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OO

STATUS EPILEPTICUS
Usama A. Hanhan, MD, Mariano R. Fiallos, MD,
and James P. Orlowski, MD

Status epilepticus (SE) is a common neurologic medical emergency, affecting

65,000 to 150,000 persons in the United States each year?, It may be life-
threatening to the patient and a challenge to the treating physician. It is esti-
mated that 1.3%to 16% of all patients with epilepsy will develop SE at some
point in their lives. In some patients, it is the presenting initial seizure.
Although definitions of SE have evolved, the main feature of this epileptic
state is a continuous seizure lasting longer than 30 minutes or repeating convul-
sions lasting 30 minutes or longer without recovering consciousness between
them. SE is commoner in childhood than in adulthood, and there is no clear
sexual predominance. Its onset may be partial (focal) or generalized. This article
focuses only on the most dramatic and dangerous type of SE generalized
convulsive SE (GCSE).

ORIGIN
The cause of SE varies according to the age group studied. In adults, the
largest group of patients are those with an underlying seizure disorder in whom
SE develops as a result of drug withdrawal or in whom alcohol use is a f a ~ t o r . ~
Other causes include acute central nervous system (CNS) injury, such as stroke,
anoxic insults, tumors, and meningitis.
In a group of children with SE, Aicardi and Chevrie' reported that 26% of
the patients had an acute insult to the CNS or a metabolic disorder and that
21% had an underlying chronic seizure disorder or static encephalopathy. In this
group of children, sudden discontinuation of antiepileptic medications and fever
were the commonest precipitants. The remaining 53% had no apparent cause.
Of this group of patients, however, fever was thought to have provoked the SE
in half.
In another study, Maytal et all3 reported that approximately one fourth of

From the Division of Pediatrics, Department of Critical Care Medicine, University Commu-
nity Hospital, Tampa (UAH, MRF, PO); Department of Pediatrics, NOVA Southeast-
em University, Ft. Lauderdale (UAH); and Department of Pediatrics, Critical Care,
and Medical Ethics, University of South Florida, Tampa, Florida (JPO)

PEDIATRIC CLINICS OF NORTH AMERICA

VOLUME 48 NUMBER 3 JUNE 2001 683

684 HANHAN et a1

children with SE had fever as the precipitant event; one fourth had a previous
neurologic problem; one fourth had an acute symptomatic event, such as anoxia,
trauma, hemorrhage, anticonvulsant withdrawal, or CNS infection; and one
fourth had no apparent cause of SE.

MORTALITY AND MORBIDITY

The outcome of SE varies according to the age of the patient, the underlying
cause of the SE, and the duration, with the risk for complications increasing
substantially if the GCSE lasts longer than 60 minutes.
Some early studies3,25 suggested that the mortality rate among people with
SE ranged from 6% to 30%. Death can be caused by the underlying disease or
result from respiratory, cardiovascular, or metabolic complications. In addition,
a significant proportion of patients recovering from SE demonstrate residual
neurologic abnormalities.
One reviewI3 of morbidity and mortality rates among children with SE
showed neurologic complication rates of 29% among infants younger than 1
year, 11%among children ages 1 to 3 years, and 6% among children older than
3 years of age. In 30% of patients, a chronic seizure disorder developed. The
mortality rate was approximately 3%.
It seems that, in general, infant and younger children tend to exhibit a
higher risk for neurologic sequelae, which may include mental retardation,
behavioral disorders, focal motor deficits, and chronic epilepsy, than older chil-
dren." This higher risk among infants may reflect the increased frequency of
severe, acute neurologic insults causing SE in infants.

