You are on page 1of 34

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

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

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

Injured Brain

NO and Free Radicals


R
E
P
E
R
F
U
S
I
O
N

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

Cytochrome c release  Apoptosis

PARS Activation

NADPH
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

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

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

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.
2.
3.
4.

Glutamate receptor antagonists,


Free radical scavengers,
Calcium antagonists and
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 headinjured 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)