EFNS guidelines (Meierkord et al. 2010) [1]
NCS guidelines (Brophy et al. 2012) [2]
Survey of experts (Riviello et al. 2013) [12]
Post-convulsive subtle SE
Treat as GCSE and proceed to anesthetic treatment
No recommendation on the type of agent
GCSE
Subtle SE
N/A
Complex partial SE/NCSE
Postpone anesthetic treatment and try additional antiseizure medications
Try additional antiseizure medications in patients who are hemodynamically stable and have not required intubation
N/A
Environment of treatment
N/A
ICU with expertise in RSE
cEEG available
N/A
Initial anesthetics
Midazolam, propofol, or pentobarbital/thiopental
Midazolam, propofol, or pentobarbital/thiopental
Midazolam, propofol or, pentobarbital/thiopental in adults
Propofol avoided in children
Intensity and duration of treatment
At least 24 h
Titrate to burst suppression if propofol or barbiturates
Titrate to seizure suppression if midazolam
24–48 h
Titrate to seizure suppression or burst suppression
24 h
Taper
N/A
Gradual
Phenobarbital helpful during pentobarbital withdrawal
N/A
Intensity and duration of treatment if SE recurs after the anesthetic is tapered
N/A
Return to prior or higher doses of anesthetic
± Addition of the second anesthetic
Duration not discussed
24–48 h
The decision to resort to general anesthesia is based on the careful assessment of the need for urgent control of SE and of the risks associated with treatment. The uninterrupted and intense motor activity of refractory GCSE poses a serious life threat as it rapidly leads to shock, multiple organ failure, and malignant cerebral edema. The potential risks associated with an aggressive treatment are thus usually considered justified, and both the NCS and EFNS guidelines recommend the urgent administration of an anesthetic agent for refractory GCSE and post-convulsive subtle SE, a form of NCSE [1, 2].
Although this systemic stress does not occur with the same urgency in refractory NCSE, there is increasing evidence that NCSz and NCSE are harmful for the brain [3–5]: the occurrence of NCSz and NCSE after GCSE is associated with higher mortality; failure to rapidly diagnose and treat NCSE is also associated with poorer outcome; seizure burden is directly related to functional outcome in critically ill children, especially in the absence of an acute brain injury; in patients with acute brain injury, the occurrence of NCSz is associated with adverse hemodynamic and metabolic effects and ICP crisis. Altogether, this suggests that aggressive treatment of NCSE might be justified, although the risks of a prolonged and deep sedation need to be carefully weighted before deciding to resort to anesthetic agents. This is reflected in the EFNS guidelines, which recommend postponing general anesthesia and trying additional nonsedating anticonvulsants in refractory complex partial SE [1]. The NCS guidelines also recommend postponing anesthesia in patients who are hemodynamically stable and have not required intubation yet [2]. However, if NCSE fails to respond to these additional trials of nonsedating agents, anesthesia becomes unavoidable.
When deciding to use an anesthetic treatment, the following questions arise:
- 1.
Which anesthetic drug should be used?
- 2.
How long should the patient be treated with anesthetics?
- 3.
What should the EEG target be?
- 4.
How should the treatment be initiated, maintained, and tapered?
- 5.
What should be done if treatment fails?
By answering these questions, an institutional protocol for anesthetic treatment of RSE can be developed and will avoid unnecessary delay in treatment and will make local practices more uniform. Such a protocol is shown in Fig. 1.
Fig. 1
Suggested protocol for anesthetic treatment of refractory SE
Available Drugs
Barbiturates have been prescribed at sub-anesthetic doses to treat SE for over 60 years. The development of intensive care and the widespread availability of mechanical ventilation have allowed the use of anesthetics at deeply sedating doses for RSE, initially with barbiturates (pentobarbital in the USA and thiopental in Europe and other regions of the world), followed by midazolam and propofol. More recently, ketamine has gained some interest, due to its unique mechanism of action and safety profile. More limited anecdotal evidence is also available with etomidate and inhalational compounds. The pharmacologic properties and suggested doses of the available anesthetics are summarized in Table 2.
Table 2
Pharmacological properties of available anesthetic drugs
Midazolam | Propofol | Pentobarbital | Thiopental | Phenobarbital | Ketamine | Etomidate | Inhaled (Desflurane/isoflurane) | |
|---|---|---|---|---|---|---|---|---|
Use | CIV | CIV | CIV | CIV | IV or CIV, including very high doses | CIV | CIV | Continuous inhalation |
Mechanism of action | GABA(A) | GABA(A) NMDA Na+, Ca2+ | GABA(A) NMDA, AMPA nACh | GABA(A) NMDA, AMPA nACh | GABA(A) NMDA, AMPA nACh | NMDA DA, NA, 5HTA Opioid (μ, δ, k) mACh Substance P | GABA(A) A | GABA(A) NMDA Glycine K+ |
Vd (l/kg) | 3 | 60 | 64 | 160 | 0.55 | 4 | 4.5 | 0.7/4 |
Lipid/plasma distribution | 3.1 | 3.8 | 2.1 | 2.9 | 1.4 | 2.9 | 3.1 | 2.1 |
Protein binding | 95–97 % | 95–99 % | 35–50 % | 50–80 % | 20–50 % | 45 % | 75 % | N/A |
Metabolism | >99 % Oxidation and glucuronidation | >95 % (Oxidation and glucuronidation) | >99 % (Oxidation and glucuronidation) | >99 % | 50–75 % | >99 % | >99 % (ester hydrolysis) | Minimal |
Interactions | CYP3A4 substrate | CYP2B6 substrate CYP2C9 substrate | CYP3A4 inducer CYP2A6 inducer CYP2C19 substrate | CYP3A4 inducer CYP2C19 substrate | CYP3A4 inducer CYP2C19 substrate | CYP2B6 substrate CYP3A4 substrate | CYP3A4 inhibitor CYP1A2 inhibitor CYP2C19 inhibitor | None |
Active metabolites (relative activity) | 1-Hydroxy-midazolam (20 %) 4-Hydroxy-midazolam (7 %) | 4-Hydroxy propofol (30 %) | None | Pentobarbital | None | Norketamine (25 %) | None | None |
Elimination | Renal | Renal | Renal | Renal | Renal | Renal | Renal | Respiratory Renal |
Half-life | 2–6 h | 0.5–30 h | 15–50 h | 3–22 h | 53–118 h | 2.5–3 h | 1–5 h | Dependent on minute ventilation |
Preparation | Solution Hydrochloride | Emulsion | Powder Sodium salt | Powder Sodium salt | Solution | Solution Hydrochloride | Solution | Vaporizable liquid |
Solubility | Hydrophilic | Lipophilic (no PG) | Lipophilic (PG) | Hydrophilic | Lipophilic (PG) | Hydrophilic | Lipophilic (PG) | N/A |
Adverse effects | Respiratory depression Hypotension | Respiratory depression Myocardial depression Hypotension PRIS | Respiratory depression Myocardial depression Hypotension Propylene glycol toxicity Paralytic ileus Bowel ischemia Immune paresis Cutaneous fibrosis Shivering Bronchospasm Laryngospasm | Respiratory depression Hypotension Myocardial depression Paralytic ileus Bowel ischemia Immune paresis Cutaneous fibrosis Shivering Bronchospasm Laryngospasm | Respiratory depression Hypotension Propylene glycol toxicity | Cardiovascular stimulation Respiratory stimulation | Respiratory depression Hypotension Propylene glycol toxicity Non-epileptic myoclonus Adrenocortical suppression | Hypotension Fluoride nephrotoxicity (isoflurane) Airway irritation (isoflurane) |
Induction bolus
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