Ketamine for the treatment of refractory status epilepticus

Open ArchivePublished:May 19, 2015DOI:https://doi.org/10.1016/j.seizure.2015.05.010

      Highlights

      • Ketamine plays an anticonvulsant role via antagonism of NMDA receptors.
      • Ketamine appears to be effective on refractory SE but based on low level of evidence.
      • Ketamine is often selected after 5–6 anticonvulsants have failed.
      • Ketamine administration involves intravenous and oral routes.
      • Ketamine is rapid onset and relatively safe for refractory status epilepticus.

      Abstract

      Status epilepticus (SE) is an acute and severe illness of the central nervous system, and prolonged SE can lead to brain damage and even death. Ketamine is a noncompetitive antagonist of glutamatergic N-methyl-d-aspartate (NMDA) receptors. During prolonged seizures, the numbers and activities of GABA receptors gradually decrease; thus, the commonly used first-line and second-line antiepileptic drugs gradually fail. Simultaneously, the numbers and activities of glutamatergic NMDA receptors increase, often causing refractory status epilepticus (RSE) and thus providing the possibility of the use of ketamine to treat RSE. To improve the prognosis of SE, we present a narrative review of ketamine for the treatment of RSE in the extant literature. We draw the conclusion that ketamine appears to be effective and relatively safe for the control of multidrug-resistant RSE in children and adults.

      Keywords

      1. Introduction

      Refractory status epilepticus (RSE) refers to status epilepticus (SE) that cannot be resolved in terms of clinical manifestations or epileptiform discharges following the rational administration of anticonvulsants including a benzodiazepine [
      • Hocker S.
      • Tatum W.O.
      • LaRoche S.
      • Freeman W.D.
      Refractory and super-refractory status epilepticus—an update.
      ]. Super-refractory status epilepticus (super-RSE) refers to drug-resistant status epilepticus that persists or recurs following the continuous administration of intravenous anesthetics for more than 24 h [
      • Kramer U.
      • Chi C.S.
      • Lin K.L.
      • Specchio N.
      • Sahin M.
      • Olson H.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
      ], and the primary etiologies of super-RSE are brain insults, such as intracranial infection, brain trauma or stroke [
      • Kramer U.
      • Chi C.S.
      • Lin K.L.
      • Specchio N.
      • Sahin M.
      • Olson H.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
      ,
      • Nabbout R.
      FIRES and IHHE: delineation of the syndromes.
      ]. SE is an acute and severe illness of the central nervous system. When the seizure duration exceeds 30 min, the mortality rate is 19% [
      • Hunter G.
      • Young B.
      Status epilepticus: a review, with emphasis on refractory cases.
      ]. Among RSE patients, the mortality rate is as high as 23–61% [
      • Brophy G.M.
      • Bell R.
      • Claassen J.
      • Alldredge B.
      • Bleck T.P.
      • Glauser T.
      • et al.
      Guidelines for the evaluation and management of status epilepticus.
      ], and approximately 90% of RSE survivors ultimately relapse [
      • Hunter G.
      • Young B.
      Status epilepticus: a review, with emphasis on refractory cases.
      ,
      • Claassen J.
      • Hirsch L.J.
      • Emerson R.G.
      • Bates J.E.
      • Thompson T.B.
      • Mayer S.A.
      Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus.
      ,
      • Mayer S.A.
      • Claassen J.
      • Lokin J.
      • Mendelsohn F.
      • Dennis L.J.
      • Fitzsimmons B.F.
      • et al.
      Refractorystatus epilepticus: frequency, risk factors, and impact on outcome.
      ]. Ketamine could play an important role in the treatment of RSE by altering glutamate metabolism, particularly in patients who exhibit a poor response to benzodiazepines.

      2. Background

      Ketamine was developed by the Parke-Davis (USA) pharmaceutical company in 1962. Three years later, McCarthy et al. [
      • McCarthy D.
      • Chen G.
      • Kaump D.H.
      • Ensor C.
      General anesthetic and other pharmacological properties of 2-(O-chlorophenyl)-2-methylamino-cyclohexanone HCl (CI-58L).
      ] found the first evidence that ketamine exerts an anticonvulsant effect in epilepsy animal models that were electrically or chemically created. These results were soon confirmed in patients [
      • Corssen G.
      • Miyasaka M.
      • Domino E.F.
      Changing concepts in pain control during surgery: dissociative anesthesia with CI-581. A progress report.
      ], raising the possibility of treating SE using ketamine, although this possibility was soon questioned. The experiments by Kayama and Iwama [
      • Kayama Y.
      • Iwama K.
      The EEG, evoked potentials, and single-unit activity during ketamine anesthesia in cats.
      ] using cat models revealed that ketamine could induce epileptic changes, based on EEG recordings. However, a similar study of human volunteers conducted by Corssen et al. [
      • Corssen G.
      • Little S.C.
      • Tavakoli M.
      Ketamine and epilepsy.
      ] rejected this conclusion. These authors found that ketamine did not cause epileptiform discharges in epilepsy patients or in normal subjects and that no evidence was available to support the notion that ketamine could induce or exacerbate convulsions, in contrast with the conclusions of Kayama [
      • Celesia G.G.
      • Chen R.C.
      • Bamforth B.J.
      Effects of ketamine in epilepsy.
      ,
      Letter: effects of ketamine on the EEG in normals and epileptics.
      ].
      In recent years, many researchers have reported that, during prolonged seizures, the number of activated GABA-A receptors on the postsynaptic membrane gradually decreases, whereas the number of inactive GABA-A receptors increases [
      • Deeb T.Z.
      • Maguire J.
      • Moss S.J.
      Possible alterations in GABAA receptor signaling that underlie benzodiazepine-resistant seizures.
      ,
      • Feng H.J.
      • Mathews G.C.
      • Kao C.
      • Macdonald R.L.
      Alterations of GABAA-receptor function and allosteric modulation during development of status epilepticus.
      ]. These changes cause a significant reduction in the efficacy of antiepileptic drugs (AEDs) that target the GABAergic system, such as diazepam, clonazepam, valproic acid, midazolam, propofol, and phenobarbital. Increased doses of AEDs might restore their efficacy, but the side effects of AEDs on cardiopulmonary function are simultaneously significantly increased, thus limiting the clinical applications of such increased doses. However, a study by Dingledine et al. [
      • Dingledine R.
      • Borges K.
      • Bowie D.
      • Traynelis S.F.
      The glutamate receptor ion channels.
      ] reported that the number and activities of glutamate-sensitive N-methyl-d-aspartate (NMDA) receptors significantly increased when the activity of GABA receptors decreased. Subsequently, this process induced continuously amplified neuronal hyperexcitability, leading to the development of RSE. Ketamine is a noncompetitive NMDA receptor antagonist [
      • Dingledine R.
      • Borges K.
      • Bowie D.
      • Traynelis S.F.
      The glutamate receptor ion channels.
      ] that might play a role in treating SE by blocking NMDA receptor-mediated glutamatergic neurotransmission [
      • Freeman F.G.
      • Jarvis M.F.
      • Duncan P.M.
      Phencyclidine raises kindled seizure thresholds.
      ,
      • Aram J.A.
      • Martin D.
      • Tomczyk M.
      • Zeman S.
      • Millar J.
      • Pohler G.
      • et al.
      Neocortical epileptogenesis in vitro: studies with N-methyl-d-aspartate, phencyclidine, sigma and dextromethorphan receptor ligands.
      ]. Moreover, by blocking glutamate-mediated NMDA receptor-induced neurotoxicity, ketamine also exerts neuroprotection [
      • Mazarati A.M.
      • Wasterlain C.G.
      N-methyl-d-aspartate receptor antagonists abolish the maintenance phase of self-sustaining status epilepticus in rat.
      ,
      • Kapur J.
      • Lothman E.W.
      NMDA receptor activation mediates the loss of GABAergic inhibition induced by recurrent seizures.
      ,
      • Fujikawa D.G.
      Neuroprotective effect of ketamine administered after status epilepticus onset.
      ]. Therefore, ketamine has been proposed as a new therapeutic agent for the treatment of SE [
      • Sinner B.
      • Graf B.M.
      Ketamine.
      ,
      • Gofrit O.N.
      • Leibovici D.
      • Shemer J.
      • Henig A.
      • Shapira S.C.
      Ketamine in the field: the use of ketamine for induction of anaesthesia before intubation in injured patients in the field.
      ,
      • Annetta M.G.
      • Iemma D.
      • Garisto C.
      • Tafani C.
      • Proietti R.
      Ketamine: new indications for an old drug.
      ].

