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Anesth Analg 2000;91:596-600
© 2000 International Anesthesia Research Society

AMBULATORY ANESTHESIA

Spontaneous Recovery Profile of Rapacuronium During Desflurane, Sevoflurane, or Propofol Anesthesia for Outpatient Laparoscopy

Tian J. Zhou, MD*, Margarita Coloma, MD*, Paul F. White, PhD*, Jun Tang, MD, FANZCA, MD{dagger}, Tom Webb, MD{dagger}, John E. Forestner, MD*, Nancy B. Greilich, MD*, and Larry L. Duffy, MD*

Departments of Anesthesiology and Pain Management, *University of Texas Southwestern Medical Center at Dallas, Texas; and {dagger}Cedars Sinai Medical Center in Los Angeles, California

Address correspondence to Paul F. White, PhD, MD, FANZCA, 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 paul.white{at}email .swmed.edu.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We evaluated the spontaneous recovery characteristics of rapacuronium during desflurane-, sevoflurane-, or propofol-based anesthesia in 51 consenting women undergoing laparoscopic tubal ligation procedures. After the induction of the anesthesia with standardized doses of propofol and fentanyl, 1.5 mg/kg IV rapacuronium was administered to facilitate tracheal intubation. Patients were randomized to receive either 1 minimum alveolar anesthetic concentration of desflurane, 1 minimum alveolar concentration of sevoflurane, or 100 µg · kg-1 · min-1 propofol infusion in combination with 66% nitrous oxide in oxygen for maintenance of anesthesia. Neuromuscular blockade was monitored at the wrist by using electromyography. The degree of maximum blockade and the times for first twitch recovery (T1) to 5%, 25%, 50%, 75%, and 90%, as well as the recovery index, were similar in all three anesthetic groups. However, recovery times for the train-of-four ratio to achieve 0.7 and 0.8 were significantly longer with desflurane (44.4 ± 18.9 and 53.5 ± 22.4 min) and sevoflurane (44.8 ± 15.1 and 53.2 ± 15.8 min) compared with propofol (31.8 ± 5.3 and 36.5 ± 6.5 min). Eight patients (16%) required a maintenance dose of 0.5 mg/kg rapacuronium and reversal of rapacuronium residual block occurred in three (6%) patients. We conclude that spontaneous recovery after an intubating dose of 1.5 mg/kg rapacuronium was significantly prolonged by both desflurane and sevoflurane compared with propofol-based anesthesia. Routine monitoring of neuromuscular activity is recommended even when a single bolus dose of rapacuronium is administered during ambulatory anesthesia.

Implications: When administered for laparoscopic surgery, the duration of action of an intubating dose of rapacuronium was prolonged 40%–50% by desflurane and sevoflurane, respectively, (versus propofol). Monitoring recovery of neuromuscular blockade produced by rapacuronium is particularly important when desflurane or sevoflurane is administered to ensure that an adequate recovery (train-of-four >= 0.8) is achieved by the end of anesthesia.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Rapid spontaneous recovery from neuromuscular blocking drugs can be advantageous in the ambulatory setting because it may facilitate recovery from anesthesia and decrease side effects (1). Rapacuronium, a structural analog of vecuronium, has a rapid onset and short duration of action, suggesting that it might be a useful alternative to succinylcholine for outpatient laparoscopic surgery.

The use of newer, less soluble, volatile anesthetics (desflurane and sevoflurane) as alternatives to propofol for the maintenance of anesthesia provides a more rapid emergence from general anesthesia, thereby facilitating the fast-tracking process in the ambulatory setting (2). Because rapacuronium appears to be a viable alternative to succinylcholine and mivacurium in outpatients undergoing short surgical procedures requiring tracheal intubation (3,4), its interaction with the newer volatile anesthetics desflurane and sevoflurane during routine clinical use should be studied.

We designed this study to test the hypothesis that the spontaneous recovery after an intubating dose of rapacuronium would not be prolonged by the volatile anesthetics desflurane and sevoflurane, compared with propofol when administered to women undergoing short laparoscopic tubal ligation procedures. The need for supplemental maintenance doses, as well as the requirement for reversal drugs, were also assessed in this outpatient population.


   Methods
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 Abstract
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 Methods
Results
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After obtaining institutional review board approval and written informed consent, 51 healthy outpatients scheduled to undergo laparoscopic tubal ligation procedures were enrolled in this prospective, randomized study. Patients with known hepatic, renal, or neuromuscular disease, taking any medications known to modify the action of muscle relaxants or with a body weight 30% above or below their ideal weight were excluded.

