NMDA Antagonists for Refractory Seizures

Neurocrit Care DOI 10.1007/s12028-013-9939-6 REVIEW ARTICLE NMDA Antagonists for Refractory Seizures F. A. Zeiler • J. Teitelbaum • L. M. Gillman M. West • Ó Springer Science+Business Media New York 2014 Abstract Refractory status epilepticus (RSE) poses significant challenge, with a variety of novel therapeutics employed. Our goal was to evaluate the effectiveness of N-methyl Daspartate (NMDA) receptor antagonists in the control of RSE. We performed a systematic review of all the literature, with all articles pulled from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to September 2013), reference lists of relevant articles, and gray literature. Two reviewers independently identified all manuscripts pertaining to the administration of NMDA receptor antagonists in humans for the purpose of controlling refractory seizures. Secondary outcome of adverse NMDA antagonist effects and patient outcome was assessed. Two reviewers Electronic supplementary material The online version of this article (doi:10.1007/s12028-013-9939-6) contains supplementary material, which is available to authorized users. independently extracted data including population characteristics, treatment characteristics, and outcomes. The strength of evidence was adjudicated using both the Oxford and GRADE methodology. Our search strategy produced a total of 759 citations. Twenty-three articles, 16 manuscripts, and seven meeting proceedings, were considered for the review with all utilizing ketamine for seizure control. Only three studies were prospective studies. Fifteen and nine studies pertained to adults and pediatrics, respectively. Across all studies, of the 110 adult patients described, ketamine was attributed to electroencephalogram seizure response in 56.5 %, with a 63.5 % response in the 52 pediatric patients described. Adverse events related to ketamine were rare. Outcomes were poorly documented in the majority of the studies. There currently exists Oxford level 4, GRADE C evidence to support the use of ketamine for refractory seizures in the adult and pediatric populations. Further prospective study of early ketamine administration is warranted. F. A. Zeiler (&)
M. West Section of Neurosurgery, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada e-mail: [email protected] Keywords Status epilepticus
Refractory status
Ketamine
NMDA antagonists F. A. Zeiler
J. Teitelbaum Section of Neurocritical Care, Montreal Neurological Institute, McGill University, Montreal, QC, Canada Introduction J. Teitelbaum Section of Neurology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada L. M. Gillman Section of Critical Care Medicine, Department of Medicine, University of Manitoba, Winnipeg, MB, Canada L. M. Gillman Section of General Surgery, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada The protocoled management of status epilepticus (SE) is quite variable throughout the literature [1–3]. Standard initial medication options for SE are derived from the literature on general seizure management, and can vary depending on a variety of etiologies [4]. To date the level of evidence supporting the majority of medication choices for seizure control is based on level II or worse recommendations [1], with the only level I evidence stemming from the use of short acting benzodiazepines to abort early seizure activity. 123 Neurocrit Care Medically refractory status epilepticus (RSE) poses significant challenges pharmacologically. For those patients that fail initial medical management of their SE and continue on toward the half-hour mark of uncontrolled either clinical or electrographic seizure activity, the cessation of seizures utilizing standard pharmacological means decreases steadily with time. Based on a few very important neurochemical changes within the brain (as documented in animal models), it can be predicted that a large number of standard antiepileptics will have impaired function with prolonged seizure duration. First, GABAA receptor number decreases with prolonged seizure activity, followed by a return in number of non-functioning GABAA receptors (likely related to receptor sub-type changes) [5, 6]. These GABAA receptor changes lead to impaired responsiveness to GABA mediated antieplieptics. Second, SE has been known to induce P-glycoprotein expression leading to increased export of phenytoin and phenobarbital across the blood brain barrier, potentially leading to reduced brain concentration of these medications and pharmacoresistant seizures [7–9]. Finally, SE can lead to up-regulation of N-methyl D-aspartate (NMDA) receptors, causing glutamate