Treatment of Refractory Status Epilepticus with Inhalational Anesthetic Agents Isoflurane and Desflurane

Home , Inhalational anesthetic

ORIGINAL CONTRIBUTION Treatment of Refractory Status Epilepticus With Inhalational Anesthetic Agents Isoflurane and Desflurane

Seyed M. Mirsattari, MD; Michael D. Sharpe, MD; G. Bryan Young, MD, FRCPC

Background: Refractory status epilepticus (RSE) is de- dition received desflurane anesthesia 21 days after the fined as continued seizures after 2 or 3 antiepileptic drugs onset of RSE for a total of 19 days. Regardless of seizure have failed. Several intravenous agents have been used type, isoflurane and desflurane consistently stopped epi- for RSE; however, problems occur with their toxicity leptic discharges with adequate, sustained electroen- and/or effectiveness. cephalographic burst suppression within minutes of initiating IA therapy. Four patients had good outcomes, 3 Objective: To report our experience with inhalational died (1 of acute hemorrhagic leukoencephalitis, 1 of bowel anesthesia (IA) in patients who were refractory to other infarction, and 1 of toxic encephalopathy, who re- antiepileptic drugs. mained in a persistent vegetative state until death 5.5 months after the onset of seizures). Complications dur- Design, Setting, and Participants: Retrospective re- ing IA therapy included hypotension (7/7), atelectasis view during a 4-year period of patients with RSE treated (7/7), infections (5/7), paralytic ileus (3/7), and deep ve- with isoflurane and/or desflurane. nous thrombosis (2/7). No patient developed renal or hepatic dysfunction. Main Outcome Measure: Efficacy of IA on therapy in terminating RSE. Conclusions: Isoflurane and desflurane adequately sup- pressed RSE in all cases. Complications were common, Results: Seven patients (4 male) aged 17 to 71 years re- but mortality and long-term morbidity were related to ceived 7 to 15 (mean, 10) antiepileptic drugs in addi- the underlying disease and duration of RSE. Prolonged tion to IAs. The IAs were initiated after 1 to 103 (mean, use of isoflurane and desflurane is well tolerated. 19) days of RSE and were used for a mean±SD 11±8.9 days. All patients received isoflurane, and 1 patient in ad- Arch Neurol. 2004;61:1254-1259

EFRACTORY STATUS EPILEP- adult patients with RSE who were treated ticus (RSE) is usually de- with pentobarbital between 1970 and 2001, fined as seizure activity that 8% experienced acute failure; 12%, break- continues after first- and through seizures; 43%, withdrawal sei- second-line therapy has zures within 48 hours; and 8%, refractory failed.R1 Definitions differ primarily in the hypotension during the therapy.11 Its use number of antiepileptic drugs (AEDs) that is also often accompanied by prolonged se- have been used (eg, 22-6 or 37-10) or the du- dation and life-threatening infections.16 ration of seizures (eg, ranging from Ͻ1,2,6,8,10 Midazolam and propofol have been used at least 1,4 or 23,5 hours). Despite the var- more recently in an attempt to overcome ied definitions, RSE represents a medical these limitations.5 Neither agent is uni- emergency with a mortality rate of approxi- formly successful in stopping RSE, and each mately 50% and a significant morbidity; has its own complications.5,6 Inhalational only about one third of patients return to anesthesia (IA) represents an alternative ap- their premorbid state.6 Refractory status epi- proach to the treatment of RSE. Its attrac- Author Affliations: lepticus can occur in 9% to 40% of the pa- tive features include efficacy, rapid onset Departments of Clinical tients with status epilepticus.11,12 Barbitu- of action, and the ability to titrate the dose Neurological Sciences rate anesthesia with pentobarbital or according to the effects demonstrated on (Drs Mirsattari and Young) and 17,18 Anesthesia and Perioperative thiopental sodium is commonly recom- the electroencephalogram (EEG). Of the Medicine (Dr Sharpe), mended as the ultimate treatment of choice various IA agents, isoflurane and desflu- University of Western Ontario, for RSE,8,13-15 although its effectiveness has rane are the 2 agents that have been ad- London. not been studied systematically. Among 109 ministered for RSE because of their safety

