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ANTAGONISM OF INTENSE ATRACURIUM-INDUCED NEUROMUSCULAR BLOCK IN CHILDREN
British Journal of Anaesthesia 1991; 67: 13-16
ANTAGONISM OF INTENSE ATRACURIUM-INDUCED NEUROMUSCULAR BLOCK IN CHILDREN C. L. GWINNUTT, R. W. M. WALKER AND G. MEAKIN
SUMMARY
KEY WORDS Anaesthesia: paediatric. Antagonists: neuromuscular relaxants, edrophonium, neostigmine. Monitoring: neuromuscular function.
It has been shown that pharmacological antagonism of neuromuscular block in adults and children may be accomplished reliably when the first twitch of train-of-four stimulation reaches 10% of the control twitch height [1, 2]. Despite claims that more profound levels of block may be antagonized easily [3], attempts to achieve this have usually met with failure [4—6]. This may reflect the use of long-acting neuromuscular blockers, ignorance of the level of block or the use of an inadequate dose of anticholinesterase. More-
PATIENTS AND METHODS
The study was approved by the District Ethics Committee. Thirty children aged 1-10 yr were studied during elective surgical procedures for which non-depolarizing neuromuscular blocking agents would be used normally as part of the anaesthetic technique. All were ASA class I and none was receiving drugs known to interfere with neuromuscular transmission. Patients were allocated randomly to one of five groups (A-E), to receive a predetermined dose of either neostigmine or edrophonium (table I). Premedication with oral trimeprazine 3 mg kg"1 was given 2 h before surgery. Anaesthesia was induced with thiopentone 5 mg kg"1 and maintained throughout with 66% nitrous oxide and 1 % halothane in oxygen. Tracheal intubation was achieved without the aid of neuromuscular blocking drugs and ventilation of the lungs was controlled using the paediatric attachment of the Blease ventilator. Minute volume was adjusted to maintain the end-tidal carbon dioxide at 5.05.5 kPa. The ECG and systemic arterial pressure were monitored throughout the procedure and rectal temperature was kept at 36.5-37.5 °C.
C. L.
GWINNUTT,
M.B.,
B.s.,
F.C.ANAES.,
Department
of
Anaesthesia, Hope Hospital, Eccles Old Road, Salford M6 8HD.
R. W. M. WALKER, M.B., CH.B., F.C.ANAES. ; G. MEAXTO,
M.B., CH.B., F.C.ANAES.; Department of Anaesthesia, Royal Manchester Childrens Hospital, Pendlebury, Manchester M27 1HA. Accepted for Publication: January 5, 1991.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 20, 2015
Antagonism of intense neuromuscular block induced by atracurium 0.5 mg kg'1 was attempted in four groups of six children using one of two doses of neostigmine (0.05 mg kg'1 and 0.1 mg kg'1) or of edrophonium (0.5 mg kg'1 and 1.0mgkg~1) when the first twitch of the post-tetanic count (PTC1) was 10% of control. For comparison with normal practice, a fifth group received neostigmine 0.05 mg kg'1 when the first twitch of the train-of-four was 10% of control. Total recovery time from PTC1 10% to a train-of-four ratio of 0.8 was not reduced by early administration of the anticholinesterases, compared with conventional administration of neostigmine at T1 10%. However, recovery from intense block was faster after neostigmine than edrophonium (P < 0.01). Doubling the doses of the anticholinesterases did not reduce the recovery time and had the effect of increasing variability. We conclude that there is no clinical advantage in attempting to antagonize intense neuromuscular block in children using normal or increased doses of neostigmine or edrophonium.
over, there have been no studies in children, in whom both spontaneous and induced recovery from neuromuscular block is known to be faster than in adults [1, 7]. In the present study we have attempted to antagonize a quantified level of intense atracurium-induced neuromuscular block in children using either edrophonium or neostigmine.
