Medications Used In The Treatment Of Seizures
Several medications are available for the management of the various pediatric seizure disorders. Pediatric patients presenting to the ED actively seizing or with a history of recent seizure activity may be on one or more chronic medications to control their seizure disorder or they may be on no medication. The ED physician should be aware of the various medications that children may be taking as well as the impact that these medications may have on therapeutic decision making for these children in the ED. While ED physicians should be familiar with the various antiepileptic medications including phenytoin, phenobarbital, carbamazepine, oxcarbazepine, valproic acid, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, zonisamide, ethosuximide, vigabatrin, and benzodiazepines such as clonazepam and diazepam, this article will focus on those medications used most commonly in the ED setting. Vigabatrin is not currently FDA approved for use in the U.S. Other agents for seizure control in patients include ACTH for the management of infantile spasms. The recommended therapies for seizure pediatric seizure disorders are shown in Table 4.42
Several classes of medications are available for the acute management of seizures in the emergency department including benzodiazepines, hydantoins, barbiturates, general anesthetics, and miscellaneous anticonvulsants such as valproic acid, levetiracetam, and carbamazepine. There is a relative paucity of data regarding the use of many of these agents in children in the emergency department for the rapid termination of seizure activity. Most data comes from usage in intensive care settings or from adult experience. Medications that may be used in the emergency department setting for the acute management of seizures will be reviewed. Commonly used agents and their reported doses are shown in Table 5.
Benzodiazepines are potent anesthetic agents that demonstrate a rapid antiepileptic effect and are commonly used as initial drug therapy for the acute management of seizures. Benzodiazepines terminate seizure activity through the enhancement of gamma amino-butyric acid (GABA) transmission in the central nervous system. The potency of benzodiazepines is related to their affinity for binding on the benzodiazepine receptor site making lorazepam most potent and diazepam least potent.43,44 Common adverse effects of benzodiazepine therapy include somnolence, transient cognitive impairment, respiratory depression, and hypotension. The most commonly utilized benzodiazepines for the management of seizures include diazepam, lorazepam, and midazolam.
Diazepam is a highly lipid soluble compound, allowing rapid penetration of the blood brain barrier and resulting in a quick onset of action with seizure termination reported in a median time of 2 minutes.45 Diazepam has a short duration of antiepileptic activity, 30 minutes or less, and thus the subsequent administration of a longer acting agent is often necessary to prevent seizure recurrence.46 Diazepam is extensively metabolized by the liver through the cytochrome P450 isoenzyme system to active metabolites that are further hepatically metabolized by glucuronidation before renal elimination. Diazepam may be administered by intravenous injection or rectal instillation for seizure termination, allowing for use in the community, prehospital, and ED settings. Drug absorption via the intramuscular route is erratic with a delayed onset of antiepileptic activity and is not generally recommended.47
Intravenous access is often difficult to achieve in a seizing child; therefore, rectal diazepam represents an alternative treatment option. Rectal administration allows for drug absorption over a large surface area that is well vascularized. Dreifuss et al conducted a randomized, double blind, parallel group, placebo-controlled study comparing rectal diazepam to placebo for the home management of acute repetitive seizures in children and adults over the age of 2 years. Rectal diazepam, dosed by an age-adjusted weight based protocol (0.5 mg/kg for children 2 to 5 years, 0.3 mg/kg for children 6 to 11 years, and 0.2 mg/kg for children 12 years and older) was shown to be superior to placebo in reducing seizure frequency and improving global assessment of treatment outcome in children. Pediatric patients received an initial dose of rectal diazepam at the time of seizure followed by a second dose 4 hours later. Adverse effects were reported in 40% of patients treated with rectal diazepam compared to 22% of patients treated with placebo, with somnolence being reported most frequently, 33% versus 11% respectively. The authors did not analyze the adverse effects according to patient population.48 Diazepam rectal gel is approved by the FDA for rectal use during management of intermittent seizure episodes in patients with seizure disorders.49 Use of rectal diazepam gel can be difficult in the older pediatric patient and may be a non preferred route of drug administration for both the patient and the caregiver. Bowel incontinence during a seizure may expel the drug from the rectum, thus requiring readministration of the medication.
