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ANESTH ANALG 1 Y90;7 1:16-22

Mivacurium Infusion Requirements in Pediatric Surgical Patients During Nitrous Oxide-Halothane and During Nitrous OxideNarcotic Anesthesia Barbara W. Brandom, MD, Joel B. Sarner, MD, Susan K.Woelfel, MD, Mai-Li Dong, MD, Michael C. Horn, MD, Lawrence M. Borland, MD, D. Ryan Cook, MD, Vicki J. Foster, MSPH,Barbara F. McNulty, MPH,and J. Neal Weakly, PhD BRANDOM BW, SARNER JB, WOELFEL SK, DONG M-L, HORN MC, BORLAND LM, COOK DR, FOSTER VJ, McNULTY BF, WEAKLY JN. Mivacurium infusion requirements in pediatric surgical patients during nitrous oxide-halothane and during nitrous oxide-narcotic anesthesia. Anesth Analg 1990;71:1&22.

We were interested iri determining the infusion rate of iiiivacuriurn required to maintain approximately 9570 neuroinuscular lilockade during nitrous oxide-halothane (0.8% end- t idaii or nitro u5 oxide- na rco t ic anesthesia . Neti ro ni uscular blockade was monitored by recording the electromyographic actizlity (Datex NMT) of the adductor pollicis rnusclc resulting from suprarnaxiinal stimulation of the ulizar nerz'e at 2 H z for 2 s at 10-s intervals. Mivacurium steady-state infusion requirements averaged 315 L 26 pxcLn -'.min -' during nitrous oxide-halothane anesthesia arid 375 2 19 pg.m-'.niiriC' (mean ? S E M ) during nitrous oxide-narcotic anesthesia. Higher levels of pseudocholiiiesterase activity were generally associated with a

Mivacurium chloride is a new nondepolarizing neuromuscular blocking agent with a relatively short duration of action. When administered in a dose of 0.25 mg/kg (approximately 2.5 times the ED,,) to children, mivacurium produces complete neuromuscular blockade in 1-2 min with complete spontaneous recovery within 15-30 min (1,2). Succinylcholine, the Supported in part by a grant from Burroughs Wellcome Company, Research Triangle Park, North Carolina. Received from the Departments of Anesthesiology, Children's Hospital of Pittsburgh and the University of Pittsburgh, Pittsburgh, Pennsylvania, and the Department of Clinical Neurosciences, Burroughs Wellcome Company, Research Triangle Park, North Carolina. Accepted for publication February 23, 1990. Address correspondence to Dr. Brandom, Department of Anesthesiology, Children's Hospital of Pittsburgh, One Children's Place, 3705 Fifth Avenue at DeSoto Street, Pittsburgh, PA 152132583. 1990 by the Internationdl Anesthesla Research Society

higher rniz~acurium infusion requirement. During both anesthetics, younger age was associated with a higher infusion requirement ziilzen the infusion requirement was calculated in terms of pgkg-'.min-'. This diference was not present when the infusion rate was calculated in terms of pg.ni-'.inin--'. There was no evidence of cumulation during prolonged miziacurium infusion. There was no difference in the rates of spontaneous or reversal-mediated recoaery between anesthetic groups. After the termination of the itifusion, spontaneous recovery to T4lTI 2 0.75 occurred in 9.8 ? 0.4 nzin, with a recovery index, T25-75r of 4.0 k 0.2 min (mean 2 SEMI.In summary, pseudocholinesterase activity is the major factor infi'ueiicing mivacurium infusion rate in clrildren during nitrous oxide-narcotic or nitrous oxide-halothane (0.8% end-tidal) anesthesia. Key Words: NEUROMUSCULAR RELAXANTS, MIVACURIUM-infUSiOn. ANESTHESIA, PEDIATRICmivacurium.

only short-acting relaxant now in clinical use, may be associated with numerous undesirable side effects in children (3-9). Because of its relatively rapid onset and short duration of action, mivacurium may be used as an alternative to succinylcholine in pediatric patients. Mivacurium has been compared with succinylcholine in adults (10). There are, however, agerelated differences in bolus dose requirements (i.e., ED,, in mg/kg) and in the duration of action of mivacurium after bolus doses between children and adults (1). During nitrous oxide-oxygen-narcotic anesthesia, the ED,, in adults is 70 pg/kg, whereas the ED,, in children is 103 pg/kg. After a bolus of five times the ED,,, children recover to 5% neuromuscular transmission (T5) in 7 min, whereas adults recover to the same degree in 14 min. In addition, potent inhalation anesthetics potenti-

MIVACURIUM INFUSION IN CHILDREN

ate the neuromuscular blocking effects of mivacurium and, hence, decrease infusion requirements in adults (11,12).Therefore, we studied the infusion rate (IR) of mivacurium required to maintain neuromuscular blockade at 89%-99% in children during nitrous oxide-oxygen-halothane and nitrous oxide-oxygennarcotic anesthesia.

