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

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.