Case
Presentation
A 37-year old male is brought
to the emergency department by EMS because of a seizure at home. The
patient had a generalized tonic-clonic seizure prior to going to bed.
The seizure lasted for approximately ten minutes, followed by a period
of unresponsiveness during EMS transport. The patient has a long history
of post-traumatic seizures that are managed with phenytoin and phenobarbital.
There has been neither recent illness nor recent head trauma.
In the emergency department,
the patient is still unresponsive. There are no focal neurological
findings or any evidence of any other medical condition that would
precipitate a seizure. The patient then goes on to have another seizure
in the Emergency Department. The seizure is generalized with tonic-clonic
seizure activity. The seizure lasts for over two minutes while medications
are being obtained.
Key Clinical Questions
-
What
% of ED seizure patients will not respond to initial treatment with
benzodiazepines?
-
Is there
a difference in outcome in patients treated with diazepam vs. lorazepam?
-
What
is the role of the following therapies in patients who continue
to seize after being administered full, weight based doses of benzodiazepines?
IV phenytoins?
IV phenobarbital?
IV valproic acid?
IV propofol?
IV continuous benzodiazepine infusions?
IV pentobarbital?
-
There
are a significant number of patients who may present with seizures
or SE to the Emergency Department.
-
The
initial use of the benzodiazepines in treating actively seizing
patients is well established and supported by the medical literature
and current recommendations.
-
There
are many different agents that can be used top treat patients who
continue to seize despite the administration of the benzodiazepines.
-
The
most important consideration is to have a protocol that allows for
the rapid use of multiple agents when patients continue to seize
and are diagnosed with SE, in order to minimize morbidity and mortality.
-
Having
the medications available in the ED and using them quickly in full
mg/kg doses is the most important aspect of the use of the seizure
medications.
Introduction
Management of the ED Patient
in Status Epilepticus
Epidemiology
There are an estimated
2.5 million patients with epilepsy in the US, based on a prevalence
of about 6.6 per 1000 Americans.1 Up to 28% of all epilepsy patients
require treatment in Emergency Departments annually.2 In addition
to these patients who have an established seizure diagnosis, another
150,000 patients are newly diagnosed with a seizure, and most are
treated in the Emergency Department at some time during this process.3
A recent multi-center ED study has demonstrated that 1-2% of all ED
patients is being treated for a complaint related to seizures.4 Applying
this percentage to the 100 million ED visits recorded in 1995, up
to two million patients are treated annually for seizures in the ED.5
Status epilepticus (SE)
occurs in 50-150,000 patients per year (based on an incidence of 50
per 100,000 Americans), and is most common at the extremes of age.6;7
The reported mortality rate for patients in SE ranges from 5-22%,
and has been reported to be as high as 65% in those whose SE is refractory
to first line therapies.6-10 Status epilepticus is seen in up to 7%
of ED seizure patients, and a survey reported that at least five SE
patients are treated annually by each Emergency Medicine physician.4;11
What percent of ED seizure patients will not respond to initial
treatment with benzodiazepines? Does efficacy differ between diazepam
and lorazepam?
These questions address
how often patients should be expected not to respond to the initial
EMS or ED therapy with benzodiazepines.
