Head Trauma
Pathophysiology of
Traumatic Brain Injury
Primary Injury
Impact: epidural, subdural,
contusion, intracerebral
hemorrhage, skull fractures
Inertial: concussion, diffuse
axonal injury
Hypoxic/Ischemic
Secondary Injury
Hypoxic-ischemic injury
Release of excitatory amino acids
Excess NMDA receptor activity
Concurrent hypotension and
hypoxemia may be present
Inflammatory response
Glutamatergic
Exitotoxicity
Intracranial
Mass Lesions
Extracranial
Injuries
Secondary Insults
Acute Interventions
Hypotension
Hypoxia
Cerebral ischemia
Intracranial hypertension
Vasospasm
Seizures
Alcohol withdrawal
Hyperthermia
Hypo-osmolality
Coagulopathy
Infection
CPR Resuscitation
Stabilization of extracranial injuries
Evacuation of intracranial hematomas
Maintenance of adequate CPP
Normalization ICP
Pharmacologic protection
Seizures prophylaxis
Correction of coagulopathy
Fluid & electrolyte homeostasis
Temperature control
Nutritional support
OUTCOME
Ischemia
Injured Brain
Rolling
Adhesion
Transmigration
Selectins
Integrins
VESSEL
ENDOTHEL
TISSUE
DNA Strand Breaks
Hypoxanthine + XO Xanthine
L-Arg + iNOS
NO
O2O2-
Superoxide
OONO-
O2
O2
NADP+
NADPH
PEROXYNITRITE
PARS Activation
NADPH
oxidase
Neuroprotective Strategies
Non-pharmacolocical (Hypothermia)
Pharmacological
Hypothermia
Potential Mechanisms of Action of
hypothermia
Reduces cerebral metabolism
Preserves ATP levels
Decreases energy utilization
Suppresses Excitotoxic AA accumulation
Reduces NO synthase activity
Suppresses free radical activity
Inhibits apoptosis
Prolongs therapeutic window?
Neuroprotection by hypothermia
CA1 region of rat hippocampus 3 days after 20 min of
global forebrain ischemia
36 during ischemia
30 during ischemia
Hypothermia in TBI
Animal experiments demonstrated clear
benefits of mild to moderate hypothermia
on outcome in experimental TBI.
1990s : 13 clinical studies with 1321 pts.
End point of these studies were ICP,
neurological outcome, and survival.
All author reported that hypothermia was
able to reduce ICP.
The effects of hypothermia on survival and
outcome have been conflicting.
Hypothermia in TBI
A systematic review and meta-analysis
(Henderson WR et al, 2003) *.
8 studies efficacy of hypothermia in
management of TBI
OR mortality in hypothermic group 0.81
(95%CI=0.59-1.13, p=0.22)
OR of poor neurological outcome (GOS 1,2 or 3)
was 0.75 (95%CI=0.56-1.01, p=0.06)
OR for pneumonia in normothermic 0.42
(95%CI=0.25-0.70), p=0.001)
*Intensice Care Med 2003;29:1637-44.
Hypothermia in TBI
Multicenter, prospective, RCT
(Clifton et al)*
392 pts (199 - hypothermia to 33C x 48
hrs)
Overall results negative (no benefits in
survival or neurological outcome, although,
as in previous studies, hypothermia was
able to decreased ICP).
Positive results in patients < 45 years who
were normovolemic.
* NEJM 2001; 344: 556-63
Hypothermia in TBI
Hypothermia in TBI
Summary, level of evidence and
recommendations
Hypothermia is clearly effective in
controlling ICP (class I)
Fever should be prevented in all TBI
pts in first 24-48 h (class IIa).
Pharmacological
Neuroprotection
1.
2.
3.
4.
2. Calcium Antagonist
Nimodipine
Trials
No. pts
Results
HIT I
351
HIT II 852
(+)
(-)
Calcium Antagonist
Nimodipine
Not recommended for severely headinjured patients.
Treatment of the TBI patients without
signs of subarachnoid bleeding is not
indicated.
4. Cyclosporin A
Cyclosporin is a cyclic polypeptide,
consisting of 11 amino acids.
Transplantation medicine as an
immunosuppressant
Protective effect on mitochondrial
ultrastructure, and most likely
mitochondrial function, and on
cytoskeletal derangements after TBI
(animals study).
No clinical phase II or III trials evaluating
the efficacy of cyclosporin A in the
treatment of human severe TBI
Citicholin
Mechanisms:
Preserving cardiolipin (an exclusive inner
mitochondrial membrane component) and
sphingomyelin;
Preserving the arachidonic acid content of
PtdCho and Ptd-ethanolamine;
Partially restoring PtdCho levels;
Stimulating glutathione synthesis and
glutathione reductase activity;
Attenuating lipid peroxidation; and
Restoring Na/K-ATPase activity.
Citicholin vs Meclofenoxate in
TBI
Comparative Double Blind Study.
25 pts TBI:
14 ptsin CDP cholin.
11 pts in meclofenoxate group
Citicholin vs Meclofenoxate in
TBI (results)
Conclusions
Pathophysiological cascades initiated by injury of
brain have many features in common, and brain
ischemia and mitochondria dysfunction frequently
are the common denominator.
The effort of mitigating brain injury include:
Conclusions
Neuroprotective Strategies:
Non Pharmalogical (Hypothermia).
Pharmacological Neuroprotetion.
CDP-Choline is one of
Pharmalclogical Neuroprotection can
used in the treatment of TBI