Refractory status epilepticus (RSE) poses significant challenges for both medical and surgical management.Reference Brophy, Bell and Claassen 1 - Reference Hunter and Young 3 The standard front-line medications used for control of shorter duration seizures, and those patients in status epilepticus, are commonly ineffective in the setting of RSE.Reference Hunter and Young 3
Changes in gamma aminobutyric acid-A (GABAA) receptors leads to unresponsiveness to GABA-mediated medications.Reference Deeb, Maguire and Moss 4 - Reference Loscher 6 Upregulation of p-glycoprotein leads to rapid export of phenytoin and phenobarbital molecules, impairing the action of these antiepileptic drugs (AEDs).Reference Loscher and Potscha 7 , Reference Rizzi, Caccia and Guiso 8 In addition, significant upregulation of N-methyl D-aspartate receptors with prolonged seizures leads to glutamate mediated excitoxicity, further potentiating epileptic activity. All of these described mechanisms are thought to be time-dependent.Reference Fujikawa 9
Thus, the rapid control of seizure activity in RSE is paramount. Numerous emerging therapies for those patients with RSE include but are not limited to therapeutic hypothermia, electroconvulsive therapy, and ketamine.
A potential last resort in RSE has been the use of volatile inhalational anesthetic agents to provide general anesthesia and suppress cortical activity. Few studies exist in the literature focusing on the use of modern inhalational anesthetics for control of refractory seizures.Reference Alexopoulos, Lachwani and Gupta 10 - Reference Sharpe, Young and Mirsattari 28
The goal of our study was to perform a systematic review of the literature on the effectiveness of modern inhalational anesthetic agents in controlling refractory seizures.
Methods
A systematic review using the methodology outlined in the Cochrane Handbook for Systematic ReviewersReference Higgins and Green 29 was conducted. The data were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.Reference Moher, Liberati, Tetzlaff and Altman 30 The review questions and search strategy were decided upon by the primary author and supervisor.
Search Question, Population, and Inclusion and Exclusion Criteria
The question posed for systematic review was: What is the effectiveness of modern inhaled anesthetic gas on control of RSE in humans? All studies, prospective and retrospective of any size based on human subjects, were included. The reason for an all-inclusive search was based on the small number of studies of any type identified by the primary author during a preliminary search of MEDLINE.
The primary outcome measure was electrographic seizure control, defined as: excellent (100% of patient response), moderate (greater than 50% of patient response), mild (less than 50% of patient response), and failure (0% response). This qualitative seizure response grading was used given the heterogeneous treatment response data on electrographic seizure control reported within the studies found. Secondary outcome measures were patient outcome (if reported), and adverse effects of the inhalational anesthetics.
Inclusion criteria were: All studies including human subjects whether prospective or retrospective, all study sizes, any age category, and the use of modern inhalational anesthetic gases (sevoflurane, isoflurane, desflurane, xenon) for seizure control in RSE. Exclusion criteria were: animal and non-English studies and treatment with the inhalational gases other than those mentioned in the inclusion criteria.
Search Strategy
MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, SCOPUS, and Cochrane Library from inception to March 2014 were searched using individualized search strategies for each database. The search strategy for MEDLINE can be seen in Appendix A of the supplementary material, with a similar search strategy used for the other databases. In addition, the World Health Organization’s International Clinical Trials Registry Platform was searched looking for studies planned or under way.
As well, meeting proceedings for the past ten years looking for ongoing and unpublished work based on inhalational anesthetics for seizures were examined. The meeting proceedings of the following professional societies were searched: Canadian Neurological Sciences Federation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, European Neurosurgical Society, World Federation of Neurological Surgeons, American Neurology Association, American Academy of Neurology, European Federation of Neurological Science, World Congress of Neurology, Society of Critical Care Medicine, Neurocritical Care Society, World Federation of Societies of Intensive and Critical Care Medicine, American Epilepsy Society, the International League Against Epilepsy, American Society for Anesthesiologists, World Federation of Societies of Anesthesiologist, Australian Society of Anesthesiologists, International Anesthesia Research Society, Society of Neurosurgical Anesthesiology and Critical Care, Society for Neuroscience in Anesthesiology and Critical Care, and the Japanese Society of Neuroanesthesia and Critical Care.
