Pediatric Status Epilepticus Medication

This section primarily addresses dosages and pharmacologic properties of anticonvulsant medications used to treat generalized tonic-clonic status epilepticus (GTCSE). Benzodiazepines, hydantoins, and barbiturates have anticonvulsant properties. Choose a parenteral preparation with rapid onset and long duration of action and the least amount of sedation and respiratory depression. Titrate for clinical response by waiting an adequate length of time for attainment of therapeutic levels in the brain.

Class Summary

This class of medications has long been used to treat generalized tonic-clonic status epilepticus (GTCSE) and is often mentioned as first-line treatment for seizures in general. Diazepam has been advocated as a first-line agent alone or in combination with phenytoin.

Whether a benzodiazepine followed by phenytoin is really the ideal sequence for this combination or if phenytoin (or fosphenytoin) should be followed by a benzodiazepine is unclear. Although the latter sequence appears better in animal models of GTCSE, human data are lacking. Experience with benzodiazepines in the treatment of status epilepticus (SE) is large. This class of drugs has been described as the most potent used in SE management.

Diazepam (Valium, Diastat)

Diazepam depresses all levels of CNS (eg, limbic system, reticular formation), possibly by increasing activity of gamma-aminobutyric acid (GABA). It is a highly lipophilic drug that quickly crosses the blood-brain barrier but is also rapidly redistributed to lipid-rich tissues. Thus, the duration of seizure control is very short with diazepam, and the drug must be followed by administration of the longer-acting phenytoin or phenobarbital.

Per rectum (PR) diazepam has been found to be effective in the control of cluster and prolonged seizures. Diazepam tends to be more effective when administered within 15 minutes of seizure onset. Do not administer faster than 1-2 mg/min IVP in children or faster than 5 mg/min in adults.

Lorazepam (Ativan)

Lorazepam is a sedative hypnotic with short a rapid onset of action, equivalent to that of diazepam, but a longer effective duration of action against GTCSE (6-8 h) than diazepam. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it may depress all levels of CNS, including the limbic and reticular formation. Monitoring of the patient's blood pressure after administering a dose of lorazepam is important. Adjust the dose as necessary.

Midazolam (Versed)

Midazolam depresses all levels of CNS (eg, limbic system, reticular formation), possibly by increasing activity of GABA. IM midazolam is the drug of choice for the child without immediate IV or IO access.

Although midazolam is not approved by the FDA for treatment of seizures in the United States, it has a long record of safety that probably is similar to other benzodiazepines. It is used in at least 2 scenarios: (1) for initial treatment of relatively brief seizures (>5-10 min) as an alternative to diazepam or lorazepam and (2) to treat SE refractory to other benzodiazepines, phenytoin, and phenobarbital.

Because midazolam is water soluble, the peak EEG effect takes approximately 3 times longer than diazepam; thus, 2-3 minutes are required to fully evaluate sedative effects before initiating a procedure or repeating the dose. Commercially available solutions contain 1% benzyl alcohol and 0.01% edetate sodium.

Class Summary

These agents stabilize neuronal membranes. They may act in the motor cortex, where they may inhibit the spread of seizure activity.

Phenytoin (Dilantin)

Phenytoin slows the rate of recovery of voltage-activated sodium channels in the inactivated state, preventing rapid repetitive firing of neurons. The activity of brainstem centers responsible for the tonic phase of grand mal seizures may also be inhibited.

Phenytoin should not be mixed with dextrose-containing solutions because of risk of precipitation; instead, dissolve drug in NaCl 0.9%. Propylene glycol and sodium hydroxide in IV preparation are thought to be responsible for pain during infusion, phlebitis, and local tissue damage.

Approximately 90% of serum phenytoin is bound to protein, mainly albumin, and an increase in unbound phenytoin is observed in patients with lower albumin levels (eg, neonates, people with renal or hepatic failure, nephrotic syndrome, pregnancy, or severe burns). Phenytoin demonstrates fast brain uptake equivalent to that of phenobarbital and diazepam. The cerebrospinal fluid (CSF) concentration is similar to the unbound serum fraction.

Phenytoin is effective for idiopathic, posttraumatic, focal, and psychomotor SE. Individualize doses. Maximal IV infusion rates (1 mg/kg/min in children and 50 mg/min in adults) are to be respected because of the many cardiovascular actions from its quinidinelike effects.

Fosphenytoin (Cerebyx)

A key drug for the treatment of GTCSE, fosphenytoin is a diphosphate ester salt of phenytoin that acts as water-soluble prodrug of phenytoin. Following administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin. Phenytoin in turn stabilizes neuronal membranes and decreases seizure activity.

