Clinical Analysis Based on Midazolam and Phenytoin

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Abstract and Introduction

The efficacy of a combination of midazolam and phenytoin in treating generalized convulsive status epilepticus in children was studied retrospectively. The patient group comprised all patients admitted for generalized convulsive status epilepticus to the pediatric intensive care unit over 7 years. Patients treated according to the protocol were included (N = 122). These patients were treated with the following regimen; each subsequent step was taken if clinical evidence of epileptic activity persisted: midazolam 0.5 mg/kg rectally or 0.1 mg/kg intravenously. After 10 minutes: midazolam 0.1 mg/kg intravenously. After 10 minutes: phenytoin 20 mg/kg intravenously in 20 minutes. After phenytoin load: midazolam 0.2 mg/kg intravenously followed by midazolam 0.1 mg/kg/hour continuously, increased by 0.1 mg/kg/hour every 10 minutes to maximum 1 mg/kg/hour. Phenobarbital 20 mg/kg intravenously or pentobarbital 2 to 5 mg/kg intravenous load, 1 to 2 mg/kg/hour continuously intravenously. Patients who received initial rectal diazepam were included. Patients were categorized according to the cause of generalized convulsive status epilepticus. These categories were then related to the level of antiepileptic therapy needed. Patients' ages ranged from 0.5 to 197.4 months. The cause of generalized convulsive status epilepticus was idiopathic or febrile convulsions in two thirds of cases. Most (89%) patients were managed on midazolam and phenytoin. Generalized convulsive status epilepticus was terminated with midazolam alone in 58 patients, with the addition of phenytoin in 19 patients and with continuous midazolam in 32 patients. Thirteen patients needed additional barbiturates. The relationship between the level of antiepileptic therapy and etiology was not significant. Fifty-two patients needed artificial ventilation. Seven patients died; no deaths were directly attributable to generalized convulsive status epilepticus itself. With the use of the proposed protocol, combining midazolam and phenytoin, 89% of the cases of generalized convulsive status epilepticus could be successfully managed.

Generalized convulsive status epilepticus in children is a life-threatening event, with an associated mortality of 3% to 11%, depending on the etiology.^{[1,2,3,4,5,6,7,8]} It requires immediate medical intervention to limit morbidity.^[3,9] Generalized convulsive status epilepticus is defined as a single seizure lasting more than 30 minutes or multiple seizures relapsing within 30 minutes without recovery of consciousness between each seizure.^[10] Many emergency physicians believe that this time criterion is too long, and drug administration is considered in practice whenever a seizure has lasted 10 minutes.^[3,11,12] Generalized convulsive status epilepticus is more common in children than in adults, with 64% of all cases occurring in the first 5 years of life.^[4,6] The incidence of generalized convulsive status epilepticus in childhood is not well known and is estimated at 0.1%.^[13]

There is still a lot of discussion on treatment of generalized convulsive status epilepticus in children. Initial treatment with a benzodiazepine, followed by phenytoin or phenobarbital, is generally accepted.^{[1,2,7,9,14,15,16,17]} Historically, diazepam is the most widely used benzodiazepine. There are advantages to the use of benzodiazepines, but the clinical superiority of a specific drug in this group has not been demonstrated.^{[1,8,12,18,19,20,21]} There are several reasons for using midazolam in the treatment of generalized convulsive status epilepticus. It is a water-soluble benzodiazepine and is highly lipophilic, resulting in a rapid diffusion across the capillary wall into the central nervous system. It has a rapid onset of action, and its serum half-life in adults is short, 1.0 to 3.5 hours.^{[7,8,9,18,19,22]} Its adverse effects predominantly involve respiratory depression and hypotension. This seems to be related to high, single doses of midazolam intravenously when administered with other drugs that have an effect on the cardiovascular and respiratory systems or when given in combination with drugs that can affect the metabolism of midazolam (eg, CYP3A4 inhibitors).^[23,24]

Midazolam is an effective agent for seizure control.^[22,25] Several studies in small numbers of children have described the effective use of intravenous, intramuscular, rectal, nasal, or sublingual midazolam.^{[8,19,22,26,27,28,29]} It has also been used effectively in generalized convulsive status epilepticus in children as a last resort, after other anticonvulsant treatment has failed.^[5,30] In 1995, we developed a treatment protocol for generalized convulsive status epilepticus combining midazolam with phenytoin as initial treatment. The aim of this study was to evaluate the clinical efficacy of this treatment protocol for generalized convulsive status epilepticus in patients admitted to a pediatric intensive care unit.

Cite this: Status Epilepticus: Clinical Analysis of a Treatment Protocol Based on Midazolam and Phenytoin - Medscape - Jun 01, 2005.

Classification of Generalized Convulsive Status Epilepticus
Etiology	Description
Idiopathic	Absence of an acute precipitating central nervous system insult or systemic metabolic dysfunction
	Neurologically normal individuals with an established seizure disorder
	Children with a first unprovoked seizure
Remote symptomatic	No acute provocation in a patient with a history of central nervous system insult known to be associated with an increased risk of seizures
Febrile	Acute provocation with fever (temperature greater than 38.4°C); the patient may be neurologically normal or abnormal
Acute symptomatic	An acute illness with a known central nervous system insult or systemic metabolic dysfunctioning within 1 week after abrupt discontinuation of antiepileptic drugs
Progressive encephalopathy	Progressive neurologic disorder; included are neurodegenerative diseases and malignancies not in remission

Etiology of Generalized Convulsive Status Epilepticus
Etiology	Frequency (%)
Idiopathic	46 (37.7)
Acute symptomatic	24 (19.7)
Progressive neurologic	3 (2.5)
Remote symptomatic	5 (4.0)
Febrile	44 (36.1)
Total	122 (100.0)

Level of Antiepileptic Therapy Needed for Cessation of Epileptic Activity Stratified for Initial Rectal Diazepam
Antiepileptic Therapy	Level				Total
Antiepileptic Therapy	1	2	3	4	Total
No diazepam	19	6	9	6	40
Diazepam	39	13	23	7	82
Total	58	19	32	13	122

Relationship Between Etiology of Generalized Convulsive Status Epilepticus and Level of Antiepileptic Therapy
Etiology	Level				Total
Etiology	1	2	3	4	Total
Idiopathic	23	9	11	3	46
Acute symptomatic	10	2	5	7	24
Progressive neurologic	1	1	0	1	3
Remote symptomatic	4	1	0	0	5
Febrile	20	6	16	2	44
Total	58	19	32	13	122

Cause of Death in Seven Patients
Patient	Cause of Death
1	Near-drowning
2	Brain death as complication of pneumococcal meningitis
3	Cardiac failure following cardiac surgery
4	Cardiac failure owing to mitochondrial respiratory chain deficiency
5	Hemorrhagic shock and encephalopathy
6	Brainstem tumor
7	Congenital defect of glycosylation complicated by pneumonia and sepsis

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Status Epilepticus: Clinical Analysis of a Treatment Protocol Based on Midazolam and Phenytoin

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