Anesth Analg 2001;92:1199-1202
© 2001 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Duration of Action of Vecuronium After an Intubating Dose of Rapacuronium, Vecuronium, or Succinylcholine
Tong J. Gan, MB, FRCA, FFARCS (I)*,
Raman Madan, MB, FRCA, FFARCS (I)*,
Ratan Alexander, MB, FRCA*,
Rajiv Jhaveri, MB, FRCA*,
Habib El-Moalem, PhD*,
Kevin Weatherwax, BS, CCRC*, and
Peter S. A. Glass, MB, FFA (SA)
*Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; and University Medical Center at Stony Brook, Department of Anesthesiology Health Sciences Center, Stony Brook, New York
Address correspondence and reprint requests to T. J. Gan, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710. Address e-mail to gan00001{at}mc.duke.edu
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Abstract
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Rapacuronium (RAP) is a new, rapid-onset, short-duration, nondepolarizing neuromuscular blocker. If RAP is used to facilitate endotracheal intubation, what will the duration of a subsequent maintenance dose of vecuronium (VEC) be? We investigated the duration of action of a maintenance dose of VEC after intubation with RAP, VEC, or succinylcholine (SUC). Adult surgical patients under general anesthesia were randomly allocated to receive a tracheal intubating dose of RAP 1.5 mg/kg, VEC 0.1 mg/kg, or SUC 1 mg/kg. The anesthetic was induced with propofol and maintained with propofol, nitrous oxide, and oxygen. Neuromuscular function was monitored with electromyography. Recovery of the intubating dose of neuromuscular blocker was allowed to occur spontaneously until the first twitch of the train-of-four (T1) reached 50% of baseline, and then VEC 0.025 mg/kg (0.5 x 95% effective dose [ED95]) was administered. The onset, duration, and recovery to T1 = 25% and 50% were recorded. The durations of action (recovery of T1 25%) after intubating doses of RAP, VEC, and SUC were 13.7 ± 5.3, 43.2 ± 13.2, and 9.2 ± 3.7 min (mean ± SD), respectively (P < 0.0001). The times to maximum depression of T1 after a maintenance dose of VEC (0.5 x ED95) were 5.4 ± 2.9, 5.1 ± 2.5, and 5.3 ± 2.8 min (mean ± SD) for the RAP, VEC, and SUC groups, respectively. Recoveries to T1 25% after VEC for the RAP, VEC, and SUC groups were 18.9 ± 11.5, 21.5 ± 8.03, and 12.8 ± 8.4 min, and at T1 50% they were 21.5 ± 9.1, 30.8 ± 9.5, and 15.5 ± 9.7 min (mean ± SD), respectively (P < 0.001, RAP and VEC versus SUC). The duration of action of a maintenance dose of VEC was similar after an intubating dose of RAP or VEC but was shortened when preceded by an intubating dose of SUC.
Implications: The duration of action of a maintenance dose of vecuronium was longer after an endotracheal intubating dose of rapacuronium compared with succinylcholine.
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Introduction
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Rapacuronium (RAP) is a new nondepolarizing neuromuscular blocker (NMB) that has a rapid onset and offset of neuromuscular blockade similar to that of succinylcholine (SUC) (1). With the brief duration of action and the potential for prolongation of effect after subsequent maintenance doses, it is likely that another NMB will be used after endotracheal intubation during a RAP block. Vecuronium (VEC) is a likely choice as a maintenance drug for subsequent neuromuscular blockade.
Prior administration of a nondepolarizing NMB may prolong the clinical duration of VEC (2). The pharmacodynamic interactions between a maintenance dose of VEC after an intubating dose of RAP have not been reported. This study was therefore undertaken to assess the time course of neuromuscular blockade with a maintenance dose of VEC after an intubating dose of RAP, VEC, or SUC.
