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PROLONGED INFUSION OF SUXAMETHONIUM IN INFANTS AND CHILDREN
Br. J. Anaesth. (1986), 58, 839-843
PROLONGED INFUSION OF SUXAMETHONIUM IN INFANTS AND CHILDREN J. C. BE VAN, F. DONATI AND D. R. BEVAN
JOAN C. BEVAN,* M.D., F . F ^ . R . C J . ; FRANfois DoNATi.f M.D., PH.D., F.R.C.P.(C).; DAVID R. BEVAN.t M.B., M.R.C.P.,
F.F.A.R.C.S; Departments of Anaesthesia, 'Montreal Children's Hospital, fRoyal Victorial Hospital, and McGill University, Montreal, Quebec. Correspondence to: D.R.B., Royal Victoria! Hospital, 687 Pine Avenue West, Quebec, Montreal, Canada, H3A 1A1.
SUMMARY The neuromuscular blockade produced by a prolonged ( > 90 min) continuous infusion of suxamethonium and measured with train-of-four stimulation was studied in 20 infants and 20 children during nitrous oxide and halothane in oxygen anaesthesia. The results were compared with a previous study in adults. Suxamethonium requirement was increased in infants and children. Mean peak infusion rates were 297 and 284 fig kg~x min^1 in infants and children, compared with 134 fig kg'1 min'1 in adults. An initial tachyphylaxis was followed by bradyphylaxis, and the peak requirement occurred earlier in infants than in children and adults (40 v. 80-100 min). Phase II block developed during the tachyphylaxis. Recovery of neuromuscular activity commenced after stopping the infusion and was accelerated with neostigmine.
related to the patient's age (Cook and Fischer, 1978; Goudsouzian and Liu, 1984). Some infants demonstrated considerable resistance to suxamethonium which could not be explained by dilution from an increase in extracellular fluid volume (Cook and Fischer, 1975). In that study the duration of the suxamethonium infusion was limited to about 40 min, so that tachyphylaxis was not observed, neither were attempts made to antagonize the phase II block with anticholinesterases. The present study was designed to determine the pattern of neuromuscular blockade during the prolonged continuous infusion of suxamethonium in infants and children. In particular, the changing dose requirement was observed closely and attempts were made to antagonize the blockade at the end of anaesthesia.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 11, 2015
The pattern of neuromuscular blockade during the infusion of suxamethonium in adults is well established. To maintain constant blockade the requirement for suxamethonium increases ("tachyphylaxis") over the first 60-90 min (Lee, 1975; Ramsay et al., 1980; Carnie, 1982), and decreases thereafter (" bradyphylaxis") at least in the presence of the inhalation anaesthetic agents halothane (Futter, Donati and Bevan, 1983), enflurane (Donati and Bevan, 1982) and isoflurane (Donati and Bevan, 1983). During the stage of tachyphylaxis, the characteristics of the block change. The initial depolarizing block develops fade in response to tetanic or train-of-four stimulation (Lee, 1975). The appearance of this "phase II block" is dose- and time-related and is associated with prolonged spontaneous recovery (Futter, Donati and Bevan, 1983; Donati and Bevan, 1982, 1983). However, recovery can be accelerated by the administration of the anticholinesterases neostigmine (Futter et al., 1983) or edrophonium (Lee, 1976). The response in infants and children is less well denned. DeCook and Gpudsouzian (1980) demonstrated that children appear to develop tachyphylaxis and phase II block after doses similar to those in adults. Using mean doses of 10.3 mg kg"1 administered over 71 min, they demonstrated that phase II block was associated with slow, spontaneous recovery of neuromuscular activity. In infants and children, the requirement to maintain constant neuromuscular blockade was inversely
BRITISH JOURNAL OF ANAESTHESIA
840 PATIENTS AND METHODS
RESULTS
The demographic data, duration of infusion and total dose of suxamethonium are shown in table I. The durations of the suxamethonium infusions were shorter than in the previous study in adults (Futter et al., 1983), although the doses of suxamethonium were considerably greater. Also, the doses and durations exceeded previously reported studies in infants and children (Cook and Fischer, 1975; DeCook and Goudsouzian, 1980; Goudsouzian and Liu, 1984). However, the anaesthetic techniques, including the concentrations of halothane, were similar in the adult and paediatric studies. Infusion rates
