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ANTAGONISM OF BLOCKADE PRODUCED BY ATRACURIUM OR VECURONIUM WITH LOW DOSES OF NEOSTIGMINE
Br. J. Anaesth. (1988), 61, 560-564
ANTAGONISM OF BLOCKADE PRODUCED BY ATRACURIUM OR VECURONIUM WITH LOW DOSES OF NEOSTIGMINE J. E. JONES, C. J. R. PARKER AND J. M. HUNTER
PATIENTS AND METHODS
SUMMARY Neostigmine 1.25 mg or 0.625 mg was used to antagonize neuromuscular blockade produced by either atracurium 0.5 mg kg~' or vecuronium 0.1 mg kg'1 in four groups of patients (x\ = 45) when the first EMG response of the train-of-four (A) had recovered to 10% of control (A).The time for A' IA and the train-of-four ratio (D'/A'J to reach 70% was recorded. It was found that, after both atracurium and vecuronium, neostigmine 1.25 mg considerably accelerated recovery and, when compared with previous results, differed little from neostigmine 5.0 mg or 2.5 mg. Neostigmine 0.625 mg also significantly accelerated recovery after atracurium and was comparable to neostigmine 1.25 mg. However, with neostigmine 0.625 mg after vecuronium, recovery of D'/A' (but not A' IA) was little faster than spontaneous. Neostigmine 1.25 mg appears to be almost as effective as neostigmine 5.0 mg or 2.5 mg in antagonizing considerable block (90% depression of twitch height) produced by either atracurium or vecuronium, but neostigmine 0.625 mg is not sufficient, especially after vecuronium.
Permission for the study was granted by the hospital Ethics Committee and informed consent to four groups. Patients in group I («=11) was obtained from each patient. Forty-five pat- received atracurium and were given neostigmine ients (table I) were investigated; all were healthy 0.625 mg to antagonize blockade; group II and were scheduled to undergo general surgical or (M = 13) received atracurium and neostigmine gynaecological procedures. They were allocated 1.25 mg; group III (« = 10) received vecuronium and were given neostigmine 0.625 mg to antagonize blockade and group IV (w = 11) received J.E.JONES*, M.B., F.F.A.R.C.S.; C. J. R. PARKER, M.B., vecuronium and neostigmine 1.25 mg. F.F.A.R.C.S.; JENNIFER M. HUNTER, M.B., F.F.A.R.C.S.; University Department of Anaesthesia, Royal Liverpool Hospital, The initial dose of atracurium was 0.5 mg kg~l Prescot Street, P.O. Box 147, Liverpool L69 3BX. Accepted and of vecuronium O.lmgkg" 1 ; up to two for Publication: April 12, 1988. increments, of 0.2 mg kg"1 or 0.04 mg kg' 1 , •Present address: Southport General Hospital, Scarisbrick respectively, were given if the ratio A'/A recovered New Road, Southport, Merseyside PR8 6LF. to 10% during surgery. The anticholinesterase Correspondence to J. M. H.
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The action of atracurium and vecuronium can be reversed readily by neostigmine 2.5 mg even when the degree of residual neuromuscular blockade is considerable [1,2]. Thus, using the compound action potential of the electromyograph, Fox, Keens and Utting [1] showed that neostigmine 2.5 mg produced rapid reversal of residual atracurium blockade if given when the recovery of the first response of the train-of-four (TOF) stimuli (A') was only 10 % of control (A) and that there was no advantage in using neostigmine 5 mg at this degree of block. Using an identical procedure, Jones, Hunter and Utting [2] reported similar results with vecuronium, again finding recovery to be as rapid with a dose of neostigmine 2.5 mg as with 5.0 mg. The results from these two studies suggested that doses of neostigmine less than 2.5 mg might be clinically effective. We have studied, therefore, the efficacy of neostigmine 1.25 mg and 0.625 mg in the antagonism of block produced by atracurium or vecuronium, in an attempt to assess if these lower doses of anticholinesterase were sufficient to produce prompt recovery.