There are data from uncontrolled
studies that determine the rate of active seizing and SE are seen
in the ED. The multi-center prospective study by Huff reported a 17%
seizure recurrence rate among all ED seizure patients, and a 6% prevalence
of SE in these ED patients.4 A retrospective study of EMS patients
reported a 7% rate of active seizing among all EMS seizure patients,
and a 1% active seizure rate at the time of ED admission.12 A retrospective
review of adult seizure patients demonstrated a 1.5% rate of active
seizing at the time of ED admission.5 Retrospective studies of ED
pediatric seizure patients reported that 5-7% of these patients will
seize while in the ED, regardless of the etiology, febrile vs. afebrile
seizure.13-15
Four prospective randomized
studies compare the use of IV diazepam and IV lorazepam in the treatment
of SE. Leppik's 1983 study of 78 patients demonstrated seizure control
in 89% of lorazepam-treated patients and 76% of diazepam-treated patients,
a difference that was noted not to be statistically different.16 A
1995 pediatric study of lorazepam and diazepam from the UK demonstrated
that a single dose of lorazepam was able to terminate seizures or
SE in 76% of patients, and that a single dose of diazepam was effective
in 51% of patients.17 In this pediatric population, respiratory complications
were noted in 15% of diazepam-treated patients and 3% of lorazepam-treated
patients. Treiman compared the use of lorazepam with diazepam and
phenytoin in a VA study of patients in SE.10 This 1998 study of 384
patients, which also did not focus specifically on ED patients, reported
effective termination of clinical seizing and EEG evidence of seizures
at 20 minutes in 67% of those treated with lorazepam and 60% of those
treated with diazepam and phenytoin. The pre-hospital trial of SE,
published in 2001, compared the use of lorazepam (2 mg IVP x 2), diazepam
(5mg IVP x 2), and placebo.18 This study demonstrated SE termination
in 59% of lorazepam-treated patients, 43% of diazepam-treated patients,
and 21% of patients who received neither of these anti-epileptic therapies
in the EMS setting. These data demonstrated a 1.9x greater odds of
SE termination in patients treated with lorazepam vs. those treated
with diazepam, with complication rates of 10% in both treatment groups.
In addition to these prospective studies, Treiman also noted that
benzodiazepines have been found to effectively treat 79% of 1,346
SE patients analyzed from uncontrolled clinical studies.19
Conclusions:
1. Up to 2% of all ED patients
will present because of problems related to a seizure disorder.
2. 5-17% of all seizure
patients will seize while in the Emergency Department.
3. 6% of ED patients will
be classified as having SE.
4. Lorazepam is expected
to terminate seizures and SE in 59-89% of seizure patients
5. Diazepam is expected
to terminate seizures and SE in 43-76% of seizure patients.
6. The use of lorazepam
in pediatric patients with seizures and SE is associated with fewer
pulmonary complications than is the use of diazepam.
What is the role of the following second line therapies in SE patients:
IV phenytoins? IV phenobarbital? IV valproate? IV propofol? IV continuous
benzodiazepine infusions? IV pentobarbital?
IV Phenytoins:
Although IV phenytoin is
an accepted therapy for patients whose seizures cannot be successfully
terminated with benzodiazepines, few controlled trials have addressed
its use in SE. The 1998 Treiman VA study, as mentioned before, showed
a 56% success in terminating SE using a diazepam/phenytoin combination.10
The 1988 Shaner study evaluated the use of diazepam and phenytoin
in 18 patients in a clinical trial comparing this regimen with 18
patients treated with phenobarbital.20 The use of diazepam and phenytoin
was associated with longer seizure duration than with the use of phenobarbital
(5 vs. 9 minutes, p < .06). Complications in these two treatment
groups were comparable. In a published abstract, IV fosphenytoin was
studied in ED SE patients, most of who were treated with benzodiazepines
prior to receiving their fosphenytoin infusion.21 Following the infusion
of fosphenytoin, which could occur at rates up to 150 mg PE/min, 97%
were noted to remain seizure-free during the two-hour observation
period. There have been no published prospective studies of fosphenytoin
in the treatment of SE patients who have failed benzodiazepine treatment.
The issue of high-dose
phenytoins in the treatment of SE is only addressed in one case series
and one published guideline.22;23 Osorio reported that of 13 SE patients
who were given high-dose phenytoin (mean dose 24 mg/kg), five (38%)
did not require pentobarbital therapy. The Epilepsy Foundation of
America's Working Group on SE recommends that up to 30/mg/kg of phenytoin
be given prior to using another AED.
Conclusions:
1. The combination of diazepam
and phenytoin will terminate between 38 and 56% of seizures in patients
with SE.
2. No published articles
demonstrate any enhanced efficacy of fosphenytoin over phenytoin.
3. One case series suggests
that high dose phenytoin may be useful in SE patients.
