This document discusses the management of intracranial pressure and cerebral edema in neurocritical care patients. It covers topics such as how patients typically present with brain injuries, important caveats in neurological examinations, principles of cerebral resuscitation, mechanisms of primary and secondary brain injury, the pathophysiology over time, imaging techniques including CT scans and MRI, monitoring techniques like intracranial pressure monitoring, and treatment approaches like the use of hyperosmolar therapy with mannitol or hypertonic saline. The goal is to prevent secondary brain injury after the initial primary injury occurs.

1. Intracranial Pressure and
Cerebral Edema Neuro-ICU
2009
PJ Papadakos MD FCCM
Director CCM
Professor Anesthesiology, Surgery
and Neurosurgery
Rochester NY USA

2. Is there a debate?

3. HOW DO PATIENTS PRESENT ?
• Obvious--motor vehicle accident, car vs
pedestrian, fall from height, etc
• Less obvious--sports injuries (football), delayed
deterioration (epidural)
• Hidden--shaken baby syndrome, older child
maltreatment
• Inter cranial Hemorrhage
• Stroke

5. CAVEATS IN BRAIN INJURY
• Neurologic examination - the most
important information you have
• Accurate history is often unavailable or
inaccurate
• Potential for associated injuries or illness
(cardiovascular, respiratory,
cervical spine)

6. CEREBRAL RESUSCITATION
• Primary survey - airway, breathing, and
circulation
• Neurologic evaluation
• Secondary survey - “head to toe”
• Neuroradiologic evaluation
• Ongoing evaluation and transport

7. MECHANISMS OF INJURY-PRIMARY
• Impact: epidural, subdural, contusion,
intracerebral hemorrhage, skull fractures
• Inertial: concussion, diffuse axonal injury
• Hypoxic Ischemic

8. MECHANISMS OF 2nd INJURY
• Global
– Hypoxia and ischemia of brain
– Decreased cerebral blood flow due to
increased intracranial pressure
• Local
– impairment of cerebral blood flow or extra
cellular milieu due to the presence of injured
brain

9. PATHOPHYSIOLOGY
• Primary damage – the only treatment is by
prevention.
• Secondary damage – multifactorial and
time dependent.

10. SOME of the SECONDARY EVENTS IN TRAUMATIC BRAIN INJURY
diffuse axonal
inflammation injury
BBB
disruption apoptosis
necrosis
edema
formation
ischemia
Brain trauma
energy failure
cytokines
Eicosanoids
Calcium
polyamines
Acetyl
ROS
endocannabinoids Choline
Shohami, 2000
Green – pathophysiological processes; Yellow – various mediators

11. Time is Important

12. Dynamic Changes Following Brain Injury
Days Weeks / Months
Hours
Weeks/Mont
hs
2 7
8 hrs 14
Ca , Na+
Glut, ROS
I
Necrosis Apoptosis
N
J
Inflammation
U
R Repair
Remodeling
Y
Plasticity
Functional
Recovery
Barone &Feuerstein JCBF, 1999

13. Physiology

14. The Lund Concept
• January 1989, Lund
University Hospital
Department of
Neurosurgery
• Protocol aimed at non-
surgical reduction of ICP
• Bedside measurements of
CBF and vasoreactivity
identified subgroup of
patients with severe TBI,
intractable ICP, and 100%
mortality

15. Lund concept
• Volume-targeted therapy
• Reduction of capillary
hydrostatic pressure
• Maintenance of colloid
osmotic pressure and
control of fluid balance
• Reduction of cerebral
blood volume
• Controlled ICP

16. Blood Brain Barrier in Trauma

17. The Lund Concept
• Avoid hyperglycemia and hyperthemia.
• Avoid hypovolemia and stress response: increased
baroreceptor reflex and cathacholamine release
• Avoid hyperosmotic therapy: transient effects with
adverse rebound and renal effects
• Avoid vasopressors: vasoconstriction increases
BP and CPP but may compromise brain
microcirculatory perfusion (esp. pericontusional)
and other organ system perfusion (ARDS)