LOW-DOSE NEOSTIGMINE TO ANTAGONIZE BLOCKADE TABLE I. Mean (SD) age and weight of the four groups of patients studied, together with the number of patients in each group and the male: female ratio No. patients
Age (yr)
Weight (kg)
Group I
11
Group II
13
Group III
10
Group IV
11
38.6 (9.2) 42.3 (12.9) 39.1 (13.1) 38.4 (13.6)
71.5 (19.4) 63.4 (14.3) 58.8 (14.6) 65.0 (7.6)
Sex
(M:F) 5:6
3:10 4:6 3:8
The unpaired Student's t test was used for statistical comparisons. The times to reach 70% A'/A and D'/A' were compared between group I and group II (both received atracurium, but neostigmine 0.625 mg and 1.25 mg, respectively). A similar comparison was made between groups III and IV (both received vecuronium, but neostigmine 0.625 mg and 1.25 mg, respectively). In addition, statistical comparison was extended to previous work [1,2] in which the results from spontaneous recovery and from using larger doses of neostigmine (2.5 mg and 5.0 mg) were recorded. RESULTS
Atracurium The mean times to 70 % recovery of A'/A and D'/A' in groups I (receiving neostigmine 0.625 mg) and II (neostigmine 1.25 mg) were compared with each other and with previous results [1] from patients who received neostigmine 2.5 mg, neostigmine 5.0 mg or no neostigmine (spontaneous recovery) (table II). Each dose of neostigmine significantly shortened the period of recovery of both A'/A and D'/A' to 70 % compared with the group in which spontaneous recovery was studied. Neostigmine 2.5 mg and 5.0 mg produced significantly more rapid recovery than neostigmine 0.625 mg, but there was no significant difference between the rate of recovery after neostigmine 1.25 mg compared with neostigmine 2.5 mg or 5.0 mg, or between neostigmine 0.625 mg and 1.25 mg. The mean height of A'/A in group I at the completion of monitoring, when D'/A' was 70 % was 94.1 % (range 82-100 %) and in group II was 92.3% (range 77-100%). Vecuronium
The mean times for 70% recovery of A'/A and D'/A' in group III (receiving neostigmine 0.625 mg) and group IV (neostigmine 1.25 mg) were compared with each other and with previous results from patients who received neostigmine 2.5 mg, neostigmine 5.0 mg or no neostigmine (spontaneous recovery) (table III). When the results from patients receiving neostigmine 0.625 mg are compared with those in whom spontaneous recovery was allowed, it can be seen that recovery of A'/A, but not D'/A', was significantly more rapid. In contrast, neostigmine 1.25 mg, 2.5 mg or 5.0 mg significantly increased the rate of recovery of both variables compared
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was also given when A'/A was 10%. Atropine 0.6 mg was administered with the neostigmine. All patients were premedicated with promethazine 50 mg by mouth the night before surgery, followed either by diazepam 10 mg by mouth 2 h before operation or by morphine 10 mg with cyclizine 50 mg (Cyclimorph) i.m. 1 h before operation. The anaesthetic technique and methods used were identical to those reported in detail previously [1,2]. Anaesthesia was induced with thiopentone, fentanyl and droperidol and the patient breathed 70 % nitrous oxide in oxygen via a Magill circuit. No other inhalation agent was used. Ventilation was assisted if necessary and normocapnia maintained with the aid of a Normocap (Datex). A control recording of the electro-, myograph (EMG) was obtained using the Medelec MS6 electromyograph. Train-of-four (TOF) supramaximal stimuli (0.2 ms; 2 Hz) were delivered to the ulnar nerve at 12-s intervals and a control compound muscle action potential (CMAP) recorded, at least 10 responses being obtained. The initial dose of the myoneural blocker was given and the trachea intubated when it was thought to be clinically appropriate. TOF monitoring continued at 1-min intervals throughout the study. At the end of surgery and when A'/A had returned to 10%, TOF monitoring was returned to 12-s intervals and the appropriate dose of neostigmine accompanied by atropine 0.6 mg was given. The times taken for A'/A and D'/A' (TOF ratio: ratio of fourth response to first) to reach 70 % were measured and the height of A'/A when D'/A' had reached 70% noted. Some time after this (5-15 min) anaesthesia and monitoring were discontinued and the patient allowed to recover from anaesthesia whilst breathing oxygen.
