Doi:10.1016/j.pediatrneurol.2008.01.00

Review Article
Treatment of Refractory Status Epilepticus:
Literature Review and a Proposed Protocol
Nicholas S. Abend, MD*† and Dennis J. Dlugos, MD, MSCE*†
Refractory status epilepticus describes continuing sei-
conditions. The prognosis is dependent on management of zures despite adequate initial pharmacologic treatment.
the underlying condition and on treatment of seizures.
This situation is common in children, but few data are
Status epilepticus was initially defined as “an enduring available to guide management. We review the literature
epileptic condition,” without specifying exact durations.
related to the pharmacologic treatment and overall man-
Since then, the definition has undergone multiple revisions agement of refractory status epilepticus, including mida-
to include and then modify the required duration, shorten- zolam, pentobarbital, phenobarbital, propofol, inhaled
ing the required seizure duration from 30 minutes to 5 anesthetics, ketamine, valproic acid, topiramate, leveti-
minutes This shortening of time was based largely on racetam, pyridoxine, corticosteroids, the ketogenic diet,
data demonstrating that seizures that do not cease in 5-10 and electroconvulsive therapy. Based on the available
minutes are less likely to terminate without intervention data, we present a sample treatment algorithm that
To describe this time period better, it may be divided emphasizes the need for rapid therapeutic intervention,
into the impending or early stage of status epilepticus employs consecutive medications with different mecha-
(5-30 minutes), and the established stage of status epilep- nisms of action, and attempts to minimize the risk of
ticus (30-60 minutes). Impending status epilepticus was hypotension. The initial steps suggest using benzodiaz-
defined as “an acute epileptic condition characterized by epines and phenytoin. Second steps suggest using leveti-
continuous generalized convulsive seizures for at least 5 racetam or valproic acid, which exert few hemodynamic
minutes or by continuous non-convulsive seizures or focal adverse effects and have multiple mechanisms of action.
seizures for at least 15 minutes, or by two seizures without Additional management strategies that could be em-
full recovery of consciousness between them” Many ployed in tertiary-care settings, such as coma induction
of these seizures will not end independently, and there is guided by continuous electroencephalogram monitoring
an urgent need for treatment to prevent the development of and surgical options, are also discussed. 2008 by
full status epilepticus. Established status epilepticus is Elsevier Inc. All rights reserved.
defined as “an acute epileptic condition characterized bycontinuous seizures for at least 30 minutes, or by 30 Abend NS, Dlugos DJ. Treatment of refractory status epilep- minutes of intermittent seizures without full recovery of ticus: Literature review and a proposed protocol. Pediatr In some children with status epilepticus, seizures persist despite treatment with adequate doses of an initial two orthree anticonvulsant medications, and this condition con- Introduction
stitutes refractory status epilepticus. The exact definition isstill unclear, with different studies defining refractory Status epilepticus is a medical emergency consisting of status epilepticus with varying durations (no time criteria, persistent or recurring seizures. It is not a single entity, but 30 minutes, 1 hour, or 2 hours) and a lack of response to can be divided into subtypes and has multiple underlying different numbers (two or three) and types of medications.
etiologies. Care involves both the termination of seizures Refractory status epilepticus occurs in 10-70% of adults and the identification and management of any underlying and children with status epilepticus. Studies in *From the Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; and †Department of Neurology, University Dr. Abend; Division of Neurology, Children’s Hospital of of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Philadelphia; 34th St. and Civic Center Blvd.; Philadelphia, PA 19104.
E-mail:Received July 2, 2007; accepted January 14, 2009.
2008 by Elsevier Inc. All rights reserved.
Abend and Dlugos: Refractory Status Epilepticus doi:10.1016/j.pediatrneurol.2008.01.001 ● 0887-8994/08/$—see front matter children indicated that status epilepticus lasted Ͼ1 hour in Data Search
26-45% Ͼ2 hours in 17-25% and Ͼ4hours in 10% In a recent prospective, population- A literature search of MEDLINE was performed using based study of children with status epilepticus that led to the search terms “refractory status epilepticus” and “status emergency room presentation, the incidence of status epilepticus,” cross-referenced in series with specific med- epilepticus lasting Ͼ60 minutes was higher than the ications and treatment modalities, including benzodiaz- incidence of status epilepticus lasting Ͻ60 minutes across epine, midazolam, diazepam, lorazepam, phenytoin, phe- all ages and etiologies However, some children with nobarbital, pentobarbital, thiopental, propofol, isoflurane, nonrefractory status epilepticus may not have been trans- desflurane, anesthetic, valproic acid, topiramate, levetirac- ported to the emergency room. Refractory status epilepti- etam, ketamine, pyridoxine, the ketogenic diet, surgery,resection, hemispherectomy, vagal nerve stimulator, adre- cus is associated with high morbidity and mortality nocorticotropic hormone, steroid, and plasmapheresis. The results of these searches were reviewed to identify articles In a subgroup of patients, refractory status epilepticus pertaining to children (non-neonates). Further articles may last for weeks or months, despite treatment with were identified in the reference lists of the literature multiple anticonvulsant and coma-inducing medications.
identified by the MEDLINE search. Clinical studies, This lengthy course was reported in 20% of adults with meta-analyses, case series, and case reports were included.
refractory status epilepticus and was referred to as Publications that did not include significant primary data, malignant, refractory status epilepticus de novo, such as commentaries or reviews, were excluded. When cryptogenic, refractory, multifocal, febrile status epilepti- multiple larger studies have been reported, the initial case cus or new-onset, refractory status epilepticus reports that may have prompted further investigation are Malignant refractory status epilepticus was associated not discussed. However, when only case reports and series with an encephalitic etiology, younger age, previous good are available for a medication, these publications are health, and high morbidity and mortality Similar cases were described in children It remains unclear To be broadly inclusive of studies addressing refractory whether this condition represents a specific disease entity, status epilepticus, we reviewed studies in which at least or simply a particularly severe variant of refractory status two medications failed to terminate status epilepticus, and epilepticus because of certain etiologies.
we did not require specific seizure durations. In reviewing Most seizures terminate spontaneously within several the literature, we noted that efficacy was defined variably minutes possibly due to a ␥-aminobutyric acid- as seizure cessation, reduction, termination without recur- mediated recurrent inhibition that occurs in response to rence, and termination without side effects. Termination seizures. However, with continuing seizures, inhibitory was sometimes defined clinically, and sometimes electro- ␥-aminobutyric acid receptors are internalized in clathrin- graphically. Moreover, the efficacy and adverse-event coated vesicles, some of which are recycled to the cellular profiles of various medications are difficult to ascertain, membrane, and some of which are destroyed in lysosomes.
