British Journal of Anaesthesia 1990; 64: 300-305
EDROPHONIUM ANTAGONISM OF ATRACURIUM DURING ENFLURANE ANAESTHESIA S. S. GILL, D. R. BEVAN AND F. DONATI
To determine the influence of enflurane on the ability of edrophonium to antagonize atracurium block, dose-response curves were constructed for edrophonium in the presence of 0%, 1% and 2% enflurane, and for 2% enflurane discontinued at the time of administration of edrophonium. One hundred ASA Physical Status I or II patients (four groups of 25), selected randomly and undergoing elective surgery, received atracurium 0.5 mg kg'7, with thiopentone, nitrous oxide and enflurane. Supplementary doses of fentanyl were given if needed. Train-of-four (TOF) stimulation was applied every 12 s, and the force of contraction of the adductor pollicis muscle was recorded. When first twitch height (T1) had recovered spontaneously to 10% of initial value, edrophonium 0.1, 0.2, 0.4 or 1 mg kg'1 was administered by random allocation. Enflurane concentrations remained constant, except that enflurane was discontinued in 50% of the patients who had received 2% enflurane. Monitoring was continued for at least 10 min, at which time T1 and TOF ratio (T4/T1) were measured. The ED go for T1 recovery depended on the dose of enflurane: 0.08 (seM0.03). 0.21 (0.06) and 0.42 (0.18) mg kg'1 for 0%, 1 % and 2% enflurane, respectively (?< 0.005). With enflurane 2% discontinued, the ED go was 0.095 (0.050) mg kg'1 (P < 0.02 compared with 2% enflurane). The ED so for TOF responses were 0.13 (0.05). 0.46 (0.10) and 1.04 (0.38) mg kg-1 for 0%, 1 % and 2% enflurane, respectively (? < 0.001). With 2% enflurane discontinued, the ED so for TOF was 0.17 (0.12) mg kg-1 (? < 0.05 compared with 2% enflurane). It is concluded that, even when given at the same degree of spontaneous recovery, the effect of edrophonium is markedly attenuated by enflurane.
KEY WORDS Anaesthetics, volatile: enflurane. Antagonists: neuromuscular relaxants. edrophonium. Drug interactions: edrophonium. enflurane.
Inhalation agents potentiate the effect of nondepolarizing neuromuscular blocking drugs. In this respect, enflurane appears to be more potent than either halothane or isoflurane [1-4]. Two studies [5,6] examined the influence of the inhalation anaesthetic used during antagonism of neuromuscular block. In both cases, neostigmineassisted antagonism was found to be delayed in the presence of enflurane. However, these studies involved only one dose of the antagonist drug, and one concentration of enflurane. Furthermore, the effect of reducing the end-tidal concentration of inhalation agents as the antagonist drug is given, as commonly happens in clinical practice, has not been evaluated. In addition, none of the previous studies [5, 6] has dealt with the effect of edrophonium. The purpose of this study was to determine the effect of enflurane on edrophonium-assisted recovery of atracurium-induced neuromuscular block. Several doses of edrophonium were given to establish dose-response relationships for the drug. These were constructed in the presence of 0%, 1% and 2% enflurane end-tidal. An additional group had 2 % enflurane end-tidal discontinued at the time of administration of edrophonium.
SATWANT S. GILL, M.B., F.F.A.R.C.S. ; DAVID R. BEVANf, M.B., M.R.C.P., F.F.A.R.C.S. J FRANCOIS DONATI, PH.D., M.D., F.R.C.P.C.;
Departments of Anaesthesia, Royal Victoria Hospital and McGill University, Montreal, Quebec, Canada. Accepted for Publication: September 19, 1989. tAddress for correspondence: McGill Department of Anaesthesia, Room F3.01, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1.
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SUMMARY
ENFLURANE AND EDROPHONIUM ANTAGONISM PATIENTS AND METHODS
the first twitch height (Tl) recovered to 10% before surgery was completed. At the end of surgery, when Tl had recovered to 10% of initial value, edrophonium 0, 0.1, 0.2, 0.4 or 1 mg kg"1 was given randomly with atropine 0.3-1.2 mg. Five patients received each dose of edrophonium in each group. No further edrophonium was given for at least 10 min. In groups 1-3, the end-tidal enflurane concentration was kept constant. In group 4, the inspired enflurane concentration was decreased to 0%, and a fresh gas flow of at least 100 ml kg"1 min"1 was given. After 10 min, an additional dose of edrophonium was given if required to bring the TOF ratio (T4/T1) to at least 0.7. Dose-response curves for overall recovery were constructed using Tl and T4/T1 measured 10 min after administration of edrophonium. The logit transformation of Tl and T4/T1 was plotted against the logarithm of the dose [7]. The dose of edrophonium required to produce 80 % recovery of Tl (ED8O,T1) was derived for each concentration of enflurane. Similarly, dose—response relationships involving T4/T1 were derived, and the dose required to produce 50% T4/T1 (ED5O,T4/T1) was calculated for each concentration of enflurane. The standard error of estimate for the mean [8] was used as an index of dispersion. Dose-response relationships were used also to estimate the effect of edrophonium 0.5 mg kg"1, 10 min after its administration, on Tl and T4/T1, for the various concentrations of enflurane. Unless otherwise specified, the results are expressed as means (standard error of estimate for the mean (SEE) [8]. The effect of enflurane was evaluated by plotting a measure of edrophonium effect (ED8O,T1 or ED6O,T4/T1) against dose of enflurane. Linear regressions were used in this case. The effect of discontinuing 2 % enflurane was compared with that of maintaining this concentration constant, using a Student's t test. P < 0.05 was assumed to indicate statistically significant differences.
