The Effects of Desflurane on the Nervous System: From Spinal Cord to Muscles

Pereon, Yann MD, PhD; Bernard, Jean-Marc MD, PhD; The Tich, Sylvie Nguyen MD; Genet, Robert; Petitfaux, Florence MD; Guiheneuc, Pierre MD

Anesthesia & Analgesia:
doi: 10.1213/00000539-199908000-00046
General Articles

Monitoring of motor pathways via muscle contraction recording is sensitive to anesthetics, particularly volatile anesthetics.However, the specific action sites of these anesthetics on the spinal cord and the peripheral nervous system are not well known in humans. Therefore, we studied proximal and distal motor and sensory nerve conduction, neuromuscular junction transmission, and spinal cord excitability (H/M amplitude ratio and F-wave amplitude and persistency) using standard neurophysiological techniques in 10 patients who underwent orthopedic surgery. Muscle potentials evoked by spinal cord stimulation were recorded in five additional patients. Desflurane was introduced to achieve end-tidal concentration of 3.7% and 7.4%, in 50% O2/N2 O and in 100% O2. Measurements were obtained before desflurane administration and 20 min after obtaining a stable level of each concentration. Peripheral nerve conduction and neuromuscular function were not significantly affected by desflurane. However, spinal cord excitability was significantly decreased by desflurane administration (H/M ratio 37% +/- 9%, 12% +/- 5%, 7% +/- 4% at desflurane concentration 0.0%, 3.7%, and 7.4% in 100% O2, respectively). Muscle potentials evoked by spinal cord stimulation were abolished by desflurane. These data rule out the possibility that desflurane specifically alters peripheral nerve conduction or synapse transmission at the neuromuscular junction. They demonstrate that desflurane acts preferentially at the level of the spinal motoneuron. Implications: We used neurophysiological techniques to assess the effects of desflurane on spinal cord conduction and excitability, motor and sensory peripheral nerve conduction, and neuromuscular transmission. Our data demonstrate that desflurane acts preferentially at the level of the spinal motoneuron, providing useful information for neurophysiological monitoring and immobilization during surgery and for minimum alveolar anesthetic concentration definition.

(Anesth Analg 1999;89:490-5)

Author Information

(Pereon, The Tich, Genet, Guiheneuc) Department de Neurophysiologie Clinique, Laboratoire d'Explorations Fonctionnelles, Hotel-Dieu, Nantes; (Bernard) Department d'Anesthesie-Reanimation Chirurgicale, Polyclinique Jean-Villar, Bruges-Bordeaux; and (Petitfaux) Department d'Anesthesie-Reanimation Chirurgicale, Hotel-Dieu, Nantes, France.

Accepted for publication April 12, 1999.

Address correspondence and reprint requests to Yann Pereon, MD, PhD, Laboratoire d'Explorations Fonctionnelles, Hotel-Dieu, F-44093 Nantes Cedex, France. Address e-mail to

Article Outline

Intraoperative recording of muscle activity evoked by transcranial stimulation is often used to monitor spinal cord motor pathways. Activation of muscle contraction by cortical stimulation involves both direct and transsynaptic activation of corticospinal neurons and requires fully effective conduction or transmission along the corticospinal tracts at the corticospinal to alpha-motoneuron synapse level, along the roots and peripheral nerves, at the neuromuscular junction, and, finally, in muscle. Volatile anesthetics, even at low end-tidal concentrations, are responsible for major depressive effects on muscle potentials evoked by cortical stimulation, especially when magnetic stimulation is used [1], which almost prevents successful intraoperative monitoring even with adapted protocols of transcranial stimulation [2,3].

Action sites of volatile anesthetics on motor pathways are not fully documented. These drugs act on motor pathways at the cortical level [4], but they might also depress transmission at the corticospinal to alpha-motoneuron synapse level [5,6]. The peripheral nervous system is also a potential target for volatile anesthetics. Previous studies reported that these anesthetics do not alter nerve conduction velocities [7] but that they might depress muscle contraction evoked by peripheral stimulation.1 Some authors have reported that effects of neuromuscular blockade on train-of-four (TOF) are amplified by volatile anesthetics [8-10], whereas others have reported the relative resistance of the neuromuscular junction to halothane or enflurane [11].

(1) Sloan T, Sloan H. Isoflurane depresses evoked compound action muscle potentials in the ketamine anesthetized monkey [abstract]. Anesthesiology 1995;83:A509.

