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From the Department of Anaesthetics and Intensive Care Medicine, The Queen's University of Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL N. Ireland, UK.
Address correspondence to: Dr. R.K. Mirakhur, Phone: 44-28-9033-5785; Fax: 44-28-9032-9605; E-mail: r.mirakhur{at}qub.ac.uk
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Abstract |
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 TOP Abstract Patients and methodsResultsDiscussionReferences |
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Methods: One hundred and twenty patients, divided into three equal groups, were randomly allocated to maintenance of anesthesia with sevoflurane, isoflurane or propofol. Neuromuscular block was induced with rocuronium and monitored using train-of-four (TOF) stimulation of the ulnar nerve and recording the force of contraction of the adductor pollicis muscle. Neostigmine was administered when the first response in TOF had recovered to 25%. At this time the volatile agent administration was stopped or propofol dosage reduced in half the patients in each group (n = 20 in each group). The times to attain TOF ratio of 0.8, and the number of patients attaining this end point within 15 min were recorded.
Results: The times (mean ± SD) to recovery of the TOF ratio to 0.8 were 12.0 ± 5.5 and 6.8 ± 2.3 min in the sevoflurane continued and sevoflurane stopped groups, 9.0 ± 8.3 and 5.5 ± 3.0 min in the isoflurane continued and isoflurane stopped groups, and 5.2 ± 2.8 and 4.7 ±1.5 min in the propofol continued and propofol stopped groups (P < 0.5- 01). Only 9 and 15 patients in the sevoflurane and isoflurane continued groups respectively had attained a TOF ratio of 0.8 within 15 min (P < 0.001 for sevoflurane).
Conclusions: The continued administration of sevoflurane, and to a smaller extent isoflurane, results in delay in attaining adequate antagonism of rocuronium induced neuromuscular block.
PREVIOUS studies have shown that antagonism of block with relaxants such as vecuronium is impeded in the presence of potent volatile agents such as sevoflurane and isoflurane.1–3 It has also been shown that sevoflurane anesthesia potentiates the effect of rocuronium compared with isoflurane and propofol anesthesia.4 Although there are reports of antagonism of rocuronium block with neostigmine, these have generally examined the influence of the dosage or the timing of administration of the anticholinesterase.5–7 The aim of the present study was to examine the effect of the sevoflurane on the antagonism of rocuronium by neostigmine, and compare it with the effects of isoflurane, and intravenous anesthesia.
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Patients and methods |
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TOPAbstractPatients and methodsResultsDiscussionReferences |
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Patients were premedicated with 10-20 mg temazepam po 90 min preoperatively, if desired by them. Anesthesia was induced with 1-2 µg•kg–1 fentanyl and 1-3 mg•kg–1 propofol, and maintained with nitrous oxide 66% in oxygen, and sevoflurane, isoflurane, or propofol, as allocated by a computer generated randomization list. Ventilation was assisted to maintain the PETCO2 between 35 and 45 mm Hg, and skin temperature over the adductor pollicis was maintained above 32°C by wrapping the arm in cotton wool. The end-tidal concentration of the volatile agents was monitored using a respiratory gas monitor and adjusted to 1.5 MAC adjusted for age and concomitant use of nitrous oxide (1.5-1.8% sevoflurane, 0.8-1.0% isoflurane) as described previously.4 Patients whose anesthesia was maintained with iv propofol received a standard propofol infusion at 6-12 mg•kg–1•hr–1. Further doses of propofol or fentanyl were administered as required.
The ulnar nerve was stimulated transcutaneously at the wrist, with supramaximal stimuli of 0.2 msec duration in a train-of-four (TOF) mode at 2 Hz every 12 sec. The resulting force of contraction of the adductor pollicis muscle was measured and recorded using a force displacement transducer and a neuromuscular function analyser (Myograph 2000, Biometer, Denmark). Baseline neuromuscular responses were allowed to stabilize for about 10 min, during which time the end-tidal concentration of volatile anesthetics was also stabilized.
Patients received a bolus dose of 0.6 mg•kg–1 rocuronium as a single iv injection over five seconds, followed by increments if required when the T1 had recovered to 25% of the control value. Tracheal intubation was carried out at the development of maximum block. At the end of surgery all patients had neuromuscular block antagonised with 50 µg•kg–1 neostigmine and 10 µg•kg–1 glycopyrrolate whenT1 (the first response in TOF) was 20-25%. Administration of sevoflurane, isoflurane or propofol was continued throughout the reversal in half the patients in each group (propofol-continued, sevoflurane-continued or isoflurane-continued groups), while the rest had the volatile agent discontinued or propofol infusion run at a lower (about 2 mg•kg–1•hr–1) rate (propofol-stopped, sevoflurane-stopped or isoflurane-stopped groups). Nitrous oxide 66% in oxygen was continued in all patients until completion of reversal.