Finally, reference lists of any review articles or systematic reviews on seizure management were hand-searched for relevant studies on inhalational anesthetic usage for seizure control.
Study Selection
Using two reviewers (FZ and MW), a two-step review of all articles returned by our search strategies was performed. First, the reviewers independently screened all titles and abstracts of the returned articles to decide if they met the inclusion criteria. Second, the full text of the chosen articles was then assessed to confirm if they met the inclusion criteria and that the primary outcome of seizure control was reported in the study. Any discrepancies between the two reviewers were resolved by a third party (JT or LG).
Data Collection
Data were extracted from the selected articles and stored in an electronic database. Data fields included: patient demographics, type of study (prospective or retrospective), number of patients, type of anesthetic gas used, dose of anesthetic gas used, timing to administration of drug, duration of drug administration, time to effect of drug, how many other AEDs were used before implementation of inhalational anesthetic gas, degree of seizure control (as described previously), adverse effects, and patient outcome.
Quality of Evidence Assessment
Assessment of the level of evidence for each included study was conducted by an interdisciplinary panel of three independent reviewers using the Oxford criteriaReference Phillips, Ball, Sackett, Straus, Haynes and Dawes 31 and the Grading of Recommendation Assessment Development and Education (GRADE) criteriaReference Guyatt, Oxman and Vist 32 - Reference Jaeschke, Guyatt and Dellinger 37 for level of evidence. We elected to use two different systems to grade level of evidence given that these two systems are among the most commonly used. We believe this would allow a larger audience to follow our systematic approach in the setting of unfamiliarity with a particular grading system.
The Oxford criteria consist of a five-level grading system for literature. Level 1 is split into subcategories 1a, 1b, and 1c, which represent a systematic review of randomized control trials (RCTs) with homogeneity, individual RCTs with narrow confidence interval, and all or none studies, respectively. Oxford level 2 is split into 2a, 2b, and 2c, representing systematic review of cohort studies with homogeneity of data, individual cohort study or low-quality RCTs, and outcomes research, respectively. Oxford level 3 is split into 3a and 3b, representing systematic review of case-control studies with homogeneity of data and individual case-control study, respectively. Oxford level 4 represents case series and poor cohort studies. Finally, Oxford level 5 represents expert opinion.
The GRADE level of evidence is split into four levels: A, B, C, and D. GRADE level A represents high evidence with multiple high-quality studies having consistent results. GRADE level B represents moderate evidence with one high-quality study or multiple low-quality studies. GRADE level C evidence represents low evidence with one or more studies with severe limitations. Finally, GRADE level D represents very low evidence based on either expert opinion or few studies with severe limitations.
Any discrepancies between the grading of the three reviewers were resolved by a fourth reviewer.
Statistical Analysis
A meta-analysis was not performed in this study because of the heterogeneity of data within the articles and the presence of a small number of low-quality retrospective studies.
Results
The results of the search strategy across all databases and other sources are summarized in Figure 1. Overall, 3633 articles were identified, with 3630 from the database search and 3 from the search of published meeting proceedings. After removing duplicate references, there were 2563 articles. By applying the inclusion/exclusion criteria to the title and abstract of the articles, we identified 70 articles that fit these criteria. Of the 70 identified, 67 were from the database search and 3 were from published meeting proceedings. Applying the inclusion/exclusion criteria to the full text documents, only 19 articles were eligible for inclusion in the systematic review, with 16 from database and 3 from meeting proceeding sources. The 51 articles that were excluded were done so because they either did not report details around the administration of inhaled anesthetic agents for seizure control, or because they were review articles. Reference sections from these review articles were searched by hand for any other articles missed in the database search, with none being identified.
