Drugs (2015) 75:1499-1521
`DOI 10.1007/s40265-015-0454-2
`
`CrossMark
`
`Pharmacotherapy for Status Epilepticus
`
`Eugen Trinkal'34 • Julia litifler" • Markus Leitinger" • Francesco Brigo2
`
`Published online: 27 August 2015
`© The Author(s) 2015. This article is published with open access at Springerlink.com
`
`Abstract Status epilepticus (SE) represents the most
`severe form of epilepsy. It is one of the most common (cid:9)
`neurologic emergencies, with an incidence of up to 61 per (cid:9)
`100,000 per year and an estimated mortality of 20 %. (cid:9)
`Clinically, tonic-clonic convulsive SE is divided into four
`subsequent stages: early, established, refractory, and super- (cid:9)
`refractory. Pharmacotherapy of status epilepticus, espe- (cid:9)
`cially of its later stages, represents an "evidence-free (cid:9)
`zone," due to a lack of high-quality, controlled trials to (cid:9)
`inform clinical decisions. This comprehensive narrative (cid:9)
`review focuses on the pharmacotherapy of SE, presented
`according to the four-staged approach outlined above, and
`providing pharmacological properties and efficacy/safety (cid:9)
`data for each antiepileptic drug according to the strength of
`scientific evidence from the available literature. Data (cid:9)
`sources included MEDLINE and back-tracking of refer- (cid:9)
`ences in pertinent studies. Intravenous lorazepam or (cid:9)
`
`intramuscular midazolam effectively control early SE in
`approximately 63-73 % of patients. Despite a suboptimal
`safety profile, intravenous phenytoin or phenobarbital are
`widely used treatments for established SE; alternatives
`include valproate, levetiracetam, and lacosamide. Anes-
`thetics are widely used in refractory and super-refractory
`SE, despite the current lack of trials in this field. Data on
`alternative treatments in the later stages are limited. Val-
`proate and levetiracetam represent safe and effective
`alternatives to phenobarbital and phenytoin for treatment of
`established SE persisting despite first-line treatment with
`benzodiazepines. To date there are no class I data to sup-
`port recommendations for most antiepileptic drugs for
`established, refractory, and super-refractory SE. Limiting
`the methodologic heterogeneity across studies is required
`and high-class randomized, controlled trials to inform
`clinicians about the best treatment in established and
`refractory status are needed.
`
`121 Eugen Trinka
`e.trinka@salk.at
`
`Department of Neurology, Christian Doppler Klinik,
`Paracelsus Medical University Salzburg,
`Ignaz Harrerstrasse 79, 5020 Salzburg, Austria
`
`Department of Neurological and Movement Sciences,
`University of Verona, Verona, Italy
`
`Centre for Cognitive Neurosciences Salzburg, Salzburg,
`Austria
`
`2
`
`3
`
`4 (cid:9) University for Medical Informatics and Health Technology,
`UMIT, Hall in Tirol, Austria
`
` ARGENTUM Exhibit 1065
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`4$ (cid:9)
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`EXHIBIT
`1690//-A5-
`1/,-,,
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`Adis
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`1500
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`Key Points
`
`Initial treatment of early status epilepticus (SE) with
`intravenous lorazepam or intramuscular midazolam
`is able to control seizures in 63-73 %; buccal
`midazolam may be an alternative whenever
`intravenous or intramuscular application of other
`benzodiazepines is not possible.
`
`In established SE, intravenous antiepileptic drugs
`(phenytoin/fosphenytoin, valproate, levetiracetam,
`phenobarbital) are most commonly used, but there is
`no class I evidence for choosing one over the other;
`valproate and levetiracetam represent safe and
`effective alternatives to phenobarbital and
`phenytoin; lacosamide is another potential
`alternative to phenytoin and phenobarbital, but
`current evidence is too sparse to give
`recommendations.
`
`Refractory and super-refractory SE is treated with
`anesthetics (propofol, midazolam, thiopental/
`pentobarbital) with lower success rates and a high
`morbidity and mortality. Potential drugs to be
`considered in super-refractory SE are ketamine,
`magnesium, and immunomodulatory treatments, as
`well other cause-directed and non-medical
`treatments.
`
`Other drugs which might be useful in the treatment
`of SE, such as clonazepam, paraldehyde,
`chlormethiazole (clomethiazole), or lidocaine, have a
`long history, but there is no higher-class evidence to
`support their use other than as second or third
`alternatives in refractory cases.
`
`1 Introduction
`
`Status epilepticus (SE) can be regarded as the most severe
`and extreme form of an epileptic seizure. Tonic-clonic SE
`(i.e., convulsive SE, CSE) can be defined as ongoing con-
`vulsive seizure activity or repeated convulsive seizures,
`without regaining consciousness between seizures, for more
`than 5 min [1]. Non-convulsive SE (NCSE) can be defined as
`an "enduring epileptic condition with reduced or altered
`consciousness, behavioral and vegetative abnormalities, or
`merely subjective symptoms like auras, but without major
`convulsive movements for more than 30 min" [2, 3]. A Task
`Force of the International League Against Epilepsy (ILAE)
`recently defined SE as "a condition resulting either from the
`
`L\ Adis
`
`E. Trinka et al.