because studies of refractory status epilepticus generally At the same time, excitatory N-methyl-d-aspartate recep- include patients undergoing treatment with multiple med- tors may be mobilized to the membrane. This receptor- ications, and their refractory status epilepticus is often due trafficking results in a decreased inhibitory control and to etiologies that may lead to similar adverse reactions as increased excitation that may lead to continuing status do the anticonvulsant medications employed to treat re- epilepticus. Alterations in neuropeptide and other gene fractory status epilepticus, such as respiratory depression expressions over several hours may also contribute to and cardiovascular dysfunction. We aimed to describe the sustained status epilepticus The internalization of definitions used for each particular study. A systematic ␥-aminobutyric acid receptors may explain the clinical meta-analysis was not performed because of the very finding that bezodiazepines, which work via ␥-aminobu- limited number of trials that defined refractory status tyric acid mechanisms, are less effective as seizure dura- epilepticus similarly and that compared similar popula- tions increase and may suggest a role for N-methyl- tions, medications, and overall treatment strategies. Only d-aspartate-modulating medications such as ketamine.
the English-language literature was reviewed.
To date, there have been no randomized trials for refractory status epilepticus, although there is increasing Refractory Status Epilepticus Treatment
published experience regarding various treatment options.
Most published protocols list several options for the Midazolam
treatment of refractory status epilepticus, because there isno clear standard. Here, we review the treatment options Midazolam is an injectable benzodiazepine that is fast- for pediatric refractory status epilepticus, provide an acting, rapidly penetrates the blood-brain barrier, and example of a protocol based on our experience and the exerts a short duration of action. The mechanism of limited available data, and highlight key issues that future midazolam involves the positive allosteric modulation of ␥-aminobutyric acid type A receptors (fast, chloride- permeable, and ionotropic), which suppresses neuronal and specifically pentobarbital, are the treatments of excitability Midazolam is hydroxylated in the liver, choice for refractory status epilepticus A meta- and the metabolite is excreted by the kidneys, so that analysis of 28 articles that included 193 adults with levels are affected by other medications metabolized by refractory status epilepticus compared pentobarbital, mi- this isozyme and by hepatic or renal dysfunction. With dazolam, and propofol. Pentobarbital was associated with more prolonged use, midazolam may accumulate, ex- a significantly lower incidence of short-term treatment tending the terminal half-life, and tachyphylaxis may failure, breakthrough seizures, and the need to change to a different medication, but was also associated with a Several studies reported on the use of midazolam in significantly higher frequency of hypotension How- refractory status epilepticus, using different dosing and ever, patients treated with pentobarbital tended to be treatment goals A meta-analysis of 111 children treated to the point of burst suppression, whereas those indicated that midazolam was as effective as other coma- treated with midazolam or propofol tended to be treated to inducing medications and involved a lower mortality (zero with midazolam) A multicenter, retrospective study Studies of pentobarbital for refractory status epilepticus suggested the efficacy of both midazolam boluses and in children reported an efficacy of 74-100% continuous infusion Another study compared midazo- and a high incidence of hypotension The largest of lam and diazepam in 40 children and indicated a similar these studies included 26 children aged 1 day to 13 years, efficacy (86% and 89%, respectively), but midazolam was and employed a loading dose of 5 mg/kg followed by an associated with a higher recurrence (57% versus 16%) and infusion of 1-3 mg/kg/hr, and after 48 hours of seizure higher mortality (38% versus 10.5%) Other studies freedom, a reduction to 0.5 mg/kg/hr. Efficacy was re- suggested efficacy in 71-97% of patients ported for 74% of patients, and there was relapse in 22% Seizure control was reported as rapid, occurring in 0.3-1.1 These studies suggest that pentobarbital is effective in promptly controlling seizures and producing a burst- studies reported a longer time to control seizures when lower suppression pattern. The initial bolus is generally 5 mg/kg dose boluses were used. Breakthrough seizures were reported followed by an infusion of 1 mg/kg/hr, which can increase in 47-57% of patients and relapse was reported in as needed to 3 mg/kg/hr. Continuous blood-pressure mon- 6-19% Some studies reported no adverse reac- itoring is important, because hypotension may occur with tory depression Whereas some studies described hypo-tension requiring intravenous fluid administration or, High-Dose Phenobarbital
rarely, vasopressor support other studies describedcardiovascular stability even in children receiving high doses Phenobarbital is a barbiturate that depresses neuronal of midazolam (24 ␮g/kg/min or 32 ␮g/kg/min excitability by enhancing the ␥-aminobutyric acid recep- Together, these studies suggest that an initial bolus of tor-coupled response, and that has a longer half-life than 0.1-0.5 mg/kg, followed by an infusion of 1-2 ␮g/kg/min pentobarbital. Studies reported a high efficacy of pheno- that is increased as needed to 30 ␮g/kg/min, controls barbital in treating initial status epilepticus in children. A refractory status epilepticus in most children. Higher prospective study of 36 children with status epilepticus boluses and more rapid escalation may be associated with indicated that phenobarbital stopped seizures faster than more prompt seizure control. Side effects are minimal, but did a combination of diazepam and phenytoin, and the may rarely include hypotension. Breakthrough and recur- safety profiles were similar Thus, phenobarbital is often one of the first-line medications administered forstatus epilepticus. In cases where the initial treatment with Pentobarbital
phenobarbital is ineffective and refractory status epilepti-cus ensues, several studies reported on the efficacy of Pentobarbital is an intravenous anesthetic barbiturate high-dose phenobarbital in refractory status epilepticus. A that depresses neuronal excitability by enhancing ␥-ami- retrospective report of 50 children with refractory status nobutyric acid-coupled responses. Pentobarbital is the first epilepticus treated with high-dose phenobarbital to metabolite of thiopental. Compared with phenobarbital, achieve serum levels of up to 1481 ␮mol/L described that pentobarbital has faster brain penetration (allowing faster seizures were controlled in 94%. Intubations were com- control of seizures) and a shorter half-life (allowing faster mon, but hypotension was unusual and mild A recent waking from coma upon weaning), although due to lipid report described three children with presumed viral en- solubility, accumulation may occur with prolonged admin- cephalitis causing refractory status epilepticus that per- istration. Pentobarbital is associated with respiratory de- sisted despite treatment with midazolam and thiopental pression, myocardial depression, hypotension, and low infusions, who were treated with phenobarbital at doses of 70-80 mg/kg/day, resulting in serum levels of Ͼ1000 Surveys of epileptologists and critical-care physicians ␮mol/L. All three had improved seizure control, although in the United States and Europe reported that barbiturates breakthrough seizures occurred In addition, after a Abend and Dlugos: Refractory Status Epilepticus coma is achieved with pentobarbital, high-dose phenobar- appropriate. The maximum dose or duration of infusion bital (to achieve a maximum serum level 1249 ␮mol/L) is that is safe and effective has not been established. Labo- reported to improve seizure control during pentobarbital ratory testing to monitor for side effects seems advisable.