The general patterns of infusion rates required to maintain constant neuromuscular blockade were similar in all age groups (fig.l): an initial increase was followed by a decrease in the requirement for suxamethonium. Peak infusion rates occurred earlier (P < 0.05) in infants (40 min) compared with children and adults (80 min). The peak requirements in infants and children were similar (297 ±35 v. 284 ±39 ng kg"1 min"1, although the earlier peak in infants showed that, for thefirst40 min of the infusion, the requirement for each 10-min interval was significantly greater for infants than children (P < 0.05). The requirement in adults was less than that in children at all times, and in infants during the first 90 min of infusion (P < 0.05). Train-of-four fade Initially, T4/T1 was close to unity; no fade was
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 11, 2015
The design of the investigation was approved by the Hospital Ethics Committee, and 40 paediatric patients undergoing elective surgical procedures lasting more than 1 h were studied. No patient with hepatitis, renal or neuromuscular disease, or any electrolyte abnormality, or who was receiving drugs known to interfere with neuromuscular transmission, was included. Patients were studied in two groups of 20, according to age. Group 1 consisted of "infants" aged less than 1 yr; group 2 consisted of children aged from 1 to 8 yr. Premedication for infants consisted of hyoscine 0.01 mg kg"1 i.m. and the children received pentobarbitone 3 mg kg"1 rectally 2 h before surgery, followed by morphine 0.1 mg kg"1 and hyoscine 0.01 mg kg"1 i.m. 1 h later. Anaesthesia was induced with thiopentone 3-5 mg kg"1, and was maintained with 70% nitrous oxide and 0.5-1 % inspired halothane in oxygen. Ventilation was controlled using the Bain system and fresh gas flow rates were set to achieve normocapnia according to the recommendations of Rose and Froese (1979). Oesophageal temperature was monitored and maintained between 35.5 and 37 °C. Neuromuscular transmission was monitored according to the method of Ali, Utting and Gray (1970). The ulnar nerve was stimulated supramaximally at the elbow or forearm using silver-silver chloride electrodes. Trains-of-four with square pulses of 0.2 ms duration at a frequency of 2 Hz and a train duration of 2 s, were repeated every 10 s using a Grass S48 stimulator and an SIU5 isolation unit. The hand and forearm were immobilized in a splint, and the force of adduction of the adductor pollicis was measured with a force displacement transducer (Grass FT 03) and recorded using a pen-and-ink recorder (Grass polygraph). After a stable base line had been established, an infusion of 0.4% suxamethonium was started using an IMED constant infusion pump, initially at a rate of 0.1-0.4 mg kg"1 min"1, to produce at least 90% depression of the first twitch of the train-of-four. At this point, the trachea was intubated if this had not been done already. The infusion rate was then adjusted to maintain the height of the first twitch (Tl) at 10-15% of its preinfusion value. With the approach of the end of the operation, the infusion was stopped and spontaneous recovery allowed to occur for 10 min. If the ratio of the fourth to thefirsttwitch (T4/T1)
of the train-of-four was then less than 0.7, neostigmine 0.036 mg kg"1 and atropine 1 0.02 mg kg" were given to assist further recovery. Infusion rates were calculated for every 10-min period after starting the infusion and the T4/T1 calculated at the end of each of these periods. Mean values are presented with the standard error of the mean as the index of dispersion. Where applicable, Student's t tests were used, the null hypothesis being rejected when P < 0.05. Multiple comparisons were made using one-way analysis of variance and Bonferroni's modification of the t test. Regressions were constructed by the least squares regression method. The results have been compared with data from a previous adult study using similar methodology (Futter et al., 1983).
SUXAMETHONIUM INFUSION IN INFANTS AND CHILDREN
841
TABLE I. Demographic data Patient data Wt (kg)
Age
SEM Range Adults (n = 20) Mean SEM Range
E
7.0 0.5 (3.3-11.6)
88.0 6.3 (40-130)
20.8 3.3 (8.9-69.3)
40.9 months 4.9 (16-84)
14.9 0.9 (10.2-23.0)
100.5 9.9 (40-180)
21.0 2.5 (6.1-44.1)
55.8 yr 4.1 (21-79)
68.5 2.9 (42.4-102)
131.0 9.6 (90-220)
13.3 1.0 (5.1-21.7)
o—_o Infants •
.Children
»
»Adulti
300
S
train-of-four fade to T4/T1 ratios of 0.25 and 0 occurred more rapidly in infants than children, and at lower cumulative doses in adults than in infants or children (P < 0.001). The mean doses producing T4/T1 of 0.5 for infants (3.2 ug kg"1) and children (3.5 ug kg"1) were less than those reported previously, 5.3 and 4.1 ug kg"1, respectively (Goudsouzian and Liu, 1984). Recovery
200-
S £
Dose (mg kg"1)
5.7 months 0.7 (0-11)
400-r
T
Infusion duration (min)
100-
a
0-10
I ' I ' I
20
40
60
80
I ' I ' I ' I
100
120
140
160
Time (min)
FIG 1. Infusion rates of suxamethonium required to maintain 85-90% depression of T l in infants, children and adults.
