By Matilda Dervisevic1, Chetan Sateesh Nayak2 and Francisco Gomez3
1Univeristy of Missouri Medical School
2Department of Neurology, University of Missouri
3Department of Neurology, University of Missouri
Refractory status epilepticus (RSE) is a condition in which there is continuing seizure activity despite the administration of two first-line agents. Super-refractory status epilepticus (SRSE) is described as continual RSE for 24 hours, or with recrudescence upon withdrawal of anesthetic agents.
As a neurological emergency, RSE confers high morbidity and mortality. Molecular studies have demonstrated rapid internalization of GABAA receptors and upregulation of p-glycoprotein with subsequent induction of cellular export of phenytoin and phenobarbital molecules. N-Methyl-D-Aspartate (NMDA) receptors are also upregulated and facilitate excitotoxicity. Hence, first-line antiepileptics lose effectiveness over time.
Standard management for these patients includes anesthetic medications, such as a pentobarbital, propofol and midazolam. Pentobarbital was one of the earliest anesthetic medications utilized but has fallen out of favor due to several undesirable side effects, such as myocardial suppression and hypotension, immunosuppression, hepatic and renal dysfunction. It was also associated with increased incidence of withdrawal seizures. Midazolam and propofol are more frequently used recently, although they have their own side effects, and their efficacy in stopping seizures are not superior by a wide margin.
Thus, the search for an efficacious and effective drug in RSE continues. Inhalational anesthetics have been used as alternative agents or as a last resort in this disease, given their rapid onset and superior efficacy in controlling seizures. Furthermore, new devices have made the deployment of anesthetic gases outside the OR more simple and cost-effective.
Inhalational anesthetics are considered near ideal general anesthetic agents as they confer hypnosis, analgesia and skeletal muscle relaxation. Halothane is among the earliest synthesized fluorinated anesthetics and was created by Charles Suckling in 1951. This was followed by the discovery of a flurry of compounds in the 1960s, including methoxyflurane, enflurane and isoflurane. Finally, desflurane and sevoflurane were also synthesized in the late 1960s and are still the newest agents to be discovered.
Role of Inhalational Anesthetics in Refractory Status Epilepticus
Summary of case series reporting inhalational anesthetics in the setting of status epilepticus, modified from Zeiler, F., Zeiler, K., Teitelbaum, J., Gillman, L., & West, M. (2015)
Due to their potential neuroprotective effects, easy titration to attain burst suppression, rapid onset of action and reliable efficacy, inhaled anesthetics have proven advantageous, thus emerging as an alternative treatment of RSE. Halothane was one of the earliest agents to be used, but its use declined overtime due to it’s hepatotoxic potential. Isoflurane was found to be superior to halothane, attributed to it undergoing less conversion into toxic metabolites. Currently, isoflurane and desflurane have been the preferred agents because of their safety profile and their ability to reliably produce burst suppression on EEG. Beyond the United States, anesthetic gases are routinely utilized in the treatment of RSE. For example, isoflurane is routinely administered in this setting at the London Health Sciences Centre in Ontario, Canada
Several cohorts have evaluated anesthetic gases in RSE. Isoflurane seemed to effectively control status epilepticus in four patients following surgical resection of a lesion in the motor area with minimal side effects. Isoflurane in association with hypothermia has also been shown to be effective in patients with super-refractory status epilepticus.
Complications of Inhalational Anesthetics
Cardiovascular complications due to various etiologies may be induced through use of inhaled anesthetics. Such etiologies include myocardial depression, decreased systemic vascular resistance, suppression of baroreceptor responses or arrhythmogenic properties. Additionally, it has been reported isoflurane exclusively or isoflurane with desflurane induces hypotension in RSE patients. Administration of anesthetic gases may necessitate vasopressors to maintain mean arterial pressure. However, this is an issue also faced in the use of IV barbiturates.
Inhaled agents are not without side effects, however. Sevoflurane has been shown to lower seizure threshold and has not been used in the treatment of status epilepticus; this agent probably should be avoided as it can induce epileptiform discharges in non-epileptic patients. Isoflurane may cause coronary steal and may cause airway irritation, along with desflurane. Furthermore, the metabolism of inhaled anesthetics via the CYP-P450 enzymatic system leads to formation of toxic metabolites. It is said metabolites, rather than the initial anesthetic compounds, precipitate the hepatotoxicity and nephrotoxicity seen with inhaled anesthetics.
Dose dependent effects have been observed with inhaled agents. High doses are associated with postoperative cognitive dysfunction (POCD); however, prolonged use of low doses has yet to indicate any neuro impairments or organ toxicity. In studies with mice, isoflurane anesthesia increased proinflammatory cytokines: IL-1 β, IL-6, and TNF-α in brain tissues; however, the mechanism remains uncertain. Additionally, in mice studies, the observed neuroinflammation and POCD was improved by administering inflammatory inhibitors: IL-1 antagonist and anti-TNF agent.
Anesthetic use, especially prolonged, may exacerbate neurodegenerative processes or directly cause brain damage, such as with neurotoxicity. General anesthesia and dementia was investigated through a case-control study, which showed no associations between the two; however, when investigating a subgroup of patients above 65 years, an association between anesthetics and dementia was observed. However, regardless of the several preclinical studies supporting cognitive impairments from anesthetic use, the clinical data still remains inconclusive.
In RSE patients, hippocampal signal changes have been observed with isoflurane use. However, said signal changes may also correlate with the number of seizure days prior to MRI and use of multiple anesthetic agents. RSE induces hippocampal signal changes itself, hence it is possible these signal changes are related to seizure severity more than treatment itself.
Current evidence for isoflurane in particular for the treatment of RSE in children and adults is classified at Oxford level 4, GRADE D. The value added of anesthetic gases in ICU sedation has been discussed previously, and they are currently utilized routinely at several centers. It is likely the evidence for anesthethic gases in the treatment of RSE will become more robust as their use becomes more widespread and more data emerges.
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