Consensus Protocol for the Treatment of Super-Refractory Status Epilepticus

Abstract

Introduction: Super-refractory status epilepticus is defined as status epilepticus that persists or recurs 24 hours after anaesthetic therapy onset or after its withdrawal. It is mostly found in intensive care units and carries high mortality but good long-term prognosis for those who survive. In contrast with the initial phases of status epilepticus, treatment lacks strong scientific evidence and is mostly derived from case reports or small case series.Objective: To propose a protocol for the treatment of super-refractory status epilepticus in level III intensive care units, focusing on the treatment strategies to control clinical and/or electroencephalographic epileptic activity.Material and Methods: Narrative review of the literature by PubMed search. Available evidence was discussed in consensus meetings by intensive care and neurology experts’ from a level III intensive care unit and one of the Portuguese reference centres for the treatment of refractory epilepsy, respectively.Results: Anaesthetics with the highest level of evidence are propofol, midazolam, thiopental and ketamine. These represent the basis of the treatment of super-refractory status epilepticus and should be used in combination with antiepileptic drugs. The level of evidence for the latter is lower, however, levetiracetam, topiramate, pregabalin, lacosamide, valproic acid, phenytoin and perampanel may be recommended. Alternative therapeutic strategies with very low level of evidence are recommended in cases of total absence of clinical response, such as magnesium sulphate, pyridoxine, ketogenic diet, therapeutic hypothermia and immunosupression.Conclusion: We propose a treatment protocol based on a sequential combination of anaesthetics, anti-epileptic drugs and alternative therapies. Strategies to evaluate treatment response and to wean drugs based on clinical results are also proposed.

Antiepileptic Drug Therapy for Status Epilepticus

“…[60][61][62] Hypotension and respiratory suppression are common with the continuous infusion of barbiturates, and other adverse events include hepatotoxicity and immunosuppression. It is recommended that thiopental be administered at a loading dose of between 1 mg/ kg and 5 mg/kg, with continuous infusion at 0.5-5 mg/kg/ h. 12,23,63,64 Pentobarbital can be administered at a loading dose of 5-15 mg/kg, 12,21,63 and its infusion rate should not exceed 50 mg/min, with continuous infusion at 0.5-5 mg/kg/h being recommended. For both drugs, continuous infusion should begin at a relatively low rate and then subsequently be titrated to achieve a burst-suppression pattern on EEG.…”

“…69,70 The recommended loading dose ranges from 0.5 mg/kg to 4.5 mg/ kg, and the recommended dosage range for continuous infusion is 0.3-5 mg/kg/h. 23,60,64 The EEG pattern related to the clinical efficacy of ketamine is heterogeneous. 69 The cessation of seizure activities rather than burst-suppression is recommended as a therapeutic target.…”

Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine

“…In a hospital setting, PHB is administered to treat SE after intravenous benzodiazepines and ASDs have failed to stop seizures (Arif and Hirsch, 2008;Gomes et al, 2018;Gainza-Lein et al, 2019).…”

Pharmacotherapy for Pediatric Convulsive Status Epilepticus

“…Refractory SE (RSE) is seen in 23-44% of patients with CSE and there is no clear evidence to direct therapy in this phase [13,49]. Pharmacotherapy includes additional boluses of second-line medications (e.g., fosphenytoin, levetiracetam, valproate, and phenobarbital, among others) and consideration of medically induced coma with IV continuous infusions of anesthetic agents (e.g., midazolam, propofol, barbiturates) with critical care treatment and EEG monitoring [50] (see Table 2 and Fig. 1).…”

“…Due to lack of evidence to support a standardized regimen for the intensity and duration of therapy in this phase, treatment is guided by continuous EEG with the goal to titrate continuous infusions until electrographic seizure cessation, or until burst suppression is achieved. Burst suppression or electrographic seizure cessation is typically maintained for at least 24-48 h before gradual withdrawal of the continuous infusion agents [11,50]. If there is recurrence of RSE during the weaning period or when SE persists for 24 h or more after administration of anesthesia, patients are said to be in super-refractory SE (super-RSE).…”