Antiepileptic drugs in critically ill patients

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).

When using multiple AEDs, it is reasonable to select medications with different mechanisms of action.

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.

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).

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.

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].

Administration of multiple AEDs is common in the ICU to manage refractory seizures and SE. Satisfactory seizure control is not achieved in 30–40% of patients with monotherapy, making it necessary to use two or more AEDs [19, 20]. Although synergistic anticonvulsant activity between medications may be desirable, concurrent use of multiple AEDs generally increases the risk of drug interactions. Table 4 lists common AED-AED drug-drug interactions.

Interactions of AEDs with other agents is seen more frequently with drugs that are metabolized in the liver, and therefore are more common with older AEDs. Tables 5 and 6 describe AED-nonAED and nonAED-AED interactions.

The incidence of post-traumatic seizures accounts for 6% of overall symptomatic epilepsy [21‐23] and is estimated to occur in up to 15% and 53% in civilian and military populations, respectively [24, 25]. Clinical studies have divided post-traumatic seizures into either immediate (< 24 h), early (within 1 week, with a seizure incidence of 2.1–16.9%), or late (with an incidence of 1.9% to > 30.0%) [22, 23, 26]).

Early seizures occur in about 10–15% of patients not treated with anticonvulsants, and this incidence can be reduced to about 2–3% with the use of phenytoin [27]. There is, however, little evidence that such use reduces the occurrence of late seizures or the incidence of death and neurologic disability [28]. It thus appears that anticonvulsants are suppressive during the early period following traumatic brain injury (TBI), but are not prophylactic for the time period beyond the first week. The American Academy of Neurology (AAN) [29] and the Brain Trauma Foundation [30] advocate prophylactic use of AED only during the first 7 days after a head injury [31, 32]. Phenytoin has been shown to decrease the incidence of early post-traumatic seizures [30] and to be more cost-effective than levetiracetam [33]. Although levetiracetam was shown in small early studies to be as effective as phenytoin [33, 34], there are recent data suggesting a lack of any prophylactic action in a comparative study of levetiracetam versus no prophylaxis [35]. A trial that incorporated a blinded design and the use of continuous electroencephalography (cEEG) monitoring demonstrated no difference in early or late seizure incidence between drugs, but did favor levetiracetam over phenytoin in the 6-month Glasgow Outcome score measure [36].

The use of valproic acid, as compared with phenytoin, failed to demonstrate benefit and its use correlated with higher mortality [37]. However, a recent Cochrane analysis failed to discriminate between phenytoin and other anticonvulsants with regards to reduced incidence or mortality [37].

Seizures following ischemic stroke occur within an incidence range of 4% to 14% [38‐40]. According to a large recent registry from France, early seizures are not associated with higher mortality or unfavorable outcomes at 1 month or at 1 year [41]. Patients with late-onset seizures have a greater than twice the risk for subsequent stroke, although the causal relationship is unclear [42].

Given the rather low incidence of seizures following most ischemic stroke syndromes, neither the American Heart Association (AHA) nor the American Stroke Association guidelines recommend prophylactic use of anticonvulsants following ischemic stroke [43]. However, some patients may be at greater risk for seizures. An increase in seizure risk has been reported following cardioembolism [39], hyperglycemia [41], intravenous thrombolysis with alteplase [44], in patient with SE following poststroke seizures, and either large cortical or hemorrhagic infarction [38, 45‐48].

If “prophylaxis” is considered, then the agent used should be selected for its adverse effect profile. In recent years there has been some interest in ascribing statins as a “first-line” anticonvulsant in stroke patients, although supportive data are by association only and this type of intervention is not readily practiced [49, 50].

In contrast to ischemic stroke, intracerebral hemorrhage (ICH) portends a somewhat higher risk of seizures, ranging from two- to seven-times that from ischemic stroke [38, 47, 51, 52]. If cEEG is performed during the acute admission period, nonconvulsive epileptiform activity is commonly observed and may affect more than 20% of ICH patients [53‐56]. As expected, lobar or supratentorial ICHs have the highest incidence of seizures; those in the posterior fossa have almost zero [38, 54]. Surgical evacuation confers an increased incidence, and subarachnoid or subdural blood also increases the risk for seizures [57].

Prophylactic anticonvulsant treatment in ICH patients is currently not strongly advocated. cEEG is suggested by some for ICH patients with a depressed mental status out of proportion to that expected for the severity of the stroke [58]. Levetiracetam has become the most widely prescribed agent despite a lack of evidence [59], likely due to its ease of use. Uncontrolled study data have suggested that phenytoin confers worse outcomes than others (primarily against levetiracetam) [60‐62], but these data are not supported by other recent studies [63, 64].

Early and late-onset seizures are observed in patients with subarachnoid hemorrhage (SAH). Risk factors include the severity of SAH, concomitant intracerebral or intraventricular blood, and treatment with craniotomy [65]. A recent study noted a 10% incidence of seizures, with almost half (47%) occurring within the initial 24 h [66]. Interestingly, the use of prophylactic anticonvulsants did not reduce the overall risk. As seizures dramatically increase cerebral blood flow and blood pressure, rebleeding from a recently ruptured aneurysm during seizures may pose a serious risk.

Current guidelines from the AHA state that the use of anticonvulsants for a brief period is reasonable, without specific drug recommendation [67]. Beyond the immediate posthemorrhagic period, routine use of anticonvulsants is advocated by the AHA only in patients with a high risk for delayed seizures, such as prior seizure, intracerebral hematoma, intractable hypertension, infarction, or middle cerebral artery aneurysm. The Neurocritical Care Society (NCS) specifically recommended against the routine use of phenytoin for prophylaxis [68].

The incidence of seizures in cerebral malignancy broadly ranges from about 10% to as high as 90%, and is correlated with tumor type (glioma and oligodendroglioma being amongst the highest risk) and also the rate of progression, with slow growing tumors tending towards higher seizure incidence [69]. Prophylactic use of AEDs in brain tumors remains controversial. There are strikingly little data in support of seizure prophylaxis for brain tumor patients [70‐72], and guidelines by the AAN and the European Federation of Neurosciences do not support this practice [73, 74]. Since these guidelines were written prior to the widespread use of cEEG and prior to the introduction of newer, less toxic anticonvulsants (levetiracetam, lamotrigine, lacosamide, and so forth), some have suggested that such a recommendation should be reassessed [75].

Whenever patients require adjuvant chemotherapy, it is prudent to avoid the use of potent CYP3A4 coenzyme inducers such as carbamazepine, phenytoin, and phenobarbital because of the risks of compromising concurrent chemotherapy [74]. Based on more recent evidence, more patients are being managed with levetiracetam than phenytoin or sodium valproate [71], but evidence of superior efficacy remains absent [72].

Seizures manifest as a common presentation, occurring in 29% to 50% of patients with cerebral venous sinus thrombosis [76, 77]. Approximately a third to one half of seizures occur early—as the presenting symptom or within 2 weeks of diagnosis, [77‐79]. Despite the lack of controlled studies, prophylaxis appears prudent where forthcoming seizures appear highly probable. There is some evidence that early seizures are predictive of a remote epilepsy condition [80] but, in and of themselves, seizures in the context of cerebral venous sinus thrombosis do not appear to be associated with death or 6-month worse outcomes [81].