Figure 1 Flow diagram of search results
Of the 19 articles included in the review,Reference Alexopoulos, Lachwani and Gupta 10 - Reference Sharpe, Young and Mirsattari 28 all were original studies. Kofke et alReference Kofke, Snider and O’Connell 18 included patient data from 2 of the other 19 articles.Reference Kofke, Snider, Young and Ramer 17 , Reference Robakis and Hirsch 25 Similarly, Kofke et alReference Kofke, Young and Davis 19 contained data from 1 of the 19 articles.Reference Kofke, Snider, Young and Ramer 17 The patient data repeated in these two studiesReference Kofke, Snider, Young and Ramer 17 , Reference Robakis and Hirsch 25 were not included in the tabulation of data for this review in order to avoid including the same individual patient data multiple times. Three articles were published meeting abstracts.Reference Demulder, Ferster and Pelc 12 , Reference Kofke, Snider and O’Connell 18 , Reference Sakaki, Abe and Hoshida 27
There were 18 retrospective studiesReference Alexopoulos, Lachwani and Gupta 10 , Reference Demulder, Ferster and Pelc 12 - Reference Sharpe, Young and Mirsattari 28 and 1 prospective study.Reference Azzopardi, Roberston and Kapetanakis 11 Thus the potential for significant publication bias is present. Within the retrospective studies, eight were retrospective case seriesReference Alexopoulos, Lachwani and Gupta 10 , Reference Demulder, Ferster and Pelc 12 , Reference Kofke, Snider, Young and Ramer 17 - Reference Kofke, Young and Davis 19 , Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 , Reference Ropper, Kofke, Bromfield and Kennedy 26 , Reference Sakaki, Abe and Hoshida 27 and the remaining ten were retrospective case reports.Reference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 - Reference Hughes, Sharpe and McLachlan 16 , Reference Kofke, Bloom, Van Cott and Brenner 20 - Reference Meeke, Soifer and Gelb 22 , Reference Mirsattari, Sharpe and Young 24 , Reference Robakis and Hirsch 25 , Reference Sharpe, Young and Mirsattari 28 The retrospective case series were composed of six single-center reviewsReference Alexopoulos, Lachwani and Gupta 10 , Reference Demulder, Ferster and Pelc 12 , Reference Kofke, Snider, Young and Ramer 17 , Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 , Reference Ropper, Kofke, Bromfield and Kennedy 26 , Reference Sakaki, Abe and Hoshida 27 and two multicenter reviews.Reference Kofke, Snider and O’Connell 18 , Reference Kofke, Young and Davis 19 The one prospective study included in the systematic review was a prospective cohort study with no control group.Reference Azzopardi, Roberston and Kapetanakis 11 Fourteen articles described the use of inhaled anesthetic in adults,Reference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 - Reference Hughes, Sharpe and McLachlan 16 , Reference Kofke, Snider and O’Connell 18 - Reference Kofke, Bloom, Van Cott and Brenner 20 , Reference Meeke, Soifer and Gelb 22 - Reference Sharpe, Young and Mirsattari 28 with Ropper et alReference Robakis and Hirsch 25 containing duplicate patient data. Nine studies described pediatric patients,Reference Alexopoulos, Lachwani and Gupta 10 - Reference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 , Reference Kofke, Snider, Young and Ramer 17 - Reference Kofke, Young and Davis 19 , Reference Lippert 21 , Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 with one containing duplicated data.Reference Kofke, Snider, Young and Ramer 17 Four of the 19 studies have combined adult and pediatric patient populatons,Reference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 , Reference Kofke, Snider and O’Connell 18 , Reference Kofke, Young and Davis 19 , Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 with Kofke et alReference Kofke, Snider and O’Connell 18 not separating adult from pediatric data and thus being included in the adult summary.
Four different inhalational anesthetic agents were reported. Isoflurane was used in 18 studies,Reference Alexopoulos, Lachwani and Gupta 10 , Reference Demulder, Ferster and Pelc 12 - Reference Sharpe, Young and Mirsattari 28 desflurane in 2,Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 , Reference Sharpe, Young and Mirsattari 28 and xenon in 1.Reference Azzopardi, Roberston and Kapetanakis 11 Halothane was used in two studies,Reference Demulder, Ferster and Pelc 12 , Reference Robakis and Hirsch 25 but its effect was not analyzed given its current lack of use as a modern anesthetic gas.
