J Pediatr (Rio J).

2017;93(s1):84---94

www.jped.com.br

REVIEW ARTICLE

Management protocols for status epilepticus in the

pediatric emergency room: systematic review article夽
Cheuk C. Au a,b , Ricardo G. Branco c,∗ , Robert C. Tasker a,d

a
Boston Children’s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine, Division of Critical Care Medicine,
Boston, United States
b
Queen Mary Hospital, Department of Paediatric and Adolescent Medicine, Hong Kong, China
c
Cambridge University Hospitals NHS Trust, Paediatric Intensive Care Unit, Cambridge, United Kingdom
d
Boston Children’s Hospital, Department of Neurology, Boston, United States

Received 7 June 2017; accepted 23 July 2017

Available online 21 September 2017

KEYWORDS Abstract
Status epilepticus; Objective: This systematic review of national or regional guidelines published in English aimed
Seizure; to better understand variance in pre-hospital and emergency department treatment of status
Protocol; epilepticus.
Guideline Sources: Systematic search of national or regional guidelines (January 2000 to February 2017)
contained within PubMed and Google Scholar databases, and article reference lists. The search
keywords were status epilepticus, prolonged seizure, treatment, and guideline.
Summary of findings: 356 articles were retrieved and 13 were selected according to the inclu-
sion criteria. In all six pre-hospital guidelines, the preferred route of medication administration
was to use alternatives to the intravenous route: all recommended buccal and intranasal
midazolam; three also recommended intramuscular midazolam, and five recommended using
rectal diazepam. All 11 emergency department guidelines described three phases in therapy.
Intravenous medication, by phase, was indicated as such: initial phase --- ten/11 guidelines rec-
ommended lorazepam, and eight/11 recommended diazepam; second phase --- most (ten/11)
guidelines recommended phenytoin, but other options were phenobarbital (nine/11), valproic
acid (six/11), and either fosphenytoin or levetiracetam (each four/11); third phase --- four/11
guidelines included the choice of repeating second phase therapy, whereas the other guide-
lines recommended using a variety of intravenous anesthetic agents (thiopental, midazolam,
propofol, and pentobarbital).
Conclusions: All of the guidelines share a similar framework for management of status epilep-
ticus. The choice in route of administration and drug type varied across guidelines. Hence, the

夽 Please cite this article as: Au CC, Branco RG, Tasker RC. Management protocols for status epilepticus in the pediatric emergency room:

systematic review article. J Pediatr (Rio J). 2017;93:84---94.

∗ Corresponding author.

E-mail: [email protected] (R.G. Branco).

http://dx.doi.org/10.1016/j.jped.2017.08.004
0021-7557/© 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Emergency seizure protocols 85

adoption of a particular guideline should take account of local practice options in health service
delivery.
© 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).

PALAVRAS-CHAVE Protocolos de manejo de estado de mal epiléptico no pronto socorro pediátrico:

Estado de mal análise sistemática
epiléptico;
Resumo
Convulsão;
Objetivo: Esta análise sistemática de diretrizes nacionais ou regionais publicadas em inglês
Protocolo;
tem como objetivo entender melhor a diferença no tratamento do estado de mal epiléptico
Diretriz
pré-hospitalar e no departamento de emergência.
Fontes: Pesquisa sistemática de diretrizes nacionais ou regionais (janeiro de 2000 a fevereiro
de 2017) contidas nas base de dados do Pubmed e do Google Acadêmico e listas de referência
de artigos. As palavras-chave da busca foram estado de mal epiléptico, convulsão prolongada,
tratamento e diretriz.
Resumo do achados: 356 artigos foram identificados, e 13 foram selecionados de acordo com
os critérios de inclusão. Em todas as seis diretrizes pré-hospitalares, o caminho preferencial
de administração da medicação foi utilizar alternativas à via intravenosa: todas recomen-
daram midazolam bucal e intranasal; três também recomendaram midazolam intramuscular; e
cinco recomendaram utilizar o diazepam via retal. Todas as 11 diretrizes de departamento de
emergência descreveram três fases na terapia. No que diz respeito à medicação intravenosa,
por fase, temos: fase inicial --- 10/11 diretrizes recomendaram lorazepam e 8/11 recomendaram
diazepam; segunda fase --- a maioria (10/11) das diretrizes recomendou fenitoína, porém out-
ras opções foram fenobarbital (9/11), ácido valpróico (6/11) e fosfenitoína ou levetiracetam
(individualmente, 4/11); terceira fase --- 4/11 diretrizes incluíram a opção de repetir a ter-
apia da segunda fase, ao passo que as outras diretrizes recomendaram utilizar diversos agentes
anestésicos intravenosos (tiopental, midazolam, propofol e pentobarbital).
Conclusões: Todas as diretrizes compartilham uma estrutura semelhante para manejo do estado
de mal epiléptico. A escolha da via de administração e do tipo de medicamento variou em todas
as diretrizes. Assim, a adoção de uma diretriz específica deve levar em consideração as opções
da prática local na prestação de serviços de saúde.
© 2017 Sociedade Brasileira de Pediatria. Publicado por Elsevier Editora Ltda. Este é um artigo
Open Access sob uma licença CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.
0/).