18. The Lund Concept
• Stress reduction: sedatives midazolam and
thiopental (0.5-3.0 mg/kg/h) combined with alpha-
2 agonism and beta-1 blockade. Avoid propofol.
• Normovolemia: by normalizing plasma oncotic
pressure via RBC infusion to normal S-Hb (125-
140 g/L) and albumin transfusion (20-25%)
• Normalize BP: Clonidine (0.3-1.0 ug/kg X 4-6)
and Metoprolol (0.04-0.08 mg/kg). Refrain from
using vasopressors. Dihydroergotamine induce
venous vasoconstriction with great volume in
venous side. No fixed limits for CPP

19. MONRO-KELLIE DOCTRINE
Vintracranial vault=Vbrain+Vblood +Vcsf

20. BRAIN: CEREBRAL EDEMA-VASOGENIC
(Caused mainly by activation of NMDA receptors by glutamate)

21. BRAIN: CEREBRAL EDEMA-CYTOTOXIC
(Caused mainly by activation of cytokines, ROS and other
pro-inflammatory mediators)

22. BLOOD: CEREBRAL BLOOD FLOW
o The brain has the ability
to control its blood
supply to match its
metabolic requirements
o Chemical or metabolic
byproducts of cerebral
metabolism can alter
blood vessel caliber and
behavior

23. BLOOD: CEREBRAL BLOOD FLOW
(VOLUME)
• Increases in cerebral metabolic rate
– Hyperthermia
– Seizures
– Pain, anxiety

24. CSF: CEREBROSPINAL FLUID
• 10% of intracranial volume
• Initial displacement of CSF from ventricles
• Ventriculostomy to drain CSF

25. Intracranial Compliance
• Calvarium is composed of three fluid
compartments: Cerebral Blood Volume,
CSF, and cerebral parenchyma

27. GUIDELINES – GENERAL ASPECTS
• Standards: accepted principles of patient
management that reflect a high degree of
clinical certainty
• Guidelines: strategies that reflect moderate
clinical certainty
• Options: unclear clinical certainty

28. Prehospital

29. Basic Principles: Airway
• Resuscitation ABCs
• Rapid sequence
intubation
• Retrospective studies
report increased
mortality: skill and
optimal ventilation
• Bag-valve-mask or
LMA

30. PREHOSPITAL AIRWAY MANAGEMENT
• Hypoxia must be avoided, and correct
immediately . 13%-27% O2
• Supplemental oxygen should be administered
• No advantage of ETI (ET intubation) Vs. BVM
(Bag / valve / mask) ventilation for the pre-
hospital airway in pediatric TBI
420 TBI; 115 BVM; 177 ETIno change (Gausche,
JAMA 2000)
• TBI + ETI  ETCO2

31. RESUSCITATION OF BP AND O2 AND PREHOSPITAL BRAIN-
SPECIFIC TX’S FOR SPTBI PATIENTS
• Hypotension should be identified and corrected
as rapidly as possible with fluid resuscitation.
(G)
• Hypotension on arrival to ER (Pigula, J Ped Surg 1993)
18% ER: mortality 61% Vs. 22%, ↓BP+↓O2 –
mortality  85% !
• Levine (Neurosurg 1992): TBI 0-4y ↓BP – 32% poor
outcome.
• Laurssen (J Neurosurg 1988):↑BP ↓EX; White (CCM
2001): syst BP > 135  X19 in survival !

32. PREHOSPITAL TREATMENTS
• No evidence of efficacy: sedation, NMB,
Mannitol, saline 3%, hyperventilation.
• The prophylactic administration of
mannitol is not recommended.
• Mannitol may be considered for use in
euvolemic patients who show signs of
cerebral herniation or acute neurological
deterioration.

