Antiepileptic Drugs in Critically Ill Patients

Salia Farrokh; Pouya Tahsili-Fahadan; Eva K. Ritzl; John J. Lewin III; Marek A. Mirski


Crit Care. 2018;22(153) 

In This Article

Dosing and Therapeutic Drug Monitoring in the ICU Setting

Dosing of AEDs should be individualized to achieve seizure control with minimal adverse effects. The 1-h postloading dose is commonly recommended as a time to measure peak serum concentration. Pharmacokinetic alterations are frequently observed in critically ill patients; hence, frequent therapeutic drug monitoring (TDM) may be required. Basic dosing and TDM recommendations for AEDs commonly used in the ICU are summarized below and in Table 3.


Phenytoin has an average half-life of 24 h, but this ranges from 7 to 40 h, increasing with dose escalation due to its nonlinear kinetics.[8] Phenytoin is insoluble in water and is dissolved in a basic solution including ethylene glycol, the mixture being linked to tissue necrosis ("purple hand syndrome") if extravasated.[9] Fosphenytoin, the prodrug of phenytoin, is water soluble and hence free of the toxic emulsion. This difference in solubility allows intramuscular and faster intravenous administration of fosphenytoin, but the need for plasma conversion to the active drug (phenytoin) results in a comparable time to peak plasma levels when compared with phenytoin administration itself.[10]

Because phenytoin follows nonlinear or saturable metabolism pharmacokinetics, it is possible to attain excessive concentrations much easier than medications that follow linear pharmacokinetics. Phenytoin TDM is therefore clinically important in the critically ill and should be followed closely.

At normal serum levels, patients may experience minor central nervous system depression and adverse effects such as nystagmus, drowsiness, or fatigue. Beyond the normal target range, ataxia, slurred speech, and incoordination often occurs. Drug-induced seizure activity has been reported at concentrations over 50–60 μg/mL.[8]

Typically, protein binding accounts for 90% of total plasma concentrations, hence the therapeutic range for unbound phenytoin (free) concentrations is 1–2 μg/mL. In patients suspected of having altered drug plasma protein binding, monitoring of free phenytoin serum concentration is of value.

Valproic Acid

Although the accepted therapeutic range for total valproic acid concentration for seizure therapeutics is 50–100 μg/mL, levels up to 175 μg/mL have been suggested in cases of refractory status epilepticus (SE) cases. Concentration-related side effects include ataxia, lethargy, tremor, and coma.[11] The common adverse effects—thrombocytopenia and hyperammonemia (via carnitine depletion)—can often be limited by dose reduction and by carnitine replacement in the latter condition. Due to significant interpatient differences in valproic acid metabolism, there is a poor correlation between valproic acid dose and total serum concentrations.[11,12]

Valproic acid is highly (90–95%) protein bound and is saturable within the therapeutic range which results in higher unbound fractions at higher concentrations. Although not often monitored, a therapeutic free valproic acid range of 2.5–10 μg/mL can be used as an initial guide.[11]


Phenobarbital has a long half-life of approximately 100 h, which limits its use when short-term AED use is desired. As with other AEDs, treatment of SE in particular may require higher than normal dosing, and this may reach upwards of even 10 mg/kg/day (serum levels of > 100 μg/mL) with solid efficacy demonstrated.[13] Concentration-related adverse effects of phenobarbital are sedation, confusion, and lethargy, with high doses leading to obtundation and respiratory depression.[14] As phenobarbital is only about 50% protein-bound, free drug monitoring is not warranted. However, in severe hepatic impairment (Child-Pugh score > 8) a decrease of 25–50% in the initial daily maintenance dose may be required.[15]


Pentobarbital is often used in the ICU setting to treat SE or elevated intracranial pressure. Initiation of pentobarbital involves sequential bolus doses followed by a continuous infusion.[16,17] The average half-life of pentobarbital in adults is reported to be about 22 h and it is 20–45% protein-bound. Serum pentobarbital TDM (reference range is 1–5 μg/mL) is of limited utility in determining treatment clinical response or toxicity; the direct measure of intracranial pressure (ICP) control or inducement of "burst suppression" by electroencephalography (EEG) are monitored instead. Serum concentrations, however, may be useful in assessing residual effects of pentobarbital-induced coma once discontinued.[18]