Seizures and status epilepticus (SE) are among the most common neurologic emergencies in children and adolescents. SE occurs in approximately 60,000 people of different ages annually.1 It is critical that pediatricians, paramedics responding to "911" calls, and emergency department (ED) personnel be well versed in the treatment protocols for managing seizures. SE can be a life-threatening event and has a mortality rate of 8% to 32%.2 More recently, parents are being instructed, by their pediatricians, on the initial treatment for their child's acute seizure so this can begin outside the hospital prior to the arrival of paramedics or transport to the ED. This article reviews these initial treatment options for acute seizures and SE by the family or caregiver and in the pediatrician's office, as well as the management of acute seizures or SE once the patient arrives in the ED.
No matter the clinical setting, prompt control of the acute seizure or SE should be the primary goal of treatment. The pharmacologic treatment options are similar for acute seizures and SE, with the primary objective being to give adequate initial treatment to terminate the seizure and prevent seizure recurrence or progression to SE. Attention should be given to maintaining adequate oxygenation and cardiorespiratory function. If subtherapeutic doses of medication are administered, the seizure or seizures may not stop and instead may progress to SE. Drug selection should be based on ease of administration, onset and duration of action, and therapeutic safety margin.
MANAGEMENT OF ACUTE SEIZURES OUTSIDE THE HOSPITAL
It is a common clinical scenario for the pediatrician's office to receive an urgent phone call from a parent or caregiver when a child with epilepsy is having a prolonged seizure or an acute seizure cluster. It is also not uncommon for children with intractable generalized or mixed seizure disorders to have abrupt changes in their seizure pattern with fever, illness, or adverse drug reaction. This presents as a significant increase in their seizure frequency or as an alteration in mental status because they are in nonconvulsive SE.
Prompt intervention at home often prevents the seizures from progressing to major motor seizures or SE, and can significantly reduce the number of ED visits and hospitalizations. Before the use of benzodiazepines in the home is recommended, parents should receive instruction in basic CPR and seizure first aid. It is also essential that parents understand their child's seizure type and the specific parameters in which to implement acute treatment. Benzodiazepines are the first line of drug therapy in the home, and they can be administered orally and rectally. The most commonly used benzodiazepines are diazepam, lorazepam, and clonazepam.
Pharmacologic Treatment Options for Acute Seizures In Children
Diazepam is one of the shorter-acting benzodiazepines. It has a rapid onset of action and can be adrninistered either orally or rectally outside the hospital setting. Seizures usually stop 3 to 5 minutes after the drug is administered. The duration of maximum anticonvulsant action is 20 to 30 minutes, but effects can last up to 4 hours. Orally, diazepam should be given at a dose of 0.1 mg /kg at the end of a seizure to prevent further seizure activity. It may also be given between the cheek and the gum during a seizure, where it will quickly dissolve (Table).
Another safe route for diazepam adininistration is rectally, using either the intravenous diazepam formulation or the rectal gel. The intravenous diazepam formulation is less expensive, but has to be drawn up prior to rectal administration. The rectal gel is available in prefixed doses of 2.5, 5, 10, 15, and 20 mg.
The recommended dosing is based on age and weight. Children between 2 and 5 years old should receive 0.5 mg /kg, those 6 to 11 years old should receive 0.3 mg/ kg, and those 12 and older should receive 0.2 mg /kg. This pediatrician recommends using oral administration for seizure prevention or prophylaxis (eg, seizure cluster or when the child is susceptible to flurries of seizures with fever or illness). Rectal diazepam should be used for the acute management of ongoing seizures.2,3
Lorazepam, which can be given orally, is another option for acute seizures. It has a slower onset than diazepam, but a much longer duration of action (12 to 24 hours).4 The oral dose is 0.1 mg /kg and can be repeated up to a maximum dose of 4 mg if needed for seizure control. Rectal administration is not advised because of lorazepam' s slow and variable absorption. The peak plasma concentration may not be achieved for 30 to 120 minutes after administration. The side effects are similar to those of other benzodiazepines. It is also important to note that if a patient is receiving chronic benzodiazepine therapy (such as clonazepam and clorazepate), he or she is more likely to have tachyphylaxis after repeated dosing.43
Clonazepam is a longer-acting benzodiazepine with a plasma half -life of 20 to 43 hours.6 Its use is typically reserved for adjunctive therapy in patients with intractable epilepsy or for treatment of acute seizure flurries. Dosing recommendations are that children weighing less than 30 kg should receive 0.01 to 0.03 mg/kg/d with increments of 0.025 to 0.05 mg/kg/d, up to a maximum of 0.1 to 0.2 mg/kg/d. Peak levels are usually reached within 1 hour of administration. One of the main drawbacks of clonazepam is the development of tolerance. However, this can occur with all benzodiazepines.7'8 It is also important to be aware of its potential side effects, which include drowsiness, ataxia, behavioral and personality changes, and irritability; young children can have hypersalivation with daily use.
