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67-1
STATUS EPILEPTICUS
Tempest in a Tom Collins . . . . . . . . . . . . . . . . . . . . . . . . Level I
Jennifer A. Donaldson, PharmD
A 20-year-old man with a history of tonic–clonic seizures now in
status epilepticus due to acute alcohol ingestion is brought to the
emergency department. Students should differentiate status epilepticus from other types of seizure disorders and recognize the steps
that must be taken immediately to prevent permanent organ system
damage. Medications used to terminate status epilepticus includes
benzodiazepines (eg, lorazepam, diazepam) and phenytoin or fosphenytoin. Second-line agents such as levetiracetam, phenobarbital,
or valproic acid may be used for persistent seizures.
QUESTIONS
Problem Identification
1.a. What are this patient’s drug therapy problems?
• Status epilepticus requiring immediate pharmacologic therapy
• Acute alcohol ingestion and possible toxicity
1.b. What steps should be taken when the patient is first seen in
the ED?
• Begin standard measures of emergency care and initiate anticonvulsant therapy immediately, followed by laboratory studies, medical history, and physical exam.1,2
✓Establish an airway. Generally, the quickest way to establish an airway is successful termination of status epilepticus. Most patients in status epilepticus breathe adequately
provided that their airway remains clear. If intubation is
required, a neuromuscular blocker with a short half-life
and preferably one without significant hemodynamic effects
should be used.
✓Assess cardiopulmonary function. Administer oxygen if
necessary. Initiate ECG monitoring in patients with neuromuscular blockade. Do not treat hypertension until status is
resolved since the treatment of status often corrects hypertension. Maintain blood pressure in hypotensive patients to
normal or high-normal levels with vasopressors if needed.
✓Obtain a blood glucose level to rule out hypoglycemiainduced seizures.
✓Obtain venous access.
✓Obtain laboratory tests (CBC, electrolytes, arterial blood
gas, BUN, SCr, drug screen, and serum concentrations of
antiepileptic drugs).
✓Begin pharmacotherapy to terminate status epilepticus (see
below). Start an IV infusion of normal saline as standard
protocol for unconscious patients. Adequate hydration can
help prevent myoglobin-induced renal failure secondary to
muscle breakdown resulting from continuous seizures.
✓Administer thiamine 100 mg IV (standard ED protocol for
unconscious patients to prevent Wernicke’s encephalopathy).
✓Perform a physical examination, including a full neurological evaluation.
✓Identify possible precipitating factors. In this case, the most
likely etiology is acute alcohol ingestion. However, it is
important to not overlook other precipitating factors such as
medication nonadherence, infection, metabolic disorder, or
illicit drug use.
• For more detailed information on acute treatment measures,
refer to the textbook chapter on status epilepticus.
Desired Outcome
2.What are the goals of pharmacotherapy in this case?
• Maintain adequate brain oxygenation and cardiopulmonary
function: Because of the muscle contraction of the chest,
respiration is suspended and patients often become cyanotic
as the hemoglobin becomes desaturated and venous return
is diminished secondary to increased intrathoracic pressure.
The cardiovascular system becomes increasingly stressed from
the increased demand of the skeletal system during tonic
contractions.
• Terminate seizure activity (both clinical and electrographic)
using pharmacologic therapy: Termination of electrical seizures
must be determined by EEG monitoring. In nonconvulsive status epilepticus, when neuromuscular blockers have been used,
or when the patient is comatose, the use of EEG monitoring is
the only mechanism to determine when seizures have stopped.
• Correct metabolic imbalances: Glucose and electrolyte imbalances are readily correctable precipitants of seizures. Seizures
from hypoglycemia, hyponatremia, and other metabolic complications do not respond to anticonvulsants.
• Minimize morbidity and prevent mortality from status epilepticus: Morbidity includes impaired mental capacity and neurologic deficits. Significant complications can occur because
of prolonged or repeated seizures. The increased demand on
the heart can cause tachycardia or bradycardia depending on
the CNS-mediated vagal tone. Desaturation and suspended
respiration can cause anoxic injury to the CNS and other
organ systems. Repeated seizures can cause hypoglycemia
and alterations in electrolytes. Serious arrhythmias can occur
from hyperkalemia. Repeated contractions can cause muscle
damage (rhabdomyolysis), releasing proteins and myoglobin,
which can result in renal failure. Mortality can be caused
by prolonged seizure activity but is usually as a result of the
underlying cause of the seizures.
• Identify any possible precipitating factors and correct them,
if possible.
• Prevent seizure recurrence.
Therapeutic Alternatives
3.What pharmacotherapeutic options are available to treat
status epilepticus?
