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Anesth Analg 2000;90:689-693
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

Reversal of Rapacuronium Block During Propofol Versus Sevoflurane Anesthesia

Tian J. Zhou, MD*, Jun Tang, MD{dagger}, Paul F. White, PhD, MD, FANZCA*, Girish P. Joshi, MB, BS, MD, FFARCSI*, Ronald Wender, MD{dagger}, Mark T. Murphy, MD*, Jen W. Chiu, MD*, and Tom Webb, MD{dagger}

*Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, Texas, and {dagger}Department of Anesthesiology, Cedars-Sinai Medical Center, Los Angeles, California

Address correspondence and reprints to Paul F. White, MD, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., F2.208, Dallas, TX 75235-9068. Address e-mail to pwhite{at}mednet.swmed.edu


   Abstract
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 Abstract
Introduction
 Methods
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 Discussion
 References
 
We studied the antagonism of rapacuronium with edrophonium-atropine during propofol- or sevoflurane- based anesthesia in 60 healthy outpatients. After the induction of anesthesia with standardized doses of propofol and fentanyl, rapacuronium 1.5 mg/kg was administered to facilitate tracheal intubation. Patients were randomized to receive either a propofol infusion (100 µg · kg-1 · min-1) or sevoflurane (1.0%, end-tidal) in combination with nitrous oxide 66% for maintenance of anesthesia. Neuromuscular block was monitored by using electromyography at the wrist and reversed with edrophonium 1.0 mg/kg and atropine 0.015 mg/kg when the first twitch (T1) response of the train-of-four (TOF) stimulation recovered to 25% of the baseline value. The clinical duration of action (i.e., time to 25% T1 recovery) was similar during both propofol (13.1 ± 3.6 min) and sevoflu-rane (13.7 ± 4.4 min) anesthesia. The time from 25% T1 recovery to TOF ratio of 0.8 was also similar with propofol (3.4 ± 2.1 min) and sevoflurane (5.9 ± 8.7 min) (P > 0.05). Although none of the patients in the propofol group required more than 9 min to achieve a TOF ratio of 0.8, two patients receiving sevoflurane required 31 min and 37 min. Adequate antagonism of rapacuronium block with edrophonium can be achieved within 10 min during propofol anesthesia. However, more prolonged recovery may occur in the presence of sevoflurane.

Implications: We studied the reversal of rapacuronium-induced block with edrophonium and found that the residual rapacuronium block can be readily antagonized during propofol-based anesthesia. However, reversal of rapacuronium appears to be less predictable during sevoflurane-based anesthesia.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Rapacuronium (Org 9487), a new aminosteroidal nondepolarizing neuromuscular blocking drug, has a rapid onset of action (60–90 s), good-to-excellent intubating conditions at 60–90 s, and a clinical duration of <20 min (1–3). Although the onset profile of rapacuronium resembles that of succinylcholine, the spontaneous recovery of neuromuscular function is slower than that after succinylcholine (2). For example, the time to train-of-four (TOF) ratio of 0.7 after rapacuronium 1.5 mg/kg was 24.1 min compared with 10.6 min for 90% recovery of the first twitch (T1) response of TOF stimulation after succinylcholine 1.0 mg/kg. The use of volatile anesthetics for maintenance of anesthesia can enhance the action of nondepolarizing muscle relaxants (4–7), and thereby interfere with the antagonism of neuromuscular block (8–11). However, there are no reports of the effects of volatile (versus IV) anesthetics on the recovery of rapacuronium-induced neuromuscular block. Therefore, in this study, we tested the hypothesis that the reversibility of rapacuronium is influenced by sevoflurane versus propofol in outpatients undergoing short surgical procedures.


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
We studied 60 ASA grade I-II outpatients aged 18–70 yr undergoing elective surgery at two university-affiliated medical centers after obtaining written, informed consent and approval by the local institutional review boards. Patients with clinically significant hepatic, renal, or neuromuscular disease, those taking any medications known to modify the action of muscle relaxants, and those whose body weight was 30% above or below their ideal weight were excluded from participating.