Methods Sixty-two children (ASA physical status I or 11) between 2 and 10 yr of age undergoing elective surgical procedures requiring tracheal intubation were studied. The majority of patients underwent otorhinlaryngologic, dental, or plastic surgery. The study was approved by the Human Rights Committee of Children's Hospital of Pittsburgh; informed consent was obtained from a parent. No patient had a history of abnormal response to neuromuscular blocking agents. No patients received aminoglycoside antibiotics, antihistamines, or other drugs known to interfere with neuromuscular function within 48 h of the study. Blood was drawn immediately after induction of anesthesia for measurement of pseudocholinesterase activity and dibucaine number with propionylthiocholine iodide as substrate. The 59 patients who contributed to statistical analysis of infusion requirement had both pseudocholinesterase activity and dibucaine numbers in the normal range. Patients underwent induction of anesthesia with halothane and nitrous oxide or with nitrous oxide and intravenous (IV) sedatives. The expressed preference and the ability of the patient to cooperate during induction of anesthesia influenced the choice of induction technique. If the patient received halothane during induction of anesthesia, halothane was continued throughout the anesthetic. Thus, patients were nonrandomly divided into two groups. One group (group H, M = 21) was studied during nitrous oxide-oxygen-halothane anesthesia; the other group (group N, n = 38) was studied during nitrous oxide-oxygen-narcotic anesthesia. Patients in group H were generally unpremedicated; one patient received oral diazepam (0.15 mg/kg). Patients in group N were premedicated with variable combinations of oral diazepam (0.1-0.2 mg/kg), intramuscular morphine (0.1-0.2 mgkg) and scopolamine (6 pglkg), and rectal methohexital (20-30 mgikg). In patients in group H, anesthesia was induced with nitrous oxide (70%) in oxygen (30%) and halothane (3%-5% inspired concentration). An IV catheter was inserted after induction of anesthesia, and an infusion of 5% dextrose in lactated Ringer's

ANESTH ANALG 1990;71: 16-22

17

solution was begun. Atropine (10 pg/kg) was given intravenously before tracheal intubation. Tracheal intubation was accomplished without the aid of neuromuscular blocking agents or IV or translaryngeal lidocaine. After intubation the end-tidal halothane concentration was reduced to 0.8% k 0.05%, nitrous oxide (70%) in oxygen (30%) was continued, and IV fentanyl (up to 6 pg/kg) was given if needed. Endtidal halothane concentration was measured using an infrared gas analyzer (Puritan-Bennett 222) and remained stable between 0.75% and 0.85% for at least 10 min before administration of mivacurium. In patients in group N, nitrous oxide (70%-80%) in oxygen (20%-30%)was administered, an IV infusion of 5% dextrose in lactated Ringer's solution was established, and IV thiopental ( 6 1 0 mg/kg), d'iazepam (0.1-0.2 mg/kg), and fentanyl (2-6 pg/kg) were given as needed. Anesthesia was maintained with nitrous oxide (70%) in oxygen (30%) and fentanyl. In these patients the trachea was intubated after administration of mivacurium. Normal minute ventilation as judged by the attending anesthesiologist, and normal body temperature were maintained intraoperatively. On the average, core body temperature increased about 0.5"C during the period of neuromuscular monitoring. The ulnar nerve was stimulated supramaximally (pulse width, 0.1 ms) using surface electrodes on the forearm with train-of-four stimuli (2 Hz for 2 s at 10-s intervals). The electromyogram of the thenar area approximating the adductor pollicis muscle was recorded using a Datex NMT monitor. The degree of neuromuscular blockade was described as percent of control; the height of the T1 response (first train-offour response) after mivacurium administration was compared with the height of T1 before the initial bolus of mivacurium. The degree of neuromuscular blockade during recovery from infusion was referenced to the final baseline at the end of the study, when T4 equaled T1. Anesthetic administration was continued unchanged until T4 equaled T1. An initial IV bolus of mivacurium was administered, and neuromuscular blockade and recovery were observed (1). A second bolus of mivacurium was then administered to establish complete neuromuscular blockade. The total amount administered ranged from 0.10 to 0.68 mg/kg per patient. An infusion of mivacurium (500 pg/mL in 5% dextrose in water) was begun, usually at a rate between 10 and 20 pg.kg-'.min-* when neuromuscular transmission returned to approximately 10% of the initial baseline. The infusion was delivered with a Harvard infusion pump through a T-connector connected to the IV catheter. The IR was titrated to maintain neuromus-

