Loading Dose

Whether or not V.S. has a detectable serum concentration of carbamazepine, he

should be given an IV loading dose of either fosphenytoin (20 mg/kg PE IV at 150

mg/minute) or phenytoin (20 mg/kg IV at 50 mg/minute). After administration of

either of these loading doses, serum phenytoin concentrations should remain greater

than 10 mcg/mLfor approximately 24 hours; this will allow time for determination of

V.S.’s serum carbamazepine concentration and estimation of an appropriate

maintenance dose of oral carbamazepine once oral therapy can be restarted. In this

setting, the use of IV phenytoin or fosphenytoin is a temporary measure. V.S.’s

previous positive response to carbamazepine indicates that he should likely continue

to receive this drug as his oral maintenance medication.

IV phenytoin can be administered by direct injection into a running IV line. The

rate of administration should be no faster than 50 mg/minute to minimize the risk of

hypotension and acute cardiac arrhythmias. Cardiovascular status (blood pressure,

electrocardiogram) should be monitored closely during administration. Hypotension

or electrocardiographic abnormalities usually reverse if the administration of

phenytoin is slowed or stopped temporarily. Fosphenytoin can be given by either

direct IV injection or, after dilution in any suitable IV solution, by infusion at up to

150 mg PE/minute.

100 Absence of propylene glycol as a diluent renders fosphenytoin

potentially less likely than phenytoin to cause cardiovascular adverse effects, but this

advantage is not well supported.

220 Electrocardiographic and blood pressure

monitoring is recommended when this drug is given IV. Pruritus and paresthesias,

usually localized to the face and groin, are relatively common side effects during IV

fosphenytoin administration. These sensations are not allergic reactions to the

medication. Their occurrence is related to the administration rate, and they are

reversible with temporary discontinuation or slowing of the injection.

100

p. 1299

p. 1300

Maintenance Therapy

The undetectable serum carbamazepine concentration appears to confirm the role of

nonadherence in this episode of SE. Because V.S. was previously well controlled on

600 mg/day, this would be a reasonable target dose. Because V.S. may not tolerate

carbamazepine if restarted at the prior maintenance dose, gradually escalating up to

this dose should be initiated as soon as V.S. can take oral medication. V.S. should be

counseled regarding the importance of taking his medication according to directions

and any potential barriers to adherence should be addressed.

Alternative Therapies for Refractory Status Epilepticus

Phenobarbital may be useful for treatment of SE if the patient cannot tolerate

phenytoin or when seizures continue after administration of appropriate loading

doses of phenytoin. Patients who receive phenobarbital after being treated with IV

benzodiazepines should be monitored closely for respiratory depression because this

effect may be additive. Equipment and personnel to provide ventilatory assistance

should be available.

208

Status epilepticus that does not respond to lorazepam and a longer-acting agent

(e.g., phenytoin/fosphenytoin, valproate, levetiracetam, phenobarbital, or

lacosamide) is considered refractory status epilepticus. From 20% to 40% of

patients with SE will progress to refractory status epilepticus. In such circumstances,

an alternative longer-acting agent from those mentioned above may be considered;

and, in recent years, the use of such “third-line” agents was a common practice.

Recently, it has become a more common practice to escalate therapy to the use of an

anesthetic agent after failure of second-line therapy.

209 The most commonly used

anesthetic agents for refractory status epilepticus are midazolam and propofol;

pentobarbital is also sometimes used. Significant respiratory depression is expected

with these therapies; patients require intubation and mechanical ventilation. In

addition, vasopressors, such as dopamine or dobutamine, may be required to control

hypotension. Constant EEG monitoring also is required to assess the anticonvulsant

effect of the drug and to gauge the level of anesthesia.

Midazolam is given as a loading dose of 0.2 mg/kg IV and is followed by an IV

infusion of 0.2 to 0.6 mg/kg/hour.

208 Many practitioners adjust the infusion rate to

either control electrographic seizures and/or to produce a burst-suppression EEG

pattern.

221 Most protocols for anesthetic therapy of refractory SE recommend attempts

at gradually reducing the dose of medication after 12 to 24 hours of treatment. If

clinical or EEG seizure activity recurs, the dose is increased again to produce the

desired EEG pattern. Anesthetic agents may need to be continued for several days or

even weeks in some patients.