The dose of fosphenytoin is expressed as phenytoin sodium equivalents (PE). Although fosphenytoin can be administered IV and IM, IV is the route of choice and should be used in emergency situations. The drug can be readily dissolved in any of commercially available IV solutions (eg, D5W, isotonic sodium chloride solution). It is prepared with 100 mL of diluent.

Concomitant administration of an IV benzodiazepine is usually necessary to control SE. When patients become alert during infusion, they may report perineal itching. Slow the infusion for individuals appearing uncomfortable and whose seizures have stopped.

Fosphenytoin is three times more avidly bound to serum protein than phenytoin, displacing the latter from its protein-binding sites. It can be infused 3 times faster than phenytoin.

Despite these factors, when comparing the maximum phenytoin infusion rate of 50 mg/min (1 mg/kg/min in children) with that of fosphenytoin 150 mg/min (3 mg/kg/min for children), the rates at which free and total serum phenytoin levels increase show very similar curves that overlap at many points in time. The main advantage of fosphenytoin is its relatively low level of local irritation, avoiding serious local tissue damage with IV extravasation, and potential use in IM injection. Disadvantage is high price.

Class Summary

These agents have sedative, hypnotic, and anticonvulsant properties. They suppress CNS from the reticular activating system (presynaptic and postsynaptic).

Pentobarbital (Nembutal)

Use pentobarbital anesthesia when seizures persist after 60 min of appropriate treatment. Patient should be already intubated. An advantage of pentobarbital over inhalation anesthetics is that it decreases intracranial pressure whereas the latter tend to increase it.

At concentrations below 10 µmol, pentobarbital potentiates GABA-induced increase in chloride (Cl) conductance and decreases voltage-activated calcium currents in hippocampal neurons. At subanesthetic concentrations, barbiturates decrease glutamate-induced depolarizations (an effect mediated by the AMPA receptors).

At concentrations above 100 µmol, this agent is capable of increasing Cl conductance in the absence of GABA. At high (anesthetic) concentrations, it inhibits sodium (Na) channels that reduce high-frequency rapid repetitive firing. Indirect evidence suggests Na channel blockade may be a main mechanism of general anesthesia.

Pentobarbital decreases cation flux after cholinergic activation of nicotinic receptors. Interaction with nicotinic receptors at the autonomic ganglia and at the neuromuscular junction explains hypotension and potentiation of the action by neuromuscular-blocking agents.

Approximately 35-45% of serum pentobarbital is protein bound. Like all highly lipid-soluble barbiturates, the total terminal half-life of pentobarbital does not have a direct relationship with the duration of its efficacy as an anesthetic because of the redistribution effect.

Serum pentobarbital levels achieved in adults and adolescents range from 5-100 mg/L. Some authors emphasize the need to reach burst-suppression pattern on EEG, whereas others have shown that this pattern is neither necessary nor sufficient because breakthrough seizures may occur coming out of this pattern. It is much easier to teach burst-suppression pattern recognition than to diagnose seizures on EEG. EEG monitoring is often used to adjust infusion to keep the burst-suppression pattern within 2-8 bursts/min. Some authors recommend continuous EEG monitoring for the first 6 hours, followed by 10-minute samples every 30 minutes.

Patients requiring pentobarbital anesthesia after prolonged seizures lasting 16 hours to 3 weeks may have poor outcome, which may be related to underlying pathology (eg, cancer, drug overdose) rather than to use of pentobarbital. Pentobarbital anesthesia is also effective in children with SE refractory to other medications, but pediatric experience is limited, and prognosis may be somewhat better than in adults. Vasopressors are commonly needed during pentobarbital anesthesia in children.

Thiopental (Pentothal)

Thiopental differs from other barbiturates because of a sulfur replacement of the oxygen on the C2 position, which confers increased lipid solubility, faster onset of action, and accelerated degradation. This agent is widely used to treat refractory SE in Europe and Australia, but is less frequently used in the United States. The elimination half-life is directly proportional to the duration of infusion. Thiopental is slowly metabolized by the CYP450 microsomal enzyme system in the liver. The CSF concentration is more variable than that of pentobarbital.

Burst-suppression pattern is observed on EEG when serum levels above 30-40 mg/L are reached, although higher levels may be necessary in patients undergoing prolonged treatment. EEG silence is usually observed with levels above 70 mg/L. Other factors that influence the effectiveness of thiopental include protein binding, pH-dependent changes of nonionized fraction of drug, and blood flow distribution.