Inhaled Anesthetics
Propofol
Although the mechanism of action of inhalational anes- Propofol is an intravenous alkyl-phenol general anes- thetics is not well-understood, the antiepileptic effects of thetic thought to modulate ␥-aminobutyric acid receptors, isoflurane may be attributable to the potentiation of inhibitory and that is rapidly acting and is easily titratable. It is postsynaptic ␥-aminobutyric acid type A receptor-mediated primarily metabolized in the liver and generally has a short currents on thalamocortical pathways. Both isoflurane and half-life, allowing rapid awakening after drug cessation, desflurane produce dose-dependent electroencephalogram although with prolonged administration, the terminal half- changes, at first increasing the frequency and lowering the life may amount to several days. Propofol, especially in voltage, and then progressively decreasing the voltage and children, was associated with what was termed “propofol producing burst suppression Not all inhalation medica- infusion syndrome,” i.e., cardiac failure, rhabdomyolysis, tions have similar properties; some inhalational medications metabolic acidosis, renal failure, and sometimes death.
such as sevoflurane may induce epileptiform discharges at Reported risk factors include high doses, prolonged use, supportive treatments with catecholamines and corticoste- A case series reported on the use of isoflurane for 1-55 roids, and possibly a low body mass index. Fatalities were hours in 9 patients (11 episodes), including 5 children, also reported when propofol was administered in conjunc- with refractory status epilepticus. All achieved burst sup- tion with a ketogenic diet This complication limits pression, and all developed hypotension requiring vaso- the use of propofol in children However, a similar pressors. Seizures recurred after isoflurane was discontin- syndrome was also reported with thiopental administration ued in 73% (8 of 11). All three patients who survived had for status epilepticus, and components of the syndrome cognitive deficits. The authors concluded that isoflurane may be attributable to status epilepticus alone, suggesting may be administered for seizures when other agents in that the syndrome may be related not only to propofol, but anesthetic doses are ineffective or produce unacceptable to some combination of more diverse sedative-anticonvul- sant regimens, status epilepticus, and pharmacologic sup- A retrospective case series of seven patients, including one 17-year-old, with refractory status epilepticus treated A retrospective study of 33 children (aged 4 months to with inhalational anesthetic agents (isoflurane in 6, des- 15 years) with refractory status epilepticus indicated that flurane in 1) reported that seizures were consistently propofol was more effective than thiopental in terminating terminated and burst suppression was achieved within seizures (64% versus 55%). The mean treatment duration several minutes of initiation. The maximal end-tidal with propofol was 57 hours (range, 10-264 hours). Propo- isoflurane concentration ranged from 1.2-5.0%, and was fol was initiated with a bolus of 1-2 mg/kg followed by an administered for a mean period of 11 days (maximum, 26 infusion of 1-2 mg/kg/hr, which was increased as needed days). All patients had hypotension requiring vasopressor to a maximum of 5 mg/kg/hr. Complications, including support and atelectasis, and several had infections, para- rhabdomyolysis and hypertriglyceridemia, prompted dis- lytic ileus, and deep venous thrombosis. After discontin- continuation in 18% of patients, although these laboratory uation, subclinical seizures occurred in one patient, and values normalized after propofol was discontinued, and no nonconvulsive status epilepticus occurred in two patients.
Three patients died, but the four survivors had good or Studies in adults indicated that propofol infusion termi- nates seizures in 67% of patients Propofol induces These studies suggest that inhalational anesthetics (par- burst suppression within 35 minutes of initiation but ticularly isoflurane) are effective in terminating refractory maintenance of burst suppression requires frequent titra- status epilepticus and inducing burst suppression, but all tion Hypotension requiring vasopressor administra- patients will exhibit hypotension requiring vasopressors, and there is frequent seizure recurrence when the anes- These studies suggest that propofol may be effective in thetic is gradually withdrawn. Optimal protocols for initi- terminating refractory status epilepticus quickly, but ation and titration have not been established.
propofol was not demonstrated to be more effective thanother medications, and may be associated with higher risk Ketamine
and higher mortality. Optimal dosing has not been estab-lished. Given the wide range of doses reported to produce Ketamine is a noncompetitive N-methyl-d-aspartate burst suppression and the high incidence of hypotension, glutamate receptor antagonist that may be effective in later an initial low-dose bolus of 1-2 mg/kg, followed by an stages of refractory status epilepticus, because it acts infusion of 2 mg/kg/hr that is titrated as needed, seems independently of ␥-aminobutyric acid-related mecha- nisms. Animal models demonstrated a late (at 1 hour) but reactions or hemodynamic effects The safety of rapid not early (at 15 minutes) efficacy of ketamine, implying infusion in children has not been studied.
that before receptor changes occur, it will be ineffective Several studies reported that valproic acid is highly In addition, ketamine may be neuroprotective by effective in 78-100% of children with refractory status reducing N-methyl-d-aspartate receptor-mediated excito- epilepticus, with no adverse effects One study of toxic injury Ketamine is metabolized by P450 liver 18 children used a loading dose of 25 mg/kg, and reported enzymes into an active metabolite norketamine, and thus 100% seizure termination within 30 minutes, with no levels may be affected by other anticonvulsants.
adverse reactions A second study of 41 children Five children, aged 4-7 years and with known severe loaded with 20-40 mg/kg, and then infused at 5 mg/kg/hr, epilepsy with refractory nonconvulsive status epilepticus reported a 78% termination of clinical and electroenceph- lasting 2-10 weeks (mean duration, 4.4 weeks), were alogram signs of seizures, with 66% achieving control treated with oral ketamine at 15 mg/kg/day divided twice within 6 minutes. There were no adverse effects daily, and all demonstrated a response within 48 hours, as However, there are case reports of hypotension with measured by reduced seizures on electroencephalogram valproic acid infusion for status epilepticus Valproic and improved mental status. Only one child had a recur- acid may induce encephalopathy, with or without elevated rence of nonconvulsive status epilepticus several months ammonia levels, and this possibility must be considered in later, which was again treated effectively with ketamine.
patients with persisting encephalopathy.
