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© 2001 International Anesthesia Research Society
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Abstract |
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Early reversal of rapacuronium may accelerate return of neuromuscular function. This study was designed to compare early (2 min after rapacuronium) or late (at 25% recovery of the first twitch [T1] of train-of-four) reversal of rapacuronium with neostigmine. We studied 119 subjects between the ages of 18 and 75 yr. Anesthesia was induced with fentanyl and thiopental and maintained with nitrous oxide, propofol, and fentanyl. Mechanomyographic neuromuscular monitoring was performed by using train-of-four stimulation of the ulnar nerve. Two groups received 1.5 mg/kg rapacuronium followed by neostigmine (50 µg/kg) and glycopyrrolate (10 µg/kg) either at 2 min after rapacuronium bolus or at 25% T1 recovery. The other two groups received 2.0 mg/kg rapacuronium, after which neostigmine was similarly given. For each rapacuronium dose, the time from the administration of rapacuronium to the start of T1 recovery or 25% T1 recovery was significantly shorter in subjects who received the reversal 2 min after rapacuronium. However, late recovery, defined by times from administration of rapacuronium to 70%, or 80% T4/T1 recovery, was not influenced by early reversal administration. We conclude that initial recovery is accelerated by early administration of neostigmine. Time to full recovery after rapacuronium administration is, however, dose-dependent and not significantly altered by early administration of neostigmine.
IMPLICATIONS: "Rescue reversal," which includes the administration of neostigmine shortly after the administration of rapacuronium, may accelerate the return of spontaneous breathing (early recovery), but does not shorten the time to complete recovery of upper airway function.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Rapacuronium is a steroidal nondepolarizing neuromuscular blocking drug developed through modification of the vecuronium molecule (1). The onset of effect after endotracheal intubating doses of rapacuronium (1.5–2.0 mg/kg) is similar to that of succinylcholine (1.0–1.5 mg/kg), but its duration of action is longer (1–7). Neostigmine can accelerate early recovery from a rapacuronium neuromuscular blockade, and giving the reversal drug 2 min after rapacuronium (1.5 mg/kg), or at 25% recovery of the first twitch (T1) of train-of-four (TOF), produces complete recovery (T4/T1 > 0.8) in approximately 20 min (8).
With vecuronium (9), atracurium (10), and rocuronium (11), total recovery time (the interval between injection until T4/T1 
0.7) is not accelerated by early reversal compared with reversal given at 10%–25% spontaneous T1 recovery. The purpose of this study was to evaluate the neuromuscular recovery variables of two doses of rapacuronium after early (neostigmine given 2 min after rapacuronium) or late (neostigmine given at 25% spontaneous T1 recovery) reversal in adult patients. Onset, intubating condition, and safety data were also collected.
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Methods |
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This was an open-label, assessor-blinded, parallel group, comparative, randomized, multicenter, clinical investigation. After obtaining IRB approval, patients scheduled for elective surgeries under general anesthesia requiring endotracheal intubation provided written informed consent to participate in this study.
Patients ranged in age from 18 to 75 yr and were within 30% of their ideal body weight, not exceeding 100 kg. None of the patients was receiving anticonvulsants, aminoglycoside, macrolide, or polypeptide antibiotics. All patients were free of any congenital abnormalities or airway obstruction that would preclude visualization or intubation of the trachea. Patients with known renal, hepatic, and neuromuscular disorders, including a personal or family history of malignant hyperthermia, or allergy to narcotics or other medications used during anesthesia, were excluded from this study.
Patients were premedicated with 1.0–5.0 mg midazolam (IV) at the discretion of the attending anesthesiologist. After placement of monitoring devices, the patients’ hands were appropriately positioned, skin was prepared, and surface electrodes were placed on the ulnar nerve of the arm, opposite to the injection site of rapacuronium, for TOF stimulation and mechanomyographic monitoring. Anesthesia was induced with 2–3 µg/kg of fentanyl and 4–5 mg/kg of thiopental IV. If needed, additional doses of thiopental (up to 100 mg) and 50 µg of fentanyl were administered.