      3. Ketamine for the treatment of RSE

      3.1 Clinical practice

      Gaspard et al. [
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      ] retrospectively analyzed the results of intravenous ketamine treatment of RSE. This study included 58 RSE patients treated with ketamine intravenously from 1999 to 2012, among whom 46 patients were adults, and 12 patients were children. These patients experienced a total of 60 episodes of RSE. The results indicated that, among the 57% (34/60) of cases in which the seizures ultimately resolved, approximately 32% (19/60) of the seizures were halted due to the effects of ketamine, and approximately 13% (8/60) of the cases of RSE were controlled during ketamine use. Similarly, a prospective study by Rosati et al. [
      • Rosati A.
      • Erario L.M.
      • Ilvento L.
      • Cecchi C.
      • Pisano T.
      • Mirabile L.
      • et al.
      Efficacy and safety of ketamine in refractory status epilepticus in children.
      ] also demonstrated that ketamine was relatively effective and safe for the treatment of RSE. This study included 9 RSE children who received intravenous ketamine between 2009 and 2011. In 8 patients, seizures had persisted for more than 1 day prior to ketamine selection. Finally, 6 patients who experienced RSE resolution were thought to be associated with ketamine administration, 2 patients were cured surgically, and no serious adverse reactions were recorded in all of the patients. In 2003, Mewasingh et al. [
      • Mewasingh L.D.
      • Skhara T.
      • Aeby A.
      • Christiaens F.J.
      • Dan B.
      Oral ketamine in paediatric non-convulsive status epilepticus.
      ] reported 6 cases of the use of oral ketamine to treat children (4–7 years old) with nonconvulsive RSE (NCSE), including Lennox–Gastaut syndrome, pseudo-Lennox syndrome, progressive myoclonic epilepsy and myoclonic-astatic epilepsy. All of the seizures remained prolonged despite the use of many anticonvulsants, and the median duration of these seizures was 4.4 weeks (range 2–10 weeks). Thus, these authors decided to use oral ketamine to treat RSE; fortunately, all of the patients experienced resolution within 24–48 h after the initiation of ketamine, resulting in a clear reduction in epileptiform discharges on EEG and improvement of the mental state of the patients. Although one of the children experienced a relapse a few months later, the continued use of ketamine remained effective, and no apparent side effects were recorded during ketamine treatment. Herein, we have summarized the available studies on ketamine for the treatment of RSE, which are presented in Table 1, Table 2. Collectively, these results indicate that ketamine is primarily suitable for the treatment of RSE and super-RSE during prolonged seizures, which is also supported by the conclusions of an animal experiment [
      • Borris D.J.
      • Bertram E.H.
      • Kapur J.
      Ketamine controls prolonged status epilepticus.
      ]. These authors found that if ketamine treatment was initiated after 15 min of SE, none of the animals exhibited responses to ketamine (0/4); however, when ketamine was initiated after 1 h of seizures, the successful termination rate was 100% (4/4). Moreover, after a prolonged seizure duration, a corresponding increase in the dose of ketamine was found to be effective within a certain time period.
      Table 1Demographics and clinical data of ketamine treatment in RSE.
      YearNumber of patientsAge (Y)/sexHistory of epilepsyStudy typeEtiology of RSESE typeSE duration prior to KETMedications prior to KETReferences
      20141Newborn

      F
      NoCase reportBrain malformationGTCSEAbout 9d5 (PB, MDZ, LEV, PHT, PRO)
      • Tarocco A.
      • Ballardini E.
      • Garani G.
      Use of ketamine in a newborn with refractory status epilepticus: a case report.
      20135824 (0.6–74)

      Unknown
      Yes (9); unknown (49)Retrospective studyUnknown (34); acute symptomatic (20); remote symptomatic (6)GCSE (14); NCSE (42); FCSE (4)9d (0–122d)4.5 (1–10; unknown)
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      20131152 (22–82)

