Seizure 20 (2011) 115118

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Seizure
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Convulsive status epilepticus in children: Etiology, treatment protocol and outcome

Eylem Ulas Saz a, Bulent Karapinar b, Mustafa Ozcetin a, Muzaffer Polat c, Ayse Tosun c, Gul Serdaroglu c, Sarenur Gokben c, Hasan Tekgul c,*
a b c

Pediatric Emergency Department, Ege University School of Medicine, 35100 Bornova, Izmir, Turkey Pediatric Intensive Care Unit, Ege University School of Medicine, 35100 Bornova, Izmir, Turkey Pediatric Neurology Department, Ege University School of Medicine, 35100 Bornova, Izmir, Turkey

A R T I C L E I N F O

A B S T R A C T

Article history: Received 14 July 2010 Received in revised form 21 September 2010 Accepted 25 October 2010 Keywords: Protocol Efcacy Midazolam Children Outcome Status epilepticus

This study aimed to determine the etiology, treatment protocol and outcome of convulsive status epilepticus (SE) in children. An institutional treatment protocol using benzodiazepines (diazepam and midazolam) was assessed in a retrospective case study. The treatment protocol (Ege Pediatric Status Epilepticus Protocol or EPSEP) was developed based on an operational denition of pediatric SE according to the duration of seizure activity. Pediatric SE is divided into three categories: initial SE (20 30 min), established SE (3060 min) and refractory SE (>60 min). Eight (30%) of the studied episodes were initial SE, 10 (37%) were established SE, and 9 (33%) were refractory SE. With respect to the etiological spectrum of SE, 11 (40%) children had meningitis or encephalitis. Febrile SE was identied in 7 (26%) patients. Only 2 episodes of initial SE (7.5%) were controlled with rst step of the protocol (two concomitant-doses of rectal diazepam). Midazolam bolus and infusions (up to 1.2 mg/kg/min) were used to treat 22 episodes of SE (9 refractory SE, 10 established SE and 3 initial SE). Complete arrest of convulsive SE was achieved in 21 of 22 (95%) episodes with midazolam infusion. We concluded that the combined use of benzodiazepines (diazepam + midazolam) was safe and effective in the treatment of convulsive SE in children. 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction Status epilepticus (SE) is a serious neurological problem in children. Both convulsive and nonconvulsive SE affects people of all ages, though it is more common and causes greater morbidity and mortality in infants.15 Age, etiology, and the duration of seizure activity correlate with mortality.6 Convulsive SE dened as a seizure lasting more than 30 min or recurrent seizures lasting more than 30 min from which the patient does not regain consciousness (ILAE, 1981). However the current denition of 30 min is not universally accepted, and several clinical studies have been published using duration of 10 or 20 min.6,7 It has been reported that the mortality is nearly 10-fold higher for seizure lasting 30 min or longer than for those lasting 1029 min.7 The optimal management of children with SE remains unclear, and large, controlled studies comparing the various agents are

lacking. All patients with SE must be managed with aggressive monitoring of their hemodynamic and respiratory status and continuous EEG monitoring. There are multiple regimens for treating SE in children.810 The choice of initial agent may depend on individual patient characteristics, prior antiepileptic drug therapy, and physician preference. However more information is needed to develop a structured treatment regimen based on an operational denition for SE. In this study we aimed to determine the etiology and outcome of SE in children treated according to an institutionalized treatment regimen (Ege Pediatric Status Epilepticus Protocol or EPSEP). 2. Subjects/methods This study included 27 children suffering from convulsive SE admitted to the intensive care unit of Ege University Hospital. The children were managed according to a structured protocol for pediatric status epilepticus. SE is diagnosed according to the established criteria of continues seizures for 30 min or longer or several seizures occurring with impairment of consciousness between seizures.6,7,11,12 Initial SE consists of the rst 1020 min of the epileptic state, during which physiological mechanisms

* Corresponding author at: Ege University School of Medicine, Department of Pediatrics, Division of Pediatric Neurology, 35100 Bornova, Izmir, Turkey. Tel.: +90 5327218586; fax: +90 2324218900. E-mail address: hasan.tekgul@ege.edu.tr (H. Tekgul).