On arrival at the operating room, standard anesthesia monitors were attached and all patients were premedicated with 2 mg of IV midazolam. Anesthesia was induced with 2–2.5 mg/kg IV propofol, and 1–2 µg/kg IV fentanyl. After the patient lost consciousness, neuromuscular function was monitored by electromyography (EMG) (Relaxograph; Datex Instrumentarium, Helsinki, Finland). The EMG response of the adductor pollicis was obtained by stimulating the ulnar nerve at the wrist with a supramaximal square wave train-of-four (TOF) stimulation of 0.2 ms duration every 10 s by using surface electrodes. After obtaining a stable baseline response, 1.5 mg/kg IV rapacuronium, was injected over 5 s (into a fast-flowing IV line in the forearm opposite to the arm used for neuromuscular monitoring) to facilitate tracheal intubation.

For maintenance of anesthesia, patients were randomized by a computer-generated random number table to receive either desflurane, sevoflurane, or propofol infusion in combination with 66% nitrous oxide (N2O) in oxygen using a semiclosed circuit with a total flow of 3 L/min. The inspired concentration of desflurane and sevoflurane was adjusted to maintain the end-tidal concentrations at 1.0 minimum alveolar anesthetic concentration (MAC). The MAC values were adjusted for the concomitant use of N2O to 4% and 1.1% for desflurane (5) and sevoflurane (6), respectively. In the control group, 100 µg · kg-1 · min-1 IV propofol was infused. Boluses of 50 µg IV fentanyl were administered to treat clinical signs of inadequate analgesia (e.g., increases in heart rate). Ventilation was controlled to maintain the end-tidal carbon dioxide concentration between 35 and 40 mm Hg. A skin thermistor was taped to the hand close to the monitoring site, and the arm was wrapped in a blanket to reduce cooling. Skin temperature was maintained >32°C and central temperature (measured at the esophagus) remained >35°C by covering the patient with warmed blankets. The end-tidal concentrations of desflurane, sevoflurane, and N2O were monitored continuously by using a respiratory gas analyzer (Capnomac UltimaTM; Datex Instrumentarium, Helsinki, Finland). All patients received prophylactic antiemetics 10 to 15 min before the end of surgery (consisting of 0.625 mg of IV droperidol and 4 mg of IV ondansetron), as well as 30 mg of IV ketorolac and 1300 mg of rectal acetaminophen for preventative analgesia.

Neuromuscular blockade was allowed to recover spontaneously until a TOF ratio of 0.8 was attained. Thereafter, a supplemental dose of 0.5 mg/kg IV rapacuronium was administered, if clinically indicated (i.e., increased peak inspiratory pressure, coughing, or "bucking"). At the end of surgery, 50–80 mg IV edrophonium in combination with 0.5–0.8 mg IV atropine was administered, if the TOF ratio was <0.8. The degree of maximum neuromuscular blockade, times for first twitch recovery (T1) to 5%, 25%, 50%, 75%, and 90% and TOF ratios to 0.7 and 0.8, as well as time interval from TOF ratio of 0.4 to 0.8, were determined via the EMG recordings. Assessments of recovery of T1 to 25%, 50%, 75%, and 90% were made by using the final EMG baseline as a reference to calculate neuromuscular recovery (7). The recovery index was calculated as the time between 25% T1 and 75% T1 recovery. The number of patients who received a maintenance dose of rapacuronium and reversal drugs was recorded.

Each patient was carefully observed for any adverse effects after rapacuronium injection (flushing, wheezing, and acute hemodynamic changes). An adverse event was defined as any unusual or unexpected clinical sign manifesting itself or worsening during the intraoperative period regardless of its relationship to the study drug.

Data were analyzed by using the Number Cruncher Statistical System version 6.0 (NCSS, Kaysville, UT). An a priori power analysis suggested that a sample size of 15 patients for each of the three groups should be adequate to detect a 30% difference in recovery time for the TOF ratio to return to 0.8 between the desflurane or sevoflurane and propofol groups with a power of 0.8 ({alpha} = 0.05), assuming that the recovery time to a TOF ratio of 0.8 during propofol anesthesia would be 40 min (with a SD of 10 min) (8). The primary outcome variables (recovery times), anesthesia and surgery durations, and demographic data were compared by using one-way analysis of variance followed by the Bonferroni test for multiple comparisons. Categorical data (ASA physical status, use of a supplemental dose of rapacuronium and reversal drugs) were analyzed by using the {chi}2 test or Fisher’s exact test as appropriate. Data were expressed as mean ± SD (range), numbers, or percentages, with P <0.05 considered statistically significant.