Immediately after loss of consciousness, the ulnar nerve was stimulated at the wrist by using TOF square wave impulses of 0.2-ms duration administered at 2 Hz. A constant current stimulator was used to deliver a TOF every 10 s and was continuously recorded on a polygraph.
After stable anesthesia had been achieved (as evidenced by lack of patient’s movement and stable cardiovascular status), and 1–3-min baseline TOF had been obtained, patients randomly received rapacuronium (either 1.5 or 2.0 mg/kg) over 5 s through a fast-flowing IV infusion line. Patients were further randomized into two subgroups; one group received neostigmine (50 µg/kg) and glycopyrrolate (10 µg/kg) 2 min after the end of rapacuronium administration, whereas the other group received the same reversal when T1 was at 25% of baseline. Neostigmine and glycopyrrolate were injected IV over 5 s.
In the group of subjects randomized to receive reversal at 2 min, intubation was attempted 60 s after rapacuronium administration. If intubation was not possible at the first attempt, another attempt was made at 90 s. Intubation in the group randomized to receive reversal at 25% T1 recovery was attempted at 90 s, and if not possible, the second attempt was made 120 s after rapacuronium administration.
A blinded assessor using a four-point scale as either "excellent," "good," "poor," or "impossible," evaluated intubating conditions. The scoring was based on the grade of laryngoscopy, the position and movement of vocal cords, and the reaction of the subject to the intubation as described by Viby-Mogensen et al. (12). Anesthesia was maintained with 60%–70% nitrous oxide in oxygen with supplemental doses of fentanyl and/or propofol as clinically indicated. No additional muscle relaxants were administered until at least 80% T4/T1 recovery had occurred.
Percent depression of T1 at 1 and 2 min, as well as times to the maximal depression of T1, start of T1 recovery (return of detectable T1), 25% T1 recovery (clinical duration), 70% and 80% T4/T1 recovery, and recovery index (time from 25% to 75% T1 recovery), were calculated. The area under the twitch response-time curve for clinical duration was calculated for each patient by using the trapezoidal method.
Summary statistics, unpaired Student’s t-test, analysis of variance followed by least squares means, and Mantel-Haenszel 
2 were used to analyze the data. A P < 0.05 was considered statistically significant. Data were reported as mean ± SD.
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Results |
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One hundred nineteen subjects completed the study. There were no significant differences in any of the demographic variables among the groups (Table 1). Mean age, height, and weight were comparable among the four treatment groups. There were more women than men in all treatment groups. In all four groups, the majority of the subjects were Caucasian.
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The majority of the subjects in the four treatment groups had excellent or good tracheal intubating conditions (Table 2). In the group that received 1.5 mg/kg rapacuronium, 26 subjects (89%) tracheally intubated 60 s and 26 (93%) at 90 s had good-to-excellent intubating conditions. In the groups that received 2.0 mg/kg rapacuronium, 94% of the subjects had good-to-excellent intubating conditions at either 60 s (29 subjects) or 90 s (29 subjects). One subject in the 1.5 mg/kg group and one subject in the 2.0 mg/kg group could not be tracheally intubated with the first attempt at 90 s. There were no significant differences between doses, or between times within each dose, with respect to clinically acceptable (good or excellent) intubating conditions (Table 2).
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One min after the injection of rapacuronium, the mean T1 blocks were 81% ± 21% and 87% ± 21% in the groups receiving 1.5 mg/kg (n = 56) and 2.0 mg/kg (n = 61), respectively. The corresponding values at 2 min were 98% ± 5% and 99.5% ± 1.2%. There were no significant differences in mean % T1 block at either 1 or 2 min between the two doses of rapacuronium. There was no significant difference in the onset time between the 1.5 mg/kg and the 2.0 mg/kg dose groups. The mean onset of maximum T1 block occurred at 101 ± 36 s and 88 ± 41 s after the 1.5 mg/kg and 2.0 mg/kg doses, respectively.