RESULTS
We studied 39 males and 61 females. The mean (SD) age was 45.5 (16.5) yr and mean (SD) weight was 70.1 (15.5) kg. All groups were comparable (table I). Cardiovascular variables remained within normal limits during anaesthesia. In particular,
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After approval by the Hospital Ethics Committee, 100 patients, ASA Physical Status I or II, were studied during various elective surgical procedures of at least 60 min duration. Patients with hepatic, renal or neuromuscular disease were excluded, as were those with electrolyte abnormalities, those taking medication known or suspected to interfere with neuromuscular function and those in whom blood loss exceeded 500 ml. Premedication with atropine 0.006-0.01 mg kg"1 or glycopyrrolate 0.003-0.005 mg kg"1, and morphine O.lmgkg" 1 or pethidine lmgkg" 1 , was given i.m. 1 h before the scheduled start of the surgical procedure. On arrival in the operating room, the patient's ECG and arterial pressure were monitored. Anaesthesia was induced with thiopentone 3-5mgkg~1. The ulnar nerve was stimulated supramaximally at the elbow with square-wave pulses of 0.2 ms duration, delivered at a frequency of 2 Hz for 2 s (TOF) and repeated every 12 s. The hand and forearm were immobilized in a splint and the force of contraction of the adductor pollicis muscle was measured with a force displacement transducer (Grass FT-10) and recorded. A baseline was established after induction of anaesthesia, while the patient's lungs were ventilated manually via a mask. Atracurium 0.5 mg kg"1, was given i.v. as a single bolus and intubation of the trachea was accomplished when maximal neuromuscular block had been achieved. The patients were allocated randomly to four groups of 25, each group being subdivided into five subgroups of five. In group 1, anaesthesia was maintained with 70 % nitrous oxide and fentanyl 5-10 ug kg"1 given at induction of anaesthesia, followed by 1-2 ug kg"1 increments as required. In group 2, 70 % nitrous oxide was supplemented with 1 % enflurane end-tidal, as measured by mass spectrometry. In group 3, 2% enflurane end-tidal was given in oxygen. In group 4, 2% enflurane end-tidal was given (as in group 3), but enflurane was discontinued at the time of administration of edrophonium. In all groups, mechanical ventilation utilized a circle system and carbon dioxide absorber. The fresh gas flow rate was 1-2 litre min"1, frequency of ventilation 10 b.p.m., and tidal volume adjusted so that the measured end-tidal carbon dioxide was maintained in the range 4-4.7 kPa. Incremental doses of atracurium 0.1 mgkg"1 were administered if
301
BRITISH JOURNAL OF ANAESTHESIA
302 TABLE I.
Enflurane concn (%) Sex (M/F)
98
Demographic data Age (yr) (mean (SD))
Weight (kg) (mean (SD))
44.3 (3.0) 50.4 (2.9) 40.6 (3.3) 46.9 (3.8)
76.8 (3.8) 69.4 (2.3) 67.6 (3.0) 66.7 (2.9)
95
0 1 2 2-0
8/17 9/16 11/14 11/14
i
9080 7060 50 0.1
0.2 0.4 Dose of edrophonium (mg kg'1)
1.0
FIG. 1. Relationship between Tl (height of first twitch) on the logit scale and log of edrophonium dose, 10 min after administration of edrophonium, for enflurane 0 % ( ), 1 % ( ), 2% (—) (end-tidal concentrations), and 2% discontinued at the time of administration of edrophonium ( ). Standard errors are omitted for clarity.
continued, but the difference was not significant (table II). The effect appeared qualitatively similar on T4/T1 (table III), but the differences were not significant. At all doses, recovery of T l and T4/T1 decreased with increasing concentrations of enflurane, and this effect was reduced by discontinuation of enflurane (tables II, III). This can be demonstrated in the dose-response curves for first
TABLE II. Effect (%, mean (SEB)) of edrophonium on Tl, 10 min after administration to patients receiving one of four dose regimens of enflurane Dose of edrophoniumi (mg kg"1) Enflurane concn (%) 0 1 2 2-0
TABLE III. Effect (%,
0
0.1
0.2
0.4
1.0
41.0(2.3) 33.6 (3.9) 28.0 (3.4) 40.4 (5.7)
78.4 (2.0) 59.6 (5.3) 52.8 (10.3) 79.6 (5.2)
84.8 (6.3) 75.6 (3.4) 65.8 (8.9) 83.8(1.7)
93.4 (4.3) 91.2(3.3) 79.4 (4.6) 82.0(7.1)
94.8 (2.2) 90.0(3.1) 86.2 (3.2) 88.4(5.1)
mean (SEE)) of edrophonium on T4/T1, 10 min after administration to patients receiving one of four dose regimens of enflurane Dose of edrophonium (mg kg"1)
Enflurane concn (%) 0 1 2 2-0
0
0.1
0.2
0.4
1.0
12.6 (4.5) 12.0 (2.4) 8.0 (4.6) 1.8(2.7)
47.2 (3.0) 23.8 (4.6) 23.8(1.2) 40.4 (2.2)
54.0 (5.7) 33.8 (4.2) 28.6 (2.3) 54.8 (4.9)
64.4 (3.6) 54.4 (7.5) 35.6 (5.6) 64.2 (4.2)
72.8 (4.4) 60.4 (3.7) 51.6(5.4) 60.6 (4.5)
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systolic arterial pressure did not decrease to less than 100 mm Hg in any patient. The time from first injection of atracurium to 10% T l recovery increased with administration of greater concentrations of enflurane. This interval was 41.8 (1.6), 44.4 (1.8) and 46.4 (1.4) min for enflurane concentrations of 0%, 1 % and 2 % (P < 0.05) by linear regression. For the purpose of these calculations, both groups which received 2% enflurane were amalgamated. Because of additional doses given in some patients, mean total dose was 0.67 mg kg"1 (range 0.5-1.1 mg kg"1). The mean time between administration of the first dose of atracurium and injection of edrophonium was 67 min. In the absence of edrophonium, T l recovery was affected by the enflurane concentration (table II). For example, with 0% enflurane, T l was 41 (2.3)% 10 min after it had reached 10%. In the presence of 2% enflurane, the Tl value reached only 29 (3.4)% (P < 0.01). Recovery of T l appeared greater if 2% enflurane was dis-
ENFLURANE AND EDROPHONIUM ANTAGONISM
303
70-, 70
£ 60 c
^i 60-
E o w
Jso
50
40 30-
0.1
0.2
0.4
1.0
Dose of edrophonium (mgkg")
FIG. 2. Relationship between T4/T1 (train-of-four ratio) on the logit scale and log of edrophonium dose, 10 min after administration of edrophonium, for enflurane 0 % ( ), 1 % ( ), 2% (—) (end-tidal concentrations), and 2% discontinued at the time of administration of edrophonium ( ). Standard errors are omitted for the sake of clarity.