      F (4); M (7)
      Yes (6); no (5)Retrospective studyLow AED levels (3); CNS infection (2); systemic infection (3); sepsis (2); metabolic disturbance (1)GTCSE (6); NCSE (5)5d (1–11d)3–8 (DZP, LZP, VPA, LEV, TPM, CBZ, MDZ, PB, PHT, GBP, PRO)
      • Synowiec A.S.
      • Singh D.S.
      • Yenugadhati V.
      • Valeriano J.P.
      • Schramke C.J.
      • Kelly K.M.
      Ketamine use in the treatment of refractory status epilepticus.
      2013266; 57

      F (1); M (1)
      NoCase reportElective aneurysm clippingGTCSE (1); NCSE (1)18d and 4d8 (PHT, MDZ, PRO, LEV, TPM, PB, VPA, CLB)

      5 (PHT, MDZ, PRO, VPA, LEV)
      • Zeiler F.A.
      • Kaufmann A.M.
      • Gillman L.M.
      • West M.
      • Silvaggio J.
      Ketamine for medically refractory status epilepticus after elective aneurysm clipping.
      2013127

      F
      NoCase reportViral encephalitisGTCSEUnknown9 (LZP, LEV, MDZ, PHT, LCM, PRO, TPM, PB, VPA)
      • Esaian D.
      • Joset D.
      • Lazarovits C.
      • Dugan P.C.
      • Fridman D.
      Ketamine continuous infusion for refractory status epilepticus in a patient with anticonvulsant hypersensitivity syndrome.
      201295.2 (1.3–10.4)

      F (5); M (4)
      Yes (7); no (2)Prospective studyUnknown (5); malformative (2); Rett syndrome (1); MELAS (1)GCSE (3); focal (1); focal ± SG (5)6d (5 h–26d)5 (4–7; MDZ, TPM, CBZ, LEV, THP, PRO, VPA, PHT, PB, CZP, ETM, NZP, RUF)
      • Rosati A.
      • Erario L.M.
      • Ilvento L.
      • Cecchi C.
      • Pisano T.
      • Mirabile L.
      • et al.
      Efficacy and safety of ketamine in refractory status epilepticus in children.
      2012160

      M
      YesCase reportUnknownNCSEWithin hours4 (PHT, MDZ, PRO, LEV)
      • Kramer A.H.
      Early ketamine to treat refractory status epilepticus.
      2011176

      F
      YesCase reportSystemic infection; low AED levelsNCSE9d10 (VPA, MDZ, LEV, PHT, PRO, PB, LTG, CBZ, RGT, TPM)
      • Yeh P.S.
      • Shen H.N.
      • Chen T.Y.
      Oral ketamine controlled refractory nonconvulsive status epilepticus in an elderly patient.
      2010126

      M
      NoCase reportUnknownGTCSE; NCSE58d8 (DZP, VPA, MDZ, LEV, PHT, TPM, PRO, THP)
      • Hsieh C.Y.
      • Sung P.S.
      • Tsai J.J.
      • Hwang C.W.
      Terminating prolonged refractory status epilepticus using ketamine.
      2008122

      F
      YesCase reportUnknownGCSE13d5 (LZP, PHT, THP, LEV, PRO)
      • Prüss H.
      • Holtkamp M.
      Ketamine successfully terminates malignant status epilepticus.
      2005115

      M
      NoCase reportUndefined, maybe encephalitisUnknownUnknown4 (TPM, MDZ, PRO, PB)
      • Kramer U.
      • Shorer Z.
      • Ben-Zeev B.
      • Lerman-Sagie T.
      • GoldbergStern H.
      • Lahat E.
      Severe refractory status epilepticus owing to presumed encephalitis.
      2003144

      M
      YesCase reportNeurosyphilisGTCSE; NCSE5d5 (LZP, PHT, LTG, VPA, PRO)
      • Ubogu E.E.
      • Sagar S.M.
      • Lerner A.J.
      • Maddux B.N.
      • Suarez J.I.
      • Werz M.A.
      Ketamine for refractory status epilepticus: a case of possible ketamine-induced neurotoxicity.
      200354 (4–7)

      F (3); M (2)
      Yes (5)Prospective studyEpilepsy syndromeNCSE (5)4.4w (2–10w)0–3 (LZP, MDZ, prednisolone)
      • Mewasingh L.D.
      • Skhara T.
      • Aeby A.
      • Christiaens F.J.
      • Dan B.
      Oral ketamine in paediatric non-convulsive status epilepticus.
      1998113

      F
      NoCase reportUnknownGTCSE28d8 (DZP, PHT, PB, LZP, LIDO, VPA, PRO, MDZ)
      • Sheth R.D.
      • Gidal B.E.
      Refractory status epilepticus: response to ketamine.
      19961Unknown

