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Anesth Analg 2004;99:1398-1401
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000132970.64413.E7

ANESTHETIC PHARMACOLOGY

Xenon Does Not Prolong Neuromuscular Block of Rocuronium

Oliver Kunitz, MD, Jan-Hinrich Baumert, MD, Klaus Hecker, MD, Thorben Beeker, MD, Mark Coburn, MD, André Zühlsdorff, MD, and Rolf Rossaint

Department of Anesthesiology, University Hospital of the RWTH Aachen, Aachen, Germany

Address correspondence and reprint requests to Kunitz Oliver, MD, Department of Anesthesiology, University Hospital of the RWTH Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany. Address e-mail to okunitz{at}ukaachen.de


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
With the exception of xenon, the interaction between muscle relaxants and inhaled anesthetics is known. We therefore compared the pharmacodynamics of rocuronium during xenon anesthesia versus a total IV anesthesia with propofol. Anesthesia was induced with propofol and remifentanil in both the xenon and propofol groups (each n = 20). The xenon group received xenon via face mask until an end-expiratory concentration of 60% was maintained for 1 min. Meanwhile, the acceleromyograph (TOF-Watch SX®) was calibrated and a frequent train-of-four stimulation of the musculus adductor pollicis was started. After stabilization of the signal for 5 min, a single bolus of 0.6 mg/kg rocuronium was injected. Anesthesia was maintained with xenon and remifentanil (xenon group) or with propofol and remifentanil (propofol group). There were no significant differences between the groups concerning the onset time (xenon group 125 ± 33 and propofol group 144 ± 43 s), duration (xenon group 33.2 ± 10.8 and propofol group 32.6 ± 8.4 min), recovery index (xenon group 9.4 ± 6.6 and propofol group 8.4 ± 5.3 min), and clinical recovery (xenon group 18.0 ± 10.2 and propofol group 17.1 ± 8.5 min). We conclude that the neuromuscular blocking effects of rocuronium are not different when given during propofol versus xenon anesthesia.

IMPLICATIONS: Except for xenon, the interactions of inhaled anesthetics with neuromuscular blocking drugs are known. Therefore, the influence of xenon on the onset time, duration, recovery index, and recovery time of rocuronium during propofol and xenon anesthesia was compared. No differences were found.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Previous studies have shown interactions of inhaled anesthetics with nondepolarizing neuromuscular blocking drugs in variably prolonging and enhancing neuromuscular blocking effects (1,2).

Xenon, an inhaled anesthetic with an extreme low blood-gas partition coefficient of 0.115–0.14 (3) and a minimum alveolar anesthetic concentration (MAC) of 63%–71% (4), has proven its clinical safety and efficacy (5). Xenon has shown its cardio- and neuroprotective effects in many studies (5–9). With its ecological and pharmacological qualities, xenon is an interesting alternative to other inhaled anesthetics. Our aim was to measure the influence of xenon on the neuromuscular blocking effects of rocuronium, because there are no studies on the effect of xenon on rocuronium. Our hypothesis was that xenon had no influence on onset time, duration, recovery index, and clinical recovery after a single dose (2 x 95% effective dose) of rocuronium compared with a total IV anesthesia (TIVA) with propofol.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With approval from the local ethics committee, 40 adults (ASA physical status I–II; Mallampati classification I–II; aged 18–60 yr) were informed and gave their written consent to take part in either the xenon or the propofol group. The study was designed as a prospective randomized controlled trial based on the guidelines of the "Good Clinical Research Practice (GCRP)" in pharmacodynamic studies of neuromuscular blocking drugs (10). Randomization was computer generated and stratified by gender and blinded to the patient. Blinding to the anesthesiologist would have been possible (albeit difficult), but was not necessary in this type of study. Individuals were excluded if they were pregnant or breast-feeding women, had expected difficult intubation, body weight more or less than 20% of ideal, any known allergic diathesis, and preoperative medications known to interact with nondepolarizing neuromuscular blocking drugs, or neuromuscular diseases.

Standard monitoring was used including xenon concentrations. The IV line and arterial blood pressure monitoring were placed on the contralateral arm of the neuromuscular monitoring.

