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ANTAGONISM OF VERCURONIUM-INDUCED NEUROMUSCULAR BLOCKADE WITH EDROPHONIUM OR NEOSTIGMINE
Br. J. Anaesth. (1987), 59, 473-477
ANTAGONISM OF VERCURONIUM-INDUCED NEUROMUSCULAR BLOCKADE WITH EDROPHONIUM OR NEOSTIGMINE R. K. MIRAKHUR, F. M. GIBSON AND G. G. LA VERY
PATIENTS AND METHODS
SUMMARY Antagonism of vecuronium-induced neuromuscular blockade was attempted, at varying degrees of spontaneous recovery, with edrophonium 0.5 mg kg*1 or neostigmine 0.05 mg kg^ in two groups of 20 patients. Neuromuscular blockade was monitored using a train-of-four (TOF) stimulation. Adequate antagonism of neuromuscular blockade, defined as a sustained TOF ratio of 0.7 or more, was attained in all 20 patients given neostigmine and in 13 out of 20 given edrophonium. Five of the remaining seven patients given edrophonium had shown three or less responses to TOF stimulation before antagonism. While the time to onset of the action of edrophonium (22 s) was not significantly shorter than neostigmine (26 s), the time taken to attain a TOF ratio of 0.7 was significantly shorter with edrophonium (67 s compared with 194 s with neostigmine). It is concluded that edrophonium 0.5 mg kg-1 does not consistentiy antagonize vecuronium-induced neuromuscular blockade, particularly if there are three or less responses to a TOF stimulation present before antagonism.
Following approval from the Regional Ethical Committee, 40 patients (ASA grade I) scheduled for elective surgery requiring neuromuscular blockade were included after their informed in oxygen, plus fentanyl 2-3 ug kg"1. Ventilation consent had been obtained. was adjusted to maintain normocarbia (end-tidal Patients were premedicated with diazepam carbon dioxide concentrations of 4.5-5.0%). 10 mg orally about 1 h before operation. Anaes- Neuromuscular transmission was monitored by thesia was induced with thiopentone and main- applying supramaximal square wave stimuli of tained with nitrous oxide and 0.5-1.0% enfiurane 0.2 ms duration to the ulnar nerve at the wrist in a train-of-four sequence (TOF) at 2 Hz every 10 s. The contractions of the adductor pollicis R. K. MIRAKHUR, M.D. PH.D., FJ>.A.R.C.S., Department of Clinical Anaesthesia, Royal Victoria Hospital, Belfast, were recorded using a neuromuscular function N. Ireland. F. M. GIBSON, M.B., F.F.A.R.C.S.; G. G. LA VERY, analyser (Myograph 2000, Biometer Limited). MA., F.F.A.R.OS.; Department of Anaesthetics, The Queen's Vecuronium was given in an initial dose of University of Belfast, N. Ireland. Accepted for Publication: 1 O.lmgkg" , further increments of 0.025September 10, 1986.
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 8, 2015
Edrophonium has recently been recommended as the antagonist of choice with which to antagonize non-depolarizing blockade (Bevan, 1979; Baird, Bowman and Kerr, 1982; Cronnelly and Morris, 1982; Cronnelly, Morris and Miller, 1982; Baird and Kerr, 1983; Jones, Pearce and Williams, 1984). Its main advantages are a rapid onset of action and minimal muscarinic side-effects (Cronnelly, Morris and Miller, 1982; Mirakhur, 1985). In most of these studies, neuromuscular blockade was antagonized at a standard and appreciable degree of recovery from blockade—a situation not always prevalent in routine anaesthetic practice. Antagonism of relatively more profound degrees of blockade may be difficult with edrophonim (Kopman, 1979; Lavery, Mirakhur and Gibson, 1985). In the present study we have assessed the effectiveness of edrophonium 0.5 mg kg"1 in the antagonism of vecuroniuminduced neuromuscular blockade at varying degrees of recovery. A group given neostigmine 0.05 mg kg"1 was included for comparison.