One prospective trial comparing lorazepam and diazepam for the treatment of acute seizures in the pediatric patient has been reported in the literature. Eighty-six patients presenting to the ED actively convulsing received either intravenous or rectal diazepam or lorazepam. The authors concluded that lorazepam was a safe and effective therapy for the management of acute pediatric seizures.50 A comparative audit conducted by Qureshi et al found intravenous lorazepam and diazepam to be equally efficacious and safe for the management of pediatric convulsive status epilepticus.52 At this time, there is no evidence indicating lorazepam to be a more effective or safer drug compared to diazepam for the management of acute pediatric seizures.53
Midazolam is a rapid acting, potent, hydrophilic benzodiazepine in its chemical form. At physiologic pH, midazolam becomes highly lipophilic resulting in quick entry into the CNS and rapid antiepileptic effect. Midazolam has a short duration of action so it may require a continuous intravenous infusion after a bolus injection.46 Midazolam may be administered via the intravenous, intramuscular, endotracheal, rectal, buccal, or intranasal routes.
Intravenous midazolam has been investigated for use in management of childhood status epilepticus and refractory status epilepticus. Hayashi et al conducted a retrospective multicenter study to evaluate the efficacy and safety of intravenous midazolam for the management of pediatric status epilepticus. Seizure control was achieved in 64.5% of the patients. A bolus injection of midazolam effectively terminated seizures in 56.6% of the patients, without further need for an intravenous midazolam infusion in 17% of these patients. Efficacy of intravenous midazolam was significantly decreased if therapy was started more than 3 hours after seizure onset. Adverse effects possibly attributed to midazolam included respiratory depression in 8.1% of cases and cardiovascular depression in 0.6% of cases; these adverse effects appeared to be dosing related.54 Intravenous midazolam has been shown to be an effective therapy for management of refractory status epilepticus, with doses ranging from 0.15 to 0.2 mg/kg followed by mean infusion rates varying from 2.1 to 14 mcg/kg/min at the time of seizure suppression.55-59 An audit of 17 consecutive pediatric patients evaluated the efficacy of high dose midazolam therapy for the management of refractory status epilepticus in children. The midazolam protocol utilized in this study required an initial bolus of 0.5 mg/kg with an infusion rate to commence at 2 mcg/kg/min with the option for subsequent boluses and aggressive titration of the continuous infusion. Thirteen patients (76%) had seizure control within 30 minutes of midazolam therapy initiation. A total of 88% of patients eventually achieved seizure control. The midazolam infusion ranged from 2 to 32 mcg/kg/min with a median peak infusion rate of 4 mcg/kg/min. Two patients experienced transient hypotension during co-administration of phenytoin.60
Due to the water-soluble properties of midazolam, intramuscular administration is an alternative to intravenous administration. In a prospective trial, Shah and Deshmukh compared the efficacy of intramuscular midazolam 0.2 mg/kg to intravenous diazepam 0.2 mg/kg in pediatric patients with and without intravenous access upon ED arrival. In patients who did not have intravenous access upon ED presentation, seizure control was obtained significantly faster in the patients receiving intramuscular midazolam compared to patients who required the establishment of intravenous access prior to receiving intravenous diazepam (97.22 seconds versus 250.35 seconds, respectively, p < 0.005). Time to seizure control in patients receiving diazepam who had IV access upon ED arrival was 119.44 seconds compared to 97.22 seconds for patients receiving intramuscular midazolam. Thrombophlebitis occurred in 10.8% of patients receiving IV diazepam, but no cardiovascular or respiratory depression was observed with either study medication.61 Therefore, intramuscular midazolam may represent an alternative and effective route of drug administration to control pediatric seizures.
