Potential Consequences of High-Dose Infusion of Ketamine for Refractory Status Epilepticus: Case Reports and Systematic Literature Review

Abstract

Our goal was to provide comprehensive data on the effectiveness of ketamine in refractory status epilepticus (RSE) and to describe the potential consequences of long-term ketamine infusion. Ketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, blocks excitatory pathways contributing to ongoing seizure. While ketamine use is standard in anaesthetic induction, no definitive protocol exists for its use in RSE, and little is known about its adverse effects in long-term, high-dose administration. We present two cases of RSE that responded rapidly to ketamine infusion, both with fatal outcomes secondary to metabolic acidosis and cardiovascular collapse. We performed a systematic review of the application and consequences of ketamine use in RSE. PubMed, Ovid, MEDLINE and PMC were searched for articles describing ketamine treatment for RSE according to a predetermined search strategy and inclusion criteria. The systematic review revealed wide discrepancies in ketamine dosing (infusion maintenance dose range 0.0075-10.5 mg/kg/hour), but good outcomes in medically managed RSE (75% of studies reported moderate or complete seizure control in adults, 62.5% in paediatrics). Additionally, literature review elucidated a potentially causal relationship between prolonged ketamine infusion and both cardiovascular and metabolic dysregulation. Ketamine is effective in RSE by antagonising excitotoxic NMDA receptors. However, there is high variability in ketamine dosing and scarce data on its safety in long-term infusion. Metabolic acidosis and haemodynamic instability associated with the use of long-term, high-dose ketamine infusions must be of concern to clinicians administering ketamine to critically ill patients.

Anesthetic Use In Status Epilepticus: A Concise Review

“…Although ketamine is a standard medication for anesthesia induction, there is no definitive protocol for its use in SE. 41 Initial bolus doses of 1-2 mg/kg IV push given every 3-5 minute until there is the cessation of seizure are recommended, followed by the initiation of IV continuous infusion. Significant variations in dosing have been described with most infusions ranging from 0.0075 to 10.5 mg/kg/h.…”

“…Significant variations in dosing have been described with most infusions ranging from 0.0075 to 10.5 mg/kg/h. 41 However, a more recent review described typical ketamine dosing for RSE as 1-5 mg/kg IV push, 42 , which is similar to anesthesia induction doses, followed by continuous infusions of 0.07-15 mg/kg/h. 18,42 Ketamine can be utilized in combination with another anesthetic and has been shown to have synergistic effects with benzodiazepines and propofol.…”

“…40 A recent systematic review demonstrated excellent outcomes in SE management, with 75% of studies reporting moderate or complete seizure control in adult patients. 41 There is developing interest in using ketamine due to the potential neuroprotective effects through NMDA receptor blocking, 47 , anti-inflammatory properties, optimization of peripheral circulation, and balancing transport and consumption of oxygen. 39 There are two ongoing clinical trials of ketamine in RSE which should provide more robust data to support its use for this indication: Ketamine in Refractory Convulsive Status Epilepticus (KETASER01), ClinicalTrials.gov Identifier: NCT02431663; and Efficacy of Ketamine Infusion Compared With Traditional Anti-epileptic Agents in Refractory Status Epilepticus, ClinicalTrials.gov Identifier: NCT03115489.…”

“…50 Since ketamine is mostly used for short intervals for anesthesia induction, there is not much information on complications related to long term or high dose administration. 41 Ketamine induces a positive, sympathetic response. Use is cautioned in patients with coronary artery disease and/or cardiomyopathy as it may induce hypertension 40,51 tachyarrhythmias, including atrial fibrillation 51 , even cardiac arrest.…”

“…Rarely, severe metabolic acidosis has been reported with doses of 4-4.5 mg/kg/hr in combination with midazolam infusion. 41 Additionally, encephalopathy, confusion, agitation, or psychosis can be seen even after discontinuation of ketamine. 18,51 Cerebellar atrophy has been reported with ketamine use.…”