48

The following organizations have endorsed this guideline:

Epilepsy Foundation

Child Neurology S ociety

Amer ican College of Emergency Physicians

Association of Child Neurology Nurses

Amer ican Association of Neuroscience Nurses

Epilepsy Cur rents,Vol. 16, No. 1 ( Januar y/Februar y) 2016 pp. 48Œ61

© Amer ican Epilepsy Societ y

Amer ican Epilepsy Society Guideline

Evidence -Based Guideline: Treatment of Convulsive Status

Epilepticus in Children and Adults: Repor t of the Guideline
Committee of the American Epilepsy S ociet y
Trac y Glauser, MD,
1
Shlomo Shinnar, MD, PhD,
2
David Gloss, MD,
3
Brian Alldredge, Phar mD,
4
Ravindra Ar ya,
MD, DM,
1
Jacquelyn Bainbr idge, Phar mD,
5
Mar y Bare, MSPH, RN
1
, Thomas Bleck , MD,
6
W. Edwin D odson, MD,
7

Lisa G ar r it y, Phar mD,

8
Andy Jagoda, MD,
9
Daniel Lowenstein, MD,
10
John Pellock, MD,
11
James R iviello, MD,
12
Edward Sloan, MD, MPH,
13
David M.Treiman, MD
14
1
Division of Neurology, Comprehensive Epilepsy Center, Cincinnati Children™s
Hospital M edical Center and University of Cincinnati College of
M edicine, Cincinnati, OH
2
D epar tments of Neurology, Pediatr ics, and Epidemiology and Population Health,
and the Comprehensive Epilepsy M anagement Center, M onte
-
˜ore M edical Center, Alber t Einstein College of M edicine, Bronx, NY
3
C AMC Neurology Group, Charleston, WV
4
S chool of Phar mac y, Universit y of Califor nia, San Francisco, C A
5
D epar tment of Clinical Pharmacy, Universit y of Colorado, Sk aggs S chool of Phar
mac y and Phar maceutical S ciences, Aurora, CO
6
D epar tments of Neurological S ciences, Neurosurger y, Medicine, and
Anesthesiology, Rush Universit y M edical Center, Chicago, IL
7
D epar tments of Neurology and Pediatr ics,Washington University S chool of M
edicine, St. Louis, MO
8
Division of Phar mac y, Cincinnati Children™s Hospital M edical Center, Cincinnati,
OH
9
D epar tment of Emergency M edicine, M ount Sinai Hospital, M ount Sinai S chool of
Medicine, NewYor k , NY
10
D epar tment of Neurology, Universit y of Califor nia, San Francisco, C A
11
Division of Pediatr ic Neurology,Virginia Commonwealth Universit y, R ichmond,VA
12
NYU Comprehensive Epilepsy Center, NewYork , NY
13
D epar tment of Emergency M edicine, Universit y of I llinois at Chicago, Chicago,
IL
14
Division of Neurology, Bar row Neurological I nstitute, Phoenix, AZ
Address cor respondence toTrac y Glauser, MD, Cincinnati Children™s Hospital
Medical Center, Division of Neurology, MLC 2015, 3333 Bur net Ave.,
Cincinnati, OH 45229-3026.

E-mail: trac [email protected]

CONTEX T:
The optimal pharmacologic treatment for ear ly convulsive status epilepticus is
unclear.
OBJEC TIVE:
To analyze ef
-
˜cac y, tolerabilit y and safet y data for anticonvulsant treatment of children and
adults with convulsive status epilepticus and use

this analysis to develop an evidence -based treatment algorithm.

DATA SOURCES:
Struc tured literature review using MEDLINE,
Embase, Cur rent Contents, and Cochrane librar y supplemented with article
reference lists.
STUDY SELEC TION:
R andomized
controlled trials of anticonvulsant treatment for seizures lasting longer than 5
minutes.
DATA EX TR AC TION:
I ndividual studies
were rated using prede˜ned criter ia and these results were used to for m
recommendations, conclusions, and an evidence -based

treatment algorithm.
RESULTS:
A total of 38 randomized controlled trials were identi˜ed, rated and contr ibuted
to the assess
-
ment. Only four tr ials were considered to have class I evidence of e˚cac y. Two
studies were rated as class II and the remaining

32 were judged to have class III evidence. In adults with convulsive status
epilepticus, intramuscular midazolam, intravenous

lorazepam, intravenous diazepam and intravenous phenobarbital are established as

e˚cacious as initial therapy (Level A). I ntra
-

muscular midazolam has superior e˛ec tiveness compared to intravenous lorazepam in

adults with convulsive status epilepticus

without established intravenous access (Level A). I n children, intravenous

lorazepam and intravenous diazepam are established

as e˚cacious at stopping seizures lasting at least 5 minutes (Level A) while rec

tal diazepam, intramuscular midazolam, intranasal

midazolam, and buccal midazolam are probably e˛ec tive (Level B). No signi˜cant
di˛erence in e˛ec tiveness has been demon
-

strated between intravenous lorazepam and intravenous diazepam in adults or

children with convulsive status epilepticus (Level

A). R espirator y and cardiac symptoms are the most commonly encountered treatment-
emergent adverse events associated

with intravenous anticonvulsant drug administration in adults with convulsive

status epilepticus (Level A).The rate of respirator y

depression in patients with convulsive status epilepticus treated with

benzodiazepines is lower than in patients with convul
-

49
Convulsive Status Epilepticus Guideline
Background
Tra
ditionally, brief seizures are de˜ned as lasting less than 5
minutes, while prolonged seizures last between 5 and 30 min
-

utes; status epilepticus is de˜ned as more than 30 minutes of

either 1) continuous seizure ac tivity or 2) t wo or more sequen

-

tial seizures without full recover y of consciousness between

seizures (1). The 30-minute de˜nition is based on the duration

of convulsive status epilepticus that may lead to per manent

neuronal injury by itself (2). Since the majorit y of seizures are

br ief, and once a seizure lasts more than 5 minutes it is likely

to be prolonged (3), status treatment protocols have used

a 5-minute de˜nition to minimize both the risk of seizures

reaching 30 minutes and the adverse outcomes associated

with needlessly inter vening on brief, self-limited seizures (2,

4).This guideline follows this convention and, for pur poses of

treatment, uses the term status epilepticus to represent stud

-

ies involving both prolonged seizures and traditionally de˜ned

status epilepticus.
Status epilepticus presents in several forms: 1) convulsive
status epilepticus consisting of repeated generalized tonicŒ

clonic (GTC) seizures with persistent postictal depression of

neurologic function between seizures; 2) nonconvulsive status

epilepticus where seizures produce a continuous or ˝uc tuat

-
ingfiepileptic twilight fl state; and 3) repeated partial seizures

manifested as focal motor signs, focal sensory symptoms, or

focal impairment of func tion (e.g., aphasia) not associated with

altered awareness (epilepsia partialis continua).

B et ween 50,000 and 150,000 Americans each year have
status epilepticus (5Œ7), with mortalit y estimated at less than

3% in children but up to 30% in adults (5, 6, 8). The goal of

therapy is the rapid termination of both clinical and electr ical

seizure activit y, since appropr iate and timely therapy of status

epilepticus reduces the associated mor tality and mor bidity (9).

Ultimately, the prognosis is most strongly related to the etiol

-

ogy, duration of status epilepticus, and the age of the patient

(10Œ12). Basic critical care and emergency pr inciples of therapy

such as supporting respiration, maintaining blood pressure,

gaining intravenous (IV ) access, and identifying and treating

the underlying cause have achieved widespread acceptance

and are routinely implemented by both neurologists and non

-

neurologists. D espite this recognition of the need to address

status epilepticus as a critical care emergenc y, the goals of

therapy and approaches to the phar macologic treatment of

status epilepticus continue to var y dramatically. Unfor tunately,

patients still receive inadequate treatment for a var iety of rea

-

sons including, but not limited to, therapy aimed at reduction

instead of ter mination of seizures, use of ine˚cient therapies

such as sedatives and paralytics, and administration of insuf

-

˜cient anticonvulsant doses.