induced intra-cellular calcium influx and excitoxicity that may further potentiate seizure activity [7, 10]. Thus, based on the mentioned mechanisms of pharmacoresistance, novel approaches to anti-epileptic choices need to be made to achieve adequate and rapid seizure control. Given the literature on excitotoxicity and the NMDA mediated potentiation of SE, numerous studies have emerged in the last 15 years focusing on the use of NMDA receptor antagonists in the setting of refractory seizures [11– 33]. The goal of our study is to perform a systematic review of the current literature on the use of ketamine or any other NMDA receptor antagonist for the control of RSE. Methods A systematic review using the methodology outlined in the Cochrane Handbook for Systematic Reviewers [34] was conducted. The data was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [35]. The review questions and search strategy were decided upon by the primary author and supervisor. Search Question, Population, Inclusion and Exclusion Criteria The question posed for systematic review was: What is the effectiveness of ketamine, or NMDA antagonists, for 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 123 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: complete (100 % of patients response), moderate (>50 % of patients response), mild (<50 % of patients 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 NMDA antagonists. Inclusion criteria were, All studies including human subjects whether prospective or retrospective, all study sizes, any age category, and the use of ketamine or NMDA antagonists for seizure control in RSE. Exclusion criteria were, animal and non-English studies. Search Strategy MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, SCOPUS, and Cochrane Library from inception to September 2013 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 utilized for the other databases. In addition, the World Health Organizations International Clinical Trials Registry Platform was searched looking for studies planned or underway. As well, meeting proceedings for the last 10 years looking for ongoing and unpublished work based on NMDA antagonists for seizures were examined. The meeting proceedings of the following professional societies were searched: Canadian Neurological Sciences Federation (CNSF), American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS), European Neurosurgical Society (ENSS), World Federation of Neurological Surgeons (WFNS), American Neurology Association (ANA), American Academy of Neurology (AAN), American Epilepsy Society (AES), European Federation of Neurological Science (EFNS), World Congress of Neurology (WCN), Society of Critical Care Medicine (SCCM), Neurocritical Care Society (NCS), and the World Federation of Societies of Intensive and Critical Care Medicine (WFSICCM). Finally, reference lists of any review articles or systematic reviews on seizure management were reviewed for relevant studies on ketamine or NMDA antagonist usage for seizure control. Study Selection Utilizing two reviewers, a two-step review of all articles returned by our search strategies was performed. First, the Neurocrit Care reviewers independently screened all titles and abstracts of the returned articles to decide if they met the inclusion criteria. Second, 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 discussion. Statistical Analysis A meta-analysis was not performed in this study due to the heterogeneity of data within the articles and the presence of a small number of low quality retrospective studies. Results Data Collection Data was 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, dose and route of NMDA antagonist used, timing to administration of drug, duration of drug administration, time to effect of drug, how many other AED were utilized prior to NMDA antagonists, 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 two independent reviewers, utilizing the Oxford criteria [36] and the Grading of Recommendation Assessment Development and Education (GRADE) criteria [37–42] for level of evidence. The Oxford criteria consists of a 5 level grading system for the literature. Level 1 is split into subcategories 1a, 1b, and 1c which represent a systematic review of randomized control trials (RCT) with homogeneity, individual RCT 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 RCT, 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 4 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 two reviewers were resolved via discussion, and a third reviewer if required. The results of the search strategy across all databases and other sources are