The buccal route of administration provides an alternative to intravenous and rectal drug administration. The mouth has a large, highly vascularized surface area allowing for rapid drug absorption. Buccal administration avoids first-pass metabolism in the liver, allowing for rapid CNS drug delivery and therapeutic effect.62,63 Buccal administration offers ease of administration and an administration route that may be more acceptable to patients and caregivers. A prospective study of 19 pediatric patients ranging in age from 1 month to 15 years presenting to an ED with convulsions demonstrated that a buccal midazolam dose of 0.3 mg/kg safely and effectively terminated seizures within 10 minutes of drug administration in 84.2% of patients. The patients who failed to respond to drug therapy were noted to be in status epilepticus. No respiratory or cardiovascular depression was reported in this study.64 Buccal midazolam has been shown to be as efficacious as rectal diazepam for management of acute pediatric seizures in multiple studies.65,66 One study reported buccal midazolam to be more effective than rectal diazepam for ED management of pediatric seizures. Buccal midazolam at a dose of 0.5 mg/kg terminated seizures in a median of 8 minutes compared to rectal diazepam at a dose of 0.5 mg/kg with a median of 15 minutes. Seizures recurred within 1 hour of drug therapy less often in the patients who received buccal midazolam compared to rectal diazepam. Respiratory depression was reported in 5% and 6% of patients receiving buccal midazolam and rectal diazepam, respectively.67
Intranasal administration is another alternative route of drug administration in the management of pediatric seizures. The nasal mucosa provides a large, highly vascularized surface area allowing for rapid drug absorption into the CNS. Small volumes of the drug are required to thinly line the nasal mucosal for optimal drug absorption, requiring concentrated dosages. Absorption is further enhanced if the drug is aerosolized.68 The impact of upper respiratory tract infections on efficacy of intranasal midazolam therapy is unknown. Increased blood flow to the nasal mucosa may lead to increased drug absorption, or the presence of nasal secretions may serve to decrease drug absorption by diluting the drug and decreasing drug contact with the nasal mucosa.69 Intranasal midazolam at a dose of 0.2 mg/kg was found to be as efficacious and safe as intravenous diazepam. Time from seizure onset to drug administration was faster in the patients receiving intranasal midazolam; however, the time to seizure control from drug administration was faster in the intravenous diazepam group. The authors did not factor in the impact of time required to obtain intravenous access into their results.70 Another study by Lahat et al confirmed intranasal midazolam 0.2 mg/kg to be safe and efficacious compared to intravenous diazepam for the management of febrile pediatric seizures. Again, the authors noted that intravenous diazepam had a more rapid onset of therapeutic effect but that administration of intranasal midazolam resulted in a quicker termination of seizures from time of ED presentation without an increase in adverse effects.69 Multiple studies have found intranasal midazolam to be more efficacious then rectal diazepam, with a faster time to drug administration and seizure termination.71,72 Thus there may be a role for intranasal midazolam in the community and prehospital setting. Holsti et al found that administration of intranasal midazolam via a Mucosal Atomization Device (MAD) in the prehospital setting reduced the likelihood of seizure occurrence in the ED compared to rectal diazepam. Of note, total seizure time was longer in patients receiving diazepam and fewer patients received treatment with diazepam during the study.73
Further studies are warranted to investigate the safety and efficacy of the various routes of benzodiazepine administration as well as the use of a continuous midazolam infusion in pediatric patients.