BRITISH JOURNAL OF ANAESTHESIA
474
RESULTS
There were no significant differences in the ages and weights in the groups, or in the degree of neuromuscular blockade present before the administration of the relevant anticholinesterase agent (table I). Seven patients in the edrophonium group and eight in the neostigmine group showed three or less responses to TOF stimulation before antagonism. In these patients the average heights of T l were 22 and 16% of control, respectively (ns). A representative TOF recording is shown in figure 1. It is clear that adequate antagonism
TABLE I. Physical characteristics and degree of blockade present before antagonism {mean values ± SEM (range)) Edrophonium Age(yr) Weight (kg) T l before antagonism (%) TOF ratio before antagonism Number showing three or fewer twitches before antagonism
Neostigmine
34 ±3.7 42±4.5 71 ±3.4 69 ±3.2 38±3.7 33 ±4.2 (8-76) (8-76) 0.17 ±0.035 0.19±0.031 (0.04-0.50) (0.06-0.04) 7
8
FIG. 1. Representative TOF recordings from four patients during antagonism of vecuronium-induced block. The top two recordings refer to patients in whom blockade was antagonized at TOF ratios of 0.09 and 0.08, respectively. Blockade was adequately antagonized in both, but more rapidly following edrophonium. In the two lower traces antagonism was attempted at relatively deeper degrees of block (no TOF responses). It is clear that neostigmine did antagonize the block adequately, whereas edrophonium failed to do so (TOF 0.61).
(TOF ratio of 0.7) was achieved more rapidly following edrophonium than following neostigmine. However, figure 1 also shows that when antagonism was attempted at more profound degrees of neuromuscular blockade, adequate antagonism was not attained even though the edrophonium started to act rapidly.
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 8, 2015
0.05 mg kg"1 being administered at the recovery of all four responses to TOF stimulation. Enflurane was discontinued at the end of surgery when antagonism of blockade was attempted irrespective of the degree of block present — provided that at least one response was evoked by TOF stimulation. Twenty patients each were randomly allocated to receive edrophonium 0.5 mg kg"1 or neostigmine 0.05 mg kg"1, in a mixture with atropine or glycopyrrolate. The subsequent recovery of neuromuscular transmission was recorded for at least 10 min in all patients. A TOF ratio of 0.7 or more was considered to indicate adequate antagonism (Ali and Savarese, 1976; Ali et al., 1981). If adequate antagonism was not attained in 10 min, a further dose (or doses), of the anticholinesterase, equivalent to half the initial dose, was given. Adequacy of antagonism was assessed for at least the next 30 min in the recovery ward using recognized clinical criteria such as the ability to breathe deeply, cough and maintain a sustained head lift. The height of the first twitch (Tl) in the TOF sequence as a percentage of control value obtained before the administration of the neuromusculai blocker, and the TOF ratio (ratio between the fourth and first twitches in the same TOF sequence), were measured before the administration of the anticholinesterase. The highest sustained values for these measurements were again recorded after the administration of the antagonist. In addition, the time to the onset of a measurable effect, the time taken to attain a TOF ratio of 0.7 and the TOF ratios at 50,75 and 100 % recovery of T l were measured. The groups were compared using a Student's t test, non-parametric data being analysed using a Chi-square test with Yates' correction.
475
ANTAGONISM WITH EDROPHONIUM OR NEOSTIGMINE
TABLE II. Times to onset of action and to the attainment of a TOF ratio of 0.7 {mean values ± SEM). * Significant differences between the groups: *P < 0.05 (Student's t test), f P < 0.025 (x1 with Yates' correction). ^Refers to only 13 patients in the edrophonium group (see text) Edrophonium Time to onset of effect (s) Time to TOF ratio of 0.7 (s)$ Number failing to attain TOF ratio of 0.7
1.0-
L
Neostigminc
67 ±8.3*
26 ±2.4 194 ±45.6*
7t
0+
22±1.9
•
0.9-
Peak TDF rath
o
0.80.7-
r !
t * TE2Q
0.6-
TABLE III. TOF ratios at 50, 75 and 100% recovery of Tl (first twitch in the TOF sequence) (mean values ± SEAf). *Significant difference (P < 0.05) between edrophonium and neostigmine
TOF ratio
Height of T l ( % ) 50 75 100
Edrophonium
Neostigmine
0.34 ±0.026 0.56 ±0.032 0.70 ±0.026
0.26 ±0.029 0.47 ±0.029 0.67 ±0.031
in the neostigmine group, and from 0.53 to 0.96 with a mean value of 0.74 ±0.028 (SEM) in the edrophonium group (E!0 in figure 2). This difference in the average peak TOF ratios between the groups was significant (P < 0.01). However, if the seven patients in the edrophonium group who did not attain a TOF ratio of 0.7 are excluded, the average peak TOF in the remaining 13 patients (E13 in figure 2) in this group was 0.82 ±0.021 (SEM), which was not significantly different from that in the neostigmine group. Five of the seven patients who failed to attain a TOF ratio of 0.7 with edrophonium showed three or less responses to TOF stimulation before the administration of the antagonist. The two remaining patients in whom antagonism was inadequate with edrophonium had TOF ratios of 0.11 and 0.18 before antagonism. Adequate antagonism in all these patients was attained following a further period of ventilation and the administration of one or two further doses of edrophonium. In contrast, in all patients given neostigmine, including the eight who did not show all four responses to TOF stimulation before antagonism, blockade was reversed adequately. The TOF ratios at 50, 75 and 100% Tl twitch height in patients in the two groups are shown in table III. The TOF ratios during antagonism are higher after edrophonium, being significantly so at 50 and 75 % heights of Tl (P < 0.05).
