US Pharm. 2013;38(1):HS-12-HS-16.
ABSTRACT: Generalized convulsive status epilepticus (GCSE) is a
neurologic emergency requiring immediate medical attention. Pharmacists
are front-line health care providers when it comes to the management of
GCSE, and they must be equipped with an in-depth knowledge of the
appropriate agents used in its management, including benzodiazepines
(BZDs) and antiepileptic drugs (AEDs). A BZD should be used initially to
control seizure activity, with an AED given as soon as possible after
BZD administration. During any GCSE presentation, the route,
adverse-effect profile, monitoring necessity, and proven efficacy of
each agent under consideration should be evaluated to determine the
appropriate BZD and AED.
Generalized convulsive status epilepticus (GCSE), a neurologic
emergency requiring immediate medical attention, has a reported fatality
rate of up to 30% to 40% after diagnosis.1-3 GCSE occurs in
children, as well as in adults; however, this article will focus only on
management in adults. Other forms of status epilepticus (SE) exist,
such as nonconvulsive status epilepticus (NCSE), but they are less
common than GCSE and will not be discussed here.4
The definition of SE is constantly fluctuating, which creates a
dilemma in the determination of whether a patient fits the clinical
picture of SE. Historically, the disorder has been defined as seizure
activity for more than 30 minutes leading to irreversible neuronal
damage, but the duration of seizure activity for diagnosis has been
continually shortened.1,2,5-9 Most recently, Brophy et al
developed guidelines that define SE as either 5 or more minutes of
continuous seizure activity or recurrent seizure activity without an
appropriate return to baseline.10 Physiological alterations—including internalization of gamma-aminobutyric acid (GABA)A receptors
and increased sensitivity to excitatory neurotransmitters—occur that
make it unlikely for seizure activity lasting longer than 5 minutes to
stop spontaneously, which supports the aforementioned shortened
Because of the emergent nature of GCSE, prospective, randomized data
regarding appropriate pharmacologic management are limited. Guidelines
have been developed by the Neurocritical Care Society and the European
Federation of Neurological Societies for appropriate pharmacotherapeutic
management of GCSE.1,10 Pharmacists are front-line health
care providers in the management of GCSE, and knowledge of these
guidelines and proper medication use in specific GCSE patient
populations should not be underestimated or undervalued. This requires
an in-depth evaluation of each available drug in terms of dosing, route,
common or serious adverse effects (AEs), and data supporting efficacy
for GCSE. The following review focuses on these aspects so that
hospital-based pharmacists will be fully armed with the knowledge to
make appropriate initial pharmacotherapy decisions when managing GCSE in
Initially, if the cause of GCSE is known (e.g., hypoglycemia
requiring glucose and thiamine to reverse the hypoglycemia while
preventing Wernicke’s encephalopathy), reversal of the cause is of
primary importance.2,6 Other commonly associated reversible
causes of GCSE include acidosis, hypoxia, and electrolyte disturbances
(including hyponatremia and hyperkalemia).2,14 Additionally,
subtherapeutic antiepileptic drug (AED) levels in epileptic patients
presenting with GCSE should be assessed and immediately addressed.2,7,10
In concert with the evaluation of reversible causes, aggressive
treatment should be initiated as soon as possible, without a delay for
diagnostic workup.13 The current pharmacotherapy
recommendations for GCSE stress the use of benzodiazepines (BZDs) and
AEDs through nonenteral routes of administration (e.g., IV,
intramuscular [IM], per rectum [PR]); recommended dosing is summarized
in TABLE 1. Control of SE should be gained within 60 minutes of the initial insult.10
Unfortunately, current literature suggests that only 30% to 60% of GCSE
patients respond to the initial agent or the second agent selected.1,3,10,15
The roles of individual agents in GCSE management remain ill-defined despite the aforementioned guidelines.1,3,10 The VA Cooperative Study (Treiman et al) attempted to determine the most effective regimen for GCSE control.15
However, this study examined four treatment arms containing diazepam
plus phenytoin, lorazepam, phenytoin, or phenobarbital, neglecting newer
AEDs as well as the commonly used combination of lorazepam plus an AED.15
Additionally, patients with SE often require three or more AEDs for
managing GCSE, presenting another challenge for appropriate medication
selection.3 The following sections will focus on agents available in nonenteral routes for the management of SE.