No side effects were noted A previously healthy These studies suggest that valproic acid exhibits high 13-year-old girl with refractory status epilepticus of un- efficacy in promptly treating refractory status epilepticus, known etiology persisting for 4 weeks received an intra- with few adverse reactions. It may be particularly useful in venous bolus of 2 ␮g/kg of ketamine, and within 90 situations when successful intubation is unlikely, because seconds, clinical and electrographic seizures terminated.
there is a lower risk of respiratory failure than with other She was then treated for 2 weeks with intravenous ket- agents. The initial bolus may be 20-30 mg/kg. If seizures amine (maximum dose, 7.5 ␮g/kg/hr), which improved are terminated, then a continuation of periodic (twice per seizure control such that she had only several seizures per day) dosing may be appropriate. If seizures continue, a continuous infusion of 5 mg/kg/hr may be efficacious.
It remains unclear whether ketamine can be used safely In the outpatient setting, valproic acid is estimated to in patients with neurologic injury. There may be adverse cause hepatotoxicity in 1 in 500 children aged Ͻ2 years, effects such as cerebellar toxicity with prolonged ket- and in children with metabolic disease, and thus must be amine administration Some studies reported in- used with caution in young children with status epilepticus creased intracranial pressure with ketamine administra- of unclear etiology. According to a recent practice param- tion for lumbar-puncture sedation but a recent eter for status epilepticus in children, the data from nine review of the literature did not find evidence that ketamine class III studies revealed that an inborn error of metabo- raised intracranial pressure. In fact, ketamine was associ- lism was diagnosed in 4.2% of children with status ated with improved cerebral perfusion Ketamine may epilepticus although this testing was generally per- improve cerebral blood flow by increasing blood pressure formed on children with suspected metabolic disease; thus, because of its sympathomimetic properties, in contrast the true incidence among all patients with status epilepti- with most medications used for refractory status epilepti- cus is likely lower. Hepatotoxicity occurs with more prolonged outpatient use, and has not been reported with Thus, ketamine may be a useful adjuvant in the treatment briefer intravenous use for status epilepticus.
of refractory status epilepticus, especially in late stages whenmedications that rely on ␥-aminobutyric acid enhancement Topiramate
are ineffective. However, further study is needed todetermine the optimal dosing, timing of administration, Topiramate exhibits several mechanisms of action, in- and effects on intracranial pressure and cerebral blood cluding blockage of voltage-sensitive sodium and calcium channels, enhancement of ␥-aminobutyric acid activity viamodulation of the ␥-aminobutyric acid type A receptor,and modulation of glutamate receptors via interaction with Valproic Acid
kainite and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors Because it exhibits mecha- Valproic acid is a broad-spectrum anticonvulsant nisms independent of ␥-aminobutyric acid receptors, topi- thought to modulate sodium and calcium channels, as well ramate may be effective later in refractory status as inhibitory ␥-aminobutyric acid transmission It is epilepticus, after ␥-aminobutyric acid receptors have been available as an intravenous formulation. A study in adults targeted by other agents. Studies suggest that rapid titra- with epilepsy (but not actively manifesting seizures) indi- cated that rapid infusion (10 mg/kg/min) was not associ- In children, topiramate was reported to be effective in ated with adverse effects, including local infusion-site controlling seizures, such that coma-inducing medications Abend and Dlugos: Refractory Status Epilepticus could be weaned using various dosing regimens more frequent than two per hour). All responders received Some protocols slowly titrated the medication, resulting in levetiracetam within 4 days of the onset of status epilep- control in 3-6 days whereas others started at a ticus, at doses of Ͻ3000 mg daily. These data suggest that higher dose and produced a response within 1 day levetiracetam may be efficacious when administered early, without any noted side effects. Three adult reports totaling and that high doses are unlikely to provide benefits 10 patients, including 5 without previous epilepsy, de- We administered intravenous levetiracetam to five chil- scribed control of refractory status epilepticus with naso- dren with refractory status epilepticus, achieved the ex- gastric topiramate at doses of 300-1600 mg/day pected serum levels, and noted no adverse events. A None of these studies reported on serum levels, and so the 9-year-old with refractory epilepsy developed nonconvul- effect of prolonged coma on absorption could not be sive status epilepticus that resolved with a 2-week titration determined. However, pharmacokinetic studies suggest of levetiracetam from 10 mg/kg/day to 40 mg/kg/day that an absence of food slightly increases the rate but not However, in view of this long period of titration, the the eventual extent of absorption and the reported seizures may have terminated spontaneously. Further efficacy of topiramate in refractory status epilepticus study is needed to determine the role of levetiracetam in suggests at least some absorption. Whereas topiramate was not demonstrated to be useful in initial status epilepticusmanagement, these studies suggest that it may serve as a Pyridoxine
useful add-on medication after patients have been treatedwith coma induction.