      M
      YesRetrospective studyCortical dysplasiaNCSEUnknownUnknown
      • Walker M.C.
      • Howard R.S.
      • Smith S.J.
      • Miller D.H.
      • Shorvon S.D.
      • Hirsch S.D.
      Diagnosis and treatment of status epilepticus on a neurological intensive care unit.
      AED: antiepileptic drug; CBZ: carbamazepine; CLB: clobazam; CNS: central nervous system; CZP: clonazepam; d: days; DZP: diazepam; ETM: ethosuximide; F: female; FCSE: focal convulsive status epilepticus; GCSE: generalized convulsive status epilepticus; GTCSE: generalized tonic-clonic status epilepticus; GBP: gabapentin; h: hours; KET: ketamine; LCM: lacosamide; LEV: levetiracetam; LTG: lamotrigine; LZP: lorazepam; M: male; MDZ: midazolam; MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; NCSE: nonconvulsivestatusepilepticus; NZP: nitrazepam; PB: phenobarbital; PGB: pregabalin; PHT: phenytoin; PRO: propofol; RGT: retigabine; RSE: refractory status epilepticus; RUF: rufinamide; SE: status epilepticus; SG: secondary generalization; TPM: topiramate; THP: thiopental; VPA: valproate; w: weeks; Y: years.
      Table 2Ketamine treatment regime and efficacy.
      YearNumber of patientsAdministrationDosagesDuration of treatmentOnset timeTime from ketamine initiation to seizure cessationSeizure responseOutcomeReferences
      BolusInfusionOral
      20141Intravenous2 bolus of 2 mg/kg10–24 μg/kg/min02dUnknownUnknown15d without seizuresSE reappeared and died
      • Tarocco A.
      • Ballardini E.
      • Garani G.
      Use of ketamine in a newborn with refractory status epilepticus: a case report.
      201358IntravenousMedian 1.5 mg/kg (max 5 mg/kg)Median: 2.75 mg/kg/h (max 10 mg/kg/h)06 h–27dUnknownUnknown57% resolvedGood outcome (5%); mortality (45%)
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      201311Intravenous1–2 mg/kg1.3 mg/kg/h (0.45–2.1 mg/kg/h)09.8 (4–28d)Unknown9.8 (4–28d)Completely resolvedHome/rehabilitation (5); need nursing (4); died (2)
      • Synowiec A.S.
      • Singh D.S.
      • Yenugadhati V.
      • Valeriano J.P.
      • Schramke C.J.
      • Kelly K.M.
      Ketamine use in the treatment of refractory status epilepticus.
      20132Intravenous010–40 μg/kg/min03d and 12dWithin several hours; Within 30 min3d and 12dCompletely resolvedRehabilitation (2)
      • Zeiler F.A.
      • Kaufmann A.M.
      • Gillman L.M.
      • West M.
      • Silvaggio J.
      Ketamine for medically refractory status epilepticus after elective aneurysm clipping.
      20131Intravenous1.5 mg/kg1.2–3.75 mg/kg/h012dUnknownWithin 3dCompletely resolvedRehabilitation
      • Esaian D.
      • Joset D.
      • Lazarovits C.
      • Dugan P.C.
      • Fridman D.
      Ketamine continuous infusion for refractory status epilepticus in a patient with anticonvulsant hypersensitivity syndrome.
      20129Intravenous0.75 mg/kg0.6–3.3 mg/kg/h02dImmediately12 hCompletely resolvedHome
      • Rosati A.
      • Erario L.M.
      • Ilvento L.
      • Cecchi C.
      • Pisano T.
      • Mirabile L.
      • et al.
      Efficacy and safety of ketamine in refractory status epilepticus in children.
      20121Intravenous2 bolus of 2–3 mg/kg every 5 min36.5 μg/kg/min (10–60 μg/kg/min)06d (3–17d)UnknownUnknownCompletely resolved in 6Unknown
      • Kramer A.H.
      Early ketamine to treat refractory status epilepticus.
      20111Intravenous followed with oral1.5 mg/kg0.05–4 mg/kg/h1500–2000 mg/dUnknownUnknownUnknownCompletely resolvedHome
      • Yeh P.S.
      • Shen H.N.
      • Chen T.Y.
      Oral ketamine controlled refractory nonconvulsive status epilepticus in an elderly patient.
      20101Intravenous0.5 mg/kg0.38–1.5 mg/kg/h07d2d5dCompletely resolvedRehabilitation
      • Hsieh C.Y.
      • Sung P.S.
      • Tsai J.J.
      • Hwang C.W.
      Terminating prolonged refractory status epilepticus using ketamine.
      20081Intravenous0.5 mg/kg0.4–3.2 mg/kg/h014dUnknown10dCompletely resolvedComatose, tetraplegic
      • Prüss H.
      • Holtkamp M.
      Ketamine successfully terminates malignant status epilepticus.
      20051IntravenousUnknownUnknownUnknownUnknownUnknownUnknownFailureDied
      • Kramer U.
      • Shorer Z.
      • Ben-Zeev B.
      • Lerman-Sagie T.
      • GoldbergStern H.
      • Lahat E.
      Severe refractory status epilepticus owing to presumed encephalitis.
      20031Intravenous2 mg/kg2–7.5 mg/kg/h05dUnknown2dCompletely resolvedDiffused cerebral atrophy
      • Ubogu E.E.
      • Sagar S.M.
      • Lerner A.J.
      • Maddux B.N.
      • Suarez J.I.
      • Werz M.A.
      Ketamine for refractory status epilepticus: a case of possible ketamine-induced neurotoxicity.
      20035Oral001.5 mg/kg/d in two divided doses5dUnknownWithin 1–2dCompletely resolvedGood outcome (5)
      • Mewasingh L.D.
      • Skhara T.
      • Aeby A.
      • Christiaens F.J.
      • Dan B.
      Oral ketamine in paediatric non-convulsive status epilepticus.
      19981Intravenous2 μg/kg7.5 μg/kg/h014d90s2dCompletely resolvedShort-term memory and cognitive deficits
      • Sheth R.D.
      • Gidal B.E.
      Refractory status epilepticus: response to ketamine.
      19961Intravenous0100 mg/h0UnknownUnknownUnknownFailureControlled by sub-pial transection
      • Walker M.C.
      • Howard R.S.
      • Smith S.J.
      • Miller D.H.
      • Shorvon S.D.
      • Hirsch S.D.
      Diagnosis and treatment of status epilepticus on a neurological intensive care unit.
      d: day(s); h: hour(s); kg: kilogram; min: minutes; s: seconds; SE: status epilepticus; μg: microgram.

      3.2 An evidence-based clinical study on the use of ketamine to treat RSE

      In 2014, Zeiler et al. [
      • Zeiler F.A.
      • Teitelbaum J.
      • Gillman L.M.
      • West M.
      NMDA antagonists for refractory seizures.
      ] published a systematic review of NMDA-receptor antagonists for the treatment of RSE. Twenty-three studies were ultimately included in this analysis, which included a total of 162 patients consisting of 110 adults (range 19–88 years old) and 52 children (range 2 months–18 years old). In all of these studies, ketamine was used to treat RSE. This study revealed that ketamine was effective for 56.5% (59/110) of the adults and 63.5% (33/52) of the children and that the rate of side effects related to ketamine administration was 1.8% (2/110) in the adults and 17.3% (9/52) in the children, supporting the use of ketamine for the treatment of RSE in children and adults and indicating that adverse reaction rates related to ketamine administration were relatively small. However, this review also has some limitations such as the retrospective heterogeneous nature of the data, the small sample sizes of the studies included, and the heterogeneity of the medications prior to ketamine treatment, the timing of ketamine use, and the dosage and duration of this drug. Thus, larger prospective studies are necessary to assess the efficacy and safety of ketamine treatment in RSE.