SYSTEMIC COMPLICATIONS DURING GENERALIZED

CONVULSIVE STATUS EPILEPTICUS
Several systemic changes occur during tonic-clonic seizures. Some of these
changes, if prolonged, can be life-threatening and undoubtedly contribute to the
morbidity and mortality of patients with SE. Early recognition, appropriate
intervention, and prevention of such complications are imperative during treat-
ment of SE.
Hypoxia is a common occurrence in patients with SE. It is a result of
impaired ventilation, excessive salivation, tracheobronchial secretions, and in-
creased oxygen consumption. Hypoxia is responsible for most of the complica-
tions seen in SE. Brain adenosine triphosphate is depleted to the greatest degree
during seizures associated with hypoxia. In addition, brain glucose levels are
reduced significantly only when prolonged seizures are accompanied by hy-
poxia.17 Furthermore, seizures during hypoxia result in the greatest degree of
lactic acidosis, the highest brain lactate levels, and the lowest brain intracellular
pH levels.z6Hypoxia, in combination with the insults of prolonged seizures and
acidosis, results in impaired cardiac ventricular function, reduced cardiac output,
and hypotension, further compromising neuronal and tissue cell function.
Metabolic and respiratory acidosis are also common. The respiratory acido-
sis is the result of mechanical impairment of ventilation by the tonic-clonic
activity, secretions, and increased metabolic production of carbon dioxide. The
metabolic acidosis is mainly a lactic acidosis from impaired tissue oxygenation
and perfusion in the face of increased metabolic needs and energy expenditure.
With the onset of SE, there is massive catecholamine release and sympathetic
discharge resulting in increased blood pressure, heart rate, and central venous
pressure. There is also an increase in cerebral blood flow (CBF) in the range of
 STATUS EPILEPTICUS 685

200% to 7oo%.15 This increase in CBF is presumably compensatory for the

increased metabolic needs of the brain. As the seizure persists, however, blood
pressure tends to decrease, often to hypotensive levels. CBF also is reduced,
although it remains higher than normal levels. As seizure activity continues, the
brain metabolic rate remains high. The observed increase in CBF, however, is
incapable of supplying adequate substrate and oxygen to meet the increased
cerebral metabolic demands. Furthermore, animal studies9suggest that, although
cerebral oxygen delivery seemed to be adequate to meet metabolic demands
during the initial seizure, prolonged seizures were not accompanied by an
increase in oxygen delivery and therefore compromised cortical oxygenation.
Intracranial pressure also increases early in SE and remains elevated
throughout prolonged seizures. Brain edema becomes a risk because cerebral
demands exceed supply, especially in the presence of hypoxia, acidosis, hypoten-
sion, and a nonautoregulated cerebral vascular bed. Cerebral herniation has
been observed in animal studies.15
Serum glucose levels also change during prolonged seizures. Within the
first few minutes of a seizure and as a result of the massive adrenergic discharge,
blood glucose levels increase and may remain elevated for 15 to 40 minutes.
Prolonged seizures often are accompanied by hypoglycemia, however.
In patients with uncontrolled seizures, generalized muscular contractions
are responsible for an increase in body temperature and even hyperpyrexia.
Prolonged seizure activity also results in hyperkalemia; increased muscle en-
zymes, especially creatinine phosphokinase; and myoglobinuria caused by rhab-
domyolysis. In combination with hypotension and severe metabolic acidosis,
myoglobinuria may compromise renal function, resulting in acute renal failure.
Peripheral blood leukocytosis is another common finding, occurring in 50% to
60% of patients: even in the absence of infection, potentially resulting in some
diagnostic confusion. Also, minimal cerebrospinal fluid pleocytosis, which also
can complicate the differential diagnosis by suggesting meningitis or encephalitis
as a cause of the SE, has been observed in 10% to 15% of patients.'j

PATHOPHYSIOLOGY OF STATUS EPILEPTICUS

The basic pathophysiology of SE involves failure of the mechanisms that

normally prevent isolated seizures. This failure can OCCLU when the stimuli
producing seizures are overwhelming and excessive or when the intrinsic mecha-
nisms that inhibit or terminate seizures are ineffective. Excitatory neurotransmit-
ters that have a major role in SE include glutamate, aspartate, and acetylcholine,
and the dominant inhibitory neurotransmitter is gamma-aminobutyric
Neuronal inhibitory mechanisms include the calcium ion (Ca+z)-dependentpo-
tassium ion (K+) current and the blockage of N-methyl-d-aspartate (NMDA)
channels by magnesium ions (MgZ+).The NMDA-linked channels seem to be
particularly important in the pathogenesis of neuronal damage in SE.lZWhen
these neuronal cells are depolarized, the Mg2+ blocking the channel diffuses
outward, allowing sodium ions (Na2+)and Caz+to flood the cell, resulting in a
cascade of Ca +rmediated cytotoxic events, leading to neuronal injury, cell lysis,
and cell death. The destruction triggered in this manner may be reversible if SE
is terminated within the first hour.
Evidence also shows that heat-shock protein (72 kDa, HSP-72) is induced in
some neurons in SE and that it may have a neuroprotective role.23Although
prolonged seizures may be sufficient to cause neuronal cell injury, the superim-
position of hypoxia, hypotension, acidosis, and hyperpyrexia exacerbate the
degree of damage to the CNS.
686 HANHANetal