Within each dose group, the time from the administration of rapacuronium to the start of T1 recovery or 25% T1 recovery (clinical duration) was significantly shorter in subjects who received the reversal 2 min after rapacuronium injection (Table 3). The T4/T1 ratio at 25% T1 recovery was larger in the group given neostigmine at 2 min relative to spontaneous recovery of T1 to 25% of baseline (Table 3). The recovery index, defined as the time between 25% to 75% T1 recovery, was significantly (P < 0.05) faster in the groups receiving neostigmine at 25% spontaneous T1 recovery. Times from the administration of rapacuronium to 70% or 80% T4/T1 recovery were not influenced by early reversal administration within either dose group (Table 3). However, there were significant differences (P < 0.001) in times to 70% T4/T1 or 80% T4/T1 recovery between both dose groups, irrespective of the time of reversal administration.
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In general, within the two rapacuronium dose groups, no statistically significant differences in the recovery from 25% T1 to 70% T4/T1 and 80% T4/T1 were observed. Furthermore, there were no significant differences in the observed neuromuscular function when data were analyzed by gender.
Bronchospasm occurred in three patients in the 1.5 mg/kg group and in five patients in the 2.0 mg/kg rapacuronium dose groups. Five of these patients were either smokers, had a history of allergic reactions, or a history of asthma. Patients from both treatment groups recovered from bronchospasm either spontaneously or after receiving albuterol or pirbuterol. One patient in the 1.5 mg/kg group and two patients in the 2.0 mg/kg group experienced erythema. Two patients (one in the 1.5 mg/kg group and one in the 2.0 mg/kg group) experienced prolonged muscle weakness. Both of these patients had received neostigmine 2 min after rapacuronium and had received additional doses of rocuronium during maintenance of anesthesia. One patient in the 1.5 mg/kg rapacuronium treatment group and one patient in the 2.0 mg/kg rapacuronium treatment group experienced clinically significant increases in heart rate. Heart rate in the first patient increased from 73 to 119 bpm and in the second patient from 84 to 128 bpm.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The notion of "rescue reversal" after rapacuronium administration was advocated in cases in which intubation was not successful (9). Although neostigmine given two or five minutes after rapacuronium accelerates recovery compared with no reversal at all (9), this study shows that time from administration of rapacuronium to complete recovery (T4/T1 = 0.7 or 0.8) is not shortened by the administration of neostigmine at two minutes compared with the more traditional approach of giving neostigmine when spontaneous recovery has begun (25% T1). In this respect, rapacuronium is not different from other nondepolarizing neuromuscular blocking drugs. Early reversal of vecuronium (9,11) and rocuronium (11) does not accelerate time to T4/T1 = 0.7 compared with reversal at T1 = 10% or 25%. However, whether reversal is given early or not, the time to neuromuscular recovery is shorter with rapacuronium (17–20 minutes with 1.5 mg/kg dose) than with vecuronium or rocuronium (40–45 minutes). This difference is probably related to the shorter time course of rapacuronium, not to the specific effect of neostigmine on rapacuronium.
In this study, a 1.5 or 2.0 mg/kg dose of rapacuronium resulted in good-to-excellent (clinically acceptable) intubating conditions in the majority of patients in one minute. Our data are consistent with those reported for rapacuronium and obtained after a 1–1.5 mg/kg dose of succinylcholine by other investigators (1–7). Although the time to onset of neuromuscular effect was shorter after a 2.0 mg/kg dose, there was no significant difference in clinically acceptable intubating conditions between the two doses at either 60 or 90 seconds. However, excellent intubating conditions were less often seen 60 seconds after a 1.5 mg/kg dose than with a 2.0 mg/kg dose or at 90 seconds.