      4. The possible antiepileptic and neuroprotective mechanisms of ketamine action

      4.1 The possible mechanism of the effects of ketamine on SE

      With decreased GABA-receptor activity, the expression of the NMDA receptor is up-regulated, and the activity of this receptor is also increased in late SE. The NMDA receptor is one of the main receptor subtypes that mediates glutamatergic neurotransmission, and it is also a nonspecific cation channel that contains the NMDA binding site and the phencyclidine (PCP) binding site [
      • Lodge D.
      • Johnson K.M.
      Noncompetitive excitatory amino acid receptor antagonists.
      ]. When the cell is at rest, Mg2+, located on the inner side of the channels, blocks the channels. When the cell membrane is depolarized, the combined actions of glutamate and glycine on the NMDA receptor remove the blocking effect of Mg2+, and the activation of the receptor can induce influxes of calcium and sodium, which participate in the transmission of excitatory nerve impulses in different brain circuits [
      • Dingledine R.
      • Borges K.
      • Bowie D.
      • Traynelis S.F.
      The glutamate receptor ion channels.
      ]. However, ketamine, which is a noncompetitive antagonist of the NMDA receptor, can block the flow of Ca2+ and Na+ by combining with the PCP site inside of the ion channel of the NMDA receptor and can thereby reduce epileptiform burst discharges and after-potentials, thus inhibiting the conduction of excitation and playing an anticonvulsive role [
      • Aram J.A.
      • Martin D.
      • Tomczyk M.
      • Zeman S.
      • Millar J.
      • Pohler G.
      • et al.
      Neocortical epileptogenesis in vitro: studies with N-methyl-d-aspartate, phencyclidine, sigma and dextromethorphan receptor ligands.
      ].

      4.2 The neuroprotective effects of ketamine

      With prolonged SE, cell depolarization also continues, leading to the excessive release of excitatory neurotransmitters that can bind to a variety of receptors to produce neurotoxicity. Among these receptors, the NMDA receptor might play a critical role in this effect [
      • Olney J.W.
      • Collins R.C.
      • Sloviter R.S.
      Excitotoxic mechanisms of epileptic brain damage.
      ,
      • Gardoni F.
      • Di Luca M.
      New targets for pharmacological intervention in the glutamatergic synapse.
      ,
      • Kew J.N.
      • Kemp J.A.
      Ionotropic and metabotropic glutamate receptor structure and pharmacology.
      ,
      • Kohl B.K.
      • Dannhardt G.
      The NMDA receptor complex: a promising target for novel antiepileptic strategies.
      ,
      • Stone T.W.
      • Addae J.I.
      The pharmacological manipulation of glutamate receptors and neuroprotection.
      ]. do Nascimento et al. [
      • do Nascimento A.L.
      • Dos Santos N.F.
      • Campos Pelágio F.
      • Aparecida Teixeira S.
      • de Moraes Ferrari E.A.
      • Langone F.
      Neuronal degeneration and gliosis time-course in the mouse hippocampal formation after pilocarpine-induced status epilepticus.
      ] detected hippocampal neuronal damage in rats in which SE had been induced by pilocarpine. Using Fluoro-Jade (FJB) and cresyl violet staining, these authors detected multiple sites of neuronal damage 3 h, 6 h, 12 h, 24 h, 1 week, and 3 weeks after prolonged SE. These sites of damage were primarily located in the hippocampal dentate gyrus, the CA1 zone, and the CA3 zone. Moreover, the neuronal damage was most extensive in the dentate hilus after 3 and 12 h of seizures (P < 0.05). However, one week after the seizures, the greatest neuronal damage was located in the pyramidal cell layer of the CA1 and CA3 regions in the hippocampus (P < 0.05), and the most serious neurotoxicity was observed in the hippocampal CA1 pyramidal cell layer (P < 0.05). The NMDA receptor antagonist ketamine not only blocks the influx of Ca2+ but also exerts anti-inflammatory and antioxidant effects [
      • Potter D.E.
      • Choudhury M.
      Ketamine: repurposing and redefining a multifaceted drug.
      ,
      • Aroni F.
      • Iacovidou N.
      • Dontas I.
      • Pourzitaki C.
      • Xanthos T.
      Pharmacological aspects and potential new clinical applications of ketamine: reevaluation of an old drug.
      ]. Therefore, ketamine exerts protective effects in the central nervous system. Fujikawa [
      • Fujikawa D.G.
      The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus.
      ] used pilocarpine to induce epilepsy in a rat model and then administered 100 mg/kg ketamine or saline to the rats via intraperitoneal injection after 10 min of seizures. Three hours later, the seizures were terminated with intraperitoneal injections of diazepam and phenobarbital. After 24 h, these authors performed perfusion fixation to obtain slices of the rat brains, which were observed under a microscope. They found that, in the 5 rats that had been injected with saline, neuronal damage was observed in 24 of 25 brain regions; however, in the 7 rats that received ketamine treatment, the drug was found to exert neuroprotective effects in 22 of the 24 damaged brain regions. Regardless of whether the seizures were ultimately terminated, this neuroprotection remained present and was beneficial to the recovery from SE.

      5. Onset time

      Ketamine displays relatively high fat solubility and a low plasma protein binding rate, causing it rapidly penetrate the blood–brain barrier; thus, ketamine exhibits the property of rapid onset. It has been reported that, when ketamine is administered intravenously, the interval to the maximum plasma concentration (Tmax) is from 1 to 5 min, and when ketamine is administered orally, the Tmax is from 15 to 30 min [
      • Craven R.
      Ketamine.
      ]. As observed by Kramer [
      • Kramer A.H.
      Early ketamine to treat refractory status epilepticus.
      ], when a bolus of 50 mg of ketamine was intravenously administered, followed by infusion at an initial rate of 0.6 mg/kg/h, reduced seizure frequency, shortened seizure duration, and decreased epileptiform discharge amplitude were immediately observed, indicating that ketamine acts rapidly in the treatment of RSE. This conclusion has been supported by other studies [
      • Sheth R.D.
      • Gidal B.E.
      Refractory status epilepticus: response to ketamine.
      ,
      • Andrade C.
      • Franca S.
      • Sampaio M.
      • Ribeiro A.
      • Oliveira J.M.
      • Ribeiro J.A.M.
      • et al.
      Successful use of ketamine in pediatric super-refractory status epilepticus—case report.
      ]. Additionally, Sheth and Gidal [
      • Sheth R.D.
      • Gidal B.E.
      Refractory status epilepticus: response to ketamine.
      ] noted that the onset time of intravenous ketamine was within 90 s after initiation. However, in the majority of cases, seizures are often completely terminated within 24 h when ketamine is selected for the treatment of SE [
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      ]. When ketamine is administered orally, the interval to complete seizure control is within 24–48 h [
      • Mewasingh L.D.
      • Skhara T.
      • Aeby A.
      • Christiaens F.J.
      • Dan B.
      Oral ketamine in paediatric non-convulsive status epilepticus.
      ].