   Results
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 Abstract
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 Methods
 Results
Discussion
 References
 
Although 51 patients were enrolled in this study, four were excluded from complete analysis: i) two patients in the desflurane group because reversal of residual neuromuscular blockade was required (end of operation) before a TOF ratio of 0.8 was achieved; ii) one patient in the propofol group because a supplemental dose of rapacuronium was administered before a TOF ratio of 0.8 was attained; and iii) one patient in the sevoflurane group required additional rapacuronium because of hiccuping with a TOF ratio of <0.7. Additionally, the calculation of recovery time for T1 to 5% was not possible in two patients (one in the desflurane group and another in the sevoflurane group) because the maximum degree of blockade was <95%. The three anesthetic treatment groups were comparable demographically (Table 1). In addition, there were no differences in the intraoperative analgesic drug requirement or the duration of surgery among the three study groups (Table 1).


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  		Table 1. Demographic Data, Anesthesia and Surgery Times, and Analgesic Requirements for the Three Study Groups
 
The degree of maximum blockade and the times for recovery of T1 to 5%, 25%, 50%, 75%, and 90%, as well as the recovery index from T1 25% to 75% were similar in the three anesthetic groups (Table 2). However, recovery times for the TOF ratio to return to 0.7 and 0.8, as well as time interval from TOF ratio of 0.4 to 0.8 were significantly longer in the desflurane and sevoflurane groups compared with the propofol group (Table 2). A higher degree of interpatient variability in recovery times of TOF ratio to 0.8 was also evident in the desflurane and sevoflurane (versus propofol) groups (Fig. 1). There were no differences in any of the recovery variables between the two volatile anesthetic groups.


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  		Table 2. Neuromuscular Recovery Variables After a Single Bolus Injection of Rapacuronium
 


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  		Figure 1. Spontaneous recovery time for the train-of-four ratio to return to 0.8 after a single dose of 1.5 mg/kg rapacuronium during desflurane- (n = 15), sevoflurane- (n = 16), and propofol-based (n = 16) anesthesia. A higher degree of interpatient variability was evident in the desflurane and sevoflurane (versus propofol) groups.

 
Eight patients received a supplemental (maintenance) dose of rapacuronium—four patients in the propofol group and two in each of the desflurane and sevoflurane groups. In only two of eight patients was the additional rapacuronium administered before the TOF ratio returned to 0.8. The neuromuscular recovery after the "top up" dose of rapacuronium was prompt, with a TOF ratio of 0.8 or greater achieved in all but one of these patients by the end of surgery. For the 41 patients in whom neither a maintenance dose of rapacuronium nor reversal drugs were administered, a TOF ratio of >=0.85 was observed in all patients by the time neuromuscular monitoring had to be discontinued because of patient awakening.

Adverse events possibly related to the administration of rapacuronium were recorded in four patients. Two patients in the sevoflurane group experienced transient tachycardia. One patient in the propofol group experienced transient cutaneous flushing 2.5 min after rapacuronium administration, and another patient had tachycardia, hypotension, and excessive salivation 1 min after the injection of rapacuronium. None of these adverse events required therapeutic intervention and all resolved spontaneously. No "wheezing" or bronchospasm was noted in any of the study patients.


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Spontaneous recovery after a tracheal intubating dose of rapacuronium was significantly prolonged by both desflurane and sevoflurane compared with propofol. The time from injection of rapacuronium until the TOF ratio returned to 0.7 was prolonged by 40% and 41%, respectively, and the time until TOF ratio returned to 0.8 was prolonged by 47% and 46%, respectively. The recovery time of the TOF ratio to 0.7 during propofol anesthesia was in agreement with those previously reported by Kahwaji et al. (8) (30 min), Purdy et al. (9) (38 minutes), and Debaene et al. (10) (30 minutes) during propofol-based anesthesia. However, rapacuronium’s spontaneous recovery in the presence of these newer volatile anesthetics has not been previously reported.

Enhancement of nondepolarizing muscle relaxant activity by volatile anesthetics usually results in either a prolongation in the duration of relaxant action or a decrease in the dosage requirement of the muscle relaxant (11,12). Because volatile anesthetics do not usually alter the pharmacokinetics of a muscle relaxant, this enhancement is presumed to result from increased neuromuscular sensitivity (12). In general, our results are in accordance with previous reports of enhancement of nondepolarizing neuromuscular blockade by inhaled anesthetics.

Both desflurane and sevoflurane (1.5 MAC) have previously been shown to significantly reduce the 50% effective dose and 95% effective dose of rocuronium compared with an IV anesthetic technique (13). Compared with propofol-based anesthesia, maintenance with sevoflurane (1 MAC) reduced the infusion rate of mivacurium required to maintain 90%–95% neuromuscular blockade and delayed the neuromuscular recovery after discontinuation of the relaxant infusion in both adults and children (14). In examining the effects of volatile anesthetics on the duration of neuromuscular blockade, Kaplan et al. (15) reported a prolongation of recovery after 0.2 mg/kg IV mivacurium was administered during 1 MAC sevoflurane anesthesia in children, similar to when 0.6 mg/kg IV rocuronium was administered during 1 MAC desflurane anesthesia (16).

