Rapacuronium recovery characteristics and infusion requirements during inhalation versus propofol-based anaesthesia

W. Fu1, K. W. Klein1, P. F. White1, J. W. Chiu1, H. J. M. Lemmens2, D. G. Whalley3, D. R. Drover2 and C. P. Greenberg4

1Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas, TX, USA, 2Stanford University, Stanford, CA, USA, 3Cleveland Clinic Foundation, Cleveland, OH, USA, and 4Columbia University, New York, NY, USA*Corresponding author

Accepted for publication: February 29, 2000

Abstract

We examined the effect of four maintenance anaesthetics on the neuromuscular blocking activity and spontaneous recovery characteristics after a short-term infusion of rapacuronium. Eighty ASA I–III adult patients undergoing elective surgery were studied at four centres. Anaesthesia was induced with propofol 1.5–2.5 mg kg–1 and fentanyl 1–2 µg kg–1, followed by a bolus of rapacuronium 1.5 mg kg–1. The patients were randomized to receive either desflurane (2–4% end-tidal, ET), sevoflurane (0.75–1.5% ET), isoflurane (0.4–0.8% ET), or a propofol infusion (75–150 µg kg–1 min–1) for maintenance of anaesthesia in combination with nitrous oxide (60–70%) in oxygen. When the first twitch (T1) of a train-of-four stimulus (using the TOF Guard® accelerometer) returned to 5%, an infusion of rapacuronium was started at 3 mg kg–1 h–1 and adjusted to maintain T1/T0 at 10%. The duration of infusion lasted between 45 and 60 min, and the average infusion rates of rapacuronium were similar in all groups, ranging from 1.6 to 2.5 mg kg–1 h–1. There were no significant differences among the groups in the times for T1/T0 to return to 25%, 75% or 90%, or for T4/T1 to return to 70% and 80% upon discontinuation of the infusion. When potent inhalation anaesthetics are used in clinically relevant concentrations for maintenance of anaesthesia, the neuromuscular recovery profile of rapacuronium administered as a variable-rate infusion for up to 1 h is similar to that found with a propofol-based anaesthetic technique.

Br J Anaesth 2000; 85: 302–5

Keywords: neuromuscular block, rapacuronium; anaesthetics, volatile, desflurane; anaesthetics, volatile, sevoflurane; anaesthetics, volatile, isoflurane; anaesthetics i.v., propofol; monitoring, acceleromyography

Rapacuronium (ORG 9487) is a new aminosteroidal non-depolarizing neuromuscular blocking drug which has a rapid onset and short duration of action following an i.v. bolus dose.1 In a preliminary study, van den Broek and colleagues reported that when a short-term (1 h) infusion of rapacuronium was administered during isoflurane anaesthesia, its time course of recovery was altered from that of a short- to an intermediate-acting neuromuscular blocking drug.2 However, there are a lack of data pertaining to the relative potentiating effect of different maintenance anaesthetics on rapacuronium-induced blockade.

Thus, we evaluated the neuromuscular blocking effects and spontaneous recovery profile when a continuous infusion of rapacuronium was administered during general anaesthesia maintained with equipotent concentrations of either desflurane, sevoflurane or isoflurane versus propofol in combination with nitrous oxide (N2O).

Methods and results

After obtaining institutional review board approval and written informed consent, 80 ASA I–III patients aged between 18 and 70 yr, undergoing elective orthopaedic and general surgery procedures with an anticipated duration of at least 2 h, were enrolled at four United States medical centres. Exclusion criteria included clinically significant hepatic, renal or neuromuscular disease, pregnancy, anticipated difficult intubation, drug therapy known to modify neuromuscular blockade (e.g. anticonvulsants, aminoglycoside/polypeptide antibiotics) and those whose body weight was 30% above or below their ideal body weight. The investigation was designed as an open-label, parallel-group comparative, multicentre study in which patients were randomized in groups of 20 at each centre to receive either desflurane (n=5), sevoflurane (n=5), isoflurane (n=5) or propofol (n=5) in combination with nitrous oxide for maintenance of general anaesthesia.

Midazolam 1–3 mg i.v. was administered for premedication 10–15 min prior to induction of anaesthesia. Non-invasive blood pressure, electrocardiogram (ECG) and haemoglobin oxygen saturation (SpO2) were monitored. Anaesthesia was induced with propofol 1.5–2.5 mg kg–1 and fentanyl 1–2 µg kg–1 i.v.. Mask ventilation with 100% oxygen was instituted while the baseline measurements of neuromuscular function were obtained using a TOF Guard® accelerometer (Organon Teknika NV, Belgium). The TOF Guard® electrodes, temperature thermistor-sensor and accelerometric transducer were positioned on the patient’s arm prior to induction of anaesthesia, and the arm was carefully secured to the operating table armboard during the study period in order to obviate inadvertent movements which may produce artifactual readings. After obtaining a stable T1 recording (baseline value), rapacuronium 1.5 mg kg–1 was injected over 5 s into a rapidly flowing peripheral i.v. line in the opposite arm. The patient was intubated within 90 s and mechanical ventilation was initiated to maintain the end-tidal (ET) carbon dioxide (CO2) at 4.5–5.0 kPa.