I n 1993, the Epilepsy Foundation of America asked its
professional advisory board to convene a work ing group of ex
-
per ts to develop a treatment protocol and related educational

mater ials depicting the best current medical management

of convulsive status epilepticus.The subsequent consensus

guideline provided physicians with a consistent, rational ap

-
proach (2). Over the past 2 decades, new medical therapies

and new clinical trial data have emerged relating directly

to the treatment of this most feared t ype of seizure activit y.

Coupled with the acceptance of evidence-based rather than

consensus-based guidelines, the Epilepsy Foundation in 2004

and the American Epilepsy Societ y in 2012 began the process

of reevaluating the existing medical literature and develop
-
ing a new guideline. This writing team started their activit y on

behalf of the Epilepsy Foundation and completed their task

with the support of the American Epilepsy Society.

Purp ose of This Guideline and De˜nition of Terms
The goal of this current guideline is to provide evidence -based

answers to e˚cac y, safety, and tolerability questions regarding

the treatment of convulsive status epilepticus and to synthe

-
size these answers into a treatment algor ithm. This guideline

focuses on convulsive status epilepticus because it is both the

most common type of status epilepticus and is associated with

substantial morbidit y and mortality. Anticonvulsantfie˚cacy fl

is the ability of the drug to stop convulsive status epilepticus,

fi tolerability fl involves the fiincidence, sever it y and impact fl of

anticonvulsant related adverse e˛ec ts (13, 14), fie˛ec tivenessfl

encompasses both anticonvulsant e˚cac y and tolerabilit y,

andfisafety fl refers to life -threatening adverse events.

The guideline™s recommendations aim to help clinicians
wor ldwide understand the relevant existing evidence for

treatment of patients with status epilepticus.The guideline

is intend
ed for use by individual clinicians, hospitals, health

author ities, and providers. We recognize that this guideline

sive status epilepticus treated with placebo indicating that respiratory problems
are an impor tant consequence of untreated
convulsive status epilepticus (Level A).When both are available, fosphenytoin is
prefer red over phenytoin based on tolerabilit y
but phenytoin is an acceptable alternative (Level A). In adults, compared to the
˜rst therapy, the second therapy is less e˛ec tive
while the third therapy is substantially less e˛ec tive (Level A). I n children,
the second therapy appears less e˛ective and there are

no data about third therapy e˚cacy (Level C).The evidence was synthesized into a
treatment algor ithm.
CONCLUSIONS:
D espite
the paucity of well-designed randomized controlled tr ials, prac tical conclusions
and an integrated treatment algor ithm for the
treatment of convulsive status epilepticus across the age spectrum (infants through
adults) can be constructed. Multicenter, mul
-
tinational e˛or ts are needed to design, conduc t and analyze additional randomized
controlled tr ials that can answer the many

outstanding clinically relevant questions identi˜ed in this guideline.

50
Convulsive Status Epilepticus Guideline
will need local scrutiny and adjustment in order to make it
relevant to the social and economic environments in which it

will be used.This process should lead to a sense of ownership

of any adjusted guideline, which will be essential for e˛ective

implementation and will lead to improvement in healthcare

outcomes for people with convulsive status epilepticus.

S cop e of This Guideline
This guideline will address the evidence regarding the treat
-
ment of convulsive status epilepticus. For the purposes of this

guideline, only studies that enrolled subjects having a seizure

duration of at least 5 minutes were considered.The guideline™s

analysis is presented by subject age (adult studies, pediatr ic

studies), since studies arbitrar ily focused on either adult or

pediatr ic subjects.The guideline™s treatment algor ithm is not

age speci˜c since 1) the disease pathophysiology of prolonged

seizures and status epilepticus and 2) anticonvulsant drug ef

-

fec ts on neuronal receptors are the same from infants through

adults, permitting a uni˜ed approach for all patients older

than neonates.The following issues are not examined in this

guideline: merits of var ious de˜nitions of status epilepticus,

treatment of refrac tor y status epilepticus, treatment of neo

-
natal status epilepticus, subsequent chronic anticonvulsant

therapy, etiology-speci˜c therapy (e.g., for cerebral malar ia),

the role of di˛erent diagnostic tests (e.g., EEG, C T, MRI) for

patients with status epilepticus, the role of epilepsy surger y,

neurostimulation, or the ketogenic diet in the treatment of

patients with status epilepticus.There is an American Academy

of Neurology prac tice parameter on the diagnostic evaluation

of the child with status epilepticus (15).
The var iability in anticonvulsant costs makes it di˚cult
for this guideline to address or incor porate issues of cost-

e˛ec tiveness and related economic analyses. However, it is

recognized that cost and for mulary availability are prac tical

parameters modifying the selection of initial anticonvulsant

therapy.This guideline should not be construed as rigid.

R ather, therapy choice ultimately must include consideration

of the individual patient ™s clinical data along with the local

availability and cost feasibility of di˛erent treatment options.

Methods
The methodology used to construct the evidence -based

por tion of this guideline was based on elements of guideline

development used by the American Academy of Neurology

(http://ww w.aan.com/Guidelines/) and the Inter national

League Against Epilepsy.The methodology was speci˜ed

before the searches were conducted. A literature search

was perfor med, including MEDLINE and Cur rent Contents,

for relevant ar ticles published between Januar y 1940 and

S eptember 2014 (inclusive). I n addition, the Cochrane Librar y

(Database of Systematic Reviews, Central Register of Con

-

trolledTr ials, M ethodology Register, Database of Abstracts of

R eviews of E˛ec ts, Health Technology Assessment Database,

and NHS Economic Evaluation Database) was serially searched

(last in April 2015). Studies were considered potentially rel

-

evant if they included the ter mfistatus epilepticus,fl examined

anticonvulsant e˚cac y, safety, tolerability, or mode of use, and

were a randomized controlled tr ial (RCT ), cohort study, case

control study, observational study, case series, meta-analysis,

or systematic review. All languages were included. No sex or

age limits were imposed, but searches were limited to human

subjects. No studies published only as abstrac ts were included.

Ar ticles were excluded from further an

alysis if they related

to nonepilepsy uses of anticonvulsants or focused on basic

anticonvulsant mechanisms.
Each potentially relevant study found through this search
methodology was abstrac ted for speci˜c data, which were

placed in evidence tables for further analysis. The review

panel consisted of a group of neurologists, neurology nurses,

emergenc y medicine physicians, clinical phar macists, meth

-

odologists, and neurocr itical care physicians with exper ience

in status epilepticus and anticonvulsants. Potentially relevant

studies were evaluated for their class of evidence using

cr iter ia detailed inTable 1.The guideline™s conclusions and

recommendations were based on cr iter ia detailed inTable 2.

These tables integrate the United States Agenc y for Health

Care and Polic y R esearch (16) and the Amer ican Academy of

Neurology scor ing system (17). However, t wo major modi˜ca

-

tions to the scor ing system were made owing to the ethi
-

cal and logistic di˚culties in conduc ting convulsive status

epilepticus tr ials:
1)

A 10% noninfer ior it y margin bet ween test drug and com
-

parator drug was considered to be clinically appropr iate

for noninfer iorit y analyses and failed superior it y studies

( Table 1).
2)

Fewer class I or II studies were needed to reach a Level A or

B recommendation than for other neurologic conditions

because of the challenges in conduc ting randomized, con

-

trolled, double-blind, status epilepticus studies (Table 2).

The analysis addressed ˜ve questions involving adults/chil
-
dren with seizures lasting more than 5 minutes:

Q1.Which anticonvulsants are e˚cacious as initial and subse

-
quent therapy?
Q2.What adverse events are associated with anticonvulsant
administration?
Q3.Which is the most e˛ective benzodiazepine?

Q4. Is IV fosphenytoin more e˛ec tive than IV phenytoin?

