Emergent Treatment of Status Epilepticus in Children

US Pharm. 2015;40(5):HS25-HS31.

ABSTRACT: Status epilepticus is a neurologic disorder that can lead to serious complications in children if it is not treated effectively. The incidence of status epilepticus decreases with increasing age. Current first-line treatments are primarily benzodiazepines; medications such as phenytoin, fosphenytoin, phenobarbital, and valproate are reserved for second-line treatment, owing to their adverse-effect profile. Patients who experience refractory status epilepticus (nearly one-third of all patients) may be treated with midazolam, propofol, or pentobarbital. Patients who do not achieve full seizure resolution are at risk for neurologic, cardiac, and respiratory complications.

Status epilepticus (SE), a serious neurologic condition that can occur in individuals of all ages, can lead to significant morbidity and mortality if not promptly and accurately treated. For more than three decades, SE has been defined as seizures, either continuous or intermittent, that last for longer than 30 minutes without complete recovery of consciousness.¹ This traditional definition is not universally accepted, as most seizures are self-limiting within 5 minutes. In 2012, the updated Neurocritical Care Society (NCS) guidelines on SE proposed an operational definition in which SE is ≥5 minutes of either 1) continuous clinical and/or electrographic seizure activity or 2) recurrent seizure activity without recovery between seizures.² Researchers who have adopted the operational definition have referred to this as “impending” or “early” SE. The International League Against Epilepsy is currently considering a revision of the traditional SE definition.

Classification

SE may be subclassified as convulsive (generalized tonic-clonic movements, mental-status impairment, postictal focal neurologic impairment), nonconvulsive (wandering confused, mental status impairment with or without motor movements), or refractory (not responsive to standard treatment).² Convulsive SE accounts for 90% of all SE episodes in children.³ Refractory SE, defined by the NCS as clinical or electrographic seizures that continue despite adequate benzodiazepine doses and at least one acceptable antiepileptic drug (AED), occurs in approximately 30% of pediatric SE cases.^2-4

Although febrile seizures are the most common cause of SE in children aged <5 years, there are a number of additional underlying causative syndromes, including, but not limited to, central nervous system (CNS) infection, drug toxicity, withdrawal, stroke, CNS tumors, and disruptions of AED therapy in epileptic patients.^2,5 Less common causes include complications from autoimmune disease, mitochondrial disorders, genetic disorders, infections, and cortical malformations. Prolonged seizure activity is typically attributed to an imbalance of endogenous mechanisms that leads to either reduced inhibition (via gamma-aminobutyric acid) or excessive excitation (via N-methyl-d-aspartate) at the synaptic membrane.⁶

Epidemiology

The overall incidence of SE in children is 10 to 38 episodes per 100,000 children.⁷ The incidence decreases with increasing age, with the highest risk in children aged <1 year (<1 year, 51/100,000; 1-4 years, 29/100,000; 5-9 years, 9/100,000; 10-15 years, 2/100,000). Children with epilepsy have a 10% to 25% chance of developing SE, a rate much higher than that in adults.⁵ The rate of mortality from SE for infants and neonates has been reported to be 10% to 16%. In children with refractory SE, up to 50% can develop neurologic sequelae. SE is slightly more likely to occur in males (sex ratio ~1.7:1).³ In children experiencing SE, those aged <2 years are more likely than those aged >2 years to have no abnormal neurologic history or history of unprovoked seizure activity.

Sixteen percent of children with a first SE episode have a recurrence within 1 year.⁷ Children with preexisting neurologic conditions or abnormalities are three to 20 times more likely to have a recurrence after the first SE episode. The likeliest time for SE recurrence is about 1 year after the first occurrence. A subsequent diagnosis of epilepsy is made in 25% to 40% of children experiencing SE. Additional complications include respiratory and cardiac instability, electrolyte disturbances, organ instability (hepatic, renal, and pancreatic), and adverse effects (AEs) from pharmacologic treatments for SE.