BRITISH JOURNAL OF ANAESTHESIA
14
TABLE I. Patient characteristics (mean (range)), n = 6 m each group
Group
Anticholinesterase
(yr)
Weight (kg)
A
Neostigmine 0.05 mg kg"1 Neostigmine 0.1 rag kg"1 Edrophonium 0.5 mg kg"1 Edrophonium 1.0 mg kg"1 Neostigmine 0.05 mg kg"1
6.2(3.9-9.6) 4.2(1.8-8.3) 4.3 (3.0-6.5) 3.8(1.4-8.3) 3.5(1.4-7 2)
22.4(15.5-29.5) 17.1(11.0-37.3) 17.9(11.8-28.9) 15.2(10.0-22.0) 15.3(10.8-25.5)
Age
B C D E
RESULTS
There were no significant differences between the five groups of children in age or weight (table I). After administration of neostigmine or edrophonium at PTC1 10% (groups A-D) the time taken to reach Tl 10% was shorter than when recovery was allowed to proceed spontaneously (group E) (P < 0.001) (table II). Recovery times from T l 10% to a TOF ratio of 0.8 were not significantly different with either dose of neostigmine or edrophonium. When data from these
pairs of groups were combined, the Tl 10% to TOF 0.8 interval was shorter in patients who received neostigmine (P < 0.01). However, the shortest Tl 10% to TOF 0.8 interval was observed when neostigmine was administered at T l 10% (P< 0.001). Data from groups who received neostigmine or edrophonium at PTC1 10% were combined also for analysis of total recovery time. The time was shorter after neostigrhine than after edrophonium (P < 0.01) (table II). However, there were no significant differences in the total recovery times between groups when anticholinesterases were administered at either PTC1 10% or Tl 10%. No patient in the present study required additional doses of atropine to treat bradycardia. DISCUSSION
The results of the present study demonstrate that pharmacological antagonism of neuromuscular block in children is achieved best when the first twitch of the TOF has recovered spontaneously to 10% of the control twitch height. When antagonism was attempted at PTC1 10 %, there was no clinically useful shortening of the recovery time with either neostigmine or edrophonium. It has been demonstrated in adults and children that, when there is a degree of spontaneous recovery from neuromuscular block (Tl > 10%), antagonism of residual block can be achieved safely and is significantly faster after edrophonium than after neostigmine [1, 2, 11, 12]. Studies in adults have shown that when the degree of block is more profound (Tl < 10% or TOF < 0.1), complete antagonism is slower with edrophonium than with neostigmine [6, 13, 14]. However, in those studies, the degree of block at which antagonism was attempted was not accurately quantified. In order to overcome this problem, Engboek and colleagues measured recovery times after administration of neostigmine at various post-tetanic counts in adults [15]. They found
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 20, 2015
Neuromuscular transmission was monitored initially by train-of-four (TOF) stimulation [8] and force of adduction of the thumb measured using a Grass FTO3 force displacement transducer. After a 10-min period during which the response was allowed to stabilize, atracurium 0.5 mg kg"1 was administered. When the response to TOF stimulation had been abolished, neuromuscular transmission was monitored using the post-tetanic count (PTC) every 2 min [9]. When the first response of the PTC reached 10% of the control twitch height (PTC1 10%), patients in groups A-D received the predetermined dose of anticholinesterase, preceded by atropine 20|igkg" 1 . The method of monitoring in all groups then reverted to a TOF sequence every 12 s. Patients in group E were given neostigmine 50 ug kg"1 when the first twitch of the TOF reached 10% of the control twitch height (Tl 10 %). All patients were monitored until the TOF ratio reached 0.8 [10]. The following were determined from the recordings: interval PTC1 10% to T l 10%; interval T l 10% to TOF ratio 0.8; total recovery time, PTC1 10% to TOF ratio 0.8. Differences between the groups were determined using the statistical package Minitab to fit a repeated measures analysis of variance (ANOVA) (Minitab Inc., 1989). A value of P < 0.05 was considered significant.