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Methods
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After IRB approval and written informed patient consent, 91 adult patients, aged 18–70 yr, ASA physical status I–III, with an expected surgical duration of longer than 120 min were randomly allocated in a double-blinded fashion to receive either RAP 1.5 mg/kg, VEC 0.1 mg/kg, or SUC 1 mg/kg to facilitate tracheal intubation. Patients taking steroids, anticonvulsants, or aminoglycoside or macrolide antibiotics; who had a history of neuromuscular disease or significant renal or hepatic dysfunction; were morbidly obese; or whose medical history or physical examination suggested possible difficulty with airway management were excluded from participation.
Neuromuscular function was recorded by using an electromyograph (EMG) monitor (RelaxographTM; Datex Instrumentarium Inc., Helsinki, Finland). Stimulating electrodes were applied to the ulnar nerve, and EMG activity was recorded from surface electrodes applied to the adductor pollicis muscle on the hand opposite the IV catheter. Randomization was achieved with a random number generation by a computer; the numbers were placed in sealed envelopes. Before the induction of anesthesia, all patients received 1–5 mg midazolam and 2–5 µg/kg fentanyl before calibration of the EMG monitor. A period of twitch height stabilization of the baseline EMG was allowed to occur. Anesthesia was then induced with propofol 1–2.5 mg/kg over 30 s titrated to loss of consciousness followed immediately by the randomized NMBs. The study drug was prepared by a pharmacist in equal volumes. Anesthesia was then maintained with a propofol infusion (100–180 µg · kg-1 · min-1) and boluses of fentanyl and 66% N2O in oxygen. Ventilation was maintained to keep end-tidal CO2 tension between 33 and 42 mm Hg, and body temperature was kept >35.5°C by use of an esophageal temperature probe. Recovery of neuromuscular blockade was allowed to occur spontaneously until the first twitch of the train-of-four (T1) reached 50%. VEC 0.025 mg/kg diluted to 5 mL was then administered, and the times for the maximal reduction in T1 and the return of T1 to 25% and 50% were recorded.
For estimation of sample size, 25 patients were required to detect a difference of 10 min in the duration of action of the maintenance dose of VEC after an intubating dose between any two groups, with an 
= 0.05 and ß = 0.2. The demographic characteristics of the three groups were compared by Kruskal-Wallis test. The neuromuscular recovery data were analyzed with the Kruskal-Wallis test for the three groups, and Wilcoxon’s two-sample ranked sum test was used for multiple comparisons between any two groups. A Bonferroni correction was made to account for the pairwise comparisons. P < 0.05 for the Kruskal-Wallis test and P < 0.017 for the Wilcoxon test were considered statistically significant.
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Results
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There were 33, 25, and 33 patients in the RAP, VEC, and SUC groups, respectively. Patient demographic variables, age, weight, sex, ASA physical status, and duration of anesthesia were similar among groups ( Table 1). Patients in the RAP and SUC groups formed part of a subset of patients that were included in a multicenter study assessing intubating conditions of these two NMBs. The findings of this potion of the study were reported as part of the results of the multicenter study (3).
The time (mean ± SD) from the initial drug administration (intubating dose) to T1 = 25% and 50% was significantly longer in the VEC group, compared with the RAP and SUC groups (P < 0.001, significant differences among three groups and pairwise comparisons between any two groups) ( Table 2). The time to T1 = 25% and 50% was similar between RAP and VEC groups but shorter in the SUC group (P < 0.001) ( Table 3).
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Table 3. Maximum Depression of Twitch Height and Time to Maximum Twitch Depression and to Recovery of the First Twitch of the Train-of-Four (T1) to 25% and 50% of the Maintenance Dose of Vecuronium-Induced Neuromuscular Blockade After Intubating Doses of Rapacuronium, Vecuronium, and Succinylcholine
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Discussion
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We demonstrated that the duration of action of a maintenance dose of VEC is prolonged after an intubating dose of either RAP or VEC compared with SUC. However, the time to maximum depression of neuromuscular blockade after the administration of a maintenance dose of VEC was similar in the three groups.