summarized in Fig. 1. Overall, a total of 759 articles were identified, with 752 from the database search and 7 from the search of published meeting proceedings. By applying the inclusion/exclusion criteria to the title and abstract of the articles, we identified 103 articles that fit these criteria. Of the 103 identified, 96 were from the database search and 7 were from published meeting proceedings. After removing duplicates, there were a total of 34 articles. Applying the inclusion/exclusion criteria to the full text documents, only 23 articles were eligible for inclusion in the systematic review, with 16 from database and 7 from meeting proceeding sources. The 11 articles that were excluded were done so because they either did not report details around the administration of NMDA antagonists for seizure control or because they were review articles. Reference sections from these review articles were searched for any other articles missed in the database search, with none being identified. Of the 23 articles included in the review, 22 were original studies, with one a companion abstract publication [13] expanding on the original data set [21]. There were 20 retrospective studies [11, 12, 14–19, 22–33] and 3 prospective studies [13, 20, 21], two of which were companion publications [13, 21]. Within the retrospective studies, 10 were retrospective case series and the remaining 10 were retrospective case reports. The retrospective case series were composed of 6 single center reviews and 4 multicenter reviews. The 3 prospective studies included in the systematic review were all prospective cohort studies with no control groups [13, 20, 21]. Nine studies focused on pediatric patients [13, 15, 19–21, 23–25, 29], with a total of 52 patients treated with ketamine for seizures. The only NMDA antagonist studied in all articles was ketamine. Across all studies, a total of 162 patients were studied utilizing ketamine for control of their seizures (mean 7 patients/study; range 1–58 patients/study). Fifty two patients were pediatric (age range from 2 months to 18 years), and 110 were adult (age range of 19–88 years). Study demographics and patient characteristics for the adult studies can be seen in Table 1, while treatment characteristics and seizure outcome are reported in Table 2. Similarly, the study/patient characteristics for the pediatric studies can be seen in Table 3, with treatment characteristics and seizure outcome in Table 4. 123 Neurocrit Care Fig. 1 Flow diagram of search results Ketamine Treatment Characteristics Adults The literature on ketamine use for seizure control in the adult population yielded 15 studies. Within these 15 studies [11, 12, 14, 16–18, 22, 26–28, 30–33], 9 utilized bolus dosing of ketamine, ranging from 0.5 to 5 mg/kg, followed by continuous infusions, ranging from 0.12 to 10 mg/kg h. The remaining six studies utilized only bolus dosing in five and unknown ketamine administration detail in one. Duration of treatment prior to ketamine administration was documented in 11 studies, ranging from 16 h to 140 days, with patients on various numbers of AEDs prior to ketamine, ranging from 1 to 11 with all patient treatments typically consisting of a combination of oral AED and intravenous anesthetic agents. All AED’s reported were typically on board during the ketamine treatment. Similarly, the duration of ketamine treatment was described in 10 of the 15 adult studies, with treatment duration ranging 123 from 2 h to 27 days intravenously, and one patient discharged on oral ketamine indefinitely [32]. Ketamine treatment characteristics for the adult studies can be seen in Table 2. Pediatrics Within those nine studies describing ketamine use in the pediatric population, 3 studies documented bolus dosing, ranging from 2 mcg/kg to 3 mg/kg, followed by continuous intravenous infusions, from 7.5 mcg/kg h to 10 mg/kg h. The remaining six studies documented isolated continuous infusions of ketamine in two studies [13, 23], ranging from 7 to 60 mcg/kg min, oral dosing in one study [20], and not documented in 3 studies [19, 24, 25]. Duration of treatment prior to ketamine administration was documented in 2 pediatric studies, ranging from 5 h to 28 days, with patients on various numbers of AEDs prior to ketamine, ranging from 1 to 10 with all patient treatments typically consisting of a combination of oral AED and intravenous Reference Number of patients treated with ketamine Study type Study setting Singh et al. [11] 14 Retrospective case series Single Center Meeting abstract 55.1 (range 22–88 years) Synowiec et al. [30] 11 Retrospective case series Single center Journal