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Patient/Age, y/Sex History of Seizures Etiology of RSE Seizure Type During RSE 1/19/F Cryptogenic RSE with multiple seizure Cryptogenic, preceded by increased NCSE (generalized, maximum left types (GTC, CPS, atypical absences, frequency of seizures (especially drop hemisphere) drop attacks); onset at age 1 y attacks), precipitated by corpus callosotomy and right frontal resection 2/51/M Cryptogenic epilepsy with GTC for 3 y Poor compliance with AEDs (serum PHT GCS and NCSE level Ͻ0.5 µg/mL) 3/51/M Symptomatic epilepsy with partial motor Oligodendroglioma (left frontal) Partial motor (rolandic) and secondary (rolandic) seizures due to a low-grade generalized convulsive status epilepticus oligodendroglioma of left frontal lobe for and NCSE 3y 4/71/M None Silver toxicity Multifocal and general myoclonus; stimulus-sensitive myoclonus; partial motor with secondary GCS and NCSE 5/17/F None Encephalitis of unknown cause GCS and NCSE (multifocal, generalized) 6/56/F Cryptogenic epilepsy with GTC and Acute hemorrhagic leukoencephalitis GCS and NCSE (generalized, multifocal) absences from age 4-38 y; then seizure free while taking PB and CBZ 7/32/M Seizures with meningitis as an infant Cryptogenic NCSE (partial)

Abbreviations: AED, antiepileptic drug; CBZ, carbamazepine; CPS, complex partial seizure; GCS, generalized convulsive status; GTC, generalized tonic-clonic seizure; NCSE, nonconvulsive status epilepticus; PB, phenobarbital; PHT, phenytoin. SI conversion factor: To convert phenytoin to micromoles per liter, multiply by 3.96.

