Vecuroniurn Infusion Requirements in Children During Halothane-Narcotic-Nitrous Oxide, Isoflurane-NarcoticNitrous Oxide, and Narcotic-Nitrous Oxide Anesthesia Susan K. Woelfel, MD, Mai-Li Dong, and D. Ryan Cook, MD
MD,
Barbara W. Brandom,
MD,
Joel B. Sarner,
MD,
Departments of Anesthesiology and Critical Care Medicine, Children's Hospital of Pittsburgh and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
We were interested in determining the infusion rate of vecuronium required to maintain approximately 95% neuromuscular blockade in children during halothane-narcotic-nitrous oxide (0.8% end-tidal concentration), isoflurane-narcotic-nitrous oxide (1.0% end-tidal concentration), or narcotic-nitrous oxide anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity (Datex NMT) of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s at 10-s intervals. Effective vecuronium infusion requirements averaged 1.5 ? 0.1 pg.kg-'-min-' (mean ? SEM) during isoflurane-narcotic-nitrous oxide anesthesia, 1.9 ? 0.1 pg.kg-'.min-' during
B
ecause of its intermediate duration of action and noncumulative effects, vecuronium should be useful as a continuous infusion. Indeed, vecuronium has been administered as an infusion to children (1) and to adults (2-5) during narcoticnitrous oxide anesthesia. Vecuronium infusion requirements (IRs) during narcotic-nitrous oxide anesthesia differ with age. It is likely, therefore, that the vecuronium IRs of children differ from those of adults during potent inhalation anesthesia as well. There are no published reports of vecuronium IR in children during anesthesia with halothane or isoflurane. It is to be expected that these potent inhalation anesthetics would increase the neuromuscular blocking effect of vecuronium and hence decrease IR (2,3). Therefore, we were interested in determining the infusion rate of vecuronium required to maintain a clinically effective state of neuromuscular blockade in children
Accepted for publication February 5, 1991. Address correspondence to Dr. Woelfel, Department of Anesthesiology, Children's Hospital of Pittsburgh, 3705 Fifth Avenue at DeSoto Street, Pittsburgh, PA 15213-2583. 01991 by the International Anesthesia Research Society 0003-2999/91/$3.50
halothane-narcotic-nitrous oxide anesthesia, and 2.4 ? 0.3 pgkg-l-min-' during narcotic-nitrous oxide anesthesia. Infusion requirements significantly decreased after the first 30 min of infusion in the presence of both potent inhalation anesthetics, but did not change with time during narcotic-nitrous oxide anesthesia. There was no evidence of decreasing infusion requirements during prolonged vecuronium infusion (2.5 h). There was no difference in the rate of spontaneous or pharmacologically induced recovery between anesthetic groups. The mean recovery index (T,,) after termination of the infusion was 13.7 min. (Anesth Analg 1991;73:33-8)
during narcotic-nitrous oxide anesthesia in the presence of halothane or isoflurane.
Methods The study was approved by the Human Rights Committee of the Children's Hospital of Pittsburgh. Informed consent was obtained from a parent. Thirtynine children (ASA status I and 11) aged 2-10 yr were studied. All were undergoing low-to-moderate risk elective surgical procedures that required endotracheal intubation. No patient received aminoglycoside antibiotics, or antihistamines within 48 h of the study. Most patients received no premedication; three were given 0.1-0.2 mg/kg of diazepam orally or midazolam intramuscularly. The children were randomly assigned to one of three study groups: 15 patients received halothane-nitrous oxide, oxygen, and fentanyl (group H); 14 patients received isoflurane-nitrous oxide, oxygen, and fentanyl (group I); and 10 patients received nitrous oxide, oxygen, and fentanyl (group N). In all patients, anesthesia was induced with nitrous oxide, oxygen, and a potent inhalation anes33
34
PEDIATRIC ANESTHESIA WOELFEL ET AL. VECURONIUM INFUSION IN CHILDREN
ANESTH ANALG 1991;73.3=
Table 1. Demographic Data ~~
Group H ( n = 15) Group I (n = 14) Group N ( n = 10)
~~
Height (cm)
Weight (kg)
69.5 9.2 (26.8-130.7)
116.1 f 4.6 (90.0-140.0)
0.84 2 0.06 (0.5-1.2)
54.4 2 5.9 (22.6-101.4)
106.9 ? 3.4 (91.0-133.0)
21.8 2.3 (11.5-37.0) 18.2 2 1.2 (13.630.0)
55.6 _t 9.7 (22.5-113.8)
100.5 k 4.6 (88.0-124.0)
17.5 2 1.8 (12.629.0)
0.70 f 0.05 (0.6-1 .O)
Age (mo)
*
*
BSA (m')
0.76 f 0.04 (0.6-1.1)
BSA, body surface area. Values are expressed as mean & SEM, with the range given in parentheses. There were no statistically significant differences between anesthetic groups.
