James Lee, MD, Linda Huh, MD, FRCPC, Paul Korn, MD, FRCPC, Kevin Farrell, MD, MBChB

Guideline for the management of convulsive in infants and children

Children treated more aggressively and those with shorter episodes of status epilepticus have been found less likely to develop neuro- logical deficits.

ABSTRACT: Convulsive status epi - onvulsive status epilepticus underlying cause is considered to be lepticus is a accounts for 70% of episodes the most important determinant of out- requiring early and effective treat- Cof status epilepticus (SE) oc- come, and the morbidity appears to be ment. Airway, respiratory, and circu- curring in infants and children.1 Status less in those with febrile and unpro- latory support should be provided epilepticus, whether convulsive or non- voked status epilepticus.6 Studies of immediately. Initial investigations convulsive, is “an epileptic status epilepticus in primates have should then focus on possible meta- that is sufficiently prolonged or re - demonstrated a direct relationship bolic derangements and conditions peated at sufficiently brief intervals between the duration of the seizure that require immediate treatment, so as to produce an unvarying and and the development of permanent such as . The recommen - enduring epileptic condition.”2 Early injury that probably occurs as a ded first-line therapy includes a fast- studies used a definition of continu- result of the depletion of energy sub- acting followed by a ous seizure activity lasting for 30 min- strate.10 In addition, children treated longer-acting antiepileptic. In cases utes or recurrent without any more aggressively and those with of refractory status epilepticus, fur- intervening recovery of full con- shorter episodes of SE are less likely ther treatment will depend on the sciousness.3 However, most seizures to develop subsequent neurological setting. When pediatric intensive in children that last for longer than 7 deficits or .9 Similarly, resist- care is not available, minutes will last for at least 30 min- ance to first- and second-line treat- or might be used. When utes.4 Consequently, it is generally ments for SE is directly related to the pediatric intensive care is available, recommended that seizures lasting for duration of seizures prior to treat- , , and pro - more than 5 minutes should be treated ment.11,12 These studies demonstrate pofol are options. Neuroimaging by as for status epilepticus.5 Because of that a prolonged seizure per se can either CT or MRI should be under- the significant morbidity and mortali- result in brain injury and emphasize taken only after the patient has been ty associated with SE, early and effec- stabilized and the convulsive seizure tive treatment is essential. Dr Lee is a pediatric resident at activity controlled. BC Children’s Hospital (BCCH). Dr Huh is Morbidity and mortality an assistant professor in the Division of More effective treatment of status Pediatric Neurology at the University of epilepticus has reduced the mortality British Columbia. Dr Korn is a clinical asso- rate in children to between 1% and ciate professor in the Department of Pedi- 5%.6-9 However, status epilepticus can atrics at UBC. Dr Farrell is a neurologist at be associated with significant morbid- BC Children’s Hospital (BCCH) and a pro- ity, including epilepsy, motor disor- fessor in the Department of Pediatrics at This article has been peer reviewed. ders, and cognitive abnormalities. The the University of British Columbia.