100i
95 *c 90 E o
r 85 8075
ENFO
ENF1
ENF 2
ENF2->0
FIG. 3. Expected effect of edrophonium 0.5 mg kg"1 on Tl (first twitch height) 10 min after its administration, according to dose of enflurane (0%, 1%, 2% or 2% end-tidal discontinued).
ENFO
ENF1
ENF 2
ENF2->0 1
FIG. 4. Expected effect of edrophonium 0.5 mg kg" on T4/ Tl (train-of-four ratio) 10 min after administration, according to dose of enflurane (0%, 1 %, 2% or 2% end-tidal discontinued).
and 1.04 (0.38) mg kg"1, for 0%, 1% and 2% enflurane, respectively (P < 0.001). With 2% enflurane discontinued, the ED60 was 0.17 (0.12) mg kg"1 {P < 0.01 compared with 2 % enflurane). The expected effect of edrophonium 0.5 mg kg"1 was calculated for the various groups from the dose-response relationships (figs 3, 4). After 10 min, Tl was expected to be (mean (SEE)) 96 (1) %, 90 (2) % and 82 (3) % for 0 %, 1 % and 2 % enflurane, respectively (P < 0.0005 by linear regression). With 2% enflurane discontinued, Tl was expected to reach 91 (2)% (P < 0.02 compared with no discontinuation of 2 % enflurane). The expected T4/T1 values were 66 (2)%, 52 (3)% and 40 (2)%, for 0%, 1% and 2% enflurane, respectively (P < 0.00001). If enflurane was discontinued, T4/T1 was calculated to be 60 (6)% (P < 0.01 compared with 2% enflurane continued). DISCUSSION
This study has demonstrated that, when edrophonium is used to antagonize atracurium neurotwitch height, as shown in figure 1. The ED g0 ,Tl, muscular block, the residual concentration of 10 min after administration of edrophonium were enflurane is important. When 2 % enflurane end0.08 (0.03), 0.21 (0.06) and 0.42 (0.18) mgkg- 1 , tidal was used, five times as much edrophonium for 0 %, 1 % and 2 % enflurane, respectively (P < was required to obtain Tl = 8 0 % within 10 min 0.005). With 2% enflurane discontinued, the than if no enflurane had been used. The effect on dose-response curve was flatter. The ED80 was T4/T1 was even more pronounced. To achieve 0.095 (0.050) (P < 0.02 compared with main- T 4 / T l = 5 0 % within 10 min, eight times as tenance of 2% enflurane). The dose-response much edrophonium had to be given with 2% relationships for T4/T1 10 min after edro- compared with 0% enflurane end-tidal, even phonium was given are shown in figure 2. In this though all patients received edrophonium at the case, the EDS0 values were 0.13 (0.05), 0.46 (0.10) same degree of neuromuscular block. However,
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30
20-
304
potentiation of enflurane, a phenomenon which has also been suggested for tubocurarine block [14]. The time dependence of potentiation of enflurane can explain, at least in part, the adverse effects of edrophonium on recovery of neuromuscular function. Total recovery can be considered as consisting of two parts: the effect of spontaneous recovery, associated with decreasing concentrations of the blocker, while elimination or redistribution takes place; and assisted recovery, which is the added effect of the antagonist drug. When greater concentrations of enflurane are given, potentiation of neuromuscular block by the volatile agent increases in intensity with time as the antagonist drug is given. Thus although enflurane may not affect the disposition of the neuromuscular blocker (pharmacokinetics), it may affect the receptor at the neuromuscular junction (pharmacodynamics). As a result, spontaneous recovery is impaired and total recovery is less. Other results suggest that the effects of enflurane are based not only on a time-dependent potentiation of atracurium block. Discontinuation of administration of enflurane tended to restore neuromuscular transmission to the state which would have prevailed in the absence of inhalation agent. Although the end-tidal concentration of enflurane decreased to 0.3-0.4 % after 10 min, it is probable that concentrations of enflurane at the neuromuscular junction were not affected greatly by this manoeuvre. Assuming a 40-min equilibration half-time [14] of enflurane in muscle, which is consistent with the slow time course of enflurane potentiation of atracurium neuromuscular block, it appears that discontinuation of enflurane would have led to a negligible decrease in muscle concentrations of enflurane. It is possible that some other factors may play a role, such as central influences. Catecholamines have been shown in animals to potentiate the effect of neostigmine [15], and the same could be true of edrophonium. In particular, light levels of anaesthesia, which are associated with low concentrations of end-tidal enflurane, could improve the degree of neuromuscular recovery. The variability of response when 2% enflurane was discontinued could result from the variability of this effect among patients. The predicted effect of edrophonium 0.5 mg kg"1 reported here is consistent with that obtained in an earlier study [11]. With end-tidal enflurane
