Volatile anaesthetic agents used at clinical concentrations have an inhibitory effect on the acetylcholine nicotinic receptor [1-3]. The neuromuscular junction has been suggested as the site of interaction between volatile anaesthetic agents and non-depolarizing neuromuscular blocking agents, and experimental studies have demonstrated a synergistic effect at the nicotinic muscular receptor . Furthermore, it has been shown that there is a higher affinity of volatile agents for the neuronal nicotinic receptor than for the muscular receptor . An inhibitory effect of propofol on the nicotinic receptor has only been shown at supraclinical concentrations [6,7]. Our hypothesis was that if the interaction between neuromuscular blocking agents and volatile agents at the neuromuscular junction occurs both at the nicotinic postjunctional receptor (muscular) and the prejunctional receptor (neuronal), it should be expressed clinically both by an enhancement of neuromuscular block and by an increased train-of-four (TOF) fade. The purpose of this study was to compare the effects of sevoflurane and propofol on the time course of recovery and TOF fade of a mivacurium neuromuscular block in order to evaluate any differences in both the prejunctional and postjunctional actions between the two anaesthetic techniques.
Twenty adult patients, ASA I-II, were included in the study after obtaining their informed consent. Patients whose weight was 30% above or below the ideal for their height, or who were receiving medications known to interact with neuromuscular blocking drugs, or with kidney, liver or neuromuscular diseases, or with abnormal plasma cholinesterase activity were excluded from the study. Midazolam 2 mg was administered intravenously and anaesthesia induced with 1 μg kg−1 remifentanil over 1 min and 2-3 mg kg−1 propofol. Ventilation was assisted using a laryngeal mask or tracheal intubation without the use of neuromuscular block. For anaesthesia maintenance, patients were allocated by a computer-generated randomization scheme into two groups: a propofol infusion (4-8 mg kg−1 h−1), and nitrous oxide 66% in oxygen and the sevoflurane group in which anaesthesia was maintained with remifentanil, sevoflurane (end-tidal concentration 2%) and oxygen enriched air. In both groups ventilation was adjusted to maintain normocapnia (PCO2 34-40 mmHg) and the skin temperature over the adductor pollicis muscle was maintained at >32°C.
Neuromuscular monitoring was performed using the acceleromyograph (TOF-Watch, Organon-Teknika). The arm was immobilized with an arm board. The ulnar nerve was stimulated at the wrist using surface electrodes with supramaximal stimuli of 0.2 ms duration in TOF mode (2 Hz every 12 s). After calibration, single twitch mode at 1 Hz was selected and maintained for at least 10 min then a second calibration was performed. TOF mode was then selected and 0.15 mg kg−1 mivacurium administered over 5 s. In the sevoflurane group, mivacurium was not administered until after 30 min of maintenance with the sevoflurane end-tidal concentration at 2%. The height of the first response of the TOF (T1) and the TOF ratio (TOFR) were recorded until the TOFR had returned to 95% of its initial value.
The TOFR values during the recovery of the neuromuscular block were calculated at levels of T1 of 50%, 75% and 90% and T1 values were calculated at levels of TOFR of 0.7 and 0.9. Recovery times between T1 of 25% and 75% (T1 25-75%), and T1 25% and TOFR of 0.8 (T1 25%-TOFR0.8) were compared in both groups.
All results are presented as mean with 95% CI and were tested using t-test for independent samples. A P-value <0.05 was considered significant.
Patients in both groups were comparable with respect to age, sex, weight, plasma cholinesterase activity and surgical procedure (Table 1). Two patients in the sevoflurane group did not recover to 100% of the reference value, the T1 value being <75%.
Table 2 shows the comparison of means between the groups. There was a significant prolongation of recovery time in the sevoflurane group (T1 25-75%, 11.3 (8.1-14.5) min; T1 25%-TOFR0.8, 19.1 (15.7-22.5) min) compared to the propofol group (T1 25-75%, 6.5 (5.2-7.7) min; T1 25%-TOFR0.8, 9.1 (7.8-10.3) min). No differences were found in the relations between TOFR and T1. When the TOFR had returned to 0.7, the mean T1 for the propofol group was 81.1 (73.5-88.7)% and 73.1 (61.6-84.6)% for the sevoflurane group. For a TOFR of 0.9 the mean T1 of the propofol group was 92.2 (86.0-98.4)% and for the sevoflurane group 86.1 (76.7-95.5)%. The mean TOFR required for a 90% T1 recovery was 0.83 (0.72-0.93) for the propofol group and 0.82 (0.73-0.91) for the sevoflurane group.
Nicotinic acetylcholine receptors are members of the superfamily of the fast neurotransmitter-gated receptor channels, which also includes gamma aminobutyric acid (GABA), glycine and 5-hydroxytryptamine receptors [1,8]. The muscular nicotinic receptor in the adult is formed by five subunits (α1, α2, β1, γ, δ); the neuronal nicotinic receptor is formed only by α and β subunits, although up to seven α and three β subunits have been described that can form multiple combinations [1,8,9]. There are two main groups of neuronal receptors defined depending on their α-bungarotoxin inhibitory capacity and the agonist capacity of epibatidine. One group is characterized by being inhibited by α-bungarotoxin and not being activated by epibatidine and is formed exclusively by subunits α7 and α8; the second group is not sensitive to α-bungarotoxin inhibition, is activated by epibatidine and is a heterogenous group; the most common distribution in the central nervous system is α4β2 and in the peripheral nervous system is α3β4 [1,8-10]. The neuronal nicotinic receptor at prejunctional level can facilitate or induce secretion of acetylcholine or other neurotransmitters [1,11].
