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Potential neuroprotective properties of atracurium and cisatracurium in neurosurgical anaesthesia

Fodale, V.; Praticò, C.; Santamaria, L. B.

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European Journal of Anaesthesiology: April 2004 - Volume 21 - Issue 4 - p 333-334


We read with great interest the review article by Hans and Bonhomme [1] reporting the use of muscle relaxants in neurosurgical anaesthesia. Until recently, this has been considered common practice but it is becoming increasingly more questionable today. The authors came to the conclusion that the benefit of muscle relaxants should be balanced against their potential stimulating effects on the central nervous system (CNS) because they may cross the blood-brain barrier under certain circumstances.

We agree with many of the comments in the article by Hans and Bonhomme [1]. We do believe, however, that more data are available in the literature about the effects of the muscle relaxants (and their metabolites) on the CNS.

Vecuronium has not been detected in the cerebrospinal fluid (CSF) of neurosurgical patients up to 8 h after administration [2]. Thus, it can be assumed that it does not directly affect CNS functions. Atracurium and cisatracurium are widely used in neurosurgical practice. Cisatracurium is preferred because it provides a satisfactory level of neuromuscular blockade and has minimal haemodynamic effects, as described by Hans and Bonhomme [1]. Moreover, cisatracurium produces less laudanosine [3], a metabolite of both of the neuromuscular blocking drugs, atracurium and cisatracurium. This potentially toxic metabolite has aroused concern because of possible excitement and seizure activity in the CNS. Although sensitivity to laudanosine in human beings is not known, seizures occur in animals at laudanosine CSF concentrations in the micromolar range which are approximately 100-1000-fold higher than encountered in clinical anaesthesia [2]. The CNS effects of laudanosine may not be limited to eliciting seizures, however, and in the last few years interest in laudanosine has increased further because of the recognized interaction between laudanosine and central nicotinic α4β2 acetylcholine sub-type receptors [4]. These receptors are ubiquitously present in the CNS and involved in chemical signalling. At concentrations comparable to those measured in the CSF during and after neurosurgical anaesthesia (14-38 ng mL−1), laudanosine can activate central α4β2 receptors [2,4]. Recent research has showed α4β2 receptor activation to represent a primary molecular target for neuroprotection [5,6]. As a consequence, it was hypothesized that laudanosine, at clinical concentrations reported in the CSF during and up to several hours after the end of neurosurgery, might elicit a long-acting neuroprotective action [7].

This hypothesis is further supported by other interesting observations. Laudanosine, in concentrations seen clinically in blood, and approaching those measured in CSF after administration of atracurium, displayed an interaction at δ- and κ-opioid receptors, eliciting a neuroprotective action against hypoxia and ischaemia [3].

These hypotheses suggest several clinical implications. In patients who undergo surgery, a long-acting laudanosine-mediated neuroprotective action may be elicited when atracurium or cisatracurium are administrated as part of anaesthesia. Therefore, in the article by Hans and Bonhomme [1], we disagree with the critical appraisal showing only the negative effects of all muscle relaxants in neurosurgical anaesthesia. We would like to draw attention to the potential positive effects of some of the newer and more currently used muscle relaxants. Finally, we agree with the suggestion that appropriate monitoring of neuromuscular transmission to assess neuromuscular function is important in neurosurgical anaesthesia.

V. Fodale

C. Praticò

L. B. Santamaria

Department of Neuroscience, Psychiatric and Anesthesiological Sciences; University of Messina; Messina, Italy


1. Hans P, Bonhomme V. Muscle relaxants in neurosurgical anaesthesia: a critical appraisal. Eur J Anaesthesiol 2003; 20: 600-605.
2. Tassonyi E, Fathi M, Hughes J, et al. Cerebrospinal fluid concentrations of atracurium, laudanosine and vecuronium following clinical subarachnoid hemorrhage. Acta Anaesthesiol Scand 2002; 46: 1236-1241.
3. Fodale V, Santamaria LB. Laudanosine, an atracurium and cisatracurium metabolite. Eur J Anaesthesiol 2002; 19: 466-473.
4. Chiodini F, Charpantier E, Muller D, Tassonyi E, Fuchs-Buder T, Bertrand D. Blockade and activation of the human neuronal nicotinic acetylcholine receptors by atracurium and laudanosine. Anesthesiology 2001; 94: 643-651.
5. Ferchmin PA, Perez D, Eterovic VA, De Vellis J. Nicotinic receptors differentially regulate N-methyl-D-aspartate damage in acute hippocampal slices. J Pharmacol Exp Ther 2003; 305: 1071-1078.
6. Gopalakrishnan M, Monteggia LM, Anderson DJ, et al. Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine α4β2 receptor. J Pharmacol Exp Ther 1996; 276: 289-297.
7. Fodale V, Santamaria LB. The possible neuroprotective effect of laudanosine, an atracurium and cisatracurium metabolite. Acta Anaesthesiol Scand 2003; 47: 780-781.
© 2004 European Academy of Anaesthesiology