1059-1311/$ see front matter 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2010.10.034

116 Table 1 Patients demographics and classication of status epilepticus. Initial SE (2030 min) Number of patients (%) Boys/girls Age years (range) Febrile/afebrile Lethargy (%) Coma 8 (30%) 3/5 2.6 (15) 5/3 8 (30%)

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Established SE (>30 min) 10 (37%) 7/3 3.4 (0.610) 6/4 10 (37%)

Refractory SE (>60 min) 9 (33%) 7/2 5.5 (0211) 2/7 5 (18%) 4 (15%)

Total 27 17/10 3.8 (0.211) 13/14 23 (85%) 4 (15%)

compensate for the greatly enhanced metabolic activity. Established SE is dened as the stage beyond 30 min, where the status continues despite early-stage treatment. It is during this phase that physiological compensation mechanisms begin to fail. If seizures continue for 6090 min after the initiation of therapy, SE is considered refractory. In this study SE patients were divided it into three group based on the duration of continuing convulsive seizure activity: initial SE (2030 min seizure activity), established SE (>30 min) and refractory SE (>60 min). EEG was not used for the diagnosis of convulsive SE. Instead it was performed after the seizures had been controlled to monitor the electrical suppression of seizure discharges. However, EEG was used initially to conrm any diagnosis of nonconvulsive SE. The diagnosis of nonconvulsive SE was based on established criteria.13 All children underwent imaging of the brain (computed tomography or magnetic resonance imaging) and relevant investigations, including metabolic work-up, when indicated. Other demographic characteristics such as age, sex, mental status and underlying disease, were recorded for each patient. A structured institutional treatment regimen of pediatric status epilepticus (Ege Pediatric Status Epilepticus Protocol or EPSEP) has been used since 2004 in the emergency room (ER) and the pediatric intensive care unit (PICU) of Ege University Hospital. The protocol was developed based on the characteristics of the ER and the PICU. Since the release of rectal diazepam in Turkey we have not used intravenous diazepam in the initial management of SE. Phenytoin and midazolam were introduced as second-line medication in the protocol because of the lack of certain medications (e.g., lorazepam and fosphenytoin) in Turkey.  Step I: Children who presented with prolonged seizure (>5 min) received two repeated doses of 0.5 mg/kg of rectal diazepam during the rst 10 min of the episode.  Step II: After 15 min of episodes, one of the following second line drug was administered (1) 20 mg/kg of intravenous phenytoin or (2) a bolus of midazolam (0.15 mg/kg iv).  Step III: If the child continued to exhibit SE, the amount of intravenous midazolam was increased every 5 min up to 0.6 mg/ kg/min. After achieving seizure control, the infusion was continued for at least 24 h. Subsequently, midazolam infusion was gradually decreased by 0.05 mg/kg/min every 6 h until tapering was completed. If a seizure continued for 60 min after the infusion (0.6 mg/kg/min), the amount of midazolam the maintenance infusion was increased up to 1.2 mg/kg/min. During this infusion, vital parameters such as the respiratory rate, heart rate, blood pressure, and arterial oxygen saturation were monitored continuously.  Step IV: If seizures continued for 6090 min after the initiation of therapy propofol infusion (1 mg/kg/h) was introduced. 3. Results There were 17(63%) boys and 10(37%) girls admitted with status epilepticus (SE). The age of the patients ranged from 2.5 months to 11 years, with a mean of 3.8 1.8 years. Eight episodes

