Clinical trial of piracetam in disorders of consciousness due to head injury


Calliauw, L.; Marchau, M.

Acta Anaesthesiologica Belgica 26(1): 51-60

1975


The authors first remind some toxicological and some pharmacological properties of piracetam (Nootropil), then present the results of a test giving evidence of the presence of this drug in the cerebrospinal fluid after intravenous administration to man. In a double blind study, the activity of piracetam is tested on 31 patients suffering from coma after head injury. Only 27 patients without intracranial space occupying lesions are taken into account. Methods and results are described. Piracetam, although showing no activity on mortality, improves the level of consciousness.

51
Clinical
trial
of
piracetam
in
disorders
of
consciousness
due
to
head
injury
by
L.
CALLIAUW
and
M.
MARCHAU
Department
of
Neurosurgery.
Sint
Janshospitaal,
Brugge
(Belgium)
SUMMARY
The
authors
first
remind
some
toxicological
and
some
pharmacological
pro-
perties
of
piracetam
(Nootropil®),
then
present
the
results
of
a
test
giving
evidence
of
the
presence
of
this
drug
in
the
cerebrospinal
fluid
after
intra-
venous
administration
to
man.
In
a
double
blind
study,
the
activity
of
piracetam
is
tested
on
61
patients
suffering
from
coma
after
head
injury.
Only
27
patients
without
intracranial
space
occupying
lesions
are
taken
into
account.
Methods
and
results
are
described.
Piracetam,
although
showing
no
activity
on
mortality,
improves
the
level
of
consciousness.
(Acta
Anaesth.
belg.,
1975,
26,
51-60).
Key
words
:
cerebrospinal
fluid
(drug
dosage
in)
;
clinical
trial
;
coma
;
head
injury
;
piracetam.
Piracetam*
or
2-pyrrolidone
acetamide
is
a
drug
active
on
the
central
nervous
system.
This
molecule
shows
no
toxicity
on
dogs
at
high
dosa-
ges
(10
g/kg
daily
during
the
last
thirteen
weeks
of
a
twelve
months
toxicological
study).
Oral
administration
of
2.4
g
daily
for
three
and
six
months
induces
no
modification
of
blood
values
in
man.
Piracetam
inhibits
the
central
nystagmus
induced
in
rabbits
by
elec-
tric
stimulation
of
the
lateral
geniculate
body
(2).
In
cats,
piracetam
selectively
increases
the
amplitude
of
the
monosynaptic
transcallosal
evo-
ked
potential
in
the
homotopic
area
after
cortical
stimulation
of
the
suprasylvian
gyms
(1).
The
fact
that
piracetam
improves
the
recuperation
of
brain
function
after
hypoxia
seems
to
us
the
important
property
evidenced
by
animal
experiments.
These
experiments
can
be
summarised
as
follows
:
Nootropile
(Nootropy1110)
or
ucb
6216
is
manufactured
by
ucb,
Pharmaceutical
Division,
B-1060
Brussels.
Belgium.
Acta
Arlsthesiologica
Belgica,
I.
April
1975
52
L.
CALLIAUW
AND
M.
MARCHAU
Rabbits
enclosed
in
an
air-tight
container
are
made
hypoxic
by
progres-
sively
replacing
oxygen
in
the
container
by
nitrogen
(NO.
EEG
and
respiratory
frequency
are
monitored
simultaneously
by
polygraphic
recording.
Every
3
minutes,
an
arousal
reaction
is
provoked
by
auditory
stimulation.
At
the
moment
when
EEG
goes
flat,
with
the
animal
still
breathing
spasmodically,
N
Z
exchange
is
stopped
and
normal
air
is
reintroduced
into
the
container.
Slow
infusion
of
piracetam
starts
at
the
same
time
as
the
N
2
admission.
It
is
interrupted
at
the
moment
that
normal
air
is
readmitted.
The
post-hypoxic
recovery
period
is
shorter
in
animals
treated
with
pira-
cetam
(3)
(fig.
1).
It
has
also
been
shown
that
in
rats,
treated
with
piracetam,
the
cellular
glucose
level
returns
quicker
to
normal
after
hypoxia
than
in
control
animals
(4).
Oxygen-deprivation
anoxia
EEG
recording
CONTROL
GROUP
NORMAL
EEG
CEREBRAL
RESISTANCE
32'
Electrical
silence
CEREBRAL
RESISTANCE
36
RECOVERY
TIME
17'
PIRACETAM
GROUP
NORMAL
EEG
FIG.
1.
Recuperation
of
brain
hypoxia
in
piracetam
treated
and
control
animals.