Pyridoxine-dependent seizures constitute a rare autosomal- recessive condition that generally presents in the early Levetiracetam
neonatal period. The seizures are refractory to commonantiepileptic medications, but are effectively treated with Levetiracetam is an anticonvulsant medication, thought to pyridoxine (vitamin B6). Pyridoxine and related com- have multiple sites of action including calcium channels, pounds can be converted to pyridoxal phosphate, which is glutamate receptors, and ␥-aminobutyric acid modulation an active cofactor in multiple metabolic pathways. The Recent animal studies demonstrated that treatment with diagnosis of pyridoxine-related seizures is made when the levetiracetam during the maintenance phase of status epilep- administration of intravenous pyridoxine (vitamin B6, 100 ticus diminished or aborted seizures is neuroprotective mg, from 1-5 doses) terminates seizures, sometimes for in animals experiencing status epilepticus and may several months after administration. If refractory status reduce the epileptogenic effects of status epilepticus epilepticus terminates, it may be unclear whether this was Levetiracetam is available as oral and intravenous prepara- attributable to pyridoxine, time, or other co-administered tions, although the intravenous form is not approved for use medications. After several months, other anticonvulsants and in children. Refractory status epilepticus is often associated then pyridoxine must then be withdrawn. If seizures recur with systemic disorders, such as coagulopathy, liver failure, following pyridoxine cessation and are then controlled by a and hypotension, that could be complicated by traditional re-initiation of pyridoxine, then pyridoxine-dependent sei- anticonvulsants. Intravenous levetiracetam may provide an zures are diagnosed Some children who do not respond alternative because it is not metabolized by the liver, has low to pyridoxine may respond to oral pyridoxal phosphate protein binding, is renally excreted, and exhibits limited With lifelong administration, the seizures are generally well- controlled. Characteristic cerebrospinal fluid findings include Studies in adults suggest that levetiracetam is safe in critically ill patients and that it may be effective in There are reports of older infants (up to 18 months of refractory status epilepticus. In adults, intravenous infu- age) with status epilepticus controlled by pyridoxine sion and oral tablets are bioequivalent and intra- Patients with a neonatal onset of pyridoxine- venous infusion is well-tolerated A study of six deficient seizures may also have seizures and status patients, including an adolescent with static encephalopa- epilepticus later in life when pyridoxine is discontinued thy, indicated that nasogastric doses of 500-3000 mg/day controlled seizures in 12-96 hours, with no noted adverse These data suggest that, for patients in whom the effects In eight adults with nonconvulsive status treatable condition of pyridoxine-dependent seizures may epilepticus, a cessation of ictal electroencephalogram- not be recognized, all infants (at least up to 2 years of age) activity occurred within 3 days of levetiracetam initiation, without a clear symptomatic etiology could benefit from a without side effects A study of 23 adults (39% with trial of intravenous pyridoxine and possibly oral pyridoxal refractory status epilepticus) receiving nasogastric leveti- racetam at a median dose of 2000 mg (range, 750-9000mg) indicated that 43% responded (status epilepticus or Ketogenic Diet
refractory status epilepticus resolved within 72 hours ofthe start of, or an increase in, levetiracetam administration, The ketogenic diet is high-fat and low-carbohydrate, without recurrence of seizures lasting Ͼ10 seconds or and is useful in drug-resistant epilepsy. It requires a precise nutrition regimen and can be administered via fractory epilepsy and status epilepticus are listed as indi- modified parenteral nutrition solutions. Most complica- cations for electroconvulsive therapy by the American tions are mild and reversible, including hypoglycemia, Psychiatric Association Task Force Two children acidosis, and hyperlipidemia, but there are rare occur- with intractable epilepsy demonstrated a marked decrease rences of cardiomyopathy and pancreatitis There in seizures after electroconvulsive therapy, and in one of have been no studies of the ketogenic diet in refractory these children, electroconvulsive therapy effectively status epilepticus, although it is sometimes employed in treated two episodes of nonconvulsive status epilepticus refractory status epilepticus (personal experience at the In one adult, six electroconvulsive therapy treatments authors’ institution). The occurrence of propofol infu- terminated status epilepticus and allowed a gradual with- sion syndrome with the initiation of a ketogenic diet drawal from barbiturate coma; there was complete recov- was reported in a 10-year-old with refractory status ery in 1 month In another adult with nonconvulsive epilepticus possibly related to an impairment of status epilepticus, electroconvulsive therapy terminated fatty-acid oxidation with propofol, which suggests that status epilepticus, allowing the patient to be weaned off the two approaches should not be used simultaneously.
coma-inducing medication, but the patient remained in acoma Electroconvulsive therapy may also induce Corticosteroids, Adrenocorticotropic Hormone,
seizures and nonconvulsive status epilepticus. Hence, and Plasmapheresis
continued electroencephalogram monitoring after electro-convulsive therapy is essential.
Immune-modulating therapies are sometimes em- In an adult with multifocal refractory status epilepticus, ployed in refractory status epilepticus treatment, includ- stimulation of the ictal onset zones by subdural electrodes, ing corticosteroids, adrenocorticotropic hormone, and placed as part of a surgical evaluation, temporarily termi- plasmapheresis. There are a few case reports of these nated seizures, but did not result in a favorable outcome interventions. Some neuro-intensivists reported good outcomes with plasmapheresis and there are de- It remains unclear whether an earlier use of electrocon- scriptions of the efficacy of adrenocorticotropic hor- vulsive therapy or subdural electrode stimulation to termi- nate status epilepticus might result in better outcomes.
other than infantile spasms. These therapies may beuseful in the context of autoimmune etiologies for Surgery
refractory status epilepticus, such as Rasmussen’s en-cephalitis or vasculitis.
Epilepsy surgery is known to improve seizure control in some patients with intractable epilepsy. Several case Hypothermia
reports and series described the efficacy of various surgi-cal procedures in children with refractory status epilepti- Human studies demonstrated the benefit of hypother- cus. Etiologies include focal cortical dysplasias, hypotha- mia after cardiac arrest in adults and neonatal enceph- lamic hamartoma, cortical tubers, cerebral cavernous alopathy, but there are few data regarding efficacy or malformations, Rasmussen’s encephalitis, and prenatal safety in epilepsy or status epilepticus. Animal studies anterior circulation infarcts In one patient, a demonstrated clear neuroprotective effects of moderate dysplastic lesion was noted on 3-T but not 1.5-T magnetic therapeutic hypothermia, and suggest that hypothermia resonance imaging scans In other patients, no has anticonvulsant properties especially when lesions were visible on magnetic resonance images, but administered with a benzodiazepine In one adult, resection was performed based on magnetoencephalogra- before resection of a frontal tumor, a 4°C saline phy identified unilateral clustered interictal spike sources application for 30 seconds resulted in a transient but or ictal-electroencephalogram and single-photon complete termination of interictal spikes One case emission computed tomography localization with series described three children with refractory status successful refractory status epilepticus termination. Proce- epilepticus successfully treated with hypothermia (30- 31°C) along with barbiturate coma, but the effect of hypothermia could not be separated from that of med- ication Further data are necessary to determine One case series of 5 children indicated that 4 children whether therapeutic hypothermia is of benefit in refrac- exhibited a termination of seizures, and one had a reduc- tion in seizures A second series of 10 children withpreexisting epilepsy in refractory status epilepticus re- Electroconvulsive Therapy
ported that refractory status epilepticus was terminated inall, and at follow-ups of 4 months to 6.5 years, seven Electroconvulsive therapy may enhance ␥-amino- patients remained seizure-free A third series of five butyric acid transmission, and thus was proposed to be children evaluated with magnetoencephalography in addi- useful in the treatment of intractable epilepsy Re- tion to standard tests reported that refractory status epilep- Abend and Dlugos: Refractory Status Epilepticus ticus terminated in all. One of the patients, a 2.5-year-old clear how long the patient should be maintained in a coma.