• The ideal drug for treating status epilepticus is one that can
be administered rapidly, enters the brain immediately, has
an immediate anticonvulsant activity, does not depress consciousness or respiration, has a long half-life, and blocks both
the somatic symptoms and neuronal discharges.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Status Epilepticus
CASE SUMMARY
✓Obtain medical history from the medical record. Additional
information may be available from the patient’s roommate
and the RA who accompanied him to the ED.
CHAPTER 67
67
✓Administer dextrose 25 g (50 mL of a 50% solution)
IV (adult dose) to treat hypoglycemic seizures, if present.
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SECTION 6
• Therapy is started with emergent initial therapy (Step 1), then
urgent control therapy (Step 2), and then treatment of refractory status epilepticus if seizure activity has continued despite
therapy from the first two steps. The patient’s history and clinical status may determine which medications are used within a
step of treatment.2–4
Neurologic Disorders
• Emergent initial therapy (Step 1): Benzodiazepine therapy has
shown the best evidence for seizure cessation in the initial steps
of treatment.5 This drug class has advantages of rapid onset of
action and ease of administration. The major disadvantages
of benzodiazepines include short duration of action and CNS
depression, which makes assessment of consciousness difficult.
Benzodiazepines can also cause respiratory depression, further
compromising oxygenation capacity. While IV administration
is ideal, there are other non-IV options depending on the clinical situation. If the seizure has not stopped within 5–10 minutes,
a second dose of a benzodiazepine may be administered.
✓Lorazepam is the preferred agent for IV administration.
While other IV benzodiazepines are equally effective in
aborting seizure activity, lorazepam has a substantially longer duration of action. This allows for fewer repeat doses to
be administered and seizures recur less frequently.
✓Diazepam is quick acting and crosses the blood–brain barrier rapidly because of its lipid solubility. However, it binds
weakly to the benzodiazepine receptor and rapidly redistributes to the more abundant fatty tissue. The duration of
effectiveness in the CNS is only 30 minutes. Because of this,
use of diazepam may necessitate adjunctive therapy with
a longer-acting agent such as phenytoin or fosphenytoin.
Diazepam does have the dosage-form option of rectal
administration which is often used in the prehospital setting
for seizure cessation.
✓Midazolam is the preferred agent for intramuscular (IM)
administration of a benzodiazepine. The hydrophilic and
lipophilic balance of the drug allows for rapid absorption
into the bloodstream and CNS. When compared to IV lorazepam, IM midazolam was found to be as effective in seizure
cessation with a comparable safety profile. Midazolam may
also be administered intranasally (IN) and buccally. Either
route offers an alternative that may be initiated prior to
hospitalization.1,6
• Urgent control therapy (Step 2): Further drug therapy is used
to control seizures that did not stop after initial therapy or
to establish therapeutic blood levels of an antiepileptic agent
for continued maintenance dosing. Agents used in this step
include fosphenytoin/phenytoin, phenobarbital, valproic acid,
or levetiracetam. All of these agents may be administered IV
and have advantages and disadvantages depending on the
clinical situation.
✓Fosphenytoin or phenytoin is favored as a next-line agent due
to the lack of CNS depression and a long half-life. Phenytoin
is an effective anticonvulsant but has cardiovascular toxicity
when given too rapidly, necessitating slow IV administration. Venous sclerosis and skin necrosis at the infusion site
may also occur. Phenytoin has limited compatibility with
other IV fluids. Fosphenytoin is the water-soluble prodrug
of phenytoin. It has overcome many of the administration
difficulties associated with phenytoin because it does not
contain propylene glycol as an excipient. The advantages of
fosphenytoin are that it can be administered IV more rapidly
than phenytoin, has fewer adverse infusion reactions, and
can be given intramuscularly. Antiarrhythmic effects may be
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
similar to phenytoin. Although fosphenytoin can be infused
faster than phenytoin, the prodrug must be converted by
phosphatases to the active phenytoin. For equivalent doses
of fosphenytoin and phenytoin, the time to reach therapeutic
phenytoin concentrations are the same. Thus, fosphenytoin
is dosed in “phenytoin equivalents (PE).” Use of either of
these agents may be avoided in patient with cardiac instability. If the patient is taking phenytoin as the maintenance
antiepileptic drug, a serum level should be obtained to determine if boluses should be administered in order to avoid
phenytoin toxicity.
✓Phenobarbital was one of the first effective pharmacologic
therapies used in the treatment of status epilepticus and may
still be a drug of choice depending on the patient situation.