Thus, the aim of our study was to characterize these effects by conducting a complete electrophysiological examination in patients receiving desflurane, including direct spinal cord stimulation, and to determine whether the observed changes were due to modifications in nerve conduction, neuromuscular junction transmission, and/or the segmental spinal cord level.

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Fifteen ASA physical status I or II patients (4 men, 11 women) aged 15-63 yr with a normal preoperative neurological examination were enrolled in this open study with institutional review board approval and after obtaining written informed consent. Ten patients underwent major orthopedic surgery. The other five underwent scoliosis surgery routinely monitored in our institution by neurogenic mixed potentials evoked by spinal cord stimulation.

In all patients, induction of anesthesia was accomplished with 3 mg/kg propofol and 1 [micro sign]g/kg sufentanil IV. After endotracheal intubation without muscle relaxants, ventilation was controlled using an open circuit and a fresh gas flow of 6-8 L/min. Ventilation was adjusted to maintain the end-tidal CO2 partial pressure between 32 and 35 mm Hg. Anesthesia was maintained using a continuous infusion of 4-5 mg [middle dot] kg-1 [middle dot] h-1 propofol and 50% N2 O in O2. Desflurane was introduced via a calibrated vaporizer to achieve 3.7 vol% and, later, 7.4 vol% end-tidal concentrations, controlled via a calibrated Capnomac Ultima anesthetic analyzer (Datex, Helsinki, Finland). Usual monitoring was used.

Electrophysiological recordings were obtained using surface electrodes and a Nicolet Viking IV machine (Nicolet Corp., Madison, WI). Data were inspected on-line and stored on a disk for subsequent analysis. All measurements were performed in the absence of desflurane, then repeated 15-20 min after obtaining a stable level of each end-tidal desflurane concentration, both in 100% O2 and 50% N2 O. All measurements were recorded in duplicate for each patient. Higher concentrations of volatile anesthetics were not tested to avoid an excessive decrease in blood pressure.

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Motor and Sensitive Peripheral Nerve Conduction

Nerve conduction studies (n = 10) were performed according to conventional techniques [12]. Conduction was measured from the latencies at the top of the negative response peak. Stimulation was performed using a square-wave pulse 1 ms in duration, up to 100 mA in intensity. The stimulus intensity was increased until a maximal response was obtained, i.e., no further incrementation with higher stimulus intensity.

Compound muscle action potential (CMAP) was recorded from the abductor pollicis brevis muscle after median nerve stimulation at the wrist and at the elbow. Recorded variables included distal latency (delay between the stimulation at the wrist and the onset of the muscular response), CMAP amplitude (measured between initial deflection from the baseline and the negative peak), and peripheral motor nerve conduction velocity between the elbow and the wrist. The CMAP area of the negative peak after wrist and elbow stimulation was compared to search for possible conduction block.

Sensory nerve action potentials were recorded from the median nerve at the wrist after index stimulation using ring electrodes (10 averaged sweeps). Amplitude and nerve conduction velocity were measured at the negative peak.

Neuromuscular transmission was assessed through thenar muscle group response to repetitive stimulation (five shocks at 3 Hz) of the median nerve at the wrist. The area of the fifth response (A5) was compared with the area of the first response (A1), and the decrement was expressed as: (Equation 1).

Proximal conduction was assessed through H-reflex and F-wave measurements. H-reflex is a monosynaptic reflex produced by electrical stimulation of afferent fibers in a mixed peripheral nerve. It was elicited from the right soleus muscle after stimulation of the sciatic nerve at the popliteal fossa; both maximal peak-peak M-wave amplitude (Mmax, recorded after supramaximal stimulation) and maximal H-reflex amplitude (Hmax, recorded after a low-intensity stimulation) were recorded. Proximal S1 root conduction was assessed through H index calculation [13]: (Equation 2) where Delta t represents the conduction time between M and H responses. F-waves, which are late, and small potentials generated by antidromic activation of the spinal motor neuron, were recorded from the right thenar muscle group after supramaximal stimulation of the median nerve at the wrist. Proximal motor nerve conduction was assessed through F-wave latency. Moreover, H/M amplitude ratio and F-wave amplitude and persistency (i.e., the number of recorded F waves expressed as a percentage of total number of stimulations) were also measured as partly reflecting motoneuron excitability.