Introduction This article discusses some of the issues related to

emergency anticonvulsant treatment of acute, prolonged
Status epilepticus (SE) is defined as ‘‘a condition result- seizures and SE in children with particular emphases on
ing either from the failure of mechanisms responsible pre-hospital, emergency medical services (EMS), and emer-
for seizure termination or from the initiation of mecha- gency department (ED) guidelines, as well as protocols
nisms which lead to abnormally prolonged seizures (after used by national and regional societies, organizations, and
time point t1 ), and a condition that can have long-term authorities. The reader interested in other management,
consequences (after time point t2 ), including neuronal investigations, and subsequent clinical follow-up in the out-
death, neuronal injury, and alteration of neuronal networks, patient department or by the primary care practitioner
depending on the type and duration of seizures, etc. In the should review recent practice reviews and the American
case of convulsive (tonic---clonic) SE, both time points (t1 at Academy of Neurology recommendations.2,3
5 min and t2 at 30 min) are based on animal experiments and
clinical research’’.1
Therefore, in children, there are two subgroups of
patients presenting with a seizure: those with brief episodes Methods
<5 min duration (before t1 ) that are highly likely to resolve
without treatment; and those with episodes >7 min, who are Source of data
more likely to progress to prolonged episodes necessitat-
ing acute treatment to stop the seizure. The consensus of A systematic review of articles available in the PubMed and
the International League Against Epilepsy (ILAE) task force Google Scholar databases was carried out. Reference lists
on the classification of SE is that treatment of convulsive of articles identified were also checked. The search strat-
seizures should therefore be initiated at around 5 min.1 egy included the combination of the following keywords in
86 Au CC et al.

English: status epilepticus, prolonged seizure, treatment, guidelines, one at 5 min11 and the other at 10 min.13
and guideline. All of the guidelines stated a preference for alternative
non-intravenous routes of administration rather than gain
Selection criteria intravenous access on arrival. Two of the guidelines11,13
recommended attempting to place either intravenous or
intraosseous access in specific situations. Finally, only one
In this qualitative review, articles were selected for con-
of the guidelines provided criteria for patient transfer to
sideration using the PRISMA (Preferred Reporting Items
ED.13
for Systematic Reviews and Meta-Analyses) group 2009
statement.4 Published articles were included in the review
when they met the following criteria: (1) protocol or
Comment on pre-hospital EMS guidelines
guideline on the use of anticonvulsant drug treatment for
Midazolam through the buccal or intranasal route was rec-
prolonged seizure or SE published January 1st, 2000 to
ommended in the six pre-hospital guidelines. This guidance
February 28th, 2017; (2) publication that featured a national
likely reflects the efficacy of midazolam versus diazepam,
or regional guideline for the pediatric population in the EMS
and the ease of administration by these access routes.
or ED setting; and (3) when more than one article was iden-
However, rectal diazepam was still present in most of the
tified from the same organization or society, the most recent
pre-hospital guidelines. Buccal midazolam is more effec-
publication was included.
tive than rectal diazepam for stopping seizures and reducing
All articles that met the inclusion criteria were submitted
their recurrence within 1 h of onset, and as safe as rec-
to data extraction and critical evaluation by each author.
tal diazepam in relation to the incidence of respiratory
The main characteristics were summarized following data
depression.18 The effectiveness of intranasal midazolam
extraction: authorship; period of management; EMS or ED;
is similar to, or more effective than rectal diazepam.
time course of treatment; and recommended medication
Intranasal midazolam also has a shorter drug administra-
and administration route.
tion time and faster action to seizure cessation than rectal
diazepam. Intranasal midazolam is easy to administer, but it
Data synthesis/analysis has a short-lasting nasal irritant effect. A systematic review
demonstrated that midazolam, by any route, is superior in
The search strategy of the databases identified a total of seizure cessation than diazepam, by any route.19
356 listed titles. Each abstract was screened and 344 were Besides efficacy and ease of administration, the choice
excluded because they did not meet the inclusion criteria. of non-intravenous benzodiazepines depends on local avail-
Twelve articles were eligible for full review, and their refer- ability, expertise, and preference. For example, according
ence lists identified one further article. A total of 13 articles to Osborne et al.,13 ambulances in the United Kingdom
were therefore included in the qualitative synthesis, and did not carry midazolam, and so EMS staff would admin-
their findings were descriptively analyzed.5---17 ister the patient’s own buccal or intranasal midazolam,
if available; otherwise, rectal diazepam would be used
Results and discussion because of the difficulty gaining intravenous access in chil-
dren. For similar reasons, rectal diazepam was commonly
available and recommended in the Italian League Against
Table 1 describes the characteristics of the treatment guide-
Epilepsy pre-hospital guideline.10 The World Health Orga-
lines. Table 2 presents use of immediate (‘‘STAT’’ or statim
nization (WHO) pediatric emergency triage assessment and
[Latin]) anticonvulsant drug by type, dosing and route of
treatment (ETAT) guideline14 recommends that, when oral
administration covered in the guidelines. It is evident that
and intranasal preparations of midazolam and lorazepam
the guidelines do not recommend exactly the same dosing
are not readily available, especially in resource-limited
for each anticonvulsant drug. However, these differences
settings, the available intravenous preparations could be
may be due to regional preference, history, or experience.
administered through the oral or intranasal routes. Last,
Developers of new guidelines should take into account the
intramuscular midazolam was recommended in three of the
spread in dosing and the maxima recommended, as well as
six guidelines.10,11,14 Such administration requires additional
any new clinical drug studies that are published after 2017.
expertise, and it is effective and safe. For example, in
the Rapid Anticonvulsant Medication Prior to Arrival Trial
Pre-hospital management (RAMPART), intramuscular midazolam was as effective as
intravenous lorazepam in the pre-hospital setting.20 Similar
Six guidelines focused on EMS management.7,10---14 Fig. 1 rates of endotracheal intubation and recurrence of seizures
presents the algorithm by the Emergency Medical Services were observed in both the midazolam and lorazepam groups.
for Children (EMSC) for comparison.11 This guideline should Considered together, all of the guidelines recommended the
be applied to children with a witnessed seizure that was not non-intravenous route of administration.
due to trauma, and was ongoing at the time of arrival of the Two of the guidelines recommend attempting intra-
EMS. venous or intraosseous access only in specific situations.11,13
Overall, all six guidelines recommended buccal mida- The EMSC algorithm11 in the United States considers obtain-
zolam or intranasal midazolam, and three recommended ing intravenous or intraosseous access when the expected
intramuscular midazolam.10,11,14 Five guidelines recom- transport time was long, or when it would be required for
mended rectal diazepam as an option.7,10,12---14 A second other aspects of patient care such as intravenous fluid or
dose of benzodiazepine was recommended in two of the other medications. The United Kingdom Joint Royal Colleges
Emergency seizure protocols 87