Phenobarbital is as effective as phenytoin but is considered
to have a slower onset of action and has more respiratory
depression. The advantages of using phenobarbital include
its reliability and effectiveness in status epilepticus, longlasting duration of action, and safety in high doses and
with rapid administration. Phenobarbital may be continued as chronic therapy although this is not desirable. The
disadvantages include the risk of accumulation because of
its long elimination half-life and the potential for sedation,
respiratory depression, and hypotension. Administering
phenobarbital in conjunction with a benzodiazepine may
cause additive respiratory depression.
✓Valproic acid and levetiracetam have been alternative Step
2 agents for status epilepticus. The greatest advantage with
either agent is lack of cardiovascular effects. Valproic acid
and levetiracetam are well tolerated and may be converted
to maintenance therapy if needed. Until more data become
available on the precise role of valproic acid and levetiracetam for treatment of status epilepticus, their use is considered on a case-by-case basis and clinician experience.2
✓Intravenous lacosamide may also be considered as an
alternative Step 2 agent. While data are limited thus far,
some patients have been treated safely and effectively with
lacosamide.1
• Refractory status epilepticus (RSE): Treatment of RSE is initiated 20–60 minutes after Step 2 treatment if clinical seizures
have not stopped or the EEG shows persistent epileptiform
activity. Treatment options include midazolam, propofol, and
pentobarbital. This aggressive treatment requires admission to
the critical care unit with continuous EEG monitoring.
Optimal Plan
4.What is the best pharmacotherapeutic plan for this patient?
• Administer a benzodiazepine IV if venous access is in place:
✓Lorazepam 0.1 mg/kg (maximum 4 mg) IV given at a rate of
2 mg/min. If a second dose is needed, it may be administered
after 5–10 minutes.
• If IV access was lost or not obtained:
✓Diazepam 0.2 mg/kg (maximum 20 mg) per rectum. If
a second dose is needed, it may be administered after
5–10 minutes.
✓Midazolam 0.2 mg/kg (maximum 10 mg) IM. If a second
dose is needed, it may be administered after 5–10 minutes.
✓Midazolam 0.2 mg/kg (maximum 10 mg) IN (using the
5 mg/ml concentration of the injectable solution and administering via an atomizer). If a second dose is needed, it may
be administered after 5–10 minutes.
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✓ Phenobarbital 20 mg/kg IV at a rate of 50–100 mg/min. May
give an additional 5–10 mg/kg.
or
or
✓ Levetiracetam 1000–3000 mg IV at a rate of 2–5 mg/kg/min,
or over a total of 15 minutes.
• If phenytoin levels are immediately available and phenytoin
toxicity is not present, give a loading dose of phenytoin or
fosphenytoin. This dosing assumes nondetectable levels; a
partial bolus may be given depending on the level if phenytoin
is detectable:
✓Phenytoin 20 mg/kg IV at a rate of 50 mg/min. Give repeat
doses of 5–10 mg/kg at 30-minute intervals to a maximum
of 1500 mg (in 24 hours). Because this patient is already on
phenytoin, the loading dose can be followed by restarting his
daily oral maintenance dose.
or
✓Fosphenytoin 20 mg phenytoin equivalents (PE)/kg at a rate
of 100–150 PE/min. May give an additional 5 mg PE/kg.
• If seizures persist after the above measures have been implemented, one of the following regimens may be given with
continuous EEG monitoring in the critical care unit:2,3
✓ Midazolam 0.2 mg/kg IV loading dose (at a rate of 4 mg/min),
followed by an infusion of 0.05–0.4 mg/kg/hour.
✓Pentobarbital 5–15 mg/kg IV loading dose followed by an
infusion of 0.5–3 mg/kg/hour.
✓Propofol 1–2 mg/kg IV loading dose, followed by an infusion of 2–10 mg/kg/hour.
Outcome Evaluation
5.What clinical and laboratory parameters are needed to evaluate the therapy to ensure the best possible outcome?
• Clinical and/or electrical evidence that seizures have been
stopped must be obtained. If neuromuscular blockers have
been used, electrical evidence with an EEG is needed.
• With benzodiazepine use (and phenobarbital if necessary),
monitor the patient for CNS depression (which is impossible
in an unresponsive patient) and respiratory depression. Respiratory depression is monitored by obtaining vital signs (specifically the respiratory rate) every 15 minutes and by monitoring
gas exchange (by arterial blood gases or pulse oximetry).
✓If reversal of the benzodiazepine is necessary, flumazenil
0.2 mg (2 mL) IV may be administered. If the desired effects
of flumazenil are not seen after 45 seconds, additional doses
of 0.2 mg may be given at 1-minute intervals to a maximum
dose of 1 mg (10 mL).
