EDITORIAL
Refractory status epilepticus What to put down: The anesthetics or the patient?
Nathan B. Fountain, MD Status epilepticus is a well-recognized medical emerJennifer E. Fugate, DO gency that must be treated urgently to prevent permanent neuronal injury, prolonged unconsciousness, and even mortality. There is a high level of evidence Correspondence to that first-line treatment with benzodiazepines is indiDr. Fountain: cated over other treatments based on a seminal [email protected] double-blind randomized controlled trial of then® common treatments.1 Second-line treatment is typiNeurology 2014;82:650–651 cally with IV antiepileptic drugs (AEDs), and while any drug might be used, the most common in clinical practice in the United States are phenytoin, levetiracetam, and valproate. At this stage of management there are a few comparative studies, but a doubleblind randomized controlled trial is needed.2 The definition of refractory status epilepticus (RSE) is variable, but most would agree that patients who fail first- and second-line therapy have RSE. Standard third-line therapy consists of IV anesthetics; pentobarbital was historically favored but now midazolam or propofol are more often preferred. IV anesthesia is considered so effective that some have suggested moving directly to IV anesthesia and skipping second-line therapy to avoid major time delays that could contribute to ongoing excitotoxicity and neuronal injury. In this issue of Neurology®, Sutter et al.3 bring into question the safety of IV anesthesia for RSE. They took advantage of a standardized status epilepticus treatment protocol in their hospital to compare the outcome of patients with RSE who received IV anesthesia to those who only received standard IV AEDs. Their retrospective review of 171 patients with RSE had the surprising finding that infectious complications were more common in those who were treated with IV anesthetics compared to those who were not (43% vs 11%, p , 0.001), and the relative risk for death was more than 3-fold higher, independent of measured confounders.3 The findings at first glance might suggest that we are harming our patients with RSE with IV anesthetics. The study has the potential to change clinical practice; therefore, it must be scrutinized carefully. The rationale for IV anesthetics in RSE is clear, but the findings of this study force us to reconsider
the associated risks of such aggressive treatment. IV anesthesia is obviously not benign. It necessitates intubation and mechanical ventilation, causes marked hypotension, increases infection rates, and can cause severe ileus, renal failure, or life-threatening propofol infusion syndrome, depending on the specific agent used.4 On the other hand, the consequences of suboptimal electrographic seizure control can be formidable and the association between longer duration of status epilepticus and higher mortality is well-known. The question that must be answered is whether the increased mortality from IV drugs outweighs the mortality from status epilepticus. The findings of Sutter et al. are intriguing but it is concerning that while the authors went to great lengths to counteract bias and control for potential confounders, the study is still limited by problems commonly associated with retrospective studies. The most important limitation is that study physicians could choose whether to give IV anesthesia or continue to give standard AEDs. Severity of RSE was assessed and adjusted for by the validated Status Epilepticus Severity Score,5 but it is still possible or even likely that physicians chose one form of treatment or another because of other patient characteristics that are not readily available in the medical record. Perhaps most importantly, one should take into account that patients were selected to receive IV anesthetic drugs because physicians thought they needed more aggressive treatment and therefore might have a higher mortality because of other unidentified characteristics. A second limitation of the study is that patients were not subdivided by type of status epilepticus or etiology. The mortality of generalized convulsive status epilepticus is in the range of 20% but is highly dependent on the etiology, so some subgroups, such as those with cardiac arrest, have a mortality rate as high as 60%, while in those with epilepsy and low AED drug level it is only 8%.6 Nonconvulsive status epilepticus is surrounded by controversy but it is generally agreed that the mortality of absence status is generally low, while in most forms of nonconvulsive status epilepticus requiring intensive
See page 656 From the Department of Neurology (N.B.F.), University of Virginia, Charlottesville; and Department of Neurology (J.E.F.), Mayo Clinic, Rochester, MN. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 650
© 2014 American Academy of Neurology
care unit admission it approximates 20% to 60%.7 Although Sutter et al. examined 171 patients, this number is not sufficient to parse out the effects that IV anesthesia may have had on any one type of status epilepticus or any one etiology. Could IV anesthesia for RSE be doing more harm than good? Should we change our current practice to avoid IV anesthesia? These findings raise important concerns, but it is far too early to advocate adopting such a drastic change without external validation and further prospective investigation. However, we should pay close attention to the retrospective results reported here, and detailed analysis of subtypes of status epilepticus and other etiologies should be pursued. If the results are reproduced from a more controlled setting then it could change the paradigm for treatment of RSE. Ideally the question will be answered by a well-designed blinded randomized controlled clinical trial. Until then, clinicians will continue to rely on judgment and experience to decide which patients with RSE should receive IV anesthesia. AUTHOR CONTRIBUTIONS Drs. Fountain and Fugate developed the outline of this manuscript together. Dr. Fountain wrote the first draft and Dr. Fugate further modified it and both authors reviewed and edited the final version.