Table 1 Guideline or protocol characteristics.

Year, Ref # Country or Region Endorsed by Population (A, P) Scope

EMS ED
2014,11 USA Emergency Medical Services for Children P Y ---
2015,13 UK Joint Royal Colleges Ambulance Liaison Committee A, P Y ---
2011,7 Canada Canadian Paediatric Society Acute Care Committee P Y Y
2013,10 Italy Italian League Against Epilepsy P Y Y
2014,12 India Association of Child Neurology (Indian) P Y Y
2016,14 Global World Health Organization ETAT P Y Y
2000,5 UK British Paediatric Neurology Association P --- Y
2009,6 Aus/NZ Paediatric Research in EDs International Collaborative P --- Y
2012,8 USA Neurocritical Care Society A, P --- Y
2012,9 UK NHS National Institute of Health and Care Excellence A, P --- Y
2016,15 USA American Epilepsy Society A, P --- Y
2016,16 Spain Spanish Society of Neurology A, P --- Y
2017,17 Hong Kong Hong Kong Epilepsy Society A, P --- Y

A, adult; P, pediatric; Aus/NZ, Australia and New Zealand; ED, Emergency Department; EMS, Emergency Medical Services; ETAT, pediatric
emergency triage assessment and treatment; NHS, National Health Service; UK, United Kingdom; USA, United States of America; Y, yes.

Ambulance Liaison Committee (JRCALC) algorithm13 recom- second anticonvulsant drug, when benzodiazepines have
mends a second dose of diazepam if the seizure continues failed. The third phase of therapy is the administration of a
after rectal diazepam, and that must be given via the general anesthetic drug under intensive care support when
intravenous or intraosseous route. Establishing intravenous SE has become refractory to at least two anticonvulsant
access could be difficult, however, in a child with an ongoing drugs from the first and second therapy phases.
seizure in the pre-hospital setting. It requires trained EMS The time to starting each phase of therapy was similar
providers and equipment, which may be lacking in resource- across the guidelines. In the initial phase of therapy, nine
limited settings (see ETAT guideline14 ). Furthermore, the of the guidelines reported a start time equal to, or earlier
seizure may stop before intravenous access is obtained, than the AES algorithm.5---7,9,10,12,15---17 The onset of the second
making the procedure unnecessary11 ; the time needed to and third phases of therapy were equal to, or earlier than,
set-up intravenous access may prolong the time at the the AES start times in five of the guidelines that stated the
scene and delay drug administration.13 start time.5---7,12,15 Endotracheal intubation was considered
Two of the guidelines recommended administering a sec- in the stabilization phase in two of the guidelines,8,15 and
ond dose of benzodiazepines in the pre-hospital setting.11,13 in the context of rapid sequence intubation in four of the
The other four guidelines did not include this option. Main- guidelines.5---7,9
taining adequate airway, breathing, and circulation while In regard to the route of anticonvulsant drug admin-
the patient is transferred to the ED,7,10,12,13 as well as com- istration, intravenous access may be available after the
municating with the medical control center for advice, pre-hospital stage of therapy (Fig. 1). When there is no intra-
are recommended.11 One guideline provided guidance on venous access at the start of the ED stage of treatment,
criteria for transfer to hospital. The JRCALC guideline13 the guidelines recommend intraosseous access in the ini-
recommends transfer to hospital for children under 1 year of tial (n = 1)6 or second phase of treatment (n = 2).5,7 In both
age, cases with their first seizure or first febrile convulsion, of these phases, benzodiazepines and phenytoin could be
and cases with serial seizures or difficulty monitoring. The administered through the intraosseous route.
JRCALC guideline13 also recommends a time-critical transfer
to the hospital if any of the following are present: difficulty
with airway, breathing, circulation, or disability problems;
serious head injury; SE after failed treatment; or, underlying
infection.
Comment on ED time course
No significant discrepancies were observed among the guide-
Emergency department management lines in regard to the timing for starting each phase of
anticonvulsant drug therapy. All guidelines recommended
Eleven guidelines focused on ED management.5---10,12,14---17 ‘‘starting the clock’’ when a seizure lasts longer than 5 min,
For comparison, the authors have selected the American which can be assumed to be whenever an actively seizing
Epilepsy Society (AES) algorithm for convulsive seizure patient arrives in the ED. This time point is also consistent
lasting at least 5 min.15 The structure of this algorithm with the new ILAE definition and classification of SE.1 A minor
follows three phases of therapy (Figs. 2---4, and Table 3). difference in timing in the guidelines is observed in the
The first phase of therapy is initial stabilization and the period needed for a stabilization phase, and the different
administration of a benzodiazepine. The second phase intervals between administering the options in anticonvul-
of therapy is the administration of a non-benzodiazepine sant drugs.
88 Au CC et al.