Q5.When does anticonvulsant e˚cac y drop signi˜cantly (i.e.,

af ter how many di˛erent anticonvulsants does status epi
-
lepticus become refrac tor y)?
The completed evidence -based guidelines and algorithm
were reviewed and approved by the American Epilepsy S ociet y
Guidelines Committee (members of which were not part of the

wr iting group). I t was also reviewed and commented on by the

Council on Clinical Ac tivities, whose comments were incor po

-
rated and subsequently approved. Following committee and

council approval, it was submitted to the American Epilepsy

S ociet y Board; and after review, comments, and revisions, the

guideline was approved prior to submission for publication.

51
Convulsive Status Epilepticus Guideline
TABLE 2.
Tra nslation of Ar ticle Ratings to Conclusions and Re commendations
Translation of Evidence to Recommendation
Conclusion and Recommendation
Level A rating:

One or more class I studies

or
t wo or more
consistent class II studies
Conclusion, level A:

Established as e˛ec tive, ine˛ective, or har mful for the given condition in

the speci˜ed population

R ecommendation:

Should be done or should not be done

Level B rating:
One or more class II studies
or
three or more
consistent class III studies
Conclusion, level B:

Probably e˛ec tive, ine˛ective, or harmful for the given condition in the

speci˜ed population
R ecommendation:

Should be considered or should not be considered

Level C rating:

Two or more consistent class III studies

Conclusion, level C:

Possibly e˛ec tive, ine˛ective, or har mful for the given condition in the

speci˜ed population
R ecommendation:

M ay be considered or may not be considered

Level U:

Lack of studies meeting level A, B, or C

designation
Conclusion, level U:

Data inadequate or insu˚cient. Given current k nowledge, treatment is

unproven.
R ecommendation:

None
TABLE 1.
Rating of Ar ticles
Class I: Prospec tive, randomized, controlled clinical trial with masked outcome
assessment in a representative population.The
following are also required:

a. No more than t wo primar y outcomes speci˜ed

b. Concealed allocation

c. Exclusion/inclusion criter ia clear ly de˜ned

d. R elevant baseline charac ter istics presented and substantially equivalent

between treatment groups, or appropr iate

statistical adjustment for di˛erences

e. Adequate accounting for dropouts (with at least 80% of enrolled subjec ts

completing the study) with numbers su˚ciently
low to have minimal potential for bias

f. D emonstration of superior it y in a superior it y study design or demonstration

of noninfer ior it y using a 10% margin in a

noninfer iorit y design

Class II: A prospec tive, randomized, controlled clinical trial with masked outcome
assessment that lacks one or t wo cr iter ia aΠe
(see class I) or a prospective matched group cohor t study in a representative
population with masked outcome assessment

that meets criter ia aΠe

Class III: All other controlled trials in a representative population, where
outcome is independently assessed, or inde
pendently
der ived by objec tive outcome measurements
Class IV: Evidence from uncontrolled studies, case series, case repor ts, or exper
t opinion

52
Convulsive Status Epilepticus Guideline
Results
A r ticle and Meta-Analysis/Systematic Review Identi˜cation

Four search strategies yielded the following results (all

searches were per for med for the time frame of January 1,

1940 through S eptember 30, 2014). For Pubmed, the following

ter ms were used:

1)

S earchŠstatus epilepticus, LimitsŠhumans (

n
= 6,953

ar ticles);
2)

S earchŠstatus epilepticus, LimitsŠhumans, clinical trial,

randomized controlled trial (

n
= 210 articles);
3)

S earchŠstatus epilepticus AND ((clinical [Title/Abstrac t]

AND tr ial[Title/Abstract]) OR clinical trials[M eSHTerms]

OR clinical trial[Publication Type] OR random*[Title/Ab

-
strac t] OR random allocation[MeSHTer ms] OR therapeu
-

tic use[MeSH Subheading]); LimitsŠhumans (

n
 = 3,101

ar ticles);
4)

S earchŠstatus epilepticus
and
systematic[sb]; LimitsŠhu
-

mans (
n
= 159 articles).
Similar searches were per formed on the other databases.
These computer ized searches were last perfor med on
O c tober 9, 2014. The resulting studies were reviewed for rele
-
vance.The reference lists of all included studies were reviewed

to identify any additional relevant studies not identi˜ed by

the above searches. I n total, 38 relevant RC Ts were identi

-

˜ed. A search of the Cochrane Librar y yielded four additional

completed and relevant published meta-analyses (18Œ21).

Phar maceutical companies provided requested additional

infor mation on three RC Ts.

Q1. Which Anticonvulsants Are E˚cacious as Initial and
Subsequent Therapy?

Adult Studies
N ine RCTs (three class I [22Œ24], one class II [25], and ˜ve
class III [26Œ30]) addressed the e˚cacy of initial therapy.The

1998 Veteran™s A˛airs status epilepticus study was a multi

-

center randomized compar ison of four di˛erent IV treatments:

lorazepam (0.1 mg/kg), diazepam (0.15 mg/kg) followed by

phenytoin (18 mg/kg), phenobarbital (18 mg/kg), and phe

-
nytoin alone (18 mg/kg) in adults with either over t or subtle

status epilepticus (22). Over t status epilepticus was de˜ned as

a continuous GTC seizure lasting 10 minutes or longer, or two

or more GTC seizures without full recover y of consciousness.

A treatment was successful if the status epilepticus stopped

within 20 minutes after infusion started with no recur rence

pr ior to 60 minutes. Overall, 570 patients were randomized to

either lorazepam (
n =
146), diazepam plus phenytoin (
n =
146),

phenobarbital (
n =
133), or phenytoin (
n =
145). Di˛erential

anticonvulsant e˚cac y was found in over t status epilepticus

where the four treatment arms had an overall di˛erence

(
p
= 0.02) for the primar y outcome var iable. Only one head-to -

head comparison met the prespeci˜ed statistical signi˜cance

di˛erence: lorazepam was superior to phenytoin (

p
= 0.001).

There was no di˛erence on the intent to treat (ITT ) analysis

(22).
A second class I study in adults (older than 18 years)
with status epilepticus was initiated outside the hospital by

paramedics (23). I n this 2001 study, patients were random

-

ized to receive 2 mg IV lorazepam or 5 mg IV diazepam or

IV placebo in the ambulance.The protocol allowed a repeat

dose if the seizure continued af ter 4 minutes (for a maxi

-

mum lorazepam dose of 4 mg and diazepam dose of 10 mg).

For this study, status epilepticus was de˜ned as continu

-

ous or repeated seizure for >5 minutes without recover y

of consciousness. O verall, 205 patients were randomized

(lorazepam,
n =
66; diazepam,
n =
68; placebo,
n =
 71). The
treatment was deemed successful if the status epilepticus

had terminated at the time of ar r ival in the emergenc y

department. B oth lorazepam and diazepam were super ior to

placebo: lorazepam (59.1%) > placebo (21.1%) (OR, 4.8; 95%

CI: 1.9Œ13.0) and diazepam (42.6%) > placebo (21.1%) (OR,

2.3; 95% CI: 1.0Œ5.9) (23).

A third class I study, the 2012 R AMPART tr ial, was a multi
-
center, double -blind randomized noninfer ior it y compar ison

of intramuscular (IM) midazolam (test drug) to IV lorazepam

(comparator) in adults and children with status epilepticus

(24). D osing was standardized to 10 mg (5 mg in children

weighing 13Œ40 kg) IM midazolam or 4 mg (2 mg in children

weighing 13Œ40 kg) IV lorazepam. Status epilepticus was

de˜ned as convulsions persisting for longer than 5 minutes

that were still occur r ing after paramedic ar r ival.Treatment

success was de˜ned as absence of seizures without addi

-

tional rescue therapy at time of ar r ival in the emergenc y de

-
par tment, with a prespeci˜ed noninferior it y margin of 10%.