profile associated with long-term adminstration.19-23 This G-A:OV; Datex-Ohmeda, Helsinki, Finland) was placed into article is a review of our overall experience with IA as a the ventilator circuit near the end of the endotracheal tube. This management strategy for RSE. monitor determined the end-tidal concentration of the IA to indicate the dose the patient was receiving. During the initial administration, the concentration of the anesthetic agent was METHODS gradually increased until an adequate suppression of the seizure and background activity was achieved on the continuous We conducted a retrospective medical record review of all pa- EEG recording, and this dose was maintained. Therapy with tients with RSE treated with isoflurane or desflurane IA at Lon- the IA was reassessed every 12 to 24 hours by gradually reduc- don Health Sciences Centre, London, Ontario, from 1996 to 2001. ing the concentration of the anesthetic agent while observing We included all cases of convulsive and nonconvulsive, partial, the continuous EEG monitor. This allowed adjustment of the or generalized RSE with the exception of epilepsia partialis con- patient’s parenteral anticonvulsant therapy as guided by drug tinua or RSE secondary to metabolically reversible causes such levels or titration paradigms. For example, standard AEDs ini- as hypoglycemia. We defined RSE as clinical and/or electro- tiated before the anesthetic agent were maintained in thera- graphic seizures refractory to loading or protracted mainte- peutic doses, and additional agents were administered as indi- nance doses of at least 3 AEDs. All patients had either continu- cated clinically. The minimum dose of anesthetic agent to achieve ous EEG monitoring before and during IA or a minimum of 2 suppression of EEG seizures was determined daily, and the an- EEGs per day for a minimum of 2 h/d. The following EEG fea- esthetic agent was gradually discontinued once it was deter- tures were documented: background activity, interictal epilep- mined that the patient’s current parenteral anticonvulsant regi- tic activities, clinical and electrographic seizures, and periods of men was achieving adequate suppression of seizures. The total burst suppression. Burst suppression was considered adequate IA administered to each patient was calculated by dividing the if the suppression lasted longer than 10 seconds with epileptic percentage concentration of IA per hour ϫ the total number bursts lasting less than 1 second. A sustained burst suppression of hours by the IA’s minimal alveolar concentration (MAC) referred to recordings that contained greater than 90% of a sus- (1.15% for isoflurane and 6.0% for desflurane24). tained burst-suppression pattern. The EEG recording was clas- To demonstrate the safety profile of the IA, we reviewed all sified as a partial burst-suppression pattern if suppression lasted medical complications encountered during the course of therapy. less than 10 seconds in more than 90% of the record. Inad- Patients who survived RSE were followed up for a minimum equate burst suppression referred to records with frequent sei- of 6 months using the Glasgow Outcome Scale.25 zures and epileptic bursts lasting longer than 10 seconds. All patients underwent detailed investigations including cranial magnetic resonance imaging and computed tomography, cere- RESULTS brospinal fluid sampling, and connective tissue disease, micro- bial, and toxicology screens. Patients 4 and 5 were investigated Seven patients (4 male, 3 female) met our inclusion cri- for Hashimoto thyroiditis with antithyroglobulin antibodies and teria. Mean±SD age at the time of RSE was 42±20 years antimicrosomal antibodies. Patient 4 had a detailed survey per- (range, 17-71 years). Four patients had epilepsy prior to formed for a potential