Upsala J Med Sci 87: 143-149, 1982 

Neonatal Convulsions Treated with Continuous, Intravenous 
Infusion of Diazepam 

I. Gamstorp and G .  Sedin 
Department of Paediatrics, University Hospital, Uppsala, Sweden 

ABSTRACT 
Eight infants born at term in the years 1 9 7 4 - 7 6 ,  with neonatal 

convulsions due to severe perinatal asphyxia, were treated for 
6 - 1 1  days with continuous intravenous infusion of diazepam. Doses 
of 1 . 0 - 1 . 5  mg per hour (mg/h) were usually required to stop the 
convulsions. In one infant 2 . 7 5  mg/h was needed. During the treat- 
ment, all infants had measurable serum concentrations of diazepam, 
half of them above 3 5  umol/l. The convulsions stopped in all eight 
infants, and did not return after discontinuation of the infusion. 
Side-effects were noted in all infants, but they were all able to 
breathe adequately. At follow-up the psychomotor development was 
normal in all cases and there were no signs of neurological dis- 
orders, except in one patient, in whom mild epilepsy was observed. 

Continuous infusion of diazepam should be given in doses of at 
least 1 mg/h (corresponding to around 0.3 mg/kg h) to stop convul- 
sions in full-term infants efficiently and should be increased 
under close supervision and with monitoring of respiration and 
heart rate until treatment is effective. 

INTRODUCTION 
Neonatal convulsions remain a serious problem, and in recent 

studies (3, 4, 6 ,  7 )  the same grave prognosis has been found as in 
many earlier ones, that is, roughly half of the infants die or be- 
come handicapped and at most half survive without handicap. The 
main deciding factor for the prognosis is the background of the 
convulsions., i.e. the severity of the brain injury wnich causes 
them. It must always be an advantage to the infant if the fits are 
brought under effective control as early as possible. Each fit is 
often so short that measures started at the onset of a fit may not 
influence its duration. To prevent fits a continuous intravenous 

143 



infusion of an anticonvulsive drug can be given. 
Benzodiazepines are effective anticonvulsants, particularly 

when given intravenously ( 7 ) .  Their metabolism differs in the neo- 
natal period from that in later life ( 5 ) .  The clinical effect of 
continuous intravenous infusion of diazepam was studied in eight 
newborn infants with convulsions, and at the same time repeated 
measurements were made of the serum concentration of diazepam and 
of its main metabolite, N-desmethyldiazepam. 

MATERIAL AND METHODS 

In an investigation of infants with neonatal convulsions due to 
perinatal asphyxia, 8 infants - 2 girls and 6 boys - born at term 
in 1 9 7 4 - 7 6  were subjected to a special study concerning the effects 
of diazepam therapy. The only reason for selecting these patients 
was that several blood samples for determination of the serum le- 
vel of diazepam and of its metabolite N-desmethyldiazepam could be 
obtained. 

In 6 of the infants the convulsions started during the first 
day of life, in one during the second day and in one during the 
sixth day. All infants were born within 2 weeks of the expected 
date and their birth weights varied between 2 . 9 3 0  and 4 . 4 5 0  kg. 

A standard diazepam preparation (Stesolid R I  Dumex Lakemedel AB, 
Helsingborq, Sweden, 5 mg/ml) was used and added to the infusion 
of isotonic glucose solution which the infant needed for other 
reasons. A new solution for infusion was prepared every 1 2  hours. 
Before the diazepam infusion was finally stopped, peroral pheno- 
barbital therapy was started. 

During the neonatal period the 8 infants were admitted to a 
neonatal intensive care unit where they were under the close ob- 
servation of trained nurses and where their problems - e.g. re- 
spiration metabolism, nutrition, infections - were taken care of. 
After discharge they were repeatedly examined at the Outpatient 
Unit of the Department of Paediatrics, Uppsala, either by a pacdia- 
tric neurologist or by a neonatologist. An EEG was performed at 
the ac;e of one year before discontinuation of phenobarbital treat- 
ment and again at the age of two years. Those infants who showed 
a comDletely normal development and physical condition were checked 
after about two years by general paediatricians at child health 
centres. This examination included careful history-takingl parti- 
cularly concerning development and symptoms suggesting fits, and 

144 



physical examination with emphasis on the psychomotor development 
and neurological status. 