18

BRANDOM ET AL.

ANESTH ANALG 1990;71:16-22

cular blockade between 89% and 99% (i.e., 1%-11% neuromuscular transmission). The mivacurium infusion was continued for as long as required by the surgical procedure (range, 35206 min). For each patient, the mivacurium IR and percent neuromuscular blockade was recorded at the beginning of each 3-min period. Early in the course of infusion administration, rate adjustments were often necessary to maintain neuromuscular blockade in the desired range (89%-99% blockade). For this reason, an average effective IR that excluded the first 15 min of infusion was calculated for each patient. After the initial 15 min, all patients had at least 15 min of infusion (i.e., five additional 3-min intervals) during which neuromuscular blockade was maintained between 89% and 99%. Data from periods during which neuromuscular blockade was outside this range were not included in the analyses. Within each anesthetic group the average IR for individual patients was averaged to yield a group mean. No weighting based on duration of infusion was used. Mivacurium IRs were calculated on both a pg.kgp1-rnin-l and a pg.m-2.min-1 basis. The IR of mivacurium required to maintain neuromuscular blockade between 89% and 99% during the first 15 min of infusion was calculated and compared with the IR calculated after the first 15 min of infusion for each patient. A subset of patients in each group that had the longest infusions was also analyzed separately; eight patients in group H received infusions of mivacurium for at least 75 min, and nine patients in group N received infusions of mivacurium for at least 135 min. Stepwise multiple linear regression was used to assess potential interactions between IR, age, pseudocholinesterase activity, and anesthetic background. Correlation coefficients were calculated to demonstrate associations between independent variables (i.e., age, pseudocholinesterase activity, recovery index) and IR. Paired f-test and repeated measures analysis of variance were used to assess changes in infusion requirement with time. T-test was used to assess differences in demographic characteristics between groups H and N. Standard errors are shown for all mean values. Statistical differences were considered significant when P 5 0.05.

Results There were statistically significant differences between groups H and N in age, weight, height, and body surface area: group H, 76.6 5 6.0 mo, group N, 60.9 ? 4.3 mo; group H, 23.1 f. 1.6 kg, group N,

Table 1. Stepwise Multiple Linear Regression Analysis Equation (1): IR (pgkg-'.min-')

Equation (2): IR (itg.rn-'.rnin-')

=

=

2.1 pseudocholinesterase (UIL) -5.6 (lo-') age (mo) +2.1 anesthetic +5.7

[P = 0.0081

47 pseudocholinesterase (U/L) +55 anesthetic + 69

[P = 0.0121

[P = 0.0191 [P = 0.1081 [ R = 0.51, P = 0.0011.

[P = 0.0731 [ R = 0.40, P = 0.0071.

IR, infusion rate. N = 59. For group H, anesthetic = 0; for group N, anesthetic = 1. Note that anesthetic background does not reach statistical significance in Equations (1)and (2). Removing anesthetic from the equations produces the following: Equa tion(3): IR (Fgkg-'.min-')

= 2.1 pseudocholinesterase

-6.5 (lo-') age (mo) +7.2 Equation(4): IR (wgrn-'.min-')

= 49 pseudocholinesterase

+94.