source of malignancy, which included se- RSE, and presumed causes of RSE are listed in Table 1. rum anti-Hu antibody. Patient 5 underwent cerebral angio- grams brain, muscle, and nerve biopsies. Patients 4, 6, and 7 had Analysis of EEG features revealed adequate and sus- extensive postmortem examinations. tained burst-suppression pattern with isoflurane, which Once it was determined by the attending care team that the was dose dependent, easy to achieve, and rapidly revers- patient warranted a trial of IA therapy for RSE, an end-tidal an- ible. This robust effect of both IAs was not seen consis- esthetic monitor connector (Datex Gas analyzer bench, model tently with the other agents (Table 2).

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 2. Predominant Electroencephalographic Features of Patients With Refractory Status Epilepticus (RSE) During Treatment

Patient At the Onset of RSE Midazolam Propofol Thiopental Sodium IA (Isoflurane/Desflurane) After RSE 1 Generalized NCSE Partial, nonsustained Partial, nonsustained Adequate, sustained BS Sustained, adequate BS Electrographic (maximum left BS with up to 35 BS with up to 580 for 60 h with boluses up with 0.7%-2.0%; after IA seizures; MISF hemisphere); spikes; mg/h and boluses mg/h; onset, 2.5 to 1125 mg and 7 mg/kg therapy ended, NCSE polyspikes; min; duration, per h; after thiopental polyspike waves 8.5 min treatment stopped, BS lasted 60 h 2 Focal seizure with 2° Partial, nonsustained Partial, nonsustained Adequate, sustained BS Adequate, sustained BS Mild asymmetry of generalization; BS with 5 mg/h and BS with boluses and with up to 625 mg/h with 0.6%-0.9%; after IA background generalized spikes; boluses; NCSE up to 200 mg/h; therapy ended, no NCSE NCSE seizures or spikes up to 8 d before hospital release 3 Focal seizures with 2° No effect with 1-30 Adequate but Not used because of Adequate, sustained BS Focal ␦ (Յ 4 Hz) generalization of left mg/h; NCSE nonsustained BS history of multiple drug with 1.7%-2.5%; Ͻ1%; activity and rolandic origin with 50-550 mg/h; hypersensitivity seizures and NCSE; after generalized slowing seizures and NCSE syndrome IA ended, normal on EEG background in Ͻ24 h, no seizures 4 Generalized No effect with boluses Nonsustained, partial Nonsustained, partial BS; Adequate, sustained BS Myoclonic seizures, polyspikes; of up to 5 mg BS with Յ300 mg/h; myoclonic seizures and with both isoflurane and alpha coma, maximum anterior myoclonic seizures NCSE desflurane; desflurane, nonreactive, head; myoclonic and NCSE 1%-4%; rare permanent seizures; NCSE stimulus-sensitive vegetative state, BS myoclonus; after IA therapy ended, BS; isoflurane, 0.1%-0.66%; same 5 Generalized NCSE; No effect; NCSE No effect; NCSE Sustained, adequate BS Adequate, sustained BS Mild diffuse slowing multifocal spikes after 24 h with up to 720 with 1.7%-2.1%; partial mg/h and boluses up to BS with 1%-1.6%; 600 mg; Ͻ100 mg/h; inadequate BS with Ͻ1% inadequate BS; NCSE with seizures; after IA and seizures; total 21 d; therapy ended, seizures after thiopental therapy 24 h later but seizure and stopped, NCSE 24 h later spike free 12 d later and alpha coma for 4 d 6 Generalized NCSE; Nonsustained, partial Not used Not used Adequate, sustained BS NCSE generalized spikes BS with boluses up with 1.4%-2%; after IA to 7.5 mg and 60 therapy ended, NCSE mg/h; onset in 60 s; seizures 7 MISF; EDE; PLEDS; Partial, nonsustained Adequate, Not used Adequate, sustained BS NCSE NCSE; multifocal and BS with boluses up nonsustained BS with 2%; no PLEDs or generalized seizures to5mgandՅ15 with up to 400 mg/h seizures; partial, mg/h; onset in 30 s; for 3 d; seizures; nonsustained BS with duration, 220 s; total, 4 d 1.4%-1.7%; inadequate seizures and PLEDs; BS with Ͻ1.4%; total, 8 d seizures; after IA therapy ended, NCSE