• Fosphenytoin typically does not cause many infusion site
reactions, but the patient should be monitored for possible
phlebitis and/or burning (if the patient is conscious). A serum
phenytoin level may be obtained 12–24 hours after the initiation of the infusion. Vital signs, especially blood pressure,
should be obtained while the infusion is running.
Patient Education
6.What information should the patient receive to ensure successful therapy and to minimize adverse effects?
• The single most important issue is patient education. In adults,
the most likely etiology of status epilepticus is withdrawal of anticonvulsants. It is imperative to stress the importance of medication adherence. Studies have shown that adherence correlates
with the number of times per day a patient must take medications. Changing the carbamazepine 500 mg PO TID to extendedrelease carbamazepine 700 mg PO BID may aid in adherence.
• The presence of an abnormal baseline EEG is predictive of
recurrent seizures and is an added risk in this patient. In addition, counseling on recreational drug and alcohol use is needed.
• Another factor in patient adherence is the presence of adverse
effects. Patients on multiple AED may have additive CNS
effects from the medications. If the patient has intolerable
side effects at therapeutic doses, it may warrant a change in
medication. Other agents to consider for an adult with primary
generalized tonic–clonic seizures include lamotrigine, oxcarbazepine, topiramate, and valproic acid. While current data are
not as strong to support the use, gabapentin and levetiracetam
may also be alternative medications to consider.7
General information:
• It is important to take your medications as directed every day
to prevent seizures.
• You should carry identification (such as a medical alert bracelet or necklace) stating your medical condition. A wallet card
should state the medications and doses you are taking.
• Fill your prescriptions at a single pharmacy so any potential
drug–drug interactions or contraindications may be identified
and addressed.
• Alcohol should be avoided if possible as it may cause an interaction with your current seizure medications and increase the
side effects such as drowsiness. If alcohol cannot be avoided, it
should be limited.
• Avoid illicit drug use because some of them can lower the
seizure threshold and cause breakthrough seizures or status
epilepticus.
Phenytoin:
• Take this medication with food to decrease GI discomfort.
• Phenytoin may cause dizziness or drowsiness.
• Phenytoin may cause increased gum growth. Routine dental
care consisting of brushing your teeth two to three times a
day, flossing, and regular check-ups with your dentist will help
prevent this effect.
• Do not change brands or dosage forms of this medication
without checking with your physician.
• Notify your healthcare provider if there is a big change in balance or persistent dizziness. Also inform the provider if any of
these develop: skin irritation or rash, bruising or bleeding, or
acute changes in thinking clearly.
• Small blood samples will need to be collected periodically for
laboratory testing.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Status Epilepticus
✓Valproic acid 20–40 mg/kg IV at a rate of 3–6 mg/kg/min.
May give an additional 20 mg/kg.
• Evaluate the patient’s recent medication history to determine
adherence and serum levels based on dosing schemes of phenytoin and carbamazepine. Both of these agents induce hepatic
metabolism. The history should assist in determining the serum
levels and doses that correlated with best seizure control.
CHAPTER 67
• Acute ingestion of alcohol can cause increased phenytoin
blood levels due to inhibition of metabolism. Due to the history
of alcohol use, phenytoin toxicity should be ruled out prior to
administering additional phenytoin. If phenytoin levels are not
readily available, a second-line agent can be initiated:
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Carbamazepine:
SECTION 6
• Take this medication with food to minimize the stomach upset
it sometimes causes.
• This medication may cause drowsiness or dizziness.
• Notify your physician if there is any unusual bleeding or bruising, abdominal pain, fever, chills, sore throat, skin rash, or
ulcers in the mouth.
Neurologic Disorders
• Small blood samples for periodic laboratory testing will need
to be drawn.
REFERENCES
1. Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet
Neurol 2015;14:615–624.
2. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and
management of status epilepticus. Neurocrit Care 2012;17(1):3–23.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
3. Sharvon S. The treatment of status epilepticus. Curr Opin Neurol
2011;24:165–170.
4. Trinka E. What is the relative value of the standard anticonvulsants:
phenytoin and fosphenytoin, phenobarbital, valproate, and levetiracetam? Epilepsia 2009;50(Suppl 12):40–43.
5.Prasad M, Krishnan PR, Sequeira R, Al-Roomi K. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev
2014;10(9):CD003723. doi: 10.1002/14651858.CD003723.pub3.
6. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus
intravenous therapy for prehospital status epilepticus. N Engl J Med
2012;366:591–600.
7.Glauser T, Ben-Menachem E, Bourgois B, et al. Updated ILAE
evidence review of antiepileptic drug efficacy and effectiveness as
initial monotherapy for epileptic seizures and syndromes. Epilepsia
2013;54:551–563.