The times to onset of effect of neostigmine (increase of 5% or more of T1), attaining the TOF ratio of 0.8, and the recovery of T1 from 25-75% were recorded. The number of patients who had not attained a TOF ratio of 0.8 by 15 min of neostigmine administration was also recorded. The end point of TOF ratio of 0.8 was chosen to represent adequate recovery according to recent guidelines compared with the previously used end point of 0.7.8 The data of various time end points were subjected to analysis of variance, followed by post tests as indicated. The number of patients achieving reversal within the 15 min time period was subject to x2 analysis. P < 0.05 was considered to represent a significant difference. Sixteen patients per group would have been required for the study for a power of 80% assuming a difference of 10 min between the fastest and the slowest reversing groups in the time taken to attain a TOF ratio of 0.8 we decided to include 20 subjects per group.
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Results |
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TOPAbstractPatients and methodsResultsDiscussionReferences |
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The groups were comparable in terms of age, weight, height, gender distribution and T1 at reversal (Table I
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. The times for onset of action of neostigmine (average of 0.6-0.7 min) did not differ among the six groups. The time to attaining a TOF ratio to 0.8 was longer (P < 0.01) in the sevoflurane-continued group being an average of 12.0 min. Although the time (mean of 9.0 min) was longer in the isoflurane-continued group also, the difference was not statistically significant when compared with the time in the isoflurane stopped group. The differences between the propofol groups and the groups where volatile agents were stopped at reversal were not different and averaged about five minutes. The data for four patients in the sevoflurane-continued and in one patient in the isoflurane-continued were not available as they had not attained the TOF ratio of 0.8 even after 30 min of neostigmine administration when, due to logistic reasons, their anesthesia had to be discontinued. All of them achieved the TOF ratio of 0.8 within a few minutes after discontinuation of the volatile agent. T1 25-75% recovery indices although slightly longer in the groups where the volatile anesthetic administration was continued during reversal, were not significantly different.
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Discussion |
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TOPAbstractPatients and methodsResultsDiscussionReferences |
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It has previously been shown that residual concentrations of isoflurane augment vecuronium induced neuromuscular block and that even after discontinuation of the volatile agent, impaired antagonism is not eliminated although there is some improvement.1 In our study also, the reversal was slowed in the presence of sevoflurane, and to some extent isoflurane anesthesia, and in some patients the block had not reversed even by 30 min. However, when the volatile agent administration was discontinued at the time of neostigmine administration, the reversal times were not different from the propofol groups. This was the case with those patients also whose reversal was very slow in the presence of volatile agents but recovered on discontinuation of the volatile agent. Our study, therefore, shows that discontinuing administration of the volatile anesthetics improves the speed of reversal of block with neostigmine.
The continued administration of isoflurane during reversal of rocuronium-induced neuromuscular blockade, also tended to prolong the time to attaining the TOF ratio of 0.8 when compared with propofol anesthesia, a finding which has been reported by others.9,10 The concurrent administration of enflurane has been shown to impair neostigmine antagonism of both pancuronium and vecuronium blocks,11,12 and stopping administration of enflurane at the time of neostigmine administration decreases the potentiation of atracurium block produced by enflurane.13 The recovery in the groups where the volatile agent administration was discontinued in the present study was fairly rapid and similar to that in the propofol groups. This would not be surprising given the rapid elimination of both sevoflurane and isoflurane due to their relatively low blood-gas solubilities. This was further evident in the cases where continued administration of sevoflurane and isoflurane resulted in slow and prolonged recovery which was accelerated once the volatile agent administration was discontinued.
Some previous studies have shown that the effects of isoflurane and sevoflurane are similar in prolonging the effects of muscle relaxants when the volatile agents have been administered for about 40 min before relaxant administration allowing enough time for equilibration of volatile agents between various compartments.14–16 This may be the reason why in a recent study there was no marked prolongation in average reversal time of rapacuronium during sevoflurane compared to propofol anesthesia as the reversal was carried out within only about 15 min of relaxant and anesthetic administration.17 These results are at variance with the findings of Lowry et al. who showed a more marked effect of sevoflurane on rocuronium block during spontaneous recovery even after shorter periods of volatile agent administration.4 The greater effect of sevoflurane compared with isoflurane would, from the results of our study, appear to be present during the reversal of block as well indicating that sevoflurane may have inherently greater potentiating effect on muscle relaxants such as rocuronium. In our study, both sevoflurane and isoflurane were administered for similar average times (longer than those reported by others for equilibration between blood and muscle compartments), yet the reversal was slower in those receiving sevoflurane.
Although the T1 25-75% recovery index also showed a tendency to be prolonged in the volatile agent continued groups, the difference was not statistically significant. This is in contrast to a previous study where the recovery index for rocuronium was prolonged during sevoflurane anesthesia.4 However in that study recovery was taking place spontaneously and was considerably more prolonged.
Several reasons have been postulated as the cause of the potentiation of muscle relaxants by volatile agents. These include pre-junctional effects, increased blood flow to muscles during anesthesia, and a centrally mediated relaxation.18–20 Whatever the mechanism, it appears that these effects are extended to the time of the reversal of the block as well. It would appear that sevoflurane potentiation of muscle relaxants is more marked than that of isoflurane. Any differences in muscle-gas solubility of the various volatile agents would not account for the effect of the volatile agents because when examining reversal, as in our study, enough time (approximately 40 min) would have elapsed to ensure equilibration between blood and muscle compartments.
