Ketamine in Refractory and Super-Refractory Seizures: A Retrospective Observational Study
Article information
Abstract
Background
Super-refractory status epilepticus refers to drug-resistant status epilepticus that persists or recurs following the continuous administration of intravenous anaesthetics for more than 24 hours or when tapered after 24 hours. Ketamine could play an important role in terminating such seizures.
Methods
This retrospective observational study was conducted in a tertiary care Neurosciences hospital of eastern India. Records of patients of refractory status epilepticus (SE) who received ketamine and underwent scalp EEG/ continuous EEG in the intensive therapy unit were reviewed and their clinical, detailed treatment and investigation records were analysed. Records of patients admitted from 2019 to 2023 with a diagnosis of super-refractory status epilepticus (SRSE) were screened. There were 14 cases of SRSE who received ketamine infusion. Seizure control (both clinical and/or electroencephalographic), cardiovascular and intracranial haemodynamic parameters, and final outcome of the patients were analysed.
Results
Majority had new onset SE of varying etiology and were treated with antiseizure medications prior to anesthetic drug administration. The median ketamine infusion dose was 5mg/kg/hr and duration ranged from 1-30 days. All required mechanical ventilation and 71.4% were on vasopressor support. Combination of ketamine and low dose midazolam effectively suppressed epileptic discharges and improved haemodynamic stability in 42.9 % cases. Except for two patients who had associated sepsis, the rest had a favorable outcome.
Conclusion
This study has generated data about the effectiveness and safety of ketamine in controlling seizures in a cohort of SRSE patients. However, further studies are required to establish its efficacy and safety.
INTRODUCTION
Refractory status epilepticus is defined as status epilepticus (SE) which can not be controlled in terms of clinical manifestations or epileptiform discharges following the administration of benzodiazepines (midazolam, lorazepam and alike) and anticonvulsants (phenytoin, fosphenytoin, valproate, levetiracetam and alike)1). Super-refractory status epilepticus (SRSE) refers to drug-resistant status epilepticus that persists or recurs following the continuous administration of intravenous anaesthetic agents for more than 24 hours or when tapered after 24 hours2). If the seizure duration exceeds 30 minutes, the mortality rate is reported to be about 19%3) and in patients with RSE, the rate is 23-61%4). Treatment often requires anaesthetic drugs which have their own adverse effects. Ketamine could play an important role in the treatment of SRSE by altering glutamate metabolism, particularly in patients who exhibit a poor response to benzodiazepines.
Prolonged seizures result in a decline in the number of gamma aminobutyric acid (GABA) A receptors on the postsynaptic receptors, but the number of inactive GABA-A receptors increases5,6). These changes cause a significant reduction in the efficacy of antiepileptic drugs targeting the GABAergic system. Increased doses of AEDs might restore the efficacy but are often associated with adverse effects on cardiopulmonary function, thus limiting their clinical applications at increased doses. It has been reported that the number and activities of glutamate-sensitive N-methyul-D-aspartate (NMDA) receptors increase when the activity of GABA receptors decrease7). Ketamine is an NMDA receptor antagonist which blocks neurotransmission8,9). Thus it has been proposed as a new therapeutic agent for the treatment of status epilepticus10-12).
We used ketamine in refractory status epilepticus in few patients in the intensive therapy unit of our hospital.
METHODS
Cases of RSE and SRSE treated with intravenous ketamine from 2019 to 2023 were retrospectively identified from hospital records. Their clinical, pharmacy records and investigation reports were reviewed. Data were collected using a standardised data sheet (Table 1) and all variables were available including loading dosages, maximum infusion rates, duration of infusions and outcomes (clinical and electroencephalographic). Anaesthetic drugs included midazolam, propofol and ketamine. Control of SE was defined as cessation of clinical, electroencephalographic ictal manifestations and burst suppression as ascertained by continuous video-EEG monitoring (4 cases) or clinical evaluation and intermittent EEG. Adverse events were attributed to ketamine if they occurred after initiation of ketamine and if they led to lowering of the dose or discontinuation.
Patient and seizure characteristics (14 cases of SRSE)
RESULTS
Amongst 14 cases of RSE, most of the patients had new onset refractory status epilepticus of unknown etiology. There had been variability in the administration of ketamine. Loading dose was 2mg/kg followed by a continuous infusion 2-8 mg/kg/hr (median 5mg/kg/hr). Ketamine was a part of a multi-drug regimen for super refractory status epilepticus. The duration of infusion ranged from1 day to 30 days (Table 2).
Usage of ketamine
There were no specific drug combinations that improved response to ketamine. But timely combination of ketamine and low dose midazolam effectively suppressed epileptic discharges and improved haemodynamic stability in 42.9 % (6 out of 14 cases). The overall mortality rate was 14.3% (2 out of 14 cases). Dose and duration of exposure to ketamine were not related to mortality.
Analysis of the trend in seizure control showed that 3 patients had seizure control within 24 hours of ketamine initiation while another 3 had seizure control within 48 hours of ketamine initiation. None of the patients had seizure after ketamine discontinuation, thus all had responded to ketamine.
The two patients who died had their seizures controlled but succumbed to sepsis.
The mean dose of midazolam when ketamine was initiated was 0.19 mg/kg/hr.
Analysis of the effects of ketamine on MAP revealed that in 5 patients, nor-adrenaline support requirement did not decrease after starting ketamine, while in the others, they were haemodynamically stable and there was subsequent decrease in the requirement of vasopressors/ no need of vasopressors. None of the patients had increase in intracranial pressure (ICP) while on ketamine infusion.