Table 2 Commonly used immediate anticonvulsant drug, administration route and dose.

Drug Administration route

Rectal Buccal (B)/Intranasal (N) Intraosseous Intravenous

(IO)/Intramuscular (IM)
Diazepam Bolus Bolus Bolus
0.2---0.5 mg/kg/dose15,17 IO: 0.25 mg/kg × 2 0.15---0.2 mg/kg × 2
doses6 doses15,17
0.5 mg/kg/dose5,6 0.2---0.3 mg/kg × 2
doses12
0.5 mg/kg × 2 doses7 0.25 mg/kg × 2 doses6
0.3 mg/kg × 2 dose7
0.5 mg/kg10
Maximum dose Maximum dose
10 mg6 ; 20 mg15,17 <5 year, 5 mg7 ; ≥5 year,
10 mg7 ; 10 mg10,12,15,17
Lorazepam Bolus Bolus Bolus
0.1 mg/kg × 2 doses7 B: 0.1 mg/kg × 2 0.1 mg/kg × 2
doses7,10 doses5,7,10,12,15,17
Maximum dose Maximum dose Maximum dose
4 mg7 B: 2.5 mg10 ; 4 mg7 4 mg5,7,10,12,15,17
Midazolam Bolus Bolus Bolus
B: 5---10 mg17 IO: 0.15 mg/kg × 2 0.15 mg/kg × 2 doses6
doses6
IN: 0.2 mg/kg7 IM: 0.15 mg/kg × 2 0.15 to 0.2 mg/kg × 2
doses6 doses12
IM: 0.2 mg/kg × 2 0.2 mg/kg × 2 doses10
doses7,10
Maximum dose Maximum dose
IN: 5 mg/nostril7 IM: 5 mg10 ; 13---40 kg,
5 mg15 ; >40 kg, 10 mg15 ;
10 mg17
Fosphenytoin Bolus Bolus
(PE, phenytoin
equivalents)
IM: 20 mg PE/kg7 20 mg PE/kg7,12,15
Maximum dose Maximum dose
IM: 1000 mg PE7 1000 mg PE7 ; 1500 mg
PE15
Phenytoin Bolus Bolus
IO: 20 mg/kg6 15---20 mg/kg16,17
18 mg/kg5
18---20 mg/kg10
20 mg/kg6,7,12
Maximum dose Maximum dose
IO: 1000 mg7 1000 mg11,16
Phenobarbital Bolus
10---20 mg/kg16
15 mg/kg/dose15,17
15---20 mg/kg10
20 mg/kg6,12
Maximum dose
1000 mg10
Emergency seizure protocols 89

Table 2 (Continued)

Drug Administration route

Rectal Buccal (B)/Intranasal (N) Intraosseous Intravenous

(IO)/Intramuscular (IM)
Valproic acid Bolus
20 mg/kg12
25---45 mg/kg16
30---45 mg/kg10
40 mg/kg15,17
Maximum dose
1500 mg10 ; 3000 mg15,17
Levetiracetam Bolus
20 mg/kg16
20---30 mg/kg12
60 mg/kg15,17
Maximum dose
4500 mg15,17