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Spinal Cord Conduction and Corticospinal to alpha-Motoneuron Synapse Transmission

Spinal cord electrical stimulation (n = 5) was performed, and motor evoked potentials (MEPs) were recorded from the soleus muscle. Stimulation was delivered through sterile platinum needle electrodes inserted by the surgeons above the surgical field into the epidural space at the high thoracic or low cervical level. MEPs were recorded via needle electrodes inserted inside the right soleus muscle, and stimulation intensity was arbitrarily adjusted at 40 mA (1-ms duration rectangular shock).

Data were compared by using a two-way analysis of variance for repeated measurements where the two factors were treatments (O2 or N2 O) and concentrations (0.0%vol, 3.7%vol, and 7.4%vol end-tidal desflurane). When indicated by a significant F-ratio, multiple comparisons within and between groups were performed using Student's t-tests, followed by Bonferroni corrections. A P < 0.05 was considered significant. Descriptive statistics are expressed as mean +/- SEM.

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(Table 1) contains demographic characteristics. Core temperature decreased significantly from the first to the last recordings (P < 0.01).

Motor nerve conduction velocity was not altered by desflurane administration. No significant change was observed in the presence of N2 O. Amplitude of the CMAP after distal stimulation was not significantly modified. There was no conduction block. Distal latency did not change significantly (Table 2).

Neither median nerve sensory conduction velocity nor sensory nerve action potential amplitude was modified by desflurane administration (Table 3). No significant change was observed in the presence of N2 O.

Neuromuscular function, assessed by decrement in amplitude and/or area after repetitive stimulation, was not modified by desflurane. No further significant change occurred in the presence of N2 O (Table 4).

Desflurane induced a dramatic dose-dependent decrease of the H/M amplitude ratio in 100% O2 and in 50% N2 O (Table 5, Figure 1). The baseline latency of the F wave recorded from the thenar muscle group was not modified by desflurane administration. F-wave amplitude dose-dependently decreased with increasing desflurane concentration in both O2 and N2 O. F-wave persistency (number of F-waves recorded expressed as a percentage of total number of stimulation) significantly decreased in O2 and in N2 O (P < 0.001) (Table 5, Figure 2).

MEPs recorded from the soleus muscle after spinal cord stimulation were dramatically affected by desflurane administration. Good baseline recordings were obtained in all patients before desflurane administration. Muscle potentials were absent in four of five patients with a 3.7% end-tidal desflurane concentration; MEP amplitude was reduced by 33% in the remaining patient. A 7.4% end-tidal desflurane concentration abolished MEPs in all patients (Figure 3).

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Electrophysiological examinations are useful for studying the effects of anesthetics on the nervous system and may contribute to a better understanding of their action mechanisms. Our findings indicate that desflurane, in clinical concentrations in humans, has no significant effect on nerve conduction velocities and CMAP amplitude and latency and that it does not significantly alter neuromuscular transmission. Our results confirm that volatile anesthetics reduce spinal alpha-motoneuron excitability, as evaluated by H-reflex and F-wave recording. They show for the first time that motor potentials evoked by spinal cord stimulation are also dramatically affected by desflurane administration. Therefore, the present data eliminate the possibility that the depression of the motor potentials evoked by transcranial stimulation results from altered peripheral nervous system and clearly demonstrate a major effect of desflurane at the level of the corticospinal to alpha-motoneuron synapse.

At the membrane level, isoflurane or enflurane inhibits the nicotinic acetylcholine receptor of the neuromuscular junction [14,15]. The primary effect at the single-channel level seems to be a reduction in channel mean open time by binding to an inhibitory site of the acetylcholine receptor [16]. In addition, volatile anesthetics enhance the effects of muscle relaxants by reducing the relaxant doses required to depress CMAP amplitude [8,9]. However, Rupp et al. [11] described a relative resistance of the neuromuscular junction to halothane or enflurane. Desflurane administered alone at inspired concentrations as high as 10% is not responsible for a significant decrease in TOF responses [10]. No significant depression of the amplitude of CMAP was observed after single or repetitive stimulation. Accordingly, few or no reductions have been reported with halothane after nerve root stimulation [17]. Thus, it is likely that the desflurane concentration was not sufficient to affect the acetylcholine receptor in a recordable way.