(U/L) [P = 0.006] [P = 0.0061 ( R = 0.48, P = 0.001] (UIL) [P = 0.0101 iR = 0.33, P = O.OlO]

19.1 ? 0.1 kg; group H, 117 ? 3 cm, group N, 108 ? 3 cm; group H, 0.88 ? 0.04 m2, group N, 0.77 ? 0.03 m2 (mean t SEM). When stepwise multiple linear regression analysis was used to assess the effects of pseudocholinesterase activity, patient age, and anesthetic background on IR, pseudocholinesterase had a statistically significant effect on IR (Table 1). There was a significant positive correlation between pseudocholinesterase activity and IR (Table 2). There were no interactions between any of the independent variables in the regression analysis. Fifty-nine of the 62 patients studied had both pseudocholinesterase activities and dibucaine numbers in the normal range. Two patients from group H had pseudocholinesterase activities more than 20% above normal, and one patient in group N had a dibucaine number more than 20% below normal (Table 3). These three patients were excluded from group analyses (Tables 1-5). The one patient with apparent heterozygous dibucaine resistance and normal pseudocholinesterase activity had a similar response to mivacurium infusion as did other patients in group N with normal pseudocholinesterase activity and normal dibucaine inhibition. The IR of this patient was 15.3 pg.kg-l.min-'. There was no statistically significant difference in the average pseudocholinesterase activity or dibucaine inhibition between groups H and N.

MIVACURIUM INFUSION IN CHlLDREN

Table 2. Correlation Coefficients Between Infusion Rate

and Independent Variables IR (pgkg-l-min ')

(PI Pseudocholinesterase activity (UIL) Age (mo)

T,

@in)

0.33 (0.01) -0.34 (0.01) -0.36 (0.03)

19

ANESTH ANALG 1990;71:16-22

IR (pgm 2*min ') -

(0

n

0.33 (0.01) -0.16" (0.23) -0.32' (0.06)

59 59

36"

IR, infusion rate. Because multiule linear regression demonstrated that useudocholinesterase was a moie significanr determinant of mivacurium IR than was anesthetic background, the two anesthetic backgrounds were combined to assess the correlation between pseudocholinesterase, age, and IR. 'Not significantly different from zero. All other correlations were statistically significant. P values (two-tailed) are reported in parentheses below the correlation coefficient. bThere were only 36 patients for whom T, was available.

Although there was no correlation between pseudocholinesterase and age, age did have a significant independent effect on IR when IR was calculated in pg.kg-'-min-'. Patient age had no effect on IR of mivacurium calculated in pg.mp2.minP' (Tables 1 and 2). There was no statistically significant difference between the IRs for groups H and N when the infusion requirement was referenced to body surface area (Tables 1 a n d 4). The average IR, in pg.m-2.min-1, was approximately 20% greater during narcotic than during halothane anesthesia (Table 4). However, the variability in the IRs ( 6 / / (=~ 0.5) was such that this difference in mean IR did not reach statistical significance with a one-tailed t-test. When IR in pgkg-'.min-' was the dependent variable, both patient age and pseudocholinesterase activity were more significant descriptors of IR than was anesthetic background (Table 1). The average infusion rate administered during the first 15 min of the infusion of mivacurium was greater than the IR thereafter (paired t-test, n = 59). In the nine patients in group N who received a mivacurium infusion for 135 min or longer, repeated measures analysis of variance confirmed a significant change in the rate of infusion with time ( P < 0.01) (Figure 1).A similar analysis of group N excluding the first 15 min of infusion administration demonstrated no significant change in rate of infusion with time ( P > 0.6). In the eight patients in group H who had a mivacurium infusion for 75 min or longer, repeated measures analysis of variance confirmed a significant change in rate of infusion with time with or without the first 15 min of infusion administration included in the calculations ( P < 0.01) (Figure 2). The slight decrease in

rate of infusion of mivacurium in the second hour in group H was so small, however, that it was not statistically significant by multiple range tests (Student-Newman-Keuls). There was no difference in rate of recovery of neuromuscular function between anesthetic groups in terms of 25%-75% recovery index (T,,,) or time to recovery of the train-of-four ratio to 20.75 (Table 5). After termination of the infusion, spontaneous recovery from 89%-99% blockade to a train-of-four ratio of 20.75 occurred in 9.8 k 0.4 min (n = 34). The T2575 after discontinuation of the infusion was 4.0 0.2 min ( n = 36). There was no correlation between duration of infusion and T,,. There was a significant negative correlation between IR in pg.kg-l.min-l and T25-75 (Table 2). Neostigmine (0.04-0.06 mg/kg) was administered to 22 patients at levels of spontaneous recovery ranging from 10% to 50% (90%-50% blockade), Recovery to a train-of-four ratio of 20.75 occurred within 1.2-3.8 min after administration of neostigmine in these 22 patients.