4. The Epilepsy Foundation
of America Consensus Guideline suggests that high dose phenytoins
may be effective in treating SE.
IV Phenobarbital:
The use of IV phenobarbital
is commonly accepted as a therapy for patients who fail to respond
to benzodiazepines and who are in SE. Two non-blinded studies have
examined the efficacy of this drug in seizures and SE. The 1988 Shaner
study compared the use of diazepam and phenytoin with the use of phenobarbital
and optional phenytoin in 36 patients in SE.20 SE duration was noted
to be shorter with the use of phenobarbital (5 vs. 9 minutes, p <
.06), and 61% of phenobarbital patients did not require the addition
of phenytoin in order to terminate SE. Complication rates were comparable
in the two treatment groups, suggesting phenobarbital as an alternative
to the use of diazepam and phenytoin. The second phenobarbital study
by Painter compared phenytoin with phenobarbital in the treatment
of neonatal seizures.24 This study demonstrated comparable efficacy,
with 43% efficacy with phenobarbital and 45% efficacy with phenytoin.
Combined treatment with both agents increased the efficacy in treating
seizures and SE to 57-62% in these neonatal patients.
Conclusions:
1. Phenobarbital is comparable
to the use of diazepam in phenytoin in the termination of seizures
and SE.
2. 43-61% of patients with
seizures and SE are effectively with phenobarbital.
3. When used with phenytoin,
phenobarbital will effectively treat 57-62% of seizures and SE.
IV Valproate:
IV valproate has been show
to be effective in one 1993 French study of SE patients.25 In this
study, valproate was used to treat SE patients irrespective of initial
anti-epileptic drug therapy, and seizure termination was achieved
within 20 minutes of infusion for 83% of the SE patients. Another
European study, from Spain, demonstrated 58% control of SE in pediatric
patients with SE.26 IV valproate has also been reported in other case
series to be effective in the treatment of myoclonic seizures and
generalized convulsive and non-convulsive SE in the US.27-29 In the
2000 Limdi study, 16 of 20 patients were effectively treated with
a rapid infusion of valproate for intractable seizures. In the 2000
Sinha study, 13 hypotensive geriatric patients were effectively infused
with IV valproate with an exacerbation of their hypotension. Another
US study by Venkataraman demonstrated that IV valproate could be infused
at rates up to 6 mg/kg/min, or up to 300 mg/min, although this was
not studied in the setting of SE.30
Conclusions:
1. When used for the treatment
of SE, valproate will control seizures in 58-83% of patients.
2. IV valproate has been
shown to be infused without hypotension in geriatric patients and
at rapid rates in pediatric patients.
IV Propofol:
IV propofol has been reported
to be effective in an EMS case report from Finland, as well as in
hospitalized patients from Switzerland and the West Indies.31-33 This
drug is thought to provide burst suppression in patients with refractory
SE, and it can be used in the ED. In one US study of 16 patients that
compared propofol with high-dose barbiturates, propofol was noted
to terminate fewer cases of SE (63 vs. 82%, p = NS), but the time
to termination was much shorter with the use of propofol (3 vs. 123
min, p < .002).34 In a study of 20 refractory SE patients from
Virginia, the use of propofol was compared with midazolam.35 Propofol
achieved a 64% rate of clinical seizure suppression, as compared to
67% for midazolam. Mortality, however, tended to be higher with propofol
(57 vs 17%, p = .16), especially in those with an APACHE II score
> 20.
Conclusions:
1. The use of propofol
provides a 63-64% efficacy in treating SE patients.
2. Propofol may be less
effective than high-dose barbiturates, and comparable to the use of
midazolam in the treatment of SE patients.
3. Propofol may be associated
with a higher mortality than the use of midazolam in more critically
ill patients.