INTENSE NEUROMUSCULAR BLOCK
15
TABLE II. Mean (range) recovery intervals after administration of anticholinesterases. Significant differences: **P < 0.01 compared with edrophonium given at PTC1 10%; ***P < 0.001 compared with early antagonized groups
Group
Anticholinesterasc
Point of antagonism
A B C D E
Neostigmine 0.05 mg kg"1 Neostigmine 0.1 mg kg"1 Edrophonium 0.5 mg kg"1 Edrophonium 1.0 mg kg"1 Neostigmine 0.05 mg kg"1
PTC1 10% PTC1 10% PTC1 10% PTC1 10% Tl 10%
PTC1 10% to Tl 10% (min) 2.4(1.7-3.2) 1.6(1.4-2.1) 1.2(1.0-1.6) 1.3(0.9-1.8) 9.7(6.8-13.2)***
11.8(10.2-13.9)** 10.3(5.7-14.2)** 18.8(10.4-24.7) 15.2 (6.3-26.9) 4.8 (3.2-7.5)***
PTC1 10% to TOF 0.8 (min) 13.9(12.2-15.5)** 11.9(7.2-15.6)** 20.1(11.9-25.7) 16.5(7.4-28.1) 14.3(11.2-18.1)
atracurium-induced neuromuscular block in children [19]. The mean total recovery time of 13.9 min in children given neostigmine 50 ug kg"1 at PTC1 10% was much shorter than reported previously in adults (31 min) [15]. Increasing the dose of neostigmine had no significant effect on the total recovery time. However, patients who received the large doses of either neostigmine or edrophonium showed increased variability in total recovery time, consistent with previous findings in adults [15, 20]. In conclusion, the present study has demonstrated that there is no clinical advantage in attempting to antagonize intense neuromuscular block in children by administration of normal or increased doses of anticholinesterases. When compared with standard techniques of antagonism, the total recovery time was not reduced significantly and tended to become more unpredictable, particularly after edrophonium. ACKNOWLEDGEMENT The authors thank Miss Sally Hollis for advice with statistical analyses. REFERENCES 1. Meakin G, Sweet PT, Bevan JC, Bevan DR. Neostigmine and edrophonium as antagonists of pancuronium in infants and children. Anesthesiology 1983; 59: 316-321. 2. Ferguson A, Egerszegi P, Bevan DR. Neostigmine, pyridostigmine and edrophonium as antagonists of pancuronium. Anesthetiology 1980; S3: 390-394. 3. Norman J. Neuromuscular block. In: Aitkenhead AR, Smith G, eds. Textbook of Anaesthesia, 2nd Edn. Edinburgh: Churchill Livingstone, 1990; 211-224. 4. Katz RL. Neuromuscular effects of d-tubocurarine, edrophonium and neostigmine in man. Anesthesiology 1967; 28: 327-336. 5. Kopman AF. Edrophonium antagonism of pancuroniuminduced neuromuscular blockade in man. Anesthesiology 1979; 51: 139-142.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 20, 2015
that the more intense the block, the longer the time to a safe level of antagonism (TOF = 0.7). They concluded that early administration of anticholinesterase failed to antagonize neuromuscular block rapidly enough to be clinically useful. In the present study, the administration of neostigmine or edrophonium at PTC1 10% resulted in an initial rapid recovery to T l 10%. Consistent with findings of earlier studies, initial recovery tended to be slightly quicker with edrophonium. This may be related to the smaller molecular weight of edrophonium allowing more rapid diffusion to the site of action [13]. In addition, edrophonium may function presynaptically to increase the output of transmitter from the nerve terminals [16]. Another possible explanation is provided by the Law of Mass Action, which states that the rate of reaction between a drug and receptor is proportional to the molar concentration of the drug [17]. The application of this principle to anticholinesterases may explain the more rapid onset after edrophonium, compared with neostigmine, as a much greater molar concentration of the former is used. Although the initial antagonism of intense block (PTC1 10% to Tl 10%) was rapid after both neostigmine and edrophonium, this was not maintained. Moreover, subsequent recovery (Tl 10% to TOF 0.8) was significantly slower in patients who received edrophonium, possibly as a result of rapid depletion of acetylcholine stores by a presynaptic action of edrophonium [14]. Furthermore, the duration of action of edrophonium may be insufficient to sustain recovery when administered at profound levels of block [18]. This is supported by the fact that the recovery interval Tl 10% to TOF 0.8 in children who received edrophonium (15.2-18.8 min) is similar to the times reported by Brandom and colleagues of 13-17 min for spontaneous recovery from
Tl 10% to TOF 0.8 (min)
16