0.5 DISCUSSION Neostigmine
Edrophonium
FIG. 2. Peak TOF ratios in individual patients after the administration of the anticholinesterase agents. Horizontal line and bars represent mean ± SEM values. E,, refers to average peak TOF ratio in all 20 patients in the edrophonium group and E,, refers to peak TOF ratio in the 13 patients in this group who attained a TOF ratio of 0.7 or more (adequate antagonism).
The present study confirms that, when considered overall, edrophonium, in a dose of 0.5 mg kg"1 as used in the present study and recommended by Cronnelly, Morris and Miller (1982) and Jones, Pearce and Williams (1984), antagonized vercuronium-induced blockade significantly more rapidly than neostigmine. However, neuromuscular blockade could not be adequately antago-
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 8, 2015
The average onset times and the times taken to attain TOF ratios of 0.7 in the two groups are given in table II. There was no significant difference in the time to onset of effect (22 s for edrophonium, 26 s for neostigmine), but the time taken to attain a sustained TOF ratio of 0.7 was significantly less (P < 0.05) with edrophonium (67 s) in comparison with neostigmine (194 s). However, seven patients given edrophonium failed to attain a TOF ratio of 0.7 (table II) and, hence, the time to TOF ratio of 0.7 refers to only 13 patients in this group. The individual peak TOF ratios attained with the two anticholinesterase agents are shown in figure 2. These varied from 0.7 to 1.0 with a mean of 0.85 ± 0.022 (SEM)
476
It is possible that a larger initial dose of edrophonium may have been successful in antagonizing relatively more profound blockade, since the administration of one or two additional doses (of edrophonium) produced adequate antagonism in these patients. However, with a neuromuscular blocking agent such as vecuronium, which has a short recovery index, it is likely that further spontaneous recovery of blockade was taking place in the intervening period of more than 10 min. Moreover, other workers using edrophonium, even in larger doses than those used in the present study, have failed to show adequate antagonism of relatively deeper blockade induced by vecuronium — or atracurium, an agent not dissimilar to
vecuronium in its recovery characteristics (Hughes, Astley and Payne, 1984; Engbaek et al., 1985). In addition, it has been shown that larger doses of edrophonium would exert greater muscarinic effects and require larger doses of atropine, thus losing one of the major benefits of the use of edrophonium (Engbaek et al., 1985). The potency ratio between edrophonium and neostigmine has been given as 11.6:1 by Cronnelly, Morris and Miller (1982), and as 16:1 by Breen and his colleagues (1985) using different methods of estimation. The ratio of 10:1 used in the present study is closer to that given by Cronnelly and his colleagues (1982). The present study was, however, not comparing strictly equipotent doses, but looking at the efficacy of commonly advocated doses of the two anticholinesterase drugs. Presence of higher TOF ratios and, consequently, less fade with edrophonium at similar heights of Tl probably reflects its greater presynaptic activity and has previously been reported during antagonism of pancuronium and atracurium-induced blockade (Donati, Ferguson and Bevan, 1983; Jones, Pearce and Williams, 1984; Lavery, Mirakhur and Gibson, 1985). However, this does not appear to be of any beneficial value in relatively more profound vecuronium-induced blockade. In conclusion, edrophonium in a dose of 0.5 mg kg"1 does not adequately and reliably antagonize vecuronium-induced neuromuscular blockade — particularly where three or less responses to a TOF stimulation are present before antagonism. Neostigmine 0.05 mg kg"1 provides better and more reliable antagonism in such situations. ACKNOWLEDGEMENTS The authors are thankful to the nursing and other theatre staff of the Royal Victoria Hospital for their help with the study. Drs Gibson and Lavery were in receipt of Fellowships from the Endowments and Gifts Fund of the Royal Victoria Hospital, Belfast.
REFERENCES Ah', H. H., and Savarese, J. J. (1976). Monitoring of neuromuscular function. Anesthesiology, 45, 216. Lebowitz, P. W., and Ramsey, F. M. (1981). Twitch, tetanus and train-of-four as indices of recovery from non-depolarising neuromuscular blockade. Anesthesiology, 54,294.