During the diazepam infusion, capillary blood was drawn and 
kept deep-frozen until analysed. The analyses, which were per- 
formed by gas chromatography ( 2 1 ,  comprised diazepam and N-des- 
methyldiazepam determinations and were made at the laboratory of 
Dumex Lakemedel, Helsingborg, Sweden. 

RESULTS 
The initial diazepam dose was 0.5 mg/h ( 6  patients) or 1.0 mg/h 

( 2  patients). The lower dose was ineffective and had to be in- 
creased to 0 . 7 - 2 . 7 5  mg/h for all infants before the convulsions 
definitely disappeared. In one patient a dose higher than 2.0 mg/h 
was necessary: 1-1.5 mg/h was the highest dose neededinthe other 
7 patients. 

When the infant had been convulsion-free for 1 2 - 2 4  hours, the 
dose was slowly decreased in steps of 0 . 1 - 0 . 2 5  mg/h with one or 
two such changes per 2 4  hours. One patient was treated for 3 days, 
one for 1 1  days, and the rest for 6 - 8  days. No fits occurred du- 
ring infusion of the highest dose used in each patient, and all 
patients remained convulsionfree during the dose-decreasing phase 
and after infusion of the drug had been stopped. All patients 
showed obvious side-effects - they were drowsy and floppy to va- 
rying degrees. They also needed feeding through a gastric tube 
and initially parenteral fluid and nutrition. All 8 infants 
breathed spontaneously and assisted ventilation was not needed. 

In two patients the first measurements of the serum diazepam 
and N-methyldiazepam concentrations were made within 2 hours after 
the start of the infusion: in one of them the serum diazepam le- 
vel was 1 . 2 8  umol/l: one of them never received more than 0.7 mg/h 
and the other two never more than 1 mg/h. In the other 5 one or 
several values exceeded 3.5 umol/l, and 4 had at least one value 
above 35 l J m o l / l .  

The highest diazepam concentrations were 8 0 . 5  pmol/l (on a dose 
of 1.5 mg/h; birth weight 4 . 4 5 0  kg) and 5 5  umol/l (on a dose of 
1.0 mg/h; birth weight 3 . 0 3 0  kg). The highest dose used among 
these 8 infants, 2 . 7 5  mg/h for 5 hours in a boy weighing 3 . 8 7 0  kg 
gave a maximum serum concentration of 2 1 . 7  umol/l. The serum le- 
vel of diazepam, at which the convulsions stopped, varied so 
much that no "anticonvulsant level" can be defined, but it seems 

145 10-822857 



to be higher than the level of 0.5-1.2 umol/l (150-350 nq/l) which 
is considered anticonvulsant in older children (3). 

Fig.1 summarizes all serum diazepam concentrations recorded in 

relation to the diazepam dose, expressed as mg per kg and hour 
(mg/kg h). From the figure it is obvious that a dose of 0.35 mg/kg 
h always gave a stable and high serum level. In full-term infants 
this corresponds to a dose of 1.0-1.5 mg/h. 

umol/ 1 

E 
tu 
Q 
a, 
N 
tu 
U 

0 

C 
0 
V 

.- 

cc 

ci 

E 
3 

a, 
0 
L 

10 

1 

0.1 

0.01 

, . .  
. .  

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I L I I 1 1 

0 0.2 0.4 0.6 0.8 rng/&.h 

Dose of diazepam 

Firj. 1. Serum concentration of diazepam (log scale) 
in relation to the given doses of the drug 
in all eight infants. 