Propagation of action potential along peripheral nerves is dependent on voltage-gated channels. Our data are in accordance with experimental data suggesting that most voltage-gated ion channels involved in action potential generation, i.e., sodium and potassium channels, are relatively insensitive to volatile anesthetics and that axonal conduction is virtually unaffected in vitro [15]. Halothane has long been known to respect nerve conduction velocities [7]. In our study, desflurane had no apparent effect on either distal (motor and sensory nerve recordings) or proximal (H-reflex and F-wave latencies) nerve conduction in vivo. The core temperature decrease observed between the first and the last recordings (Table 1) could have been responsible for a moderate decrease of nerve conduction velocities [18], but this was not the case.

The H reflex and F waves are motor responses to nerve stimulation widely used for clinical purposes, especially when information about proximal nerve conduction is needed. Both somehow reflect spinal motoneuron excitability. Our data show that desflurane anesthesia was responsible for major effects on H-reflex and F-wave amplitude and on F-wave persistency. Similar findings in humans have been reported by Zhou et al. [19] with isoflurane, and in rats with several halogenated drugs by Rampil and King [5], King and Rampil [6], and Friedman et al. [20]. However, care should be taken before establishing strict correlations between electrophysiological changes and motoneuron excitability alteration. The H reflex, which was originally described by Paulus von Hoffmann in 1910, results from a monosynaptic reflex and measures conduction on both the afferent Ia fibers and efferent alpha motor fibers. It is used to assess conduction in neuropathies, identify root lesions, and examine interneuronal excitability [13]. In the latter case, this technique suffers from methodological limits: it is influenced not only by the motoneuronal excitability, but also by changes in inhibitory mechanisms acting at the level of the Ia-afferent synapses, which convey the reflex; moreover, it cannot be excluded that the H reflex is partly conveyed by additional nonmonosynaptic pathways. Thus, changes in excitability of interneurons of these pathways may contribute to the size of the H reflex. The F response is evoked by antidromic reactivation of the motoneurons through suprathreshold stimulation of the motor axons in the nerve. It probably consists mainly of the fastest motor units. The precise determinants for a motoneuron to generate an F wave are unknown, but important factors include motoneuron pool excitability, motor neuron size, and interneuronal discharges. The generation of F waves is influenced by the balance of excitatory and inhibitory postsynaptic potentials on spinal motoneurons. F waves are usually inhibited under conditions that cause a reduction of spinal excitability [21]. Decreased F responses may be seen both with strong facilitation and inhibition of motoneurons [22]. The F response is also much less sensitive to changes in motoneuronal excitability than the H reflex [22].

Thus, the H-reflex and F-wave attenuation reported in our study could be due to several separate effects of inhaled drugs on spinal cord neurons: direct inhibition of the Ia fiber, direct effect on the alpha-motoneuron membrane, and altered balance between supraspinal excitatory and inhibitory pathways projecting on the alpha-motoneuron. In our study, disappearance of MEPs at clinical concentrations of desflurane provided new information in this context. In previous studies, a higher minimum alveolar anesthetic concentration equivalent of isoflurane did not slow the propagation of action potentials along the spinal cord sensory or motor pathways; latencies of subcortical somatosensory evoked potentials [23], spinal potentials evoked by transcranial electrical stimulation [4], or neurogenic mixed evoked potentials evoked by spinal stimulation [24] remained unchanged. Therefore, the depressant effect of desflurane on muscle potentials evoked by spinal stimulation cannot be explained by a direct action on spinal conduction pathways. Together with the absence of effect on the peripheral nerve conduction, the present data obtained after spinal stimulation show that desflurane exerts a major effect at the precise level of the corticospinal to alpha-motoneuron. This explains the depressant effect of the drug on muscle potentials after spinal cord stimulation and certainly contributes to the changes observed in H-reflex and F-wave characteristics.

In conclusion, our data rule out the possibility that the attenuation by desflurane in the compound muscle potentials after central stimulation results from altered peripheral nerve conduction or from blocked synapse transmission at the neuromuscular junction. They demonstrate that it preferentially acts on the spinal cord at a segmental level, probably on both corticospinal to alpha-motoneurons and interneuron synapses.