561
BRITISH JOURNAL OF ANAESTHESIA
562
TABLE II. Mean (SD) times to 70% recovery from block by atracurium after neostigmine 0.625 mg or 1.25 mg (groups I and II) compared also with results previously reported [1] for neostigmine 2.5 mg and 5.0 mg and for spontaneous recovery. Statistical significance: comparing each dose of neostigmine with spontaneous recovery—** P < 0.01; *** P < 0.001; between the smallest dose of neostigmine (0.625 mg) and the three larger doses (1.25 mg, 2.5 mg and 5.0 mg)—+ P < 0.05 Dose of neostigmine (mg) Group I 0.625 No. of patients Time (min) to: 70% A'/A 70% D'/A'
Group II
ref. [1]
1.25
2.5
11
13
10
13.0** (4.3) 19.3** (5.6)
9.9*** (4.7) 14.2** (6.9)
8.2***t (2.9) 12.0***t (3.5)
ref. [1] 5.0
Spontaneous recovery
5 7.4**+ (1.7) 11.2**+ (2.3)
10 25.0 (9.5) 32.3 (10.4)
++P<0.0/; +++P< 0.007 Dose of neostigmine (mg) Group III 0.625
No. of patients Time (min) to: 70 % A'/A 70% D'/A'
10
9.2* (5.15) 19.7 ns (11.8)
Group IV 1.25
ref. [2]
ref. [2]
2.5
5.0
11
10
10
5.05***+ (3.25) 10.4***+ (6.44)
3.9**++ (2.24) 9.2**+ (5.3)
3.4**++ (1.3) 5.6**+++ (3.7)
with spontaneous and with neostigmine 0.625 mg. However, there was no significant difference between the rate of recovery of A'/A or D'/A' in the group who received neostigmine 1.25 mg compared with neostigmine 2.5 mg or 5.0 mg. The mean height of A'/A in group III on completion of monitoring was 91.1% (range 81.5-100%) and in group IV was 92.0% (range 83-97%). DISCUSSION
Neostigmine 1.25 mg was nearly as rapid at antagonizing a considerable degree of residual block produced by both atracurium or vecuronium, as was neostigmine 5.0 mg or 2.5 mg; although the mean times to 70% recovery of D'/A' after vecuronium were certainly longer
Spontaneous recovery 10
15.5 (6.8) 24.2 (11.2)
after neostigmine 1.25 mg than neostigmine 5 mg it is doubtful if this is clinically important. With the smallest dose of neostigmine (0.625 mg) the situation was different. For atracurium, there was a significant difference in the times at which 70 % recovery was reached when compared with spontaneous recovery; in other words the small dose of neostigmine accelerated recovery. However, recovery was slower than with neostigmine 2.5 mg (and 5.0 mg) and, as it took a mean time of 19 min for D'/A' (perhaps the best criterion of recovery) to reach 70%, it might be considered clinically unacceptable. When neostigmine 0.625 mg was administered to those who had received vecuronium, the time to 70 % recovery of D'/A' was not different from the mean time when recovery was spontaneous, but was different from the larger doses, including
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TABLE III. Mean (SD) times to 70% recovery from block by vecuronium after neostigmine 0.625 mg and 1.25 mg (groups III and IV) compared also with the results previously reported [2] following neostigmine 2.5 mg and 5.0 mg and spontaneous recovery. Statistical significance: comparing each dose of neostigmine with spontaneous recovery—*P<0.05; **P < 0.01; ***P < 0.001; between the smaller dose of neostigmine (0.625 mg) and the three larger doses (1.25 mg, 2.5 mg and 5.0 mg)—+P< 0.05;
LOW-DOSE NEOSTIGMINE TO ANTAGONIZE BLOCKADE
ed, 3 min later, by 0.04 mg kg"1) and the results compared with a single bolus dose of neostigmine 0.05 mg kg"1 [6]. Abdulatif and Naguib [6] administered the first dose of neostigmine when A'/A was 10%, as in this study, and found a more rapid recovery of D'/A' to 75 % when neostigmine was given in divided doses. These workers reported that, 3 min after the initial smaller dose of neostigmine (0.01 mg kg"1) and immediately before the second dose was given, A'/A had reached a mean of 44 %—an even faster rate of recovery than that found in this study for a comparable dose of neostigmine (0.625 mg). The apparently effective use of a smaller dose of neostigmine to antagonize profound neuromuscular block is an interesting contrast to the inconsistent effects reported after the use of the shorter acting anticholinesterase, edrophonium, even in large doses. Caldwell, Robertson and Baird [7] demonstrated that, although the onset of action of edrophonium 0.8 mg kg"1 was faster than neostigmine 0.07 mg kg"1 when used to antagonize both atracurium and vecuronium, edrophonium did not produce as fast a clinical recovery. Indeed, when edrophonium was used after vecuronium, recovery was more variable than after atracurium and was considered, on occasions, to be delayed unacceptably. These results have been substantiated by other workers for both vecuronium [8] and atracurium [9]. The inconsistent effects of edrophonium, even in larger doses, contrast markedly with the results reported in this study. Even with low doses neostigmine would seem to be a more reliable anticholinesterase than edrophonium. In addition, it would seem preferable to use neostigmine, even in low doses, than to allow spontaneous recovery to occur, especially if neuromuscular monitoring is not used. We would suggest that the concept that anticholinesterases are not required if atracurium or vecuronium are used should be viewed with caution. ACKNOWLEDGEMENT This work was supported in part by a grant from the Mersey Regional Health Authority.