Routine intraoperative monitoring was used. After premedication with midazolam 2 mg IV, anesthesia was induced with propofol 2–2.5 mg/kg IV and fentanyl 1–2 µg/kg IV. Neuromuscular monitoring was performed by using electromyography (EMG) (Datex RelaxographTM, Helsinki, Finland). The EMG response of the adductor pollicis was obtained by stimulating the ulnar nerve at the wrist with supramaximal square-wave TOF stimulation of 0.2-ms duration every 10 s by using surface electrodes. The EMG recording apparatus was connected to the patient before the induction of anesthesia, and baseline calibration sequence was performed after the patient lost consciousness. After obtaining the baseline recording, rapacuronium 1.5 mg/kg was injected over 5 s into a fast-flowing IV line in the forearm to facilitate tracheal intubation.

Then, patients were randomly allocated to receive propofol infusion (100 µg · kg-1 · min-1) or sevoflurane (1.0%, end-tidal), in combination with nitrous oxide (N2O) 66% in oxygen for maintenance of anesthesia. Incremental doses of fentanyl (50 µg IV) were given to treat clinical signs of inadequate analgesia. Ventilation was controlled to maintain the end-tidal carbon dioxide (ETCO2) concentration between 35 and 40 mm Hg. Central and peripheral temperatures were maintained >36.5°C and >32.5°C, respectively, by using an external warming device. The end-tidal concentrations of sevoflurane and N2O were monitored continuously by using a respiratory gas analyzer (Datex Capnomac UltimaTM, Helsinki, Finland).

Neuromuscular block was allowed to recover spontaneously until the T1 height of the TOF stimulation returned to 25% of its baseline value, and then, edrophonium 1.0 mg/kg IV, in combination with atropine 0.015 mg/kg was administered over 30 s. Anesthetic maintenance with either propofol or sevoflurane in combination with N2O was continued after reversal until a TOF ratio of 0.8 was achieved. The following neuromuscular variables were determined from the EMG recording: 1) degree of maximum block; 2) time from injection of rapacuronium to 25% T1 recovery (i.e., clinical duration); and 3) times from 25% T1 recovery to TOF ratio of 0.7 and 0.8.

An a priori power analysis was performed based on detecting a difference of 30% or more in the time interval from 25% T1 recovery to TOF ratio of 0.8 after reversal between the two study groups. A group size of 30 was considered adequate ({alpha} = 0.05, power = 0.8, and SD = 1.0 min). For statistical analysis, the {chi}2 test and unpaired Student’s t-test were used for analyzing demographic data, anesthetic requirements and clinical duration of action between the two treatment groups and between the two study sites. The time intervals from 25% T1 recovery to TOF ratio of 0.7 and 0.8 were analyzed by using Mann-Whitney U-test. P < 0.05 was considered statistically significant.


   Results
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 Abstract
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 Methods
 Results
Discussion
 References
 
Thirty patients were enrolled at each of our medical centers. The two anesthetic treatment groups were comparable with respect to age, height, body weight, sex distribution, ASA physical status, and anesthetic drug usage (Table 1). Similarly, there were no differences in the variables between the two study sites. The time to recovery of a TOF ratio of 0.8 after reversal was not attainable from five patients in the propofol group and three, in the sevoflurane group because of the clinical situation.


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  		Table 1. Demographic Data and Anesthetic Drug Requirements for the Two Study Groups
 
The mean maximal block after rapacuronium 1.5 mg/kg was 99.2 ± 2.0%, with complete neuromuscular block achieved in 82% of the cases. The clinical duration of rapacuronium’s action was similar during both sevoflurane or propofol-based anesthesia (Table 2). The times from 25% T1 recovery to TOF ratio of 0.7 and 0.8 after reversal did not significantly differ between the sevoflurane and propofol groups (Table 2). A higher degree of interpatient variability was evident in the sevoflurane group (Figure 1). Whereas none of the patients in the propofol group required more than 9 min to achieve a TOF ratio of 0.8 after reversal, two patients receiving sevoflurane required 30.8 min and 37.1 min, respectively. The intraoperative and postoperative courses were uneventful, and no clinical signs of histamine release were observed.