In most cases the serum level of N-desmethyldiazepam started to 

increase about 1 2  hours after the start of the infusion, and a 
high level, often still increasing, was recorded during the dose- 
decreasing phase. Unfortunately the concentration was not always 
measured after the infusion was stopped. The highest concentration 
measured was 9.74 umol/l. This was recorded in the patient who ne- 
ver received more than 0.7 mg/h and, during the dose-decreasing 
phase, when he had been on 0.4 mg/h for 14 hours. Patients showing 
the highest serum levels of diazepam had the lowest levels of N- 
desmethyl-diazepam, and vice versa. No clear relation was observed 
between the severity of the clinical findings, & the convulsions 
and the side-effects of the drug, and the serum levels of diazepam 
and N-desmethyldiazepam. 

146 



At follow-up, all patients were well, with normal psychomotor 
development and normal neurological findings. Only one patient had 
convulsions. This patient had required the highest dose and the 
longest diazepam therapy. When falling asleep he had a series of 
jerks lasting for at least half an hour, thus quantitatively ex- 
ceeding the usual type of jerks occurring, when falling asleep. He 
also had epileptic potentials on his EEG, increasing during light 
sleep and coinciding with his jerks. In spite of the lack of other 
types of seizures he is considered to have a mild form of epilepsy 
and is being treated with carbamazepine. No seizures have been re- 
ported in any of the other patients and their EEGs are normal. 

The diazepam dose and serum levels of diazepam and N-desmethyl- 
diazepam are reviewed in a patient (birth weight 3.8 kg) with a 
mild respiratory disturbance after birth. On the 3rd day of life 
convulsions started. His convulsions stopped at a dose of 1 . 5  mg/h 
when this dose had been used for 24 hours. 

DISCUSSION 
Although all eight infants recovered with no or only mild se- 

quelae, it cannot be concluded that this satisfactory outcome is 
due to the treatment used. It seems reasonable to suppose that an 
early and efficient treatment of the convulsions is advantageous 
to the infant. 

The doses of diazepam used in this study are of the same mag- 
nitude as those used successfully by Thong et al. ( 8 )  €or conti- 
nuous intravenous infusion in convulsing infants. The serum con- 
centrations are in reasonable agreement with those recorded by 
Langslet et al. (5) in newborn infants, who received a single 
intravenous injection of diazepam. As is obvious from the present 
study a dose of 0.7 mg/h in a full-term baby may in some cases be 
enough, but a dose of 1 mg/h is more likely to stop the seizures. 
If the treatment is not successful, the dose can be increased con- 
siderably. In this study the highest dose needed to stop the sei- 
zures was 2 . 7 5  mg/h. The serum concentrations of diazepam and its 
metabolite N-desmethyldiazepam, in these newborns, were extremely 
high compared with those reported in older children ( 1 ) .  Although 
the infants showed obvious side-effects, lasting several days 
longer than the duration of the therapy, none of them needed 
assisted ventilation. 

147 



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ACKNOWLEDGEMENTS 
Dumex Lzkemedel AB, Helsinqborq, Sweden, kindly supplied the 

the technical preparation of the manuscript. 
drug, performed all the chemical analyses and gave generous help 

REFERENCES 
Agurell, S. & Berlin, A., Fernqren, H. & Hellstrom, B.: Plasma 
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krampetilstander hos barn i O s l o ,  juni 1 9 7 7 ,  pp 9 - 2 1 ,  1 9 7 7 .  
Naqao, M., Hayashi, M., Komiya, K .  & Komiya, H.: A study of 
neonatal convulsions. In: Brain and development, fed. E. Fuku- 
yama) p 1 6 6 ,  Proc 1 9 t h  Ann Meet of the Japanese Society of 
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Rose, A.L.: Neonatal seizures. In: Topics in Child Neurology. 
Spectrum Publications Inc, New York, pp 7 1 - 8 3 ,  1 9 7 7 .  
Thong, Y.H. & Abrahamson, D.C.: Continuous infusion of diazepam 
in infants with severe recurrent convulsions. Med Ann DC 4 3 : 6 3 -  
6 5 .  

Received November 2 ,  1 9 8 1 .  

Address for reprints: 

I. Gamstorp, MD 
Department of Pediatrics 
University Hospital 
S - 7 5 0  1 4  Uppsala 
Sweden