The treatment of prolonged seizure activity with intravenous diazepam

PEDIATRIC AND

PHARMACOLOGY

THERAPEUTICS

The treatment of prolonged seizure activity n,itb intravenous diazepam During a 9 month period, 53 episodes of prolonged seizure activity occurring in 48 children ranging in age from I day to 18 years were treated with intravenous diazepam. The data from these patients are analyzed with regard to age, sex, and race distribution, dosage used, medical diagnosis, concomitant use of other anticonvulsants, type of seizure, response, and complications. Prolonged therapy with diazepam and its administration to neonates are discussed. The results are compared with those of previous reports.

David W. Bailey, M.D., "x"and Gerald M. Fenichel, M.D. WASHINGTON~

PROLONGED

D. C.

SEIZURE

ACTIVITY

has been defined as continuous generalized or focal seizures lasting for 10 minutes or longer, as well as 3 or more separate seizures within the prior half hour? I t may signify an exacerbation of a known chronic disorder or herald the onset of an acute neurological or systemic disease. Prompt correction of a specific metabolic imbalance is effective when indicated. Usually, however, only symptomatic emergency treatment of the seizure can be offered. Most pediatric services have advocated the use of either barbiturates or paraldehyde for this purpose. Disadvantages of both are a delay between administration of the drug and control of the seizure; untoward side effects include prolonged deFrom the Departments of Neurology and Neurological Surgery, Children's Hospital of the D. C. and George Washington University School of Medicine. *Commander (MC) USN.

pression of consciousness, respiratoly embarrassment, and cardiac arrest. ~ T h e data from several clinical reports 26 dealing with the anticonvulsant properties of diazepam (Valium, Hoffman-La Roche, Inc.) prompted the Neurology Service of the Children's Hospital of the D. C. to recommend its use in the emergency treatment of prolonged seizure activity. Fifty-three episodes in 48 patients were treated between June, 1967, and March, 1968. Reference to this experience is made in a recent publication, 9 which also includes a review of the literature on the anticonvulsant properties of chlordiazepoxide, of which diazeparn is an analogue.

METHODS All children receiving diazepam for the control of prolonged seizure activity during the period specified were included in the study. T h e undiluted parenteral preparation Vol. 73, No. 6, pp. 923-927

924

Bailey and Fenichel

The Journal of Pediatrics December 1968

was administered slowly via the intravenous route until either the seizure activity had been controlled or a suggested maximum dose of 10 to 15 mg. per square meter had been given. Appropriate clinical and laboratory data were carefully recorded in each patient's record and subsequently transferred to a form prepared specifically for this study. RESULTS

In Table I the patients are grouped according to age, sex, and race, and the average dose and range of dosage of diazepam within each group are indicated. Although a maximum dose of 10 to 15 mg. per square meter had been suggested, 4 patients were given approximately 25 mg. per square meter without any apparent ill effects. In Table II the patients are categorized according to their medical diagnoses. Two subgroups require amplification. The acute metabolic disorders included: lead poisoning (1), hypoealcemia (1), hypertonic dehydration (2), acute hyperosmolality (1), and hyponatremia (1). The subgroup of acute cerebrovascular disturbance included patients with: dural sinus thrombosis (2), leukemia (1), hemophilia (2), cardiac arrest (1), and anaphylactic shock (1). Twenty-five patients had been given no anticonvulsants for at least 12 hours prior to the administration of diazepam. In 9 instances, the onset of the seizure being treated occurred at least 30 minutes after the patient

had received other anticonvulsants. The remaining 19 patients were treated with phenobarbital parenterally and/or paraldehyde rectally, which had failed to control the same episode of seizures for which diazepam was subsequently given. The response to diazepam, in the total group and subdivided according to diagnosis and previous therapy, is indicated in Table III. An "excellent" response is defined as complete control of the seizure within 1 minute of starting the intravenous infusion of diazepam. "Good" constitutes complete cessation within 5 minutes. A "fair" response implies that the patient required large or repeated doses to obtain complete or partial control of the seizure within 5 to 10 minutes. "Poor" refers to those with either an equivocal or no response to diazepam. For the purposes of subsequent discussion, these categories will be combined into 2 groups--satisfactory (including "good" and "excellent") and unsatisfactory (including "fair" and "poor"). Table IV lists the results obtained according to the type of prolonged seizure activity being treated. All seizures with definite focal features were classified as "focal," whether or not they became generalized or were associated with unconsciousness. Two patients with epilepsia partialis continuans were included in this group. Transient apnea occurred following administration of diazepam in 2 children. A 12year-old girl convulsed during anaphylactic

