Neurocritical Care

, Volume 20, Issue 3, pp 502–513

NMDA Antagonists for Refractory Seizures

Authors

    • Section of Neurosurgery, Department of SurgeryUniversity of Manitoba
    • Section of Neurocritical CareMontreal Neurological Institute, McGill University
  • J. Teitelbaum
    • Section of Neurocritical CareMontreal Neurological Institute, McGill University
    • Section of NeurologyMontreal Neurological Institute, McGill University
  • L. M. Gillman
    • Section of Critical Care Medicine, Department of MedicineUniversity of Manitoba
    • Section of General Surgery, Department of SurgeryUniversity of Manitoba
  • M. West
    • Section of Neurosurgery, Department of SurgeryUniversity of Manitoba
Review Article

DOI: 10.1007/s12028-013-9939-6

Cite this article as:
Zeiler, F.A., Teitelbaum, J., Gillman, L.M. et al. Neurocrit Care (2014) 20: 502. doi:10.1007/s12028-013-9939-6

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 d-aspartate (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 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.

Keywords

Status epilepticusRefractory statusKetamineNMDA antagonists

Introduction

The protocoled management of status epilepticus (SE) is quite variable throughout the literature [13]. 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.

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 anti-epileptics 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 anti-eplieptics. 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 [79]. 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 [1133]. 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 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 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.

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 [3742] 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.

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

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.
https://static-content.springer.com/image/art%3A10.1007%2Fs12028-013-9939-6/MediaObjects/12028_2013_9939_Fig1_HTML.gif
Fig. 1

Flow diagram of search results

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, 1419, 2233] 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, 1921, 2325, 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.
Table 1

Adult study characteristics and patient demographics

Reference

Number of patients treated with ketamine

Study type

Study setting

Article location

Mean age (years)

Etiology of seizures

Mean # Meds prior to ketamine

Mean time until ketamine administration (days)

Singh et al. [11]

14

Retrospective case series

Single Center

Meeting abstract

55.1 (range 22–88 years)

Primary epilepsy in all; low drug level (5), systemic infection (4), unknown (5)

3

5.9 (range 1–20 days)

Synowiec et al. [30]

11

Retrospective case series

Single center

Journal

52 (range unknown)

Low AED levels (3), infection (7), and metabolic disturbance (1)

Unknown; 2nd IV Anesthetic (8); 3rd (2); 4th (1)

5.1 (range 1–11 days)

Svoronos et al. [12]

9

Retrospective case series

Multi center

Meeting abstract

“Adults” Unknown

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

Journal

24 (range for study 7 months to 74 years)a

Unknown (34); Non-anoxic injury (11), systemic cause (2), remote history of seizures (2)

4.5 (range 1–10)

Unknown

Gosselin-Lefebvre et al. [22]

9

Retrospective case series

Single center

Meeting abstract

35 (range 18–78)

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

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

0.66

Hsieh et al. [16]

1

Retrospective case report

Single center

Journal

23

Unknown, infectious prodrome

8

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

aGaspard 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

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)

Infusion: 1.45 mg/kg h (range 0.12–5.7 mg/kg h)

Synowiec et al. [30]

11

Bolus: 1–2 mg/kg

9.8 (range 4–28 days)

Complete control in all patients

Excellent

None

Home (2); rehab (3); long term care (4); died (2)

Infusion:1.3 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

Infusion: 0.3–5.8 mg/kg h

Gaspard et al. [15]a

46a

Bolus: median 1.5 mg/kg (max 5 mg/kg)

Range 6 h–27 Days

34 % response

Mild

SVT (2)

45 % mortality; only one child returned to baseline

Infusion: median 2.75 mg/kg h (max 10 mg/kg h)

Gosselin-Lefebvre et al. [22]

9

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)

Walker et al. [27]

1

100 mg/h infusion only

Unknown

Failure

Failure

None

Required sub-pial transection

Robakis et al. [28]

1

Infusion: Up to 7 mg/kg h

7

Failure

Failure

None

Vegetative; surgical attempts failed

Zeiler et al. [33]