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nized (as defined by a TOF ratio of 0.7) in seven out of 20 patients (35%) given this dose of edrophonium, the majority of these (five out of seven) showing three or less responses to a TOF stimulation before antagonism. A previously published study (Baird, Bowman and Kerr, 1982) suggested that edrophonium in doses of 0.5-1.0 mg kg"1 would be the reversal agent of choice with which to antagonize a vecuroniuminduced blockade compared with blockade produced by pancuronium or tubocurarine. We are unable to substantiate this for the 0.5-mg kg"1 dose — particularly in patients with relatively more marked degrees of blockade: in 35% of patients blockade could not be adequately antagonized. Perhaps Baird and his co-workers (1982) based their assertions on the basis of their work in cats. They studied only a total of nine patients who received edrophonium in doses ranging from 0.1 to 1 mg kg"1 and in whom twitch heights had recovered to at least 25% of control. Other workers have also reported difficulty in antagonizing relatively profound neuromuscular blockade produced by vecuronium, pancuronium or atracurium adequately with doses of edrophonium similar to that used in the present study— particularly if three or fewer responses to a TOF stimulation were present (Kopman, 1979; Foldes et al., 1981; Rupp, McChristian and Miller, 1984; Lavery, Mirakhur and Gibson, 1985). In the present study, blockade in two patients was not antagonized, despite considerable recovery (as shown by TOF ratios of 0.11 and 0.18, respectively) before antagonism. Neostigmine, on the other hand, antagonized neuromuscular blockade adequately in all 20 patients in the present study, including those not showing all four responses to TOF stimulation.
BRITISH JOURNAL OF ANAESTHESIA
ANTAGONISM WITH EDROPHONIUM OR NEOSTIGMINE
R., and Nagashima, H. (1981). Antagonism of the neuromuscular effect of Org NC 45 by edrophonium. Anesthesiology, 55, A201. Hughes, R., Astley, B. A., and Payne, J. P. (1984). Reversal of atracurium blockade by neostigmine and edrophonium. Br. J. Anaesth., 56, 796P. Jones, R. M., Pearce, A. C , and Williams, J. P. (1984). Recovery characteristics following antagonism of atracurium with neostigmine or edrophonium. Br. J. Anaesth., 56, 453. Kopman, A. F. (1979). Edrophonium antagonism of pancuronium-induced neuromuscular blockade in man. Anesthesiology, 51, 139. Lavery, G. G., Mirakhur, R. K., and Gibson, F. M. (1985). Comparison of edrophonium and neostigmine for the antagonism of atracurium-induced neuromuscular block. Anesth. Analg., 64, 867. Mirakhur, R. K. (1985). Antagonism of the muscarinic effects of edrophonium with atropine or glycorpyrrolate: a comparative study. Br. J. Anaesth., 57, 1213. Rupp, S. M., McChristian, J. W., and Miller, R. D. (1984). Neostigmine antagonises a profound neuromuscular blockade more rapidly than edrophonium. Anesthesiology, 61, A297.
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Baird, W. L. M., Bowman, W. C , and Kerr, W. J. (1982). Some actions of Org NC 45 and of edrophonium in the anaesthetized cat and in man. Br. J. Anaesth., 54, 375. Kerr, W. J. (1983). Reversal of atracurium with edrophonium. Br. J. Anaesth., 55, 63S. Bevan, D. R. (1979). Reversal of pancuronium by edrophonium. Anaesthesia, 34, 614. Breen, P. J., Doherty, W. G., Donati, F., and Bevan, D. R. (1985). The potencies of edrophonium and neostigmine as antagonists to pancuronium. Anaesthesia, 40, 844. Cronnelly, R., and Morris, R. B. (1982). Antagonism of neuromuscular blockade. Br. J. Anaesth., 54, 183. Miller, R. D. (1982). Edrophonium: duration of action and atropine requirement in humans during halothane anesthesia. Anestkesiology, 57, 261. Donati, F., Ferguson, A., and Bevan, D. R. (1983). Twitch depression and train-of-four ratio after antagonism of pancuronium with edrophonium, neostigmine or pyridostigmine. Anesth. Analg., 62, 314. Engbaek, J., Ording, H., Ostergaard, D., and Viby-Mogensen, J. (1985). Edrophonium and neostigmine for reversal of neuromuscular blocking effect of vecuronium. Ada Anaesthesiol. Scand., 29, 544. Foldes, F. F., Yun, H., Radnay, P. A., Badola, R. P., Kaplan,