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the effect of 2 % enflurane could be diminished by decreasing its inspired concentration at the time of administration of edrophonium. The effect of this manoeuvre was variable and recovery was not as good as in patients who did not receive enflurane. The study is in agreement with previous work in which the dose-response relationship for edrophonium was found to be relatively flat [9-11]. This probably accounts for the wide discrepancies in the ED8O,T1 and EDBO,T4/T1 with and without enflurane. For example, although five times as much edrophonium was required with 2% enflurane compared with 0% to obtain Tl = 80 %, the administration of 0.5 mg kg"1 was expected to yield Tl = 9 6 % with 0% enflurane and Tl = 8 2 % with 2% enflurane, a difference of only 14%. Similarly, although edrophonium was only 12.5% as potent in the presence of 2 % enflurane, a dose of 0.5 mg kg"1 was expected to produce T4/T1 = 4 0 % , compared with T4/T1 = 66% with 0% enflurane, a difference of only 26 %. Such differences may be clinically significant. Surprisingly, 2% enflurane end-tidal, or approximately 1.2 MAC [12], produced only a small prolongation of the duration of atracurium block, from 41.8 to 46.4 min. This suggests that enflurane has little effect on atracurium block, at least during the first 30-45 min after the beginning of the administration of enflurane. Rupp, McChristian and Miller [13] found the ED,6 of atracurium to be similar with enflurane and halothane anaesthesia, but the end-tidal concentrations had been stable for only 30 min. Similarly, Goudsouzian and colleagues [3] found that the duration of action of atracurium 0.4 mg kg"1 was prolonged only slightly with nitrous oxide—enflurane compared with nitrous oxidemorphine. However, the effect of enflurane on atracurium block may be time dependent. In the present study, T l recovery was slower in patients who received 2 % enflurane compared with those who did not, in the absence of edrophonium. Similarly, Rupp's group [13] found that, although the dose-response relationship of atracurium was unaltered by enflurane, its duration of action was prolonged. In children, the infusion rate to maintain neuromuscular block constant was found to be time dependent and decreased in the time interval 30-60 min after administration of enflurane was started. These results are consistent with a time dependent increase in the degree of
BRITISH JOURNAL OF ANAESTHESIA
ENFLURANE AND EDROPHONIUM ANTAGONISM
4.
5. 6.
7. 8. 9.
10.
11.
12. 13.
14. REFERENCES 1. Fogdall RP, Miller RD, Neuromuscular effects of enflurane, alone and combined with d-tubocurarine, pancuronium, and succinylcholine, in man. Anesthesiology 1975; 42: 173-178. 2. Rupp SM, Miller RD, Gencarelli PJ. Vecuroniuminduced neuromuscular blockade during enflurane, isoflurane, and halothane anesthesia in humans. Anesthesiology 1984; 60: 102-105. 3. Goudsouzian N, Martyn J, Rudd GD, Liu LMP,
15.
16.
Lineberry CG. Continuous infusion of atracurium in children. Anesthesiology 1986; 64: 171-174. Cannon JE, Fahey MR, Castagnoli KP, Furuta T, Canfell PC, Sharma M, Miller RD. Continuous infusion of vecuronium: the effect of anesthetic agents. Anesthesiology 1987; 67: 503-506. Delisle S, Bevan DR. Impaired neostigmine antagonism of pancuronium during enflurane anaesthesia in man. British Journal of Anaesthesia 1982; 54: 441-445. Demovoi 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. Norman J. Drug—receptor reactions. British Journal of Anaesthesia 1979; 51: 595-601. Dixon WJ, Massey FJ jr. Introduction to Statistical Analysis, 3rd Edn. New York: McGraw-Hill, 1969; 195. Cronnelly R, Morris RB, Miller RD. Edrophonium: duration of action and atropine requirement in humans during halothane anesthesia. Anesthesiology 1982; 57: 261-266. Donati F, McCarroll SM, Antzaka C, McCready D, Bevan DR. Dose-response curves for edrophonium, neostigmine, and pyridostigmine after pancuronium and d-tubocurarine. Anesthesiology 1987; 66: 471-476. Donati F, Smith CE, Bevan DR. Dose-response relationships for edrophonium and neostigmine as antagonists of moderate and profound atracurium blockade. Anesthesia and Analgesia 1989; 68: 13-19. Gion H, Saidman LJ. The minimum alveolar concentration of enflurane in man. Anesthesiology 1971; 35: 361-364. Rupp SM, McChristian JW, Miller RD. Neuromuscular effects of atracurium during halothane-nitrous oxide and enflurane-nitrous oxide anesthesia in humans. Anesthesiology 1985; 63: 16-19. Stanski DR, Ham J, Miller RD, Sheiner LB. Timedependent increase in sensitivity to d-tubocurarine during enflurane anesthesia in man. Anesthesiology 1980; 52: 483-187. Drury PJ, Birmingham AT, Healy TEJ. Interaction of adrenaline with neostigmine and tubocurarine at the skeletal neuromuscular junction. British Journal of Anaesthesia 1987; 59: 784-790. Gencarelli PJ, Miller RD, Eger El, Newfield P. Decreasing enflurane concentrations and d-tubocurarine neuromuscular blockade. Anesthesiology 1982; 56: 192194.
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concentrations held at 0.5-1 %, edrophonium 0.5 mg kg"1 was expected to produce 89 (2) % Tl and 61 (3) % T4/T1 after 10 min. These values are close to those reported for 1 % enflurane in this study—90 (2)% for Tl and 52 (3)% for T4/T1. It is possible that the same conclusions found here regarding edrophonium may apply also to neostigmine. In two studies, the effect of neostigmine was found to be impaired by the presence of enflurane [5, 6]. The concentrations used were less than in the present study. It is also possible that neostigmine-assisted recovery might be improved by the discontinuation of enflurane. Clinically, the presence of increased concentrations of enflurane should be expected to impair recovery. Discontinuation of enflurane when the antagonist drug is administered should improve recovery. However, total recovery should not be expected to be greater with discontinuation of enflurane compared with little or no inhalation agent. In this respect, our results contradict the suggestion that the potentiation of neuromuscular block by volatile agents "may provide additional safety for patients whose anaesthetic is one of the most potent muscle relaxants enhancing agents" [16]. For this reason, it appears prudent to plan antagonism of neuromuscular block at a greater degree of twitch height recovery when increased concentrations of enflurane are used.