STUDY FUNDING No targeted funding reported.
DISCLOSURE N. Fountain receives research grants from SK Life Sciences, UCB, Lundbeck, Neuropace, Medtronic, and NIH. J. Fugate reports no disclosures. Go to Neurology.org for full disclosures.
REFERENCES 1. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus: Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792–798. 2. Bleck T, Cock H, Chamberlain J, et al. The established status epilepticus trial 2013. Epilepsia 2013;54(suppl 6): 89–92. 3. Sutter R, Marsch S, Fuhr P, Kaplan PW, Rüegg S. Anesthetic drugs in status epilepticus: risk or rescue? A 6-year cohort study. Neurology 2014;82:656–664. 4. Wijdicks EF. The multifaceted care of status epilepticus. Epilepsia 2013;54(suppl 6):61–63. 5. Rossetti AO, Logroscino G, Milligan TA, Michaelides C, Ruffieux C, Bromfield EB. Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy. J Neurol 2008;255:1561–1566. 6. Towne AR, Pellock JM, Ko D, DeLorenzo RJ. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27–34. 7. Brophy GM, Bell R, Claassen J, et al. Neurocritical care society status epilepticus guideline writing committee: guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;1:3–23.
Neurology 82
February 25, 2014
651
Refractory status epilepticus: What to put down: The anesthetics or the patient? Nathan B. Fountain and Jennifer E. Fugate Neurology 2014;82;650-651 Published Online before print December 6, 2013 DOI 10.1212/WNL.0000000000000008 This information is current as of December 6, 2013 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/8/650.full.html
References
This article cites 7 articles, 1 of which you can access for free at: http://www.neurology.org/content/82/8/650.full.html##ref-list-1
Citations
This article has been cited by 1 HighWire-hosted articles: http://www.neurology.org/content/82/8/650.full.html##otherarticles
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Epilepsy/Seizures http://www.neurology.org//cgi/collection/all_epilepsy_seizures Antiepileptic drugs http://www.neurology.org//cgi/collection/antiepileptic_drugs Status epilepticus http://www.neurology.org//cgi/collection/status_epilepticus
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Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Refractory status epilepticus What to put down: The anesthetics or the patient?
Nathan B. Fountain, MD Status epilepticus is a well-recognized medical emerJennifer E. Fugate, DO gency that must be treated urgently to prevent permanent neuronal injury, prolonged unconsciousness, and even mortality. There is a high level of evidence Correspondence to that first-line treatment with benzodiazepines is indiDr. Fountain: cated over other treatments based on a seminal [email protected] double-blind randomized controlled trial of then® common treatments.1 Second-line treatment is typiNeurology 2014;82:650–651 cally with IV antiepileptic drugs (AEDs), and while any drug might be used, the most common in clinical practice in the United States are phenytoin, levetiracetam, and valproate. At this stage of management there are a few comparative studies, but a doubleblind randomized controlled trial is needed.2 The definition of refractory status epilepticus (RSE) is variable, but most would agree that patients who fail first- and second-line therapy have RSE. Standard third-line therapy consists of IV anesthetics; pentobarbital was historically favored but now midazolam or propofol are more often preferred. IV anesthesia is considered so effective that some have suggested moving directly to IV anesthesia and skipping second-line therapy to avoid major time delays that could contribute to ongoing excitotoxicity and neuronal injury. In this issue of Neurology®, Sutter et al.3 bring into question the safety of IV anesthesia for RSE. They took advantage of a standardized status epilepticus treatment protocol in their hospital to compare the outcome of patients with RSE who received IV anesthesia to those who only received standard IV AEDs. Their retrospective review of 171 patients with RSE had the surprising finding that infectious complications were more common in those who were treated with IV anesthetics compared to those who were not (43% vs 11%, p , 0.001), and the relative risk for death was more than 3-fold higher, independent of measured confounders.3 The findings at first glance might suggest that we are harming our patients with RSE with IV anesthetics. The study has the potential to change clinical practice; therefore, it must be scrutinized carefully. The rationale for IV anesthetics in RSE is clear, but the findings of this study force us to reconsider
