SUMMARY â The authors studied the availability of parenteral solutions of diazepam in glass bottles or polyethylene (PE) containers during infusion through ...
FACTORS AFFECTING DIAZEPAM AVAILABILITY FROM INTRAVENOUS ADMIXTURE SOLUTIONS
WALTER OLESCHKO ARRUDA * — DILERMANDO BRITO L. C. ROSA *** — PAULO S. G. FONTOURA *** — MOEMA
FILHO ** — SOLANGE DE ARAÚJO CARDOSO ****
S U M M A R Y — T h e a u t h o r s s t u d i e d t h e a v a i l a b i l i t y o f p a r e n t e r a l s o l u t i o n s o f d i a z e p a m in glass bottles o r polyethylene ( P E ) containers during infusion through polyvinyl chloride ( P V C ) a d m i n i s t r a t i o n sets. D i a z e p a m s o l u t i o n s i n c o n c e n t r a t i o n o f 10O0mg/5OOml i n 0 . 9 % s o d i u m chloride ( N S ) and 5% glucose ( G 5 W ) injection were infused at a flow rate of 3 0 m l / h , a n d s a m p l e s w e r e t a k e n f r o m t h e b o t t l e a n d a t t h e e n d o f t h e a d m i n i s t r a t i o n set, till 12 h o u r s o f i n f u s i o n . T h e samples w e r e tested in triplicate using ultraviolet spectrophotometry. T h e g r e a t e s t loss o f d i a z e p a m w a s o b s e r v e d i n all s o l u t i o n s a t 30 m i n u t e s o f i n f u s i o n (63.5% G 5 W g l a s s , 60.5% N S g l a s s , 5 5 % G 5 W P E a n d 5 8 % N S P E f r o m t h e o r i g i n a l c o n c e n t r a t i o n o f 200 u g / m l ) . T h e d i a z e p a m c o n c e n t r a t i o n s i n t h e c o n t a i n e r s d i d n o t s i g n i f i cantly changed. T h e loss o f diazepam from solutions infused t h r o u g h P V C administration s e t s s h o u l d b e k e p t i n m i n d in s e v e r e c l i n i c a l s i t u a t i o n s a s s t a t u s e p i l e p t i c u s , t e t a n u s a n d eclampsia.
Fatores que influenciam
a infusão endovenosa continua de diazepam.
R E S U M O — F o r a m estudadas as variações d e concentração d o diazepam diluído e m diferentes solventes e frascos, para emprego endovenoso contínuo. F o r a m feitas s o l u ç õ e s e m s o r o fisiológico (NS) e s o r o glicosado a 5% ( G 5 W ) , frascos d e vidro o u d e polietileno ( P E ) , volume total d e 500ml, c o n c e n t r a ç ã o i n i c i a l d e d i a z e p a m d e 200 u g / m l . Cada frasco foi conectado a equipo d e polivinilcloreto ( P V C ) e as soluções foram infundidas a r a z ã o d e 30 m l / h . A m o s t r a s c o l e t a d a s d o s f r a s c o s e d o s e q u i p o s a t é 12 h o r a s d e i n f u s ã o f o r a m t e s t a d a s e m triplicata, p o r espectrofotometria ultravioleta. O maior decréscimo da concentração d e diazepam o c o r r e u e m t o d o s o s f r a s c o s a o s 30 m i n u t o s d e i n f u s ã o , c o m c o n c e n t r a ç õ e s 6 3 , 5 % ( G 5 W v i d r o ) , 5 5 % ( G 5 W P E ) , 6 0 , 5 % ( N S v i d r o ) e 5 8 % ( N S P E ) d a c o n c e n t r a ç ã o inicial. A s concentrações nos frascos d e vidro e P E permaneceram constantes. A diminuição das concentrações d e diazepam deve-se à a d s o r ç ã o d o diazepam a o s equipos d e P V C e essa perda deve s e r levada e m conta durante s e u e m p r e g o e m situações clinicas graves c o m o status epilepticus, tétano e eclâmpsia.