thetic. A venous catheter was inserted, and atropine (10 pglkg) was given intravenously to all patients before tracheal intubation. The inspired and end-tidal concentrations of halothane and isoflurane were monitored continuously with a Puritan Bennett infrared gas analyzer. In groups H and I, respectively, anesthesia was maintained with 70% nitrous oxide in oxygen and halothane (0.8% end-tidal concentration) or isoflurane (1.O% end-tidal concentration). Patients in groups H and I received 1-6 pg/kg of fentanyl as clinically indicated. In group N, thiopental (4-8 mg/ kg) and midazolam (0.1 mg/kg) were administered intravenously, and the potent agent was discontinued. Anesthesia was maintained in group N with fentanyl (2.7-11.3 pglkg) and 70% nitrous oxide in oxygen. Normal minute ventilation and body temperature (rectal or skin) were maintained intraoperatively in all patients. After induction of general anesthesia, the ulnar nerve was stimulated supramaximally at the wrist with repetitive trains-of-four (2 Hz for 2 s at 10-s intervals) through surface electrodes. The evoked compound electromyogram (EMG) of thumb adduction was recorded by a Datex neuromuscular transmission monitor. End-tidal concentrations of anesthetic were allowed to stabilize for 10-15 min, and a stable baseline EMG was obtained for at least 3 min before the administration of vecuronium. In group N the endtidal halothane or isoflurane concentration was 0% for 5-10 min before administration of vecuronium. An intravenous bolus of 60 pg/kg of vecuronium was injected. The maximum neuromuscular blocking effect was recorded, and the trachea was intubated. When the first response (T,) of the EMG signal returned to 5% of baseline (T5), an infusion of vecuronium in lactated Ringer's solution (200 pg/mL) was administered at 1.5-2 pg-kg-lmin-' with an infusion pump. The infusion was titrated to produce 89%-99% neuromuscular blockade for as long as required by the surgical procedure (range, 36-149 min). For each patient the infusion rate of vecuronium required to achieve 89%-99% blockade was calculated and re-
corded at 3-min intervals. Data from 3-min periods during which neuromuscular blockade was outside the 89%-99% range were not included in the analyses. For each patient the mean effective IR was calculated for three periods: the first 30 min of infusion, the duration of infusion excluding the first 30 min, and the total duration of infusion. The time from termination of the infusion to 5% (T5), 10%(Tlo),25% (T25), 50% (T50), and 75% (T75)of baseline and the time until T,, 2 75% were noted. Recovery was referenced to the final EMG baseline (T, when T4 = TI). End-tidal inhalation anesthetic concentration was maintained constant until T, = T,. Twenty-five patients received 1 mgkg edrophonium when T, was greater than T50, and recovery was then monitored untiI recovery of neuromuscular function was complete. Vecuronium IR was calculated on the basis of both weight (pg.kg-'.min-') and body surface area (BSA) (pgrn-'.min-'). Standard errors are shown for all mean values. Analysis of variance and Tukey's test were used to assess the differences between groups. Paired t-tests were used to compare the IR before and after the first 30 min and the total IR. Differences were considered significant at P < 0.05.
Results There was no statistical difference in age, height, weight, or BSA among the three groups of patients studied (Table 1). There was no significant difference between anesthetic groups in time to onset of compIete block after the initial bolus dose, or in T, after bolus ad ministration of vecuronium (Table 2). The total IR for group H was 1.9 t 0.1 pg.kg-'.min-' (47.5 2 3.4 pgm-'. min-'), for group I 1.5 & 0.1 pg.kg-'min-' (36.9 ? 2.4 pgm-'-min-'), and for group N 2.4 t 0.3 pgkg-l. min-' (61.1 ? 7.5 p g m -'amin-'). There was no significant difference between these values for groups H and I; however, the total IR was significantly greater for group N (Table 3). A significant decrease in IR was
ANESTH ANALG
PEDIATRIC ANESTHESIA WOELFEL ET AL. VECURONIUM INFUSION IN CHILDREN
1991;7333-8
Table 2. Onset and Initial Recovery Times From Bolus Time to 5% neuromuscular transmission (T5)(min)
Onset time to 100% block (min) Group H
Group I
Group N
*
9.9 k 1.3 (4.8-17.0) ( n = 10) 11.5 1.1 (8.4-15.5) ( n = 6) 9.5 f 1.0 (8.0-14.3) (n = 6)
2.7 0.3 (1.& 3) I. (n = 10) 2.2 2 0.2 (15 2 . 8 ) (n = 7)
*
2.4 ? 0.3 (1.5-3.3) ( n = 6)
*
Values are expressed as mean SEM, with range given in the first set of parentheses and the number given in the second set. There were no statistically significant differences between groups.
observed after the first 30 min of infusion in groups H and I but not in group N (Figure 1) (Table 3). The average duration of infusion administration in minutes was 86 t 5 for group H, 98 7 for group I, and 85 t 12 for group N. The percentage of time that neuromuscular blockade was not maintained within the desired 89%-99% depression of function during the first 30 min of infusion administration averaged 22% t 5% in group H, 26% +- 5% in group I, and 26% t 8% in group N. In the first 30 min of administration of vecuronium nine patients had a period of 100% neuromuscular blockade. All other patients who did not have neuromuscular blockade in the desired range had less than 89% neuromuscular blockade. The percentage of time that neuromuscular blockade was outside the desired range after the first 30 rnin of infusion administration averaged 4% t 1% in group H, 6% t 3% in group I, and 4% t 3% in group N. The coefficient of variation of the IR (standard deviation divided by mean) was similar for the potent inhalation agents (20%-25%)and greater in group N (40%). After termination of the infusion, the time required for spontaneous recovery of neuromuscular transmission to T25 (n = 34) and the rate of recovery tended to be less in group N than in groups H and I, but the difference was not statistically significant (Table 4). In those patients (n = 25) who received edrophonium later than T50, T4,, increased to 75% within 0.2-1.3 min. Those patients (n = 7) with infusion duration of greater than 2 h had recovery indices that were not statistically different from those in patients receiving infusions for approximately 1 h or Iess (n = 12). The recovery indices after infusions of short versus long duration were T,: 4.9 f. 0.9 versus 4.7 t 0.7 min; TZsso: 6.3 ? 0.9 versus 6.5 -+ 1.1min; and T25-75: 13.9 -+ 1.9 versus 15.2 2 5.6 min, respectively.
*
35
Neuromuscular function (T,) when T, = T, was not always 100%of initial baseline. The final baseline of neuromuscular function averaged 90% t 11%,80% t 9%, and 85% ? 10% of the initial baseline in group H, I, and N, respectively. When neuromuscular function during infusion was referenced to the final rather than the initial baseline, a paired f-test demonstrated no significant change in IR.