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the importance of early and effective convulsive status epilepticus in infants trose administered if blood glucose is treatment of SE. and children recommended by phy - less than 3 mmol/L. Antiepileptic drug sicians at BC Children’s Hospital levels should be determined if the pa- Causes of status (BCCH). The initial management in - tient is receiving phenobarbital, phen - epilepticus in children volves stabilization of the airway, ytoin, , or valproic acid. It is important to consider the under- maintenance of adequate ventilation A computed tomography or mag- lying cause of status epilepticus. The (with oxygen administered as neces- netic resonance imaging scan of the cause will guide the investigations, sary), and circulatory support. Intra- head should be considered if there are may require immediate treatment, and venous access should then be estab- clinical indications, such as a focal has a major influence on the progno- lished as this permits the most rapid neurological abnormality, or if the sis. In approximately one-quarter of delivery of a drug to the brain. If dif- cause is unknown. If neuroimaging is children affected, status epilepticus is ficulty is encountered achieving intra- done, it should be undertaken only the sign of an underlying acute brain venous access within 3 minutes, then after the patient has been stabilized disorder, such as traumatic brain in jury intraosseous access should be estab- and the convulsive seizure activity or meningitis. Approximately one- lished if possible. During the manage- controlled.13 third of children affected will have a ment of the patient, it is important to history of previous epileptic seizures, consider the duration of the seizure Drugs developmental delay, or other neuro- both prior to and during treatment. Physicians are generally aware of the logical abnormality. One-quarter of The initial laboratory studies doses of medications children affected will have a prolonged should focus on the possible causes of used in adults, but unfamiliarity with febrile and no other cause status epilepticus, particularly those the doses and routes used in children will be demonstrated. An underlying that require immediate treatment, such sometimes results in administration of cause will not be found in the remain- as meningitis and reversible derange- inappropriate doses.14,15 Table 1 des - ing children. ments of metabolism.13 Investigations cribes the doses for initial treatment in should include complete blood count, children based on their weight. Initial management and blood culture (in febrile children), investigations serum electrolytes, and blood glucose. The accompanyingFigure describes Blood glucose should also be checked Benzodiazepines act rapidly and are the organized approach to managing at the bedside and 5 mL/kg 10% dex- the medications for first-line treatment of convulsive status epilepticus. The dose of whichever benzodiazepine is Table 1. Drugs for initial treatment of convulsive status epilepticus. used should be repeated after 5 min- Drug Dose and route Notes utes if the seizure continues. . Intravenous lorazepam Lorazepam 0.1 mg/kg (max 4 mg) IV • Can be repeated once after 5 min is the treatment of choice for status 0.3 mg/kg (max 5 mg in infants and • IV dose should be given over 2 to 5 epilepticus. It has a longer duration of 10 mg in children) IV, IO min to avoid respiratory 0.5 mg/kg (max 10 mg) PR • Can be repeated once after 5 min action and fewer adverse effects than 15,16 0.2 mg/kg (max 10 mg) IN or diazepam, and has been reported Midazolam • Can be repeated once after 5 min 0.5 mg/kg (max 10 mg) buccal to be associated with more rapid seizure • Should be given over 20 min control than IV diazepam.17 Peak con- 18–20 mg/kg IV, IO • Monitor for bradycardia, , centrations of sublingual lorazepam cardiac arrhythmia may not occur for 60 minutes18 and • IV 1.5–3.0 mg/kg/min (max 150 19 18–20 mg/kg of phenytoin rectal absorption is erratic. Conse- mg/min) equivalents IV or IM • IM in single or divided doses quently, sublingual and rectal loraze- pam are not recommended for the • Monitor for respiratory depression, Phenobarbital 15–20 mg/kg IV hypotension treatment of status epilepticus. Diazepam. 0.3–0.4 mL/kg (max total volume 10 Intravenous diazepam Paraldehyde mL) mixed in an equal amount of should be administered over 2 min- mineral or PR utes because the risk of respiratory IV = intravenous; IO = intraosseous; PR = per rectal; IN = intranasal; IM = intramuscular depression is increased with more

280 BC MEDICAL JOURNAL VOL. 53 NO. 6, JULY/AUGUST 2011 www.bcmj.org Guideline for the management of convulsive status epilepticus in infants and children

Status epilepticus is defined as a seizure that lasts for > 30 min or recurrent seizures without full recovery between seizures for > 30 min. A child who has been convulsing for > 5 minutes should be treated as for status epilepticus.