Across all studies, 46 patients were studied using modern inhalational anesthetic gas for control of their seizures (mean 2.4 patients/study; range: 1–9 patients/study). Eighteen patients were pediatric (age range: 8 months to 17 years), with the exclusion of data from Kofke et alReference Kofke, Snider and O’Connell 18 because adult and pediatric data were not separated within the abstract. Twenty-eight patients were adult (age range: 18–71 years). A variety of underlying etiologies for RSE existed in both the adult and pediatric populations.
Study demographics and patient characteristics for all studies can be seen in Table 1, whereas treatment characteristics and seizure outcome are reported in Table 2.
Table 1 Study characteristics and patient demographics
* Kofke et alReference Kofke, Snider and O’Connell 18 is a meeting abstract that reports the case from Kofke et alReference Kofke, Snider, Young and Ramer 17 and Ropper et alReference Robakis and Hirsch 25 ; patient data from Kofke et al and Ropper et alReference Robakis and Hirsch 25 were not included in the tabulation of results in order to avoid duplication of patient data.
† Kofke et alReference Kofke, Young and Davis 19 contains the patient data from Kofke et alReference Kofke, Snider, Young and Ramer 17 as well.
AVM=arteriovenous malformation; CP=cerebral palsy; ECT=electroconvulsive therapy; ODG=oligodendroglioma.
Table 2 Treatment characteristics, seizure response, and outcome
* Kofke et alReference Kofke, Snider and O’Connell 18 is a meeting abstract that reports the case from Kofke et alReference Kofke, Snider, Young and Ramer 17 and Ropper et al; patient data from Kofke et al and Ropper et alReference Robakis and Hirsch 25 were not included in the tabulation of results in order to avoid duplication of patient data.
† Kofke et alReference Kofke, Young and Davis 19 contains the patient data from Kofke et alReference Kofke, Snider, Young and Ramer 17 as well.
EEG=electroencephalogram; ICU=intensive care unit; GOS=glasgow outcome scale.
Inhalational Anesthetic Treatment Characteristics
Adults
The literature on inhaled anesthetics for seizure control in the adult population yielded 13 studies with original patient data. Ropper et alReference Robakis and Hirsch 25 was not included in the adult summary because of data duplication. Within these 13 studies,Reference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 - Reference Hughes, Sharpe and McLachlan 16 , Reference Kofke, Snider and O’Connell 18 - Reference Kofke, Bloom, Van Cott and Brenner 20 , Reference Meeke, Soifer and Gelb 22 - Reference Mirsattari, Sharpe and Young 24 , Reference Ropper, Kofke, Bromfield and Kennedy 26 - Reference Sharpe, Young and Mirsattari 28 11 used isoflurane onlyReference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 - Reference Hughes, Sharpe and McLachlan 16 , Reference Kofke, Snider and O’Connell 18 - Reference Kofke, Bloom, Van Cott and Brenner 20 . Reference Meeke, Soifer and Gelb 22 , Reference Mirsattari, Sharpe and Young 24 , Reference Ropper, Kofke, Bromfield and Kennedy 26 , Reference Sakaki, Abe and Hoshida 27 with a minimum alveolar concentration (MAC) ranging from 0.5 to 5.0% (commonly used dose across all studies was 0.5–2.0%). One studyReference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 used isoflurane in isolation at a MAC ranging from 0.5 to 5.0% in five patients, and a combination of desflurane/isoflurane with a MAC of 1.0–4.0%/0.1–0.66% for one patient. The final study for adults used desflurane for 13 days, followed by isoflurane for 13 days at a MAC of 1.0–4.0% and 0.1 and 0.66%, respectively.Reference Sharpe, Young and Mirsattari 28
Duration of treatment before inhalational anesthetic administration was documented in nine adult studies, ranging from 8 hours to 60 days (median=45 hours), with patients on various numbers of AEDs before anesthetic gas, ranging from 1 to 15 (mean=6.8, median=7). Similarly, the duration of inhaled anesthetic treatment was described in 10 of the 13 adults studies, with treatment duration ranging from 5 hours to 32 days (median=30.3 hours, mean=112.0 hours). Treatment characteristics for the adult studies can be seen in Table 2.