33. PREHOSPITAL TREATMENTS
• Mild prophylactic hyperventilation is not
recommended.
• Hyperventilation may be considered in
patients who show signs of
– Imminent cerebral herniation or
– acute neurological deterioration
• After correcting hypotension or hypoxemia

34. Pathophysiology of TBI
• Primary injury
• Secondary Injury
• Ischemia/hypoxia
• Excitotoxicity
• Energy/Mitochondrial
failure
• Proinflammatory
mediators
• Free radical release
• Neuronal death
cascades

35. How do we Image

36. Imaging/ Diagnosis of Head Injury
• CT scan remains imaging
of choice
• Regional heterogeneity of
brain metabolism
• Need information on brain
function: CBF, perfusion
and metabolism in TBI
• Xenon-enhanced CT in
the ED setting

37. Need for Portable Imaging
• Transport risk of critical
trauma patients
• Portable CT with helical
scanning capability, low
radiation exposure,
wireless links to imaging
network, user-friendly,
ability to perform
perfusion studies.

38. Magnetoencephalography

39. MRI
• As Field Strength
increases (up to 7T) see
more abnormaities
• Diffusion tensor imaging
(DTI)
• Based on fractional
anisotropic movement of
water molecules
• Non-invasive
measurement of fiber
pathway structure

40. CT SCANS and X-rays

41. Skull fracture

43. Coup-Contrecoup
• focal injury
consisting of
contusions and
hematoma at the
site of the blow,
opposite side of the
brain

44. Hemorrage

45. Intracranial Hemorrhage

47. Cerebral Edema

49. Reversible high T2 signal
abnormalities in pre-eclampsia

50. Monitoring

51. INDICATIONS FOR ICP MONITORING IN PATIENTS
WITH SEVERE TBI
• ↑ICP ≡↓Outcome; Aggressive Tx ≡↑Outcome
• Intra-cranial pressure monitoring (ICP) is
appropriate in all patients with severe traumatic
brain injury (TBI) (Glasgow Coma [GCS] score
≤8)
• The presence of open fontanels and/or sutures
in an infant with severe TBI does not preclude
the development of intracranial hypertension or
negate the utility of ICP monitoring.

52. INTRACRANIAL PRESSURE MONITORING
• STBI (GCS≤8) + Abnormal CT ≡ 53-63% ↑ICP
(adult data).
• Intra-cranial pressure monitoring is not routinely
indicated in infants and children with mild or
moderate head injury.
• However, a physician may choose to monitor
ICP in certain conscious patients with
• traumatic mass lesions or
– serial neurological examination is precluded by
sedation, neuromuscular blockade, or anesthesia.

53. INTRACRANIAL PRESSURE MONITORING
TECHNOLOGY
• ICP monitoring: a ventricular catheter; external
strain gauge transducer (??); catheter tip pressure
transducer device  All accurate & reliable (O)
• Ventricular cath. device most accurate, reliable,
low cost + enables therapeutic (CSF) drainage.
• No report of meningitis  ICP monitoring.
Jensen: 7% +tip; positive > 7.5 days

54. THRESHOLD FOR TREATMENT OF INTRA-
CRANIAL HYPERTENSION
• ICP>20-40mmHg ≡ Mort. 28%; ICP>40mmHg ≡ 100%
• Treatment for intracranial hypertension, defined as a
pathologic elevation in intracranial pressure (ICP), should
begin at an ICP ≥20 mm Hg. (O)
• Patients may herniate at ICP < 20-25mmHg.
• Is there a lower ICP threshold for younger children ?
• Interpretation and treatment of ↑ICP based on any ICP
threshold should be corroborated by frequent
– clinical examination
– monitoring of physiologic variables (CPP, Compliance)
– cranial imaging.

55. CEREBRAL PERFUSION PRESSURE
(CPP)
• A cerebral perfusion pressure (CPP) >40 mm
Hg

56. THE ROLE OF CSF DRAINAGE
• Cerebrospinal fluid (CSF) drainage can
be considered as an option in the
management of elevated ICP Drainage:
Ventriculostomy Lumber puncture.