Manage ABCs Blood tests Cardiac monitor; oximeter CBC, electrolytes and glucose; glucometer Establish IV access Measure blood level if on PHB, DPH, Place in the recovery position CBZ or VPA

Attempt IV

IV lorazepam 0.1 mg/kg over Buccal midazolam 0.5 mg/kg ½–1 min (max 4 mg) (max 10 mg) Or Rapid IV Or IV diazepam 0.3 mg/kg over Yes access No Intranasal midazolam 2 min (max 5 mg in infants obtained? 0.2 mg/kg (max 10 mg) and 10 mg in child) Or Benzodiazepine can be Rectal diazepam 0.5 mg/kg/ repeated once after 5 min Insert intraosseous (max 10 mg) needle if seizure is Benzodiazepine can be not stopped with repeated once after 5 min rectal benzo

Is child on phenytoin?

Yes No

IV phenobarbital 20 mg/kg over IV/I0 phenytoin 20 mg/kg in N 20 mins saline over 20 min Or (max 1000 mg) IV/I0 phenytoin 10 mg/kg in N Give phenytoin after the first saline over 20 min (max 500 mg) dose of benzo unless febrile Give phenytoin or phenobarbital and the seizure has stopped after the first dose of benzo unless febrile and the seizure has stopped Seizure stopped?

Admit to hospital, investigate and treat potential causes of Yes Further management after cessation status epilepticus No of seizure: Rapid sequence Obtain further history intubation Recent trauma, , ingestion, drug history, seizure history Further investigations: (as indicated by IV/IO midazolam 0.1 mg/kg loading dose (max of 8 mg) over 2–3 min clinical presentation and history if not done on initial presentation) Then NOTES • Blood culture; blood gas; clotting stud- • IV attempts should be limited to 3 tries 120 µg/kg/hour infusion. Increase by 120 µg/kg/hour ies, enzymes; or 90 seconds. Intraosseous should be every 5 min if the seizure continues (should be deferred until cessation of Maximum 1440 µg/kg/hour inserted if IV attempts fail. clinical seizure); imaging (CT head) • Rectal paraldehyde: If available, can be • In selected patients: administered prior to phenytoin or phe- Consider: High-dose plasma: ammonia, lactate, amino acids; nobarbital (0.3 to 0.5 mL/kg in same phenobarbital urine: organic acids, toxicology volume of mineral oil to a maximum of thiopental infusion Initiate appropriate therapy as indi- 10 mL). cated: • Empiric anti-meningitic does of IV anti - Rapid sequence intubation: biotics and acyclovir (in febrile patient • Atropine: 0.02 mg/kg (maximum 0.6 mg) Admit to ICU/call anesthetist without identified etiology) • : 2 mg/kg • Appropriate maintenance antiepileptic • Succinylcholine: 2 mg/kg (maximum medications 150 mg) Continue supportive care Admit to appropriate ward or ICU

Figure. Management of convulsive status epilepticus in infants and children.

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rapid administration and with more toin is preferred over phenobarbital, Peak plasma concentration of fos- than two doses.15 Rectal diazepam is which is more likely to cause respira- phenytoin is observed at the end of IV absorbed rapidly and attains a thera- tory depression and to alter the child’s infusion and 20 to 39 minutes after IM peutic level in 10 minutes.20 level of consciousness. Drugs that administration.30 Intravenous fosphen - Midazolam. Midazolam is a fast- alter consciousness complicate the ytoin can be administered at a rate of acting, water-soluble benzodiazepine assessment of the child when the con- up to 1.5 mg/kg/min (maximum 150 that can be administered intravenous- vulsion has stopped. mg/min).27,28 When IV access is not ly and is rapidly absorbed via both the Phenytoin. Phenytoin is administered possible, IM fosphenytoin (18 to 20 nasal and buccal mucosa.21,22 Studies at a dose of 18 to 20 mg/kg intraven - mg/kg of phenytoin equivalents) should be given as a single dose.