with cortical dysplasia, required two operations (cortical In a survey of 63 European epileptologists and critical- excision followed by hemispherectomy) to terminate re- care physicians that allowed for multiple responses, 34% fractory status epilepticus. At follow-up, 2 patients were aimed for clinical seizure termination, 63% aimed for seizure-free, and 3 had episodic seizures electrophysiologic seizure termination, and 69% aimed for Vagal nerve stimulators have also been used in refrac- tory status epilepticus. A 13-year-old boy with previously Studies so far yield conflicting results, and there have diagnosed refractory epilepsy, admitted because of refrac- been few investigations in children. Adult studies compar- tory status epilepticus, experienced complete cessation of ing the treatment goals of burst suppression versus seizure seizures acutely with left vagal nerve stimulator place- termination are inconclusive. One report indicated no ment, and demonstrated improved seizure control over the difference in clinical variables and outcome one report indicated that more suppression was associated with These studies suggest that neurosurgical interventions greater freedom from seizures and better survival without need not be considered a last resort in children with additional adverse reactions, including hypotension refractory status epilepticus if a focal area of ictal onset and a third report indicated that burst suppression was can be identified. A rapid surgical evaluation may be associated with fewer breakthrough seizures but a signif- indicated in children with refractory status epilepticus, and icantly higher frequency of hypotension The largest other modalities for localization, such as magnetoencepha- of these studies involved a meta-analysis of 28 articles that lography and single-photon emission computed tomogra- included 193 adults with refractory status epilepticus, and phy, may allow for successful resections, even when indicated that titration to electroencephalogram back- magnetic resonance imaging does not identify a lesion.
ground suppression, compared with seizure suppression,resulted in significantly fewer breakthrough seizures (4% Other Treatment Issues: Delay in Treatment
versus 53%) but a significantly higher frequency ofhypotension (29% versus 76%). There was no significant The impact of delay in treating status epilepticus is difference in short-term treatment failure, withdrawal challenging to study, because it is confounded by the seizures, need to change medication, or mortality etiology of the status epilepticus. However, some data are Further research is needed to determine whether treatment available. A recent series of 157 children, aged 1 month to in children should attempt to suppress all seizures or 16 years, with seizures lasting Ͼ5 minutes, reported that induce burst suppression with a significant reduction in seizures lasted 5-29 minutes in 39%, and Ն60 minutes in seizures. If burst suppression is preferred, the optimal 61%. Treatment delays of Ͻ30 minutes did not affect degree of burst suppression is also unknown.
response, but when the delay exceeded 30 minutes, there Most protocols suggest maintaining a coma for 24-48 was an association with delay in achieving seizure control hours, and this was the most common duration specified in In a study of 27 children, first-line (benzodiazepine) a survey of epileptologists and critical-care physicians and second-line (phenytoin or phenobarbital) medications but there are few data to provide guidance in the were effective in terminating status epilepticus in 86% of patients when seizure duration was Ͻ20 minutes at pre-sentation, and only 15% when seizure duration exceeded Other Treatment Issues: Weaning of
30 minutes In a retrospective study of 358 children Coma-Inducing Medications
who received midazolam for status epilepticus, the effec-tiveness of treatment decreased as the time to treatment There are few data regarding the optimal rate of increased. Efficacy was significantly lower when treat- weaning, or the amount of seizure burden or number and ment was initiated Ͼ3 hours after seizure onset, and there types of epileptiform discharges that can be tolerated.
was a trend toward reduced efficacy even at an hour, During the period of coma induction and burst suppres- especially when the etiology was epilepsy and not an acute sion, there may be some uncoupling of electrographic and symptomatic etiology Similarly, in adults with status clinical seizures. Thus, many seizures designated as re- epilepticus, response to the initial treatment occurred in fractory status epilepticus may occur during weaning from 80% of patients when treatment began within 30 minutes, coma-inducing medications, and may be solely electro- but in only 40% when treatment began Ͼ2 hours after the graphic. In a study of the prognoses of 22 children with refractory status epilepticus, all survivors manifested in-tractable epilepsy, and many children manifested persist- Other Treatment Issues: Titrating Goals and Duration
ing seizures during or shortly after weaning from antisei-zure medications Further, aggressive treatment may When coma-inducing agents are employed, it remains lead to complications such as hypotension This unclear whether the treatment goal should be termination finding suggests that a continuation of high-dose suppres- of seizures, burst suppression, or a complete suppression sive therapy because of some seizures during the weaning of electroencephalogram activity. Further, it remains un- phase may not improve the likelihood of a seizure-free outcome. Further study is needed to elucidate the optimal time, ranging from minutes to days. Defining and standard- izing these terms and aims will be important, both inpromoting comparisons and meta-analyses of case series, and Importance of Seizures on Outcome
We suggest the following definitions. Refractory status Although studies in children revealed high morbidity epilepticus involves a seizure of any type (convulsive, and mortality associated with refractory status epilepticus, subtle, or solely electrographic) that continues despite it remains unclear whether this finding reflects an under- treatment with adequate doses of a benzodiazepine and lying brain injury that is causing the seizures, or a fosphenytoin. Refractory status epilepticus may be attrib- seizure-induced injury, or a combination. A study in utable to many etiologies, and must be divided at least into children demonstrated that levels of serum neuron-specific refractory status epilepticus attributable to underlying enolase, a marker of neuronal injury, were elevated in epilepsy, and refractory status epilepticus attributable to an children with continuous electrographic discharges, even acute symptomatic etiology, because these conditions may require different management approaches, and have dif- Studies in adults indicate that the prognosis is worse ferent outcomes. We define treatment efficacy as the with seizures and especially status epilepticus, raising the termination of all seizures (convulsive and electrographic) possibility that the effective treatment of seizures, so that within 30 minutes, without seizure recurrence for 24 status epilepticus does not occur, may affect outcomes. A hours. We define effectiveness (which includes efficacy study in adults indicated that duration and time to detec- and consideration of side effects) as efficacy without tion predicted the outcomes in patients with nonconvulsive hypotension requiring vasopressors, or other serious sys- status epilepticus. Mortality amounted to 36% when non- convulsive status epilepticus was diagnosed within 30 Protocols for clinical use must be developed that are minutes of onset, and 75% when diagnosis was delayed for modular in nature, so that individual parts can be manip- Ͼ24 