ED first phase anticonvulsant therapy medicines for children, the ETAT guideline recommends
intravenous diazepam in high temperature regions with no
In regard to the choice of anticonvulsant drug treat- refrigeration facility.14
ment, a benzodiazepine was universally recommended When a repeat dose of benzodiazepine is required
in the initial phase of therapy (Fig. 2 and Table 3). because of an ongoing seizure, four of the 11 guidelines6,7,9,10
Intravenous lorazepam was recommended in ten of recommended taking account of whether any pre-hospital
the guidelines,5---10,12,14,15,17 followed by intravenous benzodiazepine dose(s) had been administered, since EMS
diazepam in eight of the guidelines.6,7,10,12,14---17 If no dosing would affect the choice of next anticonvulsant
intravenous access was available, the most commonly drug. Interestingly, these four guidelines were published
recommended anticonvulsant drug was midazolam: intra- after 2008, which is when Chin et al.22 showed that in
muscular midazolam (n = 8),6---8,10,12,15---17 buccal midazolam community-onset childhood convulsive SE there was an
(n = 8),6,7,9,10,12,15---17 or intranasal midazolam (n = 5).6,7,12,15,16 association between no pre-hospital anticonvulsant drug
As an alternative, rectal diazepam (n = 7) was commonly treatment, or use of more than two doses of benzodi-
recommended.5,7,8,12,15---17 A repeated dose of benzodi- azepines, and SE lasting more than 60 min. Moreover, their
azepine was recommended in five guidelines; four of them study demonstrated that treatment with more than two
considered the pre-hospital dose received,6,7,9,10 while doses of benzodiazepines was associated with respiratory
the other excluded the pre-hospital dose.5 Intravenous depression. Only one guideline, from 2000, recommended
phenobarbital was recommended as a non-benzodiazepine excluding consideration of prior EMS treatment,5 and that
alternative in two of the guidelines.8,15 was on the basis of possible variability in pre-hospital
dosing.
Comment on ED first phase anticonvulsant therapy
Intravenous lorazepam and diazepam were the most com-
ED second phase anticonvulsant therapy
monly recommended intravenous benzodiazepines in the
first phase of therapy. All except for one guideline (from
In the second phase of therapy (Fig. 3 and Table 3),
the Spanish Society of Neurology) recommended intravenous
guideline recommendations for intravenous medications
lorazepam.16 In Spain, in 2016, intravenous lorazepam
included: phenytoin (n = 10),5---10,12,14,16,17 phenobarbital
was not available; thus, intravenous clonazepam is recom-
(n = 9),6---10,14---17 valproic acid (n = 6),8,10,14---17 fospheny-
mended instead. Intravenous lorazepam or diazepam are
toin (n = 4),7,12,14,15 and levetiracetam (n = 4).8,15---17 If no
efficacious and safe to use. For example, in one random-
intravenous access was available, intraosseous pheny-
ized controlled trial21 comparing intravenous lorazepam and
toin was recommended in three guidelines,5---7 and the
intravenous diazepam, 72.9% of the lorazepam group and
other options presented were intramuscular fosphenytoin,7
72.1% of the diazepam group had cessation of SE within
phenobarbital,14 and rectal paraldehyde.5,7
10 min without recurrence within 30 min, with similar rates
of assisted ventilation (17.6% in the lorazepam group and
16.0% in the diazepam group). In the resource-limited set- Comment on ED second phase anticonvulsant therapy
ting, one additional consideration with lorazepam use is the Intravenous phenytoin was the most commonly recom-
need for refrigeration of the drug, because of its degradation mended therapy for benzodiazepine-refractory SE. Together
at high temperature. Although both intravenous lorazepam with intravenous fosphenytoin (the prodrug of phenytoin),
and diazepam are included in the WHO model list of essential they were the second phase therapy of choice in all
90 Au CC et al.

Pre-hospital EMS treatment

Variance (n=6) EMS arrival

Seizure ongoing

Check BG & treat

No IV/IO access

Ongoing seizure or recurrent seizures

1st midazolam
No IV/IO access
• B (6), IN (6), IM (3)
st
1 diazepam 1st midazolam
•R (5) • Buccal
1st lorazepam • or intranasal

•B (1), R (2), IN (1), IM (1) • or intramuscular

5 minutes

2nd drug timing (2) No IV/IO access IV present

Timing 2nd midazolam 2nd BDZ

•5 minutes (1) • Buccal • Midazolam
• 10 minutes (1) • or intranasal • or lorazepam
• or intramuscular • or diazepam

call control

Transport to ED

Figure 1 Pre-hospital EMS treatment. B, buccal; BDZ, benzodiazepine; BG, blood glucose; ED, emergency department; EMS,
emergency medical system; IO, intraosseous; IN, intranasal; IM, intramuscular; IV, intravenous; R, rectal. Note: the number in
parentheses is guidelines-out-of-six in this category (see text for details).

guidelines. There are a number of reasons why fospheny- phenobarbital. For example, in a randomized controlled
toin should be recommended in preference to phenytoin: trial, although rapid intravenous loading of valproic acid
it does not require the excipient propylene glycol; it stopped seizures in a comparable rate to intravenous phe-
has less risk of hypotension and cardiac dysrhythmia; it nobarbital (90% versus 77%, no statistical difference), the
does not cause the serious extravasation reaction, pur- rate of adverse effects were lower (24% versus 74%); the
ple glove syndrome; and, it can be administered via phenobarbital group experienced more lethargy, vomiting,
the intramuscular route when intravenous access is not or respiratory depression.24 In comparison with intravenous
available.7 phenytoin, valproic acid is as effective in seizure control,
Intravenous phenobarbital was recommended in nine of and better tolerated in regard to risk of hypotension and
the 11 guidelines.6---10,14---17 Of note, two guidelines recom- respiratory depression, but it does cause mild elevation of
mended phenobarbital only if the patient had received liver enzymes.25 Taken together, valproic acid can be con-
phenytoin,9,16 the reasoning being that phenobarbital sidered an effective option for second phase anticonvulsant
has more depressant side effects than phenytoin (e.g., drug therapy.
respiratory depression and sedation), especially when ben- Levetiracetam was recommended in four of the 11
zodiazepines have already been used. The evidence for using guidelines.8,15---17 It has the advantages of good tolerability,
intramuscular phenobarbital is based on pediatric practice intravenous administration over relatively short time, and
in cerebral malaria.23 For example, an intramuscular dose absence of hemodynamic and sedative effects.10 Nonethe-
of 20 mg/kg reduces seizure frequency, but it causes an less, no randomized controlled trials of levetiracetam in
increased risk of respiratory depression and mortality, espe- pediatric convulsive SE have been conducted. A randomized,
cially in those who have already received multiple doses of pilot open study has demonstrated equivalence of effec-
diazepam.23 tiveness in seizure control with lorazepam, and it has less
Valproic acid was recommended in six of the 11 associated respiratory depression and hypotension.26
guidelines.8,10,14---17 Valproic acid may be hepatotoxic and Lastly, of relevance to the future of second phase
may lead to hyperammonemia. Three of the guidelines anticonvulsant drug treatment, there is an on-going mul-
point out that it should be avoided or used with caution ticenter randomized comparative effectiveness study, the
in liver disease (or suspected metabolic disease) and in Established Status Epilepticus Treatment Trial (ESETT; Clin-
children younger than 2---3 years with uncertain seizure icalTrials.gov: NCT01960075; due to be completed on
etiology.10,12,14 Valproic acid causes less hypotension or December 2019), which aims to determine the most effec-
respiratory depression when compared with phenytoin or tive ED treatment out of fosphenytoin, levetiracetam, and
Emergency seizure protocols 91