Hydantoins, including phenytoin and fosphenytoin, have been used in the management of pediatric seizures for many years due to their prolonged antiepileptic effect and broad spectrum of activity. Hydantoins stabilize neuronal membranes by prolonging voltage dependent sodium channel refractory periods thereby inhibiting repetitive neuronal firing. Phenytoin enters the CNS rapidly with peak drug levels observed within 10 minutes of completion of an intravenous infusion.74 Phenytoin is highly protein bound, follows saturable, nonlinear kinetics, and undergoes extensive hepatic metabolism via the cytochrome P450 isoenzyme system resulting in many drug interactions.75 Phenytoin doses of 15 to 20 mg/kg have shown to be effective in pediatric patients.76 Interpretation of serum phenytoin concentrations are challenging in the critically ill child due to variability in phenytoin protein binding. Free phenytoin concentrations provide more accurate measures of phenytoin levels in these patients.77 Several characteristics of phenytoin are undesirable. Intravenous phenytoin contains a propylene glycol diluent to enhance water solubility, with a resultant pH of 12, making the drug toxic to the vasculature. The propylene glycol diluent is associated with infusion-rate-related adverse events including hypotension and cardiac arrhythmias. Infusion related adverse events are minimized by slowing the rate of infusion. Maximum infusion rates are 3 mg/kg/min, not to exceed 50 mg/min, in children.45,78 In clinical practice, slower infusion rates of 25 to 45 mg/min are often utilized in adults to enhance tolerance and minimize adverse effects.78
Fosphenytoin is the water soluble phosphate ester prodrug of phenytoin that undergoes rapid enzymatic conversion to phenytoin. Fosphenytoin is supplied at a more neutral pH without a propylene glycol diluent, resulting in fewer dermal and cardiovascular adverse effects. Fosphenytoin may be administered intravenously or via the intramuscular route.79,80 The fosphenytoin dose is expressed in phenytoin equivalents (PE) and is 15 to 20 mg PE/kg administered at a rate not to exceed 3 mg/kg/min, or a maximum of 150 mg/min.81 A review of 2 multicenter studies involving children with ages ranging from 1 day to 16 years found intravenous and intramuscular use of fosphenytoin to be safe and effective. Emesis was the most commonly reported adverse effect, and injection site reactions were reported in 6% of patients.82 Conversely, Takeoka et al reported difficulty in maintaining therapeutic drug concentration in 4 patients ranging in age from < 1 day to 1 year. All patients received treatment with phenobarbital during their care. Two of the 4 patients had further seizure activity in the presence of subtherapeutic phenytoin levels.83 Free phenytoin concentrations were not obtained in this study, making interpretation of reported phenytoin levels difficult in these critically ill children.77
Barbiturates, including phenobarbital and pentobarbital, have been used in the management of pediatric seizures for several decades. Barbiturates exert antiepileptic effects by enhancing GABA effects.74,84 Phenobarbital is a long-acting barbiturate with a half-life of up to 5 days in adults and 1.5 days in children.85 Phenobarbital is 40% to 60% protein bound and is hepatically metabolized via the cytochrome P450 isoenzyme system, and thus is subject to many drug interactions, including many antiepileptic drugs.75,84 Phenobarbital may be administered at a dose of 20 mg/kg and infused at a rate of 1 mg/kg/min, not to exceed a rate of 30 mg/min to obtain therapeutic serum concentrations ranging from 15 to 40 mcg/mL. Subsequent doses of 5 to 20 mg/kg may be administered if seizure control is not obtained.46,85 Phenobarbital is associated with several side effects including sedation and respiratory depression, and its use may require intubation for respiratory support. One group of researchers found incremental phenobarbital doses of 10 mg/kg every 30 minutes to effectively obtain high phenobarbital serum concentrations to control refractory status epilepticus and avoid the need for intubation.86 A case series of 3 patients received very high doses of phenobarbital for management of refractory status epilepticus, ranging from 70 to 80 mg/kg/day with serum concentrations ranging from 154 to levels exceeding 232 mcg/mL. All patients were receiving multiple antiepileptic medications and all patients experienced hypotension requiring vasopressor therapy.87 Painter et al conducted a randomized single blind study to compare the efficacy of phenobarbital and phenytoin in the treatment of neonatal seizures. Fifty-nine neonates received intravenous doses of phenobarbital or phenytoin to achieve free drug concentrations of 25 mcg/ml and 3 mcg/ml respectively. Therapy failed in 57% of neonates receiving phenobarbital and 52% of neonates receiving phenytoin. No respiratory or cardiovascular depression was reported. The study authors concluded that phenobarbital and phenytoin were equally and incompletely effective in controlling neonatal seizures. Due to the negative side effects associated with phenobarbital, use of phenobarbital for pediatric seizure control seems to have declined in favor of using newer agents.84
Pentobarbital is a potent barbiturate with a rapid onset of antiepileptic effect that is administered as a continuous infusion for the effective management of refractory status epilepticus. Pentobarbital is commonly administered at a loading dose of 5 to 15 mg/kg followed by a continuous infusion ranging from 0.5 to 5 mg/kg/h for 12 to 24 hours to maintain a burst suppression pattern on EEG, although no consensus exists on the most appropriate duration of infusion.46,88 Despite a reported half-life of 15 to 50 hours, gradual tapering of the infusion is performed to prevent seizure recurrence. Pentobarbital infusions are associated with multiple adverse effects including respiratory depression requiring mechanical ventilation, hypotension, cardiovascular toxicity, infection, and delayed recovery.55,88-92 In a review comparing the use of midazolam and pentobarbital for refractory status epilepticus, both drugs were found to effectively terminate seizure activity; however, midazolam therapy was associated with fewer adverse effects.89 Further investigation of pentobarbital infusion for the management of refractory status epilepticus in pediatric patients is warranted.