IV Continuous Benzodiazepine Infusions:
The continuous infusion
of benzodiazepines has been used to treat both pediatric and adult
patients with refractory SE. In one open-label study in 40 pediatric
patients, the continuous infusion of diazepam and midazolam was compared,
with the endpoint being a six hour period free of seizures.37 Both
drugs were equally effective in controlling refractory SE (86% and
89% respectively), but higher seizure recurrence and mortality rates
were seen with the infusion of midazolam. In a review article that
included 54 adult SE patients, the use of a continuous IV midazolam
infusion effectively treated 80% of adult SE patients, but was associated
with a greater rate of breakthrough seizures than were the infusions
of propofol and pentobarbital (51% vs. 15% and 12%, respectively).38
The infusion of midazolam was, however, associated with less hypotension
than were the other two infusions 30% vs 44% and 77%, respectively).
Two other studies examined the use of a continuous IV midazolam infusion
in adults, one with 33 patients38 and one with seven patients whose
outcome was compared to 13 treated with a propofol infusion.35 In
the study of 33 patients in non-convulsive SE, an infusion of IV midazolam
was effective in treating 82% of patients.39 In six patients treated
with a midazolam infusion, the rate of seizure suppression was 67%.35
Conclusions:
1. The use of continuous
IV infusions of benzodiazepines is effective in treating 67-89% of
SE patients.
2. In children, the use
of a continuous IV diazepam infusion may be preferred over the use
of a midazolam infusion, since it is associated with a lower rate
of seizure recurrence and lower mortality.
3. In adults, the use of
a continuous midazolam infusion is associated with a greater rate
of breakthrough seizures than are propofol and pentobarbital, but
it causes less hypotentsion than do the other two continuous infusions.
IV Pentobarbital:
The use of a continuous
IV infusion of pentobarbital has been studied in multiple adult case
series.34,36,38 When compared to the use of a IV infusion of propofol
in 8 patients, pentobarbital was shown to be effective in terminating
SE in 82% of patients, a rate higher than the 63% success rate seen
with IV propofol.34 The time to SE termination was, however, much
longer with pentobarbital (123 vs. 3 minutes). In the 106 patients
treated with IV pentobarbital in the Claasen review, pentobarbital
had the highest treatment success rate (92%, as compared to 80% for
IV midazolam and 73% for IV propofol).38 Pentobarbital, however, was
associated with the highest rate of hypotension requiring pressors
as compared to propofol and midazolam (77% vs. 42% and 30%, respectively).
In one of the studies summarized by Claassen, the outcome of 44 patients
treated with IV pentobarbital was reviewed.36 In this series, patient
with significant toxic and metabolic derangements or anoxia as the
cause of the refractory SE were least likely to be effectively treated
with IV pentobarbital, as compared to those with chronic epilepsy,
infections, tumors, stroke, or trauma (91% vs. 29%, respectively).
Conclusions:
1. The infusion of IV pentobarbital
is associated with the highest rate of successful adult SE treatment
as compared to propofol and midazolam.
2. IV pentobarbital has
a slower onset of action than does propofol, and is associated with
a higher rate of hypotension requiring pressors than do propofol and
midazolam.
3. IV pentobarbital was
least successful in treating refractory SE in patient with significant
toxic and metabolic derangements or cerebral anoxia.
Recommendations:
Class A:
In the treatment of seizures
and SE, both the use of diazepam followed by a phenytoin or the use
of lorazepam are acceptable acute treatment strategies, although lorazepam
may be more effective in terminating SE.
Class B:
In pediatric SE patients,
IV lorazepam should be utilized rather than IV diazepam because of
the greater risk of respiratory complications with IV diazepam use.
Phenobarbital is an effective
alternative to the use of phenytoin in SE.
Class C:
High dose phenytoin (up
to 30 mg/kg) may be more effective in treating SE than standard doses.
Because it is water-soluble,
fosphenytoin may be useful when safety concerns with the use of phenytoin
exist.
The rapid infusion of IV
valproate may be considered after benzodiazepines and phenytoins in
the treatment of SE, or when hypotension is a potential concern.
IV benzodiazepine infusions
are another option in the treatment of refractory SE. In children,
the use of diazepam and midazolam infusion are equally effective,
although IV midazolam infusions may be associated with higher breakthrough
seizure and complication rates.
IV propofol and IV pentobarbital
infusions may considered in the treatment of refractory SE, noting
that IV pentobarbital is associated with a high rate of hypotension
requiring IV pressor support.