Although the site of action of neuromuscular blocking agents is predominantly postjunctional they also have a prejunctional site of action. The degree of fade in response to TOF stimulation is correlated to the action of the neuromuscular blocking agent on the presynaptic receptor [12,13]. This action induces an inhibition of the positive feedback decreasing transmitter output . The clinical significance of this prejunctional action is not clear and it has not been correlated with the potency of the drug or the speed of onset of the neuromuscular block [12,13]. Recent studies have found no differences in TOF fade between the more frequently used agents (mivacurium, atracurium, rocuronium, vecuronium and cisatracurium), although there have been previously reported differences between pancuronium and d-tubocurarine [13,14].
Experimental studies have shown an inhibitory effect of volatile anaesthetic agents at clinical concentrations on the nicotinic receptors with a higher affinity for the neuronal nicotinic receptor than for the muscular receptor [1-3,5]. This inhibitory effect on the neuronal nicotinic receptor has been demonstrated both for the α4β2 subtype and for the α3β4 subtype although it has not been found on the α7 subtype [1-3,5,15]. The action of volatile anaesthetic agents on the nicotinic receptor has been studied in relation to anaesthetic mechanism of action and, although there is recent evidence that inhibition of the nicotinic receptor does not cause hypnosis or immobilization, there is evidence that it has consequences on nociception [1,3,8]. Contrary to volatile agents, the action of propofol on the nicotinic receptor has only been shown at supraclinical concentrations [6,7].
The neuromuscular junction has been suggested as the site of interaction between volatile anaesthetics and neuromuscular blocking agents. Paul and colleagues , in an experimental study, showed the additional inhibitory action of sevoflurane and isoflurane on vecuronium at the muscular nicotinic receptor. Our hypothesis was that if there is an inhibitory action of sevoflurane on the neuronal nicotinic receptor at clinical concentrations and if this action occurs at the prejunctional nicotinic receptor, then the interaction between sevoflurane and mivacurium should be expressed clinically both by an enhancement of the neuromuscular block due to its postjunctional action, as well as by an increase in TOF fade due to its prejunctional inhibition. Nevertheless, although the present study shows that recovery times of a mivacurium block are prolonged by the action of sevoflurane when compared to the action of propofol, we did not observe any differences in TOF fade between the two anaesthetic techniques. Therefore under normal clinical conditions we cannot verify any synergistic action of mivacurium and sevoflurane at the prejunctional level.
The times of recovery of the mivacurium block obtained after 30 min of sevoflurane action were significantly longer than those obtained in the propofol group. The recovery times obtained in the sevoflurane group are clearly different from others described in the literature; Lowry and colleagues , using a single dose of mivacurium of 0.2 mg kg−1, mechanomyography as a monitoring technique and <10 min of sevoflurane administration (end-tidal concentration 1.5-1.8%) before the neuromuscular block, did not find significant differences between the T1 25-75% recovery time of the sevoflurane group (9 ± 3.1 min) and the propofol group (7 ± 1.9 min). Kaplan and colleagues , in a paediatric population, used a dose of 0.2 mg kg−1 of mivacurium, electromyography and 5 min of sevoflurane action (end-tidal concentration 2.5%) before administering the mivacurium. They obtained a T1 25-75% for the sevoflurane group of 6.6 ± 2.8 min. Wulf and colleagues , using acceleromyography, did find significant differences between the T1 25-75% of the sevoflurane group (1.5 minimal alveolar concentration, MAC) and the propofol group although the T1 25-75% for sevoflurane was lower than ours (9 ± 4 min). The duration of administration of a volatile agent before the administration of a neuromuscular blocking agent is important when studying their interaction and it has been reported that the potentiation is not at its peak for 30-80 min [19-21]. The main methodological difference in our study with respect to others is the duration of action of sevoflurane before the administration of mivacurium. We allowed 30 min before the administration of mivacurium whereas the other studies used <10 min. Furthermore, we wanted to study the presynaptic action of sevoflurane during recovery of the neuromuscular block and with 30 min of sevoflurane action we could be fairly certain of a constant state of the volatile agent during the whole study.
The TOFR is related to the degree of neuromuscular block and classically, using mechanomyography or electromyography, a TOFR of 0.7 or higher has been correlated with a twitch return to the control value [12,22]. Kopman and colleagues  correlated a TOFR of 0.7 during recovery of mivacurium block using acceleromyography, with a mean T1 of 69 ± 8% and a TOFR of 0.9 with a mean T1 of 86 ± 5%. They concluded that it is necessary to reconsider the TOFR of security in acceleromyography, because TOFR <0.9 could represent incomplete recovery of the neuromuscular block. In our experience, using similar conditions to the study by Kopman and colleagues , we obtained very similar results and so we should also suggest that it is necessary with acceleromyography to be certain of a return of the TOFR at higher levels than 0.9 to avoid the risk of a residual block.
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