A total of 893 subjects (

n =
748; aged 21 years or older) were

randomized to either IM midazolam (

n =
448) or IV loraz
-

epam (
n =
445).The pr imar y e˚cac y endpoint was achiev
ed

in 73% of subjec ts in the IM midazolam group compared

with 63% in the IV lorazepam group, resulting in an absolute

di˛erence bet ween groups of 10% (95% CI: 4.0Œ16.1), not

only meeting the prespeci˜ed noninfer iority requirement

but also demonstrating superior it y of midazolam for both

the per protocol and IT T analyses in patients without estab

-
lished IV access (24).
A 1983 class II study compared IV lorazepam 4 mg and IV
diazepam 10 mg in adults with convulsive status epilepticus

(de˜ned as
3 GTC seizures in 1 hour or
2 in rapid succes
-

sion), absence status epilepticus, or complex par tial status

epilepticus (25). The patients could receive a second dose of

medication if the seizures continued af ter 10 minutes. For

all patients, phenytoin was given after 30 minutes. A total of

70 patients were randomized to either lorazepam (

n =
37) or

diazepam (
n =
33) (25). Lorazepam was successful for 78% of

subjects af ter one dose and 89% after t wo doses; diazepam

was successful for 58% of subjects after one dose and 76%

af ter two doses.The study found no statistically signi˜cant dif

-

ference between lorazepam and diazepam in seizure cessation

af ter one or two medication administrations.

The ˜ve open-label class III initial therapy RC Ts examined
the e˚cac y of IV valproic acid (
n =
2) (26, 27), IV phenytoin

(
n =
2) (26, 27), IV phenobar bital (
n =
1) (29), IV diazepam
plus phenytoin (
n =
1) (29), IV levetiracetam (
n =
1) (30),

rec tal diazepam (

n =
1) (28), and IV lorazepam (
n =
 1) (30)

in cohorts ranging from 9 to 41 patients.Valproic acid had

53
Convulsive Status Epilepticus Guideline
higher e˚cac y than phenytoin in one study (valproic acid,
66%, vs phenytoin, 42%;
p
= 0.046) (27) and was similar to
phenytoin in the other (valproic acid, 87.8%, vs phenytoin,

88%) (26).
Two RCTs, both class III (31, 32), addressed second-ther
-
apy efficac y in adults af ter failure of initial benzodiazepine

therapy. I ntravenous valproic acid ™s efficac y was similar to

IV phenytoin (88% vs 84%) in one study (31) and similar to

continuous IV diazepam (56% vs 50%) in the second study

(32).
Each arm of theVeterans A˛airs status epilepticus
study had a second blinded treatment if initial therapy was

unsuccessful (22). Speci˜cally, initial lorazepam therapy

was followed by IV phenytoin; phenobar bital was followed

by phenytoin; phenytoin was followed by lorazepam; and

diazepam plus phenytoin was followed by lorazepam (22).

There was no di˛erence in e˚cac y bet ween the four treat

-
ment ar ms when initial and second therapies together were

examined (33).
The following conclusions were drawn. I n adults, IM
midazolam, IV lorazepam, IV diazepam (with or without

phenytoin), and IV phenobar bital are established as e˚ca

-

cious at stopping seizures lasting at least 5 minutes (level

A). I ntramuscular midazolam has super ior e˛ec tiveness

compared with IV lorazepam in adults with convulsive status

epilepticus without established IV access (level A). Intra

-

venous lorazepam is more e˛ec tive than IV phenytoin in

stopping seizures lasting at least 10 minutes (level A).There

is no di˛erence in e˚cac y bet ween IV lorazepam followed

by IV phenytoin, IV diazepam plus phenytoin followed by IV

lorazepam, and IV phenobar bital followed by IV phenytoin

(level A). I ntravenous valproic acid has similar e˚cac y to IV

phenytoin or continuous IV diazepam as second therapy af ter

failure of a benzodiazepine (level C). I nsu˚cient data exist in

adults about the e˚cac y of levetiracetam as either initial or

second therapy (level U).

Pediatric Studies
O verall, 26 RCTs (t wo class I [24, 34] and 24 class III [27,
30, 35Œ56]) examined e˚cacy of initial therapy. In 25 of
these RCTs, benzodiazepines were one or both of the study

medications (two class I studies and 23 class III studies). In

one class I trial (34), 273 children (aged 3 months to 18 years)

were enrolled and randomized to either diazepam 0.2 mg/

kg (maximum dose 8 mg) or lorazepam 0.1 mg/kg (maximum

dose 4 mg). If seizures continued after 5 more minutes, then

half of the initial study drug dose could be repeated. If seizures

continued another 7 more minutes, then fosphenytoin was

given.There was no di˛erence between IV diazepam (101/140,

72.1%) and IV lorazepam (97/133, 72.9%) in the primary e˚ca

-

c y outcome of ter mination of status epilepticus by 10 minutes

without reappearance within 30 minutes (absolute di˛erence

of 0.8%, 95% CI: ˙11.4Œ9.8%). The study concluded that there

was no evidence to support the hypothesis that lorazepam

was superior to diazepam as initial therapy for pediatr ic status

epilepticus.
A second class I study, the RAMPAR T tr ial (24), included 120
children randomized to IM midazolam (
n =
60) or IV lorazepam

(
n =
60). No statistical di˛erence in e˚cacy was found between
the IM midazolam (68.3%) and
 IV lorazepam (71.7%), but the

relatively few children studied results in wide con˜dence inter

-
vals preventing any ˜rm conclusions (57).
The class III benzodiazepine RCTs involved diazepam
(
n =
20), midazolam (
n =
16), and lorazepam (
n =
6). The di˛er
-
ent routes of administration included IV (
n =
13), rec tal (
n =
10),

intranasal (
n =
9), buccal (
n =
6), IM (
n =
3), and sublingual

(
n =
1). The size of the studies ranged from 24 patients to 436

patients. Although all studies were prospective and random

-

ized, they were class III because treating physicians were

either not blinded to treatment allocation or lacked outcome

mask ing (meaning the outcome assessors were not blinded to

treatment allocation).
One class III study compared lorazepam (0.05Œ0.1 mg/kg)
to diazepam (0.3Œ0.4 mg/kg) administered either IV or rec tally

for children presenting to the emergenc y department with

ongoing convulsions.There was no di˛erence between the

treatments either in the time for the initial (presenting) seizure

to stop after anticonvulsant administration or in the total

number of seizures in ˜rst 24 hours of admission. However,

fewer lorazepam patients required multiple doses to stop the

seizures (lorazepam 8/33 vs diazepam 25/53;

p
 < 0.05) or ad
-

ditional anticonvulsants to ter minate the seizure (lorazepam

1/33 vs diazepam 17/53;

p
< 0.01) (35).
One class III study compared IV lorazepam (0.1 mg/kg) to
a combination of IV diazepam (0.2 mg/kg) and IV phenytoin

(18 mg/kg) in 178 children presenting with convulsive status

epilepticus to an emergency depar tment. E˚cac y in stopping

seizure activit y within 10 minutes with no recur rence dur ing

an 18-hour period after seizure control was 100% for both

groups. No signi˜cant di˛erence was demonstrated between

treatment groups either in the time to seizure cessation or the

need for additional doses of study medication to ter minate

convulsive status epilepticus (49).

