Problem: prolonged status epilepticus leads to upregulation of NMDA receptors, glutamate-mediated excitotoxicity and resistance to conventional antiepileptics.
1. Refractory status epilepticus – either generalized or complex partial status epilepticus that fails to respond to first and second line therapies
2. Superrefractory status epilepticus – status epilepticus that remains unresponsive despite 24 hours of therapy with general anesthesia
Mechanisms of conventional AEDs:
- GABA agonist – cortical inhibition / reduction of epileptogenicity and lateral spread; e.g. benzodiazeipne, valproate, propofol, barbiturates, clonazepam, clobazam, vigabatrin, and topiramate
- Na blockers – phenytoin, carbamazepine, lamotrigine, oxcarbazepine, zonisamide, and rufinamide
- Ca blockers – gabapentin and pregabalin,
Molecular Changes in Prolonged Status Epilepticus:
- GABA A downregulation – depletes receptors for benzodiazepines, etc, also subunit alterations in GABAA receptor lead to impaired binding –> resistance to GABA-mediated AEDs
- p-glycoprotein molecular transporter upregulation – occurs at the level of BBB ~20 to 30 minutes into status epilepticus; these transporters export phenytoin and phenobarbital molecules and efficacy of phenytoin and phenobarbital is greatly diminished
- upregulation of NMDA receptors – leads to glutamate-mediated activation of these receptors, leads to intracellular calcium influx and excitotoxicity
- proinflammatory mediators can also alter BBB permeability and induce neuronal damage which can lead to AED resistance and excitotoxicity
Advantages of Ketamine in RSE / SRSE:
- NMDA receptor antagonists target a receptor known to be upregulated during SE/RSE/SRSE
- NMDA receptor antagonists provide neuroprotection (studied in TBI population)
- drug is readily available and cheap
- sympathomimetic properties = vasopressor sparing effects
- side effect profile low
- mild hypertension
- ICP elevation? – old literature, should not be factored in
- Effectivity: 110 patients = 56.5% responded (cessation of SE)
- Duration of Treatment: 16 hours to 140 days
- Usual dosing: bolus 0.5 to 5 mg/Kg then continuous infusion 0.12 to 10mg/kg/hr, duration of 2h to 27d
- most common duration: 7 days, most responding within 48-72h
- Start ketamine within 24-48 hours of SE onset, after failure of first trial with anesthetics of choice (midazolam, propofol, pentobarbital)
- Suggested dosing: bolus 3mg/kg, followed by continuous infusion up to 10mg/kg/hr, duration up to 7 days
Zeiler, F. A. “Early Use Of The NMDA Receptor Antagonist Ketamine In Refractory And Superrefractory Status Epilepticus”. Critical Care Research and Practice 2015 (2015): 1-5.
- Hypothermia for Brain Enhancement Recovery by Neuroprotective and Anticonvulsivant Action after Convulsive Status Epilepticus Trial
- multicenter, open-label, parallel-group, RCT
- 11 French ICUs
- 03/2011 to 01/2015
- convulsive status epilepticus – >=5mins continuous clinical seizure activity or >2 sz without return to baseline in interval
- admitted <8hours after onset
- return to baseline state of consciousness
- need for ‘E’ surgery that would preclude therapeutic hypothermia
- post-anoxic status epilepticus
- imminent death
- DNR order
- bacterial meningitis
- lower T to 32-34C x 24h
- IV fluids at 4C, ice packs at groin and neck, cold-air tunnel around body
- repeated propofol boluses if seizures continue followed by maintenance IV infusion to maintain burst-suppression EEG pattern x 24 hours
- Outcomes assessed:
- Primary: absence of functional impairment at 90d (GOS score of 5)
- death rates: ICU, hospital, day 90
- progression to EEG-confirmed status epilepticus (coma +/- subtle convulsive movements but with generalized or lateralized ictal discharges on EEG between 6 and 12 hours after randomization
- refractory status epilepticus on day 1 (continuous or intermittent clinical seizures, EEG-confirmed seizures, or both despite two AEDs within 24 hours after onset)
- super-refractory status epilepticus (ongoing or recurrent status epilepticus between 24 and 48 hours after initiation of anesthetic treatment)
- total seizure duration
- ICU LOS
- Hospital LOS
- 268 patients included in analysis, 138 in hypothermia group, 130 in control group
- PRIMARY OUTCOME = GOS5 — 49% vs 43% (OR 1.22 95% CI 0.75-1.99 p=0.43)
- 15 (hypothermia group) vs 29 patients had progression to EEG-confirmed status epilepticus (OR 0.40 95% CI 0.2-0.79, p=0.009)
- no other secondary outcomes differed significantly
- no beneficial effect of therapeutic hypothermia vs standard care alone in patients with status epilepticus who are receiving mechanical ventilation.
Current Evidence for Therapeutic Hypothermia in Neurocritical Care:
- TBI- controversial
- refractory intracranial hypertension, ischemic stroke and ICH – incorporated into treatment
- Bacterial meningitis with coma – may be harmful
Legriel, Stephane et al. “Hypothermia For Neuroprotection In Convulsive Status Epilepticus”. New England Journal of Medicine 375.25 (2016): 2457-2467.
From an old article that I thought gave a good summary.
Goodman, D. J., and M. A. Kumar. “Evidence-Based Neurocritical Care”. The Neurohospitalist 4.2 (2013): 102-108. Web.
Uptodate Status Epilepticus Algorithm in PDF
New definition of STATUS EPILEPTICUS (Status Epilepticus: Current Treatment Strategies, by Ed Manno, published in Neurohospitalist 2015)
Status epilepticus (SE) can be defined as a seizure of sufficient duration to overcome the inherent cellular mechanisms designed to terminate the seizure. SE becomes a self-sustaining process.
Initial League against Epilepsy originally defined SE as 30 mins of sustained seizure activity or 2 or more seizures during this time period without full recovery of the patient.
Pathologically, hippocampal neurons begin to die after 30 mins of sustained seizure activity.
Newer operational definitions have suggested that seizures lasting longer than 5 mins are unlikely to discontinue spontaneously and should be treated.
There is an initiation and maintenance phase. SE is initiated through excessive excitatory stimulation but is maintained through lack of GABA-mediated neuronal suppression.
Failure to suppress initial excitatory focus may be due to development of changing GABA isoforms. With sustained seizure, hippocampal GABA A isoforms with different pharmacological properties may develop. This explains the resistance to benzodiazepines that develops during SE over time.
SE may also be sustained through excitatory NMDA’mediated neuronal stimulations. NMDA antagonists have been suggested as a possible pharmacologic strategy.