Continuous intravenous (i.v.) infusion of diazepam has been used in the treatment of convulsions , tetanus ^ and eclampsia , for i.v. anesthesia as an adjunct to analgesia during labor, and as a sedative for patients requiring prolonged artificial ventilation 17. Several reports have mentioned the problem of variable drug delivery because of diazepam interaction with the infusion system 8,9,12,14,16, The potential hazards of incomplete delivery include not only inadequate therapy because of decreased drug administration but also possible drug overdose if compensatory increases in tne infusion rate are continued atter the tubing has become saturated with the drug. 1
2
The purpose of this study was to compare glass and polyethylene containers with 0.9% sodium chloride and 5% glucose solutions of diazepam and to measure losses of diazepam during a simulated infusion through plastic infusion sets.
I n t e n s i v e C a r e Unit, H o s p i t a l d e C l í n i c a s , U n i v e r s i d a d e F e d e r a l d o P a r a n á , a n d L a b o r a t o r y of T o x i c o l o g y , I n s t i t u t o M é d i c o L e g a l d o P a r a n á : * M . D . , N e u r o l o g i s t , r e c i p i e n t o f t h e N a t i o n a l Research Council ( C N P q ) grant; ** M . D . , Chief o f L a b o r a t o r y ; *** B . A . ; **** M . D . Rua
Gonçalves
Dias,
713 — 80240 Curitiba
PR —
Brasil.
292
Arq Neuro-Psiquiat
(Sâo Paulo)
47(3J 1989
MATERIALS AND METHODS The
experiment
ditions.
Diazepam
mg/500ml
was
carried
(VALIUM,
(200 u g / m l )
in
out
Roche,
0.9%
at
room
lot
temperature
25690 262) was
sodium
chloride
(NS)
bottles
were
infusion-set
administration intermediary 128 cm. lene
made of
tubing set
has
end
semirigid
(INTRAFIX, a
part
drip
of
B.
polyethylene Braun)
was
chamber of
high
density
normal in
injection
injection in glass containers and polyethylene containers lene
under
prepared
and
5%
( P E ) , which contains
crystal
polyvinyl
polystyrene,
a
no
of
additives. (FVC).
flash
the
(G5W)
T h e polyethy
chloride latex
The lenght
ball
through
the plastic
adding the injection
and
P V C tubing
solutions
wall
in
the
upper part of
to N S and G 5 W , the
the
containers
bottles.
were
an was
Immediately after
shaken
for 20 seconds
to ensure through mixing and the administration sets were attached to the bottles. and
The Every
The injections were added to glass bottles through rubber stoppers and to polyethy
bottles
(5ml)
con
of 1000
glucose
(B. Braun, lot 8111).
made of
polyethylene.
room-light
concentration
were each
taken
2
initially
hours
in
(time
the
0)
and
subsequent
at
each
15 minutes,
10 hours
using
during
sterile
the
needles
first
and
glass
A t 0, 2, 6 and 12 hours a sample was taken from the bottle and simultaneously of the administration set.
T h e samples were analysed in triplicate.
was mantained during the
experiment.
The
absorbance
photometer purposes
of
the
(SPECTRONIC
the
Student
sample
solutions
was
measured
700, Bausch-Lomb) at a wave
t test
was
a
of
ultraviolet
of 312 nm.
hours,
syringes.
at the end
A flow rate
using
length
Samples
two
For
30ml/h
spectro statistical
employed. RESULTS
The diazepam concentrations in glass and polyethylene bottles did not differ
significantly.
A t the end of the study (12 h) the concentration was 2 0 2 ± 3 u g / m l ( G 5 W glass), 1 9 6 ± 1 u g / m l (NS
glass),
218±1 ug/ml
(G5W PE)
and 2 0 2 ± 4
ug/ml
(NS P E ) .
T h e extent
adsorption to the i.v. administration systems is shown in table 1. decrease
of
trations ug/ml
were
the
concentrations
127+0
ug/ml
(55%) ( G 5 W P E )
After of
the
which
(63.5%)
is
maximal at
( G 5 W glass),
and 1 1 6 ± 1 u g / m l
sets
in
all
systems
increase
(Fig.
the concentrations of diazepam were respectively (NS glass)
1 2 1 ± 1 ug/ml
diazepam
A t this (60.5%)
time the (NS
rapid
concen
glass), 1 1 0 ± 2
(58%) (NS P E ) .
30 minutes, there is a progressive
administration
30 minutes.
of
There is an initial
1).
of diazepam concentration A t the
end
of
the
at the
experiment
end
(12 h)
88.5% ( G 5 W glass), 97.5% ( G 5 W P E ) , 94.0%
and 98.5% (NS P E ) .