Article location Mean age (years) Etiology of seizures Mean # Meds prior to ketamine Primary epilepsy in all; 3 low drug level (5), systemic infection (4), unknown (5) 52 (range unknown) Low AED levels (3), Unknown; 2nd infection (7), and IV Anesthetic metabolic disturbance (8); 3rd (2); (1) 4th (1) Meeting abstract ‘‘Adults’’ Unknown Mean time until ketamine administration (days) 5.9 (range 1–20 days) 5.1 (range 1–11 days) Svoronos et al. [12] 9 Retrospective case series Multi center Unknown Unknown Unknown Bleck et al. [14] 7 Retrospective case series Single center Meeting abstract ‘‘Adults’’ Unknown ‘‘Critically Ill’’; Unknown Unknown 2.5 (range unknown) Gaspard et al. [15]a 46a Retrospective case series Multi center 4.5 (range 1–10) Unknown Gosselin-Lefebvre et al. [22] 9 Retrospective case series Single center Meeting abstract 35 (range 18–78) Unknown (34); Nonanoxic injury (11), systemic cause (2), remote history of seizures (2) Unknown 8 (range 5–11) 12 (range 6–25 days) Walker et al. [27] 1 Retrospective case series Single center Journal Unknown Unknown Unknown Unknown Journal 24 (range for study 7 months to 74 years)a Robakis et al. [28] 1 Retrospective case report Single center Journal 30 Query encephalitis 8 140 Zeiler et al. [33] 2 Retrospective case series Single center Journal 66 and 57 Post-craniotomy for elective aneurysm 8 and 4 18 and 4 Kramer et al. [18] 1 Retrospective case report Single center Journal 60 Past history of CP, and epilepsy 5 Unknown Kofke et al. [17] 1 Retrospective case report Single center Journal 21 Unknown 5 Hsieh et al. [16] 1 Retrospective case report Single center Journal 23 Unknown, infectious prodrome 8 0.66 58 Ubogu et al. [31] 1 Retrospective case report Single center Journal 44 Remote neurosyphilis 4 5 Yeh et al. [32] 1 Retrospective case report Single center Journal 76 Remote subdural hematoma and CVA 9 9 Pruss et al. [26] 1 Retrospective case report Single center Journal 22 Mitochondrial disease 4 13 AED anti-epileptic drug, IV intravenous, CP cerebral palsy a Gaspard et al. [15] is a multicenter retrospective study including adult and children in the entire review, data for adults has not been separated from children within the body of the paper. There were a total of 58 patients, 46 adult, and 12 pediatric Neurocrit Care Table 1 Adult study characteristics and patient demographics 123 123 Table 2 Adult articles-ketamine treatment characteristics, seizure response, and outcome Reference Number of patients treated with ketamine Ketamine dose Mean duration of ketamine administration (days) Electrographic seizure response Rating of seizure response Adverse effects to ketamine Patient outcome Singh et al. [11] 14 Bolus: 1.5 mg/kg Unknown Complete control in all patients Excellent None Home/rehab (6); long term care (5); died (3) 9.8 (range 4–28 days) Complete control in all patients Excellent None Home (2); rehab (3); long term care (4); died (2) Infusion: 1.45 mg/kg h (range 0.12–5.7 mg/kg h) Synowiec et al. [30] 11 Bolus: 1–2 mg/kg Infusion:1.3 mg/kg h (range 0.45–2.1 mg/kg h) Svoronos et al. [12] 9 Unknown Unknown No response to ketamine in any patients Failure Unknown Unknown Bleck et al. [14] 7 Bolus: 0.9–3 mg/kg Unknown Complete control (4); Failure (3) Moderate None All died Range 6 h–27 Days 34 % response Mild SVT (2) 45 % mortality; only one child returned to baseline Infusion: median 5 mg/kg h (range 2–15 mg/kg h) Unknown Complete response (4); some response (3); Failure (2) Moderate None Favorable (3); impaired (1); died (5) Unknown Failure Failure None Required sub-pial transection Failure Failure None Vegetative; surgical attempts failed Infusion: 0.3–5.8 mg/kg h Gaspard et al. [15]a 46a Bolus: median 1.5 mg/kg (max 5 mg/kg) Infusion: median 2.75 mg/kg h (max 10 mg/kg h) Gosselin-Lefebvre et al. [22] 9 Walker et al. [27] 1 100 mg/h infusion only Robakis et al. [28] 1 Infusion: Up to 7 mg/kg h Zeiler et al. [33] 2 Infusion: 10–40 mcg/kg min Kramer et al. [18] 1 Bolus: 50 mg 9 1 Kofke et al. [17] 1 7 3 and 12 Complete control Excellent None Rehab (2) 2 Complete control Excellent None Home 2h Complete control Excellent None Home with Support 7 Complete control Excellent None Home 5 Complete control Excellent None Home Infusion: 0.6–3.3 mg/kg h Bolus: 150 mg 9 4 Infusion: none Hsieh et al. [16] 1 Bolus: 0.5 mg/kg Infusion: 1.5 mg/kg h Ubogu et al. [31] 1 Bolus: 2 mg/kg Infusion: 1–7.5 mg/kg h Yeh et al. [32] Pruss et al. [26] 1 1 Indefinitely; transitioned to oral ketamine as of last follow-up Complete control; recurrence upon weaning Excellent None Unknown Infusion: 0.05–4 mg/kg h Bolus: 0.5 mg/kg 14 Complete