13. Harper NJN, Bradshaw EG, Healy TEJ. Antagonism of alcuronium with edrophonium or neostigmine. British Journal of Anaesthesia 1984; 56: 1089-1094. 14. Astley BA, Hughes R, Payne JP. Antagonism of atracurium-induced neuromuscular blockade by neostigmine or edrophonium. British Journal of Anaesthesia 1986; 58: 1290-1295. 15. Engboek J, Ostergaard D, Skovgaard LT, Viby-Mogensen J. Reversal of intense neuromuscular blockade following infusions of atracurium. Anesthesiology 1990; 72: 803-806. 16. Blaber LC. The mechanism of the facilitatory action of edrophonium in cat skeletal muscle. British Journal of Pharmacology 1972; 46: 498-507. 17. Foster RW, ed. Basic Pharmacology, 2nd Edn. London: Butterworths, 1986; 338-352. 18. Hennis PJ, Bovill JG, Kooistra M. Edrophonium is shorter acting than neostigmine when antagonizing vecuronium or atracurium. British Journal of Anaesthesia 1987; 59: 651P. 19. Brandom BW, Rudd GD, Cook DR. Clinical pharmacology of atracurium in paediatric patients. British Journal of Anaesthesia 1983; 55: 117S-121S. 20. Rupp SM, McChristian JW, Miller RD. Neostigmine antagonises a profound neuromuscular blockade more rapidly than edrophonium. Anesthesiology 1984; 61: A297.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 20, 2015
6. Caldwell JE, Robertson EN, Baird WLM. Antagonism of profound neuromuscular blockade induced by vecuronium or atracurium. British Journal of Anaesthesia 1986; 58: 1285-1289. 7. Meakin G, Shaw EA, Baker RD, Morris P. A comparison of atracurium induced neuromuscuJar blockade in neonates, infants and children. British Journal of Anaesthesia 1988; 60: 171-175. 8. Ah' HH, Utting JE, Gray C. Stimulus frequency in the detection of ncuromuscular block in humans. British Journal of Anaesthesia 1970; 42: 967-978. 9. Gwinnutt CL, Meakin G. Use of the post-tetanic count to monitor recovery from intense neuromuscular blockade in children. British Journal of Anaesthesia 1988; 61: 547-550. 10. Engboek J, Ostergaard D, Viby-Mogensen J, Skovgaard LT. Clinical recovery and train-of-four ratio measured mechanically and electromyographically following atracurium. Anesthesiology 1989; 71: 391-395. 11. Donati F, Ferguson A, Bevan DR. Twitch depression and train-of-four ratio after antagonism of pancuronium with cdrophonium, neostigmine or pyridostigmine. Anesthesia and Analgesia 1983; 62: 314-316. 12. Jones RM, Pearce AC, Williams JP. Recovery characteristics following antagonism of atracurium with neostigmine or edrophonium. British Journal of Anaesthesia 1984; 56: 453-456.
BRITISH JOURNAL OF ANAESTHESIA
ANTAGONISM OF INTENSE ATRACURIUM-INDUCED NEUROMUSCULAR BLOCK IN CHILDREN C. L. GWINNUTT, R. W. M. WALKER AND G. MEAKIN
SUMMARY
KEY WORDS Anaesthesia: paediatric. Antagonists: neuromuscular relaxants, edrophonium, neostigmine. Monitoring: neuromuscular function.
It has been shown that pharmacological antagonism of neuromuscular block in adults and children may be accomplished reliably when the first twitch of train-of-four stimulation reaches 10% of the control twitch height [1, 2]. Despite claims that more profound levels of block may be antagonized easily [3], attempts to achieve this have usually met with failure [4—6]. This may reflect the use of long-acting neuromuscular blockers, ignorance of the level of block or the use of an inadequate dose of anticholinesterase. More-
PATIENTS AND METHODS
The study was approved by the District Ethics Committee. Thirty children aged 1-10 yr were studied during elective surgical procedures for which non-depolarizing neuromuscular blocking agents would be used normally as part of the anaesthetic technique. All were ASA class I and none was receiving drugs known to interfere with neuromuscular transmission. Patients were allocated randomly to one of five groups (A-E), to receive a predetermined dose of either neostigmine or edrophonium (table I). Premedication with oral trimeprazine 3 mg kg"1 was given 2 h before surgery. Anaesthesia was induced with thiopentone 5 mg kg"1 and maintained throughout with 66% nitrous oxide and 1 % halothane in oxygen. Tracheal intubation was achieved without the aid of neuromuscular blocking drugs and ventilation of the lungs was controlled using the paediatric attachment of the Blease ventilator. Minute volume was adjusted to maintain the end-tidal carbon dioxide at 5.05.5 kPa. The ECG and systemic arterial pressure were monitored throughout the procedure and rectal temperature was kept at 36.5-37.5 °C.
