How close is ketamine to routine use in refractory status epilepticus?

1. Introduction

Status epilepticus (SE) is one of the most critical conditions in the clinic. The International League Against Epilepsy (ILAE) proposed a new definition of SE in 2015 as a continuous seizure activity lasting more than 5, 10, and 10–15 minutes according to the type of SE (tonic-clonic SE, focal SE with impaired consciousness, and absence status epilepticus, respectively) [1]. The etiology of SE is diverse, including internal chronic diseases (e.g. hyponatremia, metabolic acidosis), surgical complications (e.g. traumatic brain injury, sepsis, anesthesia accidents), obstetric and gynecological conditions (e.g. eclampsia, hypoxic-ischemic encephalopathy), pediatric conditions (e.g. newborn intracranial hemorrhage, pulmonary encephalopathy), and other diseases associated with nervous system injury. Most SE cases can be treated with commonly used first-line antiepileptic drugs, such as lorazepam, diazepam, and phenobarbital; however, there are still many patients who do not respond to these medications. This condition is called refractory status epilepticus (RSE) [2]. In 2018, Hirsch et al. [3] proposed a definition for RSE as SE persisting despite administration of at least 2 appropriately selected and dosed parenteral medications, including benzodiazepine, and proposed super-refractory status epilepticus (SRSE) as SE persisting at least 24 hours after appropriate anesthesia treatment. These definitions were fully endorsed by the Critical Care EEG Monitoring Research Consortium and ILAE posted these definitions on its website [4].

The main pathological mechanisms of SE are related to the failure of the seizure termination mechanisms and in the initiation mechanisms of self-sustainment in seizures [1]; abnormalities of neurotransmitters and synaptic receptors play important roles in the formation of SE. Glutamate-induced overexcitation of neurons produces and promotes SE. A typical example is the ingestion of contaminated mussels containing alginic acid, which is a glutamate analog that can cause SE [5]. John et al. [6] summarized the effects of neurotransmitter changes during SE and found that the numbers of N-methyl-D-aspartic acid receptors (NMDAR) on postsynaptic membranes were increased. Overexcitation of glutamatergic neurons also plays an important role in neuronal damage and death in SE, including in excitotoxicity, necrosis, apoptosis, and mitochondrial dysfunction. Thus, antiglutamate treatment has become an important treatment for SE, especially for RSE [6].

2. Ketamine in refractory status epilepticus

Ketamine, a nonselective and noncompetitive antagonist of NMDAR, blocks the influx of Ca²⁺ and Na⁺ by binding to relevant sites inside the ion channel of the NMDAR and consequently inhibiting the transmission of excitatory nerve impulses [7–11]. To understand the efficacy and safety of ketamine in patients with RSE and SRSE, Hofler et al. [12] analyzed data from 42 RSE or SRSE patients, and the results showed that 64% of the patients achieved resolution of SE with no adverse events. To evaluate the efficacy and safety of intravenous ketamine in the treatment of RSE in children, Ilvento et al. [13] analyzed 13 children with RSE, showing that a total of 19 treatments of 13 children obtained a resolution of the RSE in 14/19 episodes. Intravenous administration of ketamine is the conventional method, but enteral administration can also be effective. Pizzi et al. [14] reported a patient with nonconvulsive status epilepticus (NCSE) in whom oral ketamine treatment was continued for 6 months, suggesting that enteral ketamine may be a potential adjunct to intravenous ketamine for the treatment of NCSE. Enteral ketamine can reduce the recurrence of SE, the duration of ICU stays, and intubation-related complications. The United States Food and Drug Administration recently approved using ketamine nasal sprays for treatment-resistant depression along with oral antidepressants [9], providing a new path for ketamine use.

In recent years, ketamine has gradually been used in RSE patients with special etiologies and has achieved good outcomes [7,8]. Anti-NMDAR encephalitis is an autoimmune disease related to the production of antibodies to the NR1 and NR2 subunits of the NMDARs. Most patients have epilepsy seizures and always have RSE new onset, which is difficult to control. Santoro et al. [15] reported that three anti-NMDAR encephalitis cases with SRSE that were successfully treated with ketamine, and the clinical seizure and abnormal discharge on electroencephalogram (EEG) completely disappeared within 48 hours. Alternating hemiplegia of childhood (AHC) is a rare congenital disease and is prone to RSE. Samanta et al. [7] reported two cases of molecularly confirmed AHC patients, both of whom presented with SRSE; a variety of antiepileptic drugs were ineffective, including midazolam and propofol infusion, but they responded promptly after ketamine infusion.