57. Near-infrared spectroscopy
• Measures complex IV
cytocrome c
• Mito redox state
• Can detect changes in
PO2/ lactate-pyruvate
ratio
• Potential tool for
measuring cerebral
aerobic metabolism

58. EEG/ Bispectral Index Analysis
• Continuous EEG
monitoring shows that
20% of TBI patients
have seizures w/in 2
wks
• EEG Power spectrum
analysis to monitor
sedation and prevent
oversedation

59. Microdialysis
• Measures biochemical
changes in brain tissue
• Increased lactate, EAA,
glycerol
• Decreased glucose,
pyruvate
• Need to collect dialysate
q30 minutes for 5 days
(240 samples)
• Future role in target
delivery of agents

60. Brain Oxygen Tension Monitoring
• Direct measurement of
cerebral oxygen
metabolism
• Interpretation of
PbtO2 threshold 10-20
mmHg
• Placement in
uninjured versus
injured brain

61. Treatment

62. Osmotic gradient created between
Osmotic
• Brain and blood (intact BBB) or
theory
• ICF and ECF (impaired BBB)
Water moves out of the brain to re-establish
osmotic equilibrium
Brain volume is reduced
ICP falls

63. Lower viscosity
Rheologic and/or raise BP
theory
CBF rises
Muizelaar JP et al: Mannitol
Reflex
causes compensatory
vasoconstriction
cerebral vasoconstriction
and vasodilation in response
to blood viscosity changes. J Reduced cerebral blood
Neurosurg 59:822-828, 1983 volume (CBV)
ICP falls

64. USE OF HYPEROSMOLAR THERAPY
• Mannitol (2 X Class III) Vs. Hypertonic Saline (3 X Class II;
1 X Class III).
• Mannitol is effective.
• Euvolemia + Folly catheter
• Accepted osmolarity: Mannitol < 320mOsm/L;
Hyper NS < 360mOsm/L
• Mannitol blood viscosity  arteriolar diameter
and  osmotic effect.
• Hyper NS  Osmolar grad; membrane pot.;
cellular volume; ANP; Inflammation; C.O.

65. HYPEROSMOLAR THERAPY
• Hypertonic saline is effective for control of
increased ICP after severe head injury
• Effective doses: cont. infusion of 3% saline
0.1 - 1.0 ml/kg/h, a sliding scale.
• Goal minimum dose maintain ICP <20
mmHg.
• Mannitol bolus dose: 0.25g/Kg – 1g/Kg.

66. Hypertonic saline
• Efficacy in concentrations of 3%-7.5%-
23.4% in lowering ICP
• Therapeutic action more effective (53.9%
vs 35%) and longer lasting than mannitol
• Attenuates microcirculatory disturbances
(prevent secondary cerebral small vessel
diameter increases and aggregation of
WBCs by 90%)

67. Hypertonic saline
• Clinical studies show decreases in mean
number and duration of intracranial
hypertensive episodes
• Vasoregulatory effects: prevents vasospasm
• Lowers rate of clinical failure
• Theoretical concerns of CPM and rapid
brain shrinkage/SDH

68. USE OF HYPERVENTILATION in the
ACUTE MANAGEMENT
• Mild or prophylactic hyperventilation (paco2 <35
mm hg) should be avoided.
• Mild hyperventilation (paco2 30-35 mm hg) may
be considered for longer periods for intra-
cranial hypertension refractory to
– Sedation and analgesia
– Neuromuscular blockade
– Cerebrospinal fluid drainage
– hyperosmolar therapy

69. HYPERVENTILATION
• Aggressive hyperventilation (Paco2 < 30 mm Hg)
may be considered as a second tier option in the
setting of refractory hypertension (O).
• Cerebral blood flow (CBF), jugular venous oxygen
saturation, or brain tissue oxygen monitoring is
suggested to help identify cerebral ischemia in this
setting.
• Aggressive hyperventilation therapy titrated to
clinical effect may be necessary for BRIEF
PERIODS in cases of cerebral herniation or
acute neurologic deterioration.

