Background
The incidence of seizures in general intensive care units (ICUs) ranges from 3.3% to 34% [
1]. Risk factors include common diagnoses such as brain tumor, head trauma, stroke, history of seizure, electrolyte abnormalities, hypoglycemia, infections, and drug overdose or withdrawal [
2]. Thus, ICU management of antiepileptic drugs (AEDs) is routinely practiced by intensive care providers.
Selection of the most effective AED with the least adverse events, however, can often be challenging. About a third of patients with seizures fail on monotherapy, necessitating two or more AEDs [
3]. Several factors commonly seen in the critical care setting, such as polypharmacy, unpredictable medication pharmacokinetics, and implementation of a variety of nonpharmacological interventions, may lead to drug-drug interactions, elevated risk for drug toxicity, and subtherapeutic drug serum levels; these are discussed in this review.
Pharmacodynamics and pharmacokinetics of AEDs
Pharmacodynamics
AEDs depress abnormal neuronal firing by various mechanisms of action including altering ion channel activity, enhancing gamma-aminobutyric acid (GABA)-mediated inhibition, or reducing glutamate-mediated excitation. While some AEDs have a single mechanism of action, others have multiple mechanisms of action and, in some, the exact mechanism of action is not yet known (Table
1).
Table 1
Mechanism of action of antiepileptic drugs [
113]
Brivaracetam | SV2A modulation |
Carbamazepine | Na+ channel blockade |
Clobazam | GABA potentiation |
Clonazapam | GABA potentiation |
Diazepam | GABA potentiation |
Fosphenytoin/phenytoin | Na+ channel blockade |
Lacosamide | Enhanced slow inactivation of voltage-gated Na+ channels |
Lamotrigine | Na+ channel blockade |
Levetiracetam | SV2A modulation |
Lorazepam | GABA potentiation |
Midazolam | GABA potentiation |
Oxcarbazepine | Na+ channel blockade |
Pentobarbital | GABA potentiation |
Perampanel | AMPA glutamate receptor antagonist |
Phenobarbital | GABA potentiation |
Topiramate | Na+ channel blockade, GABA potentiation, AMPA/Kainate glutamate antagonist |
Valproic acid | GABA potentiation, glutamate (NMDA) inhibition, sodium channel and T-type calcium channel blockade |
Zonisamide | Na+ and Ca2+ channel blockade |
When using multiple AEDs, it is reasonable to select medications with different mechanisms of action.
Pharmacokinetics (absorption, distribution, metabolism, excretion)
Alterations in normal physiology and the physical properties of medications can affect the rate and extent of enteral absorption of medications in the ICU, leading to a need for parenteral administration. Deranged gastrointestinal absorption may be expected in circumstances of decreased blood flow, intestinal atrophy, dysmotility, and interactions with enteral nutrition. Pharmacokinetic parameters of selected AEDs, including their oral bioavailability, are summarized in Table
2.
Table 2
Bioavailability and pharmacokinetic data of antiepileptic drugs [
113]
Brivaracetam | Almost completely absorbed | ≤ 20% | ~ 9 h | Hydrolysis (primary route) CYP2C19 | ≥ 95% renally |
Carbamazepine | 75–85% Total daily intravenous dose should be equivalent to 70% of previous total daily oral dose | 75–95% | Range: 30–60 h After autoinduction: 12–17 h | > 90% by CYP3A4 | 72% renally |
Clobazam | 87% | 80–90% | 36 to 42 h | Hepatic via CYP3A4 and to a lesser extent via CYP2C19 | 82% renally |
Clonazapam | ~ 90% | ~ 85% | 17–60 h | Glucuronide and sulfate conjugation | < 2% renally as unchanged drug |
Diazepam | > 90% | 98% | Parent drug: ~ 60 to 72 h; metabolite ~ 152 to 174 h | CYP3A4 and 2C19 | Renally |
Eslicarbazepine | > 90% | < 40% | 13–20 h | Hydrolytic first-pass metabolism | 90% renally |
Fosphenytoin | 100% (intramuscular formulation) | 95–99% | 12–28.9 h | CYP2C9 CYP2C19 | Renally |
Lacosamide | 100% | < 15% | 13 h | CYP3A4, CYP2C9, CYP2C19 | 95% renally |
Lamotrigine | 98% | 55% | 25–70 h | Conjugation | 94% renally |
Levetiracetam | 100% | < 10% | 6–8 h | Hydrolysis | 66% renally |
Lorazepam | 90% | ~ 91% | 12–18 h | Conjugation | 88% renally |
Midazolam | | | | | |
Oxcarbazepine | Readily absorbed | 40% | Active metabolite: 9–11 h | Glucoronidation | 95% renally |
Pentobarbital | – | 45% to 70% | 15–50 h | Hydroxylation and glucuronidation | < 1% renally as unchanged drug |
Perampanel | Completely and rapidly absorbed | 95% | ~ 105 h | CYP 3A4/5 primary; lesser extent CYP 1A2/2B6 | 22% renally |
Phenytoin | 20–90% | 90–95% | 7–42 h | CYP2C9, 2C19 (major) and 3A4 (minor) | < 5% renally as unchanged drug |
Phenobarbital | ~ 95–100% | 50% | Longest half-life 46–136 h | CYP450 and UGT mediated | 25–50% renally |
Topiramate | 80% | 15–41% | IR: 21 h ER: 31–56 h | No extensive metabolism | 70% renally |
Valproic acid | 90% | 80–90% | 9–16 h | CYPs 2C9, 2C19, 2A6, UGT-glucuronidation | 70–80% renally |
Zonisamide | Rapid and complete absorption | 40% | 50–68 h | CYP 3A4 | 60% renally |
Changes in serum pH as well as both respiratory and renal failure affect the ionized state of many drugs, affecting their penetration across lipophilic-based membranes such as the blood-brain barrier. Bioavailability of active drugs is also affected by alterations in volume of distribution for hydrophilic medications, while hypoalbuminemia increases the unbound (free) fraction of highly albumin-bound medications.