Abbreviations: BS, burst suppression; EDE, electrodecremental event; EEG, electroencephalogram; IA, inhalational anesthesia; MISF, multiple independent spike foci; NCSE, nonconvulsive status epilepticus; PLED, periodic lateralized epileptiform discharge.

Mean±SD hospital stay, intensive care unit stay, and tidal isoflurane concentration ranged from 1.2% to 5.0% days receiving ventilatory care were 42±29 days (range, with a mean±SD isoflurane dose of 173±159 MAC- 9-84 days), 31±23 days (range, 9-67 days), and 28±20 hours (range, 12-277 MAC-hours). Regardless of the pre- days (range, 9-56 days), respectively (Table 3). Prior existing pattern of the EEG, all patients achieved an ad- to IA use, RSE continued for a mean of 19 days (range, equate burst-suppression EEG pattern within minutes of 1-102 days). Patients received a mean of 10 AEDs (range, initiating IA (Table 3) (Figure 1). Although patients 1, 7-15) in addition to the IA. One patient received desflu- 2, and 5 had adequate and sustained burst suppression rane anesthesia 21 days after RSE for a total of 19 days. with thiopental, this was replaced with IA because of the Isoflurane treatment was then instituted for 7 days with concerns for toxic effects on organs and prolongation of equal efficacy. The other patients had isoflurane as the action with the large doses of thiopental required to main- only anesthetic. The IA was initiated after a median of 3 tain burst suppression. days of RSE (range, 1-103 days), and it was used for a All patients required volume resuscitation and vaso- mean±SD of 11±9 days (range, 2-26 days). Maximal end- pressors/inotropes before, during, and after IA; how-