305
EDROPHONIUM ANTAGONISM OF ATRACURIUM DURING ENFLURANE ANAESTHESIA S. S. GILL, D. R. BEVAN AND F. DONATI
To determine the influence of enflurane on the ability of edrophonium to antagonize atracurium block, dose-response curves were constructed for edrophonium in the presence of 0%, 1% and 2% enflurane, and for 2% enflurane discontinued at the time of administration of edrophonium. One hundred ASA Physical Status I or II patients (four groups of 25), selected randomly and undergoing elective surgery, received atracurium 0.5 mg kg'7, with thiopentone, nitrous oxide and enflurane. Supplementary doses of fentanyl were given if needed. Train-of-four (TOF) stimulation was applied every 12 s, and the force of contraction of the adductor pollicis muscle was recorded. When first twitch height (T1) had recovered spontaneously to 10% of initial value, edrophonium 0.1, 0.2, 0.4 or 1 mg kg'1 was administered by random allocation. Enflurane concentrations remained constant, except that enflurane was discontinued in 50% of the patients who had received 2% enflurane. Monitoring was continued for at least 10 min, at which time T1 and TOF ratio (T4/T1) were measured. The ED go for T1 recovery depended on the dose of enflurane: 0.08 (seM0.03). 0.21 (0.06) and 0.42 (0.18) mg kg'1 for 0%, 1 % and 2% enflurane, respectively (?< 0.005). With enflurane 2% discontinued, the ED go was 0.095 (0.050) mg kg'1 (P < 0.02 compared with 2% enflurane). The ED so for TOF responses were 0.13 (0.05). 0.46 (0.10) and 1.04 (0.38) mg kg-1 for 0%, 1 % and 2% enflurane, respectively (? < 0.001). With 2% enflurane discontinued, the ED so for TOF was 0.17 (0.12) mg kg-1 (? < 0.05 compared with 2% enflurane). It is concluded that, even when given at the same degree of spontaneous recovery, the effect of edrophonium is markedly attenuated by enflurane.
KEY WORDS Anaesthetics, volatile: enflurane. Antagonists: neuromuscular relaxants. edrophonium. Drug interactions: edrophonium. enflurane.
Inhalation agents potentiate the effect of nondepolarizing neuromuscular blocking drugs. In this respect, enflurane appears to be more potent than either halothane or isoflurane [1-4]. Two studies [5,6] examined the influence of the inhalation anaesthetic used during antagonism of neuromuscular block. In both cases, neostigmineassisted antagonism was found to be delayed in the presence of enflurane. However, these studies involved only one dose of the antagonist drug, and one concentration of enflurane. Furthermore, the effect of reducing the end-tidal concentration of inhalation agents as the antagonist drug is given, as commonly happens in clinical practice, has not been evaluated. In addition, none of the previous studies [5, 6] has dealt with the effect of edrophonium. The purpose of this study was to determine the effect of enflurane on edrophonium-assisted recovery of atracurium-induced neuromuscular block. Several doses of edrophonium were given to establish dose-response relationships for the drug. These were constructed in the presence of 0%, 1% and 2% enflurane end-tidal. An additional group had 2 % enflurane end-tidal discontinued at the time of administration of edrophonium.
SATWANT S. GILL, M.B., F.F.A.R.C.S. ; DAVID R. BEVANf, M.B., M.R.C.P., F.F.A.R.C.S. J FRANCOIS DONATI, PH.D., M.D., F.R.C.P.C.;
Departments of Anaesthesia, Royal Victoria Hospital and McGill University, Montreal, Quebec, Canada. Accepted for Publication: September 19, 1989. tAddress for correspondence: McGill Department of Anaesthesia, Room F3.01, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1.
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SUMMARY
ENFLURANE AND EDROPHONIUM ANTAGONISM PATIENTS AND METHODS
the first twitch height (Tl) recovered to 10% before surgery was completed. At the end of surgery, when Tl had recovered to 10% of initial value, edrophonium 0, 0.1, 0.2, 0.4 or 1 mg kg"1 was given randomly with atropine 0.3-1.2 mg. Five patients received each dose of edrophonium in each group. No further edrophonium was given for at least 10 min. In groups 1-3, the end-tidal enflurane concentration was kept constant. In group 4, the inspired enflurane concentration was decreased to 0%, and a fresh gas flow of at least 100 ml kg"1 min"1 was given. After 10 min, an additional dose of edrophonium was given if required to bring the TOF ratio (T4/T1) to at least 0.7. Dose-response curves for overall recovery were constructed using Tl and T4/T1 measured 10 min after administration of edrophonium. The logit transformation of Tl and T4/T1 was plotted against the logarithm of the dose [7]. The dose of edrophonium required to produce 80 % recovery of Tl (ED8O,T1) was derived for each concentration of enflurane. Similarly, dose—response relationships involving T4/T1 were derived, and the dose required to produce 50% T4/T1 (ED5O,T4/T1) was calculated for each concentration of enflurane. The standard error of estimate for the mean [8] was used as an index of dispersion. Dose-response relationships were used also to estimate the effect of edrophonium 0.5 mg kg"1, 10 min after its administration, on Tl and T4/T1, for the various concentrations of enflurane. Unless otherwise specified, the results are expressed as means (standard error of estimate for the mean (SEE) [8]. The effect of enflurane was evaluated by plotting a measure of edrophonium effect (ED8O,T1 or ED6O,T4/T1) against dose of enflurane. Linear regressions were used in this case. The effect of discontinuing 2 % enflurane was compared with that of maintaining this concentration constant, using a Student's t test. P < 0.05 was assumed to indicate statistically significant differences.