According to GCRP guidelines, neuromuscular monitoring was performed using an acceleromyograph (TOF-Watch SX®; Organon Teknika, Boxtel, the Netherlands) for neuromuscular monitoring (10). The arm was fixed to a special board (arm board TOF-Guard®; Organon Teknika). Skin was cleaned with alcohol and hairs were removed if necessary. The electrodes for neuromuscular monitoring were placed at the ulnar nerve on the volar side of the wrist. The piezoelectric wafer was placed at the distal interphalangeal joint of the thumb, ensuring free movement of the thumb. The temperature sensor was fixed at the distal end of the forearm. The temperature was maintained at >32°C. Train-of-four (TOF) stimulation was used (supramaximal square wave impulse at 2 Hz every 15 s, 200-µs duration). The onset time is defined as time of injection of rocuronium until a 95% depression of the first twitch (T1) is reached. Duration T25 of neuromuscular recovery is defined as beginning of injection of rocuronium to a 25% recovery of the first twitch. The recovery index T25–75 is defined as the time between 25% T1 and 75% T1 response of the TOF and clinical recovery T25–0.8 as the time interval between T25 and a TOF ratio (T1/T4) of 0.8. Data were collected using the specific software (TOF-Watch SX®, version 1.1).

Bispectral index (BIS, model A-2000®; Aspect Medical Systems, Newton, MA) was monitored aiming for BIS values of <50, being in the suggested tolerance between 40–60 (11). However BIS monitoring was measured as a surrogate variable to have some extra information about depth of anesthesia knowing that it is not validated for use in xenon anesthesia. The BIS electrodes® (Aspect Medical Systems) were applied after the skin of the forehead and temple was cleaned and dried. BIS monitoring was registered at a fixed interval of every 5 min.

Premedication was performed with midazolam 7.5 mg orally, 45 min before induction. Anesthesia was induced IV with a single dose of propofol 2 mg/kg and remifentanil with 0.5 µg/kg in an infusion pump within 60 s in both groups. Variations to clinical needs (changes in arterial blood pressure and heart rate more than ±20%) were allowed. Xenon administration was started via a face mask (xenon group) or propofol was injected via infusion pump and ventilation was performed with oxygen/air (propofol group). Xenon was applied using a closed circuit anesthesia machine (PhysioFlex®; Draeger, Lübeck, Germany) with a modified software to reduce xenon consumption under minimal flow conditions (12).

Maintenance of anesthesia was achieved either by xenon (60% in O2 reflecting a MAC value of approximately 0.85, referring to a MAC of 71% xenon) or propofol (0.06–0.12 mg · kg–1 · min–1, propofol group) and remifentanil adapted to clinical needs in both groups. After an end-expiratory concentration of 60% xenon was maintained for at least 1 min, the automatic set-up procedure of the TOF-Watch was performed to determine the supramaximal stimulus. TOF monitoring was started and, after stabilization of the signal for 5 min, rocuronium 0.6 mg/kg (2 x 95% effective dose) was injected within 5 s. Intubation of the trachea was performed after the first twitch of the TOF reached 5% of the preinjection value of rocuronium. In the xenon group, the PhysioFlex® system was flushed in case xenon decreased to <55% until 60% was reached again. Ventilation was adjusted to maintain an end-expiratory carbon dioxide concentration at 4.9–6.1 kPa. Normothermia (35.5°–37.0°C) was achieved by using warming blankets. Complete recovery of neuromuscular block was reached at the end of operation in each patient. None of the patients required redosing of neuromuscular block and none of the patients required pharmacological antagonism. The depth of anesthesia was continuous during full recovery from neuromuscular block. At the end of operation, administration of the anesthetics was stopped immediately.

The sample size was calculated with a power of ß = 0.8 and a significance level of {alpha} = 5%, the clinically important difference {delta} = 30 s, and a standard deviation (SD) of 30 s for the onset time with 17 patients. The clinically important difference and SD were taken from a previous study by Lowry et al. (13). The sample size was determined at 20 patients in each group, including some reserve.

Demographic data were analyzed for homogeneity. Onset time, duration T25, recovery index T25–75, and clinical recovery T25–0.8 were presented as mean ± SD. They were analyzed using a 2-sided rank sum test of Wilcoxon. Statistical analysis was performed using SAS software version 8.0® (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Forty patients, 19 women and 21 men were investigated. The demographic data were comparable for both groups and showed no significant difference in age, sex, height, and body weight (Table 1). The induction of anesthesia was started with propofol and remifentanil at 2.0 ± 0.4 mg/kg and 0.5 ± 0.1 µg/kg in the xenon group and 2.0 ± 0.5 mg/kg and 0.5 ± 0.1 µg/kg (mean ± SD) in the propofol group. Anesthesia was maintained with 59% ± 3.6% xenon and with 0.16 ± 0.1 µg · kg–1 · min–1 remifentanil in the xenon group or with 0.09 ± 0.03 mg · kg–1 · min–1 propofol and 0.18 ± 0.1 µg · kg–1 · min–1 remifentanil in the propofol group. During the induction period, BIS monitoring was 40 ± 9 in the xenon group and 40 ± 11 in the propofol group. Throughout the study period of neuromuscular monitoring, the BIS monitoring was 37 ± 9 and 40 ± 14 in the xenon and propofol group.