REFERENCES 1. Fox MA, Keens SJ, Utting JE. Neostigmine in the antagonism of the action of atracurium. British Journal of Anaesthesia 1987; 59: 468-472.
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neostigmine 1.25 mg; the time for A'/A to reach 70% was also longer than with the other doses, although shorter than when recovery was spontaneous. Clinical deductions from these data are likely to be controversial. If there is a considerable degree of residual block following both blocking drugs (for instance, only the first twitch of the TOF present) neostigmine 2.5 mg might be considered a suitable dose to antagonize this. Neostigmine 1.25 mg should be adequate for both blockers if it be appreciated that antagonism to a safe degree of block would be slower in some patients. Even neostigmine 0.625 mg might be adequate following atracurium, although it must be emphasized that it took more than 19min in this study for D'/A' to reach 70% after this dose. Certainly little acceleration of recovery of D'/A' after vecuronium may be produced with neostigmine 0.625 mg. In this respect the difference between the two drugs is related probably to more rapid spontaneous recovery from vecuronium than from atracurium. It should be noted that recovery might be even more prolonged if a volatile agent is used. In this study a maximum of two increments of atracurium or vecuronium was given. Although atracurium is not thought to cumulate [3], it has been suggested that vecuronium may do so, especially after several increments [4]. If this is the case, smaller doses of neostigmine may be insufficient to produce adequate recovery from the residual block produced after several increments of vecuronium; thus it is possible that the number of increments of a neuromuscular blocking agent used may affect the dose of neostigmine which should be given. However, Miller, Larson and Way [5] demonstrated that the amount of neostigmine required to antagonize a profound block (5% recovery of control twitch height) produced by tubocurarine, gallamine or pancuronium was unrelated to the amount of blocker given. Using repeated boluses of neostigmine 0.25 mg every 3 min, commencing when the twitch height had recovered to 5% of control, these workers also found that little more than neostigmine 1 mg was required to produce 80% recovery of the twitch height after pancuronium and tubocurarine, although more than 2 mg was required if gallamine had been given. Attempts have also been made to antagonize residual block produced by atracurium using divided doses of neostigmine (0.01 mg kg"1 follow-
563
564 2. Jones JE, Hunter JM, Utting JE. Use of neostigmine in the antagonism of residual neuromuscular blockade produced by vecuronium. British Journal of Anaesthesia 1987; 59: 1454-1458. 3. Hughes R, Payne JP. Clinical assessment of atracurium using the single twitch and tetanic response of the adductor pollicis muscles. British Journal of Anaesthesia 1983; 55:47S-52S. 4. Hilgenberg JC. Comparison of the pharmacology of vecuronium and atracurium with that of other currently available muscle relaxants. Anesthesia and Analgesia 1983; 62:524-531. 5. Miller RD, Larson CP, Way WL. Comparative antagonism of d-tubocurarine, gallamine and pancuroniuminduced neuromuscular blockade by neostigmine. Anesthesiology 1972; 37: 503-509.
BRITISH JOURNAL OF ANAESTHESIA 6. Abdulatif M, Naguib M. Accelerated reversal of atracurium blockade with divided doses of neostigmine. Canadian Anaesthetists Society Journal 1986; 33:723-728. 7. Caldwell JE, Robertson EN, Baird WLM. Antagonism of vecuronium and atracurium: comparison of neostigmine and edrophonium administered at 5% twitch height recovery. British Journal of Anaesthesia 1987; 59: 478481. 8. Mirakhur RK, Gibson FM, Lavery GG. Antagonism of vecuronium-induced neuromuscular blockade with edrophonium or neostigmine. British Journal of Anaesthesia 1987; 59: 473-477. 9. Astley BA, Hughes R, Payne JP. Antagonism of atracurium-induced neuromuscular blockade by neostigmine or edrophonium. British Journal of Anaesthesia 1986; 58: 1290-1295.