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  		Table 2. Neuromuscular Recovery Variables with Edrophonium-Atropine Reversal of Residual Block After a Single-Bolus Injection of Rapacuronium 1.5 mg/kg
 


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  		Figure 1. Individual time interval from 25% T1 recovery to train-of-four (TOF) ratios of 0.7 (•) and 0.8 ({triangleup}) after reversal of a single dose of rapacuronium 1.5 mg/kg with edrophonium 1.0 mg/kg and atropine 0.015 mg/kg at 25% T1 recovery during propofol- or sevoflurane-based anesthesia.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Recovery of neuromuscular transmission after the administration of an anticholinesterase drug consists of two components: 1) the effect of spontaneous recovery caused by decreasing plasma concentration of a neuromuscular blocking drug because of redistribution or elimination, and 2) assisted recovery caused by the activity of the anticholinesterase drug (12). Because of the intrinsically rapid spontaneous recovery after a bolus dose of rapacuronium, early reversal of rapacuronium-induced neuromuscular block can be achieved. Wierda et al. (2) reported that the time to attainment of a TOF ratio of 0.7 after antagonism with neostigmine administered two minutes after the injection of rapacuronium 1.5 mg/kg, was similar to that of succinylcholine (11.6 vs 10.6 minutes). Recently, Purdy et al. (13) found that neostigmine 0.05 mg/kg or 0.07 mg/kg, given two minutes or five minutes after rapacuronium 1.5 mg/kg, decreased the time to achieve a TOF ratio of 0.7 from 38 minutes (with spontaneous recovery) to 17–19 minutes (after neostigmine reversal).

Although neostigmine may be a more reliable antagonist in the presence of profound neuromuscular block, the faster onset and reduced muscarinic side effects associated with edrophonium may be more advantageous for reversal of residual neuromuscular block when a greater degree of spontaneous recovery has occurred (i.e., 25% vs 10% of T1 recovery) (14). In this study, use of edrophonium provided a clinically acceptable recovery, with average times of 3.4 and 5.9 minutes to achieve a TOF ratio of 0.8 after reversal of rapacuronium-induced neuromuscular block during propofol and sevoflurane anesthesia, respectively.

Enhancement of nondepolarizing muscle relaxants by volatile anesthetics usually results in either a prolongation of the duration of relaxant action or a decrease in the dosage requirement of the muscle relaxant (4–7). Several mechanisms have been proposed for the enhancement of neuromuscular block by volatile anesthetics, including increased availability of the muscle relaxant at the neuromuscular junction because of increased muscle blood flow caused by the volatile anesthetics (15), increased muscle relaxation resulting from the central depressant effects, as well as decreased availability of acetylcholine at the neuromuscular junction (16).

In this study, the clinical duration of action after a single bolus dose of rapacuronium was similar during propofol- and sevoflurane-based anesthetic techniques. Our inability to demonstrate augmentation of the relaxant effect may be related to the time-dependent nature of the potentiating effect of volatile anesthetics. Jalkanen and Meretoja (17) showed that a 10-minute exposure to isoflurane (1.5% end-tidal) was insufficient to affect either the onset or the recovery times after a bolus dose of mivacurium. However, a 30-minute exposure to the volatile anesthetic significantly shortened the onset and prolonged the recovery times. Similar time-dependent potentiation was reported by Withington et al. (18). The time-dependent potentiation of neuromuscular block may be influenced by uptake of volatile anesthetics into skeletal muscle (17). With prolonged exposure to the volatile anesthetic, the muscle tissue achieves equilibrium with partial pressure in blood, thereby potentiating the relaxant effect. Thus, it is possible that the clinical duration of rapacuronium would have been significantly prolonged (versus propofol) had the exposure time to sevoflurane been longer.