`
`failure of the mechanisms responsible for seizure termina-
`tion or from the initiation of mechanisms, which lead to
`abnormally prolonged seizures (after time point tl)... which
`can have long-term consequences (after time point t2),
`including neuronal death, neuronal injury, and alteration of
`neuronal networks, depending on the type and duration of
`seizures". [4]. The time limits for t1 were set at 5 min for
`generalized convulsive SE, and 10 min for focal SE with
`impaired consciousness (formerly complex-partial SE). In
`the new classification NCSE is divided into those patients
`with and without coma following two broad clinical cate-
`gories: while the former are "ictally comatose", often seen as
`a progression of CSE, the "walking wounded" with aura
`continua, absence status, or focal SE with impaired con-
`sciousness have a less severe prognosis and do usually not
`need the full armamentarium of emergency treatment as
`described below.
`SE is most prevalent in the population with structural
`brain damage. In patients with epilepsy, SE can be pre-
`cipitated by drug withdrawal, intercurrent illness, or
`metabolic disturbance. The mortality of SE is around 20 %,
`but may be as high as 40 % in the elderly with acute
`symptomatic SE [5-9] and many co-morbidities [10]. The
`annual incidence has been estimated to be approximately
`18-28 cases per 100,000 per year, but may be as high as 61
`per 100,000 per year, depending on the population studied
`[11-16]. The incidence is highest in the elderly and has a
`second peak in the neonatal period [17-22].
`Although the first descriptions go back to Babylonian
`Times (Sakikku-Board, 718-614 BC) [23] and recognition
`of absence status was evident in the 16th century [24],
`detailed descriptions of the clinical picture and first
`pathophysiology considerations occurred in the 19th and
`20th centuries. In their seminal work, Clark and Prout
`recognized three phases of CSE [25-27]:
`
`(a) In patients with epilepsy, an early phase can be
`characterized, where frequency and severity of
`seizures increases in a crescendo pattern. Synonyms
`are premonitory status, impending status, and heraldic
`status. In patients without pre-existing epilepsy, the
`phase with a crescendo-like increase in seizure
`frequency and severity is missing, and SE starts
`abruptly. Ongoing convulsive epileptic activity for
`more than 5 min is now often called early SE.
`(b) Established SE designates continuous seizure activity
`with convulsions or intermittent seizures without
`regaining consciousness between the seizures. For
`more than 10 and up to 30 min, or failure of initial
`treatment (usually benzodiazepines) of early SE.
`(c) With increasing duration, a decrease in motor activity
`(electromechanical dissociation) occurs while the
`patient remains in a coma. This phase is called
`
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`Pharmacotherapy for Status Epilepticus
`
`1501
`
`advanced SE or refractory SE, referring to the failed
`treatment (usually with antiepileptic drugs, AEDs) of
`early and established SE. Other terms are subtle SE or
`stuporous SE.
`(d) At the third London-Innsbruck Colloquium on Status
`Epilepticus [28], the fourth stage of SE, called super-
`refractory SE, was characterized. At this stage
`seizures continue despite maximal treatment with
`intravenous (IV) anesthetics for more than 24 h in an
`intensive care unit. These patients have ictal EEG
`discharges when anesthesia is lessened. This stage has
`also been termed malignant SE [29] (Fig. 1).
`
`It has to be acknowledged that there is no clear defini-
`tion of the stages and one might merge into the other.
`While Clark and Prout described the stages of SE in mostly
`untreated patients, clinical practice now defines the first
`stage with a time frame (5 min of convulsive and 10 min of
`focal non-convulsive), and the later stages by treatment
`response: it has now been commonly accepted to designate
`established SE as "benzodiazepine-resistant SE," while the
`term refractory SE is used, when treatment with benzodi-
`azepines and one or more IV AEDs have failed. This also
`implies that the timeframes given above, which are used by
`most clinicians, may vary considerably with treatment. By
`nature this lack of clear definitions leads to a high degree of
`variability in the current literature.
`In 2007, at the First London-Innsbruck Colloquium on
`Status Epilepticus, a workshop was held with the purpose
`of outlining the options of optimal pharmacotherapy of the
`various forms of SE. A consensus was reached and a
`treatment protocol published, which followed the conven-
`tional pattern of tonic-clonic SE established [30, see Flow
`
`chart in "Appendix"]. The European Federation of Neu-
`rological Societies and other groups have also published
`similar recommendations [31, 32]. Recent reviews [33, 34]
`covered the history of pharmacotherapy of SE outlining the
`enormous range of therapies that have been advocated
`since the 19th century.