C. L.
GWINNUTT,
M.B.,
B.s.,
F.C.ANAES.,
Department
of
Anaesthesia, Hope Hospital, Eccles Old Road, Salford M6 8HD.
R. W. M. WALKER, M.B., CH.B., F.C.ANAES. ; G. MEAXTO,
M.B., CH.B., F.C.ANAES.; Department of Anaesthesia, Royal Manchester Childrens Hospital, Pendlebury, Manchester M27 1HA. Accepted for Publication: January 5, 1991.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 20, 2015
Antagonism of intense neuromuscular block induced by atracurium 0.5 mg kg'1 was attempted in four groups of six children using one of two doses of neostigmine (0.05 mg kg'1 and 0.1 mg kg'1) or of edrophonium (0.5 mg kg'1 and 1.0mgkg~1) when the first twitch of the post-tetanic count (PTC1) was 10% of control. For comparison with normal practice, a fifth group received neostigmine 0.05 mg kg'1 when the first twitch of the train-of-four was 10% of control. Total recovery time from PTC1 10% to a train-of-four ratio of 0.8 was not reduced by early administration of the anticholinesterases, compared with conventional administration of neostigmine at T1 10%. However, recovery from intense block was faster after neostigmine than edrophonium (P < 0.01). Doubling the doses of the anticholinesterases did not reduce the recovery time and had the effect of increasing variability. We conclude that there is no clinical advantage in attempting to antagonize intense neuromuscular block in children using normal or increased doses of neostigmine or edrophonium.
over, there have been no studies in children, in whom both spontaneous and induced recovery from neuromuscular block is known to be faster than in adults [1, 7]. In the present study we have attempted to antagonize a quantified level of intense atracurium-induced neuromuscular block in children using either edrophonium or neostigmine.
BRITISH JOURNAL OF ANAESTHESIA
14
TABLE I. Patient characteristics (mean (range)), n = 6 m each group
Group
Anticholinesterase
(yr)
Weight (kg)
A
Neostigmine 0.05 mg kg"1 Neostigmine 0.1 rag kg"1 Edrophonium 0.5 mg kg"1 Edrophonium 1.0 mg kg"1 Neostigmine 0.05 mg kg"1
6.2(3.9-9.6) 4.2(1.8-8.3) 4.3 (3.0-6.5) 3.8(1.4-8.3) 3.5(1.4-7 2)
22.4(15.5-29.5) 17.1(11.0-37.3) 17.9(11.8-28.9) 15.2(10.0-22.0) 15.3(10.8-25.5)
Age
B C D E
RESULTS
There were no significant differences between the five groups of children in age or weight (table I). After administration of neostigmine or edrophonium at PTC1 10% (groups A-D) the time taken to reach Tl 10% was shorter than when recovery was allowed to proceed spontaneously (group E) (P < 0.001) (table II). Recovery times from T l 10% to a TOF ratio of 0.8 were not significantly different with either dose of neostigmine or edrophonium. When data from these
pairs of groups were combined, the Tl 10% to TOF 0.8 interval was shorter in patients who received neostigmine (P < 0.01). However, the shortest Tl 10% to TOF 0.8 interval was observed when neostigmine was administered at T l 10% (P< 0.001). Data from groups who received neostigmine or edrophonium at PTC1 10% were combined also for analysis of total recovery time. The time was shorter after neostigrhine than after edrophonium (P < 0.01) (table II). However, there were no significant differences in the total recovery times between groups when anticholinesterases were administered at either PTC1 10% or Tl 10%. No patient in the present study required additional doses of atropine to treat bradycardia. DISCUSSION