Pediatrics
Within those nine studies describing inhaled anesthetic use in the pediatric population,Reference Alexopoulos, Lachwani and Gupta 10 - Reference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 , Reference Kofke, Snider, Young and Ramer 17 - Reference Kofke, Young and Davis 19 , Reference Lippert 21 , Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 one study was not included because of duplication of patient data,Reference Kofke, Snider, Young and Ramer 17 whereas a second studyReference Kofke, Snider and O’Connell 18 failed to separate pediatric from adult data and thus had its data included in the adult section of the review. Among the seven remaining studies, isoflurane was use in isolation in five articlesReference Alexopoulos, Lachwani and Gupta 10 , Reference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 , Reference Kofke, Young and Davis 19 , Reference Lippert 21 , Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 with a MAC of 0.5–5.0% (usual range=0.5–2.5%). One study used halothane and isoflurane at unknown concentrations.Reference Demulder, Ferster and Pelc 12 Finally, one study focused on xenon anesthetic in asphyxial neonates at a concentration of 30%.Reference Azzopardi, Roberston and Kapetanakis 11
Duration of treatment before inhalational anesthetic administration was documented in five pediatric studies, ranging from 12 hours to 103 days (median=312 hours), with patients on various numbers of AEDs before ketamine, ranging from 0 to 10 (median=4, mean=5). Similarly, the duration of inhaled anesthetic treatment was described in four studies, ranging from 1 hour to 85 days (median=29 hours). Treatment characteristics for the pediatric studies can be seen in Table 2.
Seizure Response
Adults
Seizure control upon inhaled anesthetic administration in the adult population was documented as excellent (complete response in all patients) in 12 of 14 studies, taking into account duplicate patient data. Failure of treatment response in all patients occurred in two studies with a total of two patients within these studies.Reference Mirsattari, Sharpe and Young 24 , Reference Sakaki, Abe and Hoshida 27
Across all 13 adult studies, with nonduplicate patient data, a total of 26 of 28 adult patients (92.9%) were described as having complete electrographic seizure responsiveness to inhalational anesthetics, namely isoflurane. Isoflurane was effective in all but two patients (7.7%) when used as the only inhaled anesthetic.Reference Mirsattari, Sharpe and Young 24 , Reference Sakaki, Abe and Hoshida 27 The timing of electrographic response to isoflurane anesthesia was described as “immediate” in all 26 adult patients that demonstrated a response, typically within minutes when documented. An unspecified majority of patients required titration of the isoflurane MAC to achieve burst suppression.
Desflurane was inferior to isoflurane in controlling seizure activity and achieving burst suppression in the two adult patients within which it was used.Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 , Reference Sharpe, Young and Mirsattari 28 Desflurane achieved seizure reduction in the two adult studies, but burst suppression was not achieved, even with MAC reaching 4.0%. Isoflurane was used as a salvage agent to achieve seizure control in these two studies.
Regardless of the inhaled anesthetic used, seizure activity tended to return upon cessation of the volatile gas treatment.
Pediatrics
Seizure control in the pediatric studies, with nonduplicate patient data, was documented as excellent in six of the seven studies.Reference Azzopardi, Roberston and Kapetanakis 11 - Reference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 , Reference Kofke, Snider, Young and Ramer 17 , Reference Kofke, Young and Davis 19 , Reference Lippert 21 , Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 A total of 17 of 18 pediatric patients (94.4%) had seizure control with inhalational treatment. Failure of treatment response was described in one pediatric patient (5.6%).Reference Alexopoulos, Lachwani and Gupta 10
Isoflurane failed to control the refractory seizures in 1 of 13 patients (7.7%) in which it was used. This patient had suspected Rasmussen’s encephalitis,Reference Alexopoulos, Lachwani and Gupta 10 requiring surgical intervention to halt seizure activity. The timing to response of seizures to isoflurane in children was typically immediate, but required titration to achieve burst suppression. As in the adult population, cessation of isoflurane seemed to precipitate seizures in most patients.