`Data on the pharmacotherapy of SE are most often
`observational, having a high degree of heterogeneity and
`high-class randomized, controlled trials are only available
`for the early stages of SE. Therefore we discuss the phar-
`macotherapy of SE in a narrative, rather than in a sys-
`tematic review. In this article we will review the data
`following the same principles of a staged approach as
`outlined above.
`Treatment of SE, especially of its later stages, the
`pharmacological management of which represents a terra
`incognita [28], is almost an "evidence-free zone," due to a
`lack of adequate numbers of high-quality, controlled trials
`to inform clinical decisions, especially in the later stages of
`the disorder. In most clinical trials performed in this area,
`often burdened by severe methodologic limitations
`including excessive clinical heterogeneity, investigators
`use different definitions of SE (and its stages), adopt
`inappropriate comparators, or use unclear methods of data
`presentation [35-37], so that reaching definite evidence is
`an extremely challenging task.
`Given this serious limitation, in this narrative review we
`presented the most relevant studies on this topic (Table 1)
`taking into account the "evidence-pyramid" [38]: when-
`ever available, data from controlled clinical trials (ran-
`domized/not randomized) were preferred over uncontrolled
`trials or case series, unless reporting relevant clinical
`results in terms of efficacy or tolerability. Similarly,
`
`Fig. 1 Clinical course of
`convulsive status epilepticus
`(SE)
`
`Stage I
`
`Early phase
`
`Premonitory SE, impending SE
`
`established SE
`
`Stage II
`
`Stage III
`
`Refractory SE: SE, that continues despite stage I/II treatmen
`INV SE, stuporilliaL
`
`30 to
`60 min
`
`Stage IV
`
`Super-refractory SE: SE, that continues despite treatment with
`anaesthetics > 24 hours
`
`> 24 h
`
`A Adis
`
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`
`Table 1 Main randomized, controlled clinical trials conducted in different stages of status epilepticus (SE)
`
`U
`
`Study
`
`Country (cid:9)
`
`Definition of SE
`
`Participants Interventions
`and age (cid:9)
`
`Early SE: Stage I
`France
`Remy et al. (cid:9)
`[53]
`
`Seizures >20 min or 2 GTCS within
`20 min
`
`Adults (cid:9)
`16-65 years
`
`Rectal DZP 30 mg vs. rectal DZP 20 mg
`
`Dreifuss et al. USA
`[52]
`
`Acute repetitive seizures
`
`Cereghino (cid:9)
`et al. [50]
`
`USA
`
`Multiple seizures within 12-24 h
`
`Adults (cid:9)
`>18 years
`
`Adults (cid:9)
`18-76 years
`
`Rectal DZP 0.2 mg/kg vs. placebo
`
`Rectal DZP 0.2 mg/kg vs. placebo
`
`Shaner et al. California (cid:9)
`[117] (cid:9)
`
`GTCS >30 min or 3 GTCS within 1 h or Adults
`GTCS >5 min (cid:9)
`>15 years
`
`IV DZP 2-20 mg + IV PHT 6-18 mg/kg based on initial drug
`levels vs. IV PB 10-30 mg/kg IV
`
`IV DZP 5 mg or LZP 2 mg vs. placebo
`
`IV DZP 0.2 mg/kg vs. IV LZP 0.1 mg/kg
`
`Clinical
`seizure (cid:9)
`cessation
`
`Adverse
`effects
`
`DZP 30 mg DZP 30 mg
`10/18
`13/18 (cid:9)
`DZP 20 mg DZP 20 mg
`13/21
`6/21 (cid:9)
`DZP 31/46 (cid:9)
`DZP 19/46
`Placebo (cid:9)
`Placebo
`13/49
`14/49 (cid:9)
`DZP 10/31
`DZP 22/31 (cid:9)
`Placebo (cid:9)
`Placebo 9/39
`11/39
`DZP + PHT DZP + PHT
`10/18 (cid:9)
`9/18
`PB 16/18 (cid:9)
`PB 9/18
`LZP 39/66 (cid:9)
`LZP 7/66
`DZP 7/68
`DZP 29/68 (cid:9)
`Placebo
`Placebo (cid:9)
