Research guru and PI for the ARISE study, college examiner and semi-professional forrest-based carpenter, Anthony always gives a fascinating talk. This time he gives an intelligent and considered breakdown on the nebulous topic of cerebral protection.

1. CEREBRAL PROTECTION
Anthony Delaney MBBS MSc FACEM FCICM
Staff Specialist in Intensive Care, Royal North Shore Hospital
Senior Lecturer, Sydney Medical School, University of Sydney

2. Cerebral Protection

3. Cerebral protection
 Surgical:
 Decompressive craniectomy
 Medical:
 Hypothermia

5. Decompressive craniectomyin diffuse traumatic
brain injury
 Population:
 Aged 15-59
 Severe non penetrating brain injury (GCS 3-8),
Class III Marshall score
 Exclusion: mass lesion on CT, dilated unreactive
pupils, spinal cord injury, cardiac arrest
 ICP > 20 for 15 minutes within an hour after;
 Sedation, Normal CO2, osmotic therapy, NM blockade
and CSF drainage
 Within 72 hours of injury

6. Decompressive craniectomyin diffuse traumatic
brain injury
 Intervention:
 Standardised large bifrontotemperoparietal
craniectomy with opening of the dura

7. Decompressive craniectomyin diffuse traumatic
brain injury
 Comparison:
 Second tier therapy for refractory raised
intracranial hypertension
 Hypothermia
 Barbiturate coma
 Decompression after 72 hours
 Outcome:
 Extended Glasgow Outcome Score
 Initially dichotomised
 Ordinal scale

8. Decompressive craniectomyin diffuse traumatic
brain injury
 Allocation concealment:
 Yes, automated telephone system
 Blinding:
 Outcome assessment by telephone by blinded assessors
 Complete follow-up:
 Yes
 Intention-to-treat analysis:
 Yes
 Baseline balance:
 More patients in DC group had bilateral unreactive pupils
 Concommittant interventions:
 Different between the 2 groups

9. Decompressive craniectomyin diffuse traumatic
brain injury

10. Decompressive craniectomyin diffuse traumatic
brain injury

11. Decompressive craniectomyin diffuse traumatic
brain injury

12. Decompressive craniectomyin diffuse traumatic
brain injury
 Results
 December 2002-April 2010
 15 ICUs in Australasia-ish (inc Saudi Arabia)
 Revised primary outcome

13. Decompressive craniectomyin diffuse traumatic
brain injury

14. Decompressive craniectomyin diffuse traumatic
brain injury

15. Decompressive craniectomyin diffuse traumatic
brain injury

16. Decompressive craniectomyin diffuse traumatic
brain injury

17. Decompressive craniectomyin diffuse traumatic
brain injury

18. Decompressive craniectomyin diffuse traumatic
brain injury
 However the adjusted analysis
 Age, last GCS before intubation, GCS post
resuscitation, Marshall score;
 GOSe 1.66 (95% CI 0.94 to 2.94, p=0.08)
 Good v Evil OR 2.31 (95% CI 1.10 to 4.83, p=0.03)
 And non reactive pupils
 GOSe 1.53 (95% CI 0.86 to 2.73, p=0.15)
 Good v Evil OR 1.9 (95% CI 0.95 to 3.79, p=0.07)

19. Decompressive craniectomyin diffuse traumatic
brain injury
 So…….
 RESCUE ICP
 ICP>25 for 1-12 hours
 Abnormal CT
 Primary decompression excluded but prior
surgery not an exclusion
 Recruitment commenced 2005
 334/400 recruited as of 18/9/12

20. Hypothermia for cerebral protection
 Pathophysiology:
 Reduction of CMRO2 of 6-7% per 1o drop in temp
 Reduction in ICP
 Decreases excitatory amino acids and lactate in
ischaemia/reperfusion injury
 Reduces intracellular Ca++ sequestration
 Reduces neutrophil adhesion
 Reduces apoptosis
 Reduces free radical production
• Induced hypothermia in critical care medicine: A review. Bernard et al CCM 2003;31:2041-2051
• Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising
treatment modality. Part 1: indications and evidence. Polderman. ICM 2004;30:556-575

21. Hypothermia for cerebral protection

23. Hypothermia for neuroprotection in adults after
cardiopulmonary resuscitation
 Question:
 To assess the effectiveness of therapeutic hypothermia in
patients after cardiac arrest
 Studies:
 Randomised and quasi-randomised studies
 Population:
 Adult patients who suffered cardiac arrest (in or out of hospital)
 Intervention:
 Temperature target <35oC
 Control:
 Standard treatment
 Outcome:
 Neurological recovery
 Cerebral performance category

24. Hypothermia for neuroprotection in adults after
cardiopulmonary resuscitation
 5 Studies

25. Hypothermia for neuroprotection in adults after
cardiopulmonary resuscitation
 3 studies thought suitable for pooling

26. Hypothermia for neuroprotection in adults after
cardiopulmonary resuscitation
 3 studies thought suitable for pooling

27. Hypothermia for neuroprotection in adults after
cardiopulmonary resuscitation
 Conventional cooling methods to induce
mild therapeutic hypothermia seem to
improve survival and neurological outcome
after cardiac arrest. Our review supports
the current best medical practice as
recommended by the International
Resuscitation Guidelines

32.  Higher risk of bias in existing trials ->
overestimation of treatment effect
 Low inclusion rate (8%) -> poor
generalisability
 Or better signal to noise ratio
 Target population
 Early stopping and no power calculation
 More of a type II error problem
 Non-standard change to palliative treatment
 Dude ?!?
 Adverse effects of hypothermia

34. Adverse effects of hypothermia
 Prospective observational study
 22 centres

35. Most published research findings are
false
 Really?

36. Most published research findings are
false
 Complicated statistical argument
 Prior probability
 Power of the study
 Level of significance
 Bias
 Flexibiilty in design
 Definition
 Outcomes
 Analysis

38. Contradicted research
 Original clinical research cited more than
1000 times 1990-2003
 Compared to subsequent studies bigger
and/or better
 49 studies
 45 claimed a treatment effect
 16% contradicted
 16% lesser treatment effect
 44% replicated
 24% not challenged

39. So, wherefore hypothermia
 Dilemma
 Hypothermia has a good physiological
rationale
 Supported by at least
reasonable trials

41. QUESTIONS ??