Original ArticlesMidazolam and pentobarbital for refractory status epilepticus
Introduction
Status epilepticus (SE) is a serious, life-threatening emergency characterized by prolonged seizure activity. SE is defined as a seizure or sequence of intermittent seizures persisting for at least 30 minutes during which the patient does not regain consciousness [1], [2]. Some definitions also include clinical or electrical seizure activity of at least 30 minutes duration even if consciousness is not impaired [3]. SE can be classified as convulsive or nonconvulsive, with the convulsive type being the most common and most serious. Refractory status epilepticus (RSE) refers to patients who fail to respond to appropriate first-line drug treatment and persist for longer than 60 minutes [4].
Section snippets
Epidemiology
Estimates of the annual occurrence of SE range from 50,000 to 195,000 patients, with pediatric patients representing the greatest proportion [5], [6]. Among children, SE is most likely to occur in those younger than 3 years of age [2], [4]. In one epidemiologic study a particularly high incidence was observed during the first year of life [6]. Fortunately, children experiencing SE also appear to have a lower mortality rate than adults [6], [7].
In children, SE can be the result of either an
Morbidity and mortality
SE is a medical emergency, with a potential sequela of death or permanent neurologic damage. Animal studies have demonstrated the importance of stopping SE quickly; there is considerable evidence that the prognosis worsens with the continued duration of seizures. In animal models of SE, irreversible neurologic damage becomes evident within 1.5-2 hours of prolonged seizure activity [10]. During prolonged tonic-clonic seizure activity, major metabolic disturbances occur, including hypoxia,
Treatment options
The goals of treatment in SE are to stop the seizure activity and prevent brain damage. Initial management should include stabilization of the patient, including respiratory and blood pressure support, and a diagnostic evaluation to determine the cause of the seizures when the patient’s condition permits. Drug therapy should be initiated as soon as the patient is stabilized. Prolonged seizure duration is thought to potentiate the risk of permanent brain damage and increases the difficulty of
Midazolam
Midazolam is an injectable benzodiazepine used primarily as a premedicant, sedative, and anesthetic agent. The unique chemical structure of midazolam includes a fused imidazole ring that differentiates it from related compounds (Fig 1). The imidazole moiety accounts for the basicity, stability in an aqueous solution, and rapid metabolism of midazolam. In acidic aqueous solutions, midazolam is water soluble, allowing it to be formulated as an injection without the addition of propylene glycol.
Midazolam in pediatric RSE
A number of published case reports have reported the successful use of midazolam in terminating RSE in a total of 29 pediatric patients, 24 of whom came from one center (Table 1). In each patient, midazolam was initially administered as a bolus dose and followed by a continuous infusion. Patient ages ranged from 35 weeks gestation to 12 years. Midazolam effectively stopped seizure activity in all 29 patients, generally within a matter of minutes. In the report by Rivera et al. [26], time to
Pentobarbital in pediatric RSE
High-dose pentobarbital, or pentobarbital coma, is commonly used for the treatment of RSE. Although effective in terminating epileptic seizures, pentobarbital administration is associated with myocardial depression, hypotension, and low cardiac output. It is also a potent respiratory depressant, requiring endotracheal intubation and mechanical ventilation [26]. Pentobarbital is generally given as a bolus dose of 5-15 mg/kg, followed by a maintenance infusion of 1-5 mg/kg/hour [4]. Because of
Discussion
Most cases of SE can be controlled within the first 30-60 minutes with the administration of benzodiazepines, phenytoin, or phenobarbital. In refractory cases that persist beyond this interval the few potential treatment options are less than ideal. General anesthesia with an inhaled agent, such as isoflurane, can produce respiratory depression and requires endotracheal intubation and mechanical ventilation [26]. Halothane may produce inadequate antiepileptic effects and carries risks of
Conclusions
Midazolam is a highly effective antiepileptic agent, even in patients who have not responded to other benzodiazepines [27]. Compared with pentobarbital, midazolam has fewer hemodynamic consequences, minimizing the need for invasive monitoring. The need for endotracheal intubation and mechanical ventilation also appears to be less frequent with midazolam. Patient recovery after midazolam is shorter than with pentobarbital, allowing more accurate assessment of a patient’s condition after SE and
Acknowledgements
The authors thank Clem Weinberger, PhD and Bari Samson for their editorial assistance. This work was supported by a grant to GLH from the NINDS (NS27984).
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