1st phase ED treatment

Variance (n=11) ED stabilization

ABCDEFG
Start time

0 min (4), 5 min (5) Monitoring & IVA

Ongoing seizure or recurrent seizures

5 minutes
No IV access
Alternatives Initial therapy
1st Midazolam
• B (8), IN (5), IM (8), IO (1) 1st BDZ 1st BDZ
• Midazolam (B,IN) • Midazolam (IM)
1st Diazepam
• or Diazepam (R) • or lorazepam
• R (7),IO (1)
• or, phenobarbital (IV) • or diazepam
1st Lorazepam
• R (1), IO (1)

IV present Repeat therapy

1st BDZ 2nd BDZ

• Lorazepam (10) • Lorazepam
• Diazepam (8) • or Diazepam
• Midazolam (4)
• Clonazepam (1)

20 minutes

Figure 2 First-phase ED treatment. ABCDEFG, stabilization support with intervention for Airway, Breathing, Circulation, Dextrose,
Essential neurology, Fluids, Global picture; BDZ, benzodiazepine; ED, emergency department; EMS, emergency medical system; IO,
intraosseous; IN, intranasal; IM, intramuscular; IV, intravenous; IVA, intravenous access; R, rectal. Note: the number in parentheses
is guidelines-out-of-11 in this category (see text for details).

valproic acid for benzodiazepine-refractory SE, and provide is available, and recommended the following before a
information on effectiveness and safety in children. midazolam infusion: either valproic acid and phenobarbi-
tal, or levetiracetam. The Italian League Against Epilepsy
guideline10 recommended valproic acid after second phase
ED third phase anticonvulsant therapy therapy, if delay or difficulty in endotracheal intubation was
expected.
In the third phase of therapy (Fig. 4 and Table 3), Finally, in regard to the choice of anesthetic agent,
four guidelines included the choice for repeating sec- the guidelines do not have clear recommendations for
ond phase therapy.7,10,12,15 Nine guidelines recommended preference between thiopental, midazolam, propofol, and
inducing anesthesia with thiopental5---9,12,15---17 ; all four of pentobarbital. Rather, specific drug selection is deferred to
the guidelines which recommended rapid sequence intu- local expertise. It should be noted, however, that although
bation suggested thiopental as the inducting agent.5---7,9 propofol is used in adult practice of refractory SE, the risk
Seven of the guidelines recommended using mida- of propofol infusion syndrome in children is unacceptable
zolam infusion,7,8,10,12,15---17 six recommended propofol and, therefore, continuous infusion is not recommended
infusion,6,8,10,15---17 and three recommended pentobarbital in a number of countries. In regard to the other anes-
infusion.7,8,15 thetic agents, the data on intensive care treatment of
pediatric refractory SE are of poor quality, yet they show a
Comment on ED third phase anticonvulsant therapy hierarchy in strategies: early midazolam by continuous infu-
At the time of starting the third phase of anticonvulsant sion, then barbiturates, and then trial of other anesthetic
drug treatment, four of the 11 guidelines included the therapies.27,28 Recently, a two-year prospective observa-
choice for repeating second phase therapy.7,10,12,15 The Cana- tional study assessed the use of continuous infusion of
dian Pediatric Society Acute Care Committee guideline7 anesthetic agent in pediatric patients (age range, 1 month
recommended a combination of using two second-phase to 21 years) with refractory SE not responding to two anti-
drug therapies, each separated by a 5-minute interval, convulsant drug classes.29 The United States Pediatric SE
before proceeding to the induction of anesthesia. The Research Group found that, in their 11 centers, midazo-
Association of Child Neurology (India, 2013)12 guideline lam and pentobarbital remain the mainstay of continuous
group considered the scenario when no intensive care bed infusion therapy.
92 Au CC et al.

2nd phase ED treatment

Variance (n=11) 20 minutes

Start time
• 10 minutes (3)

Ongoing seizure or recurrent seizures

• 20 minutes (2)
• 25 minutes (2)

No IV access 2nd therapy

Phenytoin (PHT) Single dose (IV)

• IO (3), IM (f-PHT 1) • Fosphenytoin
Phenobarbital • or valproate
• IM (1) • or levetiracetam
• or phenobarbital
Paraldehyde
• R (2)

IV present
• phenytoin (10)
• Phenobarbital (9)
• Valproate (6)
• Fosphenytoin (4) 40 minutes
• Levetiracetam (4)

Figure 3 Second-phase ED treatment. ED, emergency department; f-PHT, fosphenytoin; IO, intraosseous; IN, intranasal; IM,
intramuscular; IV, intravenous; R, rectal. Note: the number in parentheses is guidelines-out-of-11 in this category (see text for
details).