I ntranasal lorazepam was examined in t wo studies. A
study of 6- to 14-year- old children with ongoing seizures in

the emergenc y department compared IV lorazepam with

intranasal lorazepam (both 0.1 mg/kg/dose, maximum dose

4 mg) (52). No di˛erence was detec ted bet ween IV lorazepam

(56/70, 80%) and intranasal lorazepam (59/71, 83.1%) based

on clinical seizure remission within 10 minutes of study

drug administration.The authors concluded that intranasal

lorazepam was not infer ior to IV lorazepam (52). Another

class III study compared intranasal lorazepam (0.1 mg/kg) to

IM paraldehyde (0.2 mL/kg) in 160 pediatr ic patients present

-
ing to an emergenc y depar tment with convulsive status

epilepticus. No statistically signi˜cant di˛erence was found

bet ween intranasal lorazepam and IM paraldehyde for the

pr imar y outcome of e˚cac y in stopping seizure ac tivit y 10

minutes af ter administration (intranasal lorazepam, 75%; IM

paraldehyde, 61%;
p =
 0.06) or in time to seizure cessation or

seizure recur rence within 24 hours after administration.The

study did ˜nd that subjec ts treated with paraldehyde were

more likely to require t wo or more additional anticonvulsant

doses (intranasal lorazepam, 10%; IM paraldehyde, 26%;

p =
0.007) (44).
Sublingual lorazepam (0.1 mg/kg) was compared with
rec tal diazepam (0.5 mg/kg) in children 5 months to 10 years

old with convulsions lasting more than 5 minutes (54).This

54
Convulsive Status Epilepticus Guideline
class III RC T was conduc ted across nine hospitals in Sub -
Saharan Afr ica and involved 436 children.The e˚cac y of

sublingual lorazepam (131/234, 56%) was signi˜cantly lower

than that for rec tal diazepam (160/202, 79%;

p
< 0.001) for
ter minating seizures within 10 minutes of study drug admin
-

istration (54).
Six teen class III studies compared midazolam with diaz
-
epam. In ˜ve studies, buccal midazolam was compared with

rec tal diazepam (40Œ42, 47, 50). In one study, in 177 children

exper iencing 219 separate seizures, buccal midazolam was

more e˛ec tive than rec tal diazepam in stopping seizures

whether all seizures were considered (56% vs 27%) or just ini

-

tial episodes (42). The largest study of 330 children in Uganda

found a lower rate of treatment failure (seizures lasting longer

than 10 minutes af ter medication administration or seizure

recur rence within 1 hour) for buccal midazolam compared

with rectal diazepam (30.3% vs 43%;

p =
0.016). This superior
-
it y was limited to a subgroup of patients without malaria, with

buccal midazolam super ior to rec tal diazepam with respec t

to treatment failure (26.2% vs 55.9%;
p =
0.002) (47). In an RCT

of 98 children (aged 3 months to 12 years), buccal midazolam

was superior to rec tal diazepam for control of seizures within

5 minutes of administration (49/49, 100%, vs 40/49, 82%;

p
<

0.001), treatment initiation time (median 2 vs 3 minutes;

p
<

0.001), and drug e˛ec t time (median 4 vs 5 minutes;

p
< 0.001)

(50). In the t wo smaller studies (

n =
79 and
n
= 43), there was

no di˛erence in e˚cac y between buccal midazolam and rec tal

diazepam (40, 41).

I ntranasal midazolam was compared with IV diazepam
in four class III pediatr ic studies (38, 39, 46, 53). In one study

involving children with prolonged febr ile seizures, time to

drug administration of intranasal midazolam was faster (

p
<

0.001) but the time period between drug administration and

seizure cessation was shorter for IV diazepam (

p
< 0.001) (38).

The second study found that the mean time to achieve seizure

control was faster for IV diazepam compared with intranasal

midazolam (
p
< 0.007) (39). A third study found intranasal mid
-

azolam was signi˜cantly faster to administer than IV diazepam,

with a slower mean time to seizure cessation after medication

administration for intranasal midazolam compared with IV

diazepam, but a faster time to seizure cessation af ter hospital

ar r ival with intranasal midazolam (

p
< 0.001 for all compar i
-

sons) (46). Lastly, an RCT of 60 children (aged 2 months to 15

years), equally divided between intranasal midazolam (0.2 mg/

kg) and IV diazepam (0.3 mg/kg), found the time to control

seizures was shor ter using intranasal midazolam compared

with IV diazepam (3.16 ± 1.24 minutes vs 6.42 ± 2.59 minutes;

p
< 0.001) when the time needed to establish IV access was

included (53).
Three tr ials examined the e˚cacy of intranasal midazolam
compared with rec tal diazepam (37, 45, 51). Intranasal mid
-

azolam (0.2 mg/kg, maximum dose, 10 mg) was compared

with rectal diazepam (0.3 to 0.5 mg/kg, maximum dose, 20

mg) for prehospital seizures lasting longer than 5 minutes.

O verall, 92 children received study medication, and no dif

-

ference in total seizure time after medication administration

bet ween therapies was identi˜ed (51). Another trial involving

46 children exper iencing 188 seizures compared the e˚cacy

of intranasal midazolam 0.3 mg/kg (92 episodes) to rectal diaz

-
epam 0.2 mg/kg (96 episodes) for ter minating seizures within

10 minutes of drug administration.The time to seizure cessa

-

tion was signi˜cantly faster for intranasal midazolam (116.7

± 126.9 seconds vs 178.6 ± 179.5 seconds;

p =
0.005), with a

trend toward a higher success rate with intranasal midazolam

(89/92, 96.7%) compared with rec tal diazepam (85/96, 88.5%;

p =
0.060) (45). A third smaller trial (
n =
45) found intranasal

midazolam was more e˛ec tive than rec tal diazepam (87% vs

60%;
p
< 0.05) (37).
I ntramuscular midazolam was compared with IV diazepam
in three class III studies (36, 43, 55). In all three studies, IM mid
-

azolam had a shorter interval to seizure cessation, but there

was no signi˜cant di˛erence in overall e˚cacy for ter mination

of seizures (36, 43, 55).

One study compared buccal midazolam 0.2 mg/kg with
IV diazepam 0.3 mg/kg, with no significant difference found

in overall efficac y (defined as complete cessation of seizures

5 minutes af ter administration of study treatment) (48).

Time to seizure cessation from identification of the seizure

in the emergenc y department was significantly shor ter

for buccal midazolam compared with IV diazepam (2.39

minutes vs 2.98 minutes, respec tively), with most of the dif

-

ference dr iven by more rapid time to initiation of treatment

(48).
I ntravenous lorazepam (0.1 mg/kg over 2Œ4 minutes) was
compared with IV levetiracetam (20 mg/kg over 15 minutes)

in a class III RCT involving children with either convulsive

or subtle convulsive status epilepticus (30). As ˜rst therapy,

lorazepam success rate (29/38, 76.3%) was similar to that for

levetiracetam (31/41, 75.6%) (30).

I n one RCT, children with convulsive seizures at time of
presentation received either IV valproic acid (20 mg/kg) with

diazepam (0.3 mg/kg) (

n =
16) or IV phenytoin (20 mg/kg) with

diazepam (0.3 mg/kg) (

n =
17) (56). There was no di˛erence in
e˚cac y outcomes bet ween these two arms (56).
The only class III pediatric RC T not involving a benzo
-
diazepine compared IV phenytoin (
n =
33) and IV valproic

acid (
n =
35). Overall, valproic acid had higher e˚cacy than

phenytoin (valproic acid, 66%, vs phenytoin, 42%;

p =
0.046),

but only 23% and 12% of the cohor ts were 15 years old or

younger, with no statistical adjustment for these dissimilar

proportions (27).
Two RC Ts (one class II [58] and one class III [31]) ad
-
dressed second-therapy e˚cacy in children after failure of

initial benzodiazepine therapy.The class II study compared

IV valproic acid (20 mg/kg,

n =
30) with IV phenobarbital (20

mg/kg,
n =
30) in children 3 to 16 years old whose seizures did

not respond to IV diazepam (0.2 mg/kg) within 5 minutes. No

signi˜cant di˛erence was noted in e˚cac y between valproic

acid and phenobarbital (27/30, 90

%, vs 23/30, 77%;
p =
0.189)

for ter minating seizures within 20 minutes, but the valproic

acid group experienced signi˜cantly fewer clinically signi˜cant

adverse e˛ec ts (24% vs 74%;

p
< 0.001) (58). The second study

involved both adults and children and found that the e˚cacy

of IV valproic acid was similar to that of IV phenytoin (88% vs

84%) in patients whose seizures did not respond to 0.2 mg/kg

of IV diazepam (31).
The following conclusions were drawn. I n children, IV
lorazepam and IV diazepam are established as efficacious

55
Convulsive Status Epilepticus Guideline
at stopping seizures lasting at least 5 minutes (level A).
R ec tal diazepam, IM midazolam, intranasal midazolam,

and buccal midazolam are probably effec tive at stopping

seizures lasting at least 5 minutes (level B). I nsufficient data

exist in children about the efficac y of intranasal lorazepam,

sublingual lorazepam, rectal lorazepam, valproic acid, leve

-
tiracetam, phenobar bital, and phenytoin as initial therapy

(level U). Intravenous valproic acid has similar efficac y but

better tolerabilit y than IV phenobar bital (level B) as second

therapy af ter failure of a benzodiazepine. I nsufficient data

exist in children regarding the efficac y of phenytoin or

levetiracetam as second therapy af ter failure of a benzodi

-

azepine (level U).