seen even in the infants. Gradually, the T4/T1 ratio decreased. The times and doses required to reach T4/T1 ratios of 0.5,0.25 and 0 are shown in table II. At constant T l depression of 85-90%, phase II block (T4/T1 < 0.5) developed at a lower cumulative dose in adults than in either paediatric group (P < 0.001) and the time required in infants was significantly less than in children (P < 0.01) or adults (P < 0.05). Despite considerable variability in the infant group, further development of
Ten minutes after stopping the infusion, recovery of Tl values in infants and children was similar to that in adults but recovery of T4/T1 was more rapid in the paediatric group (P < 0.05) (table III). Atropine and neostigmine were given to 17 infants, 18 children and 19 adults in whom T4/T1 was less than 0.7, 10 min after stopping the infusion. Recovery was accelerated in each patient and all had achieved a T l of 100% and a T4/T1 > 0.7 within 6 min. The infant who had received the largest dose of suxamethonium, 69 mg kg"1, recovered spontaneously to a T l of 27% and T4/T1 of 0.31 at 10 min and 2.5 min after neostigmine T l had reached 100% with T4/T1 of 0.83. DISCUSSION
These results demonstrate that the prolonged infusion of suxamethonium had qualitative effects in infants and children which were similar to those observed in adults. To maintain constant 80-90 % neuromuscular blockade, the requirement increased rapidly over thefirst40-80 min (tachyphylaxis),
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 11, 2015
Infants (n = 20) Mean SEM Range Children (n = 20) Mean
Suxamethonium
842
BRITISH JOURNAL OF ANAESTHESIA TABLE II. Development of phase II block—time and dost
Infants
T4/T1 = 0.5 Mean SEM n
mgkg-1
min
mgkg"1
min
mgkg '
13.9
3.2 0.6 20
23.2
3.5 0.2 20
32.0
2.1 0.2 20
SEM n
7.2 1.5 20
39.7 1.8 20
6.3 0.4 20
49.7
3.0 20
T4/T1 = 0 Mean SEM n
47.8
11.9
62.2
11.6
66.3
5.8 16
2.3 16
2.5 18
26.6
TABLE III. Recovery data, 10 min after stopping suxamethonium infusion
Infants (n = 20) Children (n-20) Adults (n = 20)
Tl
T4/T1
0.52 ±0.06
0.45 ±0.04
0.73 ±0.08
0.52 ±0.06
0.63 ±0.06
0.29 ±0.04
and was followed by a bradyphylaxis. The infusion rates were similar in infants and children but greater than in adults, and the peak requirement occurred earlier in infants. Phase II block developed during the tachyphylaxis so that it appeared earlier in infants. After stopping the infusion, recovery commenced quickly and the rate of recovery was accelerated with neostigmine. In some respects, these results are similar to those of DeCook and Goudsouzian (1980) and Goudsouzian and Liu (1984). They, also, demonstrated an increase in requirement in paediatric patients and suggested that the requirement for suxamethonium was inversely related to age. However, this conclusion was based upon brief (mean 43.4 min) infusions in infants. In the present study, the longer infusions revealed an earlier maximum requirement for suxamethonium in infants than in children. This peak was followed by a decrease in requirement which was overlooked by Goudsouzian and Liu (1984), so that they exaggerated the requirement for suxamethonium in the infants. In other respects—rapid recovery, development of tachyphylaxis and phase II block—the studies were similar.