Penetration
of
the
blood-brain
barrier
We
first
studied
the
permeability
of
the
blood-brain
barrier
for
this
drug.
A
dose
of
1
g
of
piracetam
is
injected
intravenously
to
14
normal
adult
patients.
Samplings
of
CSF,
through
suboccipital
puncture,
and
of
venous
blood are
performed
together
at
various
time
points
after
drug
administration.
Dosage
of
piracetam
in
blood
plasma
and
in
CSF
allows
us
to
establish
for
each
of
the
patients
the
evolutional
curves
of
the
concentrations
with
regard
to
time.
Figure
2
A
and
2
C
illustrate
the
evolution
of
piracetam
concentra-
tion
respectively
in
CSF
and
in
plasma
after
I.V.
injection
of
1
g.
Figure
2
B
illustrates
more
clearly
the
behaviour
of
this
molecule
in
CSF.
It
represents
the
ratio
of
the
concentration
in
CSF
and
in
blood
at
the
same
moment.
Half-life
time
is
5
h
18
min
in
blood
and
7
h
43
min
in
CSF.
30'
cOVER`t
TIME
Acta
Ansthesiologica
Belgica,
N"
1,
April
1975
PIRACE
TAM
10
2
32
hr.)
METABOLISM
CEREBRO
SPINAL
FLUID
(CSF
human
19
IV
m9,kg,
01
CLINICAL
TRIAL
OF
PIRACETAM
53
FIG.
2
A.
PIRACETAM
(
P
irI
CSF
[Piriblooa
5
1.0979
0 •
184
1
2
8
tIhrs)
32
METABOLISM
human
1g
IV
FIG.
2
B.
Acta
Anmsthesiologica
Belgica,
1,
April
1975
PMACE
TAM
10
"Mt
TABOL
iSA1
BLOOD
human
tg
IV I!
V.enip/kg
54
L.
CALLIAUW
AND
M.
MARCHAU
These
results
allow
us
to
affirm
that
piracetam
crosses
the
blood-
brain
barrier.
It
seems
not
likely
that
drug
accumulation
occurs
in
the
central
nervous
system.
FIG.
2
C.
Clinical
trial
Patients
and
methods.
A
double-blind
clinical
trial
with
piracetam
was
performed
on
coma-
tose
patients
after
a
recent
head
injury.
It
was
our
aim
to
select
for
this
study
as
homogeneous
a
group
of
patients
as
possible.
It
was
attempted
to
discard
patients
with
a
rapid
spontaneous
recovery.
Therefore
strict
selection
rules
were
established.
Included
were
only
patients
deeply
comatose
and
in
whom
no
impro-
vement
whatsoever
was
apparent
after
two
days
of
conventional
the-
rapy.
Longstanding
trauma
and
cases
of
superficial
disorders
of
conscious-
ness
were
discarded.
Acta
Annsthesiologica
Belgica,
NI*
1,
April
1975
CLINICAL
TRIAL
OF
PIRACETAM
55
The
patients
selected
were
distributed
at
random
over
two
groups.
One
group
was
treated
with
piracetam,
the
other
with
placebo.
In
the
course
of
treatment,
the
level
of
consciousness
has
been
asses-
sed
daily
by
the
same
observer
by
means
of
an
observation
scale
(fig.
3)
which
includes
the
main
consciousness
parameters.
NAME
Nr
FIRST
NAME
Date
and
hour
of
accident
AGE
Motive
of
admission
State
of
consciousness
-
at
the
time
of
accident
.....
................
...................
-
at
the
time
of
admission
...............
.............
........
(in
comparison
with
the
time
of
accident)
:
=
aggravation
improvement
PATIENT
NUMBER
Month
of
Days
,
14
15
16
CONSCIOUSNESS
I
-PATIENT'S
ASPECT
(normally
awake
2
-
drowsy
1
-
asleep
01
4
4*
*
*
II
-
VERBAL
STIMULI
**
Readiness
of
answer
(no
ready
answer
4
I
answer
0
-
slow
answer
2
-
*
**
**
I
III
-SENSORIAL
STIMULI
*
**
11
Reactivity
to
pain
-
vocal
reactivity
151
**
.
-
well-adapted
defense
movements
(3-4).
.
it
ilt
*
W
IC2
6
I•
(
rh'''''Y's
will
a
"'Y
lake
into
consideration
the
highest
scare
-
non-adapted
defense
movements
121
-
facial
mimic
121
-
no
defense
movements
(11
*.*
suppression
of
corneal
reflexes
101
.....
