Introduction
Status epilepticus (SE) is a major neurological emergency associated with significant
lethality and morbidity. SE incidence increases with age; thus, with the demographic
shift of an aging population, rises in incidence rates are likely. In Germany, at
least 16 000 to 20 000 cases of SE are to be expected annually; the resulting costs
of acute in-patient SE treatment amount to over EUR 200 million per year. Mean SE
mortality is between 15 and 20% [1]
[2]
[3]
[4].
To treat SE, a large number of anticonvulsants are available which are used in very
different therapeutic sequences and in various dosage forms. Whenever possible, SE
should be treated in a neurocritical care unit; however, initial treatment should
not be delayed by patient transport times to such a unit. Especially in patients with
nonconvulsive SE or focal SE who may present with minimal neurological signs and symptoms,
an EEG investigation in a clinical neurophysiology department is required to establish
the diagnosis. In the prehospital environment, initial treatment needs to be modified
to reflect the limited monitoring capabilities available in this setting. This review
discusses the options available for prehospital and initial in-hospital treatment
of SE (corresponding to stage 1 and stage 2; see below) in non-ICU settings with limited
monitoring capabilities, taking into account the most recent SE definition of the
International League Against Epilepsy (ILAE) published in 2015 [5] and the current consensus-based (S2k) Guideline on the Management of SE in Adults,
issued by the German Neurological Society (Deutsche Gesellschaft für Neurologie, DGN)
in 2012 [6].
Definition
According to the DGN guideline on SE [6], seizures of more than 5 min duration or a series of discrete seizures between which
there is incomplete recovery of the previous neurological status is defined as SE
and should be treated as soon as possible with sufficiently high doses. The 5-minute
time limit dates back to an operational definition proposed by Lowenstein in 1999,
aimed at ensuring that patients receive treatment as soon as possible, and which considers
any seizure lasting for more than 5 min as SE [7]. The current ILAE definition sets two time points (t1, t2); while t1 defines the
transition of a seizure to SE (t1), depending on semiology, t2 marks the point in
time when neurological injury is likely to occur. Regarding the start of SE treatment
(t1), the time limit is 5 min for generalized convulsive (tonic-clonic) status epilepticus
(GCSE), 10 min for complex focal status epilepticus (focal SE with impaired consciousness)
and 10 to 15 min for absence status epilepticus [5]. SE-induced neuronal damage is assumed to occur after a time (t2) of 30 min with
GCSE and after 60 min with complex focal status epilepticus [5]. Thus, the urgency with which to start treatment is also dependent on the type of
SE and appears to be most pressing with GCSE. Clinical and experimental data show
a correlation between delayed start of treatment and reduced likelihood of successful
SE termination with the first treatment attempt [8]
[9]
[10].
Stage-adapted Therapeutic Principles
Stage-adapted Therapeutic Principles
Clinically, four phases of SE are differentiated [11] which are closely associated with the staged approach to treatment described in
the following. The time spans listed below apply to a GCSE:
-
Initial phase of SE: A seizure of 5–10 min duration or continuous seizure activity
in EEG. There is still a clinically relevant chance of spontaneous termination. Initial
treatment with a benzodiazepine is appropriate.
-
Established status epilepticus: Seizure/epileptic activity in EEG of at least 10–30
(maximum 60) minutes or series of seizures between which there is incomplete recovery
of consciousness. In addition to the initial treatment with a benzodiazepine, a conventional
anticonvulsant is administered intravenously.
-
Refractory status epilepticus: SE persisting after failure of the first and second
treatment, usually 30–60 min after start of seizure activity; escalation of therapy
is critical. At this point in time, general anesthesia with endotracheal intubation
should be administered to patients with GCSE. In patients with focal SE, there is
not the same urgency to initiate aggressive anticonvulsive therapy as with GCSE; thus,
further stage 2 treatment options should be used.
-
Super-refractory status epilepticus: Super-refractory SE is assumed when general anesthesia
was ineffective [11]
[12]. In this situation, several treatment options are available, including steroids,
hypothermia, immunoglobulins, inhalation anaesthetics, ketogenic diet, perampanel,
stiripentol, among others; however, all of these treatments lack evidence base and
some are associated with limited anticonvulsive efficacy [11]
[13]
[14]
[15]. Currently, a randomized, double-blind, placebo-controlled study (NCT02477618) on
the use of allopregnanolone in patients with super-refractory SE is being performed
[16]. Allopregnanolone is a neurosteroid, acting as a positive allosteric modulator of
synaptic and extrasynaptic GABAA receptors [17].