control Excellent None Long term care Bolus:1.5 mg/kg Infusion: 0.4–3.2 mg/kg h Gaspard et al. [15] is a multicenter retrospective study including adult and children in the entire review, data for adults has not been separated from children within the body of the paper. There were a total of 58 patients, 46 adult, and 12 pediatric Neurocrit Care mg milligram, kg kilogram, h hour, min minute, Rehab rehabilitation center a Neurocrit Care Table 3 Pediatric study characteristics and patient demographics Reference Study type Number of patients treated with ketamine Study setting Article location Mean age (years) Etiology of seizures Mean # Meds prior to ketamine Mean time until ketamine administration (days) Mewansingh et al. [20] 5 Prospective cohort Single center Journal Range 4–7 Long standing history of seizures and SE 3.2 (range 3–5) Unknown Rosati et al. [13]a 12 Prospective cohort Single center Meeting abstract Range 3 months to 12 years Unknown Unknown Unknown Rosati et al. [21]a 9 Prospective cohort Single center Journal 5.2 (range 16 months to 10 years 5 months) Not diagnosed (5), Rett (1), MELAS (1), malformative (2) 5 (range 4–7) 7.7 (range 5 h to 26 days) Retrospective case series Multi center Journal 24 (range for study 7 months to 74 years)a 4.5 (range 1–10) Not diagnosed (34); Nonanoxic injury (11), systemic cause (2), remote history of seizures (2) Unknown Gaspard et al. [15]b 12b Sheth et al. [29] 1 Retrospective case report Single center Journal 13 Unknown 6 28 Kramer et al. [19] 1c Retrospective case series Single center Journal 15 Infectious prodrome 6 Unknown Kravljanac et al. 6 [25] Retrospective case series Single center Meeting abstract 4.3 (range 2 months to 18 years) Not mentioned Unknown Unknown Andrade et al. [24] 1 Retrospective case report Single center Meeting abstract DiGeorge syndrome Unknown Unknown Al-Otaibi et al. [23] 5 Retrospective case series Single center Meeting abstract Unknown Range 4–6 Unknown 5 Range 5–17 SE status epilepticus a Rosati et al. [13, 21] companion studies, one a meeting abstract and another a formal journal manuscript b Gaspard et al. [15] is a multicenter retrospective study including adult and children in the entire review, data for adults has not been separated from children within the body of the paper. There were a total of 58 patients, 46 adult, and 12 pediatric c Kramer et al. [19] is a retrospective case series of 9 childeren with only 1 treated with ketamine, thus the focus of the review was on that one patient 123 Neurocrit Care anesthetic agents. All AED’s reported were typically on board during the ketamine treatment. Similarly, the duration of ketamine treatment was described in four studies, ranging from 6 h to 27 days. The timing of ketamine response was poorly documented in the pediatric studies. Ketamine treatment characteristics for the pediatric studies can be seen in Table 4. Seizure Response Adults Seizure control upon ketamine administration in the adult population was documented as excellent (complete response in all patients) in nine studies containing a total of 33 patients. Moderate electrographic seizure response (>50 % patients in the study responded) was documented in two studies with a total of 16 patients. Mild electrographic seizure response (<50 % of patients in the study responded) was documented in one study with 46 patients. Failure of treatment response in all patients occurred in three studies with a total of 12 patients within these studies. Across all 15 adult studies a total of 59 patients (56.5 %) were described as having complete electrographic seizure responsiveness to ketamine. Complete treatment failure with ketamine was described in 51 (46.4 %) adult patients across all 15 adult studies. The timing of ketamine response after administration was poorly documented within the majority of the adult studies. Pediatrics Seizure control in the pediatric studies was documented as excellent in four studies with a total of 19 patients. Moderate electrographic seizure response was documented in one study with a total of nine patients. Mild electrographic seizure response was documented in three studies with 23 patients. Failure of treatment response in all the patients occurred in one study with one patient. Across all nine pediatric studies, a total of 33 patients (63.5 %) were described as having seizure responsiveness to ketamine administration. Complete treatment failure with ketamine was described in 19 (37.5 %) pediatric patients across all nine pediatric studies. The timing of ketamine response after administration was poorly documented within the majority of the pediatric