`15/71 (cid:9)
`16/71
`DZP 101/140 DZP 157**
`LZP 97/133 LZP 155**
`
`Alldredge (cid:9)
`et al. [40] (cid:9)
`
`USA
`
`Seizures >5 min
`
`Chamberlain USA
`et al. [43]
`
`Leppik et al. USA
`[41]
`
`Treiman et al. USA
`[81]
`
`Seizures >5 min
`
`>3 GTCS in 1 h; confusional state with
`ongoing EEG abnormalities
`
`Seizures >10 min or 2 GTCS within
`10 min or subtle generalized convulsive
`SE (coma and ictal discharges on EEG)
`
`Arya et al. (cid:9)
`[48]
`
`India
`
`Seizures at arrival at emergency
`department
`
`Gathwala (cid:9)
`et al. [58]
`
`India
`
`Seizures at arrival at emergency
`department
`
`Adults (cid:9)
`>18 years
`
`Children (cid:9)
`3 months-
`18 years
`Adults (cid:9)
`>18 years
`Adults (cid:9)
`>18 years
`
`Children (cid:9)
`6-14 years (cid:9)
`
`Children (cid:9)
`6 months- (cid:9)
`14 years (cid:9)
`
`IV LZP 2 mg vs. IV DZP 5 mg
`
`IV LZP vs. IV PB vs. IV DZP + PHT vs. IV PHT
`
`LZP 0/37
`LZP 33/37 (cid:9)
`DZP 4/32
`DZP 25/32 (cid:9)
`LZP 42/97
`LZP 63/97 (cid:9)
`PB 46/91
`PB 53/91 (cid:9)
`DZP + PHT DZP + PHT
`53/95 (cid:9)
`48/95
`PHT 44/1 01 PHT 44/101
`IN LZP 0/71
`IN LZP (cid:9)
`59/71 (cid:9)
`IV LZP 0/70
`IV LZP
`56/70
`IV MDZ 0.1 mg/kg vs. IV DZP 0.3 mg/kg vs. IV LZP 0.1 mg/kg MDZ 36/40 MDZ 4/40
`DZP 29/40 (cid:9)
`DZP 24/40
`LZP 38/40 (cid:9)
`LZP 4/40
`
`IN LZP 0.1 mg/kg vs. IV LZP 0.1 mg/kg (cid:9)
`
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`

`
`Pharmacotherapy for Status Epilepticus
`
`Clinical (cid:9)
`seizure (cid:9)
`cessation
`
`Adverse
`effects
`
`MDZ 23/26 (cid:9) MDZ 0/26
`DZP 0/26
`DZP 24/26 (cid:9)
`
`MDZ 20/23 (cid:9) MDZ 2/23
`DZP 13/22 (cid:9)
`DZP 0/22
`
`MDZ 35/35 (cid:9) MDZ 0/35
`DZP 0/35
`DZP 35/35 (cid:9)
`
`MDZ 18/27 MDZ 0/27
`DZP 15/23 (cid:9)
`DZP 1/23
`
`MDZ 30/40* MDZ: 0/40
`DZP 23/39 (cid:9)
`DZP 0/40
`
`MDZ 5/109
`DZP 7/110
`
`MDZ (cid:9)
`71/109* (cid:9)
`DZP 45/110
`MDZ (cid:9)
`125/165 (cid:9)
`DZP 114/165
`MDZ 51/60 MDZ 0/60
`DZP 56/60 (cid:9)
`DZP 0/60
`
`MDZ 1/165
`DZP 0/165
`
`MDZ 12/13 MDZ 1/13
`DZP 10/11 (cid:9)
`DZP 1/11
`
`MDZ 45/50 MDZ 0/50
`DZP 54/65 (cid:9)
`DZP 7/65
`
`IM MDZ 5-10 mg (according to body weight) vs. IV LZP 2-4 mg MDZ
`(according to body weight) (cid:9)
`329/448
`LZP 282/445
`VPA 23/35
`PHT 14/33
`
`IV VPA 30 mg/kg bolus vs. IV PHT 18 mg/kg (cid:9)
`
`MDZ 75/448
`LZP 77/445
`
`VPA 4/35
`PHT 6/33
`
`Table 1 continued
`
`Study (cid:9)
`
`Country (cid:9)
`
`Definition of SE (cid:9)
`
`Participants Interventions
`and age (cid:9)
`
`Lahat et al. (cid:9)
`[59]
`
`Israel (cid:9)
`
`Febrile seizures >10 min (cid:9)
`
`Fisgin et al. (cid:9)
`[62] (cid:9)
`
`Turkey (cid:9)
`
`Seizures at arrival at emergency (cid:9)
`department (cid:9)
`
`Mahmoudian Iran (cid:9)
`and Zadeh (cid:9)
`[60]
`Thakker and India (cid:9)
`Shanbag [61] (cid:9)
`
`Seizures at arrival at emergency (cid:9)
`department (cid:9)
`
`Seizures >10 min (cid:9)
`
`Scott et al. (cid:9)
`[65] (cid:9)
`
`UK (cid:9)
`
`Seizures at arrival of paramedics (cid:9)
`
`McIntyre (cid:9)
`et al. [63] (cid:9)
`
`UK (cid:9)
`
`Seizures at arrival at emergency (cid:9)
`department (cid:9)
`
`Mpimbaza (cid:9)
`et al. [66] (cid:9)
`
`Uganda (cid:9)
`
`Seizures at arrival at emergency (cid:9)
`department or >5 min (cid:9)
`
`Talukdar and India (cid:9)
`Chakrabarty (cid:9)
`[64] (cid:9)
`
`Chamberlain USA (cid:9)
`et al. [217] (cid:9)
`
`Seizures at arrival at emergency (cid:9)