Discussion The vecuronium IR that we observed during narcoticnitrous oxide anesthesia in children 2-10 yr of age was similar to that reported b Mereto'a 1 . The IR in pg-kg-'.min-' or in pg.m-rmin-' :or( c!hildren 210 yr of age during narcotic-nitrous oxide anesthesia was greater than that of adults exposed to the same anesthetic (2-5). In a study by DHollander et al. involving 24 adults in three groups (i.e., 18-36 yr, 40-60 yr, and 63-85 yr) during narcotic-nitrous oxide anesthesia (5), average IR was less in the oldest group: 46.5, 45, and 29.5 pg.m-2.min-1, respectively (Figure 2). The increased IR of vecuronium in children compared with that in adults is similar in magnitude to that seen with mivacurium (6-8). The age-related difference in IR for atracurium appears to be somewhat less (9-11). There also appears to be an age-related difference in IR for vecuronium during anesthesia with potent inhalation agents. In adults anesthetized with halothane (0.5% end-tidal concentration)-nitrous oxide, an average vecuronium IR of 0.8 pg-kg-l.min-l produced a 90% depression of neuromuscular function (2). In adults anesthetized with isoflurane (1.2% end-tidal concentration)-nitrous oxide, an average vecuronium IR of 0.3 pg.kg-'.min-' also produced a 90% depression of neuromuscular function (3). It appears that the vecuronium IR in children aged 210 yr may be at least twice as great as that in adults in the presence of potent inhalation anesthesia as well as during narcotic-nitrous oxide anesthesia. Other studies of the effects of anesthetic background on the infusion requirements for neuromuscular blocking drugs in children have not always found significant differences in potentiation between halothane and isoflurane (9), or halothane and narcotic (11) anesthesia. In this study the difference in average effective infusion rate of vecuronium 30 min after the beginning of infusion during halothane and isoflurane anesthesia was only 0.3 pg.kg-'.rnin-'. The standard deviation was 0.39 pg*kg-'*min-'. The ratio, 6/u, is therefore less than 0.8. With 15 patients in each experimental group there would be about a 50% chance of demonstrating a difference between the two groups assuming an acceptable a error of 0.05 (12). More than 20 patients per experimental group
36
ANESTH ANALG
PEDIATRIC ANESTHESIA WOELFEL ET AL. VECURONIUM INFUSION IN CHILDREN
1991;73:33-8
Table 3. Changing Vecuronium Infusion Requirements Over Time Anesthetic
Group H ( n = 15) Group I (n = 14) Group N (n = 10)
Total IR (pg.kg-'.rnin-')
IR during min 1-30 (pgkg-' .min-')
IR during min > 30 (pg.kg-'.rnin-l)
1.9 2 0.1" (1.2-2.7)
2.2 IT O.lb (13-3.2)
1.5 k O.ld (1.0-2.2) 2.4 k 0.3a,d (1.54.0)
1.8 & 0.1' (1.2-2.6) 2.3 ? 0.3
1.8 & O.lb,' (1.2-2.4) 1.5 5 0.1e8f (0.9-2.2) 2.4 & 0.3',f (1.6-4.0)
(0.7-4.0) ~~
~
~~
Values are expressed as mean f SEM, with the range gwen in parentheses IR, infusion requirement '-fStatistically significant difference in infusion rate at P < 0 05 is indicated by like letters (paired t-test for the comparlson of IR before and after minute 30 of infusion)
would be necessary to expect close to an 80% chance of finding a significant difference between the IR during exposure to 0.8% end-tidal halothane and 1.0% end-tidal isoflurane. In our study, variability in vecuronium IR was noted primarily during the first 30 min of the infusion (Figures lA, B, and C). During potent inhalation anesthesia in this study, there was a significant decrease in IR of approximately 20% after the first 30 min of infusion that was not observed during narcotic-nitrous oxide anesthesia. The infusion rate was frequently adjusted before a constant IR and constant degree of paralysis were attained. A greater IR early in the administration of vecuronium was noted during narcotic-nitrous oxide anesthesia by D'Hollander et al. (5). Swen et al. found no difference in time to steady-state IR for vecuronium during nitrous oxide-fentanyl or nitrous oxide-halothane anesthesia (2). Swen et al. did not comment on the degree of variability in vecuronium IR before the attainment of a constant IR and constant effect. During the first 30 min of infusion administration of vecuronium, neuromuscular function was outside the desired range about 25% of the time. Therefore the effective IR estimated during this period may well differ from the amount infused during more efficient titration. If the infusions had been titrated most appropriately, allowing inclusion of more data during the first 30 rnin of infusion in the calculation of IR during that time, the calculated IR would have been even greater. After the first 30 min of infusion administration, neuromuscular function was outside the desired range about 5% of the time. Thus, the effective IR estimated during this period is more likely to be easily reproducible. A change in IR of neuromuscular blocking drug with continued infusion and anesthetic administration could be due to changing concentrations of the neuromuscular blocker at the effect site (presumably the neuromuscular junction) or to changing concen-
3.0 W I-
d
z
Q 2.0 0
2 z
.
F
2.5
1.5
1 .o 0
A W
i
15
45
30
60
TIME
2.5
-
z
B
1.0' 0
1 .o
C
"
'
"
15
"
"
I
'
30 TIME
"
'
I
45
"
"
'
60
i . . . . , . 15 30 45 60
0
TIME
Figure 1. Relationship of mean IR t SEM (pg.kg-'.min-') over time for each group: halothane-nitrous oxide (0), isofluraneInfusion requirenitrous oxide (A), and narcotic-nitrous oxide (0). ments are significantly decreased after the first 30 min in groups H and I. The range is greater in group N. The total IR is greater in group N.
ANESTH ANALG 1991;7333-8
PEDIATRIC ANESTHESIA WOELFEL ET AL. VECURONIUM INFUSION IN CHILDREN
37
Table 4. Recovery Data After Vecuronium Infusion T25
Group H
(min)
9.1 2 1.2 (5.0-22.7) (n = 15) 8.1 t 1.0 (4.0-15.0) (n = 13) 6.8 +. 1.0 (4.5-9.2) ( n = 6)
Group I
Group N
(mi4
TI,,,
4.7
?
T2%50
0.7
(min)
5.7 f 0.7 (3.1-8.7) ( n = 8) 6.2 t 0.7 (2.8-10.6) ( n = 12) 3.7 2 1.7 (2.0-5.3) ( n = 2)
(1.0-11.4) ( n = 13) 5.0 2 0.5 (3.0-7.0) (n = 8) 4.1 5 0.4 (2.0-5.0) ( n = 6)
T*,n
(min)
15.0 2 2.7 (6.8-18.2) (n = 4) 13.7 f 1.8 (6.8-26.3) ( n = 10) 7.9 +. 3.9 (4.0-11.7) ( n = 2)
Values are expressed as mean 5 SEM, with range given in the first set of parentheses and number given in the second There were no statistically significant differences between groups.