3rd phase ED treatment

Variance (n=11) 40 minutes

Start time
3rd therapy
• 30 min (2)
• 35 min (1)
• 40 min (2)
• 45 min (1)
Repeat 2nd therapy
Ongoing status epilepticus

Anesthesia

See figure 3 • Thiopental

• or midazolam
Repeat 2nd therapy (4) • or pentobarbital
• or propofol

Anesthesia Monitoring
• Thiopental (9) • ICU support
• Midazolam (7) • cEEG
• Propofol (6)
• Pentobarbital (3)
60 minutes

Figure 4 Third-phase ED treatment. cEEG, continuous electroencephalography; ED, emergency department; ICU, intensive care
unit. Note: the number in parentheses is guidelines-out-of-11 in this category (see text for details).

Conclusion interventions and follow-up is an important part of pedi-

atric practice.30 Guidelines on anticonvulsant drug therapy
Managing a child who presents in an emergency with a for a seizure or SE before and after arrival in the ED
seizure is a challenge; knowing how to best deal with acute serve as important reference documents in acute care. In
Emergency seizure protocols 93

Table 3 Comparison of anticonvulsant drugs used in each of the three phases of therapy and their administration routes (see
also, Tables 1 and 2).

Year, Ref # Group First-phase therapies Second-phase therapies Third-phase therapies

LZ DZ MZ PHT f-PHT PB VPA Lev Par TH MZ Pfl Pent

5
2000, BPNA iv r iv, io iv
2009,6 PREDICT iv, io iv, io im, b, in, io, iv iv, io iv iv iv
2011,7 CPS iv, r iv, r im, b, in, iv iv, io iv, im iv r iv iv iv
2012,8 NCS iv r im iv iv iv iv iv iv iv iv iv
2012,9 NICE iv b iv iv r iv
2013,10 LICE iv iv im, b iv iv iv iv iv iv
2014,12 AOCN iv iv, r im, b, in, iv iv iv iv
2016,14 WHO iv iv iv iv, im iv
2016,15 AES iv iv, r im, b, in iv iv iv iv iv iv iv iv
2016,16 SEN iv, r im, b, in, iv iv iv iv iv iv iv iv
2017,17 HKES iv iv, r im, b iv iv iv iv iv iv iv

Groups: AES, American Epilepsy Society; AOCN, Association of Child Neurology (India); BPNA, British Paediatric Neurology Association;
CPS, Canadian Paediatric Society; HKES, Hong Kong Epilepsy Society; LICE, Italian League Against Epilepsy; NCS, Neurocritical Care
Society; NICE, National Health Service National Institute of Health and Care Excellence; PREDICT, Paediatric Research in Emergency
Departments International Collaborative; SEN, Spanish Society of Neurology; WHO, World Health Organization. Therapies: DZ, diazepam;
Lev, levetiracetam; LZ, lorazepam; MZ, midazolam; Par, paraldehyde; Pent, pentobarbital; PB, phenobarbital; f-PHT, fosphenytoin; PHT,
phenytoin; Pfl, propofol; TH, thiopental; VPA, valproic acid. Routes: b, buccal; im, intramuscular; in, intranasal; io, intraosseous; iv,
intravenous; r, rectal.

this qualitative systematic review of 13 regional/national 5. Appleton R, Choonara I, Martland T, Phillips B, Scott R, White-
guidelines, we have found that each share similar frame- house W. The status epilepticus working party, members of the
works for practice and time points. Different routes of status epilepticus working party. The treatment of convulsive
benzodiazepine administration are feasible in the pre- status epilepticus in children. Arch Dis Child. 2000;83:415---9.
hospital (EMS) and first phase of ED therapy. The choice 6. Babl FE, Sheriff N, Borland M, Acworth J, Neutze J, Krieser
of benzodiazepines depends on presence of intravenous D, et al. Emergency management of paediatric status epilep-
ticus in Australia and New Zealand: practice patterns in the
access, local availability, skills of healthcare providers, and
context of clinical practice guidelines. J Paediatr Child Health.
the resource setting. Valproic acid and levetiractam have 2009;45:541---6.
better side effect profiles than phenytoin or fosphenytoin. 7. Friedman J. Emergency management of the paediatric patient
Direct comparison of effectiveness and safety of different with generalized convulsive status epilepticus. Paediatr Child
second phase therapy for SE awaits further clinical study. Health. 2011;16:91---104.
Finally, regarding the use of anesthetic agents in children, 8. Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T,
most of the experience and literature is in using midazolam et al. Guidelines for the evaluation and management of status
and then pentobarbital by continuous infusion. epilepticus. Neurocrit Care. 2012;17:3---23.
9. National Institute for Health Care Excellence. The epilepsies:
the diagnosis and management of the epilepsies in adults and
Conflicts of interest children in primary and secondary care. NICE Clinical Guide-
lines, No. 137; 2012.
The authors declare no conflicts of interest. 10. Capovilla G, Beccaria F, Beghi E, Minicucci F, Sartori S, Vecchi
M. Treatment of convulsive status epilepticus in childhood: rec-
ommendations of the Italian League Against Epilepsy. Epilepsia.
References 2013;54:S23---34.
11. Shah MI, Macias CG, Dayan PS, Weik TS, Brown KM, Fuchs SM,
1. Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar et al. An evidence-based guideline for pediatric prehospital
S, et al. A definition and classification of status epilepticus --- seizure management using GRADE methodology. Prehosp Emerg
report of ILAE task force on classification of status epilepticus. Care. 2014;S1:15---24.
Epilepsia. 2015;56:1515---23. 12. Mishra D, Sharma S, Sankhyan N, Konanki R, Kamate M, Kan-
2. Provisional Committee on Quality Improvement, Subcommittee here S, et al. Consensus guidelines on management of childhood
on Febrile Seizures. Practice parameter: the neurodiagnostic convulsive status epilepticus. Indian Pediatr. 2014;51:975---90.
evaluation of the child with a first simple febrile seizure. Pedi- 13. Osborne A, Taylor L, Reuber M, Grunewald RA, Parkinson
atrics. 1996;97:769---75. M, Dickson JM. Pre-hospital care after a seizure: evidence
3. Hirtz D, Ashwal S, Berg A, Bettis D, Camfield C, Camfield D, base and United Kingdom management guidelines. Seizure.
et al. Practice parameter: evaluating a first nonfebrile seizure 2015;24:82---7.
in children: report of the quality standards subcommittee of the 14. World Health Organization (WHO). Guideline: updates on pae-
American Academy of Neurology, The Child Neurology Society, diatric emergency triage, assessment and treatment: care of
and The American Epilepsy Society. Neurology. 2000;55:616---23. critically ill children. Geneva: WHO; 2016.
4. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. 15. Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge
Preferred reporting items for systematic reviews and meta- J, et al. Evidence-based guideline: treatment of convulsive
analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097. status epilepticus in children and adults: report of the guide-
94 Au CC et al.