`department (cid:9)
`
`Seizures >10 min (cid:9)
`
`Shah and (cid:9)
`Deshmukh (cid:9)
`[67] (cid:9)
`
`Silbergleit (cid:9)
`et al. [44] (cid:9)
`
`Misra et al. (cid:9)
`[82] (cid:9)
`
`India (cid:9)
`
`Seizures at arrival at emergency (cid:9)
`department (cid:9)
`
`USA (cid:9)
`
`Seizures >5 min (cid:9)
`
`India (cid:9)
`
`Seizures >10 min (cid:9)
`
`Children (cid:9)
`6 months— (cid:9)
`5 years
`Children (cid:9)
`1 month— (cid:9)
`13 years
`Children (cid:9)
`2 months— (cid:9)
`15 years
`Children (cid:9)
`1 month— (cid:9)
`12 years
`Children/ (cid:9)
`adults (cid:9)
`5-22 years
`Children (cid:9)
`7 months— (cid:9)
`15 years (cid:9)
`Children (cid:9)
`3 months— (cid:9)
`12 years (cid:9)
`Children (cid:9)
`Birth to (cid:9)
`12 years
`Children (cid:9)
`Birth to (cid:9)
`18 years
`Children (cid:9)
`1 month— (cid:9)
`12 years
`Children (cid:9)
`and adults (cid:9)
`0-102 years (cid:9)
`Children/ (cid:9)
`adults (cid:9)
`1-85 years
`
`IN MDZ 0.2 mg/kg vs. IV DZP 0.3 mg/kg (cid:9)
`
`IN MDZ 0.2 mg/kg vs. rectal DZP 0.3 mg/kg (cid:9)
`
`IN MDZ 5 mg/ml vs. IV DZP 0.2 mg/kg (cid:9)
`
`IN MDZ 0.2 mg/kg vs. IV DZP 0.3 mg/kg (cid:9)
`
`Buccal MDZ 10 mg vs. rectal DZP 10 mg (cid:9)
`
`Buccal MDZ 0.5 mg/kg vs. rectal DZP 0.5 mg/kg (cid:9)
`
`Buccal MDZ 0.5 mg/kg vs. rectal DZP 0.5 mg/kg (cid:9)
`
`Buccal MDZ 0.2 mg/kg vs. IV DZP 0.3 mg/kg (cid:9)
`
`IM MDZ 0.2 mg/kg vs. IV DZP 0.3 mg/kg (cid:9)
`
`IM MDZ 0.2 mg/kg vs. IV DZP 0.2 mg/kg (cid:9)
`
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`
`li (cid:9)
`
`Table 1 continued
`
`Study
`
`Country
`
`Definition of SE
`
`Participants
`and age
`
`Interventions
`
`Gilad et al.
`[84]
`
`Misra et al.
`[116]
`
`Israel
`
`Seizures >30 min
`
`India
`
`Seizures >5 min
`
`Adults
`>18 years
`Children/
`adults
`1-75 years
`
`IV VPA 30 mg/kg bolus vs. IV PHT 18 mg/kg bolus
`
`IV LEV 20 mg/kg over 15 min vs. IV LZP 0.1 mg/kg over
`2-4 min
`
`Established SE: stage H
`Shaner et al. California
`[117]
`
`GTCS >30 min or 3 GTCS within I h or Adults
`GTCS >5 min
`>15 years
`
`IV DZP 2-20 mg + IV PHT 6-18 mg/kg based on initial drug
`levels vs. IV PB 10-30 mg/kg
`
`Treiman et al. USA
`[81]
`
`Adults
`Seizures >10 min or 2 GTCS within
`10 min or subtle generalized convulsive >18 years
`SE (coma and ictal discharges on EEG)
`
`IV LZP vs. IV PB vs. IV DZP + PHT vs. IV PHT
`
`Agarwal et al.
`[83]
`
`Chen et al.
`[218]
`
`India
`
`Seizures >5 min refractory to IV DZP
`
`China
`
`Seizures >5 min refractory to IV DZP
`
`IV VPA 20 mg/kg bolus vs. IV PHT 20 mg/kg
`
`Children/
`adults
`>2 years
`Adults
`IV VPA 30 mg/kg bolus followed by infusion at 1-2 mg/kg vs. IV VPA 15/30
`15-99 years DZP 0.2 mg/kg bolus followed by infusion at 4 mg/h for 3 min
`DZP 20/36
`and then increased every 3 min by 1 µg/min until seizure
`cessation or maximal duration (1 h) reached
`IV VPA 20 mg/kg bolus vs. IV PB 20 mg/kg bolus
`
`Clinical
`seizure
`cessation
`
`VPA 13/18
`PHT 7/9
`LEV 29/38
`LZP 31/41
`
`Adverse
`effects
`
`VPA 0/18
`PHT 2/9
`LEV 62**
`LZP 94**
`
`DZP + PHT DZP + PHT
`10/18
`9/18
`PB 16/18
`PB 9/18
`LZP 63/97
`LZP 42/97
`PB 53/91
`PB 46/91
`DZP + PHT DZP + PHT
`53/95
`48/95
`PHT 44/101
`PHT 44/101
`VPA 44/50
`VPA 4/50
`PHT 42/50
`PHT 8/50
`
`VPA 5/30
`DZP 4/36
`
`7/30
`22/30
`
`VPA 27/30
`PB 23/30
`
`Malamiri
`et al. [219]
`
`Iran
`
`Refractory SE: stage III
`Singhi et al.