Whatever the treatment recommendation for a child at risk for acute seizures or SE, it is important that the parents or caregiver be familiar with the treatment protocol. This includes (1) when to begin treatment, (2) the appropriate dose of medication, (3) how to closely monitor the seizure activity and duration, and (4) a plan of action if the seizure does not stop after 10 minutes.
MANAGEMENT OF ACUTE SEIZURES IN THE PEDIATRICIAN'S OFFICE
The management of acute seizures or SE in the pediatrician's office should begin with the initial recognition of the seizure and stabilization of the child. Brief initial assessment of cardiorespiratory status should be done while obtaining a brief history on the type, duration, and clinical setting of the seizure. If the seizure has lasted longer than 10 minutes, implementation of treatment should begin while the emergency medical technicians are called for transport to the ED.
The initial treatment depends on what is available in the pediatrician's orifice. It is beneficial for every clinic or office to have appropriate medications available to manage acute seizures. This would include oral diazepam or lorazepam, intravenous diazepam for rectal use or the rectal gel formulation, or fosphenytoin sodium for intramuscular administration. Oral diazepam, lorazepam, clonazepam, or rectal diazepam can be easily administered in the office setting. The doses are the same as those recommended to parents or caregivers for use outside the hospital setting. An additional option is intramuscular fosphenytoin sodium. Fosphenytoin sodium is the prodrug of phenytoin and is rapidly converted to phenytoin after intravenous or intramuscular administration. Intramuscular fosphenytoin sodium is well tolerated and can be given safely to children. Doses of 10 to 20 mg phenytoin equivalent (PE) /kg can be given intramuscularly as a loading dose in 1 to 3 different sites if needed. A plasma phenytoin concentration of 10 ^g/ ml can be reached within approximately 20 minutes, as reported in clinical studies.9
Prehospital administration of first-line anticonvulsants has been shown to reduce the risk of seizure recurrence and to shorten the duration of seizure activity once the patient is transported to the ED.10 Early cessation of seizure activity reduces the risk of injury, as well as recurrent seizures.
MANAGEMENT OF SEIZURES IN THE ED
It has been reported that up to 10% of all ambulance calls for children and 1.5% of all pediatric ED visits are for seizure activity.1112 Most ED visits related to seizures are for febrile seizures (53%), followed by children with epilepsy (31%), new-onset seizures (10%), and SE.13 SE is defined as recurrent seizures without full recovery of consciousness or 20 to 30 minutes of continuous seizure activity. It is often difficult to determine the duration of the seizure when the patient arrives in the ED. It is reasonable to assume that patients who arrive in the ED actively having a convulsion are in SE. Those children whose seizures stop during transport and then resume after arrival in the ED are also in SE.5
The first priority in treatment of acute seizures and SE is stabilization of cardiorespiratory function and a brief assessment of the patient's clinical condition. During this time, blood pressure, temperature, pulse, respiration, and electrocardiogram should be assessed and an oral airway should be inserted and supplemental oxygen administered if needed. An intravenous access and blood for glucose, electrolytes, calcium, complete blood count, and anticonvulsant determinations should quickly be obtained. The routine laboratory measurements are often of little value in children with known seizure disorders. Toxicology screening should be obtained in children with unexplained seizures. If intravenous access is not easily established and the seizure has not stopped, rectal administration of diazepam would be the initial treatment. Once intravenous access is established, an intravenous bolus of 50% glucose (2 ml /kg per bolus) should be administered.