Q2. What Adverse Events Are Asso ciated With A nticonvulsant
Administration?

Adult Studies
Three class I studies (22Œ24) and one class II study (25)
present the best evidence about treatment- emergent adverse

events associated with IV lorazepam and diazepam therapy.

I n the 1998 class I Veterans A˛airs status epilepticus study,

there were no signi˜cant di˛erences in adverse- event rates

bet ween lorazepam, diazepam, phenobarbital, and phenytoin

(22).The treatment- emergent adverse events associated with

lorazepam administration in 97 patients with over t status epi

-

lepticus were hypoventilation, 10.3%; hypotension, 25.8%; and

cardiac r hythm disturbance, 7.2%. This is similar to the adverse

events seen with IV diazepam therapy in 95 patients with over t

status epilepticus: hypoventilation, 16.8%; hypotension, 31.6%;

and cardiac rhythm distur bance, 2.1%. A similar spectrum of

cardiorespirator y complications was seen in both the phe
-
nobar bital arm (hypoventilation, 13.2%; hypotension, 34.1%;

cardiac r hythm disturbance, 3.3%) and the phenytoin ar m

(hypoventilation, 9.9%; hypotension, 27.0%; cardiac r hythm

distur bance, 6.9%) (22).

I n the 2001 prehospital status epilepticus RCT, 10.6%
of patients receiving IV lorazepam experienced treatment-

emergent adverse events (hypotension, cardiac dysr hythmia,

respirator y inter vention). Similarly, 10.3% of patients receiving

IV diazepam experienced hypotension, cardiac dysr hythmia, or

the need for respirator y inter vention. Both of these rates were

lower (
p =
0.08) than the 22.5% treatment- emergent adverse -

event rate seen in patients with status epilepticus receiving IV

placebo (23).
I n the 2012 class I RAMPAR T trial compar ing IM midazolam
and IV lorazepam (24), treatment- emergent adverse events

were identi˜ed in 26.7% of subjects in the IM midazolam

group compared with 30.6% of subjects in the IV lorazepam

group. Most common treatment-emergent adverse events

were decreased level of consciousness (IM midazolam, 9.5%, vs

IV lorazepam, 8.8%) and respirator y depression (IM midazolam,

6.4%, vs IV lorazepam, 10%), while hypotension only occur red

in 1.2% of subjects overall (24).

The 1983 class II study compared lorazepam 4 mg and
diazepam 10 mg in adults with convulsive status epilepticus

(de˜ned as
3 GTC seizures in 1 hour or
2 in rapid succes
-

sion), absence status epilepticus, or complex par tial status

epilepticus (25). Patients were permitted to receive a second

dose of medication if the seizures continued after 10 minutes.

For all patients, phenytoin was given after 30 minutes. A total

of 70 patients were randomized to either lorazepam (

n =
37)

or diazepam (
n =
33). In this comparative tr ial, 12% of loraz
-

epam patients and 13% of diazepam patients experienced

treatment-emergent adverse events including respirator y

depression, respirator y arrest, hypotension, and sedation; the

˜rst three of these only occur red in people with signi˜cant

medical problems (25).

The following conclusions were drawn. R espirator y
and cardiac symptoms are the most common encountered

treatment-emergent adverse events associated with IV an

-

ticonvulsant administration in adults with status epilepticus

(level A). The rate of respirator y depression in patients with

status epilepticus treated with benzodiazepines is lower than

in patients with status epilepticus treated with placebo (level

A), indicating that respirator y problems are an important

consequence of untreated status epilepticus. No substantial

di˛erence
exists between benzodiazepines and phenobarbital

in the occur rence of cardiorespirator y adverse events in adults

with status epilepticus (level A).

Pediatric Studies
The single class I purely pediatr ic study (34) provides the
best adverse - event evidence about IV lorazepam and IV diaz
-
epam use in children with convulsive status epilepticus. There

were no di˛erences bet ween the two arms in the rate of as

-

sisted ventilation (lorazepam, 17.6%, versus diazepam, 16.0%;

absolute risk di˛erence, 1.6%; 95% CI: ˙9.9Œ6.8%) or aspiration

pneumonia (two subjects in each group). The incidence of

sedation was higher in the lorazepam cohort (99/148, 66.9%)

compared with the diazepam cohor t (81/162, 50%; absolute

r isk di˛erence, 16.9%; 95% CI: 6.1Œ27.7%) (34).
Class III tr ials identi˜ed similar rates of respirator y de
-
pression with IV benzodiazepine use (35, 49, 55). One class

III tr ial repor ted 21% of patients receiving IV diazepam and

4% of patients receiving IV lorazepam were repor ted to have

respirator y depression de˜ned as poor respiratory e˛or t,

reduced rate of breathing, or requir ing ox ygen administra

-

tion via face mask (35). I n another class III study, respirator y

depression was repor ted in 4.4% of children receiving IV

lorazepam and 5.6% of children receiving IV diazepam and

phenytoin, but no subjec t in either group required mechani

-

cal ventilation (49).

R espiratory depression af ter rec tal administration of
diazepam in children was repor ted in ˜ve class III tr ials,

ranging from 1.2 percent to 6.4 percent (35, 41, 42, 45,

47), while t wo class III tr ials (37, 40) and t wo class I tr ials in

acute repetitive seizures (59, 60) repor ted no incidence of

respirator y depression with rec tal diazepam use in children.

No respirator y depression was repor ted in one study of six

children treated with rec tal lorazepam (35). As noted above,

drowsiness was the most common adverse e˛ec t reported

in t wo class I tr ials of rec tal diazepam in a mixed adult and

pediatr ic study (59, 60).

Two class III studies reported respirator y depression with
use of buccal midazolam in children (42, 47), in contrast to t wo

class III studies, which reported no respirator y depression asso

-
ciated with use of buccal midazolam in the pediatr ic popula
-

tion (40, 41). Respirator y depression, de˜ned as having a need

56
Convulsive Status Epilepticus Guideline
for assisted ventilation because of a drop in ox ygen saturation
or a reduction in respirator y rate or e˛or t, was repor ted in
1.2% and 4.6% of patients in these studies (42, 47). Two of the

class III IM or intranasal midazolam studies reported signi˜cant

respirator y depression (36Œ39, 43, 45, 46, 53). Single children

in each study (6.25% and 2%) in the IM midazolam group

exper ienced respirator y failure resulting in arti˜cial ventilation

(51, 55).
Two class III studies involved intranasal lorazepam. In
one study of 80 children, a drop of ˆ5 mm Hg in systolic

and diastolic blood pressure was noted in 15 (18.8%) and 12

(15%) children, respectively, while only two (2.5%) had a fall

in ox ygen saturation below 92% (44). In a second study of 71

children, none developed signi˜cant hypotension and only

one (1.4%) required assisted ventilation (52).

The following conclusions were drawn. R espira
-
tor y depression is the most common clinically signi˜cant

treatment- emergent adverse event associated with anti

-

convulsant drug treatment in status epilepticus in children

(level A). No substantial di˛erence probably exists bet ween

midazolam, lorazepam, and diazepam administration by

any route in children with respec t to rates of respirator y

depression (level B). Adverse events, including respirator y

depression, with benzodiazepine administration for status

epilepticus have been repor ted less frequently in children

than in adults (level B).