RESULTS
We studied 39 males and 61 females. The mean (SD) age was 45.5 (16.5) yr and mean (SD) weight was 70.1 (15.5) kg. All groups were comparable (table I). Cardiovascular variables remained within normal limits during anaesthesia. In particular,
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After approval by the Hospital Ethics Committee, 100 patients, ASA Physical Status I or II, were studied during various elective surgical procedures of at least 60 min duration. Patients with hepatic, renal or neuromuscular disease were excluded, as were those with electrolyte abnormalities, those taking medication known or suspected to interfere with neuromuscular function and those in whom blood loss exceeded 500 ml. Premedication with atropine 0.006-0.01 mg kg"1 or glycopyrrolate 0.003-0.005 mg kg"1, and morphine O.lmgkg" 1 or pethidine lmgkg" 1 , was given i.m. 1 h before the scheduled start of the surgical procedure. On arrival in the operating room, the patient's ECG and arterial pressure were monitored. Anaesthesia was induced with thiopentone 3-5mgkg~1. The ulnar nerve was stimulated supramaximally at the elbow with square-wave pulses of 0.2 ms duration, delivered at a frequency of 2 Hz for 2 s (TOF) and repeated every 12 s. The hand and forearm were immobilized in a splint and the force of contraction of the adductor pollicis muscle was measured with a force displacement transducer (Grass FT-10) and recorded. A baseline was established after induction of anaesthesia, while the patient's lungs were ventilated manually via a mask. Atracurium 0.5 mg kg"1, was given i.v. as a single bolus and intubation of the trachea was accomplished when maximal neuromuscular block had been achieved. The patients were allocated randomly to four groups of 25, each group being subdivided into five subgroups of five. In group 1, anaesthesia was maintained with 70 % nitrous oxide and fentanyl 5-10 ug kg"1 given at induction of anaesthesia, followed by 1-2 ug kg"1 increments as required. In group 2, 70 % nitrous oxide was supplemented with 1 % enflurane end-tidal, as measured by mass spectrometry. In group 3, 2% enflurane end-tidal was given in oxygen. In group 4, 2% enflurane end-tidal was given (as in group 3), but enflurane was discontinued at the time of administration of edrophonium. In all groups, mechanical ventilation utilized a circle system and carbon dioxide absorber. The fresh gas flow rate was 1-2 litre min"1, frequency of ventilation 10 b.p.m., and tidal volume adjusted so that the measured end-tidal carbon dioxide was maintained in the range 4-4.7 kPa. Incremental doses of atracurium 0.1 mgkg"1 were administered if
301
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302 TABLE I.
Enflurane concn (%) Sex (M/F)
98
Demographic data Age (yr) (mean (SD))
Weight (kg) (mean (SD))
44.3 (3.0) 50.4 (2.9) 40.6 (3.3) 46.9 (3.8)
76.8 (3.8) 69.4 (2.3) 67.6 (3.0) 66.7 (2.9)
95
0 1 2 2-0
8/17 9/16 11/14 11/14
i
9080 7060 50 0.1
0.2 0.4 Dose of edrophonium (mg kg'1)
1.0
FIG. 1. Relationship between Tl (height of first twitch) on the logit scale and log of edrophonium dose, 10 min after administration of edrophonium, for enflurane 0 % ( ), 1 % ( ), 2% (—) (end-tidal concentrations), and 2% discontinued at the time of administration of edrophonium ( ). Standard errors are omitted for clarity.
continued, but the difference was not significant (table II). The effect appeared qualitatively similar on T4/T1 (table III), but the differences were not significant. At all doses, recovery of T l and T4/T1 decreased with increasing concentrations of enflurane, and this effect was reduced by discontinuation of enflurane (tables II, III). This can be demonstrated in the dose-response curves for first
TABLE II. Effect (%, mean (SEB)) of edrophonium on Tl, 10 min after administration to patients receiving one of four dose regimens of enflurane Dose of edrophoniumi (mg kg"1) Enflurane concn (%) 0 1 2 2-0
TABLE III. Effect (%,
0
0.1
0.2
0.4
1.0
41.0(2.3) 33.6 (3.9) 28.0 (3.4) 40.4 (5.7)
78.4 (2.0) 59.6 (5.3) 52.8 (10.3) 79.6 (5.2)
84.8 (6.3) 75.6 (3.4) 65.8 (8.9) 83.8(1.7)
93.4 (4.3) 91.2(3.3) 79.4 (4.6) 82.0(7.1)
94.8 (2.2) 90.0(3.1) 86.2 (3.2) 88.4(5.1)
mean (SEE)) of edrophonium on T4/T1, 10 min after administration to patients receiving one of four dose regimens of enflurane Dose of edrophonium (mg kg"1)
Enflurane concn (%) 0 1 2 2-0
0
0.1
0.2
0.4
1.0
12.6 (4.5) 12.0 (2.4) 8.0 (4.6) 1.8(2.7)
47.2 (3.0) 23.8 (4.6) 23.8(1.2) 40.4 (2.2)
54.0 (5.7) 33.8 (4.2) 28.6 (2.3) 54.8 (4.9)
64.4 (3.6) 54.4 (7.5) 35.6 (5.6) 64.2 (4.2)
72.8 (4.4) 60.4 (3.7) 51.6(5.4) 60.6 (4.5)
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systolic arterial pressure did not decrease to less than 100 mm Hg in any patient. The time from first injection of atracurium to 10% T l recovery increased with administration of greater concentrations of enflurane. This interval was 41.8 (1.6), 44.4 (1.8) and 46.4 (1.4) min for enflurane concentrations of 0%, 1 % and 2 % (P < 0.05) by linear regression. For the purpose of these calculations, both groups which received 2% enflurane were amalgamated. Because of additional doses given in some patients, mean total dose was 0.67 mg kg"1 (range 0.5-1.1 mg kg"1). The mean time between administration of the first dose of atracurium and injection of edrophonium was 67 min. In the absence of edrophonium, T l recovery was affected by the enflurane concentration (table II). For example, with 0% enflurane, T l was 41 (2.3)% 10 min after it had reached 10%. In the presence of 2% enflurane, the Tl value reached only 29 (3.4)% (P < 0.01). Recovery of T l appeared greater if 2% enflurane was dis-
ENFLURANE AND EDROPHONIUM ANTAGONISM
303
70-, 70
£ 60 c
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E o w
Jso
50
40 30-
0.1
0.2
0.4
1.0
Dose of edrophonium (mgkg")
FIG. 2. Relationship between T4/T1 (train-of-four ratio) on the logit scale and log of edrophonium dose, 10 min after administration of edrophonium, for enflurane 0 % ( ), 1 % ( ), 2% (—) (end-tidal concentrations), and 2% discontinued at the time of administration of edrophonium ( ). Standard errors are omitted for the sake of clarity.