$
50
5 40
2 30 2 20 10
0
2-10
1 8-3 6 4 0 - 6 0 AGE
63-85
Figure 2. Relationship between age (yr) and IR f SEM (pgm-*.rnin-'). Data in adults are from a study by DHollander et al. (5). The anesthetic is narcotic-nitrous oxide.
trations of the potentiating anesthetic. If delayed equilibration at the effect site with potentiating inhalation anesthetics were the major factor responsible for the variability in vecuronium IR during the first 30 min of infusion, a similar degree of variability should be apparent in studies of other drugs administered during similar types of anesthesia. Such an observation has not been reported. In a study of atracurium IR that used stimulus parameters identical to those of this study, similar EMG monitoring of neuromuscular function, and identical administration of halothane (0.8% end-tidal concentration) and isoflurane (1.O% end-tidal concentration), halothane and isoflurane significantly potentiated atracurium-induced neuromuscular blockade by about 30% (9). Differences in variability of IR with anesthetic background early in the administration of the infusion were not mentioned (9). In a similar study with mivacurium, IR in the first 12 min of infusion was greater during nitrous oxide-fentanyl anesthesia than during nitrous oxide-halothane anesthesia (6). The children in our study recovered more rapidly from vecuronium infusion than did adults observed
by others. In a study during narcotic-nitrous oxide anesthesia, the shortest recovery indices (Ti, of 8.4 2 1.2 rnin and T, of 16.2 2 4.0 min) were observed in the youngest patients (age range, 1836 yr) (5). The same recovery indices appear shorter (4.1 2 0.4 min and 7.9 2 3.9 min, respectively) in our children during narcotic-nitrous oxide anesthesia. During halothane (1.O% end-tidal concentration) anesthesia in adults, the recovery index (T,,,) was 23 8 min (13). In our current study of children, the average T25-75during halothane anesthesia was 15 2 2.7 min. Both these observations and the greater IR in children relative to adults could be due to more rapid removal of vecuronium from the effect site in children relative to adults. From a clinical standpoint, this study demonstrates that halothane-narcotic-nitrous oxide (0.8% end-tidal concentration) and isoflurane-narcoticnitrous oxide (1.0% end-tidal concentration) anesthesia reduce vecuronium IR in children to a similar extent compared with narcotic-nitrous oxide anesthesia. After a bolus of vecuronium that will produce about 95% neuromuscular blockade, 2.0-2.5 pgakg-'. min-l of vecuronium is a useful initial infusion rate in children 2-10 yr of age under all types of anesthesia, whereas this initial rate is likely to decrease to 1.51.8 pgkg-'*min-' after the first 30 min in children anesthetized with halothane or isoflurane and nitrous oxide. The mean IR can serve only as a starting point for the infusion of vecuronium, because a wide range of steady effective IR was observed in these patients. After the termination of the infusion, spontaneous recovery of neuromuscular transmission occurs rapidly. Alternatively, reversal of blockade is easily achieved with edrophonium. Children (2-10 yr) have an increased vecuronium IR compared with adults under all types of anesthesia; they also have a faster spontaneous rate of recovery after the infusion is terminated.
*
38
PEDIATRIC ANESTHESIA WOELFEL E l AL. VECURONICM INFUSION IN CHILIXtN
We thank Wayne DellaMaestra for his significant contribution to data analysis.
References 1. Meretoja OA. Vecuronium infusion requirements in pediatric patients during fentanyl-N,O-0, anesthesia. Anesth Analg 1989;68:20-4. 2. Swen J, Gencarelli PJ, Koot HW. Vecuronium infusion dose requirements during fentanyl and halothane anesthesia in humans. Anesth Analg 1985;64:4114. 3. Cannon JE, Fahey MR, Castagnoli KP, et al. Continuous infusion of vecuronium: the effect of anesthetic agents. Anesthesiology 1987;67503-6. 4. Gramstad L, Lilleaasen P. Neuromuscular blocking effects of atracurium, vecuronium, and pancuronium during bolus and infusion administration. Br J Anaesth 1985;571052-9. 5. DHollander A, Massaux F, Nevelsteen M, Agoston S. Agedependent dose-response relationship of ORG NC45 in anaesthetized patients. Br J Anaesth 1982;54653-7. 6. Brandom BW, Sarner JB, Woelfel SK, et al. Mivacurium infusion requirements in pediatric surgical patients during nitrous oxide-halothane and during nitrous oxide-narcotic anesthesia. Anesth Analg 1990;71:1622.
ANESTH ANALG 1991;73:33-8
7. Shanks CA, Fragen RJ, Pemberton D, Katz JA, Risner ME. Mivacurium-induced neuromuscular blockade following single bolus doses and with continuous infusion during either balanced or enflurane anesthesia. Anesthesiology 1989;71:3624. 8. Goldberg ME, Larijani GE, Azad SS, et al. Comparison of tracheal intubating conditions and neuromuscular blocking profiles after intubating doses of mivacurium chloride or succinylcholine in surgical outpatients. Anesth Analg 1989;69: 959-65. 9. Brandom BW, Cook DR, Woelfel SK, Rudd GD, Fehr B, Lineberry CG. Atracurium infusion requirements in children during halothane, isoflurane, and narcotic anesthesia. Anesth Analg 1985;64:471-6. 10. Haraldsted VY, Nielsen JW, Madsen JV, Hasselstrm L. Maintenance of constant 95% neuromuscular blockade by adjustable infusion rates of pancuronium and atracurium. Br J Anaesth 1988;60:491-4. 11. Goudsouzian N, Martyn J, Rudd GD, Liu LMP, Lineberry CG. Continuous infusion of atracurium in children. Anesthesiology 1986;64:171-4. 12. Glantz SA. Primer of biostatistics. 2nd ed. New York: McGraw Hill, 1987:156. 13. Shanks CA, Avram MJ, Fragen RJ, OHara DA. Pharmacokinetics and pharmacodynamics of vecuronium administered by bolus and infusion during halothane or balanced anesthesia. Clin Pharmacol Ther 1987;42:45944.