Q3. Which Is the Most E˛ec tive Benzo diazepine?
Adult Studies
I n a class I prehospital status epilepticus study (23), the
percentage of patients™ status epilepticus stopped by loraz
-

epam was higher but not signi˜cantly di˛erent than with

diazepam (odds ratio [OR], 1.9; 95% CI: 0.8Œ4.4). However,

the study™s sample size was selec ted to be able to detec t

a di˛erence between the active drugs and placebo, not to

detec t a di˛erence between the t wo active drugs (23). In a

class II lorazepamŒdiazepam comparative tr ial (25), there was

no di˛erence bet ween the two ar ms in the percentage of

patients having control of seizures af ter either one injection

(lorazepam, 78%; diazepam, 58%; not signi˜cant [NS]) or two

injec tions (lorazepam, 89%; diazepam, 76%; NS). There was

no signi˜cant di˛erence between the two ar ms in the latenc y

of ac tion (lorazepam median, 3 minutes; diazepam median, 2

minutes; NS) (25).

The class I RAMPAR T tr ial (24) reported seizures were ab
-
sent in 73% of subjects
in the IM midazolam group compared

with 63% in the IV lorazepam group, resulting in an absolute

di˛erence of 10% (95% CI: 4.0Œ16.1;

p
< 0.001) that met the

prespeci˜ed noninfer ior ity requirements plus additional su

-

per iorit y for both per protocol and ITT analyses. Median time

from ac tive treatment to cessation of convulsions was shor ter

for IV lorazepam (1.6 minutes) compared with IM midazolam

(3.3 minutes), which was o˛set by more rapid IM midazolam

administration (IV lorazepam, 4.8 minutes, vs intranasal mid

-

azolam, 1.2 minutes) (24).

There is no di˛erence in the treatment- emergent adverse -
event pro˜les bet ween lorazepam and diazepam in the three

adult class I and class II status epilepticus studies (22, 23, 25).

No di˛erences in treatment- emergent adverse -event pro˜les

were found between IM midazolam and IV lorazepam (24).

There is pharmacok inetic evidence to suggest a longer dura

-

tion of action (but not longer half-life) for lorazepam com

-

pared with diazepam (61).

The following conclusions were drawn. I n adults with
status epilepticus without established IV access, IM midazolam

is established as more e˛ec tive compared with IV lorazepam

(level A). No signi˜cant di˛erence in e˛ec tiveness has been

demonstrated between lorazepam and diazepam in adults

with status epilepticus (level A).

Pediatric Studies
As descr ibed in detail in Question 1, one class I trial
enrolled and randomized 273 children to either IV diazepam
or IV lorazepam (34). E˚cacy was similar between IV diaz
-

epam (101/140, 72.1%) and IV lorazepam (97/133, 72.9%). As

descr ibed in detail in Question 2, side- e˛ec t pro˜les of the two

treatments were similar (34).

A meta-analysis of six class III pediatr ic studies (36,
38Œ40, 42, 47) found non-IV midazolam (IM/intranasal/

buccal) was more e˛ec tive than diazepam (IV/rectal) at

achieving seizure cessation (relative r isk [RR] =1.52, 95% CI:

1.27Œ1.82) with similar respirator y complications (RR = 1.49;

95% CI: 0.25Œ8.72) (62).Time to seizure cessation was shor ter

for intranasal midazolam compared with IV diazepam in

t wo studies (38, 46) and longer in one study (39). Compar

-
ing intranasal midazolam and rectal diazepam, intranasal

midazolam was more e˛ec tive in ter minating seizures (37)

and demonstrated a shor ter time to seizure ter mination (45).

Compar ing IM midazolam to IV diazepam, a shor ter inter val

to seizure cessation was found for IM midazolam in both

studies (36, 43). Only one study found a signi˜cantly shor ter

time to seizure cessation for buccal midazolam compared

with rectal diazepam (42).

One study compar ing lorazepam to diazepam found no
di˛erence between the treatments in the time for the initial

(presenting) seizure to stop af ter anticonvulsant administra

-

tion but did ˜nd fewer lorazepam patients required multiple

doses (lorazepam, 8/33, vs diazepam, 25/53;
p
< 0.05) or ad
-

ditional anticonvulsants (lorazepam, 1/33, vs diazepam, 17/53;

p
< 0.01) for seizure cessation (35).
The following conclusions were drawn. I n children with
status epilepticus, no signi˜cant di˛erence in e˛ec tiveness

has been established between IV lorazepam and IV diazepam

(level A). In children with status epilepticus, non-IV midazolam

(IM/intranasal/buccal) is probably more e˛ec tive than diaz

-

epam (IV/rec tal) (level B).

Q4. Is IV Fosphenytoin More E˛ec tive Than IV Phenytoin?
Three class III RC Ts examined the comparative tolerabilit y of

IV fosphenytoin and IV phenytoin (63). A single - dose, random

-

ized, double -blind, class III tolerability study in patients need

-

ing infusion of phenytoin compared fosphenytoin (

n =
39,

12.7 mg/kg, 82 mg phenytoin equivalent [PE]/min [range,

40Œ103 mg PE/min]) to phenytoin (

n =
13, 11.3 mg/kg, 42.4

mg/min). I n contrast to phenytoin, there were no fosphe

-
nytoin-related signi˜cant cardiac arr hythmias, change in

heart rate, respiration or blood pressure (63). A second study

involved patients requiring a phenytoin loading dose and

57
Convulsive Status Epilepticus Guideline
then 3 to 14 days of maintenance therapy.This randomized,
double -blind, class III tolerabilit y study in patients needing

infusion and maintenance of phenytoin compared fospheny

-
toin (
n =
88, 15.3 mg/kg, 37 mg PE/min) to phenytoin (
n =
28,
15.0 mg/kg, 33 mg/min) and found pain at the infusion site

was greater for phenytoin than fosphenytoin (17% vs 2%) (63).

A third study was a single - dose, randomized, double-blind,

class III tolerabilit y study of fosphenytoin at 150 mg PE/min

(
n =
90) vs phenytoin at 50 mg/min (
n =
22) (63).The infusion
was slowed or discontinued more often with IV phenytoin

compared with IV fosphenytoin; 63.6% of phenytoin patients

experienced pain at site of infusion; 48.6% of fosphenytoin

patients encountered prur itus; and the average blood pres

-

sure decrease with fosphenytoin was 13.7 mm

Hg compared

with 5.9 mm Hg with phenytoin.

The following conclusions were drawn. I nsu˚cient data
exist about the comparative e˚cacy of phenytoin and fosphe
-
nytoin (level U). Fosphenytoin is better tolerated compared

with phenytoin (level B). When both are available, fosphe

-
nytoin is prefer red based on tolerabilit y, but phenytoin is an

acceptable alter native (level B).

Q5. When Do es A nticonvulsant E ˚cacy D rop Signi˜cantly
(i.e., Af ter How Many D i˛erent A nticonvulsants Do es Status

Epilepticus Become Refrac tory)?

Only one class I RC T (theVeterans A˛airs status epilepticus

tr ial) (22) provides clear data to address this question. Treat

-
ment success was de˜ned as status epilepticus stopping

within 20 minutes after infusion star ted with no recur rence

pr ior to 60 minutes after the star t of the infusion. I n this

four-ar m double -blind RC T, in order to maintain the blinding,

if the ˜rst administered anticonvulsant was not successful,

then the patient was randomized to another treatment ar m;

if the second anticonvulsant was not successful, then the

patient was randomized to another treatment ar m. I n adults

with over t status epilepticus, the overall success rate of the

˜rst administered therapy was 55.5%. I f the ˜rst study drug

did not succeed, the second study drug was able to stop the

status epilepticus for an additional 7.0% of the total popula

-

tion; the third drug helped only an additional 2.3% of pa

-

tients. I t took intensivefinon-study fl therapy to stop the status

epilepticus in 23.2% of the initial patient population, and no

drug was successful within 12 hours in 11.7%. I n this study, if

the patient did not respond to lorazepam or phenytoin, the

response rate to phenobar bital was 2.1% (D.Treiman, ver bal

communication).
Three other RCTs (31, 32, 58), detailed earlier, repor ted
higher rates of second-therapy e˚cac y in adults and children

af ter failure of initial benzodiazepine therapy. However, in

each of these studies, initial therapy was not part of an RC T nor

was it blinded. For second therapy, the class II RCTs reported

success ranging from 77 percent to 90 percent, while the two

class III RCTs repor ted success ranging from 50 percent to 88

percent.
The following conclusions were drawn. I n adults, the
second anticonvulsant administered is less e˛ective than the

˜rstfistandardfl anticonvulsant, while the third anticonvulsant

administered is substantially less e˛ec tive than the ˜rst fistan

-

dard fl anticonvulsant (level A). I n children, the second anticon

-
vulsant appears less e˛ec tive, and there are no data about

third anticonvulsant e˚cacy (level C ).