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ANTAGONISM OF BLOCKADE PRODUCED BY ATRACURIUM OR VECURONIUM WITH LOW DOSES OF NEOSTIGMINE J. E. JONES, C. J. R. PARKER AND J. M. HUNTER
PATIENTS AND METHODS
SUMMARY Neostigmine 1.25 mg or 0.625 mg was used to antagonize neuromuscular blockade produced by either atracurium 0.5 mg kg~' or vecuronium 0.1 mg kg'1 in four groups of patients (x\ = 45) when the first EMG response of the train-of-four (A) had recovered to 10% of control (A).The time for A' IA and the train-of-four ratio (D'/A'J to reach 70% was recorded. It was found that, after both atracurium and vecuronium, neostigmine 1.25 mg considerably accelerated recovery and, when compared with previous results, differed little from neostigmine 5.0 mg or 2.5 mg. Neostigmine 0.625 mg also significantly accelerated recovery after atracurium and was comparable to neostigmine 1.25 mg. However, with neostigmine 0.625 mg after vecuronium, recovery of D'/A' (but not A' IA) was little faster than spontaneous. Neostigmine 1.25 mg appears to be almost as effective as neostigmine 5.0 mg or 2.5 mg in antagonizing considerable block (90% depression of twitch height) produced by either atracurium or vecuronium, but neostigmine 0.625 mg is not sufficient, especially after vecuronium.
Permission for the study was granted by the hospital Ethics Committee and informed consent to four groups. Patients in group I («=11) was obtained from each patient. Forty-five pat- received atracurium and were given neostigmine ients (table I) were investigated; all were healthy 0.625 mg to antagonize blockade; group II and were scheduled to undergo general surgical or (M = 13) received atracurium and neostigmine gynaecological procedures. They were allocated 1.25 mg; group III (« = 10) received vecuronium and were given neostigmine 0.625 mg to antagonize blockade and group IV (w = 11) received J.E.JONES*, M.B., F.F.A.R.C.S.; C. J. R. PARKER, M.B., vecuronium and neostigmine 1.25 mg. F.F.A.R.C.S.; JENNIFER M. HUNTER, M.B., F.F.A.R.C.S.; University Department of Anaesthesia, Royal Liverpool Hospital, The initial dose of atracurium was 0.5 mg kg~l Prescot Street, P.O. Box 147, Liverpool L69 3BX. Accepted and of vecuronium O.lmgkg" 1 ; up to two for Publication: April 12, 1988. increments, of 0.2 mg kg"1 or 0.04 mg kg' 1 , •Present address: Southport General Hospital, Scarisbrick respectively, were given if the ratio A'/A recovered New Road, Southport, Merseyside PR8 6LF. to 10% during surgery. The anticholinesterase Correspondence to J. M. H.
Downloaded from http://bja.oxfordjournals.org/ at UQ Library on June 15, 2015
The action of atracurium and vecuronium can be reversed readily by neostigmine 2.5 mg even when the degree of residual neuromuscular blockade is considerable [1,2]. Thus, using the compound action potential of the electromyograph, Fox, Keens and Utting [1] showed that neostigmine 2.5 mg produced rapid reversal of residual atracurium blockade if given when the recovery of the first response of the train-of-four (TOF) stimuli (A') was only 10 % of control (A) and that there was no advantage in using neostigmine 5 mg at this degree of block. Using an identical procedure, Jones, Hunter and Utting [2] reported similar results with vecuronium, again finding recovery to be as rapid with a dose of neostigmine 2.5 mg as with 5.0 mg. The results from these two studies suggested that doses of neostigmine less than 2.5 mg might be clinically effective. We have studied, therefore, the efficacy of neostigmine 1.25 mg and 0.625 mg in the antagonism of block produced by atracurium or vecuronium, in an attempt to assess if these lower doses of anticholinesterase were sufficient to produce prompt recovery.