(30%) were initial SE, 10 (37%) were established SE, and 9 (33%) were refractory SE. Twenty-three patients (85%) were assessed as lethargic (10, established SE; 8, initial SE; 5, refractory SE) and 4 (15%) children were in coma when they arrived at the PICU (Table 1). At the time of admission to the PICU, children in comas were more likely to have refractory SE (p < 0.001) (95% CI). With respect to the etiological spectrum of SE, 11 (40%) children had meningitis or encephalitis. Febrile SE was identied in 7 (26%) patient. Five (19%) had cerebral cortical dysgenesis, 3 (11%) had hypoxic ischemic encephalopathy, and 1 had trauma. While the majority (85%: 11 out of 13) febrile episodes occurred in younger patients, afebrile refractory episodes more likely to be seen in older patients (53.3%: 8 out of 15) (p = 0.004) (95% CI). Of the 9 children with refractory SE, 7 had meningitis or encephalitis and 2 had cerebral cortical dysgenesis,. None of the children with febrile SE had refractory SE. Only 2 of 27 (7.5%) episodes of SE were controlled by step I of EPSEP (two concomitant does of rectal diazepam). Three of the patients with initial SE had cardiovascular contraindications during the phenytoin infusion in step II of EPSEP that might be related to the phenytoin infusion (2 had hypotension and 1 had drug extravasation). Midazolam infusion was used to treat 22 episodes of SE (9 refractory SE, 10 established SE and 3 initial SE). Complete arrest of seizures was achieved in 21 of the 22 (95%) patients (p < 0.001) (95% CI). Continuous midazolam infusion up to 1.2 mg/kg/min was effective in 8 of 9 (89%) of the children with refractory SE without signicant side effects. One episode of refractory SE was controlled by intravenous propofol infusion (Table 2). After midazolam infusion, adverse events were seen in 4 patients (20%). There was a transient drop in oxygen saturation in 1 child. This child had received per-rectal diazepam (2 0.5 mg/kg) and phenytoin prior to midazolam infusion. To improve the childs oxygen saturation, oxygen was administrated by face mask for less
Table 2 Ege Pediatric Status Epilepticus Protocol (EPSEP) in children with convulsive status epilepticus. Pediatric convulsive status epilepticus (SE) n = 27 Initial SE (2030 min) n = 8 (30%) Step I Diazepam responsive (n = 2, 7.5%) Step II Phenytoin responsive (n = 3, 11%) Midazolam (bolus) responsive (n = 3, 11%) Step III Midazolam (infusion up to 0.6 mg) responsive (n = 10, 52%) Midazolam (infusion up to 1.2 mg) responsive (n = 8, 42%) Step IV Propofol responsive (n = 1)

n = 19 Established SE (>30 min) n = 10 (37%) Refractory SE (>60 min) n = 9 (33%)

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than 24 h. There were 3 children with mild hypotension who required only intravenous uids, after which they remained normotensive. Three children needed intubation as they experienced respiratory arrest following per-rectal diazepam plus phenytoin (2 two children) and midazolam infusion followed propofol (1 child). No serious intervention was needed. During the management of SE, the electrolytes and glucose remained normal in all patients. There were no deaths within one year of the episode of SE in the 27 children included in the cohort. However, at the one-year follow-up 4 children (14.8%) developed new either motor or visual decit in the refractory SE group (40%) and none of the patient from the initial and established SE groups had neurological decits (p < 0.001, CI 95%). All of the children with neurological sequelae had refractory SE due to encephalitis. None of the children with febrile SE had neurological sequelae. 4. Discussion Convulsive SE is the most common form of status epilepticus and is estimated to account for about 90% of all cases in children.1417 Here we report that Ege Pediatric Status Epilepticus Protocol (EPSEP) outlined in the Subjects and Methods section is an effective and safe regimen for the treatment of children with convulsive SE. Most cases of SE can be treated successfully with rst-line medications (e.g., diazepam, lorazepam, phenytoin, and phenobarbital).7,8 However, approximately 15% to 30% of SE episodes are refractory to these conventional therapies. In children, the incidence of refractory SE is not accurately known. In a study of 193 children with SE, dened by seizure duration longer than 30 min, 26% had status epilepticus that lasted longer than 60 min.3 In the present study, refractory SE was identied in 33% of children with convulsive SE, a percentage that is consistent with the results, previously published in both adult (30%) and pediatric studies (31%).18,19 The optimal management of children with refractory SE remains unclear, and large, controlled studies comparing the various treatment agents are lacking. The most commonly used agent for treating refractory SE is intravenous pentobarbital, a short-acting barbiturate with rapid onset of action. Although effective in terminating seizures and inducing a burst suppression pattern on EEG, pentobarbital administration is commonly associated with signicant hypotension, myocardial depression, and low cardiac output. Other side effects include pulmonary edema, ileus, and delayed neurologic recovery. Because of these disadvantages, alternative agents for the treatment of refractory SE have been investigated. The efcacy of continuous midazolam infusion and the corresponding rate of mortality in childhood refractory convulsive status epilepticus has been reported.2022 In this study we also found that continuous midazolam infusion up to 1.2 mg/kg/min was effective in 89% of the children with refractory SE without signicant side effects. Midazolam is a water-soluble benzodiazepine with a fast onset of action, that is commonly used as a preanesthetic agent with remarkable anticonvulsant action. It also has a short half-life and its metabolites are inactive. Midazolam has been very effective in terminating seizures refractory to diazepam, lorazepam, phenytoin, and phenobarbital.8,10 It has been shown to have a wide margin of safety and a broad therapeutic index. Furthermore, it diffuses rapidly across the capillary wall into the central nervous system and can be mixed with saline or glucose solutions to allow its administration as a continuous infusion.9,21,22 A recent retrospective multicenter study found that the efcacy of midazolam was not as high as has been reported previously (64.5% versus 75 100%).23 However, in our study we found that midazolam was effective in 21 of 22 (95%) episodes. Hypotension is the most commonest adverse event associated with the administration of intravenous midazolam, but there is