Initial Phase of Treatment (Stage 1)
Initial Phase of Treatment (Stage 1)
Strong evidence from both clinical [8]
[10] and animal model data [9] emphasizes the critical role of early initiation of treatment in patients with SE,
as therapeutic response to most anticonvulsants deteriorates over the course of SE
due to progressive decline in GABAergic inhibition [18]. Consequently, anticonvulsant treatment should be started as early as possible,
ideally already before arrival at a hospital [10]:
In the initial phase, benzodiazepines are the drug of choice. With its longer intracerebral
half-life and the resulting lower risk of seizure recurrence, lorazepam (LZP) is a
clinically suitable drug and evidence-based initial treatment for patients with SE;
it may be administered by paramedics (up to 4 mg) and emergency physicians, or in
a hospital setting (up to 0.1 mg/kg body weight [BW] intravenously) [10]
[19]. As an alternative to LZP, clonazepam (CLP), another long-acting benzodiazepine,
is often used because of its similar pharmacokinetic characteristics [20]; CLP should be slowly administered intravenously as a bolus dose of 0.015 mg/kg
BW. However, data from randomized controlled trials are not available for CLP. A cohort
study conducted in Lausanne (Switzerland) and Boston (USA) showed that LZP was more
frequently underdosed in everyday clinical practice compared with CLP and associated
with a higher risk of a more refractory treatment course [21]. Alternatively, other benzodiazepines can be used (for details on individual benzodiazepines
refer to [Table 1]). When diazepam (DZP) or midazolam (MDZ) are used, concomitant rapid loading with
another anticonvulsant (stage 2) is advisable to compensate for their shorter intracerebral
half-life and to reduce the risk of seizure recurrence.
Table 1 Summary of benzodiazepines for acute treatment of prolonged seizures and status epilepticus.
|
Midazolam
|
Lorazepam
|
Clonazepam
|
Diazepam
|
|
Typical initial dose in adults#
|
5 to 10 mg, in 2–3 mg steps
|
2 to 4 mg#
|
1 mg
|
10 mg#
|
|
Recommended intravenous dosage
|
0.1 mg/kg BW
|
0.05 bis 0.1 mg/kg BW
|
0.015 mg/kg BW
|
0.15 mg/kg BW
|
|
Maximum dosage
|
20 mg
|
8 mg
|
3 mg
|
30 mg
|
|
Routes of administration
|
intravenous, intranasal buccal, intramuscular
|
intravenous
|
intravenous
|
intravenous, rectal
|
|
Half-life
|
3–4 h
|
12–16 h
|
30–40 h
|
20–100 h*
|
|
Interactions
|
few
|
few
|
many
|
many
|
|
Tissue toxicity
|
low
|
low
|
low
|
low
|
BW: body weight
*short duration of action in CNS due to rapid redistribution
#To prevent underdosing, another dose of lorazepam and diazepam, in particular, should
be administered in addition to the typical initial dose (1–2 vials) (WARNING: risk
of respiratory depression)
The RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial) study compared
the efficacy of intramuscular administration of MDZ (total dose of 10 mg, administered
using an applicator; 5 mg for patients with body weights from 13 kg to 40 kg) with
that of intravenous administration of LZP (4 mg total dose, 2 mg for patients with
body weights from 13 kg to 40 kg) in the prehospital treatment of SE [22]
[23]
[24]. Intramuscular MDZ was superior to intravenous LZP with regard to the rate of GCSE
controlled at the time of admission to hospital. This was primarily due to the shorter
time to initial administration and emphasizes the need for rapid administration of
benzodiazepines in the treatment of SE [25]. Although the time from drug administration to termination of SE was shorter in
the arm treated with intravenous LZP, this did not result in statistical superiority
because of the longer time needed to establish a secure intravenous access [22]
[23]
[24].
For initial treatment, especially by nursing staff and family members, additional
routes of administration with rapid absorption are available, such as the buccal or
intranasal administration of MDZ and the rectal administration of DZP. These routes
of administration have been extensively studied, especially in children and adolescents,
but are often expensive in daily use. Sublingual administration of LZP orally disintegrating
tablets and oral administration of CLP or DZP drops should be avoided in the treatment
of SE, as a long absorption half-life of about 20 min can occur.