In conclusion, the present study demonstrates the extent to which recovery from rocuronium induced neuromuscular block is slowed in the presence of potent volatile agents, and that this effect is more marked in patients receiving sevoflurane. It can also be seen that discontinuing administration of the volatile agents at reversal returns the time taken to adequate recovery to that in patients receiving an intravenous infusion of propofol. Thus it may be worthwhile considering earlier administration of reversal agents although it is not known if it facilitates early reversal, and it may also not be convenient. It is also important to monitor neuromuscular blockade routinely and correctly when using rocuronium with any of the volatile agents. However, if it is considered desirable to maintain administration of sevoflurane during rocuronium reversal by neostigmine, then slower attainment of adequate reversal should be anticipated.
Accepted for publication November 24, 2000.
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References |
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2 Morita T, Tsukagoshi H, Sugaya T, Saito S, Sato H, Fujita T. Inadequate antagonism of vecuronium- induced neuromuscular block during sevoflurane or isoflurane anesthesia. Anesth Analg 1995; 80: 1175–80.[Abstract]
3 Morita T, Kurosaki D, Tsukagoshi H, Shimada H, Sato H, Goto F. Factors affecting neostigmine reversal of vecuronium block during sevoflurane anaesthesia. Anaesthesia 1997; 52: 538–43.[Medline]
4
Lowry DW, Mirakhur RK, McCarthy GJ, Carroll MT, McCourt KC. Neuromuscular effects of rocuronium during sevoflurane, isoflurane, and intravenous anesthesia. Anesth Analg 1998; 87: 936–40.
5 McCoy EP, Mirakhur RK, Maddineni VR, Loan PB, Connolly F. Administration of rocuronium (Org 9426) by continuous infusion and its reversibility with anticholinesterases. Anaesthesia 1994; 49: 940–5.[Medline]
6 van den Broek L, Proost JH, Wierda JMKH. Early and late reversibility of rocuronium bromide. Eur J Anaesthesiol 1994; 11(Suppl9): 128–32.
7 McCourt KC, Mirakhur RK, Kerr CM. Dosage of neostigmine for reversal of rocuronium block from two levels of spontaneous recovery. Anaesthesia 1999; 54: 651–5.[Medline]
8 Viby-Mogensen J, Engbæk J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996; 40: 59–74.[Medline]
9 Shanks CA, Fragen RJ, Ling D. Continuous intravenous infusion of rocuronium (ORG 9426) in patients receiving balanced, enflurane or isoflurane anesthesia. Anesthesiology 1993; 78: 649–51.[Medline]
10
Oris B, Crul JF, Vandermeersch E, Van Aken H, Van Egmond J, Sabbe MB. Muscle paralysis by rocuronium during halothane, enflurane, isoflurane, and total intravenous anesthesia. Anesth Analg 1993; 77: 570–3.
11 Delisle S, Bevan DR. Impaired neostigmine antagonism of pancuronium during enflurane anaesthesia in man. Br J Anaesth 1982; 84: 441– 4.
12 Dernovoi B, Agoston S, Barvais L, Baurain M, Lefebvre R, d'Hollander A. Neostigmine antagonism of vecuronium paralysis during fentanyl, halothane, isoflurane, and enflurane anesthesia. Anesthesiology 1987; 66: 698–701.[Medline]
13
Gill SS, Bevan DR, Donati F. Edrophonium antagonism of atracurium during enflurane anaesthesia. Br J Anaesth 1990; 64: 300–5.
14
Vanlinthout LEH, Booij LHDJ, van Egmond J, Robertson EN. Effect of isoflurane and sevoflurane on the magnitude and time course of neuromuscular block produced by vecuronium, pancuronium and atracurium. Br J Anaesth 1996; 76: 389–95.
15 Xue FS, Liao X, Tong SY, Liu JH, An G, Luo LK. Dose-response and the time-course of effect of rocuronium bromide during sevoflurane anaesthesia. Anaesthesia 1998; 53: 25–30.[Medline]
16
Bock M, Klippel K, Nitsche B, Bach A, Martin E, Motsch J. Rocuronium potency and recovery during steady-state desflurane, sevoflurane, isoflurane or propofol anaesthesia. Br J Anaesth 2000; 84: 43–7.
17
Zhou TJ, Tang J, White PF, et al. Reversal of rapacuronium block during propofol versus sevoflurane anesthesia. Anesth Analg 2000; 90: 689–93.
18 Miller RD, Way WL, Dolan WM, Stevens WC, Eger EI II. Comparative neuromuscular effects of pancuronium, gallamine, and succinylcholine during forane and halothane anesthesia in man. Anesthesiology 1971; 35: 509–14.[Medline]
19 Waud BE, Waud DR. The effects of diethyl ether, enflurane and isoflurane at the neuromuscular junction. Anesthesiology 1975; 42: 275–80.[Medline]
20 Waud BE, Ward DR. Effects of volatile anesthetics on directly and indirectly stimulated skeletal muscle. Anesthesiology 1979; 50: 103–10.[Medline]
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