MANAGEMENT

The main goals of the treatment of SE are to (1) maintain adequate vital
functions with prevention of systemic complications, (2) terminate the seizure
activity safely and quickly while minimizing treatment-related morbidity, and
(3) evaluate and treat any underlying causes.
The management of patients with SE requires prompt intervention. As with
any other acute medical emergency, the initial goals of therapy are maintenance
of adequate airway, breathing, and circulation, with particular attention to pre-
venting hypoxia. Accordingly, the first step in management, before attempting
to stop the seizures, is providing adequate oxygenation.
The patient should be positioned to avoid aspiration and physical injury.
Airway patency may be maintained by a plastic oral airway device or a nasopha-
ryngeal device, if tolerated. Tongue blades or other foreign metal objects in the
mouth should be avoided because they can cause severe oral injury. Oxygen
should be administered by a nasal cannula or a nonrebreathing mask. Patients
with SE are continuously at risk for respiratory failure and inadequate ventila-
tion, and many of the drugs used to terminate seizures are respiratory depres-
sants. Therefore, the treating physician continuously and repeatedly must assess
adequacy of oxygenation and ventilation and be prepared to intervene and
intubate the patient at any time if there is any clinical or laboratory indication
of respiratory insufficiency or if the SE becomes refractory to the standard
therapy. If intubation becomes necessary, the rapid-sequence technique should
be used.
Some patients with SE require muscle relaxants to facilitate mechanical
ventilation. In these patients, clinical seizure activity no longer can be used to
guide and titrate anticonvulsant therapy, and continuous EEG monitoring should
be considered. Maintenance of airway, breathing, and circulation is assessed best
by direct physical examination, vital signs, and monitoring of the electrocardio-
gram (ECG) and pulse oximetry.
The next steps in management are to establish a secure intravenous catheter
for obtaining blood samples for laboratory studies and to administer intravenous
fluids and anticonvulsant drugs. The patient should have a rapid determination
of the blood glucose level at the bedside. Other initial laboratory studies should
include serum chemistries and electrolytes, blood gases, pH level, calcium and
magnesium levels, and a complete blood cell count. In addition, blood samples
for toxicology screens, liver function, blood cultures, and anticonvulsant levels
should be collected and some blood kept for additional testing if indicated later.
Several crucial laboratory studies can be performed at the bedside using
point-of-care (POC) testing systems, including measurement of blood gases,
electrolytes, calcium, and glucose, which enables the treating physician to treat
and correct any abnormalities promptly. If hypoglycemia is found or suspected,
2 mL/kg of 25%dextrose solution should be administered. Maintenance intrave-
nous fluids should be started next, unless the patient clearly is dehydrated.
Metabolic acidosis is common among patients with SE, and it usually resolves
after seizure control has been achieved. If however, the patient is in shock
or hypotensive, intravenous fluid resuscitation and pressor therapy should be
administered. Intravenous bicarbonate therapy rarely is necessary.
The initial stabilization phase of patients with SE usually is accomplished
within the first 10 minutes after presentation to the emergency department.
Specific anticonvulsant therapy then is initiated.
Although the definition of SE incorporates a 30-minute duration, which is
useful for research and publications, it can be misleading in terms of treatment
 STATUS EPILEPTICUS 687