The standard treatment for acute seizures and SE in the ED includes benzodiazepines, phenobarbital, phenytoin, and fosphenytoin sodium. Lorazepam has gained favor over other benzodiazepines in the initial treatment of SE because it is not as rapidly redistributed into the fat stores as is diazepam and has a longer duration of action (12 to 24 hours). It also causes less respiratory depression than diazepam.14 The initial dose is 0.1 mg/kg at a rate of 1 to 2 mg/min, with a maximum first dose of 4 mg. A second dose can be given if needed in 5 to 10 minutes. The initial use of lorazepam often stops the seizures and allows time for an evaluation to determine their etiology. If diazepam is used, the initial dose should be 0.1 to 0.5 mg/kg, up to a maximum of 10 mg. The initial dose can be repeated in 5 to 10 minutes. The dose of rectal diazepam is 0.2 to 0.5 mg/kg and can be repeated once. Patients must be closely monitored for respiratory depression, sedation, and hypotension, especially when diazepam is to be followed by phenobarbital.
If the seizure activity has not stopped after the administration of a benzodiazepine, then either phenobarbital, phenytoin, or fosphenytoin sodium should be infused. Phenobarbital should be given in a loading dose of 10 to 20 mg/kg at a rate of 30 to 100 mg/min or 1 to 2 mg/kg/min, with an additional bolus of 10 mg/kg as needed. It has a long duration of action, and maintenance doses can be started the next day at 5 mg/kg/d. However, after intravenous administration, prolonged sedation can occur and may complicate an accurate assessment of the patient's neurologic status. There is also the risk of respiratory depression, hypotension, and bradycardia when phenobarbital is given intravenously after benzodiazepines.4,5
Phenytoin is also an alternative as a first-line agent in the treatment of acute seizures and SE. It allows better monitoring of the patient because it produces less depression than phenobarbital. Phenytoin should be given intravenously only in a 15- to 20-mg/kg bolus at a rate of 25 to 50 mg/min or 0.5 to 1.0 mg/kg/min. Intramuscular phenytoin is poorly absorbed because it has an alkaline pH of 13, and it causes local irritation and muscle necrosis. Intravenous phenytoin can also cause injury if it extra vasates into the tissues. This is because of phenytoin's solvent, propylene glycol. Propylene glycol can also cause cardiac arrythmias, respiratory depression, wide QT intervals, hepatic and renal damage, and hemolysis.
In August 1996, fosphenytoin sodium was approved for use in the United States. It is the prodrug of phenytoin and has a pH of 8, which makes it far more soluble in water than phenytoin. It is compatible with all intravenous solutions and can be given safely intramuscularly. This allows rapid administration without causing infusion site reactions. The pharmacokinetics, safety, and tolerability of fosphenytoin sodium have been studied in children, and it is well tolerated following both intravenous and intramuscular administration. The conversion half-life of intravenous fosphenytoin sodium in children is 8.5 minutes.9 The only significant side effects are mild bruising, tenderness, swelling, and erythema at the infusion or injection site. It can easily be given following a benzodiazepine as part of the initial treatment for acute seizures or SE. The loading dose is 15 to 20 mg PE /kg at a rate of 3 mg /kg /min, up to a maximum of 150 mg PE /min. The intramuscular dose is similar at 10 to 20 mg PE /kg as a single dose given in 1 to 3 sites. The maintenance dose can also be started after the loading dose at 4 to 7 mg PE / kg /d in a twice or three times a day schedule. EHiring intravenous and intramuscular administration, electrocardiogram and blood pressure monitoring is recommended.