the associated risks of such aggressive treatment. IV anesthesia is obviously not benign. It necessitates intubation and mechanical ventilation, causes marked hypotension, increases infection rates, and can cause severe ileus, renal failure, or life-threatening propofol infusion syndrome, depending on the specific agent used.4 On the other hand, the consequences of suboptimal electrographic seizure control can be formidable and the association between longer duration of status epilepticus and higher mortality is well-known. The question that must be answered is whether the increased mortality from IV drugs outweighs the mortality from status epilepticus. The findings of Sutter et al. are intriguing but it is concerning that while the authors went to great lengths to counteract bias and control for potential confounders, the study is still limited by problems commonly associated with retrospective studies. The most important limitation is that study physicians could choose whether to give IV anesthesia or continue to give standard AEDs. Severity of RSE was assessed and adjusted for by the validated Status Epilepticus Severity Score,5 but it is still possible or even likely that physicians chose one form of treatment or another because of other patient characteristics that are not readily available in the medical record. Perhaps most importantly, one should take into account that patients were selected to receive IV anesthetic drugs because physicians thought they needed more aggressive treatment and therefore might have a higher mortality because of other unidentified characteristics. A second limitation of the study is that patients were not subdivided by type of status epilepticus or etiology. The mortality of generalized convulsive status epilepticus is in the range of 20% but is highly dependent on the etiology, so some subgroups, such as those with cardiac arrest, have a mortality rate as high as 60%, while in those with epilepsy and low AED drug level it is only 8%.6 Nonconvulsive status epilepticus is surrounded by controversy but it is generally agreed that the mortality of absence status is generally low, while in most forms of nonconvulsive status epilepticus requiring intensive
See page 656 From the Department of Neurology (N.B.F.), University of Virginia, Charlottesville; and Department of Neurology (J.E.F.), Mayo Clinic, Rochester, MN. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 650
© 2014 American Academy of Neurology
care unit admission it approximates 20% to 60%.7 Although Sutter et al. examined 171 patients, this number is not sufficient to parse out the effects that IV anesthesia may have had on any one type of status epilepticus or any one etiology. Could IV anesthesia for RSE be doing more harm than good? Should we change our current practice to avoid IV anesthesia? These findings raise important concerns, but it is far too early to advocate adopting such a drastic change without external validation and further prospective investigation. However, we should pay close attention to the retrospective results reported here, and detailed analysis of subtypes of status epilepticus and other etiologies should be pursued. If the results are reproduced from a more controlled setting then it could change the paradigm for treatment of RSE. Ideally the question will be answered by a well-designed blinded randomized controlled clinical trial. Until then, clinicians will continue to rely on judgment and experience to decide which patients with RSE should receive IV anesthesia. AUTHOR CONTRIBUTIONS Drs. Fountain and Fugate developed the outline of this manuscript together. Dr. Fountain wrote the first draft and Dr. Fugate further modified it and both authors reviewed and edited the final version.
STUDY FUNDING No targeted funding reported.
DISCLOSURE N. Fountain receives research grants from SK Life Sciences, UCB, Lundbeck, Neuropace, Medtronic, and NIH. J. Fugate reports no disclosures. Go to Neurology.org for full disclosures.
REFERENCES 1. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus: Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792–798. 2. Bleck T, Cock H, Chamberlain J, et al. The established status epilepticus trial 2013. Epilepsia 2013;54(suppl 6): 89–92. 3. Sutter R, Marsch S, Fuhr P, Kaplan PW, Rüegg S. Anesthetic drugs in status epilepticus: risk or rescue? A 6-year cohort study. Neurology 2014;82:656–664. 4. Wijdicks EF. The multifaceted care of status epilepticus. Epilepsia 2013;54(suppl 6):61–63. 5. Rossetti AO, Logroscino G, Milligan TA, Michaelides C, Ruffieux C, Bromfield EB. Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy. J Neurol 2008;255:1561–1566. 6. Towne AR, Pellock JM, Ko D, DeLorenzo RJ. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27–34. 7. Brophy GM, Bell R, Claassen J, et al. Neurocritical care society status epilepticus guideline writing committee: guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;1:3–23.
Neurology 82
February 25, 2014
651
Refractory status epilepticus: What to put down: The anesthetics or the patient? Nathan B. Fountain and Jennifer E. Fugate Neurology 2014;82;650-651 Published Online before print December 6, 2013 DOI 10.1212/WNL.0000000000000008 This information is current as of December 6, 2013 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/8/650.full.html
References
This article cites 7 articles, 1 of which you can access for free at: http://www.neurology.org/content/82/8/650.full.html##ref-list-1
Citations
This article has been cited by 1 HighWire-hosted articles: http://www.neurology.org/content/82/8/650.full.html##otherarticles
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Epilepsy/Seizures http://www.neurology.org//cgi/collection/all_epilepsy_seizures Antiepileptic drugs http://www.neurology.org//cgi/collection/antiepileptic_drugs Status epilepticus http://www.neurology.org//cgi/collection/status_epilepticus
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
