Mark Weedon takes us through the increasingly utilised concept of an optimal cerebral perfusion pressure (CPPopt) for each unique patient. He discusses the background to CPPopt, including intrcranial pressure (ICP), the Monroe Kelly hypothesis, neurovascular coupling, and cerebral autoregulation in health and following brain injury. He shows how intracranial pressure is affected by intracranial compliance and how this affects ICP waveforms. Cerebral perfusion pressure in relation to the Brain Trauma Foundation guidelines is covered including management of elevated ICP (EICP). The currently recommended tiered approach to managing cerebral perfusion pressure and EICP is mentioned citing recent guidelines. He uses a clinical case of a TBI to illustrate how the CPPopt can be ascertained and used to guide therapy, including the easy to perform “MAP Challenge”. Mark also describes the Pressure Reactivity Index (PRx) and how it can be used as a target for therapy. Finally, he covers the exciting results of the preliminary COGiTATE pilot study.

1. Cerebral Perfusion
Pressure

2. CPP
Key concepts
• ICP
• CPP = MAP - ICP
• Monro-Kellie doctrine:
✴ Blood + CSF + Brain = constant
✴ CSF provides a mechanical buffer

3. CPP
Key concepts

4. CPP
https://www.nejm.org/doi/full/10.1056/NEJMvcm1805314

5. CPP

6. CPP

7. CPP
Cerebral auto-regulation - in wakefulness
• Neurovascular coupling
• Tightly regulated - demand driven
• Blood flow linked to function and can be
visualised with fMRI, PET, XeCT -
applications in psychology, functional
neurosurgery, neuropsychiatry, research
• Active brain draws blood

8. CPPopt
Regional
autoregulation

9. CPP

10. CPP and the BTF guidelines
Current TBI practice
• In severe TBI intubate - GCS 3-8, protect airway, control CO2, avoid hypoxia
• Evacuate mass lesions
• Abnormal CT - ICP monitoring whether by monitor or EVD
• Osmotherapy (HTS vs Mannitol)
• Propofol, opioid
• Treat seizures

11. Current TBI practice - don’t:
• Prophylactic decompression
• Prophylactic hypothermia
• Steroids
• Early barbituates
• Allow sodium abnormalities
• ? Prophylactic AED (except in some circumstances)
• ? Paralysis
CPP and the BTF guidelines

12. Current practice
• MAP > 65
• ICP < 22mmHg (poor outcome is associated with level above this)
• CPP > 60-70mmHg - or 50-70mmHg (BTF)
• Where do we put the transducer? How we measure MAP matters!
CPP and the BTF guidelines

13. CPP
Current practice
Hawryluk, G.W.J., Aguilera, S., Buki, A. et al. A
management algorithm for patients with intracranial pressure
monitoring: the Seattle International Severe Traumatic Brain
Injury Consensus Conference (SIBICC). Intensive Care Med
45, 1783–1794 (2019).

14. CPP
Current practice
Hawryluk, G.W.J., Aguilera, S., Buki, A. et al. A
management algorithm for patients with intracranial pressure
monitoring: the Seattle International Severe Traumatic Brain
Injury Consensus Conference (SIBICC). Intensive Care Med
45, 1783–1794 (2019).

15. CPPopt
DR MARK WEEDEN
ST GEORGE ICU

16. CPPopt
Clinical scenario
• 33M, D4 ICU, otherwise well
• MBA, GCS 4 (M2) pre intubation (BP ok)
• Isolated TBI - traumatic SAH, spine ok
• EVD at 10cm H2O
• MAP 80, ICP 21 mmHg
• CTB 1 hour ago
• ICP waveform over last hours:
DOI: 10.3171/2017.11.JNS171892

17. CPPopt
ICP wave morphology 4 hours ago (top) vs now (bottom)

18. CPPopt
Clinical scenario
• 33M, D4 ICU, otherwise well
• MBA, GCS 4 (M2) pre intubation (BP ok)
• Isolated TBI - traumatic SAH, spine ok
• EVD at 10cm H2O
• MAP 80, ICP 21 mmHg
• What therapies would you expect?
DOI: 10.3171/2017.11.JNS171892

19. CPPopt
Clinical scenario
• Propofol 250mg/hr, Fentanyl 250microg/hr,
Midazolam 20mg/hr
• Head up 30°, temp 35.5 (actively cooled)
• pCO2 35mmHg
• Na 156mmol/L
• Noradrenaline 17mcg/min
• Nurse comes to you and wants assistance with a
roll and tells you that need to suction the ETT
• Anything else we should do?
DOI: 10.3171/2017.11.JNS171892

20. CPPopt
• Are ICP and MAP independent of one
another?
CPP = MAP - ICP
• What would happen over the next half
hour if we increased the noradrenaline so
that the MAP increased from 80 to
86mmHg?