      6. Dosage

      Currently, the administration of ketamine for the treatment of RSE involves intravenous and oral routes. When ketamine is selected for RSE treatment following prolonged SE, it maybe typically suitable after 5–6 anticonvulsants have been found to be ineffective. This treatment choice is summarized from previous successful reports [
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      ,
      • Rosati A.
      • Erario L.M.
      • Ilvento L.
      • Cecchi C.
      • Pisano T.
      • Mirabile L.
      • et al.
      Efficacy and safety of ketamine in refractory status epilepticus in children.
      ,
      • Tarocco A.
      • Ballardini E.
      • Garani G.
      Use of ketamine in a newborn with refractory status epilepticus: a case report.
      ], and the rationale for its use is based on prolonged seizure duration, decreased numbers of active GABA receptors, gradual elevation of NMDA receptor activity, and increased numbers of NMDA receptors [
      • Deeb T.Z.
      • Maguire J.
      • Moss S.J.
      Possible alterations in GABAA receptor signaling that underlie benzodiazepine-resistant seizures.
      ,
      • Feng H.J.
      • Mathews G.C.
      • Kao C.
      • Macdonald R.L.
      Alterations of GABAA-receptor function and allosteric modulation during development of status epilepticus.
      ,
      • Dingledine R.
      • Borges K.
      • Bowie D.
      • Traynelis S.F.
      The glutamate receptor ion channels.
      ,
      • Loscher W.
      Mechanisms of drug resistance in status epilepticus.
      ,
      • Fujikawa D.G.
      Prolonged seizure and cellular injury: understanding the connection.
      ].

      6.1 Intravenous administration

      (1) Intravenous bolus followed by continuous infusion: when ketamine is used for adult RSE, an average loading dose of 1.5 mg/kg, followed by an average infusion rate of 2.75 mg/kg/h for 4 days (0–24 days) is recommended [
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      ]. An analysis by Gaspard et al. [
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      ] revealed that the maximum loading dose of ketamine is 5 mg/kg and that the maximum infusion rate is 10 mg/kg/h. Moreover, Synowiec et al. [
      • Synowiec A.S.
      • Singh D.S.
      • Yenugadhati V.
      • Valeriano J.P.
      • Schramke C.J.
      • Kelly K.M.
      Ketamine use in the treatment of refractory status epilepticus.
      ] found that a bolus dose of 1–2 mg/kg, followed by maintenance at an infusion rate of 1.3 mg/kg/h (range 0.45–2.1 mg/kg/h) for 9.8 days (range 4–28 days), resulted in a successful seizure control rate of 100% (11/11). When ketamine is administered to children, we recommend a 2–3 mg/kg bolus of ketamine every 5 min for a total of 2 administrations, followed by maintenance at a rate of 40 μg/kg/min (range 10–60 μg/kg/min) for 6.7 days (range 3–17 days) [
      • Rosati A.
      • Erario L.M.
      • Ilvento L.
      • Cecchi C.
      • Pisano T.
      • Mirabile L.
      • et al.
      Efficacy and safety of ketamine in refractory status epilepticus in children.
      ]. (2) Intravenous infusion: Zelier et al. [
      • Zeiler F.A.
      • Kaufmann A.M.
      • Gillman L.M.
      • West M.
      • Silvaggio J.
      Ketamine for medically refractory status epilepticus after elective aneurysm clipping.
      ] performed continuous infusion of ketamine at 10–40 μg/kg/min for the treatment of RSE, and the seizures in all of the patients were ultimately effectively controlled (2/2). In a report by Gosselin-Lefebvre et al. [
      • Gosselin-Lefebvre S.
      • Rabinstein A.
      • Rossetti A.
      • Savard M.
      Ketamine usefulness in refractory status epilepticus: a retrospective multicenter study.
      ], ketamine was initiated in 9 SE patients when 8 AEDs had failed, and the seizures had persisted for 12 days. The average rate of ketamine infusion was 5 mg/kg/h (range 2–15 mg/kg/h). Ultimately, the seizures were completely halted in 4 patients (4/9), partially controlled in 3 patients (3/9), and not controlled in only 2 patients (2/9). Finally, the recommended dosage for children is 32.5 μg/kg/min (range 10–60 μg/kg/min) when intravenous infusion of ketamine alone is selected [
      • Rosati A.
      • Erario L.M.
      • Ilvento L.
      • Pisano T.
      • Mirabile L.
      • Guerrini R.
      An ongoing open-label uncontrolled study of the efficacy and safety of ketamine in children with refractory status epilepticus.
      ].

      6.2 Oral administration

      The use of oral ketamine to treat RSE has only been reported in NCSE. The recommended dosage of ketamine is 1500–2000 mg/d for adults [
      • Yeh P.S.
      • Shen H.N.
      • Chen T.Y.
      Oral ketamine controlled refractory nonconvulsive status epilepticus in an elderly patient.
      ] and 1.5 mg/kg/d, administered as two separate doses, for children [
      • Mewasingh L.D.
      • Skhara T.
      • Aeby A.
      • Christiaens F.J.
      • Dan B.
      Oral ketamine in paediatric non-convulsive status epilepticus.
      ].
      The usage of ketamine for the treatment of RSE is summarized in Table 3.
      Table 3Usage of ketamine for the treatment of RSE.
      AdministrationIndicationContraindications
      • Fernandez A.
      • Claassen J.
      Refractory status epilepticus.
      DosagesOnset time
      • Craven R.
      Ketamine.
      AdultsChildren (0–18 y)
      OralAfter 5–6 ADEs failedAllergic

      Severe hypertension
      1500–2000 mg/d
      • Yeh P.S.
      • Shen H.N.
      • Chen T.Y.
      Oral ketamine controlled refractory nonconvulsive status epilepticus in an elderly patient.
      1.5 mg/kg/d in two divided doses
      • Mewasingh L.D.
      • Skhara T.
      • Aeby A.
      • Christiaens F.J.
      • Dan B.
      Oral ketamine in paediatric non-convulsive status epilepticus.
      15–30 min
      Bolus and infusionAfter 5–6 ADEs failedAllergic