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Hospital Ventilatory MAC-Hours of RSE Prior to Patient Stay, d ICU Stay, d Support, d Isoflurane (d) Isoflurane, d Other AEDs Tried During RSE 1 53 30 27 33.8 (2) 3 LZP, diazepam, MDL, PHT, PB, TS, PRO, VPA, LMT 2 15 12 11 43.9 (3) 4 LZP, diazepam, MDL, PHT, PB, TS, PRO 3 49 27 18 151.4 (6) 1 LZP, diazepam, clonazepam, MDL, PRO, CBZ, VPA, GBP, TPM 4 84 58 56 276.9 (26)* Isoflurane, 19 d; LZP, diazepam, clonazepam, MDL, PHT, PB, PTB, TS, PRO, CBZ, VPA desflurane, 7 d 5 67 67 57 11.6 (19) 103 LZP, diazepam, MDL, PHT, PB, primidone, PTB, TS, PRO, CBZ, VPA, clobazem, LMT, VGB, TPM, paraldehyde 6 9 9 9 248.2 (8) 2 LZP, MDL, PHT, PB, CBZ, VPA, LMT, fentanyl citrate 7 18 17 17 444.3 (13) 2 LZP, diazepam, MDL, PHT PB, PRO, CBZ

Abbreviations: AED, antiepileptic drug; CBZ, carbamazepine; GBP, gabapentin; ICU, intensive care unit; LMT, lamotrigine; LZP, lorazepam; MAC, minimal alveolar concentration; MDL, midazolam; PB, phenobarbital; PTB, pentobarbital; PHT, phenytoin; PRO, propofol; TPM, topiramate; TS, thiopental sodium; VGB, vigabatrin; VPA, valproic acid. *237.9 MAC-hours (19 days) of desflurane and 39 MAC-hours (7 days) of isoflurane.

ever, the doses required were higher during isoflurane or desflurane administration. Atelectasis was also pres- A FP1-F3 ent in all patients before, during, and after IA. All pa- F3-C3 C3-P3 tients developed an infection while in the intensive care P3-O1 FP2-F4 unit; however, infections occurred in 5 of 7 patients dur- F4-C4 ing IA therapy. These infections were successfully man- C4-P4 P4-O2 aged: respiratory tract in 5, urinary tract in 2, and fun- FP1-F7 gal catheter sepsis in 1 patient. Paralytic ileus occurred F7-T3 T3-T5 in 3 patients, necessitating total parenteral nutrition in T5-O1 FP2-F8 2 patients. Deep venous thrombosis and decubitus ul- F8-T4 T4-T6 cers occurred in 2 and 3 patients, respectively; however, 300 µV T6-O2 these conditions were present prior to the initiation of 1 s IA therapy. Indices of renal and hepatic function did not alter significantly during and following IA therapy B FP1-F3 (Figure 2). Cardiac arrhythmias and mild renal dys- F3-C3 function were seen in 2 and 1 patients, respectively, be- C3-P3 P3-O1 fore and during IA. FP2-F4 F4-C4 Two patients had excellent outcomes (Glasgow Out- C4-P4 come Scale score, 5 in patients 3 and 5), 2 had good out- P4-O2 FP1-F7 comes (Glasgow Outcome Scale score, 4 in patients 1 and F7-T3 T3-T5 2), and 3 patients (43%) died (Glasgow Outcome Scale T5-O1 score, 1). One of the 3 patients who died remained in a FP2-F8 F8-T4 persistent vegetative state for 2 months prior to death (pa- T4-T6 20 mm T6-O2 1 s tient 4). He had a known stage B adenocarcinoma of the ECG prostate for which he received an antiandrogen (bicalu- tamide), radiotherapy, and an excessive amount of a homemade colloidal silver beverage daily for 4 months C prior to RSE. This case has been previously reported, and FP1-F3 the cause of the patient’s seizures was likely silver tox- F3-C3 23 icity. Patient 6 died of autopsy-proven acute hemor- C3-P3 rhagic leukoencephalitis, and patient 7 died of bowel in- P3-O1 farction. FP2-F4 F4-C4 COMMENT C4-P4 P4-O2 140 µV 1 s The IAs, isoflurane and desflurane, effectively stopped ECG seizures in all 7 cases of RSE. Adequately sustained burst- suppression EEG patterns were obtained in all patients Figure 1. A, Longitudinal bipolar recording of left hemispheric seizure onset with secondary generalization (not shown). Sensitivity, 15 µV/mm; low- within minutes of initiation of IA therapy in a dose- frequency filter (LFF), 0.3 Hz; and high-frequency filter (HFF), 70 Hz; notch dependent manner during administration of IA. filter off. B, Longitudinal bipolar recording of termination not controlled with Most currently available anticonvulsant drugs in the boluses of lorazepam and continuous infusion of large doses of propofol treatment of RSE have GABAergic (␥-aminobutyric acid) (patient 3). Sensitivity, 15 µV/mm; LFF, 0.3 Hz; and HFF, 70 Hz; notch filter off. C, Longitudinal bipolar recording of the same patient with sustained, properties except for phenytoin, which affects the rapid adequate burst suppression while receiving isoflurane. Sensitivity, 7 µV/mm; neuronal firings.26 Experimental studies suggest that LFF, 0.3 Hz; and HFF, 70 Hz; notch filter off.