LOW-DOSE NEOSTIGMINE TO ANTAGONIZE BLOCKADE TABLE I. Mean (SD) age and weight of the four groups of patients studied, together with the number of patients in each group and the male: female ratio No. patients
Age (yr)
Weight (kg)
Group I
11
Group II
13
Group III
10
Group IV
11
38.6 (9.2) 42.3 (12.9) 39.1 (13.1) 38.4 (13.6)
71.5 (19.4) 63.4 (14.3) 58.8 (14.6) 65.0 (7.6)
Sex
(M:F) 5:6
3:10 4:6 3:8
The unpaired Student's t test was used for statistical comparisons. The times to reach 70% A'/A and D'/A' were compared between group I and group II (both received atracurium, but neostigmine 0.625 mg and 1.25 mg, respectively). A similar comparison was made between groups III and IV (both received vecuronium, but neostigmine 0.625 mg and 1.25 mg, respectively). In addition, statistical comparison was extended to previous work [1,2] in which the results from spontaneous recovery and from using larger doses of neostigmine (2.5 mg and 5.0 mg) were recorded. RESULTS
Atracurium The mean times to 70 % recovery of A'/A and D'/A' in groups I (receiving neostigmine 0.625 mg) and II (neostigmine 1.25 mg) were compared with each other and with previous results [1] from patients who received neostigmine 2.5 mg, neostigmine 5.0 mg or no neostigmine (spontaneous recovery) (table II). Each dose of neostigmine significantly shortened the period of recovery of both A'/A and D'/A' to 70 % compared with the group in which spontaneous recovery was studied. Neostigmine 2.5 mg and 5.0 mg produced significantly more rapid recovery than neostigmine 0.625 mg, but there was no significant difference between the rate of recovery after neostigmine 1.25 mg compared with neostigmine 2.5 mg or 5.0 mg, or between neostigmine 0.625 mg and 1.25 mg. The mean height of A'/A in group I at the completion of monitoring, when D'/A' was 70 % was 94.1 % (range 82-100 %) and in group II was 92.3% (range 77-100%). Vecuronium
The mean times for 70% recovery of A'/A and D'/A' in group III (receiving neostigmine 0.625 mg) and group IV (neostigmine 1.25 mg) were compared with each other and with previous results from patients who received neostigmine 2.5 mg, neostigmine 5.0 mg or no neostigmine (spontaneous recovery) (table III). When the results from patients receiving neostigmine 0.625 mg are compared with those in whom spontaneous recovery was allowed, it can be seen that recovery of A'/A, but not D'/A', was significantly more rapid. In contrast, neostigmine 1.25 mg, 2.5 mg or 5.0 mg significantly increased the rate of recovery of both variables compared
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was also given when A'/A was 10%. Atropine 0.6 mg was administered with the neostigmine. All patients were premedicated with promethazine 50 mg by mouth the night before surgery, followed either by diazepam 10 mg by mouth 2 h before operation or by morphine 10 mg with cyclizine 50 mg (Cyclimorph) i.m. 1 h before operation. The anaesthetic technique and methods used were identical to those reported in detail previously [1,2]. Anaesthesia was induced with thiopentone, fentanyl and droperidol and the patient breathed 70 % nitrous oxide in oxygen via a Magill circuit. No other inhalation agent was used. Ventilation was assisted if necessary and normocapnia maintained with the aid of a Normocap (Datex). A control recording of the electro-, myograph (EMG) was obtained using the Medelec MS6 electromyograph. Train-of-four (TOF) supramaximal stimuli (0.2 ms; 2 Hz) were delivered to the ulnar nerve at 12-s intervals and a control compound muscle action potential (CMAP) recorded, at least 10 responses being obtained. The initial dose of the myoneural blocker was given and the trachea intubated when it was thought to be clinically appropriate. TOF monitoring continued at 1-min intervals throughout the study. At the end of surgery and when A'/A had returned to 10%, TOF monitoring was returned to 12-s intervals and the appropriate dose of neostigmine accompanied by atropine 0.6 mg was given. The times taken for A'/A and D'/A' (TOF ratio: ratio of fourth response to first) to reach 70 % were measured and the height of A'/A when D'/A' had reached 70% noted. Some time after this (5-15 min) anaesthesia and monitoring were discontinued and the patient allowed to recover from anaesthesia whilst breathing oxygen.