What to do when first-line treatment fails Convulsive status epilepticus that is If the child is not in a hospital that is refractory to a benzodiazepine and an appropriate longer-acting anticonvul- able to provide pediatric intensive care sant occurs in approximately 40% of 9 including respiratory support, either cases and is associated with higher morbidity and mortality.31,32 The man- intravenous phenobarbital or rectal agement of the child in that situation paraldehyde can be used. depends partly on the setting. When pediatric intensive care and respiratory support are not available If the child is not in a hospital that is able to provide pediatric intensive in children have shown both buccal ously or by the intraosseous route26 care including respiratory support, and intranasal midazolam to be more over 20 minutes (with a maximum either intravenous phenobarbital or effective than rectal diazepam in chil- infusion rate of 50 mg/min). Adminis- rectal paraldehyde can be used. How- dren with acute .21,23 The tration should start immediately after ever, consultation with a pediatric absence of studies comparing the the first dose of a benzodiazepine. intensivist at BCCH is recommended. efficacy of IV midazolam with that of Intravenous phenytoin treatment may Phenobarbital. IV phenobarbital is lorazepam or diazepam limits our be complicated by bradycardia, hypo- administered in a loading dose of 15 ability to recommend midazolam for tension, and cardiac arrhythmia, so to 20 mg/kg.33 It is highly effective but first-line treatment of status epilepti- cardiorespiratory is rec- has a long duration of action. Pheno- cus in children. However, it is consid- ommended. In children who are re - is more likely than phenytoin ered to be of particular value in refrac- ceiving phenytoin prior to the onset of to cause sedation, respiratory depres- tory status epilepticus.24,25 status epilepticus, we recommend the sion, and hypotension, particularly if use of a smaller dose of phenytoin (5 a benzodiazpine has also been admin- Longer-acting antiepileptic mg/kg over 5 min), while awaiting the istered. medications results of a blood phenytoin level. Paraldehyde. Rectal paraldehyde is ad- A longer-acting antiepileptic drug When IV access cannot be achieved ministered mixed in an equal amount should also be administered because promptly, intramuscular (IM) fosphen- of mineral or olive oil. It is effective of the relatively short duration of ytoin or rectal paraldehyde can be in 66% to 74% of children with con- action of benzodiazepines. At BCCH, used. vulsive status epilepticus and respira- it is our practice not to do this in febrile Fosphenytoin. Fosphenytoin is a tory depression is uncommon.34 The children with a seizure lasting less water-soluble phenytoin that restricted availability of paraldehyde than 15 minutes who respond imme- can also be administered by either in- in recent years has limited its use. diately to a benzodiazepine. Pheny- travenous or intramuscular routes.27-29