Goals of Therapy

There are several goals for the immediate management of SE. The primary goal is to reduce seizure activity, both clinically and electrically.² At the same time, the patient must be hemodynamically stabilized to avoid additional complications. The airway should be protected initially via noninvasive techniques such as nasal devices and face masks.⁸ Patients requiring AEDs should be closely monitored for adverse drug reactions (ADRs), particularly from a cardiac and respiratory standpoint.^2,8-11 Following initial seizure abatement, goals shift to prevention of seizure recurrence and, if chronic medication therapy is required, long-term AED monitoring and management.

First-Line Therapies

Benzodiazepines are the preferred class of medications for initial treatment of emergent SE.^2,3,11 IV lorazepam is currently favored over IV or rectal diazepam and IM midazolam, despite lacking an indication for SE.^10,12 Dosing for first- and second-line therapies is given in TABLE 1. The preference for lorazepam is based primarily on expert opinion and is supported by the NCS guidelines.^2,11

To examine the claim that lorazepam is safer and more effective than diazepam, Chamberlain and colleagues conducted a randomized clinical trial comparing IV lorazepam with IV diazepam in patients aged 3 months to <18 years.⁹ The primary efficacy outcome was cessation of SE within 10 minutes without recurrence within 30 minutes. Lorazepam and diazepam successfully achieved the primary outcome in 72.9% and 72.1% of patients, respectively (95% CI, –11.4%-9.8%). There was no difference in time to seizure cessation after drug administration (hazard ratio [HR], 0.99; 95% CI, 0.75-1.29) or time to seizure recurrence (HR, 1.04; 95% CI, 0.77-1.4). There was a statistical difference in incidence of sedation between lorazepam and diazepam (66.9% vs. 50%, respectively), as well as a difference in time to return to baseline mental status (HR, 1.96; 95% CI, 1.35-2.84; P = .0004). As a result of these outcomes, it was concluded that lorazepam was not superior to diazepam in efficacy or safety.⁹

Although IV administration of AEDs is preferred, rectal or IM diazepam or intranasal (IN) or buccal midazolam can be considered if IV access cannot be gained.^2,13 IM midazolam was more effective than IV lorazepam at terminating seizures in children weighing >13 kg and in adults when used immediately by emergency responders prior to arrival at the emergency department (73.4% vs. 63.4%, respectively; P <.001).¹⁴ In a randomized, double-blind, noninferiority trial, Silbergleit and colleagues found that time to treatment initiation differed by >3.5 minutes (1.2 minutes vs. 4.8 minutes for IM midazolam and IV lorazepam, respectively).¹⁵ Rescue therapy was not required for these patients, and hospitalization (relative risk [RR], 0.88; 95% CI, 0.79-0.98) and ICU admission (RR, 0.79; 95% CI, 0.65-0.95) were less likely to be necessary.¹⁵

Buccal administration of midazolam may be preferred over rectal diazepam if IV access cannot be established in children. Appleton and colleagues found that termination of seizures occurred more frequently with midazolam (RR, 2.05; 95% CI, 0.8-1.14).¹⁶ IM, IN, and buccal midazolam more effectively achieved seizure cessation compared with IV or rectal diazepam (RR, 1.54; 95% CI, 1.29-1.85; number needed to treat, 7).¹⁷ Rectal diazepam exhibited erratic absorption and ultimately lower drug concentrations, including a delayed peak.¹⁸ The NCS does not currently recommend buccal midazolam in the prehospital setting.^2,17

Second-Line Therapies

Because of cardiac ADRs such as QT prolongation and arrhythmias, phenytoin and fosphenytoin have been relegated to second-line treatment following inadequate response or contraindication to benzodiazepines.² Fosphenytoin (a prodrug for phenytoin) is often preferred over phenytoin, as it does not contain propylene glycol, which contributes to cardiac abnormalities and respiratory distress. Additionally, fosphenytoin is thought to cause less pain during administration compared with phenytoin. Unless the patient possesses a central line, fosphenytoin is typically the recommended therapy. Phenobarbital has historically been used as initial therapy for SE. However, as with phenytoin, severe ADRs—coupled with increased availability of newer, safer agents—have limited its use in recent years. Common ADRs that limit use are severe lethargy, sedation, and respiratory depression that may require intubation.^12,19