561
BRITISH JOURNAL OF ANAESTHESIA
562
TABLE II. Mean (SD) times to 70% recovery from block by atracurium after neostigmine 0.625 mg or 1.25 mg (groups I and II) compared also with results previously reported [1] for neostigmine 2.5 mg and 5.0 mg and for spontaneous recovery. Statistical significance: comparing each dose of neostigmine with spontaneous recovery—** P < 0.01; *** P < 0.001; between the smallest dose of neostigmine (0.625 mg) and the three larger doses (1.25 mg, 2.5 mg and 5.0 mg)—+ P < 0.05 Dose of neostigmine (mg) Group I 0.625 No. of patients Time (min) to: 70% A'/A 70% D'/A'
Group II
ref. [1]
1.25
2.5
11
13
10
13.0** (4.3) 19.3** (5.6)
9.9*** (4.7) 14.2** (6.9)
8.2***t (2.9) 12.0***t (3.5)
ref. [1] 5.0
Spontaneous recovery
5 7.4**+ (1.7) 11.2**+ (2.3)
10 25.0 (9.5) 32.3 (10.4)
++P<0.0/; +++P< 0.007 Dose of neostigmine (mg) Group III 0.625
No. of patients Time (min) to: 70 % A'/A 70% D'/A'
10
9.2* (5.15) 19.7 ns (11.8)
Group IV 1.25
ref. [2]
ref. [2]
2.5
5.0
11
10
10
5.05***+ (3.25) 10.4***+ (6.44)
3.9**++ (2.24) 9.2**+ (5.3)
3.4**++ (1.3) 5.6**+++ (3.7)
with spontaneous and with neostigmine 0.625 mg. However, there was no significant difference between the rate of recovery of A'/A or D'/A' in the group who received neostigmine 1.25 mg compared with neostigmine 2.5 mg or 5.0 mg. The mean height of A'/A in group III on completion of monitoring was 91.1% (range 81.5-100%) and in group IV was 92.0% (range 83-97%). DISCUSSION
Neostigmine 1.25 mg was nearly as rapid at antagonizing a considerable degree of residual block produced by both atracurium or vecuronium, as was neostigmine 5.0 mg or 2.5 mg; although the mean times to 70% recovery of D'/A' after vecuronium were certainly longer
Spontaneous recovery 10
15.5 (6.8) 24.2 (11.2)
after neostigmine 1.25 mg than neostigmine 5 mg it is doubtful if this is clinically important. With the smallest dose of neostigmine (0.625 mg) the situation was different. For atracurium, there was a significant difference in the times at which 70 % recovery was reached when compared with spontaneous recovery; in other words the small dose of neostigmine accelerated recovery. However, recovery was slower than with neostigmine 2.5 mg (and 5.0 mg) and, as it took a mean time of 19 min for D'/A' (perhaps the best criterion of recovery) to reach 70%, it might be considered clinically unacceptable. When neostigmine 0.625 mg was administered to those who had received vecuronium, the time to 70 % recovery of D'/A' was not different from the mean time when recovery was spontaneous, but was different from the larger doses, including
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TABLE III. Mean (SD) times to 70% recovery from block by vecuronium after neostigmine 0.625 mg and 1.25 mg (groups III and IV) compared also with the results previously reported [2] following neostigmine 2.5 mg and 5.0 mg and spontaneous recovery. Statistical significance: comparing each dose of neostigmine with spontaneous recovery—*P<0.05; **P < 0.01; ***P < 0.001; between the smaller dose of neostigmine (0.625 mg) and the three larger doses (1.25 mg, 2.5 mg and 5.0 mg)—+P< 0.05;
LOW-DOSE NEOSTIGMINE TO ANTAGONIZE BLOCKADE
ed, 3 min later, by 0.04 mg kg"1) and the results compared with a single bolus dose of neostigmine 0.05 mg kg"1 [6]. Abdulatif and Naguib [6] administered the first dose of neostigmine when A'/A was 10%, as in this study, and found a more rapid recovery of D'/A' to 75 % when neostigmine was given in divided doses. These workers reported that, 3 min after the initial smaller dose of neostigmine (0.01 mg kg"1) and immediately before the second dose was given, A'/A had reached a mean of 44 %—an even faster rate of recovery than that found in this study for a comparable dose of neostigmine (0.625 mg). The apparently effective use of a smaller dose of neostigmine to antagonize profound neuromuscular block is an interesting contrast to the inconsistent effects reported after the use of the shorter acting anticholinesterase, edrophonium, even in large doses. Caldwell, Robertson and Baird [7] demonstrated that, although the onset of action of edrophonium 0.8 mg kg"1 was faster than neostigmine 0.07 mg kg"1 when used to antagonize both atracurium and vecuronium, edrophonium did not produce as fast a clinical recovery. Indeed, when edrophonium was used after vecuronium, recovery was more variable than after atracurium and was considered, on occasions, to be delayed unacceptably. These results have been substantiated by other workers for both vecuronium [8] and atracurium [9]. The inconsistent effects of edrophonium, even in larger doses, contrast markedly with the results reported in this study. Even with low doses neostigmine would seem to be a more reliable anticholinesterase than edrophonium. In addition, it would seem preferable to use neostigmine, even in low doses, than to allow spontaneous recovery to occur, especially if neuromuscular monitoring is not used. We would suggest that the concept that anticholinesterases are not required if atracurium or vecuronium are used should be viewed with caution. ACKNOWLEDGEMENT This work was supported in part by a grant from the Mersey Regional Health Authority.