1.4 20
1.2 18
3.6 20
3.9 19
5.3 19
3.6 0.2 19 5.3 0.3 19
Previous investigations showed that infants were more resistant than children or adults to a single i.v. dose of suxamethonium (Cook and Fischer, 1975, 1978) which was thought to be a result of dilution by the infants' larger extracellular fluid (ECF) volume. However, the pattern of neuromuscular block following i.m. injection of suxamethonium was found to be similar in infants and children (Sutherland, Bevan and Bevan, 1983; Liu et al., 1981). In the present study, peak infusion rates were similar in infants and children but 2 to 2.5 times greater than in adults. These differences cannot be explained by changes in ECF volume. The effect of changes in the volume of distribution may be modified by age-related alterations in cardiac output (Gregory, 1981), plasma cholinesterase concentration (Whittaker, 1980) and plasma clearance (Fisher et al., 1982; Matteo et al., 1984). The earlier appearance of tachyphylaxis in infants suggests that there may be differences in the neuromuscular junctions in such patients. In addition, phase II block occurred at a lower overall exposure to suxamethonium (dose x time) than in older children and adults and this may be analogous to the increased train-of-four fade observed in young infants by Goudsouzian, Crone and Todres (1981) and which they interpreted as evidence of neuromuscular immaturity. In conclusion, this study has demonstrated that continuous infusion of suxamethonium can be used to provide controllable muscle paralysis during paediatric anaesthesia. Requirements are greater than in adults and phase II block occurs more quickly. Nevertheless, recovery is rapid after stopping the infusion and can be accelerated with
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 11, 2015
min
1.9 20
T4/T1 = 0.25 Mean
Adults
Children
SUXAMETHONIUM INFUSION IN INFANTS AND CHILDREN neostigmine. However, the large doses required, the wide interpatient variation and the rapid changes in suxamethonium requirement suggest that neuromuscular function should be assessed continuously to control such administration.
mine antagonism of succinylcholine phase II block: a comparison with pancuronium. Can. Anaesth. Soc. J., 30, 575. Goudsouzian, N. G., Crone, R. K., and Todres, I. D. (1981). Recovery from pancuronium blockade in the neonatal intensive care unit. Br. J. Anaesth., 53, 1303. Liu, L. M. P. (1984). The neuromuscular response of infants to a continuous infusion of succinylcholine. Anesthesiology, 60, 97. Gregory, G. A (1981). Pediatric Anesthesia; in Anesthesia (ed. R. D. Miller), p. 1197. New York: Churchill Livingstone. Lee, C. (1975). Dose relationships of phase II, tachyphylaxis and train-of-four fade in suxamethonium induced dual neuromuscular block in man. Br. J. Anaesth., 47, 841. (1976). Train-of-four fade and edrophonhim antagonism of neuromuscular block by succinylcholine in man. Anesth. Analg., 55, 663. Liu, L. M. P., DeCook, T. H., Goudsouzian, N. G., Ryan, J. F., and Liu, P. L. (1981). Dose response to intramuscular succinylcholine in children. Anesthesiology, 55, 599. Matteo, R. S., Lieberman, I. G., Salanitre, E., McDaniel, D. D., and Diaz, J. (1984). Distribution, elimination, and action of d-tubocurarine in neonates, infants, children, and adults. Anesth. Analg., 63, 799. Ramsay, F. M., Lebowitz, P. W., Savarese, J. J., and Ali, H. H. (1980). Clinical characteristics of long-term succinylcholine neuromuscular blockade during balanced anesthesia. Anesth. Analg., 59, 110. Rose.D. K., and Froese, A. B. (1979). The regulation of Pico, during controlled ventilation of children with a T-piece. Can. Anaesth. Soc.J., 26, 104. Sutherland, G. A., Bevan, J. C , and Bevan, D. R. (1983). Neuromuscular blockade in infants following intramuscular succinylcholine in two or five per cent concentration. Can. Anaesth. Soc. J., 30, 342. Whittaker, M. (1980). Plasma cholinesterase variants and the anaesthetist. Anaesthesia, 35, 174.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 11, 2015
REFERENCES Ali, H. H., Utting, J. E., and Gray, C. (1970). Stimulus frequency in the detection of neuromuscular block in humans, Br. J. Anaesth., 42, 967. Carnie, J. (1982). Continuous suxamethonium infusion for microlaryngeal surgery. Br.J. Anaesth., 54, 11. Cook, D. R., and Fischer, C. G. (1975). Neuromuscular blocking effects of succinlycholine in infants and children. Anesthesiology, 42, 662. (1978). Characteristics of succinylcholine neuromuscular blockade in neonates. Anath. Analg., 57, 63. DeCook.T. H.,andGoudsouzian,N. G.(1980).Tachyphylaxis and phase II block development during infusion of succinylcholine in children. Anath. Analg., 59, 639. Donati, F., and Bevan, D. R. (1982). Effect of enflurane and fentanyl on the clinical characteristics of long-term succinylcholine infusion. Can. Anaesth. Soc. J., 29, 59. (1983). Potentiation of succinylcholine phase II block with isoflurane. Anesthesiology, 58, 552. Fisher, D. M., O'Keeffe, C , Stanski, D. R., Cronnelly, R., Miller, R. D., and Gregory, G. A. (1982). Phannacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology, 57, 203. Futter, M. E., Donati, F., and Bevan, D. R. (1983). Prolonged suxamethonium infusion during nitrous oxide anaesthesia supplemented with halothane or fentanyl. Br. J. Anaesth., 55, 947. Sadikot, A. S., and Bevan, D. R. (1983). Neostig-
843
PROLONGED INFUSION OF SUXAMETHONIUM IN INFANTS AND CHILDREN J. C. BE VAN, F. DONATI AND D. R. BEVAN
JOAN C. BEVAN,* M.D., F . F ^ . R . C J . ; FRANfois DoNATi.f M.D., PH.D., F.R.C.P.(C).; DAVID R. BEVAN.t M.B., M.R.C.P.,
F.F.A.R.C.S; Departments of Anaesthesia, 'Montreal Children's Hospital, fRoyal Victorial Hospital, and McGill University, Montreal, Quebec. Correspondence to: D.R.B., Royal Victoria! Hospital, 687 Pine Avenue West, Quebec, Montreal, Canada, H3A 1A1.