2

Infusion: 10–40 mcg/kg min

3 and 12

Complete control

Excellent

None

Rehab (2)

Kramer et al. [18]

1

Bolus: 50 mg × 1

2

Complete control

Excellent

None

Home

Infusion: 0.6–3.3 mg/kg h

Kofke et al. [17]

1

Bolus: 150 mg × 4

2 h

Complete control

Excellent

None

Home with Support

Infusion: none

Hsieh et al. [16]

1

Bolus: 0.5 mg/kg

7

Complete control

Excellent

None

Home

Infusion: 1.5 mg/kg h

Ubogu et al. [31]

1

Bolus: 2 mg/kg

5

Complete control

Excellent

None

Home

Infusion: 1–7.5 mg/kg h

Yeh et al. [32]

1

Bolus:1.5 mg/kg

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

Pruss et al. [26]

1

Bolus: 0.5 mg/kg

14

Complete control

Excellent

None

Long term care

Infusion: 0.4–3.2 mg/kg h

mg milligram, kg kilogram, h hour, min minute, Rehab rehabilitation center

aGaspard 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

Table 3

Pediatric study characteristics and patient demographics

Reference

Number of patients treated with ketamine

Study type

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)

Gaspard et al. [15]b

12b

Retrospective case series

Multi center

Journal

24 (range for study 7 months to 74 years)a

Not diagnosed (34); Non-anoxic injury (11), systemic cause (2), remote history of seizures (2)

4.5 (range 1–10)

Unknown

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. [25]

6

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

5

DiGeorge syndrome

Unknown

Unknown

Al-Otaibi et al. [23]

5

Retrospective case series

Single center

Meeting abstract

Range 5–17

Unknown

Range 4–6

Unknown

SE status epilepticus

aRosati et al. [13, 21] companion studies, one a meeting abstract and another a formal journal manuscript

bGaspard 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

cKramer 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

Table 4

Pediatric 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

Mewansingh et al. [20]

5

Oral dose: 1.5 mg/kg day in two divided doses

5

Stopped seizures in all patients

Excellent

None

Recurrence in one patient

Rosati et al. [13]a

12

Infusion:32.5 mcg/kg min (10–60 mcg/kg min)

Unknown

Stopped seizures in all patients

Excellent

None

Unknown

Rosati et al. [21]a

9

Bolus x 2: 2–3 mg/kg

6.7 (range 3–17 days)

Stopped seizures in 6

Moderate

Increased salivation in all, liver enzyme elevation (4)

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)

Range 6 h to 27 Days

34 % response

Mild

None

45 % mortality; only one child returned to baseline

Infusion: median 2.75 mg/kg h (max 10 mg/kg h)

Sheth et al. [29]

1

Bolus:2 mcg/kg

14

Stopped seizures in patient

Excellent

None

Unknown

Infusions:7.5 mcg/kg h

Kramer et al. [19]

1c

Unknown

Unknown

Failure

Failure

Unknown

Died

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

aRosati et al.13,21 companion studies, one a meeting abstract and another a formal journal manuscript

bGaspard 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

cKramer 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

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, 1618, 22, 2628, 3033], 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 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 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 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.
Table 5

Oxford and GRADE level of evidence

Reference

Study type

Oxford [36] level of evidence

GRADE [3742] 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]

Retrospective case series

4

D

Robakis et al. [28]

Retrospective case report

4

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

Hsieh et al. [16]

Retrospective case report

4

C

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

Rosati et al. [21]b

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].

Retrospective case report

4

D

Al-Otaibi et al. [23]

Retrospective case series

4

C

aGaspard 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

bRosati et al. [13, 21] companion studies, one a meeting abstract and another a formal journal manuscript

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 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, 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 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.

Supplementary material

12028_2013_9939_MOESM1_ESM.doc (25 kb)
Supplementary material 1 (DOC 25 kb)

Copyright information

© Springer Science+Business Media New York 2014