Valproic acid is a broad spectrum antiepileptic used for a variety of seizure disorders in children. Valproic acid is available in various oral dosing forms. In 1996, the FDA approved an intravenous formulation of the drug for use in children over the age of 10 years when oral medications cannot be administered for seizure management. Valproic acid is highly protein bound and is extensively metabolized by the liver via the cytochrome P450 isoenzyme system, leading to several drug interactions. Valproic acid has a narrow therapeutic index with desired serum concentrations ranging from 50 to 100 mg/L.93,94 Intravenous use of valproic acid for management of status epilepticus is off-label. In a clinical series of 18 patients reported by Morton et al, intravenous valproic acid was found to be safe at doses ranging from 7.5 to 41.5 mg/kg, with infusion rates ranging from 1.5 to 11 mg/kg/minute. One patient experienced burning at the injection site during infusion of 660 mg at a rate of 6 mg/kg/minute. He subsequently received 3 more doses, ranging from 165 to 330 mg at 6 mg/kg/min without consequence.95 In another study, intravenous valproic acid was administered to 41 children ranging in age from 0 to 16 years of age at a dose of 20 to 40 mg/kg over 1 to 5 minutes followed by a continuous infusion of 5 mg/kg/h. A second bolus dose of 20 to 40 mg/kg was repeated if no response was seen after 10 to 15 minutes. Overall success rate was 78%, with 65.9% of children responding within 2 to 6 minutes after the initial dose. The highest success rate was seen with doses ranging from 30 to 40 mg/kg. No adverse effects were attributed to valproic acid.96 Intravenous valproic acid has been found to be safe and effective in the management of pediatric status epilepticus and acute repetitive seizures in patients with presumed subtherapeutic valproic acid levels upon ED presentation and valproic acid na´ve patients. Doses of 10 mg/kg were administered to children with suspected subtherapeutic drug levels while valproic acid na´ve patients received 25 mg/kg. In patients with status epilepticus, seizure control was achieved within 20 minutes of completing the valproic acid infusion and mental status was noted to be at baseline within 1 hour of seizure cessation. One patient with acute repetitive seizures failed to respond to valproic acid within 20 minutes of infusion completion and ultimately required phenytoin to control her seizures. No cardiorespiratory depression was seen, and only 1 patient complained of a transient tremor after the infusion.97 Thus, intravenous valproic acid may be an appropriate ED treatment for seizing patients with subtherapeutic valproic acid levels. Intravenous valproic acid followed by oral valproic acid ED administration was well tolerated in 42 adult and pediatric patients in an epilepsy monitoring unit prior to discharge. Four patients complained of nausea and 2 patients receiving additional antiepileptic therapy complained of dizziness during the observation period. All patients were reported to have improved seizure frequencies 1 week after discharge, although 5 patients had seizures within that time frame.98 Results from this study may prove valuable in the ED setting as patients may receive prolonged protection from recurrent seizures with administration of an extended release valproate product prior to ED discharge. A continuous infusion of valproic acid following a rapid intravenous infusion loading dose was shown to be effective in 65% of pediatric patients with seizures. Patients received a loading dose of valproic acid ranging from 20 to 40 mg/kg over 1 hour followed by a continuous infusion at 1 to 1.5 mg/kg/h.99 This may represent a therapeutic option for the hospitalized patient who is unable to tolerate oral medication after seizure control has been