In our study, the neuromuscular recovery times (except for the initial recovery of T1 to 50%), as well as the recovery index, were prolonged with desflurane and sevoflurane versus propofol; however, the differences were statistically significant only for the later end points (namely, TOF ratios of 0.7 and 0.8). This finding may be related to the time-dependent nature of the potentiating effect of these volatile anesthetics. Analogous to our results, Lowry et al. (17) reported that the times of recovery of T1 to 25% and 90% and the recovery index for 0.2 mg/kg IV mivacurium were not affected by sevoflurane 1.5 MAC (versus propofol). However, the recovery time to a TOF ratio of 0.8 was significantly longer with sevoflurane. The time-dependent potentiation of neuromuscular blockade may be influenced by the uptake of the volatile anesthetics into the skeletal muscle (18). With prolonged exposure to the volatile anesthetic, the muscle tissue equilibrates with the partial pressure in the blood, thereby potentiating the neuromuscular relaxant effect.

In contrast to our findings, Xue et al. (19) reported that the times of twitch recovery of T1 to 5%, 25%, and 90% after 0.4 mg/kg rocuronium were significantly prolonged by 1.5 MAC sevoflurane anesthesia when compared with a propofol-based technique. However, in their study, the patients received the volatile anesthetic for approximately 40 minutes before the muscle relaxant was administered. The experimental design used by these investigators is not consistent with the usual clinical practice of allowing for a brief stabilization period after the induction of anesthesia and then, administering the muscle relaxant. In most cases, the administration of the volatile anesthetic begins after completion of the tracheal intubation process.

Because of rapacuronium’s intrinsically rapid spontaneous recovery, initial recovery of the T1 to 5% required only 10 minutes regardless of the maintenance anesthetic technique. This end point is of clinical importance because it represents the time at which early reversal can be achieved. When rapacuronium was reversed with neostigmine 2–5 minutes after a bolus dose of 1.5 mg/kg IV, recovery of the TOF ratio to 0.7 required 17–19 minutes compared with a spontaneous recovery time of 38 minutes (9). Rapid reversal from a profound degree of neuromuscular blockade may not be possible with other nondepolarizing neuromuscular blocking drugs (20,21).

At the end of surgery, a TOF ratio of >=0.8 was achieved in all our study patients, with 94% recovering spontaneously. The lower incidence of pharmacologic reversal in this study may have been related to the relatively short duration of rapacuronium, the type and length of the surgical procedures, as well as to the study design. Traditionally, anesthesiologists accepted a TOF ratio of 0.7 as the value that represented adequate recovery of ventilatory function (22). However, current expert opinion favors a TOF ratio of 0.8 or higher as representing adequate recovery of neuromuscular function and "street readiness" (23–25).

The time interval for the TOF ratio to recover from 0.4 to 0.8 was found to be significantly longer with desflurane or sevoflurane (versus propofol) (Table 2). Because most clinicians cannot reliably detect residual fade by using tactile (clinical) methods if the TOF ratio exceeds 0.4, this time interval could represent a "window of vulnerability" if unmonitored patients are not administered reversal drugs, particularly with desflurane or sevoflurane anesthesia. However, it was previously reported that visual observation of fading at the adductor pollicis after a 100-Hz, five-second tetanus and tactile double-burst stimulation (3,2 mode) are both highly sensitive tests for evaluating residual paralysis (26,27).

The adverse effects of rapacuronium observed in this study were few and none required clinical interventions. Although the tachycardia could be related to inadequate analgesia or rapacuronium’s relatively low vagal-to-neuromuscular blocking dose ratio (28), the cutaneous erythema noted in one case may have been secondary to histamine release. No episodes of bronchospasm were observed in this patient population.

In conclusion, the duration of action of an intubating dose of 1.5 mg/kg rapacuronium was significantly prolonged (by 40%–50%) during both desflurane and sevoflurane anesthesia compared with a propofol-based technique. Therefore, less rapacuronium may be required during the maintenance period with desflurane or sevoflurane (versus propofol) anesthesia. However, routine monitoring of neuromuscular activity is recommended even when short-acting muscle relaxants like rapacuronium are administered during ambulatory surgery.


   Acknowledgments
 
Supported, in part, by a grant from Organon Inc., West Orange, NJ, and the Ambulatory Anesthesia Research Foundation of Dallas.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 17, 2000.




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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