70. High dose barbiturate therapy
• For refractory intracranial hypertension
• Lower cerebral metabolic rate for O2 and
modulate vascular tone
• Membrane stabilization and reduced lipid
peroxidation
• Controversial evidence as to efficacy in
severe TBI
• Differential effects noted between
thiopental, methohexital and pentobarbital

71. THE USE of BARBITURATES in the CONTROL of
INTRA-CRANIAL HYPERTENSION
• High-dose barbiturate therapy may be considered
in hemodynamically stable patients with
salvageable severe head injury and refractory
intracranial hypertension.
• If high-dose barbiturate therapy is used, then
appropriate hemodynamic monitoring (CVP, Swan-
Ganz, repeated ECHOs) and cardiovascular
support (Dopamine, Adrenaline) are essential.

72. THE USE of BARBITURATES in the CONTROL of
INTRA-CRANIAL HYPERTENSION
• Gold standard – continuous EEG to achieve
a state of burst suppression.
• Serum barbiturate levels are NOT GOOD for
monitoring that therapy.
• Prophylactic therapy is not recommended
(side effects).

73. Neuromuscular blockade
• For mechanically ventilated to prevent
cough reflex in initial 24-48 hours
• Muscle relaxants cross BBB and can
activate cerebral Ach receptors causing
autonomic dysfunction, weakness and
seizures
• Resistance due to receptor up-regulation
often present so need monitoring with
peripheral nerve stimulator

74. Temperature Control

75. Concept: Brain Thermo-Pooling
Dr. Nariyuki Hayashi

76. Hypothermia
• Dr. Hugh Rosomoff :
NIH Clinical Center
1955

77. Brain Thermo-Pooling Phenomenon
• Brain thermo-pooling (elevation of brain tissue
temperature) with damage of blood-brain barrier
(BBB).
• Risk: Blood temperature higher than 38.C.,
systolic blood pressure lower than 90-100mmHg,
and cerebral perfusion pressure (CPP) lower than
70mmHg hinders washout of brain tissue
temperature by cerebral blood flow.
• Recorded brain tissue temperature of 40-44
degrees Celsius.

78. Temperature Control in TBI
• Systemic and cerebral
hyperthermia is
detrimental to outcome
• Up to 80% of TBI patients
in ICU setting with
reactive hyperthermia
• Monitoring of core
temperature, pyrexia
identified and treated
• In refractory cases
electrical surface cooling
blankets to prevent brain
hyperthermia

79. Temperature Control in TBI
• Surface cooling is
problematic: access,
time constraints,
imprecision
• Multi-trauma patients
with splinting
• Shivering increases
O2 consumption and
increases ICP

80. Intravascular Cooling Devices

81. Alsius Cooling Catheter
• Saline-filled
Polyethylene balloon
catheter
• Combines cooling
capabilities with
central venous access
• Products may be used
with femoral,
subclavian or jugular
access

82. InnerCool Catheters
• Metallic coil heating
element
• Very Rapid rate of
cooling (6 degrees
Celsius per hour)
• FDA approval for
Neurosurgical ICU
and recovery

83. Radiant Cooling Catheter
• Triple-helical coil
design
• Expandable to 27 Fr in
IVC to increase heat
exchange
• 37 to 33 degrees
Celsius in less than 1
hour

84. Transcranial Cooling

85. Intranasal cooling

86. Therapeutic Hypothermia
• Hypothermia neuroprotective in TBI
models by decreasing EAAs, augment
antioxidant activity and reduction of
inflammatory markers
• Randomized controlled trials have shown
conflicting results
• Clifton et al., showed possible outcome
benefit with mild hypothermia in patients
with GCS of 5-7

87. Therapeutic Hypothermia
• NABIS H1 (National Acute Brain Injury Study:
Hypothermia): 492 patients at 5 Centers
• Failed to show beneficial outcome
• Intercenter variability in treatment, delay in
reaching target core temp, inconsistent fluid
therapy
• Subgroup analysis showed beneficial effects in
patients age 16-45, normotensive, GCS>4 with
initial core body temp less than 35 degrees Celsius
and maintained core temperature