SUMMARY The neuromuscular blockade produced by a prolonged ( > 90 min) continuous infusion of suxamethonium and measured with train-of-four stimulation was studied in 20 infants and 20 children during nitrous oxide and halothane in oxygen anaesthesia. The results were compared with a previous study in adults. Suxamethonium requirement was increased in infants and children. Mean peak infusion rates were 297 and 284 fig kg~x min^1 in infants and children, compared with 134 fig kg'1 min'1 in adults. An initial tachyphylaxis was followed by bradyphylaxis, and the peak requirement occurred earlier in infants than in children and adults (40 v. 80-100 min). Phase II block developed during the tachyphylaxis. Recovery of neuromuscular activity commenced after stopping the infusion and was accelerated with neostigmine.
related to the patient's age (Cook and Fischer, 1978; Goudsouzian and Liu, 1984). Some infants demonstrated considerable resistance to suxamethonium which could not be explained by dilution from an increase in extracellular fluid volume (Cook and Fischer, 1975). In that study the duration of the suxamethonium infusion was limited to about 40 min, so that tachyphylaxis was not observed, neither were attempts made to antagonize the phase II block with anticholinesterases. The present study was designed to determine the pattern of neuromuscular blockade during the prolonged continuous infusion of suxamethonium in infants and children. In particular, the changing dose requirement was observed closely and attempts were made to antagonize the blockade at the end of anaesthesia.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 11, 2015
The pattern of neuromuscular blockade during the infusion of suxamethonium in adults is well established. To maintain constant blockade the requirement for suxamethonium increases ("tachyphylaxis") over the first 60-90 min (Lee, 1975; Ramsay et al., 1980; Carnie, 1982), and decreases thereafter (" bradyphylaxis") at least in the presence of the inhalation anaesthetic agents halothane (Futter, Donati and Bevan, 1983), enflurane (Donati and Bevan, 1982) and isoflurane (Donati and Bevan, 1983). During the stage of tachyphylaxis, the characteristics of the block change. The initial depolarizing block develops fade in response to tetanic or train-of-four stimulation (Lee, 1975). The appearance of this "phase II block" is dose- and time-related and is associated with prolonged spontaneous recovery (Futter, Donati and Bevan, 1983; Donati and Bevan, 1982, 1983). However, recovery can be accelerated by the administration of the anticholinesterases neostigmine (Futter et al., 1983) or edrophonium (Lee, 1976). The response in infants and children is less well denned. DeCook and Gpudsouzian (1980) demonstrated that children appear to develop tachyphylaxis and phase II block after doses similar to those in adults. Using mean doses of 10.3 mg kg"1 administered over 71 min, they demonstrated that phase II block was associated with slow, spontaneous recovery of neuromuscular activity. In infants and children, the requirement to maintain constant neuromuscular blockade was inversely
BRITISH JOURNAL OF ANAESTHESIA
840 PATIENTS AND METHODS
RESULTS
The demographic data, duration of infusion and total dose of suxamethonium are shown in table I. The durations of the suxamethonium infusions were shorter than in the previous study in adults (Futter et al., 1983), although the doses of suxamethonium were considerably greater. Also, the doses and durations exceeded previously reported studies in infants and children (Cook and Fischer, 1975; DeCook and Goudsouzian, 1980; Goudsouzian and Liu, 1984). However, the anaesthetic techniques, including the concentrations of halothane, were similar in the adult and paediatric studies. Infusion rates
The general patterns of infusion rates required to maintain constant neuromuscular blockade were similar in all age groups (fig.l): an initial increase was followed by a decrease in the requirement for suxamethonium. Peak infusion rates occurred earlier (P < 0.05) in infants (40 min) compared with children and adults (80 min). The peak requirements in infants and children were similar (297 ±35 v. 284 ±39 ng kg"1 min"1, although the earlier peak in infants showed that, for thefirst40 min of the infusion, the requirement for each 10-min interval was significantly greater for infants than children (P < 0.05). The requirement in adults was less than that in children at all times, and in infants during the first 90 min of infusion (P < 0.05). Train-of-four fade Initially, T4/T1 was close to unity; no fade was