      Severe hypertension
      Bolus: 1–5 mg/kg

      Infusion: 0.45–10 mg/kg/h
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      ,
      • Synowiec A.S.
      • Singh D.S.
      • Yenugadhati V.
      • Valeriano J.P.
      • Schramke C.J.
      • Kelly K.M.
      Ketamine use in the treatment of refractory status epilepticus.
      Bolus × 2: 2–3 mg/kg

      Infusion: 2.4 mg/kg/h (range 0.6–3.6 mg/kg/h)
      • Rosati A.
      • Erario L.M.
      • Ilvento L.
      • Cecchi C.
      • Pisano T.
      • Mirabile L.
      • et al.
      Efficacy and safety of ketamine in refractory status epilepticus in children.
      1–5 min
      InfusionAfter 5–6 ADEs failedAllergic

      Severe hypertension
      0.6–15 mg/kg/h
      • Zeiler F.A.
      • Kaufmann A.M.
      • Gillman L.M.
      • West M.
      • Silvaggio J.
      Ketamine for medically refractory status epilepticus after elective aneurysm clipping.
      ,
      • Gosselin-Lefebvre S.
      • Rabinstein A.
      • Rossetti A.
      • Savard M.
      Ketamine usefulness in refractory status epilepticus: a retrospective multicenter study.
      1.95 mg/kg/h (range 0.6–3.6 mg/kg/h)
      • Rosati A.
      • Erario L.M.
      • Ilvento L.
      • Pisano T.
      • Mirabile L.
      • Guerrini R.
      An ongoing open-label uncontrolled study of the efficacy and safety of ketamine in children with refractory status epilepticus.
      1–5 min

      7. Adverse reactions and precautions for ketamine use

      Zeiler et al. [
      • Zeiler F.A.
      • Teitelbaum J.
      • Gillman L.M.
      • West M.
      NMDA antagonists for refractory seizures.
      ] performed a systematic review, which indicated that the adverse reactions related to ketamine treatment for RSE were rare. However, due to the lack of controlled studies related to this topic, concern remains warranted, primarily regarding psychiatric symptoms during anesthesia recovery, increased intracranial pressure (ICP), increased secretion of saliva, increased intraocular pressure, and arrhythmia. Details regarding the adverse reactions and precautions for ketamine use are described as follows.

      7.1 Psychiatric symptoms

      The psychiatric symptoms caused by treatment of RSE with ketamine are primarily related to hallucinations, delirium, a floating sensation, dreams, and blurred vision [
      • Reich D.L.
      • Silvay G.
      Ketamine: an update on the first twenty five years of clinical experience.
      ]. The incidences of these symptoms are 5–30%. Children are at the lowest risk for psychiatric symptoms, which are more likely to occur in patients over 16 years old, in female patients, or when the administration rate or dosage is too high [
      • Reich D.L.
      • Silvay G.
      Ketamine: an update on the first twenty five years of clinical experience.
      ]. A quiet and relaxing environment can help to reduce the incidences of these side effects [
      • Himmelseher S.
      • Durieux M.
      Ketamine for perioperative pain management.
      ]. Additionally, prophylactic administration of 3.75–7.5 mg of midazolam could reduce the probability and severity of adverse reactions [
      • Himmelseher S.
      • Durieux M.
      Ketamine for perioperative pain management.
      ].

      7.2 Increased ICP

      As early as 40 years ago, there were reports that ketamine improved the cerebral metabolic rate and increased cerebral blood flow, thereby increasing ICP [
      • Takeshita H.
      • Okuda Y.
      • Sari A.
      The effects of ketamine on cerebral circulation and metabolism in man.
      ]. However, due to the developments of related studies, researchers have proposed new hypotheses regarding the effects of ketamine on ICP, finding that, when patients are breathing spontaneously, ketamine causes intracranial hypertension that is primarily associated with increased PaCO2 in the arterial blood; however, when patients are sedated and mechanically ventilated, the effects of ketamine on ICP are, in fact, very small [
      • Himmelseher S.
      • Durieux M.
      Ketamine for perioperative pain management.
      ]. A systematic evaluation, published in 2014, showed that, when ketamine was used for nontraumatic neurological diseases, it did not increase ICP, and in some cases, ketamine might even reduce ICP [
      • Zeiler F.A.
      • Teitelbaum J.
      • West M.
      • Gillman L.M.
      The ketamine effect on intracranial pressure in nontraumatic neurological illness.
      ]. Gaspard et al. [
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      ] studied 58 patients treated with ketamine and observed only 2 cases of mild ICP elevation. Actually, prior to the initiation of ketamine, these 2 patients had suffered from brain edema secondary to anoxic brain injury.

      7.3 Increased secretion of saliva

      Ketamine can induce the secretion of saliva, accompanied by the hypersecretion of bronchial mucus, which can lead to transient inhibition of the respiratory system or apnea. To prevent this adverse effect, anticholinergic drugs, such as scopolamine or atropine, can be prophylactically administered during the clinical application of ketamine treatment [
      • Craven R.
      Ketamine.
      ].

      7.4 Increased intraocular pressure

      The effects of ketamine on intraocular pressure remain controversial [
      • Bergman S.A.
      Ketamine: review of its pharmacology and its use in pediatric anesthesia.
      ]. Some authors believe that ketamine can cause an increase in intraocular pressure [
      • Antal M.
      • Mucsi G.
      • Faludi A.
      Ketamine anesthesia and intraocular pressure.
      ], whereas others have stated that it can reduce intraocular pressure [
      • Chandorkar A.G.
      • Jain P.K.
      • Albal M.V.
      Modulations in intraocular pressure under ketamine anaesthesia.
      ] or that ketamine exerts no effect on intraocular pressure [
      • Blumberg D.
      • Congdon N.
      • Jampe H.
      • Gilbert D.
      • Elliott R.
      • Rivers R.
      • et al.
      The effects of sevoflurane and ketamine on intraocular pressure in children during examination under anesthesia.
      ]. This discrepancy may be attributable to the many factors that can influence intraocular pressure, such as the aqueous humor circulation, extraocular muscle tension, choroidal blood flow, vitreous volume, etc. [
      • Aroni F.
      • Iacovidou N.
      • Dontas I.
      • Pourzitaki C.
      • Xanthos T.
      Pharmacological aspects and potential new clinical applications of ketamine: reevaluation of an old drug.
      ]. In fact, the influence of ketamine on intraocular pressure has been shown to be mild and even smaller than the effects of laryngoscopy [
      • Aroni F.
      • Iacovidou N.
      • Dontas I.
      • Pourzitaki C.
      • Xanthos T.
      Pharmacological aspects and potential new clinical applications of ketamine: reevaluation of an old drug.
      ]. Thus, when ketamine is used for RSE, it exerts little effect on intraocular pressure, and the combined use of benzodiazepines can alleviate this effect [
      • Bergman S.A.
      Ketamine: review of its pharmacology and its use in pediatric anesthesia.
      ].