MD,
Barbara W. Brandom,
MD,
Joel B. Sarner,
MD,
Departments of Anesthesiology and Critical Care Medicine, Children's Hospital of Pittsburgh and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
We were interested in determining the infusion rate of vecuronium required to maintain approximately 95% neuromuscular blockade in children during halothane-narcotic-nitrous oxide (0.8% end-tidal concentration), isoflurane-narcotic-nitrous oxide (1.0% end-tidal concentration), or narcotic-nitrous oxide anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity (Datex NMT) of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s at 10-s intervals. Effective vecuronium infusion requirements averaged 1.5 ? 0.1 pg.kg-'-min-' (mean ? SEM) during isoflurane-narcotic-nitrous oxide anesthesia, 1.9 ? 0.1 pg.kg-'.min-' during
B
ecause of its intermediate duration of action and noncumulative effects, vecuronium should be useful as a continuous infusion. Indeed, vecuronium has been administered as an infusion to children (1) and to adults (2-5) during narcoticnitrous oxide anesthesia. Vecuronium infusion requirements (IRs) during narcotic-nitrous oxide anesthesia differ with age. It is likely, therefore, that the vecuronium IRs of children differ from those of adults during potent inhalation anesthesia as well. There are no published reports of vecuronium IR in children during anesthesia with halothane or isoflurane. It is to be expected that these potent inhalation anesthetics would increase the neuromuscular blocking effect of vecuronium and hence decrease IR (2,3). Therefore, we were interested in determining the infusion rate of vecuronium required to maintain a clinically effective state of neuromuscular blockade in children
Accepted for publication February 5, 1991. Address correspondence to Dr. Woelfel, Department of Anesthesiology, Children's Hospital of Pittsburgh, 3705 Fifth Avenue at DeSoto Street, Pittsburgh, PA 15213-2583. 01991 by the International Anesthesia Research Society 0003-2999/91/$3.50
halothane-narcotic-nitrous oxide anesthesia, and 2.4 ? 0.3 pgkg-l-min-' during narcotic-nitrous oxide anesthesia. Infusion requirements significantly decreased after the first 30 min of infusion in the presence of both potent inhalation anesthetics, but did not change with time during narcotic-nitrous oxide anesthesia. There was no evidence of decreasing infusion requirements during prolonged vecuronium infusion (2.5 h). There was no difference in the rate of spontaneous or pharmacologically induced recovery between anesthetic groups. The mean recovery index (T,,) after termination of the infusion was 13.7 min. (Anesth Analg 1991;73:33-8)
during narcotic-nitrous oxide anesthesia in the presence of halothane or isoflurane.
Methods The study was approved by the Human Rights Committee of the Children's Hospital of Pittsburgh. Informed consent was obtained from a parent. Thirtynine children (ASA status I and 11) aged 2-10 yr were studied. All were undergoing low-to-moderate risk elective surgical procedures that required endotracheal intubation. No patient received aminoglycoside antibiotics, or antihistamines within 48 h of the study. Most patients received no premedication; three were given 0.1-0.2 mg/kg of diazepam orally or midazolam intramuscularly. The children were randomly assigned to one of three study groups: 15 patients received halothane-nitrous oxide, oxygen, and fentanyl (group H); 14 patients received isoflurane-nitrous oxide, oxygen, and fentanyl (group I); and 10 patients received nitrous oxide, oxygen, and fentanyl (group N). In all patients, anesthesia was induced with nitrous oxide, oxygen, and a potent inhalation anes33
34
PEDIATRIC ANESTHESIA WOELFEL ET AL. VECURONIUM INFUSION IN CHILDREN
ANESTH ANALG 1991;73.3=
Table 1. Demographic Data ~~
Group H ( n = 15) Group I (n = 14) Group N ( n = 10)
~~
Height (cm)
Weight (kg)
69.5 9.2 (26.8-130.7)
116.1 f 4.6 (90.0-140.0)
0.84 2 0.06 (0.5-1.2)
54.4 2 5.9 (22.6-101.4)
106.9 ? 3.4 (91.0-133.0)
21.8 2.3 (11.5-37.0) 18.2 2 1.2 (13.630.0)
55.6 _t 9.7 (22.5-113.8)
100.5 k 4.6 (88.0-124.0)
17.5 2 1.8 (12.629.0)
0.70 f 0.05 (0.6-1 .O)
Age (mo)
*
*
BSA (m')
0.76 f 0.04 (0.6-1.1)
BSA, body surface area. Values are expressed as mean & SEM, with the range given in parentheses. There were no statistically significant differences between anesthetic groups.