Several studies showed the equivalence or superiority of intranasal or buccal administration
of midazolam (0.2 mg/kg) or lorazepam (0.05 mg/kg to a maximum of 4 mg) compared with
intravenous or rectal administration [26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]. Thus, intranasal or buccal administration of midazolam (5–10 mg, repeated, if necessary,
maximum dose approx. 20 mg), intramuscular administration of midazolam (10 mg i.m.)
or rectal administration of diazepam (10–20 mg rectally, repeated, if necessary, maximum
dose approx. 30 mg) are recommended for the initial treatment of SE in adults.
Among the branded medications, Buccolam is available for buccal administration; however,
this product is only approved for the treatment of prolonged, acute, convulsive seizures
in infants, toddlers, children and adolescents (from 3 months to <18 years). The missing
approval of the product for the treatment of adults is due to the streamlined form
of the approval process for pediatric use (PUMA, pediatric-use marketing authorization);
however, prescribing this medication to adults in an outpatient setting may mean that
costs are not covered by the statutory health insurances due to the off-label nature
of its use in adults. No intranasal dosage form of midazolam has yet become commercially
available; currently, such a medication is being evaluated in a clinical trial (NCT01390220).
However, commercially available MDZ vials can be use do administer MDZ via the intranasal
route: For this, the solution for injection is to be transferred to a syringe, followed
by intranasal administration using an atomizer (mucosal atomization device). Here,
it is important to pay attention to the various commercially available MDZ dilutions
and vial sizes (MDZ 5 mg/5 ml, 5 mg/1 ml or 15 mg/3 ml). A more convenient method
of administration is to use a concentrated MDZ nasal spray which has already been
evaluated during video-EEG monitoring and established successfully [38]. It was shown that intranasal administration of MDZ significantly delayed seizure
recurrence and reduced the likelihood of generalized tonic-clonic seizures [38]. This concentrated MDZ nasal spray ([Fig. 1]) can be prepared by pharmacies; for details of the formulation refer to [Table 2]. One puff of the spray (volume of 140 μl) contains 2.5 mg MDZ. To dissolve MDZ in
an aqueous solution, an acidic pH of 3.3 is required. As a result, up to 5% of cases
may experience irritation of the nasal mucosa [38]. The clear and colorless nasal spray can be stored at room temperature in a dark
place for up to 3 months; the nasal spray must not be stored in a fridge as this could
lead to the formation of precipitations in the solution. Since the separated form
contains more than 15 mg MDZ, the prescription of the nasal spray falls under Appendix
III of the German Narcotics Act (Betäubungsmittelgesetz, BtMG); thus, the nasal spray
must be prescribed and documented for each patient individually.
Table 2 Formulation of midazolam nasal spray, 5 ml (adapted from [38]
[63]).
|
Midazolam hydrochloride*
|
99.25 mg
|
|
Sodium chloride
|
32 mg
|
|
Benzalkonium chloride
|
0.5 mg
|
|
Sodium EDTA
|
5 mg
|
|
Purified water
|
to 5 ml
|
*Midazolam hydrochloride 99.25 mg ≙ midazolam 89.3 mg; pH of 3.3 achieved with 1 N
hydrochloric acid
Fig. 1 Ready-to-use midazolam nasal spray. The nasal spray delivers reproducible and standardized
doses of 2.5 mg midazolam in 140 μl solution per puff. Rapid absorption via the nasal
mucous membrane is ensured by the low puff volume.
For rectal administration, 5 mg and 10 mg of rectal DZP are available in 2.5 ml rectal
solution and approved for the treatment of SE. For decades, DZP has been used in prehospital
treatment [39]. However, the rectal administration of medications, especially in the public, is
not fully accepted by society and associated with negative psychosocial effects, such
as embarrassment and stigmatization [40]
[41]. Currently, a trend towards buccal or intranasal administration of benzodiazepine
is noted [42]
[43].
Treatment with Intravenous Anticonvulsants (Stage 2)
Treatment with Intravenous Anticonvulsants (Stage 2)
Rapid loading with anticonvulsants is required in patients with persisting SE or after
termination of SE with benzodiazepines to prevent seizure recurrence. Intravenous
dosage forms, listed according to the approval dates of the various anticonvulsants,
are available for phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), levetiracetam
(LEV), lacosamide (LCM), and brivaracetam (BRV); refer to [Table 3]. The DGN Guideline on the Management of SE in Adults recommends the use of PHT;
as alternative medications or in case PHT is contraindicated, VPA, LEV and PB are
taken into consideration [6].