studies. Adverse Effects of Ketamine Only two patients in the adult literature reviewed were described as having cardiac arrhythmias directly related to ketamine administration [15]. Within the pediatric literature, one study [19] described hyper-salivation in nine patients 123 and elevated liver enzymes in one patient (whom was also on phenobarbital at the time). No other adverse effects/complications described in the adult or pediatric studies were directly attributable to ketamine administration. Outcome Patient outcome was reported sparingly in most studies, both adult and pediatric and can be seen in Table 2 and 4, respectively. Level of Evidence for Ketamine Based on two independent reviewers, there were a total of 23 studies reviewed with all representing Oxford level 4 evidence for the administration of ketamine for seizures. Within the adult population, 11 of 15 studies met GRADE C level of evidence, while the remaining 4 met GRADE D level of evidence. For the pediatric studies reviewed, 6 of 9 studies met GRADE C level of evidence, while the remaining 3 met GRADE D level of evidence. Summary of the level of evidence can be seen in Table 5. Discussion Status epilepticus poses significant challenges, with mortality reaching 19 % [3] for seizures lasting longer than 30 min. Similarly, for those patients with recurrent seizures, who become treatment refractory, the mortality ranges from 23 to 61 % [1]. In those who survive RSE, moderate to severe morbidity occurs in up to 90 % of cases [1, 43, 44]. Clearly, it is crucial to stop the status as rapidly as possible to avoid such a dismal outcome. In patients with status epilepticus, it is widely accepted that the longer the seizures remain uncontrolled, the more refractory they become. Numerous animal studies have demonstrated altered GABAA receptor function [5, 6] and up-regulated P-glycoprotein expression, increasing the export of both phenytoin and phenobarbital across the blood brain barrier [8, 9] once seizures reach the 30 min mark of duration. Both of these mechanisms lead to impaired responsiveness to the majority of first and second line AEDs utilized in SE. Furthermore, NMDA receptor up-regulation leads to seizure potentiation via glutamate induced excitoxicity [7]. There is little in the literature on the use of ketamine as a treatment for refractory status epilepticus. Most of the data to date focuses on small case series retrospectively reported. Results with the utilization of NMDA antagonists are promising even in the most refractory of cases of status epilepticus. The goal of our study was to perform a systematic review of all the literature on the use of NMDA Neurocrit Care Table 4 Pediatric articles-ketamine treatment characteristics, seizure response, and outcome Reference Number of patients treated with ketamine Ketamine dose Mewansingh et al. [20] 5 Oral dose: 1.5 mg/kg day in two divided doses Rosati et al. [13]a 12 Rosati et al. [21]a 9 Infusion:32.5 mcg/kg min (10–60 mcg/kg min) Bolus x 2: 2–3 mg/kg Rating of seizure Adverse effects to ketamine response Patient outcome Stopped seizures in all patients Excellent None Recurrence in one patient Excellent None Unknown 6.7 (range 3–17 days) Stopped seizures in all patients Stopped seizures in 6 Moderate Increased salivation in all, liver enzyme elevation (4) Unknown Mean duration of Electrographic seizure ketamine administration response (days) 5 Unknown Infusion: 36.5 mcg/kg min (range 10–60 mcg/ kg min) Gaspard et al. [15]b 12b Bolus: median 1.5 mg/kg (max 5 mg/kg) Infusion: median 2.75 mg/ kg h (max 10 mg/kg h) Range 6 h to 27 Days 34 % response Mild None 45 % mortality; only one child returned to baseline Sheth et al. [29] 1 Bolus:2 mcg/kg 14 Stopped seizures in patient Excellent None Unknown Unknown Failure Failure Unknown Died Infusions:7.5 mcg/kg h Kramer et al. [19] 1c Unknown Kravljanac et al. [25] 6 Unknown Unknown 3 responded Mild Unknown Unknown Andrade et al. [24] 1 Unknown Unknown Stopped all seizures Excellent Unknown Unknown Al-Otaibi et al. [23] 5 Infusion: 0.04–7 mg/kg h Unknown Improved (1); Failure (4) Mild None Unknown mg milligram, kg kilogram, h hour, min minute, Rehab rehabilitation center a Rosati et al.13,21 companion studies, one a meeting abstract and another a formal journal manuscript b Gaspard et al. [15] is a multicenter retrospective study including adult and children in the entire review, data for adults has not been separated from children within the body of the paper. There were a total of 58 patients, 46 adult, and 12 pediatric c Kramer et al. [19] is a retrospective case series of 9 childeren with only 1 treated