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© 1999 International Anesthesia Research Society
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Abstract |
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We studied the neuromuscular blocking effects of rapacuronium (Org 9487) (dose-response curve, onset, and 50% effective dose [ED50] value), and changes in heart rate and blood pressure, as well as evidence of histamine release in neonates, infants, and children in an open-label, randomized, two-center study. Fifteen neonates, 30 infants, and 30 children were studied. Anesthesia was induced and maintained with propofol, nitrous oxide:oxygen (60:40), and fentanyl. Mechanomyographic monitoring of neuromuscular function was performed at the thumb. The potency (ED50) for neonates, infants, and children were 0.32 (95% confidence interval [CI] 0.15–0.61), 0.28 (95% CI 0.11–0.61), and 0.39 (95% CI 0.17–0.85) mg/kg, respectively. Neonates who received 0.3, 0.6, or 0.9 mg/kg Org 9487 developed a maximum T1 twitch depression of 34 ± 28%, 98 ± 3%, and 99 ± 2%, respectively. Time-to-peak effect (onset time) for 0.9 mg/kg Org 9487 was 57 ± 20 s. Maximum percent T1 twitch depression (±SD) in infants who received 0.3, 0.6, or 0.9 mg/kg rapacuronium was 41 ± 34%, 96 ± 7%, and 100 ± 1%, respectively. Time-to-peak effect for 0.9 mg/kg Org 9487 was 62 ± 29 s. In children 0.3, 0.6, and 0.9 mg/kg rapacuronium resulted in an average percent T1 twitch suppression of 29 ± 23, 83 ± 11, and 90 ± 16, respectively. Time-to-peak effect of 0.9 mg/kg Org 9487 was 96 ± 33 s, respectively. There was no evidence of histamine release or significant changes in heart rate or blood pressure in either group at any dose. Rapacuronium is a low-potency nondepolarizing muscle relaxant with a fast onset of relaxation and minimal cardiovascular effects. Its potency (ED50) is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg). T1 suppression (90% ± 16) is less and time to peak effect (96 ± 33 s) is greater (0.9 mg/kg rapacuronium) in children, compared with the combined group of infants and neonates.
Implications: This study assesses the potency of rapacuronium (Org 9487) in pediatric patients. The potency of rapacuronium is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg).
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Introduction |
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Rapacuronium (Org 9487) is a new amino-steroidal nondepolarizing muscle relaxant. Rapacuronium has a fast onset and short duration in adults (1–3). The potency (90% effective dose [ED90]) of rapacuronium in adults under 0.5 minimal alveolar anesthetic concentration of halothane/nitrous oxide/fentanyl/thiopental anesthesia is estimated as 1.15 mg/kg (1). Under isoflurane anesthesia (2) a dose of 1.5 mg/kg (1.3 times the ED90) produced onset of maximum block in 88 (±20) s, excellent intubating conditions at 1 min, and re- turn of train-of-four (TOF) to T4/T1 70% in 23.6 (±6.4) min. Preliminary data on the 50% effective dose (ED50) of rapacuronium during opioid/nitrous oxide/oxygen anesthesia ranges from 0.32 to 0.35 mg/kg (18–64 yr) and from 0.2 to 0.27 mg/kg in the geriatric population (
65 yr) (3). The purpose of this study was to determine the potency (as defined by ED50) of rapacuronium in neonates, infants, and children during narcotic-nitrous oxide-propofol anesthesia. The onset, cardiovascular effects, and clinical evidence of histamine release in response to the different doses of rapacuronium used to establish the ED50 dose were also examined.
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Methods |
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This study was an open-label, randomized, two-center study. After institutional approval, parental informed consent and child assent (
7 yr), 15 neonates (aged 1–30 days), 30 infants (aged 1–12 months), and 30 children (aged 1–12 years) ASA physical status I or II requiring general anesthesia for nonemergent surgical procedures were prospectively randomized into one of three rapacuronium dosing groups (0.3, 0.6, or 0.9 mg/kg). Patients with a history of prematurity (<38 weeks), neuromuscular, renal, or hepatic disease were excluded. Anesthesia was induced in all patients before intubation via an IV catheter. Induction of anesthesia was accomplished with propofol 2.5–3.5 mg/kg and fentanyl (1–2 µg/kg), and was maintained with a propofol infusion of 200–300 µg · kg-1 · min-1 nitrous oxide/oxygen (60/40) and supplemental fentanyl (1 µg/kg boluses) as required. Three neonates considered at risk for aspiration (1—tracheo-esophageal fistula, 2—small bowel atresia) had their tracheas intubated awake and were induced with anesthesia immediately postintubation. Ventilation was maintained by assisted mask or tracheal ventilation using capnography with CO2 sidestream sampling near the mouth or proximal portion of the endotracheal tube to ensure normocarbia. No halogenated agents or vagolytic drugs were administered. Routine monitoring of vital signs using an automatic blood pressure cuff and electrocardiogram was recorded every 1 min. Forearm skin and/or axillary temperature was also monitored. Neuromuscular monitoring was performed by stimulating the ulnar nerve at the wrist via surface electrodes using a supramaximal TOF stimulus (2 Hz for 2 s at 12-s intervals) generated by a Digistim II® generator. The force of adduction of the thumb was recorded using a Myotrace adductor pollicis monitor® and a strip chart recorder. A baseline tension of 50, 100, and 200 g for neonates, infants, and children, respectively, was applied to the thumb before stimulation. After 5 min of baseline twitch stabilization, patients in the newborn, infant, and children groups randomly received either 0.3, 0.6, or 0.9 mg/kg rapacuronium administered as a bolus into the t-connector of a rapidly infusing IV solution. The time-to-peak effect, and maximum percent suppression of T1 of the TOF were measured more than 5 min postinjection. Heart rate and blood pressure were recorded prior to and every minute for 5 min after injection of rapacuronium. Adverse effects (wheezing, hypotension, dysrhythmias, rash) possibly related to rapacuronium were also monitored. ED50 values were determined by least-squares linear regression of the probit of twitch depression. Confidence intervals were determined using the inverse regression procedure (4). ED50 values were also determined using nonlinear regression analysis (Hill equation). Percent changes in heart rate and blood pressure at each minute during the 5-min postinjection period were analyzed using repeated-measures analysis of variance. Maximum suppression of T1, time-to-peak effect, and ED50 between different age groups were compared using analysis of variance for three groups. Results were considered statistically significant at P < 0.05.