Table 3 Summary of conventional anticonvulsants with intravenous application forms, listed
by date of approval.
|
Phenobarbital
|
Phenytoin
|
Valproate
|
Levetiracetam
|
Lacosamide
|
Brivaracetam
|
|
Typical initial dose in adults§
|
500–700 mg
|
1 200–1 500 mg
|
2 100 mg
|
2 000–4 000 mg
|
400 mg
|
200 mg
|
|
Intravenous dosage
|
10 mg/kg BW#
|
15–20 mg/kg BW#
|
30 mg/kg BW
|
30–60 mg/kg BW
|
5 mg/kg BW 200–600 mg
|
100–400 mg
|
|
Infusion speed
|
100 mg/min
|
max. 50 mg/min, max. 30 mg/kg
|
max. 10 mg/kg/min
|
max. 500 mg/min
|
15 min
|
bolus injection
|
|
Target serum concentration
|
30–50 μg/ml
|
20–25 μg/ml
|
100–120 μg/ml
|
not known
|
not known
|
not known
|
|
Half-life
|
60–150 h
|
20–60 h
|
12–16 h
|
6–8 h
|
13 h
|
8–9 h
|
|
Measuring serum concentration
|
recommended (toxic from 50 µg/ml)
|
recommended (toxic from 25 µg/ml)
|
no (adverse effects from 100 µg/ml)
|
no
|
no
|
no
|
|
Interactions
|
many
|
many
|
many
|
none
|
none
|
minimal
|
|
Respiratory depression
|
yes
|
no
|
no
|
no
|
no
|
no
|
|
Circulatory depression
|
monitoring required*
|
monitoring required*
|
no
|
no
|
no*
|
no
|
|
Vigilance
|
sedation
|
sedation
|
somnolence
|
somnolence
|
somnolence
|
somnolence
|
|
Tissue toxicity
|
high
|
very high
|
strict IV administration
|
very low
|
very low
|
very low
|
BW: body weight
* Acute high-dose intravenous phenytoin or phenobarbital should always be administered
with ECG und blood pressure monitoring in an ICU setting. ECG monitoring is recommended
when lacosamide is administered—especially in combination with sodium channel blockers—as
it can cause PR interval prolongation
# Treiman et al. administered phenobarbital and phenytoin at doses of 15 mg/kg and
18 mg/kg BW, respectively [44]
§ Based on a body weight of 70 kg
PHT should be administered at a dose of 20 mg/kg body weight (BW) (max. 50 mg/min,
max. 30 mg/kg BW) via a secure large-bore IV access, ideally a central venous catheter
[44]. PHT is available both as an infusion concentrate (750 mg/50 ml) and as an injection
solution (250 mg/5 ml) with distinct PHT doses. The highly alkaline PHT solution must
not be diluted with other substances as this could result in the precipitation of
free phenytoin base. For the further treatment, it should be attempted to achieve
a target phenytoin level of 20 µg/ml (up to max. 25 μg/ml). The comparably slow infusion
speed should not be exceeded in the light of PHT’s proarrhythmogenic effect—a disadvantage
of this medication. According to its summary of product characteristics, PHT is contraindicated
in patients with second- or third-degree atrioventricular block, myocardial infarction
during the last 3 months and heart failure with an ejection fraction under 35%. In
addition, similar to thiopental, phenytoin exhibits local tissue toxicity; thus, intravenous
access should be large-bore and secure to avoid tissue necrosis associated with extravasation.
Irreversible damage of the cerebellum may result from phenytoin intoxication [45]. These toxicities limit the use of phenytoin as a first-line treatment in patients
who have no indwelling central venous catheter or where continuous monitoring of vital
signs is not available; thus at our hospitals, PHT is used as drug of 4th choice after
LEV, VPA and LCM [3], and other centers pursue similar management strategies [46]
[47]
[48]. Furthermore, this approach reflects the current prescribing behavior in patients
with epilepsy in Germany: in over 50% of patients, treatment is started with LEV at
first diagnosis [49]
[50].
VPA should be infused at a dose of 20–30 mg/kg BW, max. 10 mg/kg/min, to be repeated
after 10 min, if necessary, then at a dose of max. 10 mg/kg. For the further treatment,
it should be attempted to achieve a target VPA level of 100–120 μg/ml. VPA is available
at a concentration of 100 mg/ml in various dose sizes, with 300 mg, 400 mg and 1 000 mg
per vial. A major contraindication is known mitochondriopathy. According to the summary
of product characteristics, VPA is also contraindicated in patients with insulin-dependent
diabetes mellitus or porphyria. Since VPA can cause a platelet dysfunction (thrombocytopathy),
its use in patients with increased susceptibility to bleeding and in need of surgical
treatment is problematic. Further contraindications include hepatic disorder, pancreatitis
and oral anticoagulation with vitamin K antagonists such as warfarin or phenprocoumon
(susceptibility to bleeding and INR imbalance). Furthermore, it is often difficult
to achieve adequate serum levels in patients with carbapenem antibiotics as co-medication
[51].