1. Hauser WA, Kurland
LT: The epidemiology of epilepsy in Rochester, Minnesota, 1935 through
1967. Epilepsia 1975;16:1-66.
2. Pashko S, McCord A, Sena MM: The cost of epilepsy and seizures
in a cohort of Pennsylvania Medicaid patients. Medical Interface
1993;Nov:79-84.
3. Begley CE, Annegers JF, Lairson DR, Reynolds TF, Hauser WA: Cost
of epilepsy in the United States: a model based on incidence and
prognosis. Epilepsia 1994;35:1230-1243.
4. Huff JS, Morris DL, Kothari RU, Gibbs MA: Emergency department
management of patients with seizures: a multicenter study. Acad.Emerg
Med 2001.Jun.;8.(6.):622.-8. 8:622-628.
5. Sloan EP, Silva JC, Rosenberg MS: Outcome in adult seizure patients
treated in the emergency setting. Ann Emerg Med 1999;34:S101(Abstract)
6. DeLorenzo RJ, Towne AR, Pellock JM, Ko D: Status epilepticus
in children, adults, and the elderly. Epilepsia 1992;33 Suppl 4:S15-25.
7. DeLorenzo RJ, Pellock JM, Towne AR, Boggs JG: Epidemiology of
status epilepticus. J Clin Neurophysiol 1995;12:316-325.
8. Stopping status epilepticus. Drug Ther.Bull. 1996;34:73-75.
9. Hauser WA: Status epilepticus: epidemiologic considerations.
Neurology 1990;40:9-13.
10. Treiman DM, Meyers PD, Walton NY, et al: A comparison of four
treatments for generalized convulsive status epilepticus. Veterans
Affairs Status Epilepticus Cooperative Study Group. N.Engl.J.Med.
1998;339:792-798.
11. Survey results: Acute neurologic emergencies. ACEP Satellite
Symposium, San Francisco, CA 1997;
12. Wang RS, Sloan EP, Koenigsberg M, Dorsi L, Rosenberg M: Seizure
therapy in the prehospital setting. Prehosp.Emerg.Care 1998;2:231.
13. Day M, Silva J, Sloan EP, Macariola-Coad J: Pediatric Febrile
Seizures: A Community Emergency Department Experience. Ann Emerg
Med 1999;34:S97
14. Hampers LC, Trainor JL, Listernick R, et al: Setting-based practice
variation in the management of simple febrile seizure. Acad Emerg
Med 2000;7:21-27.
15. Preciado G, Silva JC, Sloan EP: Pediatric Afebrile Seizures:
A Community Emergency Department Experience. Ann Emerg Med 1999;34:S96
16. Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick
B: Double-blind study of lorazepam and diazepam in status epilepticus.
JAMA 1983;249:1452-1454.
17. Appleton R, Sweeney A, Choonara I, Robson J, Molyneux E: Lorazepam
versus diazepam in the acute treatment of epileptic seizures and
status epilepticus. Dev.Med.Child Neurol.
1995;37:682-688.
18. Alldredge BK, Gelb AM, Isaacs M ea: A comparison of lorazepam,
diazepam, and placebo for the treatment of out-of-hospital status
epilepticus. N Engl J Med 2001;345:631-637.
19. Treiman DM: The role of benzodiazepines in the management of
status epilepticus. Neurology 1990;40:32-42.
20. Shaner DM, McCurdy SA, Herring MO, Gabor AJ: Treatment of status
epilepticus: a prospective comparison of diazepam and phenytoin
versus phenobarbital and optional phenytoin. Neurology 1988;38:202-207.
21. Runge JW, Sloan EP, Turnbull TL, Fischer J, Allen F: Intravenous
fosphenytoin loading for emergent seizure control. Ann Emerg Med
1995;25:139
22. Osorio I, Reed RC: Treatment of refractory generalized tonic-clonic
status epilepticus with pentobarbital anesthesia after high-dose
phenytoin. Epilepsia 1989;30:464-471.