477
ANTAGONISM OF VERCURONIUM-INDUCED NEUROMUSCULAR BLOCKADE WITH EDROPHONIUM OR NEOSTIGMINE R. K. MIRAKHUR, F. M. GIBSON AND G. G. LA VERY
PATIENTS AND METHODS
SUMMARY Antagonism of vecuronium-induced neuromuscular blockade was attempted, at varying degrees of spontaneous recovery, with edrophonium 0.5 mg kg*1 or neostigmine 0.05 mg kg^ in two groups of 20 patients. Neuromuscular blockade was monitored using a train-of-four (TOF) stimulation. Adequate antagonism of neuromuscular blockade, defined as a sustained TOF ratio of 0.7 or more, was attained in all 20 patients given neostigmine and in 13 out of 20 given edrophonium. Five of the remaining seven patients given edrophonium had shown three or less responses to TOF stimulation before antagonism. While the time to onset of the action of edrophonium (22 s) was not significantly shorter than neostigmine (26 s), the time taken to attain a TOF ratio of 0.7 was significantly shorter with edrophonium (67 s compared with 194 s with neostigmine). It is concluded that edrophonium 0.5 mg kg-1 does not consistentiy antagonize vecuronium-induced neuromuscular blockade, particularly if there are three or less responses to a TOF stimulation present before antagonism.
Following approval from the Regional Ethical Committee, 40 patients (ASA grade I) scheduled for elective surgery requiring neuromuscular blockade were included after their informed in oxygen, plus fentanyl 2-3 ug kg"1. Ventilation consent had been obtained. was adjusted to maintain normocarbia (end-tidal Patients were premedicated with diazepam carbon dioxide concentrations of 4.5-5.0%). 10 mg orally about 1 h before operation. Anaes- Neuromuscular transmission was monitored by thesia was induced with thiopentone and main- applying supramaximal square wave stimuli of tained with nitrous oxide and 0.5-1.0% enfiurane 0.2 ms duration to the ulnar nerve at the wrist in a train-of-four sequence (TOF) at 2 Hz every 10 s. The contractions of the adductor pollicis R. K. MIRAKHUR, M.D. PH.D., FJ>.A.R.C.S., Department of Clinical Anaesthesia, Royal Victoria Hospital, Belfast, were recorded using a neuromuscular function N. Ireland. F. M. GIBSON, M.B., F.F.A.R.C.S.; G. G. LA VERY, analyser (Myograph 2000, Biometer Limited). MA., F.F.A.R.OS.; Department of Anaesthetics, The Queen's Vecuronium was given in an initial dose of University of Belfast, N. Ireland. Accepted for Publication: 1 O.lmgkg" , further increments of 0.025September 10, 1986.
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 8, 2015
Edrophonium has recently been recommended as the antagonist of choice with which to antagonize non-depolarizing blockade (Bevan, 1979; Baird, Bowman and Kerr, 1982; Cronnelly and Morris, 1982; Cronnelly, Morris and Miller, 1982; Baird and Kerr, 1983; Jones, Pearce and Williams, 1984). Its main advantages are a rapid onset of action and minimal muscarinic side-effects (Cronnelly, Morris and Miller, 1982; Mirakhur, 1985). In most of these studies, neuromuscular blockade was antagonized at a standard and appreciable degree of recovery from blockade—a situation not always prevalent in routine anaesthetic practice. Antagonism of relatively more profound degrees of blockade may be difficult with edrophonim (Kopman, 1979; Lavery, Mirakhur and Gibson, 1985). In the present study we have assessed the effectiveness of edrophonium 0.5 mg kg"1 in the antagonism of vecuroniuminduced neuromuscular blockade at varying degrees of recovery. A group given neostigmine 0.05 mg kg"1 was included for comparison.