Table I. Age, sex, race, and dose Sex, race, dose

Age groups 1-6 years t

0-1 month

I 1-12 months I

6-18 years

1

Total

5 2

9 4

14 10

4 5

32 20

Race Caucasian Non-Caucasians

4 2

6 8

I4 I0

5 4

28 24

Dose (mg.) Average Range

2.5 1-5

3 1-7

5 2-10

5 2-10

Sex

Male Female

*2 Oriental, 22 Negro.

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Diazepam for seizure activity

Table II. Medical diagnosis Diagnosis

1 No.

Chronic

Idiopathic epilepsy Brain damage syndrome Congenital malformations Degenerative disorders Post- or chronic encephalitis

14 3 5 2 2 Total

26

Acute

CNS infections Metabolic disorders Cerebrovascular disorders Trauma, tumor, other Perlnatal brain damage

6 6 7 4 4 Total

27

Table I I I . Response to diazepam, analyzed according to diagnostic category and other therapy Diagnostic category and other antic o n v u l s a n t s "~

Response

E ; CGood n ; 1Fair -

Poor

Acute

Yes No

3 13

3 4

9 12 37 68

2 1 10 20

2 2

Chronic

Yes No Totals Per cent

2 2 4

4 8

~Administered within 30 minutes before diabepam was given.

Table IV. Response to diazepam, analyzed according to type of seizure

Type of seizure

Generalized Focal Akinetic/ myoclonic~ Temporal lobe Decorticate

Results SatisUnsatisfactory factory

23 19 2

Total

3 2 -

26 21 2

1

1

2

2

-

2

eWith bypsarrhythmia on EEG.

9 25

shock following an injection of penicillin. She became apneic 2 to 3 minutes after receiving 5 mg. of diazepam, which had controlled her generalized seizures within 1 minute. H e r respiratory failure appeared to be secondary to an airway obstruction, as part of the anaphylactic reaction. Response to administration of intravenous epinephrine, oxygen, and suctioning was prompt. There were no apparent sequelae at the time of her discharge 4 days later. A 5~-year-old girl was admitted with partially treated H. influenzae meningitis. She was severely ill and stuporous. Thirty-seven hours after admission she had a prolonged left-sided clonic seizure. Four milligrams of diazepam injected intravenously over a period of 1 minute resulted in cessation of the seizure, but 30 seconds later she became apneic. Effective respirations could be readily induced by lightly stroking the sternum or paraspinal area. Within 60 to 90 seconds, spontaneous respirations returned. H e r subsequent course was one of gradual improvement. The seizures did not recUr. Adequate laboratory data were obtained in 29 patients and failed to reveal any evidence of a toxic effect of diazepam on the hematopoietic, renal, or hepatic systems. DISCUSSION The high percentage of satisfactory results and low incidence of complications with the use of diazepam to control prolonged seizure activity make it preferable to other agents previously employed for this purpose. The undiluted parenteral preparation should be infused directly into the vein. Seizure control is usually~ established within less than 1 minute, using a small (5 to 7 mg. per square meter) dose. However, the infusion should be slowly continued until either control occurs or a m a x i m u m dose of 10 to 15 rag. per square meter is reached. Occasionally, as much as 95 mg. per square meter may be required. Intramuscular administration is reportedly a-s effective, but intravenous therapy is preferred because its prompter action allows precise determination of the required dose in most patients. Diazepam should be given