decisions. According to the Working Group on Status Epilepticus of the Epilepsy

Foundation of America, patients with seizures lasting more than 10 minutes
should be treated. Most self-limiting generalized convulsions stop within 3
minutes, and almost all stop by 5 minutes from onset.*O Furthermore, early
therapy is far more effective than is delayed therapy, so the longer the seizures
persist, the more difficult they are to stop. Therefore, patients seizing for 10
minutes should be treated on the assumption that they are in SE.
Several drugs are effective in the treatment of SE. The timing, route, and
adequacy of dosages of the medications used are probably more important than
is the choice of drugs in determining success of therapy. Although the use of a
single drug of sufficient dosage always is preferred, often, more than one agent
is needed to achieve all of the therapeutic goals. The treating physician must be
familiar with the various medications used and their possible side effects, includ-
ing respiratory and cardiovascular depression, and be prepared to manage these
side effects.
If possible, the drugs should be administered intravenously. Intramuscular
injections should be avoided because they may produce uncertain blood levels.
If intravenous access cannot be achieved in a timely manner, other emergency
alternatives exist for treating patients with SE. In critical situations, some anti-
convulsant drugs, including diazepam, valproate, thiopental, and paraldehyde
can be administered per rectum, and adequate drug levels can be obtained. In
one study,18buccal midazolam was found to be as effective as rectally adminis-
tered diazepam in the acute treatment of seizures.
Probably the best emergency alternative to intravenous access in patients
with critical, prolonged SE is the intraosseous route. Benzodiazepines, barbitu-
rates, and phenytoin are effective when administered by the intraosseous route.
Furthermore, intravenous fluids and pressors can be administered by the intraos-
seous route to resuscitate the patient until a secured intravenous access is
obtained.
The goals of anticonvulsant therapy in SE are to achieve cessation of clinical
and electrical seizure activity and prevent its recurrence. The most commonly
used drugs for the initial treatment of SE include lorazepam, diazepam, pheny-
toin, and phenobarbital. Other drugs that have been used to treat SE and
prolonged seizures include midazolam, fosphenytoin, intravenous valproic acid,
and propofol. Advantages and disadvantages, doses, onset of action, rate of
administration, and possible side effects of these agents are outlined in the
following paragraphs and in Tables 1 and 2 .
When a drug is selected to be used, sufficient time must be allowed for the
drug to act before more of the same medication or another medication is used.
If a single agent does not control the seizures, a second drug may be needed. If
the combined effects of several drugs do not achieve cessation of seizures,
alternative, aggressive treatment, including high-dose phenobarbital, thiopental,
or intravenous or general anesthesia to induce electrocerebral silence, should be
considered. In such patients with refractory SE, other contributing causes, such
as an unrecognized metabolic disorder or toxin, must be considered.

Benzodiazepines

The benzodiazepines are effective, highly potent, and rapidly acting antiepi-
leptic agents. They also are administered easily and are effective in controlling
generalized and partial seizures and therefore often are preferred as initial
therapy for SE.
Table 1. ANTIEPILEPTIC DRUGS USED IN THE MANAGEMENT OF STATUS EPILEPTICUS IN CHILDREN
Drug Initial IV Dose Rate of Infusion Maximum Single Dose Remarks
~

Diazepam 0.3 mg/kg 2 mg/min 10 mg* Sedation, apnea, respiratory depression, hypotension;
must be followed by phenytoin loading
Lorazep am 0.05-0.1 mg/kg 0.5-2 mg/min 4 mg Same side effects as diazepam; may repeat after 5-7
min if needed
Phenytoin 20 mg/kg 1 mg/kg/min 1500 m g / d t Cardiovascular collapse with rapid IV infusion;
(max, 50 mg/min) arrhythmias, hypotension; mix only with N/S
Fosphenytoin 15-20 mg PE/kg 3 mg/kg/min 1500 m g / d t Require BP and ECG monitoring; same side effects
(max, 150 mg/min) as phenytoin, less risk for hypotension and
phlebitis; limited pharmacokinetic data in children
Phenobarbital 20 mg/kg 2 mg/kg/min 1000 mg/dt Hypotension and respiratory depression, especially if
(max, 30 mg/min) used after benzodiazepines

*May require less of initial dose if seizure terminates before completing the dose.
tMonitor drug levels.
IV = intravenous; N/S = normal saline; BP = blood pressure; ECG = electrocardiogram.
Table 2. DRUGS USED IN THE MANAGEMENT OF REFRACTORY STATUS EPILEPTICUS
Drug Initial IV Dose (mgkg) Maintenance Infusion Remarks
Pentobarbital 0.5-5.0 mg/kg/h Significant respiratory and hemodynamic adverse effects;
titrate drip to seizure control or burst suppression
(EW
Midazolam 0.15 1 pg/kg/min Increase as needed every 15 min; respiratory depression;
fewer hemodynamic adverse effects than pentobarbital
Propofol 1-3 2-10 mg/kg/h Rapid infusion can cause apnea; fewer hemodynamic
adverse effects than pentobarbital; quick recovery time

IV = intravenous; EEG = electroencephalography.