21
Reactivity
to
noise
10-1
/
.•
*
*
*
3)
Reactivity
to
light
(
-
blinking
121
**.
.
**
photomotor
reflexes
present
(1)
*
I+1
Non
[.
-
Pbotomotor
reflexes
absent
10)
41
Reactivity
to
moving
objects
10-11
(not
to
be
forgotten)
*
*
IV
SPHINCTERIAL
BEHAVIOUR
tasks
for
the
urinal
(31
-
becomes
agitated
when
the
need
to
urinate
becomes
urgent
111
-
loses
urine
10)1
.
1
0
4.
kr-
V
FEEDING
feeding
(31
-
swallows
but
cannot
be
*
*
*
(eats
alone
151
-
buccal
fed
by
the
mouth
ill
-
no
deglutition
reflex
10/1
'
**
**
Total
score
of
signs
of
consciousness
..........
4
23
8
14
Stage
of
coma
it)
Example
I
=
S
before
treatment
)
FIG.
3.
Every
patient
who
entered
the
ward
in
a
comatose
state
following
head
injury,
and
who
was
likely
to
be
included
in
our
investigation,
was
submitted
to
the
conventional
intensive
care
routine.
Then
clinical
Date
and
hour
of
admission
Acta
Anmsthesiologica
Belgica,
1,
April
1975
56
L.
CALLIAUW
AND
M.
MARCHAU
and
paraclinical
examinations
required
to
establish
the
diagnosis
were
performed.
Certain
patients
were
operated
on
during
the
first
days,
if
their
condition
required
surgery.
If
the
patient's
condition
did
not
show
signs
of
improvement
after
two
days,
treatment
with
either
4
amp.
of
placebo
or
4
amp.
of
pira-
cetam
(4
g)
daily
was
started
(either
I.V.
or
I.M.).
This
dose
was
increased
up
to
6
amp.
after
five
days,
and
8
amp.
after
seven
days.
As
soon
as
the
swallowing
reflex
reappeared,
a
daily
dosage
of
4
cap-
sules
orally
(1.6
g)
replaced
the parenteral
administration.
Treatment
is
stopped
when
good
recovery
occurs
or
when
a
steady
state
is
reached,
that
can
no
more
be
improved
according
to
the
clini-
cian's
opinion.
The
duration
of
treatment
is
at
most
sixty
days.
Results.
Between
July
1971
and
May
1972
61
patients
were
studied
:
30
with
piracetam
and
31
with
placebo.
At
the
end
of
the
investigation,
cases
presenting
with
hematomas
were
discarded
because
of
the
additional
factor
which
might
have
exer-
TABLE
I
Distribution
over
various
groups
of
patients
between
the
two
treatments
Placebo
Piracelam
Patients
discarded
at
the
end
of
the
study
.
6/31
2/30
Patients
with
intracranial
hematoma
. .
.
1/31
3/30
Patients
with
subdural
hematoma
3/31
7/30
Patients
with
epidural
hematoma
4/31
3/30
Patients
with
no
space
occupying
lesions
.
.
17/31
15/30
ted
some
influence
upon
prognosis.
The
group
with
hematomas
was
too
restricted
for
a
separate
statistical
analysis.
Also
were
discarded
the
patients
with
a
too
good
pretreatment
state
or
who
were
transferred
into
another
ward.
The
proportion
of
discarded
patients
differs
not
significantly
in
the
two
groups
(Fisher
exact
probability
test)
(
table
I).
The
proportion
of
patients
presenting
the
same
type
of
lesion
in
each
drug
group
differs
not
significantly
(Fisher
test).
In
the
patients
group
with
no
space
occupying
lesion,
3
out
of
17
patients
treated
with
placebo
and
2
out
of
15
patients
treated
with
piracetam
did
not
survive.
There
is
no
significant
difference
between
Acta
Anmsthesiologica
Belgica,
N•
1,
April
1975
1
CLINICAL
TRIAL
OF
PIRACETAM
57
these
two
proportions
(Fisher
test).
No
conclusion
as
to
the
time
of
survival
can
be
drawn.
For
the
surviving
patients,
no
significant
difference
with
regard
to
age,
sex
and
duration
of
the
treatment
is
present.
No
conclusion
as
to
the
duration
of
treatment
can
be
drawn
(mean
=
28.5
days
for
pira-
cetam
and
26
days
for
placebo
;
this
difference
is
not
significant
with
the
Wilcoxon
test).