`India
`[127]
`
`Seizures >5 min, not controlled by DZP Children
`3-16 years
`
`gUZ .8
`
`IV MDZ 0.2 mg/kg bolus followed by 2-10 lig/kg/min infusion MDZ 18/21 MDZ 8/21
`vs. DZP 0.01-0.1 mg/kg/min infusion
`DZP 17/19
`DZP 9/19
`IV VPA 30 mg/kg bolus vs. IV DZP 10 gg/Kg/min increased by VPA 16/20
`VPA 0**
`10 pg/kg/h every 5 min
`DZP 17/20
`DZP 22**
`
`IV PRO 2 mg/kg bolus then titrated toward burst-suppression or PRO 6/14
`PRO15**
`2 mg/kg/h vs. IV PTB 5 mg/kg bolus then titrated toward burst- PTB or THP PTB or THP
`suppression or 2 mg/kg/h or IV THP 2 mg/kg bolus then titrated
`2/9
`12**
`toward burst-suppression or 4 mg/kg/h
`
`Mehta et al.
`[220]
`
`India
`
`Motor seizures uncontrolled after 2 doses Children
`of DZP and PHT infusion
`2-12 years
`Seizures >30 min, not controlled by DZP Children
`and PHT
`5 months-
`12 years
`Rossetti et al. Switzerland, Seizures >30 min, not controlled by
`Adults
`[135]
`USA
`benzodiazepine and PHT or VPA or PB 16-87 years
`or LEV
`
`Super-refractory SE: stage IV
`No randomized, controlled clinical trials available to inform clinical decisions
`
`Page 00006
`
`

`
`Pharmacotherapy for Status Epilepticus (cid:9)
`
`1505
`
`cumulative data obtained from high-quality systematic
`literature reviews were reported as the best available evi-
`dence on this topic.
`
`2 Early Status Epilepticus: Stage I
`
`All AEDs commonly used as first-line treatment in SE are
`benzodiazepines. These drugs bind to the gamma-
`aminobutyric acid (GABA)-A receptors, increasing chan-
`nel opening frequency at the receptor, with subsequent
`increased chloride conductance and neuronal hyperpolar-
`ization, leading to enhanced inhibitory neurotransmission
`and antiepileptic action [39].
`
`2.1 Lorazepam (Intravenous (IV) and Intranasal
`(IN))
`
`Lorazepam can be administered either intravenously or
`intranasally, although to date most evidence in the treat-
`
`ment (cid:9) of SE refers to its IV use. Although it has a longer
`initial duration of action than diazepam, lorazepam
`administered intravenously is usually preferred as initial
`treatment of early SE, because it is less lipid-soluble and
`consequently does not undergo the rapid redistribution into
`peripheral tissues seen with diazepam. This pharmacologic
`advantage has been clinically substantiated in randomized,
`controlled trials comparing IV lorazepam with placebo
`[40], IV diazepam [41-43], and IM midazolam [44]. In a
`meta-analysis, lorazepam was better than placebo for risk
`of non-cessation of seizures (relative risk (RR) 0.52; 95 %
`confidence interval (CI) 0.38-0.71), better than diazepam
`for reducing risk of non-cessation of seizures (RR 0.64;
`95 % CI 0.45-0.90), and had a lower risk for continuation
`of SE requiring a different drug or general anesthesia (RR
`0.63; 95 % CI 0.45-0.88) [36, 45]. There was no statisti-
`cally significant difference between lorazepam and diaze-
`
`pam (cid:9) administered intravenously in terms of respiratory
`failure/depression, or hypotension [36, 45].
`IM midazolam was non-inferior to IV lorazepam in a
`landmark study in early SE [44] (see Sect. 2.4 for details).
`Recently an intranasal (IN) administration of lorazepam
`has been proposed as an alternative, non-invasive delivery
`route for this drug, considering the favorable phanna-
`cokinetics with rapid absorption from the IN route leading
`to rapid blood concentrations required for seizure termi-
`nation [46, 47]. The favorable pharmacokinetics of IN
`lorazepam in relation to standard (IV) administration have
`been confirmed in one randomized, open-label non-inferi-
`ority trial conducted in 141 consecutive children aged
`6-14 years who presented with convulsions to the emer-
`gency room, showing that IN lorazepam was not inferior to
`IV lorazepam in terms of clinical seizure remission within
`
`LA Adis
`
`co E-.. (cid:9)
`a.