690 HANHANetal

Diazepam
Diazepam is highly lipid soluble and appears in the brain as quickly as 1
minute after injection, with a median time to terminate a seizure of 2 minutes.
Its antiepileptic effect, however, lasts only 20 to 30 minutes. In children, the
initial dose is 0.3 mg/kg intravenously over 2 minutes (maximum, 10 mg).
Because of its short antiepileptic effect, if diazepam is used to treat SE, a
longer-acting agent, such as phenytoin, fosphenytoin, or phenobarbital, must be
administered.
Diazepam administered per rectum (0.5 mg/kg) is valuable in premonitory
SE when intravenous access or intravenous injections are unavailable.

Lorazepam
Lorazepam is less lipid soluble than is diazepam, but it is almost as fast as
diazepam in controlling seizures, with a median time to end a seizure of 3
minutes. Unlike diazepam, lorazepam has a long antiepileptic effect (12-24 h),
giving lorazepam an important advantage over diazepam as initial therapy for
SE. If seizures are controlled with lorazepam, it becomes less imperative to use
additional long-acting drugs immediately, such as phenytoin or phenobarbital,
to maintain seizure control. The dose in children is 0.1 mg/kg intravenously
(maximum, 4 mg). It is infused over 1 or 2 minutes and may be repeated in 5
to 7 minutes, if needed. Like diazepam, its likelihood of effectiveness decreases
if multiple dosages have been unsuccessful. Adverse effects of benzodiazepines
include respiratory depression, apnea, and hypotension.

Phenytoin and Fosphenytoin

Phenytoin is an efficacious, long-acting agent that has been used widely for
more than 20 years in the treatment of acute and chronic seizures in children.
The drug is administered at a dose of 20 mg/kg, infused slowly at a rate not to
exceed 1 mg/kg/min in children or 50 mg/min in adolescents. Its antiepileptic
effect may be delayed for 10 to 30 minutes, which usually necessitates the prior
use of a rapid-acting agent, such as diazepam or lorazepam. Side effects include
hypotension and arrhythmias, partly related to the propylene glycol diluent.
These side effects are uncommon in children and can be minimized by slowing
the infusion rate.
Fosphenytoin is a new, water-soluble phosphate ester of phenytoin that
rapidly is converted to phenytoin by nonspecific serum phosphatases. In contrast
to phenytoin, fosphenytoin can be administered intramuscularly with rapid
and complete absorption. The dose of fosphenytoin is expressed in phenytoin
equivalents (PEs) and is 15 to 20 mg/kg of PE/kg, infused at a rate of no more
than 3 mg/kg/min, not to exceed 150 mg/min, which is threefold the maximum
rate for phenytoin. Although it can be infused faster than phenytoin, it is
likely that phenytoin and fosphenytoin have similar time to antiepileptic effect.
Phlebitis and soft tissue damage are less common with fosphenytoin, but its
primary disadvantage is cost. Fosphenytoin can cost as much as 20-fold more
than phenytoin.

Phenobarbital
Phenobarbital is a potent, long-acting antiepileptic agent that has been used
for many years in the treatment of seizures. It is a depressant drug and can lead
 STATUS EPILEPTICUS 691

to sedation and respiratory difficulties, especially when administered after a

benzodiazepine. For these reasons, it usually is considered second to phenytoin
as a long-acting agent and usually is recommended only when benzodiazepines
and phenytoin are ineffective. The dose is 20 mg/kg, infused at a rate not to
exceed 30 mg/min. Respiratory and hemodynamic support should be available
immediately during and after the infusion. Some investigators4have found that
using increased doses of phenobarbital, at increments of 10 mg/kg every 30
minutes, was successful in controlling ongoing seizures and achieving high
blood levels of 70 to 370 kg/mL without the need for intubation. Furthermore,
this treatment commonly avoids the need for therapy with multiple agents.
One randomized, double-blind, clinical trialz1 comparing phenobarbital
alone, phenytoin alone, diazepam followed by phenytoin, and lorazepam alone
showed that all the treatments were equally effective, except that lorazepam
alone was more effective than was phenytoin alone, and that, although lora-
zepam was no more efficacious than was phenobarbital or the combination of
diazepam and phenytoin, it was easier to use. This study suggests that treatment
with lorazepam alone as the first-line drug may be the preferred treatment in
many cases.