Xenon was used in asphyxial neonates and displayed excellent results in the five children with seizures.Reference Azzopardi, Roberston and Kapetanakis 11 Seizures seemed to return with cessation of xenon.
Adverse Effects of Inhalational Anesthetics
Adverse effects were seldom described within the 19 articles reviewed. Four studies described hypotension temporally associated to isoflurane treatment and required vasopressors.Reference Kofke, Young and Davis 19 , Reference Lippert 21 , Reference Ropper, Kofke, Bromfield and Kennedy 26 , Reference Sharpe, Young and Mirsattari 28 Finally, one studyReference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 described nonspecific MRI changes in the cerebellum and thalamus potentially attributable to long-term isoflurane administration of more than 30 days. However, these changes occurred in the setting of severe RSE and may not reflect anesthetic gas treatment.
Outcome
Patient outcome was reported sparingly in most studies, with some documentation in 17 of the 19 articles. Two manuscripts failed to document outcome.Reference Azzopardi, Roberston and Kapetanakis 11 , Reference Demulder, Ferster and Pelc 12
The overall outcome of the patients was variable, with only four studies indicating patients (n=4) returning home.Reference Hughes, Sharpe and McLachlan 16 , Reference Kofke, Snider, Young and Ramer 17 , Reference Kofke, Bloom, Van Cott and Brenner 20 , Reference Lippert 21 The majority of patients suffered moderate to severe disability or died as a result of complications or uncontrollable seizures when taken off of inhalational anesthetics.
All studies describing treatment failure had poor outcomes. Within the three studies describing treatment failure,Reference Alexopoulos, Lachwani and Gupta 10 , Reference Mirsattari, Sharpe and Young 24 , Reference Sakaki, Abe and Hoshida 27 the final outcome was unknown in one patient,Reference Alexopoulos, Lachwani and Gupta 10 vegetative state in one,Reference Mirsattari, Sharpe and Young 24 and dead in one patient.Reference Sakaki, Abe and Hoshida 27
Level of Evidence for Inhalational Anesthetics
Based on three independent reviewers, there were 19 studies reviewed, with all representing Oxford level 4 evidence in support of administering modern inhalational anesthetics for refractory seizures. Similarly, within the adult and pediatric population, all studies met the criteria for GRADE D level of evidence in support of the use of modern inhaled anesthetics for RSE.
Overall, we can recommend Oxford level 4 and GRADE D evidence for the use of isoflurane to control RSE. Given the lack of sufficient data for other inhalational anesthetics in the setting of RSE, we cannot make any formal comments on their efficacy. Summary of the level of evidence can be seen in Table 3.
Table 3 Oxford and GRADE level of evidence
* Kofke et alReference Kofke, Snider and O’Connell 18 is a meeting abstract that reports the case from Kofke et alReference Kofke, Snider, Young and Ramer 17 and Ropper et al; patient data from Kofke et al and Ropper et alReference Robakis and Hirsch 25 were not included in the tabulation of results in order to avoid duplication of patient data.
† Kofke et alReference Kofke, Young and Davis 19 contains the patient data from Kofke et alReference Kofke, Snider, Young and Ramer 17 as well.
Discussion
The use of modern inhalational anesthetic agents to control seizures has recently emerged as a salvage therapy in refractory cases. The numerous properties of inhalational anesthetics provide them with a unique means of modulating cerebral epileptogenicity. First, anesthetic gas is easily transported into the lipophilic environment of the central nervous system. Second, inhalational anesthetics are easily titrated to electroencephalographic response.Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 Finally, anesthetic gas provides cerebral protection via inhibition of glutamate-mediated N-methyl-D-aspartate receptor excitotoxicity, while also activating GABAA receptors.Reference Engelhard and Werner 38
Not all modern inhalational gases are equivalent, however. Sevoflurane has demonstrated in both animal and human studiesReference Gibert, Sabourdin and Louvet 39 - Reference Voss, Sleigh, Barnard and Kirsch 41 to be pro-epileptogenic and therefore has not emerged as a potential therapy for RSE. Thus the antiepileptic properties of isoflurane and desflurane seem to be superior, potentially via more potent N-methyl-D-aspartate inhibition.Reference Solt, Eger and Raines 42 Similarly, the safety of prolonged administration provides both isoflurane and desflurane a potential advantage over sevoflurane and its predecessors halothane and enflurane. Xenon inhalational anesthetic gas has been sparingly reported in the literature and thus conclusive comments on its efficacy in RSE are limited.