TABLE
II
Patients
with
no
space
occupying
lesion
who
survive
:
pretreatment
score
of
consciousness
Placebo
(14
patients)
Piracetam
(13
patients)
4
6
3
3
4
4
4
4
6
8
7
5
4
3
3
3
4
6
3
4
3
3
3
7
3
4
4
Variance
1.46
2.76
Mean
3.93
4.61
Comparison
of
the
2
variances
(variance
ratio)
F
=
2.28
with
12
and
13
d.f.
N.S.
Comparison
of
the
2
means
(ANOVA)
F
=
1.53
with
1
and
25
d.f.
N.S.
Before
treatment
the
consciousness
score
of
the
patients
who
survived
differs
not
significantly
in
the
two
drug
groups
(
table
II).
It
can
be
accepted
that
patients
of
both
groups
are
alike
before
trial.
The
consciousness
score
of
the
same
patients
after
treatment
is
repor-
ted
in
table
III.
There
is
a
significant
difference
between
the
means
and
the
variances
in
the
two
drug
groups
:
patients
treated
with
pira-
cetam
tend
to
have
a
better
post-treatment
score
than
patients
treated
with
placebo.
Moreover,
the
dispersion
of
the
post-treatment
scores
is
less
important
after
piracetam
than
after
placebo.
Acta
Anmsthesiologica
Belgica,
1.
April
1975
58
L.
CALLIAUW
AND
M.
MARCHAU
These
results
show
that
piracetam
improves
the
level
of
consciousness
of
the
treated
patients.
TABLE
III
Patients
with
no
space
occupying
lesion
who
survive
:
posttreatment
score
of
consciousness
Placebo
Piracetam
(14
patients)
(13
patients)
23
23
8
21
2
21
19
19
10
18
16
19
21
20
9
16
23
23
10
20
16
23
1
23
19
10
23
Variance
58.07
13.23
Mean
14.29
19.69
Comparison
of
the
2
variances
(variance
ratio)
=
4.32
with
13
and
12
d.f.
P
<0.01
Comparison
of
the
2
means
(ANOVA)
adj.
F'
=
5.65
with
1
and
18
d.f.
P
<
0.05
Example
of
the
pretreatment
state
of
the
patients.
The
pretreatment
mean
score
is
about
4.
Such
an
initial
score
of
4
corres-
ponds
to
a
comatose
patient
who
does
not
answer
questions,
but
who
reacts
to
painful
stimulations,
without
however
being
able
to
localize
them
accurately.
Corneal
and
pupillar
reflexes
are
present.
The
patient
does
not
react
to
noise,
does
not
swallow
and
is
incontinent.
This
is
a
phase
III
coma.
The
patient
who
has
the
higher
initial
score
(8
for
patient
nr.
25)
is
subcomatose
:
he
mumbles
when
addressed
to,
localizes
pain
stimulations
quite
well,
and
opens
his
eyes
when
ordered
to.
He
is
continent
and
does
not
swallow.
Example
of
the
posttreatment
state
of
the
patients.
The
maximum
score
of
23
was
reached
by
patient
14
(fig.
3).
This
patient
was
conscious,
answered
questions
readily,
localized
pain
stimulations
well,
and
followed
moving
objects
with
his
eyes.
He
was
perfectly
in
control
of
his
sphincters
and
ate
alone.
In
the
patients
who
evolved
favourably,
the
lowest
score
(fig.
3)
i.e.
8
was
reached
by
patient
nr.
15.
He
was
somnolent,
could
not
localize
pain,
Acta
Anxsthesiologica
Belgic°,
N"
1,
April
1975
CLINICAL
TRIAL
OF
PIRACETAM
59
did
not
react
to
noises
or
moving
objects.
He
was
incontinent,
but
could
be
fed
orally.
On
the
other
hand,
two
patients
of
the
placebo
group
did
not
improve.
They
had
a
post-therapy
score
that
was
very
low,
i
e.
patient
19
(score
2)
and
patient
53
(score
1).
The
mean
score
at
the
end
of
the
treatment
was
14
in
the
placebo
group
(see
fig.
3).
Such
a
score
has
been
recorded
in
a
somnolent
patient
nr.
16,
who
responded
poorly
and
slowly.
He
reacted
to
external
stimulations,
was
able
to
swallow
although
he
was
not
capable
to
eat
without
help.
The
mean
score
at
the
end
of
treatment
was
19
in
the
piracetam
group.
Such
a
score
is
recorded
in
a
conscious
patient
nr.
30
who
responded
well,
and
who
furthermore
reacted
well
to
all
the
stimulations,
although
he
did
not
control
his
sphincters
completely,
and
ate
rather
slopily.
Conclusion
and
discussion
This
study
compares
comatose
patients
with
no
space
occupying
lesion
treated
with
either
piracetam
or
placebo.