*

Discussion In this pediatric study pseudocholinesterase activity was the major factor that influenced the IR for mivacurium. Patients with pseudocholinesterase activity above normal were resistant to the neuromuscular effects of mivacurium administered by infusion. Although one might expect a homozygous dibucaineresistant patient to be very sensitive to mivacurium, the one child with low dibucaine inhibition in this study responded to an infusion of mivacurium as did children with normal pseudocholinesterase activity and dibucaine inhibition. It would appear that at the relatively low concentrations of mivacurium present in the plasma during an infusion titrated to 95% neuromuscular blockade, and at the even lower concentrations present during recovery from mivacurium, there was sufficient normal pseudocholinesterase in the blood of a presumably heterozygous child to metabolize mivacurium at a normal rate. Age was found to be an important factor in determining mivacurium IR when IR was calculated on the basis of body weight, but not for IR calculated on the basis of body surface area. There was a small but statistically significant difference between groups H and N with respect to age. The patients in group N were on average 16 mo younger than those in group H. This small but significant difference in age, and hence in body weight/surface area as well, increases the difference between the IRs in pg.kg-'.min-' of the anesthetic groups. The average IRs of groups H

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BRANDOM ET AL.

ANESTH ANALG 1990;71:16-22

Table 3. Effect of Abnormal Pseudocholinesterase Activity or Dibucaine Number on Infusion Rate Pseudocholinesterase activity Patient

(U/L)

Dibucaine inhibition (%)

1 2 3

5.2 8.5 10.6

60 87 73

IR Anesthetic group

N H H

(pgm-'.min-')

474 588" 936"

T,, NA 3.2 3.6

IR, infusion rate; NA, not available. Normal range: pseudocholinesterase activity = 2 . 5 7 . 1 UIL, dibucaine inhibition = 7 0 8 - 9 5 8 , "These two 1Rs are more than two standard deviations above the mean IR of group H.

Table 4. Mivacurium Infusion Requirements Group

n

H

21

N

38

IR (pgkg-'.min-') 12.4 t 1.0" (4.7-21.8) 15.6 t 0.8" (7.S31.4)

IR (pgrn-'.min- ') 315 t 26 (126552) 375 2 19 (197-669)

IR, infusion rate. Values are rncan ? SEM (range). "P < 0.05, statistically significant difference between anesthetic groups.

Table 5 . Spontaneous Recovery After Termination of Mivacurium Infusion Group H

N

T'W, 3.8 t (n = 4.1 ? (n =

T4/T1 2 0.75 0.3 15) 0.3 21)

10.3 2 0.8 ( n = 14) 9.4 2 0.4 ( n = 20)

There was no statistically significant difference between anesthetic groups. Values are mean 2 SEM.

and N differed by about 30% when calculated on the basis of weight and by only 20% when calculated on the basis of body surface area. The fact that age was not significant in determining mivacurium IR based on body surface area, but was an important factor in determining mivacurium IR based on body weight, suggests that the influence of age on IR is related to developmental changes in extracellular fluid volume. The infusion rate would be expected to depend on the sensitivity of the neuromuscular junction to the drug and on the clearance of the drug (13). Beyond the age of 2 yr, significant change in the sensitivity of the neuromuscular junction to nondepolarizing neuromuscular blocking agents is unlikely (14,lS). Nevertheless, a change in the volume of distribution of a neuromuscular blocking drug may well occur in patients between 2 yr of age and adulthood. The volume of distribution may be expected to decrease with increasing age and decreasing volume of extracellular fluid per kilogram