BRITISH JOURNAL OF ANAESTHESIA
474
RESULTS
There were no significant differences in the ages and weights in the groups, or in the degree of neuromuscular blockade present before the administration of the relevant anticholinesterase agent (table I). Seven patients in the edrophonium group and eight in the neostigmine group showed three or less responses to TOF stimulation before antagonism. In these patients the average heights of T l were 22 and 16% of control, respectively (ns). A representative TOF recording is shown in figure 1. It is clear that adequate antagonism
TABLE I. Physical characteristics and degree of blockade present before antagonism {mean values ± SEM (range)) Edrophonium Age(yr) Weight (kg) T l before antagonism (%) TOF ratio before antagonism Number showing three or fewer twitches before antagonism
Neostigmine
34 ±3.7 42±4.5 71 ±3.4 69 ±3.2 38±3.7 33 ±4.2 (8-76) (8-76) 0.17 ±0.035 0.19±0.031 (0.04-0.50) (0.06-0.04) 7
8
FIG. 1. Representative TOF recordings from four patients during antagonism of vecuronium-induced block. The top two recordings refer to patients in whom blockade was antagonized at TOF ratios of 0.09 and 0.08, respectively. Blockade was adequately antagonized in both, but more rapidly following edrophonium. In the two lower traces antagonism was attempted at relatively deeper degrees of block (no TOF responses). It is clear that neostigmine did antagonize the block adequately, whereas edrophonium failed to do so (TOF 0.61).
(TOF ratio of 0.7) was achieved more rapidly following edrophonium than following neostigmine. However, figure 1 also shows that when antagonism was attempted at more profound degrees of neuromuscular blockade, adequate antagonism was not attained even though the edrophonium started to act rapidly.
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 8, 2015
0.05 mg kg"1 being administered at the recovery of all four responses to TOF stimulation. Enflurane was discontinued at the end of surgery when antagonism of blockade was attempted irrespective of the degree of block present — provided that at least one response was evoked by TOF stimulation. Twenty patients each were randomly allocated to receive edrophonium 0.5 mg kg"1 or neostigmine 0.05 mg kg"1, in a mixture with atropine or glycopyrrolate. The subsequent recovery of neuromuscular transmission was recorded for at least 10 min in all patients. A TOF ratio of 0.7 or more was considered to indicate adequate antagonism (Ali and Savarese, 1976; Ali et al., 1981). If adequate antagonism was not attained in 10 min, a further dose (or doses), of the anticholinesterase, equivalent to half the initial dose, was given. Adequacy of antagonism was assessed for at least the next 30 min in the recovery ward using recognized clinical criteria such as the ability to breathe deeply, cough and maintain a sustained head lift. The height of the first twitch (Tl) in the TOF sequence as a percentage of control value obtained before the administration of the neuromusculai blocker, and the TOF ratio (ratio between the fourth and first twitches in the same TOF sequence), were measured before the administration of the anticholinesterase. The highest sustained values for these measurements were again recorded after the administration of the antagonist. In addition, the time to the onset of a measurable effect, the time taken to attain a TOF ratio of 0.7 and the TOF ratios at 50,75 and 100 % recovery of T l were measured. The groups were compared using a Student's t test, non-parametric data being analysed using a Chi-square test with Yates' correction.
475
ANTAGONISM WITH EDROPHONIUM OR NEOSTIGMINE
TABLE II. Times to onset of action and to the attainment of a TOF ratio of 0.7 {mean values ± SEM). * Significant differences between the groups: *P < 0.05 (Student's t test), f P < 0.025 (x1 with Yates' correction). ^Refers to only 13 patients in the edrophonium group (see text) Edrophonium Time to onset of effect (s) Time to TOF ratio of 0.7 (s)$ Number failing to attain TOF ratio of 0.7
1.0-
L
Neostigminc
67 ±8.3*
26 ±2.4 194 ±45.6*
7t
0+
22±1.9
•
0.9-
Peak TDF rath
o
0.80.7-
r !
t * TE2Q
0.6-
TABLE III. TOF ratios at 50, 75 and 100% recovery of Tl (first twitch in the TOF sequence) (mean values ± SEAf). *Significant difference (P < 0.05) between edrophonium and neostigmine
TOF ratio
Height of T l ( % ) 50 75 100
Edrophonium
Neostigmine
0.34 ±0.026 0.56 ±0.032 0.70 ±0.026
0.26 ±0.029 0.47 ±0.029 0.67 ±0.031
in the neostigmine group, and from 0.53 to 0.96 with a mean value of 0.74 ±0.028 (SEM) in the edrophonium group (E!0 in figure 2). This difference in the average peak TOF ratios between the groups was significant (P < 0.01). However, if the seven patients in the edrophonium group who did not attain a TOF ratio of 0.7 are excluded, the average peak TOF in the remaining 13 patients (E13 in figure 2) in this group was 0.82 ±0.021 (SEM), which was not significantly different from that in the neostigmine group. Five of the seven patients who failed to attain a TOF ratio of 0.7 with edrophonium showed three or less responses to TOF stimulation before the administration of the antagonist. The two remaining patients in whom antagonism was inadequate with edrophonium had TOF ratios of 0.11 and 0.18 before antagonism. Adequate antagonism in all these patients was attained following a further period of ventilation and the administration of one or two further doses of edrophonium. In contrast, in all patients given neostigmine, including the eight who did not show all four responses to TOF stimulation before antagonism, blockade was reversed adequately. The TOF ratios at 50, 75 and 100% Tl twitch height in patients in the two groups are shown in table III. The TOF ratios during antagonism are higher after edrophonium, being significantly so at 50 and 75 % heights of Tl (P < 0.05).