thetic. A venous catheter was inserted, and atropine (10 pglkg) was given intravenously to all patients before tracheal intubation. The inspired and end-tidal concentrations of halothane and isoflurane were monitored continuously with a Puritan Bennett infrared gas analyzer. In groups H and I, respectively, anesthesia was maintained with 70% nitrous oxide in oxygen and halothane (0.8% end-tidal concentration) or isoflurane (1.O% end-tidal concentration). Patients in groups H and I received 1-6 pg/kg of fentanyl as clinically indicated. In group N, thiopental (4-8 mg/ kg) and midazolam (0.1 mg/kg) were administered intravenously, and the potent agent was discontinued. Anesthesia was maintained in group N with fentanyl (2.7-11.3 pglkg) and 70% nitrous oxide in oxygen. Normal minute ventilation and body temperature (rectal or skin) were maintained intraoperatively in all patients. After induction of general anesthesia, the ulnar nerve was stimulated supramaximally at the wrist with repetitive trains-of-four (2 Hz for 2 s at 10-s intervals) through surface electrodes. The evoked compound electromyogram (EMG) of thumb adduction was recorded by a Datex neuromuscular transmission monitor. End-tidal concentrations of anesthetic were allowed to stabilize for 10-15 min, and a stable baseline EMG was obtained for at least 3 min before the administration of vecuronium. In group N the endtidal halothane or isoflurane concentration was 0% for 5-10 min before administration of vecuronium. An intravenous bolus of 60 pg/kg of vecuronium was injected. The maximum neuromuscular blocking effect was recorded, and the trachea was intubated. When the first response (T,) of the EMG signal returned to 5% of baseline (T5), an infusion of vecuronium in lactated Ringer's solution (200 pg/mL) was administered at 1.5-2 pg-kg-lmin-' with an infusion pump. The infusion was titrated to produce 89%-99% neuromuscular blockade for as long as required by the surgical procedure (range, 36-149 min). For each patient the infusion rate of vecuronium required to achieve 89%-99% blockade was calculated and re-
corded at 3-min intervals. Data from 3-min periods during which neuromuscular blockade was outside the 89%-99% range were not included in the analyses. For each patient the mean effective IR was calculated for three periods: the first 30 min of infusion, the duration of infusion excluding the first 30 min, and the total duration of infusion. The time from termination of the infusion to 5% (T5), 10%(Tlo),25% (T25), 50% (T50), and 75% (T75)of baseline and the time until T,, 2 75% were noted. Recovery was referenced to the final EMG baseline (T, when T4 = TI). End-tidal inhalation anesthetic concentration was maintained constant until T, = T,. Twenty-five patients received 1 mgkg edrophonium when T, was greater than T50, and recovery was then monitored untiI recovery of neuromuscular function was complete. Vecuronium IR was calculated on the basis of both weight (pg.kg-'.min-') and body surface area (BSA) (pgrn-'.min-'). Standard errors are shown for all mean values. Analysis of variance and Tukey's test were used to assess the differences between groups. Paired t-tests were used to compare the IR before and after the first 30 min and the total IR. Differences were considered significant at P < 0.05.
Results There was no statistical difference in age, height, weight, or BSA among the three groups of patients studied (Table 1). There was no significant difference between anesthetic groups in time to onset of compIete block after the initial bolus dose, or in T, after bolus ad ministration of vecuronium (Table 2). The total IR for group H was 1.9 t 0.1 pg.kg-'.min-' (47.5 2 3.4 pgm-'. min-'), for group I 1.5 & 0.1 pg.kg-'min-' (36.9 ? 2.4 pgm-'-min-'), and for group N 2.4 t 0.3 pgkg-l. min-' (61.1 ? 7.5 p g m -'amin-'). There was no significant difference between these values for groups H and I; however, the total IR was significantly greater for group N (Table 3). A significant decrease in IR was
ANESTH ANALG
PEDIATRIC ANESTHESIA WOELFEL ET AL. VECURONIUM INFUSION IN CHILDREN
1991;7333-8
Table 2. Onset and Initial Recovery Times From Bolus Time to 5% neuromuscular transmission (T5)(min)
Onset time to 100% block (min) Group H
Group I
Group N
*
9.9 k 1.3 (4.8-17.0) ( n = 10) 11.5 1.1 (8.4-15.5) ( n = 6) 9.5 f 1.0 (8.0-14.3) (n = 6)
2.7 0.3 (1.& 3) I. (n = 10) 2.2 2 0.2 (15 2 . 8 ) (n = 7)
*
2.4 ? 0.3 (1.5-3.3) ( n = 6)
*
Values are expressed as mean SEM, with range given in the first set of parentheses and the number given in the second set. There were no statistically significant differences between groups.
observed after the first 30 min of infusion in groups H and I but not in group N (Figure 1) (Table 3). The average duration of infusion administration in minutes was 86 t 5 for group H, 98 7 for group I, and 85 t 12 for group N. The percentage of time that neuromuscular blockade was not maintained within the desired 89%-99% depression of function during the first 30 min of infusion administration averaged 22% t 5% in group H, 26% +- 5% in group I, and 26% t 8% in group N. In the first 30 min of administration of vecuronium nine patients had a period of 100% neuromuscular blockade. All other patients who did not have neuromuscular blockade in the desired range had less than 89% neuromuscular blockade. The percentage of time that neuromuscular blockade was outside the desired range after the first 30 rnin of infusion administration averaged 4% t 1% in group H, 6% t 3% in group I, and 4% t 3% in group N. The coefficient of variation of the IR (standard deviation divided by mean) was similar for the potent inhalation agents (20%-25%)and greater in group N (40%). After termination of the infusion, the time required for spontaneous recovery of neuromuscular transmission to T25 (n = 34) and the rate of recovery tended to be less in group N than in groups H and I, but the difference was not statistically significant (Table 4). In those patients (n = 25) who received edrophonium later than T50, T4,, increased to 75% within 0.2-1.3 min. Those patients (n = 7) with infusion duration of greater than 2 h had recovery indices that were not statistically different from those in patients receiving infusions for approximately 1 h or Iess (n = 12). The recovery indices after infusions of short versus long duration were T,: 4.9 f. 0.9 versus 4.7 t 0.7 min; TZsso: 6.3 ? 0.9 versus 6.5 -+ 1.1min; and T25-75: 13.9 -+ 1.9 versus 15.2 2 5.6 min, respectively.
*
35
Neuromuscular function (T,) when T, = T, was not always 100%of initial baseline. The final baseline of neuromuscular function averaged 90% t 11%,80% t 9%, and 85% ? 10% of the initial baseline in group H, I, and N, respectively. When neuromuscular function during infusion was referenced to the final rather than the initial baseline, a paired f-test demonstrated no significant change in IR.