body weight. However, the ratio of extracellular fluid volume to body surface area is relatively unchanged with age. For mivacurium there was a significant difference in the ED,,, calculated in pglkg, between children and adults during nitrous oxide-narcotic anesthesia (1).When the ED,, was calculated on the basis of body surface area, there was no significant age-related difference (1).These observations suggest that there are age-related changes in the volume of distribution of mivacurium, but not in the effective plasma concentrations. If the effective plasma concentrations do not change with age, then the agerelated changes in IR (pg.kg-'.min-l) must be related to changes in clearance of mivacurium that parallel the expected age-related changes in volume of distribution. Referencing IR to body surface area rather than to weight appears to control for such age-related changes in this study, because age is not a significant factor influencing mivacurium IR (pg.m-2.min-1). There appear to be similar agerelated changes in the clearance and volume of distribution of atracurium (16). In contrast, the clearance of many other neuromuscular blocking drugs, those that are not removed from the blood predominantly by processes occurring in the plasma, does not increase proportionately with the volume of distribution (14,17). In children, referencing mivacurium IR to body surface area rather than to weight eliminated age as an important predictor of IR. However, differences in IR are present between pediatric and adult patients whether IR is calculated on the basis of body weight or body surface area. The mivacurium IR in adults during nitrous oxide-narcotic anesthesia is about 250 pg.m-2.min-1 (6.4 pg.kg-'.min-l) or less (11,12), whereas in children in this study receiving a similar anesthetic, mivacurium IR is 375 pg.m-'.min-' (15.6 pg.kg-'.min-l). It is expected that the infusion requirement at steady state will be determined by required plasma concentration and clearance (13). The disparity between children and adults in mivacurium IR based on pg.m-2.min-1 suggests that

MIVACURIUM INFUSION IN CHILDREN

ANESTH ANALG 1990;71: 1 6 2 2

21

25

20

Figure 1. x-axis, time in minutes; y-axis, infusion rate is rate (pgFkg-'.min-') required to maintain 89%-99% neuromuscular blockade (mean f SEM). Rate of mivacurium infusion at 3-min intervals from the start of infusion through the first 135 min in the nine patients in group N with the longest duration of infusion.

15

'5O I

0

15

there may be significant age-related differences in the clearance of mivacurium that are independent of the change in weight/surface area ratio with age. There may be significant changes in pseudocholinesterase activity with age that could not be identified in these studies. Pharmacokinetic studies of mivacurium may provide direct answers to questions regarding the clearance of mivacurium. At present one could only estimate the mean residence time of mivacurium from the ratio of ED,, and IR titrated to produce 95% neuromuscular blockade (18). From these data in 3 the mean children (2717 ~ g . m - ~ / 4 2pg-m-2.min-') residence time of mivacurium is about 6 min. Similar data in adults (3067 pg.mp2/290 pg.mp2.min-l) ( l , l l , l Z ) suggest that the mean residence time of mivacurium in adults is close to 10 min. Previous studies of the effects of halothane on potentiation of neuromuscular blockade in children have reported somewhat conflicting results. In a study of atracurium infusion requirements that em30.0

25.0

20.0

Figure 2. x-axis, time in minutes; y-axis, infusion rate is rate (pg.kg-'.min ') required to maintain 89%-99% neuromuscular blockade (mean t SEM). Rate of mivacurium infusion at 3-min intervals from the start of infusion through the first 75 min in the eight patients in group H with the longest duration of infusion.

1 +

r\

0-r

5.0

i

30

45

60

75

90

105

120

135

ployed stimulus parameters identical to those of this study of mivacurium infusion requirements and similar electromyographic monitoring of neuromuscular function (19),halothane (0.8% end-tidal) significantly potentiated atracurium-induced neuromuscular blockade by about 30%. In a study administering a single stimulus at 0.1 Hz (rather than a train-of-four stimuli) and force transduction monitoring (20), there was no significant potentiation by halothane of neuromuscular blockade produced by infusion of atracurium. The study of the mivacurium dose-response relationship with methods identical to those of this infusion study (1) demonstrated a significant potentiation of 15%-20% by halothane (0.8% end-tidal). A mivacurium dose-response study with similar stimulation parameters, but with force transduction monitoring (Z), failed to demonstrate potentiation by halothane. Neither of these studies of mivacurium (1,2) found a significant delay in the rate of spontaneous recovery of neuromuscular function during

22

ANESTH ANALG 1990;71:16-22

halothane anesthesia. It would appear that potentiation of mivacurium-induced neuromuscular blockade by halothane may be less than potentiation of atracurium-induced neuromuscular blockade. In any case, the interpatient variability in mivacurium infusion requirement was too large to allow observation of a statistically significant potentiation by halothane in the present study. In conclusion, mivacurium can be administered to children during either nitrous oxide-halothane or nitrous oxide-narcotic anesthesia for several hours with no evidence of cumulation and with rapid spontaneous or pharmacologically induced return of neuromuscular function after termination of infusion. The average IR calculated here would be useful as an initial IR. However, as interpatient variability is more than threefold, infusions should be titrated to effect, as documented by appropriate neuromuscular monitoring. We thank Wayne DellaMaestra for his valuable assistance with data analysis, and Lillian Hankins, without whom the study could not have progressed as scheduled.