The child who continues to have refractory SE after the administration of adequate doses of benzodiazepines and loading doses of phenytoin or fosphenytoin sodium and phenobarbital will require admission to the intensive care unit and endotracheal intubation and ventilation. Treatment of refractory SE includes the use of midazolam or pentobarbital. The use of these agents requires close intensive care along with electroencephalogram monitoring at the bedside.
Valproate sodium injection is another treatment option for breakthrough seizures for the child who is already taking oral valproic acid. This is an alternative when a child cannot take oral valproic acid and is a means to administer a bolus to increase the therapeutic levels of the drug. This is useful in the ED as well as during acute hospitalizations. Intravenous valproate sodium is available in 5-ml vials (100 mg /ml), which should be diluted in 50 ml of 5% D5W, normal saline, or Ringer's lactated solution. The adult infusion rate is 100 to 200 mg /min and the mean plasma half-life is 16 hours (± 3 hours). Intravenous valproate sodium is well tolerated. The most commonly reported side effects are dizziness, nausea, and occasionally pain at the infusion site. A slower infusion rate (eg, 20 mg/ min) is associated with substantially fewer side effects.1617 Intravenous valproate sodium has not been fully tested as a first-line drug in the treatment of SE in children.
There are a growing number of treatment options for children with acute seizures and SE. With continued new drug development and reformulation of existing antiepileptic drugs, better treatment protocols will be available. The primary goal continues to be minimizing the morbidity and mortality associated with acute seizures and SE. This is accomplished only if the pediatrician's aim is early seizure recognition and treatment with close monitoring for potential complications.
1. Pellock JM. Acute seizures in children: an overview. J Child Neurol. 1998;13(suppl 1):S1-S2.
2. Bebin EM. Additional modalities for treating acute seizures in children: overview. J Child Neurol. 1998;13(suppl 1):S23~S26.
3. Dreifuss FE, Roseman NP, Goyd JC, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med. 1998;338:1869-1875.
4. Roberts M, Eng-Bourquin J. Status epilepticus in children. Pediatr Emerg Care. 1995;13:489-507.
5. Mitchell W. Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment. Epilepsia. 1996; 37(suppl 1):S74-S80.
6. Dreifuss FE, Penry JK, Rose SW, et al. Serum clonazepam concentrations in children with absence seizures. Neurology. 1975;25:255-258.
7. Greenblat DJ, Miller LG, Shader RJ. Clonazepam pharmacokinetics, brain uptake, and receptor interaction. J Clin Psychiatry. 1987;48:4-11.
8. Sato S. Benzodiazepines: clonazepam. In: Levy R, Mattson R, Meldrum B, et al., eds. Antiepileptic Drugs, 3rd ed. New York: Raven Press; 1989:765-784.
9. Morton LD. Clinical experience with fosphenytoin in children. J Child Neurol. 1998;13(suppl 1):S19-S22.
10. Terndrup TE. amicai issues in acute childhood seizure management in the emergency department. J Child Neurol. 1998;13(suppl 1):S7-S10.
11. Suominen P, Silfvast T, Korpela R, Erosuo J. Pediatric prehospital care provided by a physician-staffed emergency medicai helicopter unit in Finland. Pediatr Emerg Care. 1996;12:169-172.
12. Johnston C, King WD. Pediatric prehospital care in a Southern regional emergency medical center service system. South Med J. 1988;81:1473-1476.
13. Smith RA, Martland T, Lowry MF. Children with seizures presenting to accident and emergency. J Acad Emerg Med. 1996;13:4058.
14. Chiulli D, Terndrup TE, Kanter RK. The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus. J Emerg Med. 1991;9:13-17.
15. Wheless JW. Pediatric use of intravenous and intramuscular phenytoin: lessons learned. J Child Neurol. 1998;13(suppl 1):S11-S14.
16. Devinsky O, Leppik I, Wilmore JL, et al. Safety of intravenous valproate. Ann Neurol. 1995;38:670-674.
17. Nitsche V, Mascher H. The pharmacokinetics of valproic acid after oral and parenteral administration in healthy volunteers. Epilepsia. 1982;23:153-162.
Pharmacologic Treatment Options for Acute Seizures In Children