Although drugs are commonly metabolized to less active compounds, prodrugs such as oxcarbazepine and fosphenytoin must be metabolized into their active forms carbamazepine and phenytoin, respectively. Drug metabolism generally occurs in two phases. Phase I involves nonsynthetic reactions to form a modified group. A cytochrome P450 (CYP450) enzyme is frequently involved in such oxidative reactions. Phase II involves synthetic reactions to conjugate the metabolite with an endogenous substance. Metabolism for most anticonvulsants occurs primarily in the liver and is dependent on hepatic blood flow, enzyme activity, and protein binding. Although critical illness often inhibits the CYP450 isoenzymes, drug metabolism may be enhanced over several days as in the cases of pentobarbital and phenytoin, resulting in potential subtherapeutic concentrations [
4‐
6]. Induced hypothermia will also reduce the systemic clearance of many medications mediated by CYP450 (such as phenytoin or propofol), between 7 and 22% for every degree of Celsius below 37 [
7].
Regardless of the route of administration, renal elimination of parent drugs or metabolites is the primary excretory pathway for most drugs. For patients on renal replacement therapy (RRT), the type of dialysis that is performed and the frequency/duration should also be considered (see section 8, special therapeutic considerations).
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.
Table 3
Dosing and monitoring of commonly used antiepileptic drugs [
8,
11,
15,
16]
Phenytoin | Load: 15–20 mg/kg Maintenance: 4–6 mg/kg/day | 10–20 | 1 h postload or ~ 7–10 days after initiation of maintenance dose (may check earlier within 2–3 days in seizing patients to ensure their metabolism is not significantly different from average patient population) | At total concentrations > 20 μg/mL, nystagmus may occur. In concentrations > 30 μg/mL, ataxia, slurred speech, and incoordination can be observed. If total concentrations are above 40 μg/mL, coma is possible. At concentrations > 50–60 μg/m drug induced seizures may occur |
Valproic acid | Load: 20–40 mg/kg Maintenance: 10–15 mg/kg/day | 50–100 (levels as high as 175 are used in RSE) | 1 h postload or 2–4 days after initiation of maintenance dose | At total concentrations > 75 μg/mL lethargy and ataxia may occur. In concentrations > 100 μg/mL tremor is observed. Coma may occur if total serum concentrations are above 175 μg/mL. Thrombocytopenia is a dose-related side effect that can be limited by reducing the dose |
Phenobarbital | Load: 20 mg/kg Maintenance: 1.5–2 mg/kg/day (dose adjustment may be required in liver impairment due to reduced clearance) | 15–40 (higher levels may be utilized in RSE) | 1 h postload or 4–7 days after initiation of maintenance dose | CNS depression is a dose-related side effect. In concentrations > 60 μg/mL respiratory depression may occur |
Pentobarbital | Load: 5–15 mg/kg Maintenance: 0.5–5 mg/kg/h | 1–5 (rarely used to assess clinical efficacy or toxicity) | May be used after discontinuation to monitor the residual effects of the drug | Drug levels have not been correlated with electroencephalography CNS depression, respiratory depression, and hemodynamic instability are dose-related side effects |
Phenytoin/fosphenytoin
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
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
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].