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  		Table 1. Demographic Data
 
Neuromuscular monitoring showed no significant differences of the neuromuscular effects of rocuronium in the two groups. Onset time was 125 ± 33 s in the xenon group compared with 143 ± 43 with propofol (P = 0.17), duration T25 was 33.2 ± 10.8 and 32.6 ± 8.4 min in the xenon/propofol group (P = 0.88). Recovery index T25–75 was 9.4 ± 6.6 in the xenon group and 8.4 ± 5.3 in the propofol group (P = 0.69) and clinical recovery T25–0.8 lasted 18.0 ± 10.2 and 17.1 ± 8.5 min (P = 0.69) in the xenon/propofol group (Table 2). The clinical recovery time of one patient in the propofol group could not be analyzed because of a data transfer error.


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  		Table 2. Neuromuscular Monitoring
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of this study confirm the hypothesis that xenon does not prolong the neuromuscular blocking effect after a single dose of 0.6 mg/kg rocuronium compared with a TIVA with propofol. There was no significant prolongation of the onset time, duration, recovery index, and recovery.

Mechanomyography, electromyography, and acceleromyography have been used for neuromuscular monitoring for scientific purposes. Engbaek et al. (14) showed that electromyography, often used for neuromuscular monitoring, could not reach full recovery to initial values after a long period of constant stimulation. Acceleromyography, validated for clinical use by Viby-Mogensen et al. (10,15) and accepted for neuromuscular monitoring in the GCRP guidelines for phase III studies, was used for neuromuscular monitoring in this study. It is important that the results of different methods should not be compared. Nakata et al. (16) confirmed that acceleromyography and electromyography cannot be used interchangeably with either xenon or sevoflurane anesthesia.

The short equilibration time of six minutes may be a possible disadvantage of the study design. Some authors demand a 30- to 40-minute period of equilibration of the muscular compartment when using inhaled anesthetics with a high blood-gas solubility (1). Xenon has the lowest blood-gas solubility of all inhaled anesthetics by a wide margin. The solubility of volatile anesthetics in muscle is influenced by body temperature and patient’s age. Solubility of xenon in muscle is 0.082 and thus extremely low compared with values for middle-aged adults for halothane (1.44 ± 0.17), enflurane (1.09 ± 0.10), isoflurane (1.52 ± 0.11), sevoflurane (1.08 ± 0.20), desflurane (0.62 ± 0.06), or even nitrous oxide (0.54) (17–19). Based on these data, it can be assumed that the equilibration of xenon in the muscle compartment is finished when a steady-state end-expiratory concentration has been achieved.

To verify the hypothesis of this study, we used a TIVA with propofol at values of 0.09 ± 0.03 mg · kg–1 · min–1 corresponding to the lower limits from the literature to have the smallest possible effect of propofol on neuromuscular transmission. We accepted the disadvantage of the comparability of xenon as an inhaled and propofol as an IV anesthetic. It is important to note that most studies that have examined the neuromuscular effects of inhaled anesthetics used MAC concentrations of 1.5–2.0. These concentrations are not achievable because of the large MAC of xenon. In this study, xenon was given at a MAC of 0.85 referring to the validated value of 71%. This limits the comparability to previous studies with other inhaled anesthetics.

The results by Kunitz et al. (20) and Nakata et al. (21) support the hypothesis of this study. Nakata et al. (21) measured vecuronium-induced neuromuscular block during xenon or sevoflurane anesthesia in humans. Anesthesia was maintained using 57% xenon and 1.6% sevoflurane equal to 0.8 MAC. The end-tidal anesthetic concentration and twitch response were stable for 45 minutes before 0.05 mg/kg vecuronium was injected. Neuromuscular block was monitored with an accelerometer. The study demonstrated that xenon had a lesser effect on recovery from vecuronium-induced neuromuscular block than sevoflurane. Kunitz et al. (20) measured onset time, duration, and recovery after a single bolus of 0.16 mg/kg mivacurium using an identical protocol as the present study. There were no significant differences between the groups concerning the onset time, duration, recovery index, and clinical recovery.

The use of xenon with its extreme low blood-gas solubility allows rapid emergence and recovery from anesthesia. In contrast to other inhaled anesthetics, it does not prolong the neuromuscular block. Xenon does not influence onset time, duration, and recovery any differently than TIVA with propofol after a single dose of 0.6 mg/kg rocuronium.


   Acknowledgments
 
This work was supported by Messer Griesheim (donor of xenon) and Organon Teknika (TOF-Watch SX® and financial support).


   Footnotes
 
None of the authors received any corporate support as speakers’ fees, honoraria, etc., from any of the sponsors of this study.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 5, 2004.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press