The results of the present study demonstrate that pharmacological antagonism of neuromuscular block in children is achieved best when the first twitch of the TOF has recovered spontaneously to 10% of the control twitch height. When antagonism was attempted at PTC1 10 %, there was no clinically useful shortening of the recovery time with either neostigmine or edrophonium. It has been demonstrated in adults and children that, when there is a degree of spontaneous recovery from neuromuscular block (Tl > 10%), antagonism of residual block can be achieved safely and is significantly faster after edrophonium than after neostigmine [1, 2, 11, 12]. Studies in adults have shown that when the degree of block is more profound (Tl < 10% or TOF < 0.1), complete antagonism is slower with edrophonium than with neostigmine [6, 13, 14]. However, in those studies, the degree of block at which antagonism was attempted was not accurately quantified. In order to overcome this problem, Engboek and colleagues measured recovery times after administration of neostigmine at various post-tetanic counts in adults [15]. They found
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 20, 2015
Neuromuscular transmission was monitored initially by train-of-four (TOF) stimulation [8] and force of adduction of the thumb measured using a Grass FTO3 force displacement transducer. After a 10-min period during which the response was allowed to stabilize, atracurium 0.5 mg kg"1 was administered. When the response to TOF stimulation had been abolished, neuromuscular transmission was monitored using the post-tetanic count (PTC) every 2 min [9]. When the first response of the PTC reached 10% of the control twitch height (PTC1 10%), patients in groups A-D received the predetermined dose of anticholinesterase, preceded by atropine 20|igkg" 1 . The method of monitoring in all groups then reverted to a TOF sequence every 12 s. Patients in group E were given neostigmine 50 ug kg"1 when the first twitch of the TOF reached 10% of the control twitch height (Tl 10 %). All patients were monitored until the TOF ratio reached 0.8 [10]. The following were determined from the recordings: interval PTC1 10% to T l 10%; interval T l 10% to TOF ratio 0.8; total recovery time, PTC1 10% to TOF ratio 0.8. Differences between the groups were determined using the statistical package Minitab to fit a repeated measures analysis of variance (ANOVA) (Minitab Inc., 1989). A value of P < 0.05 was considered significant.
INTENSE NEUROMUSCULAR BLOCK
15
TABLE II. Mean (range) recovery intervals after administration of anticholinesterases. Significant differences: **P < 0.01 compared with edrophonium given at PTC1 10%; ***P < 0.001 compared with early antagonized groups
Group
Anticholinesterasc
Point of antagonism
A B C D E
Neostigmine 0.05 mg kg"1 Neostigmine 0.1 mg kg"1 Edrophonium 0.5 mg kg"1 Edrophonium 1.0 mg kg"1 Neostigmine 0.05 mg kg"1
PTC1 10% PTC1 10% PTC1 10% PTC1 10% Tl 10%
PTC1 10% to Tl 10% (min) 2.4(1.7-3.2) 1.6(1.4-2.1) 1.2(1.0-1.6) 1.3(0.9-1.8) 9.7(6.8-13.2)***
11.8(10.2-13.9)** 10.3(5.7-14.2)** 18.8(10.4-24.7) 15.2 (6.3-26.9) 4.8 (3.2-7.5)***
PTC1 10% to TOF 0.8 (min) 13.9(12.2-15.5)** 11.9(7.2-15.6)** 20.1(11.9-25.7) 16.5(7.4-28.1) 14.3(11.2-18.1)
atracurium-induced neuromuscular block in children [19]. The mean total recovery time of 13.9 min in children given neostigmine 50 ug kg"1 at PTC1 10% was much shorter than reported previously in adults (31 min) [15]. Increasing the dose of neostigmine had no significant effect on the total recovery time. However, patients who received the large doses of either neostigmine or edrophonium showed increased variability in total recovery time, consistent with previous findings in adults [15, 20]. In conclusion, the present study has demonstrated that there is no clinical advantage in attempting to antagonize intense neuromuscular block in children by administration of normal or increased doses of anticholinesterases. When compared with standard techniques of antagonism, the total recovery time was not reduced significantly and tended to become more unpredictable, particularly after edrophonium. ACKNOWLEDGEMENT The authors thank Miss Sally Hollis for advice with statistical analyses. REFERENCES 1. Meakin G, Sweet PT, Bevan JC, Bevan DR. Neostigmine and edrophonium as antagonists of pancuronium in infants and children. Anesthesiology 1983; 59: 316-321. 