The administration of neostigmine two minutes after an intubating dose of rapacuronium reduced the times to the start of recovery of T1, 25% T1 recovery, and the area under the response-time curve of clinical duration, by approximately 25% to 45%. The early recovery variables were significantly longer after a 2 mg/kg dose but were reduced within each dose by early administration of neostigmine. This suggests that recovery of sufficient diaphragmatic function to resume spontaneous breathing occurs earlier when reversal is attempted at two minutes. Late recovery, as defined by time from administration of rapacuronium to 70%, or 80% T4/T1 recovery, was also longer after the larger dose but was not influenced by early neostigmine administration. Thus, the recovery of the muscles of the upper airway, which occurs when T4/T1 > 0.8, does not occur earlier with early neostigmine administration. Patients receiving rapacuronium in whom intubation is unsuccessful, "rescue reversal" cannot be expected to produce complete return of neuromuscular function before hypoxia occurs. However, provided that upper airway obstruction is relieved, spontaneous ventilation can resume.
More rapid recovery of muscle function is an important factor in a patient with difficult intubation, with or without difficult ventilation. The ability to reverse somewhat (if not entirely) from a relatively deep level of block would allow patients to attempt ventilation and, therefore, provide assistance. This is similar to the concept of using the rapid recovery of succinylcholine. This study suggests that diaphragmatic movement might be present six and eight minutes earlier when neostigmine is given two minutes after rapacuronium administration. Early recovery of muscle function can be important in several difficult circumstances. The difficult airway algorithm suggests that early recovery of spontaneous ventilation might be helpful. Early recovery can certainly help if a procedure is terminated abruptly after a patient is paralyzed. Both of these are situations in which succinylcholine has been helpful. Furthermore, in the early phase of recovery (T1 of 25%) T4/T1 ratio recovers to a greater degree when recovery is accelerated by neostigmine than during spontaneous recovery. This should provide increased sustained strength for activities such as respiration. This study also shows that time from injection of rapacuronium to complete recovery is not shortened by early administration of neostigmine. Patients should be monitored closely and assisted as needed until adequate return of neuromuscular function has been achieved. Two of our patients experienced prolonged muscle weakness; both had received reversal two minutes after rapacuronium and were given additional muscle relaxant (rocuronium) during maintenance of anesthesia and another dose of reversal drug. Care should be exercised so that no additional muscle relaxation is needed once the neostigmine is administered.
In conclusion, the administration of neostigmine two minutes after an intubating dose of rapacuronium will accelerate the early recovery, but has minimal or no noticeable effect on full recovery of neuromuscular function.
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Acknowledgments |
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Supported financially by Organon, Inc.
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Footnotes |
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Presented in part at the annual meeting of the American Society of Anesthesiologists, San Francisco, CA, October 16, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- Wierda JMKH, Beaufort AM, Kleef UW, et al. Preliminary investigations of clinical pharmacology of three short acting non-depolarizing neuromuscular blocking agents, Org 9453, Org 9489 and Org 9487. Can J Anaesth 1994; 41: 213–20.[Web of Science][Medline]
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Van den Broek L, Wierda JMKH, Smeulers NJ, et al. Pharmacodynamics and pharmacokinetics of an infusion of Org 9487, a new short-acting steroidal neuromuscular blocking agents. Br J Anaesth 1994; 73: 331–5.
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- Kahwaji R, Bevan DR, Bikhazi G, et al. Dose-ranging study in younger adult and elderly patients of Org 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg 1997; 84: 1011–8.[Abstract]
- Larijani GE, Zafeiridis A, Goldberg ME. Clinical pharmacology of rapacuronium bromide, a new short-acting neuromuscular blocking agent. Pharmacotherapy 1999; 19: 1118–22.[Web of Science][Medline]
- Schiere S, Van den Broek L, Proost JH, et al. Comparisons of vecuronium with Org 9487 and their interaction. Can J Anaesth 1997; 44: 1138–43.[Web of Science][Medline]
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- Kirkegaard-Nielsen H, Halbo-Hensen HS, Lindholm P, et al. Optimum time for neostigmine reversal of atracurium-induced neuromuscular blockade. Can J Anaesth 1996; 43: 952–8.
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Bevan JC, Collins L, Fowler C, et al. Early and late reversal of rocuronium and vecuronium with neostigmine in adults and children. Anesth Analg 1999; 89: 333–9.
[Abstract/Free Full Text] - Viby-Mogenson J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996; 40: 59–74.[Web of Science][Medline]
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