – some
avoidable, some
unavoidable
• Would we do it again?
• Son of RESCUEicp in
preparation!
• Decompressive craniectomy is a
treatment option for patients with
refractory posttraumatic cerebral
oedema and resultant intracranial
hypertension
• But..
• Has a significant complication
rate
• May being performed in patients
who will do well with medical
treatment alone
• Risks severe disability and
vegetative state
• RESCUEicp on going 83 more
out of 400 needed!
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Acknowledgements- thank you!• Peter Kirkpatrick
• John Pickard
• Ivan Timofeev
• Angelos Kolias
• Liz Corteen
• Lucia Li
• Marek Czosnyka
• David Menon
• Barbara Sahakian
• Medical / Nursing Staff on NCCU
• Martin Buxton
• David Mendelow
• Patrick Mitchell
• Graham Teasdale
• Franco Servadei
• Gordon Murray
• Juan Sahuquillo
• Andy Unterberg
• Local investigators
• Hugh Richards Anthony Bell
• Donald Shaw Mark Dearden
• Martin Smith Nicola Latronico
• Lennart Persson Eckhard Rickels
www.RESCUEicp.com