The limitations of inhalational anesthetic treatments for RSE are few, but important. First, prolonged administration of fluorinated anesthetic gas has been demonstrated to lead to a rise in inorganic serum fluoride levels, of which the effects are undetermined. Recent animal literature indicates a dose-dependent increase in hepatic, renal, and pulmonary injury secondary to these fluorinated by products with isoflurane administration. Second, with sevoflurane administration, fluorinated byproducts have the potential to bind with carbon dioxide molecules, leading to toxic compounds that impair renal function.Reference Arici, Karaman and Dogru 43 Similar renal dysfunction has been reported with isoflurane administration.Reference Durak, Oztürk and Dikmen 44 Third, the systemic cardiovascular effects of inhalation anesthetics need to be considered. Hypotension is a common side effect, typically requiring vasopressor to augment mean arterial pressures to within an acceptable range. Despite the cardiovascular depressant effect of inhalational gases, the effect seems to be less than compared with other standard intravenous anesthetic agents used in RSE.Reference Gibert, Sabourdin and Louvet 39 , Reference Filipovic, Wang, Michaux, Hunziker, Skarvan and Seeberger 45 , Reference Marval, Perrin, Hancock and Mahajan 46 Isoflurane is not immune to this effect, with recent animal literature implicating a calcium mediated myocardial depression in high doses.Reference Ding, Li, Shen, Martin, King and Sivakumaran 47 Finally, isoflurane has recently been implicated in neurotoxicity and apoptotic-induced neuronal death in elevated concentrations.Reference Kopp and Jobson 48 , Reference Creeley, Dikranian, Dissen, Back, Olney and Brambrink 49 This is of concern, given the goal of its use in RSE is in prevention of neurological morbidity with prolonged/uncontrolled seizures. Thus, one will have to weigh the risks and benefits of its use in RSE before implementation.
Given the paucity of literature to date using inhaled anesthetic gases in the setting of RSE, we decided to perform this systematic review to provide a summary of the effect of modern inhalational gases (sevoflurane, isoflurane, desflurane, and xenon) on control of refractory seizures. Through our review, we identified 19 articlesReference Alexopoulos, Lachwani and Gupta 10 - Reference Sharpe, Young and Mirsattari 28 —16 manuscripts and 3 meeting proceedings—using modern inhalational anesthetics to control refractory seizures. A total of 46 patients were described in these articles, with 28 being adult and 18 pediatric. The majority of the studies was retrospective case reports/series,Reference Alexopoulos, Lachwani and Gupta 10 , Reference Demulder, Ferster and Pelc 12 - Reference Sharpe, Young and Mirsattari 28 with only 1 being prospective cohort study.Reference Azzopardi, Roberston and Kapetanakis 11 Isoflurane was used in all but one study,Reference Azzopardi, Roberston and Kapetanakis 11 where xenon was used. Desflurane was used with isoflurane in two studies.Reference Savard, Dupre, Turgeon, Desbiens, Langevin and Brunet 23 , Reference Sharpe, Young and Mirsattari 28 Seizure control with inhalation gas occurred in 92.9% and 94.4% of adult and pediatric patients, respectively, with the majority responding almost immediately upon gas administration. Burst suppression was achievable with titration. Desflurane was ineffective at achieving burst suppression, even at high MAC. Isoflurane was used as a salvage treatment in these cases. Isoflurane failed to control seizures in only 2 of 26 adult patients (7.1%) and 1 of 13 pediatric patients (7.7%) in which it was used. Xenon controlled seizures in all neonates with asphyxia seizures. Epileptic activity returned in most patients after cessation of inhalational anesthetics. In the secondary outcomes, only minimal adverse events were associated with inhalational anesthetic gas administration, with hypotension commonly described. Unfortunately, patient outcome data were too sparingly documented for any strong conclusion, though there was a trend to worse outcome in those whom failed therapy. All studies were an Oxford level 4 for quality, with all of adult and pediatric studies being a GRADE D level of evidence. A meta-analysis was not possible given the heterogeneous, retrospective nature of the majority of studies available. Thus, based on this review, we can currently provide Oxford level 4, GRADE D recommendations for the use of isoflurane for RSE. Given the paucity of data, similar conclusions for desflurane and xenon cannot be made at this time.