Concentrations of diazepam ( u g / m l )
Time (h)
G 5 W (glass)
00:30
127 ± 0
110 ± 2 * * *
121 ± 1
116 ± 1 * * *
01:00
165 ± 2
155 ± 4 * *
163 ± 1
154 ± 1 * * *
02:00
169 ± 1
163 ± 1 * * *
175 ± 2
157 ± 2 * * *
04:00
168 ± 2
176 ± 3 * *
177 ± 3
163 ± 1 * * *
06:00
171 ± 1
174 ± 1 * *
177 ± 2
176 ± 1 *
08:00
173 ± 2
183 ± 2 * * *
181 ± 2
183 ± 2 *
10:00
173 ± 2
188 ± 2 * * *
182 ± 1
192 ± 3 * * *
12:00
177 ± 3
195 ± 1 * * *
188 ± 3
197 ± 2 * *
Table 1 — Student t test comparing *, non-significantj **, p < 0,05;
G5W (PE)
same ***,
solutions (G5W p 0,01.
N S (glass)
or NS)
in glass
NS (PE)
and PE
bottles:
Diazepam
availability
from
sohitions
293
TIME Ihourt)
Fig. 1 — A (above; illustrates the initial decrease (30 minu tes) and further increase of diazepam concentrations in G5W solutions, in glass and PE bottles. B fbelow; illus trates the initial decrease (SO minutes) and further increase of diazepam concentrations in NS solutions, in glass and PE bottles. TIME (hour.)
COMMENTS The use of plastic components in intravenous delivery systems has gained wides pread acceptance in clinical medicine due to its practicity. The interaction between several drugs (e.g., clomethiazole edisylate, chlorpromazine hydrochloride, heparin, insulin, nitroglycerin, promazine hidrochloride, promethazine hydrochloride, thiopental sodium, thioridazine hydrochloride, and trifluoperazine dihydrochloride) and intravenous P V C delivery systems and P V C administration sets has been reported 7,8. in fact, the use of P V C containers has been precluded 4,13 f r storage of clomethiazole, thiopental, and diazepam 7. The use of glass or PE bottles is prefered in these situations 15. T o our particular interest are the reports of adsorption of diazepam to polyvinil chloride tubing sets and PE bottles 6,11,12,16. The adsorption of diazepam to P V C tubing was clearly observed and is more important during the first 30 minutes. Thereafter a progressive increasing of diazepam concentrations is observed till an apparent steady state is noted at two hours of infusion. Then we observe a further increase of concen0
trations more marked in the effluent solution from P E bottles ( N S or G 5 W ) . This increase would be due to the presence of substances leached from the P E bottles, which would increase the absorbance of the solutions stored in these containers 8. The loss of diazepam in polyethylene bags are less important 15,16, as observed in our experiment. Changes in diazepam concentration appeared to be independent of the i.v. fluids used in this study 4,6,12,14. What measures can be taken in order to minimize the loss of diazepam during continuous i.v. administration? T w o alternatives seem suitable: the use of P V C set with the shortest possible length 8,9,12,16, and the use of the highest possible flow rate that is clinically safe i > i . Polyethylene-lined administration sets 6, polyolefin tubings 9 and pluronic surfactants io are other alternatives that are not yet available here. The monitoring of diazepam serum levels is suggested in clinical situations where continous i.v. infusion of diazepam is required for longer time (e.g. tetanus). The use of greater concentrations of diazepam in the infusion solutions to override the adsorption may be dangerous, as the actual amount of drug that is delivered to the patient is unknown. 2
6
Acknowledgements — M a r i a L ú c i a N o s s a r S i m õ e s d e D a l g o , D i r e t o r a Científica, L a b o ratórios B . Braun S.A., kindly give information concerning the chemical nature of B. Braun products as well as available literature. Diazepam ( V A L I U M ) injections were kindly supplied by D r . Coriolano Miranda, Gerente d o Departamento Médico, Laboratório Roche. W e wish t o t h a n k P r o f . M u r i l o G. B i t t e n c o u r t a n d P r o f . P a u l o R . C r u z M a r q u e t t i f o r t h e i r s u p p o r t . REFERENCES 1. 2.
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in p l a s t i c containers
Sorptive loss A m J Hosp type o f i.v. Hsop Pharm