Three BZDs are primarily used in the management of GCSE: diazepam,
lorazepam, and midazolam. All work at the postsynaptic GABA neuron in
the central nervous system (CNS).16 These agents inhibit
neuronal excitability through increased permeability to chloride ions,
leading to hyperpolarization and stabilization at the neuron. Success
rates of BZDs for SE cessation range from 60% to 90%, and the vast
majority of patients in recent studies received a BZD as initial
therapeutic treatment.3,6,17 Additionally, the aforementioned
VA Cooperative Study showed the inferiority of phenytoin to lorazepam,
thus strengthening the recommendation that BZDs are the appropriate
initial medication for any GCSE cessation attempt.15
Diazepam: Of the three BZDs, diazepam is the most lipid
soluble and enters the CNS quickly. However, it is rapidly
redistributed (usually ≤30 minutes) outside the CNS, which somewhat
limits its utility. Diazepam’s elimination half-life is roughly 24 to 48
hours, creating the possibility of accumulation if repeated
administration is needed; noted AEs include respiratory depression,
hypotension, and sedation.2,6,13,16 One benefit of diazepam
is its availability in both IV and PR routes. Multiple studies have
shown the superiority of diazepam over placebo for SE, but superiority
over other pharmacologic agents is not well documented.6
Lorazepam: This agent is considered by many practitioners to be the BZD of choice in the management of GCSE.2,6
While it is less lipid soluble than diazepam, it redistributes from the
CNS more slowly than diazepam, thus conferring a longer duration of
action and a reduced rate of recurrent seizures. While the AEs seen with
lorazepam are similar to those for diazepam, the reduced lipid
solubility lessens the risks of hypotension and respiratory depression.
Additionally, lorazepam binds to GABA receptors with greater affinity,
providing a relatively extended anticonvulsant effect of 6 to 12 hours.2,6,16
However, tolerance to lorazepam develops rapidly, so subsequent doses
may be less effective than initial doses. A recent retrospective
analysis found that patients who initially received lorazepam alone or
with an AED had a significantly shorter time to SE resolution, backing
the current practice model, which uses lorazepam as the initial agent in
Midazolam: Commonly used in Europe, midazolam is
often the third BZD option considered for initial management of GCSE in
the United States, owing to its extremely short half-life (90-150
minutes) and the need for frequent boluses.13,16 Midazolam is available in IV, IM, buccal, intranasal, and PR routes.2,16,18
In children, use of buccal midazolam has been effective and has had no
clinically significant AEs, which is an advantage when no IV access is
available.6,18 Bolus injections of midazolam tend to be
relatively ineffective because of the drug’s short half-life. In the
U.S., this agent has primarily been used in refractory SE as an IV
infusion, which is beyond the scope of this article.2,13,16
In a comparison of BZDs for the management of SE, Alldredge et al
found that seizure cessation occurred in 59.1% of patients given
lorazepam 2 to 4 mg and in 42.6% of those given diazepam 5 to 10 mg,
with both agents significantly more effective than placebo.19
Additionally, Leppik et al saw no difference in AEs in a comparison of
the two agents; seizure-cessation rates with one or two doses of
lorazepam or diazepam were 89% and 76%, respectively (not statistically
significant).20 Recently, an evaluation of IM midazolam versus IV lorazepam found similar AE profiles and recurrent seizure rates.21
However, the IM midazolam group had a statistically significant
improvement (73.4% vs. 63.4%) in seizure-cessation rates upon emergency
department arrival and in the proportion of subjects admitted to the
ICU.21 These data provide some evidence that IM midazolam is
at least as safe and effective as IV lorazepam in the management of
Phenytoin and Fosphenytoin
Phenytoin works through stabilization of neuronal membranes by
increasing the efflux or decreasing the influx of sodium ions, which can
prolong the refractory period between neuronal impulses.16
It is often the first AED chosen for GCSE management because of
practitioner familiarity with it. Disadvantages of phenytoin include a
maximum infusion rate of 50 mg per minute, which can cause difficulty in
large patients owing to its weight-based dosing (TABLE 1).16
Because of the increased incidence of hypotension in the elderly
population, it is recommended that phenytoin be infused no faster than
25 mg per minute. Additionally, hypotension occurs with the IV
formulation regardless of age, possibly because of the presence of
propylene glycol (PG), and infusion of either phenytoin or fosphenytoin
renders monitoring for cardiac abnormalities (e.g. arrhythmias,
hypotension) necessary.10 Other AEs include sedation, respiratory depression, rash, phlebitis, purple glove syndrome, dizziness, and extravasation.6,16,22
Fosphenytoin is a water-soluble prodrug of phenytoin. It contains no
PG, theoretically lowering the incidence of hypotension compared with
phenytoin. Additionally, fosphenytoin carries a lower risk of purple
glove syndrome.6 However, the difference in formulation has not reduced overall AE rates.7,23
One argued benefit is that therapeutic concentrations of phenytoin are
achieved more quickly with fosphenytoin, partly because of the faster
infusion rate (150 mg phenytoin equivalents [PE]/min). Fosphenytoin also
may be administered IM, if IV access is unavailable. One complication
of this agent is that dosing is via PEs, with 1.5 mg of fosphenytoin
equivalent to 1 mg of phenytoin, possibly creating confusing dosing