100i
95 *c 90 E o
r 85 8075
ENFO
ENF1
ENF 2
ENF2->0
FIG. 3. Expected effect of edrophonium 0.5 mg kg"1 on Tl (first twitch height) 10 min after its administration, according to dose of enflurane (0%, 1%, 2% or 2% end-tidal discontinued).
ENFO
ENF1
ENF 2
ENF2->0 1
FIG. 4. Expected effect of edrophonium 0.5 mg kg" on T4/ Tl (train-of-four ratio) 10 min after administration, according to dose of enflurane (0%, 1 %, 2% or 2% end-tidal discontinued).
and 1.04 (0.38) mg kg"1, for 0%, 1% and 2% enflurane, respectively (P < 0.001). With 2% enflurane discontinued, the ED60 was 0.17 (0.12) mg kg"1 {P < 0.01 compared with 2 % enflurane). The expected effect of edrophonium 0.5 mg kg"1 was calculated for the various groups from the dose-response relationships (figs 3, 4). After 10 min, Tl was expected to be (mean (SEE)) 96 (1) %, 90 (2) % and 82 (3) % for 0 %, 1 % and 2 % enflurane, respectively (P < 0.0005 by linear regression). With 2% enflurane discontinued, Tl was expected to reach 91 (2)% (P < 0.02 compared with no discontinuation of 2 % enflurane). The expected T4/T1 values were 66 (2)%, 52 (3)% and 40 (2)%, for 0%, 1% and 2% enflurane, respectively (P < 0.00001). If enflurane was discontinued, T4/T1 was calculated to be 60 (6)% (P < 0.01 compared with 2% enflurane continued). DISCUSSION
This study has demonstrated that, when edrophonium is used to antagonize atracurium neurotwitch height, as shown in figure 1. The ED g0 ,Tl, muscular block, the residual concentration of 10 min after administration of edrophonium were enflurane is important. When 2 % enflurane end0.08 (0.03), 0.21 (0.06) and 0.42 (0.18) mgkg- 1 , tidal was used, five times as much edrophonium for 0 %, 1 % and 2 % enflurane, respectively (P < was required to obtain Tl = 8 0 % within 10 min 0.005). With 2% enflurane discontinued, the than if no enflurane had been used. The effect on dose-response curve was flatter. The ED80 was T4/T1 was even more pronounced. To achieve 0.095 (0.050) (P < 0.02 compared with main- T 4 / T l = 5 0 % within 10 min, eight times as tenance of 2% enflurane). The dose-response much edrophonium had to be given with 2% relationships for T4/T1 10 min after edro- compared with 0% enflurane end-tidal, even phonium was given are shown in figure 2. In this though all patients received edrophonium at the case, the EDS0 values were 0.13 (0.05), 0.46 (0.10) same degree of neuromuscular block. However,
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30
20-
304
potentiation of enflurane, a phenomenon which has also been suggested for tubocurarine block [14]. The time dependence of potentiation of enflurane can explain, at least in part, the adverse effects of edrophonium on recovery of neuromuscular function. Total recovery can be considered as consisting of two parts: the effect of spontaneous recovery, associated with decreasing concentrations of the blocker, while elimination or redistribution takes place; and assisted recovery, which is the added effect of the antagonist drug. When greater concentrations of enflurane are given, potentiation of neuromuscular block by the volatile agent increases in intensity with time as the antagonist drug is given. Thus although enflurane may not affect the disposition of the neuromuscular blocker (pharmacokinetics), it may affect the receptor at the neuromuscular junction (pharmacodynamics). As a result, spontaneous recovery is impaired and total recovery is less. Other results suggest that the effects of enflurane are based not only on a time-dependent potentiation of atracurium block. Discontinuation of administration of enflurane tended to restore neuromuscular transmission to the state which would have prevailed in the absence of inhalation agent. Although the end-tidal concentration of enflurane decreased to 0.3-0.4 % after 10 min, it is probable that concentrations of enflurane at the neuromuscular junction were not affected greatly by this manoeuvre. Assuming a 40-min equilibration half-time [14] of enflurane in muscle, which is consistent with the slow time course of enflurane potentiation of atracurium neuromuscular block, it appears that discontinuation of enflurane would have led to a negligible decrease in muscle concentrations of enflurane. It is possible that some other factors may play a role, such as central influences. Catecholamines have been shown in animals to potentiate the effect of neostigmine [15], and the same could be true of edrophonium. In particular, light levels of anaesthesia, which are associated with low concentrations of end-tidal enflurane, could improve the degree of neuromuscular recovery. The variability of response when 2% enflurane was discontinued could result from the variability of this effect among patients. The predicted effect of edrophonium 0.5 mg kg"1 reported here is consistent with that obtained in an earlier study [11]. With end-tidal enflurane