with ketamine, thus the focus of the review was on that one patient 123 Neurocrit Care Table 5 Oxford and GRADE level of evidence Reference Study type Oxford [36] level of evidence GRADE [37–42] level of evidence Singh et al. [11] Retrospective case series 4 C Synowiec et al. [30] Retrospective case series 4 C Svoronos et al. [12] Retrospective case series 4 C Bleck et al. [14] Retrospective case series 4 C Gaspard et al. [15]a Retrospective case series 4 C Gosselin-Lefebvre et al. [22] Retrospective case series 4 C Walker et al. [27] Robakis et al. [28] Retrospective case series Retrospective case report 4 4 D C Zeiler et al. [33] Retrospective case series 4 C Kramer et al. [18] Retrospective case report 4 C Kofke et al. [17] Retrospective case report 4 C C Hsieh et al. [16] Retrospective case report 4 Ubogu et al. [31] Retrospective case report 4 D Yeh et al. [32] Retrospective case report 4 D Pruss et al. [26] Retrospective case report 4 D Mewansingh et al. [20] Prospective cohort 4 C Rosati et al. [13]b Prospective cohort 4 C b Rosati et al. [21] Prospective cohort 4 C Sheth et al. [29] Retrospective case report 4 C Kramer et al. [19] Retrospective case report 4 D Kravljanac et al. [25] Retrospective case series 4 D Andrade et al. [24]. Al-Otaibi et al. [23] Retrospective case report Retrospective case series 4 4 D C a Gaspard et al. [15] is a multicenter retrospective study including adult and children in the entire review, data for adults has not been separated from children within the body of the paper b Rosati et al. [13, 21] companion studies, one a meeting abstract and another a formal journal manuscript antagonists for the control of refractory seizures and hopefully determine the role of ketamine in RSE. Through our review we identified 23 articles pertaining to the reported usage of ketamine seizure control, with 16 being published manuscripts and seven published meeting abstracts. A total of 162 patients were described in these articles with 110 being adult and 52 pediatric. The majority of the studies were retrospective case reports/series, with only three being prospective cohort studies. Looking at the primary outcome of our study (seizure control), 56.5 and 63.5 % of adult and pediatric patient, respectively, were reported to have responded electrographically to ketamine administration for their RSE. In comparison to other AED utilized in status epilepticus, the control in RSE with various agents varies from 0 to 62 % [45]. In the secondary outcomes, only minimal adverse events were associated with ketamine administration. Unfortunately, patient outcome data was too sparingly documented for any conclusion. All studies were an Oxford level 4 for quality, 123 with the majority of adult and pediatric studies being a GRADE C level of evidence. A meta-analysis was not possible given the heterogeneous, retrospective nature of the studies available. The lack of RCT on the use of ketamine in the control of seizures prevents a high level of evidence for this treatment. Thus, based on this review, we can currently provide Oxford level 4, GRADE C recommendations for the use of ketamine for 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 SE 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 ketamine administration, and ketamine dosage and duration 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. Despite these limitations, we Neurocrit Care believe the data provides evidence for the potential benefit and low adverse effects of NMDA antagonists, in both the adult and pediatric RSE populations. Perhaps those that failed to respond to ketamine would have done so had they been treated earlier. This should certainly be a consideration in any future trials. Phase I clinical trials utilizing early ketamine for status epilepticus need to occur, with the hope of further prospective randomized control trials to assess the benefit of early ketamine administration for SE. Conclusions There currently exists level 4, GRADE C evidence to support the use of ketamine for RSE in the adult and pediatric populations. Further prospective studies of early ketamine administration in RSE are warranted. References 1. Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3–23. 2. Claassan J, Silbergleit R, Weingart SD, Smith WD. Emergency neurological life support. Neurocrit Care. 2012;17(Suppl. 1):S73–8. 3. Hunter G, Young B. Status epilepticus: a review, with emphasis on refractory cases. Can J Neurol Sci. 2012;39(2):157–69. 4. Trinka E, Hofler J, Zerbs A. Causes of status epilepticus. Epilepsia. 2012;53(Suppl. 4):127–38. 5. 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