hours. When nonconvulsive status epilepticus lasted ulated in randomized, clinical studies within the context of Ͻ10 hours, 60% of patients returned home. In contrast, a generally uniform management approach. Observational when nonconvulsive status epilepticus lasted Ͼ20 hours, studies, which make up much of the literature to date, may none returned home, and 85% of the patients died contain major biases and confounders, making it difficult Thus, in adults, persistent seizures are likely to result in to determine whether the efficacy in reported patients is poorer outcomes, as opposed to simply reflecting an attributable to the specific medication, the dosage, or some underlying brain injury. However, treating or preventing more complicated sequence or overall management differ- seizures was not found to improve outcomes, and because ences. Randomized, controlled studies are needed. Stan- some treatments may result in hypotension that can cause dardized treatment algorithms must be agreed upon and secondary brain injury, overly aggressive treatments may implemented at multiple centers to allow for multisite be detrimental. Thus, the optimal goals for treatment studies, because even a simple study comparing two alternatives at a given step, aiming to detect a 15%difference (where ␣ ϭ 0.05 and ␤ ϭ 0.8), would require Issues for Further Study
about 250 children. Given the occurrence of refractorystatus epilepticus at our own tertiary-care institution, about Many factors related to refractory status epilepticus 10 patients might be enrolled per year, suggesting that have not been clearly defined, and outcome measures have completion of the study in 3 years would require the not been agreed upon. Definitions of refractory status involvement of about 10 centers. Separating patients based epilepticus vary in terms of both required duration and on age and the etiology of refractory status epilepticus number of failed medications. Status epilepticus is a would require an even larger sample. Investigations of the heterogeneous term comprising a variety of seizure types, optimal management of refractory status epilepticus will including convulsive, nonconvulsive, and subclinical, and including both prolonged seizures and briefer recurrentseizures. Efficacy is defined variably as seizure cessation,seizure reduction, seizure termination without recurrence, Protocol Suggestions
and seizure termination without significant adverse ef-fects. The ideal medication would offer not only high Regardless of the many uncertainties surrounding re- efficacy (terminating seizures without recurrence), but high fractory status epilepticus, children with refractory status effectiveness (high efficacy with acceptable side effects).
epilepticus still need treatment. Treatment delay is asso- Some studies define this endpoint as based on clinical ciated with reduced response to medications. Inadequate seizures, whereas others rely on electroencephalogram crite- ria. Some define efficacy as the achievement of burst sup- predictive of treatment response The use of proto- pression, and others as the achievement of seizure termina- cols, even if based on limited data, may improve the tion. All of these endpoints are judged at various lengths of Abend and Dlugos: Refractory Status Epilepticus Several principles have guided the choice of medica- zures), or directly to coma induction. We use midazolam tions in our protocol. First, we aimed to employ medica- because more published data are available for midazolam tions that can be administered rapidly and penetrate the in children, and our experience suggests that it is less brain quickly, but will not cause prolonged systemic side associated with hypotension than is pentobarbital. After an effects. Second, assuming that intubation and skilled initial bolus, the infusion is increased every 5-10 minutes, ventilator management are available, respiratory depres- with the goal of burst suppression (approximately 50% sion may need to be tolerated, but hypotension should be burst, 50% suppression) on electroencephalogram. We avoided, because the autoregulation of cerebral blood flow maintain burst suppression for 24 hours, with electroen- may be abnormal despite the maintenance of systemic cephalogram reviews and adjustment of medication as blood pressure with vasopressors. Third, employing med- needed several times per day. Coma is then weaned over ications with different mechanisms of action at successive about 24 hours. If there is recurrence, then the midazolam steps may be useful, although this type of rational poly- is reinitiated, and high-dose topiramate is added. Epilepsy therapy has not been demonstrated to be more effective.
surgery is considered if a focal area of ictal onset is clear.
Based on our search of the literature, we developed a Weaning is again attempted after 24 hours of burst protocol for refractory status epilepticus for non-neonates There is clear evidence that earlier treatment is In September 2007, our protocol was adopted by the beneficial, and that out-of-hospital treatment is safe and neurology, emergency medicine, and pediatric intensive effective. Treatment may begin with buccal midazolam care services at our institution to guide the treatment of status and refractory status epilepticus. The protocol was hospital. During the impending and established status initially designed by the neurology service, but all related epilepticus phases, initial medications should be given services were involved in refining it, which led to great rapidly and in close succession, allowing 5 minutes improvements, both conceptually and in implementation.
between benzodiazepine doses and 10 minutes after fos- In our experience, issues related to implementation were phenytoin administration is completed to judge response.
often harder to solve than protocol design. Issues included We recommend a single, large dose of fosphenytoin rather how to provide easy physician access to the protocol, how than repeated smaller doses. Fosphenytoin was chosen as to ensure that needed medications were readily available the second antiseizure medication, because phenobarbital’s in units and did not need to be provided by the main main mechanism of action, ␥-aminobutyric acid enhance- pharmacy, and how to coordinate care and avoid delays in ment, is similar to the mechanism of action of benzodiaz- the often-needed transfer from emergency department to epines, whereas fosphenytoin acts on voltage-gated sodium intensive care unit. A database is being established to channels. In addition, phenobarbital is more likely to lead to evaluate the effectiveness of the protocol. The protocol respiratory and cardiovascular compromise.
was designed in time-locked modules such that various If seizures persist after adequate doses of a benzodiaz- steps can be adjusted and studied with most of the protocol epine and fosphenytoin, then refractory status epilepticus remaining constant. We expect that this approach will is diagnosed. Patients who are diagnosed with refractory allow us to continue to refine medication choices and status epilepticus need rapid treatment, but the initiation of treatment goals with further experience. After it is imple- coma-inducing medications is associated with a high mented consistently, we are hopeful that the module incidence of side effects and the need for intensive care design will allow us to use the protocol as a framework for admission. In the initial refractory status epilepticus stage, randomized studies comparing alternative treatments we recommend a trial of a third anticonvulsant before the initiation of coma-inducing medications. We have em-ployed intravenous levetiracetam in several patients with Conclusions
refractory status epilepticus, and produced at least atemporary termination of seizures without adverse effects.