Seizure control in the ICU
The widespread use of cEEG has made it apparent that seizures are more common in the ICU patients than previously thought, with estimates for seizures and SE ranging from 19% to 27% [
82,
83]. Bauer and Trinka introduced the distinction between nonconvulsive status epilepticus (NCSE) proper and comatose NCSE [
84]. This distinction is both important and useful as it acknowledges that treatment as well as prognosis are dependent on the underlying epileptic syndrome in the former, yet on the underlying cause of the coma in the latter. In the ICU patient population, the electrographic seizure patterns can be less distinct and harder to identify. Thus, a body of literature on the nature of, and the best treatment approach for, the “ictal-interictal continuum” has emerged and now dominates the literature. For recent reviews, see Sivaraju and Gilmore 2016 [
85] and Rodríguez et al. 2016 [
86].
As a general principle, the current consensus is that treatment of even a single ICU seizure should occur in order to prevent escalation into SE. Once airway, breathing, circulation, and “dextrose” (the “ABCDs”) have been addressed, pharmacologic seizure treatment should occur immediately. Several authors suggest an algorithm that escalates from first-line to second-line treatment in the time span of 30 min [
87,
88]. Once urgent first- and second-line agents are prescribed during the first 30 min, persistent SE should be considered refractory, and this should prompt the use of intravenous anesthetic therapy. SE is a neurological emergency and swift intervention is of the essence. While convulsive and nonconvulsive SE should be initially approached in the same way, once the need for intubation arises it is generally accepted that NCSE may warrant a less aggressive and more individualized approach to treatment with anesthetic agents (third-line agents) compared with convulsive SE.
Available evidence uniformly suggests that benzodiazepines remain the drugs of choice for the immediate control of seizures of any kind. The efficacy of intravenous lorazepam was demonstrated by Treiman et al. in 1998 [
89]. Lorazepam was most effective in the initial treatment of convulsive SE when compared with phenobarbital and diazepam plus phenytoin, although the latter were also effective. Other routes for the administration of benzodiazepines have successfully been explored, particularly for the therapy of seizures encountered outside the ICU. Silbergleit et al. reported that intramuscular midazolam was at least as safe and effective as intravenous lorazepam for prehospital seizure cessation [
90], while McIntyre et al. demonstrated the efficacy of buccal midazolam [
91].
Although an open-label use study purported to suggest equipoise between lorazepam and levetiracetam in the treatment of SE [
92], a randomized, double-blind, placebo-controlled trial (SAMU Keppra Trial) failed to show benefit from adding intravenous levetiracetam to clonazepam in the treatment of generalized convulsive SE [
93].
To monitor for ongoing seizure activity after convulsions may have ceased, cEEG is crucial. Second-line therapy for SE should be initiated within 30 min if first-line treatment has failed. Agents used as second-line therapy include fosphenytoin, valproic acid, phenobarbital, and levetiracetam. Evidence for the superiority of one over the other is generally lacking [
94]. Nonetheless, phenytoin has been the most studied drug in SE and is therefore often listed as the preferred choice over the others. Valproic acid is notable for being the only agent that has shown a trend towards superior efficacy in some studies but this has not been confirmed in a large-scale trial [
95]. Levetiracetam has a favorable side-effect profile and is therefore increasingly prescribed as a second-line drug. Phenobarbital is often avoided due to its long half-life, although data support its efficacy [
89]. Lacosamide has recently shown promise in small case studies [
96], while brivaracetam is currently under investigation [
97].
If second-line agents are ineffective, treatment is typically escalated to anesthetic agents. For patients in NCSE, however, the decision whether or not to intubate and sedate the patient will usually be made on a case-by-case basis. There is some evidence to suggest that uncontrolled NCSE will result in brain damage over time [
98]. Furthermore, DeLorenzo et al. noted that persistent NCSE after convulsive status may carry a worse prognosis than other forms of nonconvulsive status and perhaps should be treated more aggressively, although the presence of NCSE may simply be a marker for more severe brain injury [
99]. Agents used for continuous infusion are midazolam, propofol, and pentobarbital, with no data suggesting the superiority of one over the other [
100]. Ultimately, it is important not only to treat the patient with an anesthetic agent but to also continue maintenance therapy with appropriate AEDs to allow transition to a well-tolerated, long-term antiepileptic regimen.
Conclusion
Selection of the most appropriate AED in the ICU setting can be challenging for a variety of reasons. Older AEDs such as phenytoin, valproic acid, and phenobarbital are often used by clinicians due to their familiarity with these agents, intravenous formulations, and availability of evidence in certain clinical scenarios. Despite this, adverse effects of these agents, drug-drug interactions, and the need for TDM may limit their use. Newer agents such as levetiracetam and lacosamide are gaining popularity due to their relatively safe AED profile, fewer drug-drug interactions, and lack of need for TDM. The efficacy of these agents for seizure prophylaxis and as second-line treatment for SE, however, should be further evaluated in large randomized clinical trials.