`.-7 (cid:9)
`, O
`0
`t
`O
`c4 a. (cid:9)
`d‘
`5'
`>..
`=
`o
`
`o.
`E; (cid:9)
`.o- (cid:9)
`o
`c
`c)
`_a (cid:9)
`ta.
`co 0...
`cA‘ (cid:9)
`.c
`c (cid:9)
`o
`E
`E (cid:9)
`E (cid:9)
`cs)
`'El (cid:9)
`
`'..1
`a O
`a
`
`- E‘w (cid:9)
`
`- = (cid:9)
`..,C (cid:9)
`,7 cl (cid:9)
`s (cid:9)
`0
`i IA (cid:9)
`0
`E Q. (cid:9)
`
`cr3' CI,
`i'..!
`.t.., It: (cid:9)
`a (cid:9)
`• 0.
`'a .9. (cid:9)
`.5
`o
`
`.• 3-
`-c
`a (cid:9)
`.2
`P4
`- E.
`7. a (cid:9)
`8•E (cid:9)
`r,) (cid:9)
`
`o
`
`L4
`E
`c,D (cid:9)
`E -
`a .. a. - (cid:9)
`L.1 'E
`.!.,.: (cid:9)
`Jo
`y o..
`2w w (cid:9)
`N
`Q E. (cid:9)
`
`Z.,'
`-1g
`
`O
`
`MDZ 0.2 mg/kg IV vs. LZP 0.1/kg IV
`
`LZP 0.0.5-0.1 mg/kg IV vs. DZP 0.3-0.4 mg/kg IV
`
`SE not defined
`
`0
`
`o
`
`SE not defined
`Studies not explicitly reporting a definition of SE
`
`o
`
`Interventions
`
`Definition of SE
`
`U
`
`B 00
`
`Table 1 continued
`
`Page 00007
`
`

`
`1506 (cid:9)
`
`E. Trinka et al.
`
`10 min of drug administration [48]. It has to be noted that
`this study included not only children in SE, but also those
`who had a seizure in the emergency room, which can
`explain the high rate of treatment success, potentially
`leading to a bias towards non-inferiority.
`
`2.2 Diazepam (IV, Rectal)
`
`Diazepam is a highly lipophilic benzodiazepine, which
`rapidly enters into the brain but subsequently is rapidly
`redistributed into peripheral tissues [39]. This pharma-
`cokinetic property is responsible for its fast anticonvulsant
`effect in spite of its longer elimination half-life. Diazepam
`can be administered either intravenously or rectally, with
`demonstrated significantly higher efficacy over placebo in
`terms of controlling acute repetitive convulsive seizures in
`adults and children for both methods of administration [40,
`49-52]. Diazepam 30 mg intrarectal gel was found to have
`higher efficacy than 20 mg in seizure cessation without any
`statistically significant increase in adverse effects [53].
`A meta-analysis of the literature indicates that, com-
`pared with placebo, after diazepam administration there is
`a lower risk of requirement for ventilator support and
`continuation of SE requiring a different drug or general
`anesthesia with diazepam (304 patients included overall)
`[36]. In a recent double-blind, randomized, controlled,
`superiority trial IV diazepam was compared to IV lor-
`azepam in pediatric SE [43]. 273 children aged 3 months to
`<18 years were randomized to either 0.2 mg/kg diazepam
`(n = 140) or 0.1 mg/kg lorazepam (n = 133). The rates
`for cessation of SE within 10 min and without recurrence
`over 30 min were 72.1 % (101/140) in the diazepam group
`and 72.9 % (97/133) in the lorazepam group. There were
`also no differences in all secondary outcomes (e.g.,
`requirement of assisted ventilation), except that patients in
`the lorazepam group were more often sedated (66.9 vs.
`50 %).
`
`2.3 Clonazepam (IV)
`
`Clonazepam is more lipophilic than lorazepam, but less
`lipophilic than diazepam, making it therefore less prone to
`redistribution. Its long half-life of 17-55 hs and rapid onset
`of action makes it an attractive agent for emergency
`treatment of seizures and SE. To date, there is limited
`evidence to support the use of IV clonazepam in the
`treatment of early SE. In one uncontrolled case series (17
`children) with SE treated with this drug, seizure cessation
`was reported in all patients after administration of doses
`between 0.25 and 0.75 mg, with no adverse effects repor-
`ted [54]. In a subsequent uncontrolled, open-label trial (24
`patients), the administration of an IV bolus injection of
`1-2 mg clonazepam led to complete control of 100 % (7/7)
`
`IN Adis
`
`petit mal, 50 % (7/14) grand mal, and 66 % of partial
`complex cases of SE (mean time to clinical seizure ces-
`sation after administration was 1.75 min) [55]. Adverse
`effects consisted exclusively of transient mild to moderate
`drowsiness occurring in 40 % of the patients. One study
`comparing IV clonazepam alone to clonazepam followed
`by levetiracetam in generalized CSE was reported to recruit
`in 2011, but final results have not been published yet [56].