achieved. Intravenous valproic acid is not without adverse effects. Reported adverse effects include postural tremor, encephalopathy, hyperammonemia, alopecia, nausea and vomiting, weight gain, hepatotoxicity, pancreatitis, and thrombocytopenia. Hepatotoxicity occurs with much more frequency in children under the age of 2.94 A fatal case of pancreatitis associated with valproic acid therapy was reported in a 4-year-old child.100 Severe hypotension was reported in an 11-year-old girl receiving 30 mg/kg of valproic acid 39 minutes into her 1 hour infusion. She ultimately required the initiation of vasopressor therapy for 14 hours and phenytoin for seizure control.101 Several factors may have contributed to this patient's hypotension including infection, supratherapeutic levels of valproic acid during the infusion, and previous treatment with benzodiazepines. Therefore, close monitoring of pediatric patients receiving valproic acid therapy for chronic conditions is recommended.
Intravenous valproic acid therapy has been compared to other therapies for the management of status epilepticus. Intravenous valproic acid 20 mg/kg was compared to intravenous phenytoin 20 mg/kg for the management of status epilepticus refractory to diazepam therapy in patients greater than 2 years of age in a randomized trial. Intravenous valproic acid was found to be as effective as intravenous phenytoin in the management of status epilepticus in these patients. There was a significant difference in the efficacy of valproic acid based on duration of status epilepticus. One hundred percent of patients responded to valproic acid if status epilepticus had been occurring for less than 2 hours compared to 70% of patients if status epilepticus had occurred for more than 2 hours. Mild elevations in liver enzymes were reported in 8% of patients receiving intravenous valproic acid while no patients experienced hypotension. Twelve percent of patients receiving intravenous phenytoin developed hypotension and 4% developed respiratory depression. This study identified the possible role of intravenous valproic acid early in the management of status epilepticus.102 In an open label, randomized, controlled trial involving 40 children, intravenous valproic acid was compared to a diazepam infusion in the management of pediatric refractory status epilepticus. The trial included children ranging in age from 5 months to 12 years. Patients had failed previous therapy consisting of diazepam injection and 2 doses of phenytoin. Patients were randomized to receive treatment with 30 mg/kg of intravenous valproic acid followed by a continuous infusion at 5 mg/kg/h or diazepam initiated at a rate of 10 mcg/kg/min and titrated every 5 minutes to achieve seizure control. Intravenous valproate was found to be equally effective when compared to diazepam infusions, as seizure control was achieved in 80% and 85% of patients, respectively. Intravenous valproic acid achieved seizure control significantly faster than diazepam, with a mean of 8 minutes compared to 26 minutes, respectively. Significantly fewer patients receiving valproic acid required admission to the pediatric intensive care unit, and no patients receiving valproic acid required mechanical ventilation, while 60% of patients receiving diazepam did. No child in the valproic acid group developed hypotension, while this occurred in 50% of the diazepam group.103 Based on these findings, valproic acid may be an alternative therapy to diazepam infusions for the management of refractory status epilepticus in children. Further studies should be conducted to evaluate the role of intravenous valproic acid in the management of status epilepticus, including refractory status epilepticus. The need for a continuous infusion of valproic acid after a bolus dose should also be evaluated.