23. Working Group on Status Epilepticus.: Treatment of convulsive
status epilepticus. Recommendations of the Epilepsy Foundation of
America's Working Group on Status Epilepticus. JAMA 1993;270:854-859.
24. Painter MJ, Scher MS, Stein AD ea: Phenobarbital compared with
phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485-489.
25. Giroud M, Gras D, Escousse A, Dumas R, Venaud G: Use of injectable
valproic acid in status epilepticus. Drug Investigation 1993;5:154-159.
26. Campistol J, Fernandez A, Ortega J: [Status epilepticus in children.
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Rev Neurol 1999;29:359-365.
27. Hovinga CA, Chicella MF, Rose DF, Eades SK, Dalton JT, Phelps
SJ: Use of intravenous valproate in three pediatric patients with
nonconvulsive or convulsive status epilepticus. Ann Pharmacother.
1999;33:579-584.
28. Limdi NA, Faught E: The safety of rapid valproic acid infusion.
Epilepsia 2000;41:1342-1345.
29. Sinha S, Naritoku DK: Intravenous valproate is well tolerated
in unstable patients with status epilepticus. Neurology 2000;55:722-724.
30. Venkataraman V, Wheless JW: Safety of rapid intravenous infusion
of valproate loading doses in epilepsy patients. Epilepsy Res. 1999;35:147-153.
31. Borgeat A, Wilder-Smith OH, Jallon P, Suter PM: Propofol in
the management of refractory status epilepticus: a case report.
Intensive Care Med 1994;20:148-149.
32. Kuisma M, Roine RO: Propofol in prehospital treatment of convulsive
status epilepticus. Epilepsia 1995;36:1241-1243.
33. Pitt-Miller PL, Elcock BJ, Maharaj M: The management of status
epilepticus with a continuous propofol infusion. Anesth.Analg. 1994;78:1193-1194.
34. Stecker MM, Kramer TH, Raps EC, O'Meeghan R, Dulaney E, Skaar
DJ: Treatment of refractory status epilepticus with propofol: clinical
and pharmacokinetic findings. Epilepsia 1998;39:18-26.
35. Prasad A, Worrall BB, Bertram EH, Bleck TP: Propofol and midazolam
in the treatment of refractory status epilepticus. Epilepsia 2001;42:380-386.
36. Krishnamurthy KB, Drislane FW. Relapse and survival after barbiturate
anesthetic treatment of refractory status epilepticus. Epilepsia
1996; 37: 863-867.
37. Singhi S, Murthy A, Singhi P, Jayashree M. Continuous midazolam
versus diazepam infusion for refractory convulsive status epilepticus.
J Child Neurol 2002; 17: 106-110.
38. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory
status epilepticus with pentobarbital, propofol, or midazolam: a
systematic review. Epilepsia 2002; 43: 146-153.
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SA. Continuous EEG monitoring and midazolam infusion for refractory
nonconvulsive status epilepticus. Neurology 2001; 57: 1036-1042.
TOP
Management
of the ED Patient in Status Epilepticus
Patient
Outcome
The patient was initially
treated with four doses of IV lorazepam, to a total dose of 8 mg.
The patient continued to seize. The airway was patent with adequate
vital signs and pulse oximetry readings. The patient was then treated
with a rapid infusion of one gram fosphenytoin over 10 minutes, and
then a second infusion of 500 mg of fosphenytion over five minutes.
The seizure activity then stopped. The patient was stable but unresponsive.
Cardiopulmonary, metabolic and toxicology tests were negative, as
was a non-infused CT of the head. The initial levels of both phenytoin
and Phenobarbital were found to be sub-therapeutic. An EEG was arranged
for upon arrival to the ICU, and was completed within 90 minutes of
the seizure onset. The patient was consulted by a neurologist, and
was found not to be in subtle status epilepticus. The patient awoke
within 12 hours and was discharged from the ICU the next day without
any morbidity related to this prolonged seizure. The patient was discharged
home with the instruction to take his medications as prescribed.