Status epilepticus is associated with the progressive, Alternatively, in patients without known risk factors for time-dependent development of pharmaco-resistance.
hepatotoxicity such as known liver disease or metabolic Prompt and aggressive treatment of status epilepticus may disease, data suggest that valproic acid may be a useful reduce the chance of persistence and the development of third-line medication. We elect to use these medications refractory status epilepticus. Refractory status epilepticus prior to phenobarbital, because recent data suggest that is associated with high mortality and morbidity, as related they may be as efficacious. Theoretically, they may be to both the underlying etiology and seizure control. To more effective than phenobarbital, given the different date, no randomized, controlled trials address refractory mechanisms of action, and they are unlikely to produce status epilepticus, but there is increasing published expe- respiratory or cardiovascular compromise.
rience with multiple medications and treatment strategies If seizures persist, then in the later phase of refractory for refractory status epilepticus. Treatment strategies must status epilepticus, we proceed to a trial of phenobarbital employ prompt treatment, the initiation of coma-inducing (generally while plans are being made to induce coma with medications if seizures are not terminated by initial or midazolam if phenobarbital does not terminate the sei- secondary medications, and the administration of addi- Convulsive status epilepticus algorithm
Management
Consider buccal midazolam or rectal diazepam.
Lorazepam, 0.1 mg/kg IV (maximum, 5 mg) over 1 min,Diazepam, 0.2 mg/kg IV (maximum, 10 mg) over 1 min, Allow 5 minutes to determine whether seizure terminates.
Give oxygen. Stabilize airway, respiration, and hemodynamics as needed. Obtain IV access. Check bedside glucose.
Repeat benzodiazepine administration.
Administer fosphenytoin 30 mg/kg IV at 2-3 mg/kg/min (maximum, 150 mg/min), or phenytoin 30 mg/kg IV at 1 If patient’s age is Ͻ2 years, consider pyridoxine 100-mg IV push.
Testing: Draw phenytoin level (10 min after infusion).
Support airway, respiration, hemodynamics as needed. Continuous vital sign and EKG monitoring.
Consult neurology service.
If seizure continues 10 min after fosphenytoin infusion, then patient has refractory SE, regardless of time elapsed.
Administer levetiracetam 20-30 mg/kg IV at 5 mg/kg/min (maximum, 3 g).
If contraindication to levetiracetam and no specific concern regarding liver/metabolic disease, then administer If seizure continues 5 min after levetiracetam or valproate, administer phenobarbital 30 mg/kg IV at 2 mg/kg/min Admit to pediatric intensive care unit. Prepare to secure airway, mechanically ventilate, and obtain central venous access and continuous hemodynamic monitoring through arterial line.
After clinical seizure terminates, will likely need EEG monitoring to assess for subclinical seizures.
If seizure continues 10 min after completion of phenobarbital infusion, then initiate coma with midazolam 0.2 mg/ kg bolus (maximum, 10 mg) over 2 min, and then initiate infusion at 0.1 mg/kg/hr.
If clinical seizures persist 5 min after initial midazolam bolus, then administer additional midazolam bolus of 0.2 If clinical seizures persist after another 5 min, then administer another midazolam bolus of 0.2 mg/kg, and increase Repeat as needed. If seizures persist at maximum midazolam (generally, 2 mg/kg/hr) or midazolam infusion is not tolerated, consider transition to isoflurane. Also consider pentobarbital, topiramate, ketamine, valproic acid (if notalready used), or levetiracetam (if not already used).
Continue pharmacologic coma for 24 hr after last seizure, with EEG goal of burst suppression.
Continue EEG monitoring with at least t.i.d. reviews.
Continue initial medications (phenytoin goal level, 20-30 ␮g/mL; phenobarbital goal level, 40-50 ␮g/mL). Daily phenobarbital and free phenytoin levels.
Continue levetiracetam at 40-80 mg/kg IV, divided every 6 hours (maximum, 3 g).
Reduce midazolam by 0.05 mg/kg/hr every 3 hr, with frequent EEG review. If no clinical or electrographic Continue EEG for at least 24 hr after end of infusion, to evaluate for recurrent electrographic seizures.
If clinical or subclinical seizures occur, reinstitute coma with midazolam for 24 hr. Start midazolam at infusion rate that achieved burst suppression (approximately 50/50), and increase according to suggested midazolam titrationalgorithm.
Initiate topiramate 10 mg/kg NG loading dose followed by 5 mg/kg NG divided b.i.d.
Additional imaging (3-T magnetic resonance image, consider MEG) and surgical evaluation, as guided by Reduce midazolam by 0.06 mg/kg/hr every 3 hr.
If seizure persists, then manage as guided by neurology consultation.
Consider coma-inducing medications including pentobarbital, short-term propofol, or inhaled anesthetics.
Consider add-on medications including levetiracetam, topiramate, ketamine, valproic acid, and ACTH. Reconsider Abbreviations:ACTH ϭ Adrenocorticotropic hormone Abend and Dlugos: Refractory Status Epilepticus tional medications to reduce the chance of seizure recur- Van Lierde I, Van Paesschen W, Dupont P, Maes A, Sciot R.
rence during weaning. Animal models suggest that some De novo cryptogenic refractory multifocal febrile status epilepticus in of these additional medications may also be neuroprotec- the young adult: A review of six cases. Acta Neurol Belg 2003;103:88-94.
tive and reduce epileptogenesis, but this requires further Wilder-Smith EP, Lim EC, Teoh HL, et al. The NORSE
study in humans. Further study is also needed to determine (new-onset refractory status epilepticus) syndrome: Defining a disease the optimal roles of neurosurgical procedures and hypo- entity. Ann Acad Med Singapore 2005;34:417-20.
thermia. There is some evidence that coma-inducing Kramer U, Shorer Z, Ben-Zeev B, Lerman-Sagie T, Goldberg-
medications should be titrated to burst suppression rather Stern H, Lahat E. Severe refractory status epilepticus owing to presumedencephalitis. J Child Neurol 2005;20:184-7.
than seizure suppression, but the optimal duration of Chen JW, Wasterlain CG. Status epilepticus: Pathophysiology
suppression and degree of suppression remain unknown.
and management in adults. Lancet Neurol 2006;5:246-56.
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Kumar A, Bleck TP. Intravenous midazolam for the treatment
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Conflicts of interest: N.S.A. and D.J.D. have received investigator- Rivera R, Segnini M, Baltodano A, Perez V. Midazolam in the
initiated research support from UCB Pharmaceuticals. D.J.D. has served treatment of status epilepticus in children. Crit Care Med 1993;21:991-4.
as a scientific advisor for Ortho-McNeil Pharmaceuticals and UCB Koul RL, Raj Aithala G, Chacko A, Joshi R, Seif Elbualy M.
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