When elective coma induction is warranted to control RSE, the initial choice is restricted to three groups of compounds 56
(), whose common characteristic is the modulation of GABAA
receptors, although each acts on specific sites. Midazolam is a benzodiazepine that is already being used as a 1st
line treatment. Its half-life, short after single bolus, increases to 6–50 hours after prolonged administration. However, tachyphylaxis often develops within 24–48 hrs 57
, requiring the perfusion dose to be constantly increased to maintain a constant pharmacological action. Midazolam is therefore mostly used initially, or in combination with propofol. No particular problems inherent to its pharmacodynamic or pharmacokinetic properties have been described, and availability of an antidote (flumacenil) represents a theoretical advantage over the other two groups.
Propofol displays a short half-life, allowing rapid titration and withdrawal. Besides modulating GABAA
receptors, it acts on sodium and calcium channels, and possibly on NMDA receptors 58
. Due to its administration as an oil emulsion, it may induce the so-called “propofol infusion syndrome” (PRIS), a syndrome of potentially fatal cardio-circulatory collapse with lactic acidosis, hypertriglyceridaemia and rhabdomyolysis. PRIS is due to impairment of mitochondrial activity and free fatty acid utilization, with resulting mismatch between energy needs and utilization; catecholamines and glucocorticoids may represent facilitating factors 59
. Mainly described in young children (thus representing a relative contraindication in this age group) and patients with brain trauma, PRIS has also been reported in patients treated for RSE 60
. A recent retrospective series estimated the incidence of PRIS in RSE as 7% (fatal) and 38% (non-fatal) 61
. However, these proportions are in sharp contrast with other retrospective 62
and prospective studies 63, 64
reporting incidences of 0%–7%, and may represent a selection bias. Nevertheless, prolonged perfusions (more than 48 hours over 5 mg/kg/h) should be avoided, and repetitive checks of serum lactate are mandatory for an early detection of this complication 59
. Concomitant benzodiazepines could lower the needed propofol dose 62
, possibly reducing the PRIS risk.
The anesthetic barbiturate thiopental, or its metabolite pentobarbital, represents the oldest compounds used in this setting. In addition to GABAA
modulation, barbiturates show an NMDA-antagonist action in vitro
, which might be of interest considering RSE pathophysiology 65
. They have a long half-life (up to 36 hours) after continuous administration, owing to a considerable tendency to accumulate in adipose tissue. This may become challenging especially in older patients with pre-existent cardiovascular problems.
A meta-analysis of the use of barbiturates, propofol, or midazolam in RSE completed a decade ago, mostly based on retrospective and heterogeneous case series, did not reveal any significant difference in short-term mortality, although some variations were noted in both immediate efficacy (favoring barbiturates) and tolerability (favoring midazolam and propofol) 66
. Another single-center retrospective analysis failed to show any outcome difference among different anesthetics, used alone or in combination 9
. Recently, a multicenter randomized, unblinded trial assessing propofol and barbiturates in RSE, interrupted because of insufficient recruitment, found that patients receiving barbiturates had a markedly longer need for mechanical ventilation, while long-term outcome and complications were comparable 64
. In spite of the increasing elimination half-life of midazolam after prolonged infusion, this compound virtually never induces a complete suppression of cerebral activity for several days, as do barbiturates. Thus, despite lack of strong evidence (and also in view of the availability of a pharmacological antidote flumacenil), midazolam seems to represent the safest compound in this setting, but often needs to be combined with propofol to obtain seizure control. Propofol has the advantage of a short half-life, which allows for a rapid clinical assessment upon weaning. However, the risk of PRIS requires very careful metabolic monitoring, and the drug should not be used in young children. Barbiturates should probably be reserved for RSE cases refractory to the other anesthetics in view of its prolonged elimination.