TOP
Management
of the ED Patient in Status Epilepticus
Annotated
Bibliography
1. Huff JS, Morris
DL, Kothari RU, Gibbs MA. Acad Emerg Med 2001;8(6):622-8
This prospective study detailed the experience in twelve emergency
departments over 5% of the calendar year. Seizures were noted in
1.2% of the 31,580 patients seen during that time period. The majority
of patients were transported via EMS and received some type of diagnostic
evaluation. Anti-epileptic drugs were given in 55% of patients.
Half of the patients seized because of low anti-epileptic drug levels
or complications of alcohol use.
2. Trieman. N Engl
J Med 1998;12:792-798
This is a landmark study in that it attempted to define an optimal
therapy in an emergency situation, status epilepticus (SE). This
study, conducted mostly at VA hospitals, compared four accepted
therapies in patients diagnosed with SE. This study defined successful
therapy as the absence of clinical and EEG evidence of SE, an important
design feature. Although lorazepam was shown to be superior to phenytoin,
it was not shown to be superior to either phenobarbital or the combination
of diazepam and phenytoin. There needs to be caution when generalizing
these results to emergency department patients, since many of these
patients were diagnosed as having subtle SE, often as a result of
post-hypoxic encephalopathy. Also, the median seizure duration was
nearly three hours, such that many of these patients were actually
in refractory SE. Lastly, with the availability of IV fosphenytoin,
all four of these therapies would likely have been comparable.
3. Leppik et al. JAMA
1983;249:1452-1454
This study was the first study to compare diazepam and lorazepam
in the treatment of SE. These two therapies were found to be comparable
in the treatment of GCSE but the data suggests that lorazepam might
be superior in non-convulsive SE. Complication rates were comparable
in the two treatment groups. The most important limitation of the
study is the fact that the study may not have been adequately powered
to detect a difference of less than 25% absolute between groups.
Still, this study is a landmark study, using an excellent design
given that day's standard.
4. Alldredge BK, Gelb
AM, Isaacs SM, et al. N Engl J Med 2001;345:631-37
This study examined the outcome of 205 status epilepticus patients
who were treated in the prehospital setting with either diazepam
5-10 mg, lorazepam 2-4 mg, or placebo. Patients treated with benzodiazepines
were more likely to have the SE episode terminated prior to arrival
than the placebo patients, and lorazepam was more effective than
diazepam in terminating the SE episode (59% vs 43% vs 21% termination,
respectively). Respiratory or circulatory complications were 10%
in the actively treated patients, and 22% in those treated with
placebo. This article is a must read for emergency physicians.
5. Working Group on Status Epilepticus. JAMA 1993: 854-859
This is an excellent summary article regarding the treatment of
SE. It details the definition, epidemiology, and etiology of SE,
and provides a consensus expert opinion regarding optimal diagnosis
and therapy. There is also a minimal acceptable time course for
the delivery of optimal therapies. This work group recommends having
a clear plan for the treatment of SE. The use of drugs in optimal
doses and the need for diagnostic testing that allows for metabolic
changes to be optimally treated. This paper is the best overall
article regarding principles for optimal SE management.
6. Shaner DM, McCurdy
SA, Herring MO, Gabor AJ. Neurology 1988:38:202-207
This study compared the use of diazepam and phenytoin with the use
of phenobarbital and optional phenytoin in 36 patients in SE. SE
duration was noted to be shorter with the use of phenobarbital,
and 61% of phenobarbital patients did not require the addition of
phenytoin in order to terminate SE. Complication rates were comparable
in the two treatment groups, suggesting phenobarbital as an alternative
to the standard therapies including diazepam and phenytoin.
7. Giroud M, Gras D, Escousse A, Dumas R, Venaud G. Drug Investigation
1993:5:154-9
This is a pilot study from France that documents the outcome of
23 SE patients who were treated with IV valproate. Patients received
a bolus infusion of 15 mg/kg followed by a six-hour infusion of
1 mg/kg/hr. Clinical SE was terminated in 83% of the 23 patients
as was EEG evidence of subtle SE.