Valproate, which is generally viewed as a second-line option, should be considered for initial therapy in patients with increased risk of cardiac or respiratory abnormalities, which can be exacerbated by first-line agents.¹⁹ Levetiracetam, currently considered second-line, may be preferred over benzodiazepines in specific patients with respiratory compromise and/or hypotension, as it appears to have a milder ADR profile compared with other first- and second-line agents.^12,20 Further data on the use of levetiracetam in SE are required before this agent can be considered truly first-line.

Treatment of Refractory SE

In patients not fully responsive to first- or second-line SE treatment, a bolus dose is recommended, followed by AED administration via continuous infusion.² Midazolam, propofol, and pentobarbital may be employed for difficult refractory patients. Historically, sodium thiopental has been used, but because of recent controversy over its use in capital punishment, its availability in the United States has declined almost entirely. According to the NCS guidelines, no one agent can be recommended over another, but practitioners must consider potential ADRs when selecting an appropriate agent. Additional support, including vasopressors, may be required when these medications are selected, owing to an increase in cardiac and respiratory instability that can accompany their use.

Benzodiazepine Administration and Pharmacokinetics

Diazepam is available as a solution for injection in a concentration of 5 mg/mL, as well as a rectal gel in concentrations of 2.5 mg, 10 mg, and 20 mg.²¹ Diazepam has a rapid onset of action when administered IV and should terminate seizures in approximately 1 to 3 minutes.^9,22 When administered rectally, seizure termination can be expected in approximately 5 to 10 minutes.^22,23 Diazepam has a half-life of approximately 15 to 20 hours when administered IV, and 46 hours when administered rectally.^12,22 However, because of high lipophilicity, redistribution into fat occurs rapidly following administration, reducing the duration of action to 15 to 30 minutes.²² The increased lipophilicity compared with lorazepam is likely why lorazepam has been favored historically.

Lorazepam is available as a solution for injection in concentrations of 2 mg/mL and 4 mg/mL. Vials should be refrigerated, but can be kept at room temperature for 24 hours if necessary.²¹ Upon IV administration, lorazepam terminates seizures in approximately 6 to 10 minutes.²² Seizure cessation in children occurs much faster, approximately 2 minutes following administration.⁹ Lorazepam has a half-life of approximately 16 hours in pediatric patients, resulting in a very long duration of action (>12-24 hours).^8,9,12,22

Midazolam is available as a solution for IV or IM injection in concentrations of 0.5 mg/mL, 1 mg/mL, and 5 mg/mL.¹² This solution also may be used for IN administration with a nasal mucosal atomization device and administered buccally by dripping directly into the cheek.²¹ Midazolam exhibits a rapid onset of action when administered IV (3-5 minutes) or IN (4-8 minutes); owing to its short half-life (3 hours), however, it is not typically used as initial treatment for SE.^2,12,21,22 Silbergleit and colleagues found that time to seizure termination was approximately 3 minutes when administered IM.¹⁴

Benzodiazepine Safety and Tolerability

Benzodiazepines have similar safety profiles, with variable severity and frequency of ADRs. Sedation is common, but respiratory depression and hypotension are cause for heightened concern, as these may require supportive interventions including, but not limited to, mechanical ventilation and vasopressor support.^2,22

Chamberlain and colleagues found that IV lorazepam had significantly more sedation (Riker score <3) than IV diazepam (66.9% vs. 50% of children treated [absolute risk reduction, 16.9%; 95% CI, 6.1%-27.7%; P <.05]).⁹ In a meta-analysis of trials comparing midazolam with diazepam for first-line SE treatment, McMullan and colleagues noted that only 0.7% out of 750 children reported respiratory complications requiring intubation or assisted ventilation, and all cases were from a study of non-IV benzodiazepine AEDs.¹⁷ IM midazolam and IV diazepam have a similar safety profile, according to Silbergleit and colleagues.¹⁴ In fact, higher doses of benzodiazepines may be associated with a lower number of respiratory interventions, since prolonged SE requires intubation more often than can be attributed to benzodiazepine AEs.¹⁴