RAP is metabolized by the liver. The 3-desacetytl metabolite of RAP may be more potent than the parent compound (calculated 90% effective dose is 0.48 mg/kg). This metabolite has a low clearance from plasma and a long elimination half-life of 160 minutes (4). The active metabolite may account for the delayed recovery from RAP after an infusion longer than one hour (5). Thus, RAP may be the preferred drug for intubation of the trachea, but maintenance of neuromuscular blockade may be provided by another nondepolarizing NMB.
There may be an economic advantage for using RAP. Currently, the only approved muscle relaxant with a similar rapid onset and short duration of action is SUC. However, SUC has several adverse effects that range from mild (e.g., myalgia and bradycardia) to life threatening (e.g., hyperkalemia, anaphylactic reaction, and malignant hyperthermia). Dexter et al. (6) recently demonstrated that although the acquisition cost of SUC is minimal, the true cost (direct cost of the drug plus the cost of its adverse outcome) is much higher. By using a cost identification model when SUC was administered for nonemergency purposes according to manufacturers’ guidelines in adults, the true cost of a dose of SUC was estimated to be US$37, about 10 times its acquisition cost. VEC may be chosen to maintain neuromuscular blockade after an endotracheal intubating dose of RAP when cases are unexpectedly prolonged. There may also be an economic advantage to using a RAP and VEC combination versus rocuronium only for endotracheal intubation and maintenance of neuromuscular blockade in prolonged cases.
There is no study investigating the interaction between RAP and VEC. However, the prolongation of effect has been demonstrated when two NMB drugs from similar class were combined. Kay et al. (7) demonstrated a prolongation of action of the first two maintenance doses of VEC after an intubating dose of pancuronium. When nondepolarizing NMBs of different classes were used, marked prolongation of effects was seen. Kim et al. (8) found significant prolongation of the duration of action of maintenance doses of mivacurium after an intubating dose of either VEC or rocuronium. The clinical duration of the maintenance dose of mivacurium was significantly longer after an intubating dose of rocuronium (40 ± 8 minutes) and VEC (28 ± 6 minutes) than of mivacurium (12 ± 3 minutes). Similar results were reported by Erkola et al. (9) when they demonstrated that the action of mivacurium was prolonged after intubation with pancuronium. Similar prolongations were demonstrated with VEC and pipecuronium (10) and with rocuronium and mivacurium (11).
The mechanisms underlying interactions between various NMB drugs are complex. Kim et al. (8) recently described the interactions between mivacurium, rocuronium, and VEC. With consecutive administration of NMB drugs, the duration of action depends more on the dynamics of the first NMB drug rather than the subsequent NMB. However, with each subsequent maintenance dose, a smaller proportion of receptor sites is occupied by the first NMB drug. Thus the duration of action of each subsequent dose of the maintenance NMB drug will more closely mimic the drug used for maintenance of neuromuscular blockade. The duration of action of VEC or rocuronium after an intubating dose of mivacurium was significantly shorter than that after an intubating dose of VEC or rocuronium. This is in agreement with our findings, in which the duration of action of the maintenance dose of VEC was a little shorter after RAP compared with VEC.
Prior administration of an intubating dose of SUC increases potency, accelerates onset, and prolongs the duration of action of a subsequent dose of other nondepolarizing NMB drugs, such as pancuronium (12–14), VEC (12,13) and atracurium (13,15). In most of these studies, the subsequent injection of the nondepolarizing NMB was given at full recovery from SUC-induced neuromuscular blockade. One study suggests that the effect of the maintenance dose of NMB may depend on the degree of recovery after SUC. Roed et al. (15) found that as recovery from SUC progressed, the onset of neuromuscular blockade from atracurium was accelerated, the block potentiated, and the duration prolonged.
In conclusion, we have defined the duration of action of a maintenance dose of VEC after an intubating dose of RAP, VEC, or SUC. The duration of action of a maintenance dose of VEC was similar after an intubating dose of RAP or VEC but was shortened when preceded by an intubating dose of SUC. The choice of NMB drug used for tracheal intubation will determine the pharmacodynamic effect of maintenance doses of NMB drugs.
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Acknowledgments
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Supported in part by Organon, Inc.
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References
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Accepted for publication December 28, 2000.
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Abstract
Introduction