LEV is to be administered at a dose of 30 mg/kg BW with the maximum infusion speed
of 500 mg/min; if required, this can be repeated after 10 min (maximum total dose
of 60 mg/kg BW). The target level for LEV treatment has not yet been established.
In patients with renal impairment, dose adjustment is required for continuing therapy.
PB can be administered at doses of up to 20 mg/kg BW (max. 100 mg/min) [44]. Higher total doses require intensive care monitoring as well as preparedness for
intubation and mechanical ventilation; consequently, as with PHT, its use is contraindicated
where adequate monitoring cannot be ensured. In addition, drug-drug interaction as
well as intoxication risks have to be taken into consideration when PB is used in
combination with VPA. In patients with hepatic impairment, PB should not be used.
For the further treatment, it should be attempted to achieve a target PB level of
30–50 µg/ml.
Since 2008 LCM has been available as an intravenous anticonvulsant. According to a
recent systematic review, it has been used in more than 500 cases to treat SE; its
efficacy was 57% and its tolerability profile was favorable [52]. Usually, a dose of 5 mg/kg BW is administered over ≥15 min (initial dose of 200
to 400 mg) [53]
[54]
[55]. As with LEV, LCM has not yet been approved for the treatment of SE. Since PR interval
prolongation have been observed with LCM, it should be used with caution in patients
with known second-degree or higher AV block and in patients with cardiac disease.
Dose adjustment is required in patients with renal or hepatic impairment.
Approved in 2016, BRV is the latest intravenous anticonvulsant that has become available
and data on its use to treat SE are limited to just a few cases [56]. Most commonly, starting dosages of 200 to 400 mg are used; in contrast to other
intravenous anticonvulsants, undiluted solution can be used for bolus injection, further
cutting down the time to treatment in SE. BRV has not yet been approved for treatment
of SE. All in all, BRV is a well-tolerated antiepileptic drug (AED) with a lower incidence
of psychobehavioral adverse events compared with LEV [57]
[58]. Switching from LEV to BRV is possible and a ratio between 15:1 and 10:1 can be
applied [57]. Dose adjustment is required in patients with hepatic or renal impairment [59]
[60]. Since BRV crosses the blood-brain barrier significantly faster than LEV and attains
its maximum concentration in the brain within minutes after intravenous administration
[61], future studies will have to clarify whether BRV treatment starting with a bolus
injection for rapid loading offers advantages in the emergency situation.
Concepts for Management Outside Intensive Care Units
Concepts for Management Outside Intensive Care Units
Neither in the prehospital nor in the in-hospital setting should the treatment of
SE be unnecessarily delayed. An established local treatment pathway should be in place
to ensure that treatment is started immediately after diagnosis, already outside the
emergency department or intensive care unit. In patients in whom SE is suspected based
on EEG findings, the technician should inform the treating physician experienced in
EEG interpretation so that, once the diagnosis of SE is confirmed, treatment can be
started. If SE is diagnosed in the clinical neurophysiology department, it has proven
to be beneficial to bring along an SE emergency kit ([Fig. 2]) so treatment can be started while an EEG is recorded. Midazolam can be administered
intranasally if intravenous access is not yet established; once established, conventional
anticonvulsants such as LEV, VPA, LCM or BRV should be administered intravenously—the
monitoring capabilities of an emergency department or intensive care unit are not
required for this step. Further treatment is then provided in an intensive care unit.
Fig. 2 The SE emergency kit used in Frankfurt for the initial treatment of status epilepticus
in settings with limited monitoring capabilities.
Conclusion
In conclusion, besides uncontrollable factors such as etiology, comorbidity and age
of patient, rapid initiation of treatment with benzodiazepines and other anticonvulsants
in high enough doses is critical for a successful therapy. In prehospital and in-hospital
settings outside of intensive care units where monitoring capabilities are limited,
the treatment of SE has to be adapted to local conditions. Therapy should be continued
in a neurocritical care unit, especially when treatment with PHT or PB or stage 3
or 4 therapy is required. To ensure initial treatment is started without delay, it
is critical to establish a local treatment pathway [62] so that the recommended treatment can be provided immediately.