Recommendations and Algorithm
Based on the evidence -based answers to the above questions,

a treatment algorithm is proposed for convulsive status epilep

-
ticus (Figure 1). As stated earlier, clinical trials have arbitrar ily
focused on either adults or children, and only three tr ials (24,

27, 30) included both. The guideline™s treatment algorithm

is not age speci˜c because the disease pathophysiology of

prolonged seizures/status epilepticus and anticonvulsant

drug e˛ects on neuronal receptors are the same from infants

through adults, per mitting a uni˜ed approach for all patients

older than neonates.

The algor ithm star ts with a stabilization phase (0Œ5 min
-
utes), which includes standard initial ˜rst aid for seizures.The

initial therapy phase should begin when the seizure duration

reaches 5 minutes and should conclude by the 20-minute

mar k when response (or lack of response) to initial therapy

should be apparent.
A benzodiazepine (speci˜cally IM mid
-

azolam, IV lorazepam, or IV diazepam) is recommended as

the initial therapy of choice, given their demonstrated e˚ca

-

c y, safet y, and tolerabilit y (level A, four class I RC Ts)

. Although

IV phenobar bital is established as e˚cacious and well toler

-
ated as initial therapy (level A, 1 class I RCT), its slower rate

of administration, compared with the three recommended

benzodiazepines above, positions it as an alternative initial

therapy rather than a drug of ˜rst choice. For prehospital

settings or where the three ˜rst-line benzodiazepine options

are not available, rec tal diazepam, intranasal midazolam, and

buccal midazolam are reasonable initial therapy alter na

-

tives (level B). I nitial therapy should be administered as an

adequate single full dose rather than broken into multiple

smaller doses. I nitial therapies should not be given t wice

except for IV lorazepam and diazepam that can be repeated

at full doses once (level A, two class I, one class II RC T ). D oses

listed in the initial therapy phase are those used in class I tr i

-

als. Note that some consensus guidelines list slightly di˛erent

dosages; for example, phenobarbital is of ten recommended

at 20 mg/kg (2).
The second-therapy phase should begin when the
seizure du
ration reaches 20 minutes and should conclude by

the 40-minute mar k when response (or lack of response) to

the second therapy should be apparent. Reasonable options

include fosphenytoin (level U), valproic acid (level B, one

class II study) and levetiracetam (level U).

There is no clear
evidence that any one of these options is better than the

others
.The ongoing Established Status EpilepticusTreat
-
mentTr ial (ESE T T ) should provide the answer in the nex t

few years (64). B ecause of adverse events, IV phenobar bital

is a reasonable second-therapy alter native (level B, one class

II study) if none of the three recommended therapies are

available.
The third therapy phase should begin when the seizure
duration reaches 40 minutes.
There is no clear evidence to
guide therapy in this phase (level U)
. Compared with initial

therapy, second therapy is often less e˛ec tive (adultsŠlevel

A, one class I RC T; childrenŠlevel C, two class III RC Ts), and

the third therapy is substantially less e˛ec tive (adultsŠlevel

58
Convulsive Status Epilepticus Guideline
A, one class I RC T; childrenŠlevel U) than initial therapy.
Thus, if second therapy fails to stop the seizures, treat
-
ment considerations should include repeating second-line

therapy
or
 anesthetic doses of either thiopental, midazolam,
pentobarbital, or propofol (all with continuous EEG monitor
-
ing). Depending on the etiology or sever it y of the seizure,

patients may go through the phases faster or even sk ip the

second phase and move rapidly to the third phase, espe

-
cially in sick or intensive care unit patients.The evidence -

based treatment of refrac tor y status epilepticus is beyond

the scope of this guideline, though others have addressed

the issue (65).

Future D irec tions
Additional evidence to fur ther de˜ne the role of other

IV-administered anticonvulsants is crucial to future treat

-
ment of convulsive status epilepticus. Class III tr ials suppor t

e˚cac y and safet y of valproic acid as ˜rst-line therapy (26,

27), second-line therapy (31, 32), and refrac tor y therapy

(66). Evidence for use of levetiracetam and lacosamide is

limited to retrospec tive studies (67Œ72). Given the favorable

phar macok inetic charac ter istics and adverse - e˛ect pro˜les

for these medications compared with fosphenytoin and

phenobar bital, comparative tr ials of these medications as

second-line therapy will provide vital evidence to improve

future treatment of convulsive status epilepticus.The cur

-
rent National I nstitute of Neurological Disorders and Stroke

funded ESE T T tr ial compares IV fosphenytoin, levetiracetam,

and valproate in children and adults with status epilepticus

who did not respond to initial benzodiazepine therapy.

ESE T T is designed to be a class I RC T that will identify the

optimal second therapy for benzodiazepine -resistant status

epilepticus (64).
D isclosures
Drs. Glauser, Alldredge, Ar ya, Bleck , Dodson, G ar r it y, R iviello,

Sloan, andTreiman, along with Ms. Bare, have nothing to

disclose relevant to this guideline. Dr. Shinnar ser ves on

FIGURE 1.
Proposed treatment algor ithm for status epilepticus.
D isclaimer: This clinical algorithm/guideline is designed to assist clinicians by
providing an analytical framework for evaluating and treating patients with status
epilepticus. I t is
not intended to establish a communit y standard of care, replace a clinician™s
medical judgment, or establish a protocol for all patients. The clinical
conditions contemplated by this
algorithm/guideline will not ˜t or work with all patients. A pproaches not covered
in this algorithm/guideline may be appropriate.

59
Convulsive Status Epilepticus Guideline
a Data Safet y M onitor ing B oard (DSMB) for a UCB Phar ma
clinical tr ial of a nonŒepilepsy-related drug. Dr. Gloss is an

evidence -based methodologist of the Amer ican Academy of

Neurology, a level- of-evidence associate editor of Neurol

-

ogy, and has no disclosures relevant to this guideline. Dr.

Bainbr idge receives grant funding from UCB Phar ma for a

study in the elder ly. Dr. Lowenstein is a pr incipal investigator

of the Human Epilepsy Projec t (HEP), which is supported by

unrestr ic ted grants to the Epilepsy Study Consor tium from

UCB Phar ma, Finding A Cure for Epilepsy and Seizures, P˜zer,

Eisai, Lundbeck , and The Andrews Foundation.The funding

is for a study unrelated to status epilepticus. Dr. Pellock is

a paid consultant for t wo companies (P˜zer and UCB). All

grants, research suppor t, consultant fees, and honorar ia are

paid toVirginia Commonwealth Universit y or the physician

prac tice plan (MC V Physicians). Dr. Pellock has no equit y,

stock , or any other ownership interest in either of these

companies. Dr. Jagoda is a paid consultant for P˜zer,TE VA,

andThe M edicines Company for diseases unrelated to status

epilepticus.
Added during proofs: While the
AES guideline was developed
prior to the ILAE™s revised de˜nition of status epilepticus (Trinka

et al., Epilepsia 2015;56:1515Œ1523), the 5 minute de˜nition used

in this guideline is fully consistent with the operational 5 minute

time point (t
1
) for treatment initiation for convulsive status epilep
-
ticus proposed in that document.
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