0.5 DISCUSSION Neostigmine
Edrophonium
FIG. 2. Peak TOF ratios in individual patients after the administration of the anticholinesterase agents. Horizontal line and bars represent mean ± SEM values. E,, refers to average peak TOF ratio in all 20 patients in the edrophonium group and E,, refers to peak TOF ratio in the 13 patients in this group who attained a TOF ratio of 0.7 or more (adequate antagonism).
The present study confirms that, when considered overall, edrophonium, in a dose of 0.5 mg kg"1 as used in the present study and recommended by Cronnelly, Morris and Miller (1982) and Jones, Pearce and Williams (1984), antagonized vercuronium-induced blockade significantly more rapidly than neostigmine. However, neuromuscular blockade could not be adequately antago-
Downloaded from http://bja.oxfordjournals.org/ at New York University on June 8, 2015
The average onset times and the times taken to attain TOF ratios of 0.7 in the two groups are given in table II. There was no significant difference in the time to onset of effect (22 s for edrophonium, 26 s for neostigmine), but the time taken to attain a sustained TOF ratio of 0.7 was significantly less (P < 0.05) with edrophonium (67 s) in comparison with neostigmine (194 s). However, seven patients given edrophonium failed to attain a TOF ratio of 0.7 (table II) and, hence, the time to TOF ratio of 0.7 refers to only 13 patients in this group. The individual peak TOF ratios attained with the two anticholinesterase agents are shown in figure 2. These varied from 0.7 to 1.0 with a mean of 0.85 ± 0.022 (SEM)
476
It is possible that a larger initial dose of edrophonium may have been successful in antagonizing relatively more profound blockade, since the administration of one or two additional doses (of edrophonium) produced adequate antagonism in these patients. However, with a neuromuscular blocking agent such as vecuronium, which has a short recovery index, it is likely that further spontaneous recovery of blockade was taking place in the intervening period of more than 10 min. Moreover, other workers using edrophonium, even in larger doses than those used in the present study, have failed to show adequate antagonism of relatively deeper blockade induced by vecuronium — or atracurium, an agent not dissimilar to
vecuronium in its recovery characteristics (Hughes, Astley and Payne, 1984; Engbaek et al., 1985). In addition, it has been shown that larger doses of edrophonium would exert greater muscarinic effects and require larger doses of atropine, thus losing one of the major benefits of the use of edrophonium (Engbaek et al., 1985). The potency ratio between edrophonium and neostigmine has been given as 11.6:1 by Cronnelly, Morris and Miller (1982), and as 16:1 by Breen and his colleagues (1985) using different methods of estimation. The ratio of 10:1 used in the present study is closer to that given by Cronnelly and his colleagues (1982). The present study was, however, not comparing strictly equipotent doses, but looking at the efficacy of commonly advocated doses of the two anticholinesterase drugs. Presence of higher TOF ratios and, consequently, less fade with edrophonium at similar heights of Tl probably reflects its greater presynaptic activity and has previously been reported during antagonism of pancuronium and atracurium-induced blockade (Donati, Ferguson and Bevan, 1983; Jones, Pearce and Williams, 1984; Lavery, Mirakhur and Gibson, 1985). However, this does not appear to be of any beneficial value in relatively more profound vecuronium-induced blockade. In conclusion, edrophonium in a dose of 0.5 mg kg"1 does not adequately and reliably antagonize vecuronium-induced neuromuscular blockade — particularly where three or less responses to a TOF stimulation are present before antagonism. Neostigmine 0.05 mg kg"1 provides better and more reliable antagonism in such situations. ACKNOWLEDGEMENTS The authors are thankful to the nursing and other theatre staff of the Royal Victoria Hospital for their help with the study. Drs Gibson and Lavery were in receipt of Fellowships from the Endowments and Gifts Fund of the Royal Victoria Hospital, Belfast.
REFERENCES Ah', H. H., and Savarese, J. J. (1976). Monitoring of neuromuscular function. Anesthesiology, 45, 216. Lebowitz, P. W., and Ramsey, F. M. (1981). Twitch, tetanus and train-of-four as indices of recovery from non-depolarising neuromuscular blockade. Anesthesiology, 54,294.
