Neuroprotectan in

Head Trauma

Dr. Mursyid Bustami

Neurology Department
University of Indonesia
Head Trauma: Statistics

200-300/100.000 per year
(USA)

Mild (GCS > 12) 82%

Moderate to severe (GCS
<12) 14%

Fatal 5%
 Pathophysiology of
Traumatic Brain Injury
Primary vs. Secondary
Injury
Primary injury - direct
physical injury to neurons and
glial cells
Secondary injury -
physiological events after the
primary injury  further
damage.
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
 Primary Brain Injury
Post Injury Factors

Intracranial
Mass Lesions
Glutamatergic Extracranial
Exitotoxicity Injuries

Secondary Insults Acute Interventions

Hypotension CPR Resuscitation
Hypoxia Stabilization of extracranial injuries
Cerebral ischemia Evacuation of intracranial hematomas
Intracranial hypertension Maintenance of adequate CPP
Vasospasm Normalization ICP
Seizures Pharmacologic protection
Alcohol withdrawal Seizures prophylaxis
Hyperthermia Correction of coagulopathy
Hypo-osmolality Fluid & electrolyte homeostasis
Coagulopathy Temperature control
Infection OUTCOME Nutritional support
 Injured Brain
Ischemia

Adapted from Bullock R: Injury and cell function, 1997.

R
NO and Free Radicals
E Rolling Adhesion Transmigration
P Selectins
E
R Integrins
F
U
S
I
O
VESSEL
N
ENDOTHEL L-Arg + iNOS Hypoxanthine + XO  Xanthine

TISSUE
O2- O2
DNA Strand Breaks
NO O2- O2
Superoxide NADP+

NADPH
OONO-
PEROXYNITRITE
NADPH
Cytochrome c release  Apoptosis
PARS Activation oxidase

Adapted from George

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

from Ginsberg and Busto (1998) Stroke 29:529-534.

 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

China clinical trial (Zhi et al)*.

396 pts induced hypothermia 62.4 h.
Good neurological outcome were 38.8
vs 19.7%; and death 25.7 vs 36.4%
for hypothermic pts vs controls,
respectively.
Re-warming was much slower.

* Surg Neurol 2003; 59:381-85.

 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. Glutamate receptor antagonists,
2. Free radical scavengers,
3. Calcium antagonists and
4. Cyclosporin A
1. Glutamate receptor antagonists
The amino acid L-glutamate is an
extensively distributed, mostly
excitatory neurotransmitter in the
CNS.
Extracellular glutamate >> 
deleterious effects to neurons.
Glutamate receptors : NMDA,AMPA
and Kainate receptors.
Glutamate receptor antagonists
Glutamate receptor antagonists
 2. Calcium Antagonist
Nimodipine
Trials No. pts Results

HIT I 351 Improved outcome, though

without statistical significance.
HIT II 852 (-), benefit for SAH subgroup

HIT III 123 SAH (+)

HIT IV 591 SAH (-)

Calcium Antagonist
Nimodipine
Not recommended for severely head-
injured patients.
Treatment of the TBI patients without
signs of subarachnoid bleeding is not
indicated.
3. Free radical scavengers
TBI may lead to an increase in intracellular
free radical activity.
Antioxidatives agents:
Tirilazad
No significant positive influence of treatment
with tirilazad on outcome of severely TBI
(phase III)
Polyethylene glycol-conjugated superoxide
dismutase (PEG-SOD).
Trend towards better outcome compared
placebo (phase III)
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 Placebo in TBI
Double blind Controlled Trial againts
Placebo.
43 pts TBI
24 in CDP-Cholin group.
19 in placebo group.
Citicholin vs Placebo in TBI
(results)
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:
Maintenance of brain perfusion.
Maintenance to adequate oxygen delivery.
Optimizing source of brain energy.
Neuroprotective strategy
Conclusions
Neuroprotective Strategies:
Non Pharmalogical (Hypothermia).
Pharmacological Neuroprotetion.
CDP-Choline is one of
Pharmalclogical Neuroprotection can
used in the treatment of TBI
COMPLET YOUR CAR WITH AIRBAG (THE NEW MODEL)