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1. Kalkman CJ, Drummond JC, Ribberink AA, et al. Effects of propofol, etomidate, midazolam, and fentanyl on motor evoked responses to transcranial electrical or magnetic stimulation in humans. Anesthesiology 1992;76:502-9.
2. Ubags LH, Kalkman CJ, Been HD. Influence of isoflurane on myogenic motor evoked potentials to single and multiple transcranial stimuli during nitrous oxide/opioid anesthesia. Neurosurgery 1998;43:90-4.
3. Kawaguchi M, Inoue S, Kakimoto M, et al. The effect of sevoflurane on myogenic motor-evoked potentials induced by single and paired transcranial electrical stimulation of the motor cortex during nitrous oxide/ketamine/fentanyl anesthesia. J Neurosurg Anesthesiol 1998;10:131-6.
4. Hicks RG, Woodforth IJ, Crawford MR, et al. Some effects of isoflurane on I waves of the motor evoked potential. Br J Anaesth 1992;69:130-6.
5. Rampil IJ, King BS. Volatile anesthetics depress spinal motor neurons. Anesthesiology 1996;85:129-34.
6. King BS, Rampil IJ. Anesthetic depression of spinal motor neurons may contribute to lack of movement in response to noxious stimuli. Anesthesiology 1994;81:1484-92.
7. Thornton JA, Whelpton D, Brown BH. The effect of general anaesthetic agents on nerve conduction velocities. Br J Anaesth 1968;40:583-7.
8. Fogdall RP, Miller RD. Neuromuscular effects of enflurane, alone and combined with d-Tubocurarine, pancuronium and succinylcholine, in man. Anesthesiology 1975;42:173-8.
9. Cannon JE, Fahey MR, Castagnoli KP, et al. Continuous infusion of vecuronium: the effect of anesthetic agents. Anesthesiology 1987;67:503-6.
10. Caldwell JE, Laster MJ, Magorian T, et al. The neuromuscular effects of desflurane, alone and combined with pancuronium or succinylcholine in humans. Anesthesiology 1991;74:412-8.
11. Rupp SM, McChristian JW, Miller RD. Neuromuscular effects of atracurium during halothane-nitrous oxide and enfluranenitrous oxide anesthesia in humans. Anesthesiology 1985;63:16-9.
12. Oh SJ. Clinical electromyography, nerve conduction studies. Baltimore: University Press, 1983.
13. Guiheneuc P. The use of monosynaptic reflex responses in man for assessing the different types of peripheral neuropathies. In: Desmedt J, ed. Motor control mechanisms in health and disease. New York: Raven, 1983;927-49.
14. Arimura H, Ikemoto Y. Action of enflurane on cholinergic transmission in identified Aplysia neurones. Br J Pharmacol 1986;89:573-82.
15. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994;367:607-14.
16. Dilger JP, Brett RS, Lesko LA. Effects of isoflurane on acetylcholine receptor channels. I. Single-channel currents. Mol Pharmacol 1992;41:127-33.
17. Zentner J, Albrecht T, Heuser D. Influence of halothane, enflurane, and isoflurane on motor evoked potentials. Neurosurgery 1992;31:298-305.
18. Halar EM, DeLisa JA, Brozovich FV. Nerve conduction velocity: relationship of skin, subcutaneous and intramuscular temperatures. Arch Phys Med Rehabil 1980;61:199-203.
19. Zhou HH, Mehta M, Leis AA. Spinal cord motoneuron excitability during isoflurane and nitrous oxide anesthesia. Anesthesiology 1997;86:302-7.
20. Friedman Y, King BS, Rampil IJ. Nitrous oxide depresses spinal F waves in rats. Anesthesiology 1996;85:135-41.
21. Mercuri B, Wassermann EM, Manganotti P, et al. Cortical modulation of spinal excitability: an F-wave study. Electroencephalogr Clin Neurophysiol 1996;101:16-24.
22. Hultborn H, Nielsen JB. H-reflexes and F-responses are not equally sensitive to changes in motoneuronal excitability. Muscle Nerve 1995;18:1471-4.
23. Wolfe DE, Drummond JC. Differential effects of isoflurane/nitrous oxide on posterior tibial somatosensory evoked responses of cortical and subcortical origin. Anesth Analg 1988;67:852-9.
24. Bernard JM, Pereon Y, Fayet G, Guiheneuc P. Effects of isoflurane and desflurane on neurogenic motor- and somatosensory-evoked potential monitoring for scoliosis surgery. Anesthesiology 1996;85:1013-9.
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