Discussion The vecuronium IR that we observed during narcoticnitrous oxide anesthesia in children 2-10 yr of age was similar to that reported b Mereto'a 1 . The IR in pg-kg-'.min-' or in pg.m-rmin-' :or( c!hildren 210 yr of age during narcotic-nitrous oxide anesthesia was greater than that of adults exposed to the same anesthetic (2-5). In a study by DHollander et al. involving 24 adults in three groups (i.e., 18-36 yr, 40-60 yr, and 63-85 yr) during narcotic-nitrous oxide anesthesia (5), average IR was less in the oldest group: 46.5, 45, and 29.5 pg.m-2.min-1, respectively (Figure 2). The increased IR of vecuronium in children compared with that in adults is similar in magnitude to that seen with mivacurium (6-8). The age-related difference in IR for atracurium appears to be somewhat less (9-11). There also appears to be an age-related difference in IR for vecuronium during anesthesia with potent inhalation agents. In adults anesthetized with halothane (0.5% end-tidal concentration)-nitrous oxide, an average vecuronium IR of 0.8 pg-kg-l.min-l produced a 90% depression of neuromuscular function (2). In adults anesthetized with isoflurane (1.2% end-tidal concentration)-nitrous oxide, an average vecuronium IR of 0.3 pg.kg-'.min-' also produced a 90% depression of neuromuscular function (3). It appears that the vecuronium IR in children aged 210 yr may be at least twice as great as that in adults in the presence of potent inhalation anesthesia as well as during narcotic-nitrous oxide anesthesia. Other studies of the effects of anesthetic background on the infusion requirements for neuromuscular blocking drugs in children have not always found significant differences in potentiation between halothane and isoflurane (9), or halothane and narcotic (11) anesthesia. In this study the difference in average effective infusion rate of vecuronium 30 min after the beginning of infusion during halothane and isoflurane anesthesia was only 0.3 pg.kg-'.rnin-'. The standard deviation was 0.39 pg*kg-'*min-'. The ratio, 6/u, is therefore less than 0.8. With 15 patients in each experimental group there would be about a 50% chance of demonstrating a difference between the two groups assuming an acceptable a error of 0.05 (12). More than 20 patients per experimental group
36
ANESTH ANALG
PEDIATRIC ANESTHESIA WOELFEL ET AL. VECURONIUM INFUSION IN CHILDREN
1991;73:33-8
Table 3. Changing Vecuronium Infusion Requirements Over Time Anesthetic
Group H ( n = 15) Group I (n = 14) Group N (n = 10)
Total IR (pg.kg-'.rnin-')
IR during min 1-30 (pgkg-' .min-')
IR during min > 30 (pg.kg-'.rnin-l)
1.9 2 0.1" (1.2-2.7)
2.2 IT O.lb (13-3.2)
1.5 k O.ld (1.0-2.2) 2.4 k 0.3a,d (1.54.0)
1.8 & 0.1' (1.2-2.6) 2.3 ? 0.3
1.8 & O.lb,' (1.2-2.4) 1.5 5 0.1e8f (0.9-2.2) 2.4 & 0.3',f (1.6-4.0)
(0.7-4.0) ~~
~
~~
Values are expressed as mean f SEM, with the range gwen in parentheses IR, infusion requirement '-fStatistically significant difference in infusion rate at P < 0 05 is indicated by like letters (paired t-test for the comparlson of IR before and after minute 30 of infusion)
would be necessary to expect close to an 80% chance of finding a significant difference between the IR during exposure to 0.8% end-tidal halothane and 1.0% end-tidal isoflurane. In our study, variability in vecuronium IR was noted primarily during the first 30 min of the infusion (Figures lA, B, and C). During potent inhalation anesthesia in this study, there was a significant decrease in IR of approximately 20% after the first 30 min of infusion that was not observed during narcotic-nitrous oxide anesthesia. The infusion rate was frequently adjusted before a constant IR and constant degree of paralysis were attained. A greater IR early in the administration of vecuronium was noted during narcotic-nitrous oxide anesthesia by D'Hollander et al. (5). Swen et al. found no difference in time to steady-state IR for vecuronium during nitrous oxide-fentanyl or nitrous oxide-halothane anesthesia (2). Swen et al. did not comment on the degree of variability in vecuronium IR before the attainment of a constant IR and constant effect. During the first 30 min of infusion administration of vecuronium, neuromuscular function was outside the desired range about 25% of the time. Therefore the effective IR estimated during this period may well differ from the amount infused during more efficient titration. If the infusions had been titrated most appropriately, allowing inclusion of more data during the first 30 rnin of infusion in the calculation of IR during that time, the calculated IR would have been even greater. After the first 30 min of infusion administration, neuromuscular function was outside the desired range about 5% of the time. Thus, the effective IR estimated during this period is more likely to be easily reproducible. A change in IR of neuromuscular blocking drug with continued infusion and anesthetic administration could be due to changing concentrations of the neuromuscular blocker at the effect site (presumably the neuromuscular junction) or to changing concen-
3.0 W I-
d
z
Q 2.0 0
2 z
.
F
2.5
1.5
1 .o 0
A W
i
15
45
30
60
TIME
2.5
-
z
B
1.0' 0
1 .o
C
"
'
"
15
"
"
I
'
30 TIME
"
'
I
45
"
"
'
60
i . . . . , . 15 30 45 60
0
TIME
Figure 1. Relationship of mean IR t SEM (pg.kg-'.min-') over time for each group: halothane-nitrous oxide (0), isofluraneInfusion requirenitrous oxide (A), and narcotic-nitrous oxide (0). ments are significantly decreased after the first 30 min in groups H and I. The range is greater in group N. The total IR is greater in group N.
ANESTH ANALG 1991;7333-8
PEDIATRIC ANESTHESIA WOELFEL ET AL. VECURONIUM INFUSION IN CHILDREN
37
Table 4. Recovery Data After Vecuronium Infusion T25
Group H
(min)
9.1 2 1.2 (5.0-22.7) (n = 15) 8.1 t 1.0 (4.0-15.0) (n = 13) 6.8 +. 1.0 (4.5-9.2) ( n = 6)
Group I
Group N
(mi4
TI,,,
4.7
?
T2%50
0.7
(min)
5.7 f 0.7 (3.1-8.7) ( n = 8) 6.2 t 0.7 (2.8-10.6) ( n = 12) 3.7 2 1.7 (2.0-5.3) ( n = 2)
(1.0-11.4) ( n = 13) 5.0 2 0.5 (3.0-7.0) (n = 8) 4.1 5 0.4 (2.0-5.0) ( n = 6)
T*,n
(min)
15.0 2 2.7 (6.8-18.2) (n = 4) 13.7 f 1.8 (6.8-26.3) ( n = 10) 7.9 +. 3.9 (4.0-11.7) ( n = 2)
Values are expressed as mean 5 SEM, with range given in the first set of parentheses and number given in the second There were no statistically significant differences between groups.