Important trends can be seen within our review. First, isoflurane appears effective (>90% responsiveness) in controlling RSE in a variety of underlying neuropathology; however, similar comments on desflurane and xenon cannot be made. Desflurane does appear less effective, however, requiring isoflurane salvage in the studies identified. Second, the antiepileptic effects of isoflurane are present even in those cases with RSE of up to and exceeding 2 months’ duration. Third, prolonged administration of isoflurane, up to 85 days, does not seem to have any significant side effects. Hypotension was commonly described as the side effect in the studies identified, although this is also a common effect of intravenous anesthetics used in RSE. One study identified nonspecific MRI changes in the thalamus and cerebellum that potentially could be attributable to inhalational therapy.Reference Fugate, Burns, Wijdicks, Warner, Jankowski and Rabinstein 13 No reports of renal dysfunction were described. Caution must be taken, however, because the lack of adverse events with isoflurane administration is likely related to significant publication bias, reporting only those cases with positive outcomes on seizure control in RSE. Finally, both early (within 1 hour) and late implementation (at 85 days) of isoflurane seem effective in achieving burst suppression, thus supporting its potential efficacy at any point during the management of RSE.
Our review has significant limitations. First, the small number of studies identified, all with small patient populations, makes it difficult to generalize to all RSE patients. Second, the retrospective heterogeneous nature of the data makes it difficult to perform a meaningful meta-analysis, resulting in a strictly descriptive analysis. Third, the heterogeneity of prior treatments, time to inhalational anesthetic administration, and variable MAC and duration of therapy leave the data on seizure responsiveness difficult to interpret. It is even more difficult, on the basis of this data, to extrapolate to one’s own clinical practice. Fourth, our comments on the efficacy of inhalation anesthetics are limited to isoflurane, given the small amount of data for desflurane and xenon in RSE at this time. Fifth, the potential for publication bias in the articles reviewed is high; it is likely that only those cases displaying positive results to inhalational anesthetic treatment have appeared in the literature. Sixth, even though burst suppression appears attainable in these cases of RSE, this treatment provides only a means to achieve seizure control, with a transition to oral medication still required. Seventh, the timing to administration of inhalational anesthetics was variable, and comments on the appropriate time to implementation cannot be made based on this review. Finally, the logistics of administering inhalational anesthesia within an intensive care unit has not been fully addressed. The majority of studies failed to indicate if an anesthetist was involved in treatment administration and if any issues were encountered in obtaining and operating the anesthetic machine. We believe that these important details may be major limiting factors in the widespread use of this technique by intensivists without an anesthesiology background. Given these limitations, there may be Oxford 4, GRADE D evidence to suggest the usefulness of inhalational anesthetics in RSE, but the data are heterogeneous at this point and further study is needed.
We believe this systematic review provides a good reference for the use of modern inhalational anesthetics in RSE. Consideration should be made for a future prospective study of inhalational anesthetics in RSE, given the heterogeneous data and significant publication bias identified within this review. The small number of cases identified in this review highlights the need for multicenter databases for RSE to better outline the role of nonconventional therapies.
Conclusions
There currently is Oxford level 4, GRADE D evidence to potentially support the use of isoflurane to achieve burst suppression for RSE in the adult and pediatric populations. Further prospective study of inhalational anesthetics in RSE is warranted.
Disclosures
FZ is a Health Sciences Center Foundation research recipient and received a research grant for the project on optic nerve sheath diameter.