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When pediatric intensive care Table 2. Drugs used for refractory convulsive status epilepticus. is available There have been no controlled trials Drug Dose and route Notes on the management of refractory sta- Bolus: 0.1 mg/kg IV • Prolonged infusion may tus epilepticus in children. However, Midazolam Initial infusion: 2 µg/kg/min IV; titrate to effect result in accumulation in midazolam, a (thiopental, (maximum 24 µg/kg/min) peripheral tissues , or phenobarbital), and Bolus: 3–5 mg/kg IV; additional boluses of 1–2 mg/kg every 3 to 5 min to response (max total propofol are the most commonly used Thiopental dose 10 mg/kg) drugs. Table 2 describes the doses Infusion: 3–5 mg/kg/h IV used for refractory SE. However, be - • Prolonged infusion may Bolus: 10 mg/kg IV cause these drugs can cause cardio- Pentobarbital result in accumulation in Infusion: 0.5–1.0 mg/kg/h IV respiratory compromise and intuba- peripheral tissues tion may be necessary, they should Bolus: 1 mg/kg IV loading dose; additional 1–2 • Use with caution in patients mg/kg boluses every 3–5 min to response <16 years be administered only in centres with Propofol (max 10 mg/kg) • Risk of propofol infusion appropriate facilities. Overtreatment Infusion: 2–4 mg/kg/h IV syndrome of refractory status epilepticus is asso- ciated with significant mortality and the management of refractory status mg/kg, followed by a 2 µg/kg/min pental in children with refractory sta- epilepticus in children should be per- infusion. This initial infusion rate can tus epilepticus.38 Prolonged use in formed in consultation with the staff be titrated to effect, up to a maximum children (beyond 48 hours) is associ- of a pediatric intensive care unit. of 24 µg/kg/min. After prolonged in- ated with an increased risk of propo- We recommend midazolam for fusion, midazolam may accumulate in fol infusion syndrome, which is her- first-line treatment because of its rel- peripheral tissues and result in a pro- alded by and is ative ease of use and because treat- longed half-life of up to 50 hours.36,37 characterized by circulatory collapse, ment can be initiated once the airway Barbiturates (thiopental, pentobar- , and cardiac arrhyth- is appropriately secured. When mida- bital). Thiopental can be administered mias.37 It is considered to be relative- zolam fails to achieve seizure control, as a 3 to 5 mg/kg bolus, followed by ly safe when used at infusion rates up a barbiturate or propofol can be used. additional boluses of 1 to 2 mg/kg to 4 mg/kg/h for short duration and Treatment with these requires prior every 3 to 5 minutes until a clinical when the dose is reduced if the child rapid sequence induction, intubation, response is achieved, up to a maxi- develops side effects.38,39 We recom- and ventilatory support. mum total dose of 10 mg/kg. There- mend that it be used with caution in Midazolam. Several authors have after, it can be infused at a rate of 3 to children under the age of 16 years and recommended the use of midazolam 5 mg/kg/h.33 Pentobarbital is adminis- only by specialists with experience in for first-line treatment in refractory tered as a 10 mg/kg bolus, followed its use. The loading dose is 1 mg/kg; SE, citing the high response rate and by a continuous infusion at a rate of additional 1 to 2 mg/kg boluses can be low complication rate.9,32,35 One meta- 0.5 to 1.0 mg/kg/h. After continuous administered every 3 to 5 minutes analysis comparing treatments of re- administration, there is a tendency until a clinical response is achieved, fractory SE in children found that toward accumulation in body tissues, up to a maximum dose of 10 mg/kg. midazolam was associated with better resulting in the need for prolonged Continuous infusion, started at an ini- efficacy and less mortality than dia- ventilatory support even after the with- tial rate of 2 to 4 mg/kg/h, can be titrat- zepam, , pentobarbital, and drawal of medication. Hypotension is ed to achieve on thiopental.32 a common of barbitu- EEG. The infusion rate should not The short elimination half-life rates. At BCCH it is our practice to use exceed 4 mg/kg/h; if seizure control is (1.5–3.0 hours) and large volume of barbiturate doses that achieve burst not achieved rapidly, another agent distribution of midazolam make it suppression on EEG. should be used.33 Acid-base imbalance, suitable for continuous IV infusion32 Propofol. Propofol has a rapid onset increased serum creatine phosphoki- but result in an increased risk of break- of action and a short half-life (between nase, and increased serum triglycerides through seizures if not administered 1 and 2 hours), which permits rapid are markers of propofol infusion syn- as an infusion or as multiple boluses.33 titration. One study found propofol drome and should be monitored care- We recommend a loading dose of 0.1 infusion more efficacious than thio - fully. Propofol should be avoided in