REFRACTORY STATUS EPILEPTICUS

Most cases of SE can be treated successfully with first-line medications (e.g.,
diazepam, lorazepam, phenytoin, and phenobarbital); however, a few patients
continue to have persistent seizure activity for longer than 60 minutes despite
adequate doses of first-line medications. Such patients are considered to be in
refractory SE (RSE), and escalation of therapy with the administration of a
barbiturate or nonbarbiturate anesthetic agent then is recommended, with the
therapeutic endpoint of achieving seizure control, electrocerebral silence, or both.
The optimal management of such patients remains unclear, and large, controlled
studies comparing the various agents are lacking. All patients in refractory SE
must be managed in a pediatric intensive care unit, with aggressive monitoring
of their hemodynamic and respiratory status and continuous EEG monitoring.
The most commonly used agent for treating RSE is intravenous pentobarbi-
tal, a short-acting barbiturate with a rapid onset of action, given as a bolus of 5
to 15 mg/kg followed by an infusion of 0.5 to 5.0 mg/kg/h. Although effective
in terminating seizures and inducing a burst suppression pattern on EEG,
pentobarbital administration commonly is associated with significant hypoten-
sion, myocardial depression, and low cardiac output. It is a potent respiratory
depressant, and these patients usually are intubated and mechanically ventilated
before initiation of therapy with this drug and often require indwelling catheters
to monitor central venous and arterial pressures. Inotropic agents usually are
needed to support the blood pressure and cardiac output. Other side effects
include pulmonary edema, ileus, and delayed neurologic recovery. Because of
these disadvantages, alternative agents in the treatment of RSE have been
sought. Large, controlled, comparative studies of the various agents still are
needed. Some of these medications are discussed here. The recommendations
for their use are largely dependent on anecdotal case reports and small, uncon-
trolled studies.

MIDAZOLAM
Midazolam is a water-soluble imidazole benzodiazepine with a short elimi-
nation half-life of 1.5 to 3.5 hours. Commonly used as a sedative hypnotic and
692 HANHAN et a1

anesthetic agent, midazolam possesses potent antiepileptic effects. It can be

administered by the intravenous, intranasal, oral, rectal, or intramuscular routes.
At physiologic pH, it becomes extremely lipophilic, with a rapid onset of action.
Its action, however, is short-lived, necessitating continuous intravenous infusion
after the initial bolus dose to maintain the desired effects.
Its effectiveness in the treatment of RSE has been documented in several
reports.8,lo,l6 The initial bolus dose of 0.15 mg/kg is followed by continuous
intravenous infusion of 1 pg/kg/min, with increasing increments of 1 pg/kg/
min every 15 minutes until seizure control has been achieved. In one study,’6
midazolam was found to be successful in terminating RSE in 24 out of 24
children, with an average time to seizure control of 47 minutes (range, 15.0
min4.5 h) and a mean infusion rate of 2.3 pg/kg/min (range, 1-18 pg/kg/
min). Similar findings also have been reported in an additional 20 children.1°
More important, midazolam was well tolerated by all patients in these studies
with no clinically significant cardiovascular changes, which is a major advantage
over traditional pentobarbital-induced coma. Nevertheless, clinical experience
with midazolam in the treatment of RSE is limited. Furthermore, some interest-
ing questions have been raised, including:
Why would midazolam successfully terminate SE when diazepam or lora-
zepam has failed to do
Does midazolam possess unique or additional antiepileptic activity compared
with other benzodiazepines?
Would it be a suitable first-line drug?
Whether midazolam can be a suitable first-line agent in the treatment of
acute seizures and SE is unclear. Its potent antiepileptic effect, relative safety
record, and ease of administration by various routes clearly makes midazolam
a potentially important and useful drug in the treatment of SE inside and outside
of the hospital. Clearly, its optimal dosing, safety, and clinical usefulness in
various settings need further evaluation.