Continuous IV infusions of propofol or midazolam are also useful for refractory

SE. These therapies appear to be less likely than pentobarbital to cause severe

hypotension that is refractory to vasopressors.

222–225 Because no direct comparative

trials of pentobarbital, propofol, and midazolam have been performed, physician

familiarity and preference often guide the choice between these agents for the

treatment of refractory SE.

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A full list of references for this chapter can be found at

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p. 1300

Ischemic and hemorrhagic stroke are diseases involving the vascular

system of the brain. In the United States, approximately 87% of strokes

are ischemic in nature and 13% are hemorrhagic.

Case 61-1 (Question 1)

Ischemic and hemorrhagic stroke are medical emergencies, requiring

prompt medical attention at the first sign of symptoms. Signs and

symptoms of cerebrovascular disease usually occur acutely and vary

depending on the area of the brain involved. Ischemic and hemorrhagic

events have similar symptoms and must be distinguished before initiating

treatment.

Case 61-2 (Question 1)

Primary prevention is vital to reducing the risk of a stroke. Lifestyle

modifications and control of risk factors are the mainstay of primary

prevention. Important modifiable risk factors include cardiovascular

disease, hypertension, obesity, dyslipidemia, diabetes, smoking and

physical inactivity. The use of antiplatelet agents is recommended for

cardiovascular (including but not specific to stroke) prophylaxis and

reasonable for people whose 10-year risk is >10% as estimated by

cardiovascular risk calculators (see Core Principle 4).

Case 61-1 (Questions 1, 2)

Patients with atrial fibrillation and patent foramen ovale require primary

prevention pharmacotherapy according to their ischemic stroke risk.

Antiplatelet agents or anticoagulants should be used in patients with

these conditions, with selection of an agent dependent on patient

characteristics.

Case 61-1 (Question 2)

Secondary prevention of ischemic stroke and transient ischemic attacks

involves the use of antiplatelet agents. Selection of an agent is

dependent on patient characteristics.

Case 61-2 (Questions 5,6, 7,

8,

9, 10)

Acute treatment of ischemic strokes includes the use of alteplase given

intravenously. Alteplase should be started after confirming an event is

ischemic and not hemorrhagic. The treatment window for use of

alteplase is limited to 4.5 hours after the onset of neurologic symptoms.

Strict criteria for administration of alteplase must be followed to reduce

the risk of intracranial hemorrhage (ICH) and hemorrhagic

complications should be carefully monitored.

Case 61-2 (Questions 2, 3, 4,

5)

The strongest risk factor for hemorrhagic stroke because of non- Case 61-3 (Question 1)

traumatic intracerebral hemorrhage is uncontrolled hypertension.

Intracerebral hemorrhage may also occur as a result of an anatomic

abnormality in the brain or a disease process, such as a brain tumor.

Bleeding disorders, including those induced by anticoagulant drugs, also

predispose patients to intracerebral hemorrhage.

Acute treatment of intracerebral hemorrhage focuses on minimizing

hemorrhage expansion through careful blood pressure control and

reversal of coagulopathies, when appropriate, as well as prevention and

management of elevated intracranial pressure.

Case 61-3 (Questions 2-6)

Modifiable risk factors for hemorrhagic strokes include blood pressure

control, smoking cessation, and avoiding excessive alcohol and cocaine

use.

Case 61-3 (Question 7)

p. 1301

p. 1302

Rehabilitation after a cerebrovascular event is essential to patient

recovery. Common complications encountered in rehabilitation included

spasticity, depression, and neurogenic bowel or bladder.

Pharmacotherapy interventions should be directed at each of these

complications with the goal of improving the patient’s quality of life and

ability to function independently.

Case 61-5 (Question 1)

ISCHEMIC STROKE, HEMORRHAGIC STROKE,

AND TRANSIENT ISCHEMIC ATTACKS

Ischemic stroke, hemorrhagic stroke, and transient ischemic attacks result from either

inadequate blood flow to the brain (i.e., cerebral ischemia) with subsequent

infarction of the involved portion of the central nervous system (CNS) or

hemorrhages into the parenchyma or surrounding structures of the CNS and

subsequent neurologic dysfunction. This group of disorders is the fourth leading

cause of deaths among adults in the United States.

1