line committee of the American Epilepsy Society. Epilepsy Curr. mortality in childhood cerebral malaria: a randomised, con-
2016;16:48---61. trolled intervention study. Lancet. 2000;355:701---6.
16. Mercade Cerda JM, Toledo Argani M, Mauri Llerda JA, Lopez 24. Malamiri RA, Ghaempanah M, Khosroshahi N, Nikkhah A, Bavar-
Gonzalez FJ, Salas Puig X, Sancho Rieger J. The Spanish Neu- ian B, Ashrafi MR. Efficacy and safety of intravenous sodium
rological Society official clinical practice guidelines in epilepsy. valproate versus phenobarbital in controlling convulsive sta-
Neurologia. 2016;31:121---9. tus epilepticus and acute prolonged convulsive seizures in
17. Fung EL, Fung BB. Review and update of the Hong Kong children: a randomised trial. Eur J Paediatr Neurol. 2012;16:
epilepsy guideline on status epilepticus. Hong Kong Med J. 536---41.
2017;23:67---73. 25. Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, Garg N.
18. McIntyre J, Robertson S, Norris E, Appleton R, Whitehouse WP, Randomized study of intravenous valproate and phenytoin in
Phillips B, et al. Safety and efficacy of buccal midazolam versus status epilepticus. Seizure. 2007;16:527---32.
rectal diazepam for emergency treatment of seizures in chil- 26. Misra UK, Kalita J, Maurya PK. Levetiracetam versus lorazepam
dren: a randomised controlled trial. Lancet. 2005;366:205---10. in status epilepticus: a randomized, open labeled pilot study. J
19. McMullan J, Sasson C, Pancioli A, Silbergleit R. Midazolam Neurol. 2012;259:645---8.
versus diazepam for the treatment of status epilepticus in 27. Wilks R, Tasker RC. Intensive care treatment of uncontrolled
children and young adults: a meta-analysis. Acad Emerg Med. status epilepticus in children: systematic literature search of
2010;17:575---82. midazolam and anesthetic therapies. Pediatr Crit Care Med.
20. Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, 2014;15:632---9.
Palesch Y, et al. Intramuscular versus intravenous therapy for 28. Tasker RC, Vitali SH. Continuous infusion, general anesthe-
prehospital status epilepticus. N Engl J Med. 2012;366:591---600. sia and other intensive care treatment for uncontrolled status
21. Chamberlain JM, Okada P, Holsti M, Mahajan P, Brown KM, Vance epilepticus. Curr Opin Pediatr. 2014;26:682---9.
C, et al. Lorazepam vs diazepam for pediatric status epilepticus: 29. Tasker RC, Goodkin HP, Sanchez Fernandez I, Chapman KE,
a randomized clinical trial. JAMA. 2014;311:1652---60. Abend NS, Arya R, et al. Refractory status epilepticus in
22. Chin RF, Neville BG, Peckham C, Wade A, Bedford H, Scott children: intention to treat with continuous infusions of mida-
RC. Treatment of community-onset, childhood convulsive sta- zolam and pentobarbital. Pediatr Crit Care Med. 2016;17:
tus epilepticus: a prospective, population-based study. Lancet 968---75.
Neurol. 2008;7:696---703. 30. Maia C, Moreira AR, Lopes T, Martins C. Risk of recurrence
23. Crawley J, Waruiru C, Mithwani S, Mwangi I, Watkins W, Ouma after a first unprovoked seizure in children. J Pediatr (Rio J).
D, et al. Effect of phenobarbital on seizure frequency and 2017;93:281---6.