considerable variation in the prevalence of hypotension across studies. In our study, although three patients (11%) required uid administration to address hypotension they did not require inotropic support. This mirrors the nding of Igartua et al.24 in a study that is also notable for the relatively high doses of midazolam employed. Morrison et al.25 reported that in 12% of patients required uid administration, Singhi et al.26 recorded hypotension in 28% (6/21) of patients started on intravenous midazolam therapy. Status epilepticus occurs more often in young children. More than 80% of the younger children in our study had status epilepticus of febrile or acute symptomatic etiology, whereas older children were more likely to be in the cryptogenic or remote symptomatic categories. The older children were also more likely to be neurologically abnormal (55% versus 21%) and to have a history of seizures (64% versus 20%) than those children younger than two years of age.18,19 In our series, all status episodes were seen in a relatively young population (mean age 3.8 1.8 years). While the majority (85%) of febrile episodes occurred in younger patients, afebrile refractory episodes were more likely to be seen in older patients (53.3%) (p = 0.004) (95% CI). Based on these and previously reported ndings in young children, it appears that episodes in young children occur primarily in children who are neurologically normal and with no history of unprovoked seizures. In older children, status epilepticus occurs primarily in those who are known to have prior unprovoked seizures and who are often also neurologically abnormal. Although the sex ratio (male/female) of our patients was 1.7, which is similar to ratios in previous reports4,27 and this male preponderance should be investigated in future studies. Similar to most of the previous studies, the most common underlying cause of status epilepticus in these children particularly in the early and established groups were febrile seizures/CNS infections and idiopathic seizures (66%). The other main causes of status epilepticus in our series were cerebral-dysgenesis/congenital cerebral abnormalities, anoxia/hypoxic ischemic encephalopathy and trauma. Overall, our data on etiology is concordant with that from other studies in the literature.4,23 Neurological sequelae have been reported in more than 50% of patients with refractory status epilepticus.24,2833 Neurological sequelae are associated with age of the child and the underlying causes. However, the incidence of sequelae was primarily dependent on duration of follow-up (at discharge; 54%, at one month; 32%, at 1 year; 23%). In our study, this incidence was 15% among all of our study patients (4/10, 40% of patients with refractory status epilepticus). We believe that this low rate as strongly associated with the inclusion of younger patients and more febrile episodes. In the present study, we assessed our institutional treatment protocol for convulsive SE. Using this protocol, we found that midazolam infusion was successful in 95% of cases. Only 7.5% of cases responded to rst-line therapy with diazepam, which indicates that step 1 was a failure. Only 11% responded to a midazolam bolus used in the second step, which could also be interpreted as a failure, whereas eight of nine children with refractory SE responded to a midazolam infusion. Since a midazolam infusion up to 1.2 mg is safe, and there were not signicant side effects. We conclude that combined benzodiazepine therapy (diazepam in step I and midazolam in step II and step III) is effective and safe. In the present institutional protocol, intravenous (iv) valproate and iv levetiracetam were not included for the treatment of established and refractory cases. However both drugs have been suggested for treatment of established and refractory SE.3437 Refractory SE can be controlled with intravenous loading and maintenance of valproate or levetiracetam which do not cause respiratory depression or hypotension and do not require the