2. Ferguson A, Egerszegi P, Bevan DR. Neostigmine, pyridostigmine and edrophonium as antagonists of pancuronium. Anesthetiology 1980; S3: 390-394. 3. Norman J. Neuromuscular block. In: Aitkenhead AR, Smith G, eds. Textbook of Anaesthesia, 2nd Edn. Edinburgh: Churchill Livingstone, 1990; 211-224. 4. Katz RL. Neuromuscular effects of d-tubocurarine, edrophonium and neostigmine in man. Anesthesiology 1967; 28: 327-336. 5. Kopman AF. Edrophonium antagonism of pancuroniuminduced neuromuscular blockade in man. Anesthesiology 1979; 51: 139-142.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 20, 2015
that the more intense the block, the longer the time to a safe level of antagonism (TOF = 0.7). They concluded that early administration of anticholinesterase failed to antagonize neuromuscular block rapidly enough to be clinically useful. In the present study, the administration of neostigmine or edrophonium at PTC1 10% resulted in an initial rapid recovery to T l 10%. Consistent with findings of earlier studies, initial recovery tended to be slightly quicker with edrophonium. This may be related to the smaller molecular weight of edrophonium allowing more rapid diffusion to the site of action [13]. In addition, edrophonium may function presynaptically to increase the output of transmitter from the nerve terminals [16]. Another possible explanation is provided by the Law of Mass Action, which states that the rate of reaction between a drug and receptor is proportional to the molar concentration of the drug [17]. The application of this principle to anticholinesterases may explain the more rapid onset after edrophonium, compared with neostigmine, as a much greater molar concentration of the former is used. Although the initial antagonism of intense block (PTC1 10% to Tl 10%) was rapid after both neostigmine and edrophonium, this was not maintained. Moreover, subsequent recovery (Tl 10% to TOF 0.8) was significantly slower in patients who received edrophonium, possibly as a result of rapid depletion of acetylcholine stores by a presynaptic action of edrophonium [14]. Furthermore, the duration of action of edrophonium may be insufficient to sustain recovery when administered at profound levels of block [18]. This is supported by the fact that the recovery interval Tl 10% to TOF 0.8 in children who received edrophonium (15.2-18.8 min) is similar to the times reported by Brandom and colleagues of 13-17 min for spontaneous recovery from
Tl 10% to TOF 0.8 (min)
16
13. Harper NJN, Bradshaw EG, Healy TEJ. Antagonism of alcuronium with edrophonium or neostigmine. British Journal of Anaesthesia 1984; 56: 1089-1094. 14. Astley BA, Hughes R, Payne JP. Antagonism of atracurium-induced neuromuscular blockade by neostigmine or edrophonium. British Journal of Anaesthesia 1986; 58: 1290-1295. 15. Engboek J, Ostergaard D, Skovgaard LT, Viby-Mogensen J. Reversal of intense neuromuscular blockade following infusions of atracurium. Anesthesiology 1990; 72: 803-806. 16. Blaber LC. The mechanism of the facilitatory action of edrophonium in cat skeletal muscle. British Journal of Pharmacology 1972; 46: 498-507. 17. Foster RW, ed. Basic Pharmacology, 2nd Edn. London: Butterworths, 1986; 338-352. 18. Hennis PJ, Bovill JG, Kooistra M. Edrophonium is shorter acting than neostigmine when antagonizing vecuronium or atracurium. British Journal of Anaesthesia 1987; 59: 651P. 19. Brandom BW, Rudd GD, Cook DR. Clinical pharmacology of atracurium in paediatric patients. British Journal of Anaesthesia 1983; 55: 117S-121S. 20. Rupp SM, McChristian JW, Miller RD. Neostigmine antagonises a profound neuromuscular blockade more rapidly than edrophonium. Anesthesiology 1984; 61: A297.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 20, 2015
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