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Results |
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Patients receiving different doses of rapacuronium within each age group (neonates, infants, and children) were comparable with respect to height, weight, age, gender, race, and ASA physical status (Table 1). All patients were assessed to be clinically well hydrated and cardiovascularly stable before induction. Two neonates (0.6 and 0.9 mg/kg group) had small atrial septal defects that were insignificant by echocardiography. Two patients in the infant group received incorrect doses of rapacuronium that precluded analysis of neuromuscular data. Forearm skin temperatures remained above 34°C and/or axillary temperature greater than 35.5°C in all patients.
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Neuromuscular Response
The dose-response curves of rapacuronium for neonates, infants, and children are shown in Fig. 1. The estimated ED50 (95% confidence interval), using probit, as well as the Hill equation for neonates, infants, and children, is shown in Table 2. ED50 values are similar between neonates and infants. Children had higher values than neonates and infants, but the difference was not statistically significant. The maximum suppression of T1 (%) and time-to-peak effect (s) is shown for each age group and each dose (rapacuronium 0.3, 0.6, and 0.9 mg/kg) in Table 3. There were no statistical differences between the three age groups comparing maximum T1 suppression and time-to-peak effect at 0.3 and 0.6 mg/kg rapacuronium. There were also no differences in maximum suppression of T1 and time-to-peak effect at 0.9 mg/kg rapacuronium between neonates and infants. However, the combined group of neonates and infants had a significantly higher maximum suppression of T1 (P = 0.025) and a significantly faster time-to-peak effect (P = 0.005), compared with children at 0.9 mg/kg rapacuronium.
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Hemodynamic Response
There were no statistically significant differences in treatment groups with respect to changes in heart rate or blood pressure. Furthermore, no clinically significant cardiovascular changes that required intervention were noted in any individual patient due to rapacuronium.
No intraoperative signs (rash, bronchospasm, or cardiovascular changes) suggestive of histamine release were noted.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The potency of neuromuscular blocking drugs is usually estimated by comparing doses that produce 50, 90, or 95% depression of the twitch produced by the adductor pollicis muscle in response to supramaximal ulnar nerve stimulation. This study was designed to determine the ED50 of rapacuronium. ED50 values are on the linear portion of the sigmoidal dose response curve, and are more robust than values at higher extremes (e.g., ED90 or 95% effective dose) that have larger confidence intervals and are subject to wider variations with small changes in dose. Effective dose values can be analyzed using linear (probit) or nonlinear values. Both techniques give similar ED50 values in our study (Table 2). Linear regression analysis has been more often used in neuromuscular studies in children (5–7) and is therefore used in the subsequent discussion of our results.
The neuromuscular blocking effects of muscle relaxants vary with age. The least well-studied age group is the neonate. Fade to tetanic nerve stimulation in neonates without neuromuscular blocking drugs and their slow rate of muscle contraction indicate that neuromuscular transmission is immature in the neonate (8,9). The dose response of vecuronium in different pediatric age groups has been carefully studied during balanced anesthesia (10). The ED50 of vecuronium in neonates (25 µg/kg) was not different from that in infants, but was significantly lower than the ED50 of children ages 3–10 yr (44 µg/kg). It is speculated that the increased sensitivity in neonates and infants and relative resistance in children is partially due to changes in drug distribution and muscle mass in these age groups (10).
Although not statistically significant, our study also showed a higher ED50 value for children, compared with neonates and infants. This relative resistance in children is also explained by a statistically significant smaller maximum suppression of T1 and a slower time-to-peak effect of rapacuronium (dose of 0.9 mg/kg) in children, compared with the combined group of infants and neonates.