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the effect of 2 % enflurane could be diminished by decreasing its inspired concentration at the time of administration of edrophonium. The effect of this manoeuvre was variable and recovery was not as good as in patients who did not receive enflurane. The study is in agreement with previous work in which the dose-response relationship for edrophonium was found to be relatively flat [9-11]. This probably accounts for the wide discrepancies in the ED8O,T1 and EDBO,T4/T1 with and without enflurane. For example, although five times as much edrophonium was required with 2% enflurane compared with 0% to obtain Tl = 80 %, the administration of 0.5 mg kg"1 was expected to yield Tl = 9 6 % with 0% enflurane and Tl = 8 2 % with 2% enflurane, a difference of only 14%. Similarly, although edrophonium was only 12.5% as potent in the presence of 2 % enflurane, a dose of 0.5 mg kg"1 was expected to produce T4/T1 = 4 0 % , compared with T4/T1 = 66% with 0% enflurane, a difference of only 26 %. Such differences may be clinically significant. Surprisingly, 2% enflurane end-tidal, or approximately 1.2 MAC [12], produced only a small prolongation of the duration of atracurium block, from 41.8 to 46.4 min. This suggests that enflurane has little effect on atracurium block, at least during the first 30-45 min after the beginning of the administration of enflurane. Rupp, McChristian and Miller [13] found the ED,6 of atracurium to be similar with enflurane and halothane anaesthesia, but the end-tidal concentrations had been stable for only 30 min. Similarly, Goudsouzian and colleagues [3] found that the duration of action of atracurium 0.4 mg kg"1 was prolonged only slightly with nitrous oxide—enflurane compared with nitrous oxidemorphine. However, the effect of enflurane on atracurium block may be time dependent. In the present study, T l recovery was slower in patients who received 2 % enflurane compared with those who did not, in the absence of edrophonium. Similarly, Rupp's group [13] found that, although the dose-response relationship of atracurium was unaltered by enflurane, its duration of action was prolonged. In children, the infusion rate to maintain neuromuscular block constant was found to be time dependent and decreased in the time interval 30-60 min after administration of enflurane was started. These results are consistent with a time dependent increase in the degree of
BRITISH JOURNAL OF ANAESTHESIA
ENFLURANE AND EDROPHONIUM ANTAGONISM
4.
5. 6.
7. 8. 9.
10.
11.
12. 13.
14. REFERENCES 1. Fogdall RP, Miller RD, Neuromuscular effects of enflurane, alone and combined with d-tubocurarine, pancuronium, and succinylcholine, in man. Anesthesiology 1975; 42: 173-178. 2. Rupp SM, Miller RD, Gencarelli PJ. Vecuroniuminduced neuromuscular blockade during enflurane, isoflurane, and halothane anesthesia in humans. Anesthesiology 1984; 60: 102-105. 3. Goudsouzian N, Martyn J, Rudd GD, Liu LMP,
15.
16.
Lineberry CG. Continuous infusion of atracurium in children. Anesthesiology 1986; 64: 171-174. Cannon JE, Fahey MR, Castagnoli KP, Furuta T, Canfell PC, Sharma M, Miller RD. Continuous infusion of vecuronium: the effect of anesthetic agents. Anesthesiology 1987; 67: 503-506. Delisle S, Bevan DR. Impaired neostigmine antagonism of pancuronium during enflurane anaesthesia in man. British Journal of Anaesthesia 1982; 54: 441-445. Demovoi 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. Norman J. Drug—receptor reactions. British Journal of Anaesthesia 1979; 51: 595-601. Dixon WJ, Massey FJ jr. Introduction to Statistical Analysis, 3rd Edn. New York: McGraw-Hill, 1969; 195. Cronnelly R, Morris RB, Miller RD. Edrophonium: duration of action and atropine requirement in humans during halothane anesthesia. Anesthesiology 1982; 57: 261-266. Donati F, McCarroll SM, Antzaka C, McCready D, Bevan DR. Dose-response curves for edrophonium, neostigmine, and pyridostigmine after pancuronium and d-tubocurarine. Anesthesiology 1987; 66: 471-476. Donati F, Smith CE, Bevan DR. Dose-response relationships for edrophonium and neostigmine as antagonists of moderate and profound atracurium blockade. Anesthesia and Analgesia 1989; 68: 13-19. Gion H, Saidman LJ. The minimum alveolar concentration of enflurane in man. Anesthesiology 1971; 35: 361-364. Rupp SM, McChristian JW, Miller RD. Neuromuscular effects of atracurium during halothane-nitrous oxide and enflurane-nitrous oxide anesthesia in humans. Anesthesiology 1985; 63: 16-19. Stanski DR, Ham J, Miller RD, Sheiner LB. Timedependent increase in sensitivity to d-tubocurarine during enflurane anesthesia in man. Anesthesiology 1980; 52: 483-187. Drury PJ, Birmingham AT, Healy TEJ. Interaction of adrenaline with neostigmine and tubocurarine at the skeletal neuromuscular junction. British Journal of Anaesthesia 1987; 59: 784-790. Gencarelli PJ, Miller RD, Eger El, Newfield P. Decreasing enflurane concentrations and d-tubocurarine neuromuscular blockade. Anesthesiology 1982; 56: 192194.
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concentrations held at 0.5-1 %, edrophonium 0.5 mg kg"1 was expected to produce 89 (2) % Tl and 61 (3) % T4/T1 after 10 min. These values are close to those reported for 1 % enflurane in this study—90 (2)% for Tl and 52 (3)% for T4/T1. It is possible that the same conclusions found here regarding edrophonium may apply also to neostigmine. In two studies, the effect of neostigmine was found to be impaired by the presence of enflurane [5, 6]. The concentrations used were less than in the present study. It is also possible that neostigmine-assisted recovery might be improved by the discontinuation of enflurane. Clinically, the presence of increased concentrations of enflurane should be expected to impair recovery. Discontinuation of enflurane when the antagonist drug is administered should improve recovery. However, total recovery should not be expected to be greater with discontinuation of enflurane compared with little or no inhalation agent. In this respect, our results contradict the suggestion that the potentiation of neuromuscular block by volatile agents "may provide additional safety for patients whose anaesthetic is one of the most potent muscle relaxants enhancing agents" [16]. For this reason, it appears prudent to plan antagonism of neuromuscular block at a greater degree of twitch height recovery when increased concentrations of enflurane are used.
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