Valproic Acid/Sodium Valproate
Valproate is believed to work either through increased availability of GABA or through GABA enhancement or mimicry.16
In multiple small studies, valproate was as effective and safe as
phenytoin or fosphenytoin for GCSE, primarily after BZDs were given; one
study showed a statistically significant improvement in
seizure-cessation rate with valproate.4,8,18,22,24-26 In
certain European countries, valproic acid is considered an appropriate
initial AED selection after BZDs have been given, with the timing of
administration being important since efficacy is time dependent.14,22,25
Retrospective data suggest that valproate used after BZDs results in
significantly less treatment failure compared with levetiracetam.8
However, valproate patients had significantly fewer acute and deadly
etiologies, creating a difficult-to-interpret scenario. Common AEs noted
with valproate are hypotension, dizziness, thrombocytopenia, and
hepatic dysfunction, but these occur in fewer than 10% of patients and
are not rate dependent.18,22,24 Respiratory depression is not
seen with valproate, conferring a possible benefit in patients in whom
respiratory monitoring is not possible.2-3,18 Of note, valproate is also effective for the management of NCSE.2,4
Levetiracetam’s mechanism is unknown but is postulated to be due to
activity at synaptic vesicle protein 2A, which may prevent
synchronization of epileptiform burst firing and seizure activity.16,22
In recent studies, 10% to 31% of patients received levetiracetam as the
second agent chosen in the management of SE and more than 65% were
discharged on levetiracetam, evidencing its increased popularity among
AED medications in the management of SE.3,8 Multiple small studies have shown excellent efficacy and low toxicity with the use of levetiracetam in GCSE.8,9,18,22,27,28
Additionally, a small study by Misra et al argued that levetiracetam
may be an acceptable first-line agent compared with lorazepam because of
similar efficacy and a reduced rate of hypotension and respiratory
compromise.29 Completed rigorous and comparative clinical
trials of levetiracetam’s efficacy and safety are lacking, with most
data being observational in nature and involving heterogeneous patient
Somnolence, rash, thrombocytopenia, and paradoxical agitation have
been noted with levetiracetam, but respiratory depression and
hypotension are not present.3,9,27,29 An additional advantage
of levetiracetam is the presence of very limited drug-drug interactions
owing to its lack of CYP450 metabolism.14 As mentioned
earlier, a retrospective observational study found that valproate used
after BZDs had significantly less treatment failure compared with
levetiracetam.8 Add to that the initial concern that
levetiracetam would not be an effective option in SE because of multiple
modeling exercises showing a possible delay in CNS entry versus other
AEDs used in GCSE, and there is still reason to question the role of
levetiracetam in the treatment of GCSE.4,8
Lacosamide, a newer AED that may work by enhancing inactivation of
voltage-dependent sodium channels, thereby reducing excitable neuronal
firing, has shown promise in the management of GCSE.16-18,30
Two recent studies had success rates of 44% to 100% in patients
receiving lacosamide for termination of SE, with the low end of that
range comparable to rates for phenytoin and fosphenytoin.6,17,30 Additionally, a subgroup analysis showed that the earlier lacosamide was given, the greater the success rate of SE cessation.17 As
with levetiracetam, there is a lack of rigorous, comparative clinical
trials of lacosamide, and further evaluation is necessary before its
role in the management of GCSE can be determined.
Rash and pruritus have been noted as possible AEs with lacosamide.30
However, cardiorespiratory depression and hypotension were not
reported, possibly representing an added benefit compared with more
commonly used agents.3,17
Phenobarbital is similar to BZDs in that its mechanism is exerted at GABAA receptors. However, it binds to a different location on the receptor.7,16
Phenobarbital has shown 60% to 70% efficacy in SE cessation, but
because of its significant AE profile it is typically used second-line
after failure of BZDs and more commonly used AEDs.6,31 AEs
seen with phenobarbital include rash, sedation, and respiratory
depression that may require airway protection. Hypotension also is
common owing to its dilution in PG. This dilution also raises concern
about serious AEs, such as renal failure and myocardial depression.2,6,16
In general, lorazepam is the preferred IV BZD and should be given as
soon as GCSE has been diagnosed. Diazepam and midazolam should be used
in cases in which lorazepam is not a viable option owing to medication
unavailability or the need for non-IV nonenteral administration. An IV
AED should be infused immediately after lorazepam administration. There
is no definitive second agent in GCSE; correct AED selection
incorporates many factors, such as monitoring and product availability.
While an older AED like phenytoin is commonly selected based on
practitioner familiarity, newer agents are frequently used in current
GCSE treatment algorithms. Randomized, controlled trials are necessary
to determine the most appropriate initial management of GCSE, as well as
which AED should be initially selected, but they are difficult to
complete because of the emergent nature of GCSE.8,18 Until
trials of this type are completed, pharmacists will play a vital role in
AED education, including AEs, proven efficacy, and dosing
recommendations for each agent under consideration.
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