Mutations in NMDAR subunits can lead to multiple childhood epilepsy syndromes and RSE. The GRIN2D recurrent de novo dominant mutation increases the probability of channel opening and reduces the sensitivity of receptors to endogenous negative-regulatory factors and inactivation times after glutamate removal; this kind of RSE improved after treatment with ketamine [16], suggesting that NMDAR antagonists can be used as primary drugs to treat this type of patient [7].

Brain function impairment caused by SE is associated with glutamate excitotoxicity. The use of ketamine in a chemistry-induced rodent epilepsy model showed that it could protect neurons through NMDAR blockade. Patient group-studies also supported that brain damage caused by SE may be caused by glutamates and occur in the same brain regions as in animal studies [17]. Therefore, Fujikawa et al. [17] proposed that ketamine can be used as a neuron protector as early as possible in the continuous process of SE, and it should be continued until the seizures terminate.

Using ketamine to treat RSE is relatively safe. The main adverse reactions are psychiatric symptoms, increased salivary secretions, increased intracranial and intraocular pressure, and heart arrhythmia. However, using ketamine for a prolonged period of time may result in addiction. The risk of severe hypotension is lower for ketamine than for other anesthetics, and it can increase the blood flow to the brain, thus providing a further benefit to the patient [18]. Recently, Talahma et al. [19] found that ketamine is effective and safe to use for SRSE during pregnancy. Intravenous infusion of ketamine successfully controlled the onset of pregnancy RSE, and it had no effect on the outcome of the pregnancy.

However, the efficacy and safety of ketamine are relative. In 2020, Sabharwal et al. [20] studied 79 SRSE patients treated with propofol and/or ketamine and found that the temperatures of 63 patients treated with ketamine were reduced, depending on the use of ketamine in large doses and long courses. Thus, it is thought that ketamine can reduce body temperature by centrally controlled dose-dependent effects. They indicated that further research is needed to clarify the effect of ketamine on lowering body temperature and its effect on the SE.

Meaden et al. [21] also reported that 2 patients who had no epilepsy history had epileptic seizures due to the use of ketamine for programmed sedation and pain management. The authors believe that these cases of seizures following ketamine sedation should be kept in mind by emergency staff.

The most widely accepted anesthetic for the treatment of RSE is midazolam (59%), followed by propofol and barbiturates [22]. Ketamine may also be recommended for RSE cases. Recent clinical studies have supported ketamine’s effectiveness in adults and children with RSE [10,11], and the use of ketamine in RSE is gradually becoming accepted as a routine method.

A deeper understanding of the pathogenesis of SE, and the accumulation of clinical experience, may lead to ketamine become a routine drug for the treatment of RSE. Due to the lack of large randomized controlled studies, the limitations of this approach have not been completely assessed. The results of two ongoing studies (ClinicalTrials.gov identification numbers NCT02431663 and NCT03115489) may provide new information that sheds light on these issues [6,23].

3. Conclusion

In conclusion, SE is a common clinical emergency and can be caused by a large number of diseases. The failure of seizure termination mechanisms and initiation mechanisms of self-sustainment in seizures are common etiologies of SE. Excitatory glutamate participates in the initiation, propagation, and maintenance of SE and is also an important cause of neuronal degeneration and necrosis. Ketamine is a nonselective antagonist of the glutamate NMDAR that effectively antagonizes glutamate receptors that are increased at synapses after SE, thus treating RSE. When patients show resistance to benzodiazepines, ketamine should be considered as early as possible to reduce neuronal damage. Ketamine has an obvious effect on RSE in adults and children and can be administered intravenously, orally, and potentially intranasally. The availability of ketamine nasal spray may make it easier to use. A combination strategy including midazolam, other non-benzodiazepine anticonvulsants such as valproic acid, phenobarbital, and ketamine may be more effective in the treatment of SRSE. Ketamine is becoming more widely accepted and, depending on the results of ongoing clinical trials, may become routine in the future.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported by grants from the National Natural Science Foundation of China (Nos. 81471319 and 81671301) and the National Clinical Key Specialty Construction Foundation of China.