Conclusion

Although the treatment of pediatric SE has been examined in a number of trials, the current NCS guidelines are based primarily on expert opinion. Historically, IV lorazepam has been the preferred benzodiazepine for primary treatment of SE, despite the lack of FDA approval for this specific indication. Recent data support the use of diazepam and midazolam, in addition to lorazepam, for cessation of seizures in pediatric SE. Older anticonvulsants, such as phenytoin and fosphenytoin, have fallen somewhat out of favor owing to ADRs, but they maintain a place in therapy as secondary agents. Refractory SE is treated on an individual basis with potent agents such as propofol and pentobarbital, which require more sophisticated monitoring and additional medical support. The primary goals of SE treatment are urgent cessation of seizures and prevention of recurrence, since sustained and/or recurrent seizure activity can have devastating effects.

REFERENCES

1. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1981;22:489-501.
2. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17:3-23.
3. Saz EU, Karapinar B, Ozcetin M, et al. Convulsive status epilepticus in children: etiology, treatment protocol and outcome. Seizure. 2011;20:115-118.
4. Asadi-Pooya AA, Poordast A. Etiologies and outcomes of status epilepticus in children. Epilepsy Behav. 2005;7:502-505.
5. Chin RF, Neville BG, Peckham C, et al. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet. 2006;368:222-229.
6. Meierkord H, Boon P, Engelsen B, et al; European Federation of Neurological Societies. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol. 2010;17:348-355.
7. Raspall-Chaure M, Chin RF, Neville BG, et al. The epidemiology of convulsive status epilepticus in children: a critical review. Epilepsia. 2007;48:1652-1663.
8. Rose E, Claudius I. Pediatric critical care. Emerg Med Clin North Am. 2014;32:939-954.
9. Chamberlain JM, Okada P, Holsti M, et al. Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial. JAMA. 2014;311:1652-1660.
10. Chamberlain JM, Capparelli EV, Brown KM, et al. Pharmacokinetics of intravenous lorazepam in pediatric patients with and without status epilepticus. J Pediatr. 2012;160:667-672.e2.
11. Riviello JJ Jr, Claassen J, LaRoche SM, et al. Treatment of status epilepticus: an international survey of experts. Neurocrit Care. 2013;18:193-200.
12. Micromedex Healthcare Series [online database]. Greenwood Village, CO: Truven Health Analytics; 2015.
13. Shah MI, Macias CG, Dayan PS, et al. An evidence-based guideline for pediatric prehospital seizure management using GRADE methodology. Prehosp Emerg Care. 2014;18(suppl 1):15-24.
14. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366:591-600.
15. Silbergleit R, Lowenstein D, Durkalski V, Conwit R. Lessons from the RAMPART study—and which is the best route of administration of benzodiazepines in status epilepticus. Epilepsia. 2013;54(suppl 6):74-77.
16. Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev. 2008;(16):CD001905.
17. McMullan J, Sasson C, Pancioli A, Silbergleit R. Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis. Acad Emerg Med. 2010;17:575-582.
18. Rey E, Tréluyer JM, Pons G. Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes. Clin Pharmacokinet. 1999;36:409-424.
19. Malamiri RA, Ghaempanah M, Khosroshahi N, et al. Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial. Eur J Paediatr Neurol. 2012;16:536-541.
20. Misra UK, Kalita J, Maurya PK. Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study. J Neurol. 2012;259:645-648.
21. Lexicomp Online [online database]. Hudson, OH: Lexi-Comp, Inc; 2015.
22. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus. JAMA. 1993;270:854-859.
23. Midazolam oral transmucosal route. An alternative to rectal diazepam for some children. Prescrire Int. 2013;22:173-177.
24. Lapenta L, Morano A, Casciato S, et al. Clinical experience with intravenous valproate as first-line treatment of status epilepticus and seizure clusters in selected populations. Int J Neurosci. 2014;124:30-36.

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