INTRAVENOUS PROPOFOL

Propofol is a highly effective, intravenous, nonbarbiturate, anesthetic agent

originally approved for rapid induction and maintenance of anesthesia. In addi-
tion to its anesthetic, hypnotic, and sedative effects, propofol also has anticonvul-
sant properties. It is highly lipid soluble with a rapid onset of action and quick
recovery time. Its efficacy in the treatment of RSE has been demonstrated in
several case reports and few small studies.2 It usually is administered in an
intravenous bolus of 1 to 3 mg/kg followed by a continuous infusion of 2 to 10
mg/kg/h. Cessation of seizure activity or inducement of burst suppression
occurs within seconds after administration. Adverse effects include bradycardia,
apnea, hypotension with rapid infusion, and hypertriglyceridemia after pro-
longed use. The cardiovascular adverse effects are significantly fewer than those
observed with pentobarbital coma. Despite its anticonvulsant properties, propo-
fol causes seizures in some anesthetic situations. In addition, a few cases of
unexplained metabolic acidosis in children receiving propofol infusions have
been reported, although no definite causal link to propofol has been established
in these cases. The rapid onset of action, ease of titration, brief time to recovery
and fewer cardiovascular adverse effects of propofol make it a potentially useful
drug in treating RSE, and it deserves further evaluation.
 STATUS EPILEPTICUS 693

INTRAVENOUS VALPROIC ACID

Valproic acid is one of the primary antiepileptic agents, with a broad

range of efficacy in partial and generalized seizures in children. An intravenous
formulation has become available in the United States and is indicated as a
short-term replacement when oral medications cannot be administered to pa-
tients already receiving valproic acid treatment for their seizures. The drug is
also useful in patients requiring rapid attainment of therapeutic valproic acid
levels because of inadequate seizure control. The recommended dose is 15 to 20
mg/kg intravenously.
The efficacy of valproic acid in treating RSE has been reported in 41 children
who failed to respond to first-line anticonvulsants (diazepam, 0.2 mg/kg; pheno-
barbital, 20 mg/kg; and phenytoin, 20 mg/kg).22 A loading dose of 20 to 40
mg/kgZ2was used (diluted 1:l with normal saline or 5% dextrose in water)
administered over 1 to 5 minutes (repeated after 10-15 min if necessary), fol-
lowed by an intravenous infusion of 5 mg/kg/h. The overall success rate
was 78%. Approximately 66% of the patients responded immediately (within 6
minutes) after the initial bolus. Success rate varied according to the type of SE
and the loading dose used, with the highest success rate (90%) in patients with
generalized tonic-clonic SE and a loading dose of 30 to 40 mg/kg. The drug was
well tolerated with no systemic or local side effects. In another case report,”
however, significant hypotension was believed to be associated with intravenous
valproic acid when given to a child in SE.
Although intravenous valproic acid has not been approved yet by the US
Food and Drug Administration for treating SE, its wide spectrum of anticonvul-
sant activity, less sedating effect, and relatively good cardiovascular safety profile
make it a potentially useful adjunct or alternative for the treatment of refractory
generalized SE. Clinical trials are limited, however, and further evaluation of its
optimum dosing, use, and safety record in various clinical settings is unclear.

SUMMARY

Status epilepticus is a serious medical emergency that requires prompt and

appropriate intervention. Maintenance of adequate vital function with attention
to airway, breathing, and circulation; prevention of systemic complications; and
rapid termination of seizures must be coupled with investigating and treating
any underlying cause.
In most patients with SE, the use of adequate dosages of first-line antiepilep-
tic agents allows for the successful and rapid termination of SE and avoidance
of potential neurologic complications. Refractory SE requires more aggressive
treatment, often the use of intravenous anesthetic agents and intense monitoring,
and therefore must be managed in a pediatric intensive care unit with a multidis-
ciplinary approach. Large, controlled, multicenter, comparative studies are
needed urgently to clarify better the optimal management of these patients.

References

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2. Brown LA, Levin GM: Role of propofol in refractory status epilepticus. Ann Pharma-
cother 32:1053-1059,1998
694 HANHAN et a1

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Usama A. Hanhan, MD
Pediatric Intensive Care Unit
University Community Hospital
3100 E. Flecher Avenue
Tampa, FL 33613