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E.U. Saz et al. / Seizure 20 (2011) 115118 16. Pellock JM. Use of midazolam for refractory status epilepticus in pediatric patients. J Child Neurol 1998;13:5817. 17. Shorvon S. Tonic-clonic status epilepticus. J Neurol Neurosurg Psychiatry 1993;56:12534. 18. Johnston MV. Seizures in childhood. In: Behrman RE, Kliegman RM, Jensen HB, editors. Nelson textbook of pediatrics, 17th ed., vol. 2. Philadelphia: Saundres; 2004. p. 19932005. 19. Asadi-Pooya AA, Poordast A. Etiologies and outcomes of status epilepticus in children. Epilepsy Behav 2005;7:5025. 20. Philips SA, Shanahan RJ. Etiology and mortality of status epilepticus in children: a recent update. Arch Neurol 1989;46:746. 21. McIntyre J, Robertson S, Norris E, Appleton R, Whitehouse WP, Phillips B, et al. Safety and efcacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 2005;366:20510. 22. Hayashi K, Osawa M, Aihara M, Izumi T, Ohtsuka Y, Haginoya K, et al. Efcacy of intravenous midazolam for status epilepticus in childhood. Pediatr Neurol 2007;36:36672. 23. Gross-Tsur V, Shinnar S. Convulsive status epilepticus in children. Epilepsia 1993;34(Suppl. 1):S1220. 24. Igartua J, Silver P, Maytal J, Sagy M. Midazolam coma for refractory status epilepticus in children. Crit Care Med 1999;27:19825. 25. Morrison G, Gibbons E, Whitehouse WP. High-dose midazolam therapy for refractory status epilepticus in children. Intensive Care Med 2006;32:20706. 26. Singhi S, Murthy A, Singhi P, Jayasharee M. Continuous midazolam versus diazepam infusion for refractory convulsive status epilepticus. J Child Neurol 2002;17:10610. 27. Shinnar S, Pellock JM, Moshe SL, Maytal J, ODell C, Driscoll SM, et al. In whom does status epilepticus occur: age-related differences in children. Epilepsia 1997;38:90714. 28. Rivera R, Segnini M, Baltodano A, Perez V. Midazolam in the treatment of status epilepticus in children. Crit Care Med 1993;21:9914. 29. Ozdemir D, Gulez P, Uran N, Yendur G, Kavakli T, Aydin A. Efcacy of continuous midazolam infusion and mortality in childhood refractory generalized convulsive status epilepticus. Seizure 2005;14:12932. 30. Metsaranta P, Koivikko M, Peltola J, Eriksson K. Outcome after prolonged convulsive seizures in 186 children: low morbidity, no mortality. Dev Med Child Neurol 2004;46:48. 31. Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002;59:20510. 32. Sahin M, Menache CC, Holmes GL, Riviello JJ. Outcome of severe refractory status epilepticus in children. Epilepsia 2001;42:14617. 33. van Gestel JP, Blusse van Oud-Alblas HJ, Malingre M, Ververs FF, Braun KP, van Nieuwenhuizen O. Propofol and thiopental for refractory status epilepticus in children. Neurology 2005;65:5912. 34. Abend NS, Gutierrez-Colina AM, Dlugos DJ. Medical treatment of pediatric status epilepticus. Semin Pediatr Neurol 2010;17(September (3)):16975. 35. Reiter PD, Huff AD, Knupp KG, Valuck RJ. Intravenous levetiracetam in the management of acute seizures in children. Pediatr Neurol 2010;43(August (2)):11721. 36. Tripathi M, Vibha D, Choudhary N, Prasad K, Srivastava MV, Bhatia R, et al. Management of refractory status epilepticus at a tertiary care centre in a developing country. Seizure 2010;19(March (2)):10911. [Epub 2010 January 19]. 37. Trinka E. The use of valproate and new antiepileptic drugs in status epilepticus. Epilepsia 2007;48(Suppl. 8):4951.

patient to be intubated or placed in ICU care. IV valproate and levetiracetam were released into the market in Turkey in 2008. This recent release of these drugs precluded their use in this protocol. These two drugs also should be tested in the institutional treatment protocols for pediatric status epilepticus. In conclusion, Ege Pediatric Status Epilepticus Treatment Protocol (EPSEP) using combined benzodiazepines (diazepam + midazolam) as initial treatment is an effective and safe regimen for children with convulsive status epilepticus. The protocol should be studied in a large, prospective, randomized, multicenter trial so that physicians can implement evidence-based treatment strategies for the treatment of pediatric status epilepticus. References
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