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CHAPTER 85: Seizures in the Intensive Care Unit 783

Prospective data indicate that EEG patterns may also be helpful in efficacy of phenytoin in the control of seizures is well established, several
determining prognosis. One study found that the presence of burst sup- inherent properties of the drug limit its tolerability. In order to improve
pression, post-SE ictal discharges, and periodic lateralized epileptiform aqueous solubility, phenytoin is suspended in a highly alkaline solution
discharges during the initial 24 hours after control of SE were statisti- that is comprised of 40% propylene glycol. The propylene glycol vehicle
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cally significantly correlated with mortality and poor outcome. Burst has been linked to hypotension and cardiac arrhythmias during phe-
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suppression secondary to pharmacologic coma for treatment of SE must nytoin infusion; however, phenytoin itself may be partly responsible for
be differentiated from burst suppression due to widespread cortical hemodynamic instability. The caustic pH of the parenteral formulation
injury, or that seen as the last stage of the EEG evolution of SE. The can cause injection site reactions that can range from burning at the IV
availability of continuous paperless electroencephalographic monitoring site to necrosis in the event of extravasation.
allows for detection of seizure activity over a long period. In critically The phenytoin prodrug fosphenytoin is water soluble; therefore the
ill patients with an otherwise unexplained decrease in mental status, parenteral formulation is more neutral than that of phenytoin and
electrographic seizures were captured on continuous EEG monitoring contains no organic solvents. Cardiovascular side effects were initially
in 93% by 48 hours, and only 7% after 48 hours ; therefore, continuous thought to be less common with fosphenytoin, but subsequent experi-
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EEG monitoring should at least be continued for 48 hours in comatose ence suggests that hypotension and arrhythmias may follow its infusion.
patients. 6 Pain at the infusion site is significantly less common with fosphenytoin
The EEG can also provide information that is very useful in the than with phenytoin. In patients without IV access, fosphenytoin
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diagnosis and management of other neurologic conditions. 64,65 can be safely administered intramuscularly. IM doses of fosphenytoin
are well tolerated, require no cardiac monitoring, and are completely
absorbed. Fosphenytoin is rapidly converted to phenytoin in vivo and
MANAGEMENT APPROACH free phenytoin levels after fosphenytoin administration are not markedly
■ ISOLATED SEIZURES different compared to phenytoin, although the time to reach the peak
level after IM administration is several hours.
Not all patients who have seizures require anticonvulsant therapy. A 20-mg/kg loading dose of phenytoin brings most patients to the
Making the decision to administer anticonvulsants to a hospitalized desired concentration of 20 µg/mL (corresponding to an unbound or
patient who experiences one or a few seizures mandates consideration of free concentration of 2 µg/mL). Fosphenytoin is dosed by phenytoin-
a provisional cause, estimation of the likelihood of recurrence, and rec- equivalent units (PE); therefore no dosage adjustments are needed when
ognition of the utility and limitations of anticonvulsants. For example, converting patients from phenytoin to fosphenytoin. Fosphenytoin can
seizures due to ethanol or other hypnosedative withdrawal do not need be administered via intravenous infusion at rates of up to 150 mg PE/min,
chronic treatment, but short-term therapy with benzodiazepines for compared with a maximum rate of 50 mg/min for phenytoin. Both of
repeated or prolonged seizures may be warranted (Table 85-2). Seizures these drug infusions should be started at a lower rate and increased
caused by metabolic disturbances such as hyponatremia are often as tolerated. When loading doses of fosphenytoin are given IM, two
refractory to conventional anticonvulsant medications such as phe- divided doses of 10 mg/kg each are recommended. After fosphenytoin
nytoin, and are best treated with correction of the underlying disorder administration, phenytoin concentrations should not be measured
( benzodiazepines may be useful for seizure suppression if needed while until the biologic conversion to phenytoin is complete and the drug has
the metabolic problem is being corrected). Seizures related to nonketotic equilibrated throughout the body, about 2 hours after an intravenous
hyperglycemia respond best to correction of hyperglycemia with insulin infusion or 4 hours after an intramuscular injection of fosphenytoin.
and rehydration. 57 Phenytoin is approximately 90% protein bound in normal hosts, but the
A patient with CNS disease who has even one seizure should receive unbound fraction is the active component. Patients with renal or hepatic
anticonvulsant therapy because the risk of seizure recurrence is very dysfunction or those taking drugs that compete for protein binding may
high. However, this treatment should be reviewed before discharge. benefit from measuring the free (unbound) serum phenytoin concentra-
Initiating this treatment after the first unprovoked seizure may help delay tion before increasing phenytoin doses due to apparently subtherapeutic
the appearance of subsequent seizures, but probably does not influ- total phenytoin concentrations.
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ence whether epilepsy subsequently develops. Prophylactic therapy The maintenance dose for phenytoin is typically in the range of 5
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in patients at high risk for seizure, especially if the condition was seri- to 7 mg/kg per day, but is highly variable because of individual differ-
ously complicated by a convulsion, is not unreasonable. Patients with ences in metabolism and interactions with other drugs metabolized via
traumatic brain injury, intracerebral hemorrhages, and subarachnoid the cytochrome P450 system. Maintenance doses can be given either
hemorrhages are frequently placed on anticonvulsants immediately enterally or parenterally. Maintenance doses of IV or enteral liquid
upon admission, although no prospective randomized trials have proven suspension phenytoin must be given in twice-daily divided doses since
a positive effect on outcome. their half-life is less than 24 hours. Extended-release capsules can be
In the ICU setting, phenytoin is often the first drug selected due to given once a day. However, patients often do not tolerate more than 300
ease of administration and rapid assessment of blood levels. While the or 400 mg of phenytoin enterally in any one dose secondary to nausea.

TABLE 85-2 Drugs for the Treatment of Acute Convulsive Status Epilepticus
Drug Dose Rate Advantages Disadvantages
Diazepam 0.15 mg/kg IV push Quick onset of action Respiratory depression
Fosphenytoin 20 mg/kg <150 mg/min Easy transition to chronic administration Delay to onset of action; prolonged loading time; hypotension
Lorazepam 0.1 mg/kg IV push diluted 1 : 1 Quick onset of action; may prevent early recurrence Respiratory depression
Midazolam 0.2 mg/kg IV/IM push Can be given IM; quick onset of action Respiratory depression
Phenobarbital 10-20 mg/kg 50-100 mg/min Readily available Prolonged loading time; hypotension
Phenytoin 20 mg/kg <50 mg/min Readily available Prolonged loading time; cardiac arrhythmias; necrosis if extravasation
occurs; hypotension; incompatible with dextrose-containing solutions
Valproate 25 mg/kg 12-200 mg/min diluted 2 : 1 Appears safe in children Not well studied in status epilepticus

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