      7.5 Arrhythmia

      The arrhythmias induced by ketamine are often tachyarrhythmias, which might occur because ketamine can excite the sympathetic nervous system and shorten atrial conduction [
      • Haas D.A.
      • Harper D.G.
      Ketamine: a review of its pharmacological properties and use in ambulatory anesthesia.
      ,
      • Wutzler A.
      • Huemer M.
      • Boldt L.H.
      • Parwani A.S.
      • Attanasio P.
      • Tscholl V.
      • et al.
      Effects of deep sedation on cardiac electrophysiology in patients undergoing radiofrequency ablation of supraventricular tachycardia: impact of propofol and ketamine.
      ]. Gaspard et al. [
      • Gaspard N.
      • Foreman B.
      • Judd L.M.
      • Brenton J.N.
      • Nathan B.R.
      • McCoy B.M.
      • et al.
      Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.
      ] examined 58 RSE patients who received ketamine and found that only 3 patients exhibited arrhythmias. Two of these patients exhibited supraventricular tachycardia, and their symptoms were alleviated following the withdrawal of ketamine. The other patient exhibited atrial fibrillation that was relieved using amiodarone.

      7.6 Neurotoxicity

      The effects of ketamine on the human central nervous system remain controversial. In 1991, it was found that ketamine exerts toxic effects on some regions of the cerebral cortex in rats. Ketamine was found to be capable of causing regional neuronal vacuolation or even necrosis, and since this finding, clinicians have become more cautious regarding the selection of this drug. However, over the last 20 years, this conclusion has yet to be confirmed or generally accepted [
      • Olney J.W.
      • Labruyere J.
      • Wang G.
      • Wozniak D.F.
      • Price M.T.
      • Sesma M.A.
      NMDA antagonist neurotoxicity: mechanism and prevention.
      ]. Most researchers believe that regular doses of ketamine cause only mild neurotoxicity, possibly because of the short half-life of this drug in the body and the low affinity of ketamine for NMDA receptors. Moreover, this neurotoxicity is likely limited to very young patients [
      • Wang C.
      • Liu F.
      • Patterson T.
      • Paule M.G.
      • Slikker Jr., W.
      Preclinical assessment of ketamine.
      ,
      • Dorandeu F.
      • Dhote F.
      • Barbier L.
      • Baccus B.
      • Testylier G.
      Treatment of status epilepticus with ketamine, are we there yet.
      ].

      7.7 Precautions for ketamine use

      Considering about the adverse reactions stated above, precautions should be considered during ketamine use. Due to the excitatory effects of ketamine on the central nervous system, the Food and Drug Administration (FDA) recommends that ketamine use be contraindicated in patients with severe hypertension and in patients who are allergic to ketamine. Patients with coronary heart disease, heart failure, glaucoma, atherosclerosis, pulmonary heart disease, pulmonary hypertension, severe intracranial hypertension, pregnancy, a history of mental illness, hyperthyroidism, tachyarrhythmia, adrenal pheochromocytoma, and alcoholism should receive ketamine with caution [
      • U.S. Food and Drug Administration
      KETALAR-ketamine hydrochloride injection.
      ]. Additionally, the FDA has provided the following recommendations [
      • U.S. Food and Drug Administration
      KETALAR-ketamine hydrochloride injection.
      ]: (1) slower infusion rates and gradual increases in the dosage should be considered because, when the ketamine administration rate or dosage is too high, psychiatric symptoms, as well as respiratory depression and apnea, are more likely to occur during recovery from anesthesia; (2) to reduce seizures and ketamine-induced respiratory depression, mechanical ventilation should be employed prior to ketamine initiation, and vital signs, such as breathing status and blood pressure, should be closely monitored; (3) computed tomography should be performed to exclude the presence of intracranial lesions that might cause intracranial hypertension before the selection of ketamine; (4) in the elderly, the minimum possible dose of ketamine should be selected; and (5) ketamine might increase skeletal muscle tension in some patients, which should be distinguished from tonic-clonic seizures.

      8. Conclusions

      Ketamine is a noncompetitive antagonist of glutamatergic NMDA receptors, and its anticonvulsant effects have previously been confirmed. Recent studies have found that, during prolonged seizures, the numbers and activities of GABA receptors gradually decrease; thus, the commonly used first-line and second-line AEDs gradually fail. Simultaneously, the numbers and activities of glutamatergic NMDA receptors increase, often causing RSE and thus providing the possibility of the use of ketamine to treat RSE. Additionally, ketamine exerts neuroprotective effects that could ameliorate RSE-induced neuronal damage. Therefore, in recent years, ketamine has become increasingly used in clinical practice.
      We examined many clinical studies that have investigated the efficacy of ketamine in the treatment of RSE; these studies included multi-center, retrospective studies, prospective cohort studies and case reports. In addition, the results of an evidence-based clinical study, published in 2014, also suggested that ketamine might be of potential benefit, and it reported low adverse reaction rates in the treatment of RSE in children and adults. However, to the best of our knowledge, no controlled studies have been published that have examined the efficacy and safety of ketamine for the treatment of RSE, constituting a limitation of our review. However, it is not ethically permissible to establish randomized controlled trials in patients with RSE, due to the emergent nature and high mortality of this disease and the lack of effective drugs to treat RSE to use as a control. In addition, the unpredictable nature, low recruitment rates, and relatively low incidence rates of RSE have also resulted in a lack of large-sample-size studies. In addition, the first planned RCT focusing on the treatment of RSE was terminated due to insufficient recruitment [
      • Fernandez A.
      • Claassen J.
      Refractory status epilepticus.
      ]. Thus, it will be necessary to conduct robust prospective studies to investigate the regimens, efficacy, and safety of ketamine for the treatment of RSE.

      Conflict of interest

      All the authors declare that they have no conflict of interest.

      Acknowledgements

      This work was supported by the National Clinical Key Specialty Construction Foundation of China and the National Natural Science Foundation of China (grant number is 81271445 ).

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