88. Neuroprotective agents
• •
Selfotel DCppene
• •
Cerestat Trilizad
• •
Cp101-606 PEG-SOD
• •
Bradycor IGF-1/GH
• •
Dexabinol Nimodipine
• •
SNX-111 Anticonvulsants
• Steroids

89. Neuroprotective agents
• •
Selfotel DCppene
• •
Cerestat Trilizad
• •
Cp101-606 PEG-SOD
• •
Bradycor IGF-1/GH
• •
Dexabinol Nimodipine
• •
SNX-111 Anticonvulsants
• Steroids

90. Calcium Channel Blockers

91. Ca2+ influx
Plasma membrane channels
Ligand-Operated
Voltage-Operated Receptor-Operated
Ca2+/Cation
Ca2+ specific Ca2+ / Cation
Ca2+
Mitochondrial Sarco-/Endo-plasmic
Ca Uptake reticulum Ca Uptake
Ca/Mg pump
Na-Ca exchg.

92. Calcium Channel blockers
• May be membrane protective
• Affect Vasospasm

93. Coronary/Cerebral Steal
The detrimental redistribution of blood
flow in patients with atherosclerotic
disease from underperfused areas toward
better perfused areas
Stenosis
Before Vasodilator After Vasodilator

94. Dexabinol
• Cannabinoid and non-competitive NMDA-
receptor antagonist
• Safely decreases mean time of ICP
elevation above 25 mmHg and MAP <90
• Also acts as antioxidant and cytokine
inhibitor
• Phase III trials promising

95. Anti-inflammatory agents
• Anti-ICAM-1 (Enlimomab)
• Anti IL1-alpha
• Anti a4 integrin Ab
• Chemokine inhibitor (CXC/CC types)
• MEK 1 /2 (MAP/ERK kinase) inhibitor U0216
• P38 MAP kinase inhibitor SB239063
• Selective PKC inhibitor Go6976
• Caspase inhibition
• Naloxone
• Proteosome inhibitor PS519
• Indomethicin
• Celecoxib (COX-2 selective)
• Cyclosporin A
• Epoeitin A

96. Failure of Translational research
• •
Rx w/in 1 hour Rx w/in 8 hours
• •
Single dose Multiple dosages
• •
Lesion/infarct size GOS
• •
Outcome days/wks Outcome mos/yrs
• •
No adjunct therapy Multiple Rx
• •
Inbred rodents/male Variable population
• •
Single mechanism of Multiple mechanisms
injury

97. Future Trends in Preclinical
Research
• Multiple models/ complexity (secondary injury)
• Different species/gender/age
• Timing of interventions
• Range of severities
• Physiological dosages
• Drug interactions (antiepileptics)
• Multifaceted treatment cocktails
• Surrogate biomarkers (animal ICU): ICP, SjvO2,
imaging, microdialysis, etc.

98. Surgical Decompression

100. DECOMPRESSIVE CRANIECTOMY
• Decompressive craniectomy appears to be less
effective in patients who have experienced
extensive secondary brain insults
• Patients who experience
– Secondary deterioration on the Glasgow coma scale
(GCS) and/or evolving cerebral herniation syndrome
within the first 48 hrs after injury may represent a
favorable group
– Unimproved GCS of 3 may represent an unfavorable
group

101. THE USE OF CORTICOSTEROIDS IN THE
TREATMENT TBI
• With the lack of sufficient evidence for
beneficial effect and the potential for
increased complications and suppression
of adrenal production of cortisol, the routine
use of steroids is not recommended for
patients following severe traumatic brain
injury.

102. NUTRITIONAL SUPPORT
• Replace 130-160% of resting metabolism
expenditure after TBI in patients. Weight-
specific resting metabolic expenditure
guidelines can be found in Talbot's tables.
• Based on the adult guidelines, nutritional
support should
– begin by 72 hrs
– with full replacement by 7 days.

103. THE ROLE of ANTI-SEIZURE PROPHYLAXIS
FOLLOWING STBI
• Prophylactic anti-seizure therapy may be
considered as a treatment option to
prevent increased oxygen utilization

104. Questions ?