Our study shows that rapacuronium (ED50 0.32 mg/kg, 0.28 mg/kg, and 0.39 mg/kg in neonates, infants, and children, respectively) is less potent then other nondepolarizing muscle relaxants. The ED50 of vecuronium under nitrous oxide-narcotic anesthesia in infants (1 mo–1 yr) and children (2–12 yr) is approximately 0.025 and 0.041 mg/kg, respectively (5). The ED50 of rocuronium under similar conditions for infants and children is 0.147 and 0.205 mg/kg, respectively (6). The ED50 of atracurium in infants and children is 0.112 and 0.135 mg/kg, respectively (7). Rapacuronium’s low potency may explain its rapid onset in comparison with other nondepolarizing muscle relaxants. Neuromuscular drugs with low potency require more molecules to achieve the desired effect. This causes a larger gradient into the site of action (law of mass action) (1). Other potential causes for its rapid onset include high lipophilicity that promotes diffusion to the neuromuscular junction (11) or its effects on Ca2+ channels to increase muscle blood flow or decrease contractility (12).
The preliminary data of the ED50 of rapacuronium during opioid/nitrous oxide/oxygen anesthesia ranges from 0.32 to 0.35 mg/kg in adults (18–24 yr) and from 0.2 to 0.27 mg/kg in the geriatric population (65 yr) (3). Thus, the potency in children is similar to adults.
A study (13) of infants and children when thiopental/nitrous oxide/midazolam anesthesia was used confirmed the rapid onset of acceptable intubating conditions of rapacuronium. Rapacuronium (1 mg/kg) produced acceptable intubating conditions in 11 of 11 infants within 1 min. This is consistent with our data showing that a dose of 0.9 mg/kg rapacuronium produced 100 ± 1% twitch height depression in 62 ± 29 s.
In conclusion, rapacuronium’s (Org 9487’s) estimated ED50, and onset is described and compared in neonates, infants, and children under narcotic-nitrous oxide-propofol anesthesia. Its low potency is associated with a rapid onset of action. No clinically significant changes in heart rate, systolic blood pressure, or diastolic blood pressure were shown in the doses used. No evidence of histamine release was noted.
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Acknowledgments |
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This work was supported in part by Organon, Inc., West Orange, NJ.
The authors acknowledge and are grateful for technical support from P. Abraham.
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Footnotes |
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This work was performed at the Children’s National Medical Center and the Children’s Hospital of Buffalo.
Presented in part at the annual meeting of the American Society of Anesthesiologists, New Orleans, LA, October 1996.
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References |
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- Wierda JMKH, Beaufort AM, Kleef V, et al. Preliminary investigations of the clinical pharmacology of three short-acting non-depolarizing neuromuscular blocking agents, ORG 9453, ORG 9489, and ORG 9487. Anaesth 1994;41:213–20.
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Wierda JMKH, van der Broek L, Proost JH, et al. Time course and endotracheal intubating conditions of ORG 9487, a new short acting steroidal muscle relaxant, a comparison with succinylcholine. Anesth Analg 1993;77:579–84.
[Abstract/Free Full Text] - Org Inc. Investigator’s brochure—ORG 9487 (rapacuronium) for injection. West Orange, NJ: Org Inc., 1998.
- Snedecor GW, Cochran WG. Statistical methods, 8th ed. Ames:Iowa State University Press, 1989:170–2.
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Meretoja OA, Wirtavuori K, Neuvonen PJ. Age dependence of the dose-response curve of vecuronium in pediatric patients during balanced anesthesia. Anesth Analg 1988;67:21–6.
[Abstract/Free Full Text] - Meretoja OA, Taivainen T, Erkola O, et al. Dose-response and time-course of effect of rocuronium bromide in paediatric patients. J Anaesthesiol 1995;12 (Suppl 11):19–22.
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Meakin G, Shaw EA, Baker RD, Morris P. Comparison of atracurium-induced neuromuscular blockade in neonates, infants and children. Br J Anaesth 1988;60:171–5.
[Abstract/Free Full Text] - Goudsouzian NG. Maturation of neuromuscular transmission in the infant. Anaesth 1980;52:205–13.
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Goudsouzian NG, Standaert FG. The infant and the myoneural junction. Anesth Analg 1986;65:1208–17.
[Free Full Text] - Meretoja OA. Neuromuscular blocking agents in paediatric patients: influence of age on response. Anesth Intensive Care 1990;18:440–8.
- Wierda JMKH, Proost JH, Muir A, Marshall RJ. Design of drugs for rapid onset. Anaesth Pharmacol Rev 1993;1:57–63.
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Tian L, Mehta MP, Prior C, Marshall IG. Relative pre- and post-junctional effects of a new vecuronium analogue, ORG 9426, at the rat neuromuscular junction. Br J Anaesth 1992;69:284–7.
[Abstract/Free Full Text] - Motsch J, Meakin G, Meretoja OA, et al. A dose-ranging study of ORG 9487 on endotracheal intubating conditions in infants and children [abstract]. Anesthesiology 1996;85:A1084.
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