Although
piracetam
does
not
influence
the
chances
of
survival,
it
shows
some
beneficial
effect
upon
the
level
of
consciousness.
We
think
that
an
earlier
administration
of
the
drug
(immediately
after
the
trauma
occurs)
can
improve
clinical
results.
This
may
already
be
anticipated
from
the
demonstration
of
the
drug's
effects
in
brain
hypoxia
experiments
in
animals.
In
this
study
much
lower
doses
of
piracetam
were
used
than
those
in
animal
experiments.
It
is
possible
that
a
higher
dose
could
improve
the
results.
RESUME
L.
CALLIALTW
et
M.
MARCHAU.
Etude
clinique
du
piracetam
dans
les
troubles
de
conscience
apres
traumatisme
crdnien.
Apres
avoir
rappele
certaines
caracteristiques
toxicologiques
et
pharma-
cologiques
du
piracetam,
(Nootropil®),
les
auteurs
decrivent
les
resultats
d'un
travail
qui
leur
a
permis
de
constater
que
ce
produit
se
retrouve
dans
le
liquide
cephalorachidien
apres
administration
intraveineuse
chez
l'homme.
Au
cours
d'une
etude
en
double
anonymat,
les
auteurs
ont
de
plus
etudie
l'action
du
piracetam
sur
des
patients
souffrant
de
coma
consecutif
a
un
trau-
matisme
crinien,
en
ne
retenant
que
les
patients
qui
ne
presentaient
pas
de
lesion
expansive
intracranienne.
Apres
avoir
expose
leurs
methodes
de
travail
et
leurs
resultats,
les
auteurs
concluent
que
le
piracetam,
tout
en
n'influencant
pas
la
mortalite,
ameliore
l'etat
de
conscience.
SAMENVATTING
L.
CALLIAUW
en
M.
MARCHAU.
Klinische
stucEe
over
piracetam
bij
bewustzijnsstoornissen
na
craniocerebrale
traumata.
De
auteurs
geven
eerst
een
beknopt
overzicht
van
de
toxikologische
en
farmakologische
eigenschappen
van
piracetam
(Nootropil®)
en
beschrijven
Acta
Anwsthesiologica
Belgica,
Isi°
I.
April
1975
60
L.
CALLIAUW
AND
M.
MARCHAU
vervolgens
de
resultaten
van
een
test
bij
de
mens
waarbij
zij
het
produkt,
na
I.V.-toediening,
in
het
cerebrospinaal
vocht
konden
doseren.
Aan
de
hand
van
een
dubbelblindstudie
hebben
de
auteurs
de
werking
van
piracetam
nagegaan
bij
comateuze
patienten
na
schedeltrauma
;
patienten
bij
wie
zich
een intracranieel
ruimte-innemend
proces
ontwikkelde,
werden
niet
in
de
studie
opgenomen.
Na
uiteenzetting
van
hun
werkmethodes
en
hun
resultaten
besluiten
de
auteurs
dat
piracetam,
zonder
de
mortaliteit
to
beinvloeden,
het
bewustzijns-
niveau
verhoogt.
Zij
verwachten
betere
resultaten
met
vluggere
toediening
van
het
produkt
en
met
een
hogere
dosering.
REFERENCES
1.
GIURGEA
C.E.,
MOYERSOONS
F.E.
On
the
pharmacology
of
cortical
evoked
potentials.
Arch.
int.
Phartnacoclyn.,
199/1.
67-77,
1972.
2.
GIURGEA
C.E.,
MOYERSOONS
F.E.,
EVRAERD
A.C.
A
GABA
related
hypothesis
on
the
mechanism
of
action
of
the
antimotion
sickness
drugs.
Arch.
int.
Pharma-
codyn.,
166/1,
238-251,
1967.
3.
GIURGEA
C.E.,
MOURAVIEFF-LESUISSE
F.,
LEEMANS
R.
Correlations
electro-
pharmacologiques
au
cours
de
l'anoxie
oxyprive
chez
le
lapin
en
respiration
libre
ou
artificielle.
Rev.
neurol.,
122/6,
484-488,
1970.
4.
GOBERT
J.G.,
VAN
DE
WALLE
A.J.,
CLOSE
J.A.
In
vivo
modifications
of
the
rat
brain
metabolism
induced
by
piracetam
(accepted
for
publication
in
Arzneintittel-
Forsch.,
1972.
L.
CALLIAUW
M.D.
Department
of
Neurosurgery
Sint
Janshospitaal
B-8000
Brugge
(Belgium)
Acta
Aoesthesiologica
Belgica,
NI'
1,
April
1975