An effective IV anesthetic dose of 2.5% thiopental induces loss of consciousness in 10-20 s; maximal brain concentration is achieved in 30 s, and consciousness regained in 20-30 minutes after single dose. Nonetheless, when a single dose is injected IV, effects last only a few min because of redistribution to less vascular tissues (eg, muscle, fat) leading to a drop in CNS concentrations.

Prolonged administration and use of doses greater than 1 g may be associated with prolonged recovery (hours to days) because of saturation of lipid stores. Monitor levels daily during thiopental infusions.

Phenobarbital (Luminal)

Phenobarbital is effective for febrile and neonatal SE. Many pediatric neurologists and pediatricians use phenobarbital (instead of phenytoin) as a second-line treatment for seizures in infants and toddlers that did not respond to benzodiazepines. No controlled studies have demonstrated superiority of either phenobarbital or phenytoin to treat seizures.

Phenobarbital's site of action may be post-postsynaptic (eg, cortex thalamic relay nuclei, pyramidal cells of cerebellum, substantia nigra) or pre-presynaptic in the spinal cord. This agent's inhibitory action relates to interaction with the GABAa receptor, increasing duration of opening bursts of chloride channel. Barbiturates increase binding of GABA to the GABAa receptor but use a binding site different from the site to which benzodiazepines attach. Phenobarbital promotes binding of benzodiazepines to the GABAa receptor.

The efficacy of phenobarbital is similar to that of diazepam plus phenytoin and lorazepam. When administered after benzodiazepines, phenobarbital creates significant risk for respiratory impairment.

At concentrations greater than 200-300 µmol, phenobarbital is capable of increasing chloride conductance in the absence of GABA. At high concentrations, it decreases voltage-activated calcium currents in hippocampal neurons. The presence of cardiovascular complications appears to be related to the rate of rise in levels rather than to absolute values.

Given IV, phenobarbital may require approximately 15 minutes to attain peak levels in the brain. If injected continuously until convulsions stop, brain concentrations may continue to rise and can exceed that required to control seizures, resulting in subsequent toxicity. Thus, it is important to use the minimal amount required and wait for anticonvulsant effect to develop before administering a second dose.

Restrict IV use to situations in which other routes are not possible, either because patient is unconscious or because prompt action is required. IV administration should be at a rate less than 50 mg/min. The parental product contains 68% propylene glycol. Ensure monitoring for hypotension, bradycardia, and arrhythmias upon administration.

If the IM route is chosen, administer into areas where there is little risk of encountering a nerve trunk or major artery (eg, gluteus maximus, vastus lateralis). A permanent neurologic deficit may result from injecting into or near peripheral nerves.

Class Summary

General anesthetics used in SE include pentobarbital, thiopental, and propofol. Pentobarbital and thiopental are discussed under Barbiturates, above. Propofol is a phenolic compound unrelated to other types of anticonvulsants. It has general anesthetic properties when administered IV.

The development of propofol infusion syndrome, an irreversible chain of events associated with significant morbidity and mortality, is a concern. Propofol infusion syndrome was first described in 1992 by Parke et al.^[35] Since then, numerous case reports and reviews have been published.^{[36, 37, 38, 39, 40]}

Administration of general anesthesia to control SE is performed in a pediatric critical care unit. All children must be intubated and paralyzed and must have continuous cardiorespiratory and EEG monitoring. Pentobarbital may be required when seizures persist despite appropriate administration of other antiseizure agents.

Propofol (Diprivan)

The use of propofol anesthesia to treat SE has been subject of many reports in the European literature in the past decade. Although not approved by the FDA for this purpose, it now gaining acceptance in the United States. The advantages of propofol include relatively low toxicity for short-term use, quick onset of action, and fast recovery upon discontinuation. Reports of severe acidosis and movement disorder after propofol use in infants have caused a significant decrease in its use within that age group.

Metabolic acidosis may be a complication related to prolonged use of propofol, explaining the rarity of this complication in short surgical anesthesia. In contrast, metabolic acidosis in children with prolonged propofol use for sedation and treatment of SE has been reported. Also worrisome is the association of propofol-related metabolic acidosis in patients receiving the ketogenic diet.

Propofol is only slightly soluble in water, but highly soluble in lipids. CNS penetration primarily depends on cerebral blood flow. Emergence from anesthesia is faster than with thiopental, even with prolonged infusions. Accumulation effect after continued use is a theoretical risk not often observed in practice. Even though respiratory depression is likely in the doses used to treat SE, hypotension tends to be only mild.