FACTORS AFFECTING DIAZEPAM AVAILABILITY
FROM INTRAVENOUS ADMIXTURE SOLUTIONS
WALTER OLESCHKO ARRUDA * — DILERMANDO BRITO FILHO ** — SOLANGE L. C. ROSA *** — PAULO S. G. FONTOURA *** — MOEMA 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 g l a s s b o t t l e s o r p o l y e t h y l e n e ( P E ) c o n t a i n e r s d u r i n g i n f u s i o n t h r o u g h p o l y v i n y l c h l o r i d e ( P V C ) a d m i n i s t r a t i o n s e t s . 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 c h l o r i d e ( N S ) a n d 5 % g l u c o s e ( G 5 W ) i n j e c t i o n w e r e i n f u s e d a t a f l o w r a t e o f 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 s e t , till 12 h o u r s o f i n f u s i o n . T h e s a m p l e s w e r e t e s t e d i n t r i p l i c a t e u s i n g u l t r a v i o l e t s p e c t r o -p h o t o m e t r y . T h e g r e a t e s t l o s s o f d i a z e -p a m w a s o b s e r v e d i n a l l 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 ( 6 3 . 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 -c a n t l y -c h a n g e d . T h e l o s s o f d i a z e p a m f r o m s o l u t i o n s i n f u s e d t h r o u g h P V C a d m i n i s t r a t i o n 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 e c l a m p s i a .
Fatores que influenciam a infusão endovenosa continua de diazepam.
R E S U M O — F o r a m e s t u d a d a s a s v a r i a ç õ e s d e c o n c e n t r a ç ã o d o d i a z e p a m d i l u í d o e m d i f e r e n t e s s o l v e n t e s e f r a s c o s , p a r a e m p r e g o e n d o v e n o s o c o n t í n u o . F o r a m f e i t a s s o l u ç õ e s e m s o r o f i s i o l ó g i c o ( N S ) e s o r o g l i c o s a d o a 5 % ( G 5 W ) , f r a s c o s d e v i d r o o u d e p o l i e t i l e n o ( P E ) , v o l u m e t o t a l 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 . C a d a f r a s c o f o i c o n e c t a d o a e q u i p o d e p o l i v i n i l c l o r e t o ( P V C ) e a s s o l u ç õ e s f o r a m i n f u n d i d a s 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 t r i p l i c a t a , p o r e s p e c t r o f o t o m e t r i a u l t r a v i o l e t a . O m a i o r d e c r é s c i m o d a c o n c e n t r a ç ã o d e d i a z e p a m 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 i n i c i a l . A s c o n c e n t r a ç õ e s n o s f r a s c o s d e v i d r o e P E p e r m a n e c e r a m c o n s t a n t e s . A d i m i n u i ç ã o d a s c o n -c e n t r a ç õ e s d e d i a z e p a m d e v e - s e à a d s o r ç ã o d o d i a z e p a m a o s e q u i p o s d e P V C e e s s a p e r d a d e v e s e r l e v a d a e m c o n t a d u r a n t e s e u e m p r e g o e m s i t u a ç õ e s c l i n i c a s g r a v e s c o m o s t a t u s e p i l e p t i c u s , t é t a n o e e c l â m p s i a .
Continuous intravenous (i.v.) infusion of diazepam has been used in the treatment of convulsions1
, tetanus ^ and eclampsia2
, 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.
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 U n i t , 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 R e s e a r c h C o u n c i l ( C N P q ) g r a n t ; ** M . D . , C h i e f o f L a b o r a t o r y ; *** B . A . ; **** M . D .
292 Arq Neuro-Psiquiat (Sâo Paulo) 47(3J 1989
M A T E R I A L S A N D M E T H O D S
The experiment was carried out at room temperature under normal room-light
con-ditions. Diazepam ( V A L I U M , Roche, lot 25690 262) was prepared in concentration of 1000
mg/500ml (200 u g / m l ) in 0.9% sodium chloride ( N S ) injection and 5% glucose ( G 5 W )
injection in glass containers and polyethylene containers (B. Braun, lot 8111). T h e
polyethy-lene bottles were made of semirigid polyethypolyethy-lene ( P E ) , which contains no additives. The
infusion-set tubing ( I N T R A F I X , B. Braun) was made of polyvinyl chloride ( F V C ) . Every
administration set has a drip chamber of crystal polystyrene, a latex flash ball and an
intermediary end part of high density polyethylene. T h e lenght of the P V C tubing was
128 cm. The injections were added to glass bottles through rubber stoppers and to
polyethy-lene bottles through the plastic wall in the upper part of the bottles. Immediately after
adding the injection solutions to N S and G 5 W , the containers were shaken for 20 seconds
to ensure through m i x i n g and the administration sets were attached to the bottles. Samples
(5ml) were taken initially (time 0) and at each 15 minutes, during the first two hours,
and each 2 hours in the subsequent 10 hours using sterile needles and glass syringes.
A t 0, 2, 6 and 12 hours a sample was taken from the bottle and simultaneously at the end
of the administration set. T h e samples were analysed in triplicate. A flow rate of 30ml/h
was mantained during the experiment.
The absorbance of the sample solutions was measured using a ultraviolet
spectro-photometer ( S P E C T R O N I C 700, B a u s c h - L o m b ) at a wave length of 312 nm. F o r statistical
purposes the Student t test was employed.
R E S U L T S
T h e 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
( N S glass), 2 1 8 ± 1 u g / m l ( G 5 W P E ) and 2 0 2 ± 4 u g / m l ( N S P E ) . T h e extent of diazepam
adsorption to the i.v. administration systems is shown in table 1. There is an initial rapid
decrease of the concentrations which is maximal at 30 minutes. A t this time the
concen-trations were 1 2 7 + 0 u g / m l (63.5%) ( G 5 W g l a s s ) , 1 2 1 ± 1 u g / m l (60.5%) ( N S glass), 1 1 0 ± 2
u g / m l (55%) ( G 5 W P E ) and 1 1 6 ± 1 u g / m l (58%) ( N S P E ) .
After 30 minutes, there is a progressive increase of diazepam concentration at the end
of the administration sets in all systems (Fig. 1 ) . A t the end of the experiment (12 h)
the concentrations of diazepam were respectively 88.5% ( G 5 W glass), 97.5% ( G 5 W P E ) , 94.0%
(NS glass) and 98.5% (NS P E ) .
Concentrations of diazepam ( u g / m l )
Time (h) G 5 W (glass) G 5 W ( P E ) N S (glass) N S ( P E )
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 * *
Diazepam availability from sohitions 293
TIME Ihourt)
TIME (hour.)
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.
C O M M E N T S
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 f0r storage of clomethiazole, thiopental,
concen-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. W h a t 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 i2
> i6
. 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 deli-vered to the patient is unknown.
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