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ness. Neuromuscular paralysis, which 8. Maytal J, Shinnar S, Moshe SL, et al. Low Key points for may be used to facilitate respiratory morbidity and mortality of status epilep- management of support, prevents detection of clinical ticus in children. Pediatrics 1989;83: convulsive status seizures, and an EEG should be ob - 323-331. epilepticus tained if neuromuscular paralysis is 9. Lambrechtsen FA, Buchhalter JR. Abort- • Convulsive status epilepticus is being used to manage the child.42 ed and refractory status epilepticus in a medical emergency requiring children: A comparative analysis. Epilep- early treatment. Summary sia 2008;49:615-625. • Seizures lasting longer than 5 Convulsive status epilepticus in chil- 10. Meldrum BS, Brierley JB. Prolonged minutes should be treated as for dren is a medical emergency that is epileptic seizures in primates. Ischemic status epilepticus. handled most effectively with an or - cell change and its relation to ictal physi- • Benzodiazepines are the first- ganized approach. Drugs for initial ological events. Arch Neurol 1973;28: line pharmacological treatment. treatment include benzodiazepines 10-17. • Treatment with phenytoin should and longer-acting antiepileptics. The 11. Alldredge BK, Wall DB, Ferriero DM. be initiated immediately follow- treatment of refractory status epilepti- Effect of prehospital treatment on the ing benzodiazepines. cus will depend on the setting. Up- outcome of status epilepticus in children. • Initial investigations should be dates in the approach described in this Pediatr Neurol 1995;12:213-216. undertaken to identify causes article will be posted on the guidelines 12. Lewena S, Young S. When benzodiaze- that require immediate treatment section of the Child Health BC web- pines fail: How effective is second line and metabolic derangements. site: www.childhealthbc.ca. therapy for status epilepticus in children? • Management of refractory con- Emerg Med Australas 2006;18:45-50. vulsive status epilepticus in Competing interests 13. Riviello JJ Jr, Ashwal S, Hirtz D, et al. children may be associated with None declared. Practice parameter: Diagnostic assess- cardiac and respiratory compli- ment of the child with status epilepticus cations and consultation with References (an evidence-based review): Report of the staff of a pediatric intensive 1. Yager JY, Cheang M, Seshia SS. Status the Quality Standards Subcommittee of care unit is recommended. epilepticus in children. Can J Neurol Sci the American Academy of Neurology and 1988;15:402-405. the Practice Committee of the Child Neu- 2. Gastaut H (ed). Dictionary of epilepsy. rology Society. Neurology 2006;67:1542- children on the because Geneva: World Health Organization; 1973. 1550. of its interference with oxi- 3. Guidelines for epidemiologic studies in 14. Tobias JD, Berkenbosch JW. Manage- dation.40 epilepsy. Commission on Epidemiology ment of status epilepticus in infants and and Prognosis, International League children prior to pediatric ICU admission: Has the seizure really Against Epilepsy. Epilepsia 1993;34:592- Deviations from the current guidelines. stopped? 596. South Med J 2008;101:268-272. Nonconvulsive status epilepticus may 4. Shinnar S, Berg AT, Moshe SL, et al. How 15. Chin RF, Neville BG, Peckham C, et al. exist when clinical seizure activity has long do new-onset seizures in children Treatment of community-onset, childhood stopped. It occurs in up to approxi- last? Ann Neurol 2001;49:659-664. convulsive status epilepticus: A prospec- mately 20% of children after treat- 5. Lowenstein DH, Bleck T, Macdonald RL. tive, population-based study. Lancet ment of refractory convulsive status It’s time to revise the definition of status Neurol 2008;7:696-703. epilepticus.9 Nonconvulsive status epilepticus. Epilepsia 1999;40:120-122. 16. Treiman DM, Meyers PD, Walton NY, et epilepticus should be suspected if the 6. Raspall-Chaure M, Chin RF, Neville BG, al. A comparison of four treatments for child has subtle muscle jerks, eye de - et al. Outcome of paediatric convulsive generalized convulsive status epilepti- viation, or abnormal eye movements.41 status epilepticus: A systematic review. cus. Veterans Affairs Status Epilepticus Although impaired consciousness Lancet Neurol 2006;5:769-779. Cooperative Study Group. N Engl J Med after convulsive status epilepticus can 7. Chin RF, Neville BG, Peckham C, et al. 1998;339:792-798. be caused by other factors, such as Incidence, cause, and short-term out- 17. Prasad K, Krishnan PR, Al-Roomi K, et al. medications, and the , come of convulsive status epilepticus in Anticonvulsant therapy for status epilep- an EEG should be obtained if there is childhood: Prospective population-based ticus. Br J Clin Pharmacol 2007;63: persistent impairment of conscious- study. Lancet 2006;368(9531):222-229. 640-647.

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