Levetiracetam is a new antiepileptic medication indicated as an adjunct therapy for various seizures disorders. Levetiracetam may be used in children as young as 4 years of age for some indications. Recently an intravenous formulation of levatiracetam was approved for use in patients older than 16 years.104 Unlike other antiepileptic drugs discussed in this article, levetiracetam undergoes minimal hepatic metabolism, with 66% of the drug eliminated in the urine unchanged; therefore, levetiracetam is not known to interact with other antiepileptic medications. Chronic levetiracetam therapy appears to be well tolerated in children, including those under the age of 4, although behavior disturbances including aggression, hyperactivity, anxiety, and obsessive behavior have been reported.105,106 There is a paucity of data regarding the use of intravenous levetiracetam in children. A retrospective review of 10 children ranging in age from 3 weeks to 19 years reported the use of intravenous levetiracetam for multiple seizure types with daily doses ranging from 20 mg/kg to 115 mg/kg for 1 to 16 days. Intravenous levetiracetam effectively terminated seizures in 2 patients with acute repetitive seizures. In 2 patients with status epilepticus unresponsive to phenytoin and phenobarbital, intravenous levetiracetam effectively terminated the seizure in 1 patient while there was a partial decrease in seizure frequency in the other patient. No adverse effects were reported.107 A case report of a 10-year-old liver transplant patient responding to treatment with oral levetiracetam for the management of nonconvulsive status epilepticus despite therapeutic phenytoin levels was also reported. The patient received oral levetiracetam 20 mg/kg/day in 2 divided doses due to elevated liver function tests. The patient regained consciousness 1 day after levetiracetam therapy and an EEG 48 hours after initiating levetiracetam therapy demonstrated seizure resolution.108 Further studies regarding the use of levetiracetam in children, including the use of the intravenous injection, are warranted. At this time, routine use of intravenous levetiracetam in children cannot be endorsed.
Propofol is a potent intravenous hypnotic and anesthetic agent used in the induction and maintenance of anesthesia. Propofol has also been shown to have antiepileptic effects. Propofol is highly lipid soluble with a rapid onset of action and short duration of therapy, making it an attractive option for refractory seizure management. Common adverse effects of propofol include hypotension, bradycardia, and apnea which are infusion-rate related.46 Very little literature exists on the use of propofol infusions for pediatric seizure management. A case report documented the successful use of a propofol infusion in the management of prolonged, refractory seizures in a 9-month-old child. The patient received a bolus injection of propofol at a dose of 3 mg/kg followed by a continuous infusion titrated to a rate of 100 mcg/kg/min. The patient required mechanical intubation, vasopressor support, and intensive hemodynamic monitoring.109 A retrospective review was conducted involving 33 patients treated for refractory convulsive status epilepticus. Propofol was administered during 22 seizure episodes. Seizure control was achieved in 64% of the episodes with a mean duration of therapy of 57 hours. Two patients successfully treated with propofol subsequently died secondary to complications associated with bacterial meningitis. Cessation of propofol was required in 4 cases due to adverse effects. One patient developed rhabdomyolysis and 3 patients developed hypertriglyceridemia, all of which resolved upon discontinuation of propofol therapy.110 In a systematic review, researchers compared the efficacy of midazolam, propofol, and pentobarbital in the control of refractory status epilepticus in adults. Pentobarbital was found to be more effective, although its use was associated with a more frequent occurrence of hypotension than the other 2 therapies.111 The main concern with using propofol in pediatric patients is the risk of developing the propofol infusion syndrome. The propofol infusion syndrome occurs at an unknown rate in both children and adults. Clinically it manifests as metabolic acidosis, rhabdomyolysis, renal failure, arrhythmias, heart failure, hepatomegaly, hyperkalemia, and hypertriglyceridemia.112-114 Children seem to be at increased risk of developing the syndrome due to depleted glycogen stores and dependence on fat metabolism.115 Clinical symptoms include muscle weakness, myoglobinuria, and renal failure and death has been reported in both children and adults.116,117 In order to prevent the possible development of propofol infusion syndrome, the use of propofol for more than 48 hours at doses of 4 to 5 mg/kg/h should be avoided.112 The exact role of propofol in the management of pediatric seizures remains to be established. Further studies are warranted and physicians should weigh the benefit of treatment versus the risk.