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 100 Before Inhalational Anesthetic During Inhalational Anesthetic 80 After Inhalational Anesthetic

0 International Normalized Ratio Asparate Aminotransferase Alanine Aminotransferase Serum Urea Nitrogen Creatinine (Normal Range, 0.8-1.1) (Normal Range, 10-40 U/L) (Normal Range, 10-40 U/L) (Normal Range, 24.1-22.4 mg/dL) (Normal Range, 0.9-1.4 mg/dL)

Figure 2. Hepatic and renal functions before, during, and after treatment with inhalational anesthetics. Values are expressed as mean±SD. To convert urea nitrogen to millimoles per liter, multiply by 0.357; creatinine to micromoles per liter, 88.4.

GABAergic agents lose their efficacy in prolonged sei- RSE.32 Halothane was the first IA to be used for RSE33; how- zures, which may account for the refractoriness to treat- ever, the potential toxic effect on organs associated with ment that occurs in some patients with status epilepti- its toxic metabolites is a concern, particularly during pro- cus. This has been attributed to excess glutamate release, longed administration. Isoflurane and desflurane, on the which is associated with ongoing seizure activity lasting other hand, undergo significantly less metabolism (0.20% longer than 1 hour, resulting in an altered balance of ex- and 0.02%, respectively24), and their potential to produce citation vs inhibition.27 In addition, the benzodiazepine re- organ toxicity is substantially reduced. Other IAs cur- ceptor loses its affinity for its ligands, reducing their po- rently available, such as sevoflurane and enflurane, also tency.28,29 Although the mechanism of action of IA is not undergo a significant amount of metabolism, producing well understood, the antiepileptic effects of isoflurane are potentially toxic metabolites, especially during pro- likely due to potentiation of inhibitory postsynaptic GABAA longed administration. Also, sevoflurane under certain con- receptor–mediated currents; however, its effects on thala- ditions may be epileptogenic.34 Isoflurane and desflurane mocortical pathways have also been implicated.27,30,31 In are therefore among few agents of choice, particularly for our study, although patients received IA therapy late in anticipated prolonged periods of application. the course of their illness, they still maintained their re- Isoflurane has been the IA most used by several sponsiveness to these agents. Recurrence of seizures was groups.17-22 Kofke et al19 reported 9 patients with RSE who also high with discontinuation of the IA therapy. Perhaps were treated with isoflurane for a maximum of 55 hours. the early use of IA within the first 2 to 4 hours of RSE would To our knowledge, our series is the first study that dem- result in a more favorable alteration in the balance of ex- onstrates the safety of isoflurane and desflurane in the treat- citation vs inhibition so that conventional agents used in ment of RSE for up to 26 days. Although significant in- the treatment of RSE would become more efficacious. As creases in plasma organic fluoride have been reported in such, early and aggressive treatment of RSE with IA agents patients receiving isoflurane for prolonged periods, no re- may alter disease outcome. A randomized controlled trial nal toxicity was associated with this observation.32,35 Dur- is therefore needed to determine the efficacy of IA in the ing isoflurane and desflurane administration, there was a “early” management of RSE. dose-dependent reduction in systemic vascular resis- Both isoflurane and desflurane produce dose- tance due to peripheral vasodilation. As a result, all 7 pa- dependent changes in the EEG. Initially, an increase in tients required fluid resuscitation and vasopressor therapy frequency and lowering of voltage occurs with sub- during their administration. Most intravenous agents used MAC concentrations, and as the concentration in- to treat RSE are expected to produce a degree of hypoten- creases, there is a gradual decrease in voltage with in- sion; therefore, hemodynamic consequences must be con- creasing periods of electrical silence (burst suppression).24 sidered in choosing any AED. There is no evidence of toxic Upon initiation of the IA in our group of patients, the effects on the central nervous system with isoflurane, and concentration was gradually increased to obtain ad- experimental studies have generally shown a favorable effect equate burst suppression. This dose was gradually de- of isoflurane on cerebral metabolism.36-38 creased on a daily basis and eventually weaned off, if a Burst suppression and isoelectric background EEG have parenteral therapeutic regimen became effective in ad- been shown to be accompanied by fewer recurrent sei- equately controlling the patient’s seizures. zures than simply stopping seizures.11 This was consis- The pharmacokinetic and pharmacodynamic proper- tent with our findings. We considered the maintenance ties of isoflurane and desflurane make them effective agents of burst suppression for burst duration of less than 1 sec- in producing burst-suppression EEG patterns that are eas- ond and suppression duration of longer than 10 seconds ily titratable.24 Other advantages, including rapid onset of as the goal of therapy. There is, however, no general agree- action and elimination and the reduced potential for toxic ment on what constitutes adequate burst suppression. Van effects on organs owing to their relative resistance to bio- Ness39 empirically used 3 to 9 bursts per minute during transformation, make them an ideal choice of therapy for pentobarbital treatment with close attention to the hemo-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 dynamic parameters. Kofke et al,19 on the other hand, used 9. Cascino GD. Generalized convulsive status epilepticus. Mayo Clin Proc. 1996;71: 15 to 30 seconds as an empirical burst-suppression inter- 787-792. 10. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998;338:970- val. This was based on an animal study that demon- 976. strated maximal depression of cerebral metabolism with 11. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status barbiturates with burst-suppression intervals of 30 sec- epilepticus with pentobarbital, propofol, midazolam: a systemic review. Epilepsia. onds.40 Bleck41 advocates a more aggressive approach us- 2002;43:146-153. ing isoelectric EEGs as the end point of therapy. How- 12. Mayer SA, Claassen J, Lokin J, Mendesohn F, Dennis LJ, Fitzsimmons B. Re- fractory status epilepticus: frequency, risk factors, and impact on outcome. Arch ever, there is no evidence that what constitutes an optimal Neurol. 2002;59:205-210. burst-suppression interval can optimize patient out- 13. Rashkin MC, Youngs C, Penovich P. Pentobarbital treatment of refractory sta- come. Our patients had a dichotomous outcome: good to tus epilepticus. Neurology. 1987;37:500-503. excellent or death due to underlying illness; the mortal- 14. Lowenstein DH, Aminoff MJ, Simon RP. Barbiturate anesthesia in the treatment of refractory status epilepticus. Neurology. 1988;38:395-400. ity rate was 43%. This is in agreement with previous stud- 15. Young GB, Blume WT, Bolton CF, Warren KG. Anesthetic barbiturates in refrac- ies confirming that the underlying etiology of RSE is the tory status epilepticus. Can J Neurol Sci. 1980;7:291-292. major determinant of outcome.6,39 16. Yaffe K, Lowenstein DH. Prognostic factors of pentobarbital therapy for refrac- In conclusion, we suggest that isoflurane or desflu- tory status epilepticus. Neurology. 1993;43:895-900. rane may be used as a single agent for management of 17. Ropper AH, Kofke WA, Bromfield EB, Kennedy SK. Comparison of isoflurane, halothane, and nitrous oxide in status epilepticus. Ann Neurol. 1986;19:98-99. patients with RSE while their standard anticonvulsants 18. Sakaki T, Abe K, Hoshida T, et al. Isoflurane in the management of status epi- are being adjusted. These agents were also well toler- lepticus after surgery for lesion around the motor area. Acta Neurochir (Wien). ated during prolonged administration with no evidence 1992;116:38-43. of organ toxicity. We recommend a randomized con- 19. Kofke WA, Young RSK, Davis P, et al. Isoflurane for refractory status epilepti- trolled trial to determine whether IAs or other anticon- cus: a clinical series. Anesthesiology. 1989;71:653-659. 20. Kofke WA, Bloom MJ, Van Cott A, Brenner RP. Electrographic tachyphylaxis to vulsant regimens offer the best therapy for RSE. etomidate and ketamine used for refractory status epilepticus controlled with isoflurane. J Neurosurg Anesthesiol. 1997;9:269-272. Accepted for Publication: March 1, 2004. 21. Meeke RI, Soifer BE, Gelb AW. Isoflurane for the management of status epilepticus. Correspondence: G. Bryan Young, MD, FRCPC, Depart- DICP. 1989;23:579-581. ment of Clinical Neurological Sciences, London Health 22. Hughes DR, Sharpe MD, McLachlan RS. Control of epilepsia partialis continua and secondary generalized status epilepticus with isoflurane. J Neurol Neuro- Sciences Centre, 339 Windermere Rd, Room 10-OF9, surg Psychiatry. 1992;55:739-740. London, Ontario, Canada N6A 5A5 (Bryan.Young@lhsc 23. Sharpe MD, Young GB, Mirsattari S, Harris C. Prolonged desflurane administra- .on.ca). tion for refractory status epilepticus. Anesthesiology. 2002;97:261-264. Author Contributions: Study concept and design: Mirsat- 24. Eger EI II. New inhaled anesthetics. Anesthesiology. 1994;80:906-922. 25. Jennett B, Bond M. Assessment of outcome after severe brain damage: a prac- tari. Acquisition of data: Mirsattari and Sharpe. Analysis tical scale. Lancet. 1975;1:480-484. and interpretation of data: Mirsattari, Sharpe, and Young. 26. Yaari Y, Selzer ME, Pincus JH. Phenytoin: mechanisms of its anticonvulsant action. Drafting of the manuscript: Mirsattari and Sharpe. Criti- Ann Neurol. 1986;20:171-184. cal revision of the manuscript for important intellectual con- 27. Ries CR, Puil E. Mechanism of action of anesthesia revealed by shunting actions tent: Mirsattari, Sharpe, and Young. Statistical expertise: of isoflurane on thalamocortical neurons. J Neurophysiol. 1999;81:1795-1801. 28. Walton NY, Triman DM. Motor and electroencephalographic response of refrac- Mirsattari. Administrative, technical, and material sup- tory experimental status epilepticus in rats to treatment with MK-801, diaz- port: Mirsattari and Sharpe. Study supervision: Sharpe and epam, or MK-801-plus diazepam. Brain Res. 1991;553:97-104. Young. 29. Borris DJ, Bertram EH, Kapur J. Ketamine controls prolonged status epilepticus. Funding/Support: This study was supported by the Ca- Epilepsy Res. 2000;42:117-122. nadian Institute for Health Research, Ottawa, Ontario (Dr 30. Langmoen IA, Hegstad E, Berg-Johnsen J. An experimental study of the effect of isoflurane on epileptiform bursts. Epilepsy Res. 1992;11:153-157. Mirsattari). 31. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anesthesia. Acknowledgment: We thank Suzan Matijevic, BSc, for Nature. 1994;367:607-614. help with the figures. 32. Koblin DD. Characteristics and implications of desflurane metabolism and toxicity. Anesth Analg. 1992;75:S10-S16. 33. Kenna JG, Jones RM. 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