`Quite surprisingly, despite these favorable preliminary
`data, no further controlled trials has been conducted to
`evaluate efficacy and tolerability of this drug in the treat-
`ment of SE. Despite this lack of evidence, clonazepam is
`extensively used in France, The Netherlands, Belgium, and
`other European countries.
`
`2.4 Midazolam (IV, Intramuscular (IM), Intranasal,
`Buccal)
`
`Midazolam is a benzodiazepine with the advantage of
`multiple routes of administration, due to its water solubil-
`ity. At physiologic pH the ring structure of midazolam
`closes and it becomes highly lipophilic, crossing the blood-
`brain barrier rapidly [57].
`Midazolam administered intravenously was found to be
`similar in terms of seizure recurrence to IV diazepam or IV
`lorazepam in a pediatric non-randomized, controlled trial,
`with no significant differences in mean duration to clinical
`seizure cessation [58].
`A recent double-blind, randomized, non-inferiority trial
`compared the efficacy of IM midazolam with that of IV
`lorazepam for children and adults with CSE treated by
`paramedics before admission to hospital [44]. Midazolam
`was found to be at least as safe and effective as IV lor-
`azepam: at the time of arrival in the emergency department,
`seizures were absent without rescue therapy in 73.4 %
`(329/448) in the IM-midazolam group and in 63.4 % (282/
`445) in the IV-lorazepam group. The two treatment groups
`were similar with regard to the need for endotracheal
`intubation (14.1 % of subjects with midazolam and 14.4 %
`with lorazepam) and recurrence of seizures (11.4 % and
`10.6 %, respectively). Among subjects whose seizures
`ceased before arrival in the emergency department, the
`median times to active treatment were significantly lower
`in the midazolam group, although the onset of action (i.e.,
`seizure cessation) occurred sooner after IV lorazepam
`administration, and adverse-event rates were similar in the
`two groups. Overall, these findings indicate that IM
`midazolam is a practical, safe, and effective alternative to
`IV lorazepam for the treatment of prolonged convulsive
`seizures in prehospital settings.
`In general, IN and buccal routes of administration are
`more convenient than IV administration for the treatment
`of SE, because these formulations deliver the medication
`
`Page 00008
`
`

`
`Pharmacotherapy for Status Epilepticus
`
`1507
`
`non-invasively and more rapidly than by the IV route, and
`may be used also by paramedics. In three randomized,
`controlled trials comparing IN midazolam with IV diaze-
`pam, IN midazolam was equally effective as IV diazepam,
`with a lower mean time to control of seizures in the
`midazolam group than in the diazepam group, and no
`significant side effects observed in either group [59-61]. In
`addition, IN midazolam was found to be more effective
`than rectal diazepam in children with prolonged convulsive
`seizures, without serious complications [62].
`In a prospective randomized trial, buccal midazolam
`was found to be more effective than rectal diazepam in
`children with convulsive febrile seizures [63]. No statisti-
`cally significant differences in terms of efficacy were found
`in other studies comparing buccal midazolam with IV
`diazepam [64] or rectal diazepam [65, 66]. These findings
`support treatment protocols recommending its use as first-
`line treatment of acute tonic-clonic seizures in childhood
`including CSE where IV access is difficult or not available
`[31]. Time to obtain IV access may be relevant, and may
`explain a shorter time for controlling the convulsive epi-
`sodes in patients receiving buccal midazolam compared
`with patients treated with IV [64] or rectal [65] diazepam.
`Similarly, in a study in children comparing IM midazolam
`and IV diazepam, mean interval to cessation of convulsions
`with IM midazolam was found to be significantly lower
`than in the diazepam group without prior IV access [67].
`
`3 Established Status Epilepticus: Stage II
`
`3.1 Phenytoin/Fosphenytoin (IV)
`
`Phenytoin has a pKa of 8.3 and is highly lipid soluble but
`insoluble in water. To keep phenytoin in solution it has to
`be prepared in a highly alkaline solvent with pH values of
`around 12 [68]. It has been used extensively over the past
`50 years in the treatment of SE [68], but it took almost
`20 years to recognize the appropriate doses of phenytoin to
`be effective in SE [69]. Due to its slow rate of infusion
`(maximum 50 mg/min) and its delayed onset of action, it
`should not be used in early SE [30-32, 70] The recom-
`mended dose is 18-20 mg/kg for adults and 15 mg/kg in
`the elderly (>65 years). Though phenytoin is not sedative,
`hypotension (28-50 %) and cardiac arrhythmias (2 %) may
`complicate the treatment [71, 72]. Patients over the age of
`50 years and with pre-existing cardiac disease are at spe-
`cial ri