Volatile anesthetics can also impair reversal of nondepolarizing muscle relaxant-induced neuromuscular block (8–11). Morita et al. (9) demonstrated that the 50% effective dose value of edrophonium required to obtain a TOF ratio of 0.5 was significantly increased when the reversal drug was administered during 1.0 MAC sevoflurane or isoflurane anesthesia compared with a fentanyl-diazepam-nitrous oxide anesthetic technique. These authors also found that when the volatile anesthetic was discontinued at the time neostigmine was administered, the impairment of reversal was reduced, but not eliminated (11). In our study, the recovery times after reversal of rapacuronium-induced block with edrophonium were similar during either propofol or sevoflurane-based anesthesia. This finding probably relates to the time-dependent potentiation of neuromuscular block by volatile anesthetics. In the presence of volatile anesthetics, the neuromuscular block at the time of reversal drug administration is a summation of the muscle relaxant-induced paralysis and the direct effect of the volatile anesthetic on neuromuscular transmission. It is likely that the residual neuromuscular block at the time of reversal (i.e., at 25% T1 recovery) in our study was predominantly produced by rapacuronium rather than a direct effect of sevoflurane. Of interest, there were two patients in the sevoflurane group in whom prolonged recovery occurred after reversal. This finding suggests that reversal of rapacuronium-induced block may be more difficult when it is attempted during sevoflurane anesthesia. In addition to the time-dependent nature of the enhancement of volatile anesthetics on muscle relaxant activity, the failure to find a significant difference in recovery times during propofol- or sevoflurane-based anesthesia may relate to: 1) inadequate group sizes; 2) the higher degree of variability in the sevoflurane (versus propofol) group; and 3) the TOF ratio endpoints chosen to assess the reversibility of the residual block. A greater difference between the two groups may have been observed whether it had been possible to monitor the patients’ neuromuscular function until a TOF ratio of 0.9 was achieved.

The study can also be criticized because the anesthetics were continued after the administration of the reversal drugs. Although many practitioners discontinue the maintenance anesthetics when the reversal drugs are administered, such a practice was not possible in this study because of the clinical circumstances (i.e., the operation had not been completed). Moreover, discontinuing the anesthetics would have further confounded the interpretation of these reversal data. Another shortcoming of this study relates to the use of EMG for monitoring neuromuscular function. Because of the well known downward drift of the EMG amplitude with time, the first twitch height (T1) of a TOF stimulation may only recover to 70–80% of the baseline value despite TOF ratios exceeding 0.9 (19). In our study, the final T1 values recovered to 77 ± 8% of baseline values. Thus, a T1 value of 25%, which correlated with the reappearance of the fourth palpable response to TOF stimulation in 75% of the patients in this study, would be calculated to correspond to an average of 32% recovery based on the final baseline values. It is generally accepted that TOF ratios measured with EMG and those recorded with the gold standard mechanomyography provide similar information (18,20). Our results are consistent with those observed by Beemer et al. (21) who reported that the maximum depth of block effectively antagonized by edrophonium corresponds to the reappearance of the fourth response to TOF stimulation. It is also possible that the two cases of prolonged recovery after reversal in the sevoflurane group would have been prevented if neostigmine was used for reversal rather than edrophonium.

In conclusion, the clinical duration of action after a single dose of rapacuronium 1.5 mg/kg was similar during both sevoflurane and propofol-based anesthesia. In most cases, the neuromuscular block produced by rapacuronium was rapidly antagonized (<five minutes) by using edrophonium 1.0 mg/kg and atropine 0.015 mg/kg at 25% T1 recovery. Although the recovery times after reversal of rapacuronium-induced block did not differ statistically between the propofol and sevoflurane groups, greater variability was noted during sevoflurane-based anesthesia.


   Acknowledgments
 
Supported in part by a grant from Organon Inc., West Orange, NJ.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication November 9, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press