REFERENCES 1. Fox MA, Keens SJ, Utting JE. Neostigmine in the antagonism of the action of atracurium. British Journal of Anaesthesia 1987; 59: 468-472.
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neostigmine 1.25 mg; the time for A'/A to reach 70% was also longer than with the other doses, although shorter than when recovery was spontaneous. Clinical deductions from these data are likely to be controversial. If there is a considerable degree of residual block following both blocking drugs (for instance, only the first twitch of the TOF present) neostigmine 2.5 mg might be considered a suitable dose to antagonize this. Neostigmine 1.25 mg should be adequate for both blockers if it be appreciated that antagonism to a safe degree of block would be slower in some patients. Even neostigmine 0.625 mg might be adequate following atracurium, although it must be emphasized that it took more than 19min in this study for D'/A' to reach 70% after this dose. Certainly little acceleration of recovery of D'/A' after vecuronium may be produced with neostigmine 0.625 mg. In this respect the difference between the two drugs is related probably to more rapid spontaneous recovery from vecuronium than from atracurium. It should be noted that recovery might be even more prolonged if a volatile agent is used. In this study a maximum of two increments of atracurium or vecuronium was given. Although atracurium is not thought to cumulate [3], it has been suggested that vecuronium may do so, especially after several increments [4]. If this is the case, smaller doses of neostigmine may be insufficient to produce adequate recovery from the residual block produced after several increments of vecuronium; thus it is possible that the number of increments of a neuromuscular blocking agent used may affect the dose of neostigmine which should be given. However, Miller, Larson and Way [5] demonstrated that the amount of neostigmine required to antagonize a profound block (5% recovery of control twitch height) produced by tubocurarine, gallamine or pancuronium was unrelated to the amount of blocker given. Using repeated boluses of neostigmine 0.25 mg every 3 min, commencing when the twitch height had recovered to 5% of control, these workers also found that little more than neostigmine 1 mg was required to produce 80% recovery of the twitch height after pancuronium and tubocurarine, although more than 2 mg was required if gallamine had been given. Attempts have also been made to antagonize residual block produced by atracurium using divided doses of neostigmine (0.01 mg kg"1 follow-
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564 2. Jones JE, Hunter JM, Utting JE. Use of neostigmine in the antagonism of residual neuromuscular blockade produced by vecuronium. British Journal of Anaesthesia 1987; 59: 1454-1458. 3. Hughes R, Payne JP. Clinical assessment of atracurium using the single twitch and tetanic response of the adductor pollicis muscles. British Journal of Anaesthesia 1983; 55:47S-52S. 4. Hilgenberg JC. Comparison of the pharmacology of vecuronium and atracurium with that of other currently available muscle relaxants. Anesthesia and Analgesia 1983; 62:524-531. 5. Miller RD, Larson CP, Way WL. Comparative antagonism of d-tubocurarine, gallamine and pancuroniuminduced neuromuscular blockade by neostigmine. Anesthesiology 1972; 37: 503-509.
BRITISH JOURNAL OF ANAESTHESIA 6. Abdulatif M, Naguib M. Accelerated reversal of atracurium blockade with divided doses of neostigmine. Canadian Anaesthetists Society Journal 1986; 33:723-728. 7. Caldwell JE, Robertson EN, Baird WLM. Antagonism of vecuronium and atracurium: comparison of neostigmine and edrophonium administered at 5% twitch height recovery. British Journal of Anaesthesia 1987; 59: 478481. 8. Mirakhur RK, Gibson FM, Lavery GG. Antagonism of vecuronium-induced neuromuscular blockade with edrophonium or neostigmine. British Journal of Anaesthesia 1987; 59: 473-477. 9. Astley BA, Hughes R, Payne JP. Antagonism of atracurium-induced neuromuscular blockade by neostigmine or edrophonium. British Journal of Anaesthesia 1986; 58: 1290-1295.
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