All patients required mechanical ventilation and 71.4 % (10 out of 14 cases) required vasopressors. Among these 10 patients, 5 patients had infections and features of sepsis and so required vasopressors, of whom the vasopressor requirement increased even after starting ketamine in 2 patients and they ultimately died. The remaining 5 patients had hypotension due to the administration of midazolam/ propofol and the requirement of vasopressor reduced on starting ketamine infusion.
One patient had dissociative symptoms due to prolonged administration of ketamine, thus the dose was reduced and gradually tapered off in that patient and the symptoms resolved.
DISCUSSION
This observational, single centre study has provided data on the use and effectiveness and safety of intravenous ketamine in a cohort of SRSE patients. 50% of the patients had new onset refractory status epilepticus of unknown etiology (NORSE) which has a poor prognosis compared to those with an identified cause. The NORSE patients received corticosteroids, immunotherapy and other anti-epileptics (levetiracetam, lamotrigine, clobazam, phenobarbitone and perampanel) along with ketamine and it was found to be effective in seizure control. In the group of patients who had previous documented history of seizure disorder, 4 had intracranial haematomas, one each had a meningioma and left sided posterior cerebral arterial territory infarction. Seizures were controlled in these patients with the administration of ketamine when conventional anti-epileptics failed to terminate them. In our study, we found that timely administration of ketamine achieved epileptic suppression in 12 cases, while 2 had succumbed to sepsis. It also reduced the dosage of midazolam and thus improved haemodynamic stability in 42.9 % cases.
We compared our study results with other published studies globally. The study from Canada by Alkhachroum et al.13) retrospectively evaluated 68 SRSE patients on ketamine infusion. The study observed that seizure frequency decreased within 24 hours of ketamine administration in about 55% cases. The mean ketamine dose was 2.2 ± 1.8 mg/kg/h, and the median duration was 2 days. In our study the median dose of ketamine infusion was 5mg/kg/hour which was higher compared to the above study. Similarly the duration of ketamine infusion in our study was larger compared to the Canadian study. However the mean dose and duration of midazolam when ketamine infusion was initiated was comparable.
With respect to the effects of ketamine infusion on hemodynamic parameters our results were comparable as it reduced vasopressor requirements in majority of the patients and there were none who had developed raised ICP.
A systematic review published in 2014 on NMDA receptor antagonists for the treatment of RSE and found ketamine to be efficacious14). A case series15) also reported that early combination of ketamine and low dose midazolam effectively suppressed epileptic discharges and restored haemodynamic stability. A single centre retrospective study16) also suggested that ketamine was an effective drug in RSE/SRSE and suggested that earlier and prolonged infusion, as well as combination with benzodiazepines may increase its efficacy.
Information regarding the therapeutic dosage or use of ketamine for the management of status epilepticus is scarce. In a case series17) published in 2012 it was shown that doses as high as 7.5 mg/kg/hr used for up to 14 days was safe. Another case series by Gaspard et al.18) found that doses upto 10 mg/kg/hr for up to 27 days were safe. In our study administration of doses up to 8 mg/kg/hr for up to 14 days was not associated with increased complications or mortality compared to patients receiving lower doses and shorter duration of exposure. The 14.3 % mortality was due to presence of systemic infections and the patients succumbed due to sepsis related complications.
Guidelines have highlighted the role of general anaesthesia as the standard therapeutic approach for refractory status epilepticus, though this evidence mainly comes from uncontrolled studies. In majority of the published cases, anaesthetics were used as a third-line or fourth-line agent.
Thus, the efficacy of ketamine in our series is similar to that of other anaesthetic agents.
Analysis of safety of ketamine infusion in SRSE patients showed that common psychiatric adverse effects were hallucinations, delirium, dreams and blurred vision19). In our study, only one patient developed dissociative symptoms due to prolonged administration of ketamine and it subsided when the drug was tapered off.
In the systematic review also it was reported that the adverse reactions related to ketamine were rare.14 In our study no patient had increase in ICP which was similar to that reported by Mayberg et al. in 199520). Another publication where ketamine was used for nontraumatic neurological diseases also did not observe any increase in ICP and in some cases, they found that ketamine even reduced ICP21).
The limitations of our study include those that are inherent of retrospective observational studies. Additionally, there was variability in the prescribing trends as it was based on clinical judgment of various treating clinicians. Finally as we did not do a multivariate analysis due to small sample size the effects of concomitant antiepileptics and anaesthetic drugs on seizure control could not adjust for the effects of these agents.
Despite these limitations, this study documents the utility and patterns of administration of ketamine for the treatment of refractory and super-refractory status epilepticus.
CONCLUSION
The treatment of RSE and SRSE is quite challenging and early initiation of appropriate antiepileptic drugs is important. Continuous ketamine infusion appears to be safe and efficient in suppression of epileptiform discharges and provided haemodynamic stability when used with other anesthetic agents for the treatment of RSE and SRSE. But there is lack of prospective randomized studies on the efficacy of ketamine and hence recommendations cannot be made. Thus, further studies are required to investigate the role of ketamine in RSE and SRSE.
Notes
Ethics statement
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Author contributions
Conceptualization: SL, RG. Data curation: SL, SC Formal analysis: SL, SC Methodology: SL, RG. Writing - original draft: SL. Project administration: RG, BD. Visualization: RG. Writing - review & editing: RG, SC. Writing - original draft: SL.
Conflict of interest
There is no conflict of interest to disclose.
Funding
None.
Data availability
None.
Acknowledgements
None.