We read with great scientific interest the study of Vuyk et al.  1reporting three cases in which volunteers receiving combinations of propofol and midazolam remained responsive to verbal command although the Bispectral Index (BIS) values were at, or just above, 40, the area considered to be associated with adequate hypnosis for surgery (BIS, 40–60). Vuyk et al.  1note that the electroencephalographic activation induced by both propofol and midazolam has been difficult to interpret. They ascribe the particular low combination of propofol and midazolam, which at these concentrations is not part of the BIS-behavioral database on which the BIS calculation is based, as a possible cause. As a result, the electroencephalographic pattern induced by this combination may well be misinterpreted by the BIS® monitor (Aspect Medical Systems, Newton, MA) as an electroencephalographic pattern associated with a patient experiencing a surgical hypnotic sedation level instead of actually being responsive to verbal commands. This hypothesis is very interesting, but we believe that alone, it is not enough to give a reasonable explanation.

Neuromuscular activity impairs BIS monitoring. A biasing effect of the electromyogram on the BIS may explain discrepancies in previous studies assessing BIS in the presence of neuromuscular activity.2Electromyographic activity has previously been reported to elevate the BIS, whereas it may be lower in patients receiving neuromuscular blockade.3 

Midazolam and propofol have direct relaxant properties. Midazolam exhibits a well-known myorelaxant effect as a result of a block of inactivated Na channels in skeletal muscle fiber.4Moreover, interaction of midazolam, at very low concentrations, with the nicotinic acetylcholine receptor leads to a substantial reduction of the current amplitude, which suggests an additional closed channel block responsible, to some extent, for the muscle-relaxing effects of midazolam.5Midazolam is capable of attenuating opioid rigidity.6Propofol also provides some degree of muscle relaxation. Mean muscular activity recorded on an electromyography decreases from 100 mV to 10–25 mV as a result of propofol administration, with restoration to previous levels within 10 min.7At clinical concentrations, propofol acts on peripheral parts of the motor system, depressing spinal motor neuron excitability.8Motor evoked potentials are also affected by propofol.9Because of their muscle relaxation properties, propofol and midazolam are used in tetanus management not only for sedation but also for muscle relaxation.7,10 

These data, taken together, widely indicate that in sedated patients coadministration of both propofol and midazolam may result in a synergic muscle relaxant action on the motor system and therefore in a decrease in BIS value. This hypothesis is consistent with a study reporting that the central part of the motor system is also impaired when propofol is coadministered in a midazolam-fentanyl based anesthesia.11 

The clinical relevance is that when BIS is assessed during or after the coadministration of midazolam and propofol, despite the absence of a neuromuscular blockade, it is necessary to evaluate the potential synergic muscle relaxant action on BIS before making conclusions about depth of sedation or anesthesia.2Finally, this hypothesis further supports the wise statement by Vuyk et al.  1reporting that the BIS is a measure of drug effect, not an independent measure of brain function.

* University of Messina, Policlinico Universitario “G.Martino,” Messina, Italy. vfodale@unime.it

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Renna M, Wigmore T, Mofeez A, Gillbe C: Biasing effect of the electromyogram on BIS: a controlled study during high-dose fentanyl induction. J Clin Monit Comput 2002; 17:377–81
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