21. CPPopt

22. CPPopt

23. CPPopt
The MAP challenge
• Single centre observational cohort study of all
patients admitted to the ICU with TBI and ICP
monitoring
• Decompressive craniectomies excluded
• ‘Event’: ≥100 min.mmHg in the 15-min period after
increase of IV vasopressors to achieve a desired
CPP (average rise of 6.7mmHg)
• Changes in ICP burden measured using ICM+
DOI: 10.3171/2017.11.JNS171892

24. CPPopt
The MAP challenge
• 122 ‘events’ ultimately included
• 13 patients
DOI: 10.3171/2017.11.JNS171892

25. CPPopt
The MAP challenge
• 65% net negative ICP burden - median -
36.5min.mmHg over 15 mins
• 35% had a median increase of
13.9min.mmHg in first 15min
• ICP burden between 15-30min generally
trended in the same direction as the first
DOI: 10.3171/2017.11.JNS171892

26. CPPopt
The MAP challenge
• RAC: Moving correlation
coefficient between ICP
pulse amplitude and
pressure CPP
DOI: 10.3171/2017.11.JNS171892
• PRx: Moving correlation
coefficient between ICP
and MAP

27. CPPopt
Clinical scenario
• Propofol 250mg/hr, Fentanyl 250microg/hr,
Midazolam 20mg/hr
• Head up 30°, temp 35.5 (actively cooled)
• pCO2 35mmHg
• Na 156mmol/L
• Noradrenaline 17mcg/min
• MAP 80, ICP 21mmHg
• Anything else we could do?
DOI: 10.3171/2017.11.JNS171892

28. CPPopt
Clinical scenario
• We try a MAP challenge:
• Noradrenaline to 17 -> 23mcg/min
• MAP increases from 80 -> 87mmHg
• 15 mins later ICP 21 -> 20mmHg
• 30 mins later ICP 21 -> 18mmHg
• It’s Monday 8am.
…Now what?
DOI: 10.3171/2017.11.JNS171892

29. CPPopt
SIBICC guidelines

30. CPPopt
SIBICC guidelines
Similar but not identical to
BOOST III and BONANZA TRIAL

31. CPPopt
PRx
• What if we did a series of MAP challenges (or even just let the MAP passively
drift) and watched the ICP changes?
• Then plot them against each other?
• And work out a correlation coefficient

32. CPPopt
Underlying hypothesis
• CPP too low -> cerebral vasodilation - hyperaemia -> raised ICP
• CPP too high -> cerebral oedema -> raised ICP
• This relationship is likely to vary across time with the phase of illness

33. CPPopt
PRx

34. CPPopt
PRx - the Pearson correlation co-efficient
https://en.wikipedia.org/wiki/Pearson_correlation_coefficient
https://en.wikipedia.org/wiki/Pearson_correlation_coefficient

35. CPPopt
PRx
• PRx is the moving correlation co-efficient between MAP and ICP
• When PRx is least - ICP is least determined by MAP
• And hence maximally determined by other factors
• It turns out this is how you can measure cerebral auto regulation
• The CPP at which PRx is least is termed CPPopt
• This is when cerebral auto regulation is most active (the least passive)

36. CPPopt
ICM+

37. CPPopt
ICM+

38. CPPopt
History
• Pressure reactivity index (PRx) described in 1997
• CPPopt in 2002 - 20 years ago!
• Developed by the “brain physics” department in Cambridge, Neurosurgeons,
and nascent Neurocritical Care Unit.
• COGiTATE - the first (pilot) RCT published 2021

39. CPPopt
As a target for therapy
• PRx > 0.25 is associated in multiple cohorts with poor neurological outcomes
and death
• Does anything we do change it?
• Is it a therapeutic target and if so does it affect outcomes?

40. CPPopt
As a target for therapy
TIL Sub-Category Intervention
Positioning Head elevation for ICP control
Nursed flat (180o) for CPP management
Sedation Level Sedation (low-dose as required for mechanical ventilation)
Higher-dose sedation for ICP control (not aiming for burst suppression)
Metabolic suppression for ICP control with high-dose barbiturates or propofol
NMBA Neuromuscular blockade (paralysis)
CSF Drainage CSF drainage < 120 mL/d (<5 mL/h)
CSF drainage ≤ 120 mL/d (≤5 mL/h)
Fluid/Vasopressor Therapy Fluid loading for maintenance of cerebral perfusion
Vasopressor therapy required for management of cerebral perfusion
Hyperventilation Mild hypocapnia for ICP control (PaCO2 4.6–5.3 kPa [35–40 mm Hg])
Moderate hypocapnia for ICP control (PaCO2 ≤ 4 kPa [30 mm Hg])
Intensive hypocapnia for ICP control (PaCO2 < 4 kPa [30 mm Hg])
Hyperosmolar Therapy Hyperosmolar therapy with mannitol up to 2 gm/kg/24 h
Hyperosmolar therapy with hypertonic saline up to 0.3 gm/kg/24 h
Hyperosmolar therapy with mannitol > 2 gm/kg/24 h
Hyperosmolar therapy with hypertonic saline > 0.3 gm/kg/24 h
Temperature Management Treatment of fever (>38C) or spontaneous temperature of 34.5C
Mild hypothermia for ICP control with a lower limit of 35C
Hypothermia below 35C
Surgery for ICP Control Intracranial operation for progressive mass lesion, not scheduled on admission
Decompressive craniectomy