926

Bailey and FenicheI

intramuscularly for seizure activity only when an intravenous route cannot be established. Thirteen of the 48 patients required repeated administrations of diazepam over a period of days for control or prevention of recurrent seizures. In each of these the effectiveness of the drug remained consistent. One such patient deserves special emphasis. She was a 5-year-old Caucasian girl with a subacute disorder of the central nervous system, probably encephalitis, whose diagnosis was never established with certainty despite an extensive evaluation which included 2 brain biopsies. The onset was marked by epilepsia partialis continuans of the tongue. Within 6 months she deteriorated to a vegetative state and experienced frequent multifocal clonic seizures. Prophylactic therapy with diphenylhydantoin and prlmidone was only partially effective and was finally discontinued after the development of an allergic rash. Paraldehyde was of limited and transitory benefit. She was then given 5 and later 10 mg. of intravenous diazepam every 6 to 8 hours. H e r seizures were promptly controlled and did not recur. She later began to improve and was placed on oral diazepam prior to dis, charge. A total of 2,300 mg. of dlazepam was used during a 2 month period without ill effect. Convulsions subsequently recurred and additional anticonvulsants were needed for long-term prophylactic use. Intravenous diazepam was used to control prolonged seizure activity in 6 neonates. Only one other neonatal case is reported, r in which the infant received 1 rag. intravenously with good response. Our own results were satisfactory in all 6 patients, the seizure terminating within 1 minute in 5 and within 5 minutes in the other. No untoward side effects were recorded. I n 3 infants, additional doses of diazepam were required over ensuing days to control seizures which recurred despite the use of prophylactic anticonvulsants (phenobarbital or diphenylhydantoin) following the first administration of diazepam. Table V is a compilation of the results obtained with parenteral diazepam given for the control of prolonged seizure activity in children, as reported in the literature. T h e 50

The Journal oI Pediatrics December 1968

Table V. Response in children to diazepam as reported in other studies

Report

Episodes treated

Prensky et al.1 Gastaut et al.~ Lombroso4 Lalji et al. 5 Gordon6 Sawyer et al# Parsonage and Norris s Totals

Results SarisUnsatisfactory , factory

12 15 27 32 9 6 5

6 13 20 28 9 6 4

6 2 7 4 0 0 I

106

86

20

per cent satisfactory response in the report of Prensky and associates 1 probably reflects the restriction of that study to patients with acute structural, metabolic, or infectious disorders of the central nervous system. In the largest and most comparable series, that ot Lalji and associates, 5 the results were essenti. ally identical to ours. Laboratory studies of the use of diazepanl for control of prolonged seizure activity, ai well as prevention of seizures in monkeys 1-~ and cats, 1~ have shown it to be remarkabl,effective under these controlled conditions. SUMMARY

Fifty-three episodes of prolonged seizure activity were treated with intravenous diaz. epam. Satisfactory results, defined as com. plete control within 5 minutes, were obtainec in 47 (89 per cent). Two patients developec transient apnea which responded promptly, to simple supportive measures, No other comJ plications were encountered. With the excep. tion of those instances in which specific ther. apy is promptly available, intravenous diaz. epam is felt to be the treatment of choic( for prolonged seizure activity. REFERENCES

1. Prensky, A. L., Raft, M. C., Moore, M. J. and Schwab, K. S.: Intravenous diazepam il the treatment of prolonged seizure activit~ Ne~v England J. Med. 276: 779, 1967. 2. Scholl, M. L.: Epilepsy in children, in Conr. H. F., editor: Current therapy, Philadelphia 1966, W. B. Saunders Company, p. 574.

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3. Gastaut, H., Naquet, R., Poire, R. and Tassinari, C. A,: Treatment of status epilepticus with diazepam, Epilepsia 6: 167, 1965. 4. Lombroso, C. T.: Treatment of status epilepticus with diazepam, Neurology 16: 629, 1966. 5. Lalji, D., Hosking, G. S., and Sutherland, 9J. M.: Diazepam in the control of status epilepticus, M. J. Australia 1: 542, 1967. 6. Gordon, N. S.: Treatment of status epilepticus with diazepam, Develop. Med. & Child Neurol. 8: 668, 1966. 7. Sawyer, G. T., Webster, D. D., and Schut, L. J.: Treatment of uncontrolled seizure activity with diazepam, J. A. M. A. 203: I l l , 1968.

Diazepam for seizure activity

927

8. Parsonage, M. J. and Norris, J. W.: Use of diazepam in treatment of severe convulsive status epilepticus, Brit. M. J. 3: 85, 1967. 9. Fenichel, G. M.: The use of diazepam in the treatment of status epilepticus, Clin. Proc. Child. Hosp. (Washington) 24: 82, 1968. 10. Kopel0ff, L. M. and Chusid, J. G.: Diazepa~m as anticonvulsant in epileptic and normal monkeys, Internat. J. Neuropsych. 3: 469, 1967. ll. Spehlmann, R. and Colley, B.: Effect of diazepam on experimental seizures in unanesthetized cat, Neurology 18: 52, 1968.