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 11, 2015
The design of the investigation was approved by the Hospital Ethics Committee, and 40 paediatric patients undergoing elective surgical procedures lasting more than 1 h were studied. No patient with hepatitis, renal or neuromuscular disease, or any electrolyte abnormality, or who was receiving drugs known to interfere with neuromuscular transmission, was included. Patients were studied in two groups of 20, according to age. Group 1 consisted of "infants" aged less than 1 yr; group 2 consisted of children aged from 1 to 8 yr. Premedication for infants consisted of hyoscine 0.01 mg kg"1 i.m. and the children received pentobarbitone 3 mg kg"1 rectally 2 h before surgery, followed by morphine 0.1 mg kg"1 and hyoscine 0.01 mg kg"1 i.m. 1 h later. Anaesthesia was induced with thiopentone 3-5 mg kg"1, and was maintained with 70% nitrous oxide and 0.5-1 % inspired halothane in oxygen. Ventilation was controlled using the Bain system and fresh gas flow rates were set to achieve normocapnia according to the recommendations of Rose and Froese (1979). Oesophageal temperature was monitored and maintained between 35.5 and 37 °C. Neuromuscular transmission was monitored according to the method of Ali, Utting and Gray (1970). The ulnar nerve was stimulated supramaximally at the elbow or forearm using silver-silver chloride electrodes. Trains-of-four with square pulses of 0.2 ms duration at a frequency of 2 Hz and a train duration of 2 s, were repeated every 10 s using a Grass S48 stimulator and an SIU5 isolation unit. The hand and forearm were immobilized in a splint, and the force of adduction of the adductor pollicis was measured with a force displacement transducer (Grass FT 03) and recorded using a pen-and-ink recorder (Grass polygraph). After a stable base line had been established, an infusion of 0.4% suxamethonium was started using an IMED constant infusion pump, initially at a rate of 0.1-0.4 mg kg"1 min"1, to produce at least 90% depression of the first twitch of the train-of-four. At this point, the trachea was intubated if this had not been done already. The infusion rate was then adjusted to maintain the height of the first twitch (Tl) at 10-15% of its preinfusion value. With the approach of the end of the operation, the infusion was stopped and spontaneous recovery allowed to occur for 10 min. If the ratio of the fourth to thefirsttwitch (T4/T1)
of the train-of-four was then less than 0.7, neostigmine 0.036 mg kg"1 and atropine 1 0.02 mg kg" were given to assist further recovery. Infusion rates were calculated for every 10-min period after starting the infusion and the T4/T1 calculated at the end of each of these periods. Mean values are presented with the standard error of the mean as the index of dispersion. Where applicable, Student's t tests were used, the null hypothesis being rejected when P < 0.05. Multiple comparisons were made using one-way analysis of variance and Bonferroni's modification of the t test. Regressions were constructed by the least squares regression method. The results have been compared with data from a previous adult study using similar methodology (Futter et al., 1983).
SUXAMETHONIUM INFUSION IN INFANTS AND CHILDREN
841
TABLE I. Demographic data Patient data Wt (kg)
Age
SEM Range Adults (n = 20) Mean SEM Range
E
7.0 0.5 (3.3-11.6)
88.0 6.3 (40-130)
20.8 3.3 (8.9-69.3)
40.9 months 4.9 (16-84)
14.9 0.9 (10.2-23.0)
100.5 9.9 (40-180)
21.0 2.5 (6.1-44.1)
55.8 yr 4.1 (21-79)
68.5 2.9 (42.4-102)
131.0 9.6 (90-220)
13.3 1.0 (5.1-21.7)
o—_o Infants •
.Children
»
»Adulti
300
S
train-of-four fade to T4/T1 ratios of 0.25 and 0 occurred more rapidly in infants than children, and at lower cumulative doses in adults than in infants or children (P < 0.001). The mean doses producing T4/T1 of 0.5 for infants (3.2 ug kg"1) and children (3.5 ug kg"1) were less than those reported previously, 5.3 and 4.1 ug kg"1, respectively (Goudsouzian and Liu, 1984). Recovery
200-
S £
Dose (mg kg"1)
5.7 months 0.7 (0-11)
400-r
T
Infusion duration (min)
100-
a
0-10
I ' I ' I
20
40
60
80
I ' I ' I ' I
100
120
140
160
Time (min)
FIG 1. Infusion rates of suxamethonium required to maintain 85-90% depression of T l in infants, children and adults.