BRANDOM ET AL.

6. Goudsouzian NG, Liu LM. The neurornuscular response of infants to a continuous infusion of succinylcholine. Anesthesiology 1984;60:97-101. 7. Gronert GA, Theye RA. Pathophysiology of hyperkalernia induced by succinylcholine. Anesthesiology 1975;43:89-99. 8. Hannallah RS, Oh TH, McGill WA, Epstein BS. Changes in heart rate and rhythm after intramuscular succinylcholine with or without atropine in anesthetized children. Anesth Analg 1986;65:1329-32. 9. Henderson WA. Succinylcholine-induced cardiac arrest in unsuspected Duchenne muscular dystrophy. Can Anaesth SOCJ 1984;31:44&6. 10. Brandom BW, Woelfel SK, Cook DR, Weber S, Powers DM, Weakly JN. Comparison of mivacurium chloride (BW B1090U) and suxarnethonium chloride administered by bolus and infusion. Br J Anaesth 1989;62:48%93. 11. Powers D, Weber S, Brandom BW, et al. BW B1090U infusion requirements in adults during isoflurane or narcotic anesthesia. Anesthesiology 1987;67:A359. 12. Shanks CA, Fragen RJ, Pemberton D, Katz JA, Risner ME. Mivacuriurn-induced neuromuscular blockade following single bolus doses and with continuous infusion during either balanced or enflurane anesthesia. Anesthesiology 1989;71:362-6. 13. Gibaldi M, Perrier D. Pharrnacokinetics, 2nd ed. New York: Marcel Dekker, 1982:321. 14. Fisher DM, O’Keefe C, Stanski DR, Cronnelly R, Miller RD, Gregory GA. Pharrnacokinetics and pharrnacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology 1982;57:203-8.

15. Meretoja OA, Wirtavuon K, Neuvonen PJ. Age-dependence of

References 1. Sarner JB, Brandom BW, Woelfel SK, et al. Clinical pharrnacology of mivacuriurn chloride (BW B1090U) in children during nitrous oxide-halothane and nitrous oxide-narcotic anesthesia. Anesth Analg 1989;68:11&21. 2. Goudsouzian NG, Alifimoff JK, Eberly C, et al. Neuromuscular and cardiovascular effects of mivacurium in children. Anesthesiology 1989;70:23742. 3. Durant NN, Katz RL. Suxamethonium. Br J Anaesth 1982;54: 195208. 4. Innes RK, Strornme JH. Rise in serum creatine phosphokinase associated with agents used in anaesthesia. Br J Anaesth 1973;45:185-90. 5. Van Der Spek AFL, Fang WB, Ashton-Miller JA, Stohler CS, Carlson DS, Schork MA. The effects of succinylcholine on mouth opening. Anesthesiology 1987;67:459-65.

the dose-response curve of vecuronium in pediatric patients during balanced anesthesia. Anesth Analg 1988;67214. 16. Brandom BW, Stiller RL, Cook DR, et al. Pharrnacokinetics of atracurium in anaesthetized infants and children. Br J Anaesth 1986;58:1210-3. 17. Fisher DM, Castagnoli K, Miller RD. Vecuronium kinetics and dynamics in anesthetized infants and children. Clin Pharmacol Ther 1985;37:402-6. 18. Gibaldi M, Perrier D. Pharmacokinetics, 2nd ed. New York: Marcel Dekker, 1982:414.

19. 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. 20. Goudsouzian N, Martyn J, Rudd GD, Liu LMP, Lineberry CG. Continuous infusion of atracurium in children, Anesthesiology 1986;64:171-4.

Mivacurium infusion requirements in pediatric surgical patients during nitrous oxide-halothane and during nitrous oxide-narcotic anesthesia.

We were interested in determining the infusion rate of mivacurium required to maintain approximately 95% neuromuscular blockade during nitrous oxide-h...
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