$
50
5 40
2 30 2 20 10
0
2-10
1 8-3 6 4 0 - 6 0 AGE
63-85
Figure 2. Relationship between age (yr) and IR f SEM (pgm-*.rnin-'). Data in adults are from a study by DHollander et al. (5). The anesthetic is narcotic-nitrous oxide.
trations of the potentiating anesthetic. If delayed equilibration at the effect site with potentiating inhalation anesthetics were the major factor responsible for the variability in vecuronium IR during the first 30 min of infusion, a similar degree of variability should be apparent in studies of other drugs administered during similar types of anesthesia. Such an observation has not been reported. In a study of atracurium IR that used stimulus parameters identical to those of this study, similar EMG monitoring of neuromuscular function, and identical administration of halothane (0.8% end-tidal concentration) and isoflurane (1.O% end-tidal concentration), halothane and isoflurane significantly potentiated atracurium-induced neuromuscular blockade by about 30% (9). Differences in variability of IR with anesthetic background early in the administration of the infusion were not mentioned (9). In a similar study with mivacurium, IR in the first 12 min of infusion was greater during nitrous oxide-fentanyl anesthesia than during nitrous oxide-halothane anesthesia (6). The children in our study recovered more rapidly from vecuronium infusion than did adults observed
by others. In a study during narcotic-nitrous oxide anesthesia, the shortest recovery indices (Ti, of 8.4 2 1.2 rnin and T, of 16.2 2 4.0 min) were observed in the youngest patients (age range, 1836 yr) (5). The same recovery indices appear shorter (4.1 2 0.4 min and 7.9 2 3.9 min, respectively) in our children during narcotic-nitrous oxide anesthesia. During halothane (1.O% end-tidal concentration) anesthesia in adults, the recovery index (T,,,) was 23 8 min (13). In our current study of children, the average T25-75during halothane anesthesia was 15 2 2.7 min. Both these observations and the greater IR in children relative to adults could be due to more rapid removal of vecuronium from the effect site in children relative to adults. From a clinical standpoint, this study demonstrates that halothane-narcotic-nitrous oxide (0.8% end-tidal concentration) and isoflurane-narcoticnitrous oxide (1.0% end-tidal concentration) anesthesia reduce vecuronium IR in children to a similar extent compared with narcotic-nitrous oxide anesthesia. After a bolus of vecuronium that will produce about 95% neuromuscular blockade, 2.0-2.5 pgakg-'. min-l of vecuronium is a useful initial infusion rate in children 2-10 yr of age under all types of anesthesia, whereas this initial rate is likely to decrease to 1.51.8 pgkg-'*min-' after the first 30 min in children anesthetized with halothane or isoflurane and nitrous oxide. The mean IR can serve only as a starting point for the infusion of vecuronium, because a wide range of steady effective IR was observed in these patients. After the termination of the infusion, spontaneous recovery of neuromuscular transmission occurs rapidly. Alternatively, reversal of blockade is easily achieved with edrophonium. Children (2-10 yr) have an increased vecuronium IR compared with adults under all types of anesthesia; they also have a faster spontaneous rate of recovery after the infusion is terminated.
*
38
PEDIATRIC ANESTHESIA WOELFEL E l AL. VECURONICM INFUSION IN CHILIXtN
We thank Wayne DellaMaestra for his significant contribution to data analysis.
References 1. Meretoja OA. Vecuronium infusion requirements in pediatric patients during fentanyl-N,O-0, anesthesia. Anesth Analg 1989;68:20-4. 2. Swen J, Gencarelli PJ, Koot HW. Vecuronium infusion dose requirements during fentanyl and halothane anesthesia in humans. Anesth Analg 1985;64:4114. 3. Cannon JE, Fahey MR, Castagnoli KP, et al. Continuous infusion of vecuronium: the effect of anesthetic agents. Anesthesiology 1987;67503-6. 4. Gramstad L, Lilleaasen P. Neuromuscular blocking effects of atracurium, vecuronium, and pancuronium during bolus and infusion administration. Br J Anaesth 1985;571052-9. 5. DHollander A, Massaux F, Nevelsteen M, Agoston S. Agedependent dose-response relationship of ORG NC45 in anaesthetized patients. Br J Anaesth 1982;54653-7. 6. Brandom BW, Sarner JB, Woelfel SK, et al. Mivacurium infusion requirements in pediatric surgical patients during nitrous oxide-halothane and during nitrous oxide-narcotic anesthesia. Anesth Analg 1990;71:1622.
ANESTH ANALG 1991;73:33-8
7. Shanks CA, Fragen RJ, Pemberton D, Katz JA, Risner ME. Mivacurium-induced neuromuscular blockade following single bolus doses and with continuous infusion during either balanced or enflurane anesthesia. Anesthesiology 1989;71:3624. 8. Goldberg ME, Larijani GE, Azad SS, et al. Comparison of tracheal intubating conditions and neuromuscular blocking profiles after intubating doses of mivacurium chloride or succinylcholine in surgical outpatients. Anesth Analg 1989;69: 959-65. 9. Brandom BW, Cook DR, Woelfel SK, Rudd GD, Fehr B, Lineberry CG. Atracurium infusion requirements in children during halothane, isoflurane, and narcotic anesthesia. Anesth Analg 1985;64:471-6. 10. Haraldsted VY, Nielsen JW, Madsen JV, Hasselstrm L. Maintenance of constant 95% neuromuscular blockade by adjustable infusion rates of pancuronium and atracurium. Br J Anaesth 1988;60:491-4. 11. Goudsouzian N, Martyn J, Rudd GD, Liu LMP, Lineberry CG. Continuous infusion of atracurium in children. Anesthesiology 1986;64:171-4. 12. Glantz SA. Primer of biostatistics. 2nd ed. New York: McGraw Hill, 1987:156. 13. Shanks CA, Avram MJ, Fragen RJ, OHara DA. Pharmacokinetics and pharmacodynamics of vecuronium administered by bolus and infusion during halothane or balanced anesthesia. Clin Pharmacol Ther 1987;42:45944.