41. CPPopt
As a target for therapy

42. CPPopt
Underlying hypothesis
• CENTER-TBI study: Prospective
observational cohort study
• PRx mapped against semi-quantitative
“treatment intensity”
• 249 patients
• Assocated with small improvements in PRx:
• Mild hyperventilation,
• Mild hypothermia,
• High levels of sedation for ICP control,
• Vasopressor use for CPP target

43. CPPopt
As a target for therapy
TIL Sub-Category Intervention
Positioning Head elevation for ICP control
Nursed flat (180o) for CPP management
Sedation Level Sedation (low-dose as required for mechanical ventilation)
Higher-dose sedation for ICP control (not aiming for burst suppression)
Metabolic suppression for ICP control with high-dose barbiturates or propofol
NMBA Neuromuscular blockade (paralysis)
CSF Drainage CSF drainage < 120 mL/d (<5 mL/h)
CSF drainage ≤ 120 mL/d (≤5 mL/h)
Fluid/Vasopressor Therapy Fluid loading for maintenance of cerebral perfusion
Vasopressor therapy required for management of cerebral perfusion
Hyperventilation Mild hypocapnia for ICP control (PaCO2 4.6–5.3 kPa [35–40 mm Hg])
Moderate hypocapnia for ICP control (PaCO2 ≤ 4 kPa [30 mm Hg])
Intensive hypocapnia for ICP control (PaCO2 < 4 kPa [30 mm Hg])
Hyperosmolar Therapy Hyperosmolar therapy with mannitol up to 2 gm/kg/24 h
Hyperosmolar therapy with hypertonic saline up to 0.3 gm/kg/24 h
Hyperosmolar therapy with mannitol > 2 gm/kg/24 h
Hyperosmolar therapy with hypertonic saline > 0.3 gm/kg/24 h
Temperature Management Treatment of fever (>38C) or spontaneous temperature of 34.5C
Mild hypothermia for ICP control with a lower limit of 35C
Hypothermia below 35C
Surgery for ICP Control Intracranial operation for progressive mass lesion, not scheduled on admission
Decompressive craniectomy

44. CPPopt
PRx as a target for therapy
• What about differential effects of vasopressors on PRx/CPPopt?
Vasopressin, Angiotensin II, adrenaline, dexmedetomidine…
• How about ketamine?
• Other agents like glibenclamide, neurokinin 1 receptor antagonists,
remimazolam…?

45. CPPopt
SIBICC guidelines
• LiCOX probe
+ temperature
• NIRS Cerebral oximetry
• Cerebral microdialysis
• Cerebral thermal diffusion
• Continuous (spectrographic) EEG
monitoring
• Jugular venous saturations
• MMM monitoring
• AI prediction

46. CPPopt
SIBICC guidelines

47. CPPopt
& Brain tissue
oxygen

48. CPPopt
& Brain tissue
oxygen
• A multi-centre retrospective cohort study using the Canadian TBI registry
• Inclusion criteria were TBI with ICP and PbtO2 probe
• 77 patients, 260 days of data
• Collected 2011-2021

49. CPPopt
& Brain tissue
oxygen
☠️

50. CPPopt
& Brain tissue
oxygen
PRx: > 0.25 vs < 0.25

51. CPPopt
& Brain tissue
oxygen
PRx: > 0.25 vs < 0.25

52. CPPopt
SIBICC guidelines

53. CPPopt
SIBICC guidelines

54. CPPopt
& Brain tissue
oxygen
Does targeting CPPopt,
at least partially
obviate the tier 1 & 2
therapies?

55. CPPopt
COGiTATE
• COGiTATE 2021

56. CPPopt
• Enrolled/Randomised within 24 hours of ICU admission
• Excluded - decompression + expected to die
• Pilot study - enrolled 60 patients
• Powered for 20% increase in time spent within 5mmHg of CPPopt
COGiTATE

57. CPPopt
• Control: 60-70mmHg
• Intervention: ICM+ guided CPP - adjusted 4 hourly
• CPP achieved as per clinician preference
• Enrolled for up to 5 days
COGiTATE

58. CPPopt
COGiTATE

59. CPPopt
COGiTATE

60. CPPopt
COGiTATE

61. CPPopt
COGiTATE

62. CPPopt
COGiTATE

63. CPPopt
COGiTATE
• Favourable outcome:
OR 2.35 (95%-CI 0.9 – 6.12), p=0.08)
• A larger trial is warranted!

64. CPPopt
COGiTATE
• Is the putative difference due to
differences in CPP?
• Where does the arterial transducer
go?
• Should we aim at the upper end of the
CPP target range?

65. CPPopt
Guidelines
• 4th edition (2016) of brain trauma foundation guidelines - insufficient evidence
to make a reccomendation
• COGiTATE subsequently released
• Worth acknowledging that there are considerable knowledge gaps in this field