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nized (as defined by a TOF ratio of 0.7) in seven out of 20 patients (35%) given this dose of edrophonium, the majority of these (five out of seven) showing three or less responses to a TOF stimulation before antagonism. A previously published study (Baird, Bowman and Kerr, 1982) suggested that edrophonium in doses of 0.5-1.0 mg kg"1 would be the reversal agent of choice with which to antagonize a vecuroniuminduced blockade compared with blockade produced by pancuronium or tubocurarine. We are unable to substantiate this for the 0.5-mg kg"1 dose — particularly in patients with relatively more marked degrees of blockade: in 35% of patients blockade could not be adequately antagonized. Perhaps Baird and his co-workers (1982) based their assertions on the basis of their work in cats. They studied only a total of nine patients who received edrophonium in doses ranging from 0.1 to 1 mg kg"1 and in whom twitch heights had recovered to at least 25% of control. Other workers have also reported difficulty in antagonizing relatively profound neuromuscular blockade produced by vecuronium, pancuronium or atracurium adequately with doses of edrophonium similar to that used in the present study— particularly if three or fewer responses to a TOF stimulation were present (Kopman, 1979; Foldes et al., 1981; Rupp, McChristian and Miller, 1984; Lavery, Mirakhur and Gibson, 1985). In the present study, blockade in two patients was not antagonized, despite considerable recovery (as shown by TOF ratios of 0.11 and 0.18, respectively) before antagonism. Neostigmine, on the other hand, antagonized neuromuscular blockade adequately in all 20 patients in the present study, including those not showing all four responses to TOF stimulation.
BRITISH JOURNAL OF ANAESTHESIA
ANTAGONISM WITH EDROPHONIUM OR NEOSTIGMINE
R., and Nagashima, H. (1981). Antagonism of the neuromuscular effect of Org NC 45 by edrophonium. Anesthesiology, 55, A201. Hughes, R., Astley, B. A., and Payne, J. P. (1984). Reversal of atracurium blockade by neostigmine and edrophonium. Br. J. Anaesth., 56, 796P. Jones, R. M., Pearce, A. C , and Williams, J. P. (1984). Recovery characteristics following antagonism of atracurium with neostigmine or edrophonium. Br. J. Anaesth., 56, 453. Kopman, A. F. (1979). Edrophonium antagonism of pancuronium-induced neuromuscular blockade in man. Anesthesiology, 51, 139. Lavery, G. G., Mirakhur, R. K., and Gibson, F. M. (1985). Comparison of edrophonium and neostigmine for the antagonism of atracurium-induced neuromuscular block. Anesth. Analg., 64, 867. Mirakhur, R. K. (1985). Antagonism of the muscarinic effects of edrophonium with atropine or glycorpyrrolate: a comparative study. Br. J. Anaesth., 57, 1213. Rupp, S. M., McChristian, J. W., and Miller, R. D. (1984). Neostigmine antagonises a profound neuromuscular blockade more rapidly than edrophonium. Anesthesiology, 61, A297.
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Baird, W. L. M., Bowman, W. C , and Kerr, W. J. (1982). Some actions of Org NC 45 and of edrophonium in the anaesthetized cat and in man. Br. J. Anaesth., 54, 375. Kerr, W. J. (1983). Reversal of atracurium with edrophonium. Br. J. Anaesth., 55, 63S. Bevan, D. R. (1979). Reversal of pancuronium by edrophonium. Anaesthesia, 34, 614. Breen, P. J., Doherty, W. G., Donati, F., and Bevan, D. R. (1985). The potencies of edrophonium and neostigmine as antagonists to pancuronium. Anaesthesia, 40, 844. Cronnelly, R., and Morris, R. B. (1982). Antagonism of neuromuscular blockade. Br. J. Anaesth., 54, 183. Miller, R. D. (1982). Edrophonium: duration of action and atropine requirement in humans during halothane anesthesia. Anestkesiology, 57, 261. Donati, F., Ferguson, A., and Bevan, D. R. (1983). Twitch depression and train-of-four ratio after antagonism of pancuronium with edrophonium, neostigmine or pyridostigmine. Anesth. Analg., 62, 314. Engbaek, J., Ording, H., Ostergaard, D., and Viby-Mogensen, J. (1985). Edrophonium and neostigmine for reversal of neuromuscular blocking effect of vecuronium. Ada Anaesthesiol. Scand., 29, 544. Foldes, F. F., Yun, H., Radnay, P. A., Badola, R. P., Kaplan,
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