seen even in the infants. Gradually, the T4/T1 ratio decreased. The times and doses required to reach T4/T1 ratios of 0.5,0.25 and 0 are shown in table II. At constant T l depression of 85-90%, phase II block (T4/T1 < 0.5) developed at a lower cumulative dose in adults than in either paediatric group (P < 0.001) and the time required in infants was significantly less than in children (P < 0.01) or adults (P < 0.05). Despite considerable variability in the infant group, further development of
Ten minutes after stopping the infusion, recovery of Tl values in infants and children was similar to that in adults but recovery of T4/T1 was more rapid in the paediatric group (P < 0.05) (table III). Atropine and neostigmine were given to 17 infants, 18 children and 19 adults in whom T4/T1 was less than 0.7, 10 min after stopping the infusion. Recovery was accelerated in each patient and all had achieved a T l of 100% and a T4/T1 > 0.7 within 6 min. The infant who had received the largest dose of suxamethonium, 69 mg kg"1, recovered spontaneously to a T l of 27% and T4/T1 of 0.31 at 10 min and 2.5 min after neostigmine T l had reached 100% with T4/T1 of 0.83. DISCUSSION
These results demonstrate that the prolonged infusion of suxamethonium had qualitative effects in infants and children which were similar to those observed in adults. To maintain constant 80-90 % neuromuscular blockade, the requirement increased rapidly over thefirst40-80 min (tachyphylaxis),
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 11, 2015
Infants (n = 20) Mean SEM Range Children (n = 20) Mean
Suxamethonium
842
BRITISH JOURNAL OF ANAESTHESIA TABLE II. Development of phase II block—time and dost
Infants
T4/T1 = 0.5 Mean SEM n
mgkg-1
min
mgkg"1
min
mgkg '
13.9
3.2 0.6 20
23.2
3.5 0.2 20
32.0
2.1 0.2 20
SEM n
7.2 1.5 20
39.7 1.8 20
6.3 0.4 20
49.7
3.0 20
T4/T1 = 0 Mean SEM n
47.8
11.9
62.2
11.6
66.3
5.8 16
2.3 16
2.5 18
26.6
TABLE III. Recovery data, 10 min after stopping suxamethonium infusion
Infants (n = 20) Children (n-20) Adults (n = 20)
Tl
T4/T1
0.52 ±0.06
0.45 ±0.04
0.73 ±0.08
0.52 ±0.06
0.63 ±0.06
0.29 ±0.04
and was followed by a bradyphylaxis. The infusion rates were similar in infants and children but greater than in adults, and the peak requirement occurred earlier in infants. Phase II block developed during the tachyphylaxis so that it appeared earlier in infants. After stopping the infusion, recovery commenced quickly and the rate of recovery was accelerated with neostigmine. In some respects, these results are similar to those of DeCook and Goudsouzian (1980) and Goudsouzian and Liu (1984). They, also, demonstrated an increase in requirement in paediatric patients and suggested that the requirement for suxamethonium was inversely related to age. However, this conclusion was based upon brief (mean 43.4 min) infusions in infants. In the present study, the longer infusions revealed an earlier maximum requirement for suxamethonium in infants than in children. This peak was followed by a decrease in requirement which was overlooked by Goudsouzian and Liu (1984), so that they exaggerated the requirement for suxamethonium in the infants. In other respects—rapid recovery, development of tachyphylaxis and phase II block—the studies were similar.
1.4 20
1.2 18
3.6 20
3.9 19
5.3 19
3.6 0.2 19 5.3 0.3 19
Previous investigations showed that infants were more resistant than children or adults to a single i.v. dose of suxamethonium (Cook and Fischer, 1975, 1978) which was thought to be a result of dilution by the infants' larger extracellular fluid (ECF) volume. However, the pattern of neuromuscular block following i.m. injection of suxamethonium was found to be similar in infants and children (Sutherland, Bevan and Bevan, 1983; Liu et al., 1981). In the present study, peak infusion rates were similar in infants and children but 2 to 2.5 times greater than in adults. These differences cannot be explained by changes in ECF volume. The effect of changes in the volume of distribution may be modified by age-related alterations in cardiac output (Gregory, 1981), plasma cholinesterase concentration (Whittaker, 1980) and plasma clearance (Fisher et al., 1982; Matteo et al., 1984). The earlier appearance of tachyphylaxis in infants suggests that there may be differences in the neuromuscular junctions in such patients. In addition, phase II block occurred at a lower overall exposure to suxamethonium (dose x time) than in older children and adults and this may be analogous to the increased train-of-four fade observed in young infants by Goudsouzian, Crone and Todres (1981) and which they interpreted as evidence of neuromuscular immaturity. In conclusion, this study has demonstrated that continuous infusion of suxamethonium can be used to provide controllable muscle paralysis during paediatric anaesthesia. Requirements are greater than in adults and phase II block occurs more quickly. Nevertheless, recovery is rapid after stopping the infusion and can be accelerated with
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min
1.9 20
T4/T1 = 0.25 Mean
Adults
Children
SUXAMETHONIUM INFUSION IN INFANTS AND CHILDREN neostigmine. However, the large doses required, the wide interpatient variation and the rapid changes in suxamethonium requirement suggest that neuromuscular function should be assessed continuously to control such administration.