8. Venkataraman V,
Wheless JW. Epilepsy Res 1999:35:147-53
This study documents the use of IV valproate in dosed up to 28 mg/kg
at rates up to 6 mg/kg/minute in epilepsy patients as young as 2
years of age. The most rapid infusion rate in this study was 300
mg/minute. There were no significant BP or ECG changes noted in
any of these patients as a result of these rapid valproate infusions.
9. Stecker MM, Kramer
TH, Raps EC, et al. Epilepsia 1998:39:18-26
This study compared the use of a propofol infusion to high-dose
barbiturate therapy in the management of 16 patients with SE. Although
those treated with barbiturates were more likely to have the SE
terminated (82% vs. 63%), SE termination occurred much faster with
propofol (3 vs 123 minutes). In patients in whom the propofol infusion
were quickly terminated, seizures were noted to recur, suggesting
the need for slow termination of this AED therapy.
a. It is defined by two
seizures that occur without a lucid interval.
b. By definition, all SE is associated with generalized tonic-clonic
motor activity.
c. Recent SE definitions include any seizure of duration > 10
minutes.
d. The most common etiologies for SE are low antiepileptic drug
levels & alcohol withdrawal.
e. SE of longer duration is associated with a higher mortality.
2. All are true statements
about status epilepticus (SE) except:
a. By definition,
subtle SE is not associated with generalized tonic-clonic motor activity.
b. Subtle SE requires EEG monitoring in order to be diagnosed clinically.
c. In subtle SE, the EEG shows persistent ictal discharges.
d. Because subtle SE does not have generalized tonic-clonic motor activity,
it has a lower mortality rate than does GCSE.
e. Subtle SE occurs as a late finding of prolonged GCSE.
3. All are true statements
about status epilepticus (SE) except:
a.
Fever can occur as a result of GCSE without the presence of a CNS
infection as the fever source
b. Lumbar puncture is required for all SE patients who have a fever.
c. Lactic acidosis, leukocytosis, and hypercarbia can be in SE.
d. Guidelines exist that describe the role of neuroimaging in seizures
and SE.
e. The diagnosis of refractory SE is made when initial therapies fail.
4. All are true statements
regarding the use of EEG in SE except:
a. Patients who remain
comatose for > 30 minutes may be in subtle SE, requiring EEG
monitoring.
b. All patients requiring neuromuscular blockage require EEG monitoring.
c. All patients requiring pentobarbital coma require EEG monitoring.
d. EEG monitoring can only be done with a multiple lead EEG machine.
e. In pts with subtle SE, EEG monitoring should be performed emergently
in the ED or ICU.
5. All are true statements
regarding the initial management of SE except:
a.
Lorazepam has been shown to be superior to other benzodiazepines in
SE management.
b. Glucose determination, thiamine, and narcan are important initial
therapies.
c. Most treatment failures relate to inadequate dosing, not drug therapy
choice.
d. Phenytoins can be given in high doses (up to 30 mg/kg) in SE.
e. Propofol or phenobarbital can be used to treat SE after the benzodiazepines
and phenytoins
6. If IV access is not
available, the following are possible drugs and routes except:
a.
IM midazolam
b. IM fosphenytoin
c. IM phenobarbital
d. PR diazepam
e. PR diazepam gel
Answers
1. Answer: b.
Although generalized convulsive SE (GCSE) is associated with tonic-clonic
motor activity, other forms such as complex partial or absence SE
can exist with this motor activity.
2. Answer: d.
Because subtle SE is a late finding of prolonged GCSE, it carries
a much higher mortality than GCSE, up to 50-65% in some studies.
3. Answer: b.
Although a lumbar puncture should be considered in all patients with
SE and fever, in the awake patient without meaningful signs and a
fever source, an LP may not be necessary.
4. Answer: d.
Two channel EEG monitoring can be performed using the modular monitoring
systems present in most EDs.
5. Answer: a.
No simple benzodiazepine has been shown to be superior to another
for the treatment of SE.
6. Answer: c.
IM phenobarbital is not recommended because of soft tissue toxicity.
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