mine antagonism of succinylcholine phase II block: a comparison with pancuronium. Can. Anaesth. Soc. J., 30, 575. Goudsouzian, N. G., Crone, R. K., and Todres, I. D. (1981). Recovery from pancuronium blockade in the neonatal intensive care unit. Br. J. Anaesth., 53, 1303. Liu, L. M. P. (1984). The neuromuscular response of infants to a continuous infusion of succinylcholine. Anesthesiology, 60, 97. Gregory, G. A (1981). Pediatric Anesthesia; in Anesthesia (ed. R. D. Miller), p. 1197. New York: Churchill Livingstone. Lee, C. (1975). Dose relationships of phase II, tachyphylaxis and train-of-four fade in suxamethonium induced dual neuromuscular block in man. Br. J. Anaesth., 47, 841. (1976). Train-of-four fade and edrophonhim antagonism of neuromuscular block by succinylcholine in man. Anesth. Analg., 55, 663. Liu, L. M. P., DeCook, T. H., Goudsouzian, N. G., Ryan, J. F., and Liu, P. L. (1981). Dose response to intramuscular succinylcholine in children. Anesthesiology, 55, 599. Matteo, R. S., Lieberman, I. G., Salanitre, E., McDaniel, D. D., and Diaz, J. (1984). Distribution, elimination, and action of d-tubocurarine in neonates, infants, children, and adults. Anesth. Analg., 63, 799. Ramsay, F. M., Lebowitz, P. W., Savarese, J. J., and Ali, H. H. (1980). Clinical characteristics of long-term succinylcholine neuromuscular blockade during balanced anesthesia. Anesth. Analg., 59, 110. Rose.D. K., and Froese, A. B. (1979). The regulation of Pico, during controlled ventilation of children with a T-piece. Can. Anaesth. Soc.J., 26, 104. Sutherland, G. A., Bevan, J. C , and Bevan, D. R. (1983). Neuromuscular blockade in infants following intramuscular succinylcholine in two or five per cent concentration. Can. Anaesth. Soc. J., 30, 342. Whittaker, M. (1980). Plasma cholinesterase variants and the anaesthetist. Anaesthesia, 35, 174.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 11, 2015
REFERENCES Ali, H. H., Utting, J. E., and Gray, C. (1970). Stimulus frequency in the detection of neuromuscular block in humans, Br. J. Anaesth., 42, 967. Carnie, J. (1982). Continuous suxamethonium infusion for microlaryngeal surgery. Br.J. Anaesth., 54, 11. Cook, D. R., and Fischer, C. G. (1975). Neuromuscular blocking effects of succinlycholine in infants and children. Anesthesiology, 42, 662. (1978). Characteristics of succinylcholine neuromuscular blockade in neonates. Anath. Analg., 57, 63. DeCook.T. H.,andGoudsouzian,N. G.(1980).Tachyphylaxis and phase II block development during infusion of succinylcholine in children. Anath. Analg., 59, 639. Donati, F., and Bevan, D. R. (1982). Effect of enflurane and fentanyl on the clinical characteristics of long-term succinylcholine infusion. Can. Anaesth. Soc. J., 29, 59. (1983). Potentiation of succinylcholine phase II block with isoflurane. Anesthesiology, 58, 552. Fisher, D. M., O'Keeffe, C , Stanski, D. R., Cronnelly, R., Miller, R. D., and Gregory, G. A. (1982). Phannacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology, 57, 203. Futter, M. E., Donati, F., and Bevan, D. R. (1983). Prolonged suxamethonium infusion during nitrous oxide anaesthesia supplemented with halothane or fentanyl. Br. J. Anaesth., 55, 947. Sadikot, A. S., and Bevan, D. R. (1983). Neostig-
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