Maintenance of anaesthesia consisted of either desflurane (2–4% ET), sevoflurane (0.75–1.5% ET), isoflurane (0.4–0.8% ET) or propofol infusion (75–150 µg kg–1 min–1) in combination with 60–70% nitrous oxide in oxygen according to a computer-generated randomization scheme. The patients received fentanyl 1 µg kg–1 and/or labetalol 5–10 mg as needed to maintain haemodynamic stability. Central (oesophageal) and peripheral (axillary) temperatures were monitored and maintained above 36.5 °C and 32.5 °C, respectively, using a forced-air warming blanket. All patients received crystalloids (Plasmalyte®), with colloids or blood only administered if indicated.

When T1/T0 returned to 5%, a continuous infusion of rapacuronium was started at 3 mg kg–1 h–1 and adjusted to maintain T1/T0 at 10% for 45–60 min. After discontinuation of the rapacuronium infusion, the patients were allowed to recover spontaneously until the times for return of T1/T0 to 25%, 75% and 90%, as well as the times for return of T4/T1 to 70% and 80% were recorded, if clinically feasible. If the T4/T1 ratio was <70% at the end of surgery, a combination of neostigmine 50–70 µg kg–1 and glycopyrrolate 8–10 µg kg–1 was administered to reverse residual neuromuscular blockade.

Based on an earlier study involving a rocuronium infusion,3 an a priori power analysis suggested that a sample size of 20 subjects per treatment group would provide at least 80% power for detecting a difference of one standard deviation in infusion rates between any two treatment groups at the P=0.05 significance level. The SAS (version 6.09) computer software package used for data analysis was run on a VMS operating system. Frequency and univariate procedures were used for summary statistics, and two-way analyses-of-variance using general linear models procedures were used for analysis of infusion rates and recovery variables. Data are presented as mean (SD), medians or numbers (Table 1), with P-values <0.05 considered statistically significant.


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Table 1 Physical characteristics, neuromuscular recovery and infusion rate data for the four study groups.* Data are expressed as means (SD), medians or numbers (n), age, range. ASA, American Society of Anesthesiologists; NA, non-applicable; MAC h–1, sum of end-tidal concentration divided by the minimum alveolar concentration (MAC) value (adjusted for concomitant use of nitrous oxide and age) multiplied by the duration (h) at that concentration. Rapacuronium infusion rate = mean infusion rate of rapacuronium at 40 min after starting the maintenance infusion. Recovery index=time interval between recovery of T1/T0 to 25% and 75%. *There were no significant differences among the four study groups
 
Although 80 patients were enrolled, five were excluded from the analysis because of protocol violations at the onset of the study, while subsequent violations precluded analysis of one patient who received the rapacuronium infusion for only 26 min and four patients who received additional anaesthetic agents before the end of the rapacuronium infusion. There were no significant differences in the patient characteristics (Table 1), rapacuronium infusion times (group means from 53 to 55 min), total rapacuronium dosages (group means from 3.4 to 3.9 mg kg–1) and average rapacuronium maintenance infusion rates to maintain ~90% block (group means from 1.6 to 2.5 mg kg–1 h–1) among the four anaesthetic groups. The maintenance dosages (MAC h–1) of the potent inhalation agents were similar in the desflurane, sevoflurane and isoflurane groups. There were also no statistical differences in the times for T1/T0 recovery to 25%, 75% and 90%, or for T4/T1 to recover to 0.7 and 0.8 (Table 1).

Comment

In this study, the recovery times after discontinuing the infusion of rapacuronium were significantly longer than following a single intubating dose of rapacuronium.1 These findings confirm a previous report which suggested that rapacuronium was altered from a short-acting to an intermediate-acting neuromuscular blocking drug when administered as an infusion.2 The apparent pharmacodynamic change may be explained by the reduced contribution of distribution to plasma clearance, as well as the accumulation of the 3-desacetyl metabolite of rapacuronium (ORG 9488), which has a longer half-life and appears to be more potent than the parent compound.4 Van den Broek and colleagues2 demonstrated that a TOF ratio of 0.7 measured by mechanomyography (MMG) was attained 38 min after a 1 h infusion of rapacuronium, which was significantly shorter than the times reported in our study (71–92 min). This difference may be related in part to the less profound depth of neuromuscular blockade established in the earlier study (83% versus 92%, respectively), and the variations in recovery profiles as a result of using acceleromyography versus MMG monitoring.5

Desflurane, sevoflurane and isoflurane all potentiate the neuromuscular blockade produced by non-depolarizing neuromuscular blocking drugs,6 7 whereas most studies have failed to demonstrate potentiation with propofol.8 9 We compared these potent inhalation anaesthetics to a propofol infusion for maintenance of anaesthesia and no statistically significant differences were found with respect to the recovery characteristics following an equi-effective rapacuronium infusion, although the mean values in the sevoflurane group did tend to be longer. These results are analogous to those of Wulf and colleagues9 who demonstrated that spontaneous recovery of neuromuscular function following rocuronium was similar during propofol or volatile-based anaesthesia using a TOF Guard® monitor.

The failure to find any significant differences among the four anaesthetic techniques may be attributed to: (i) the limited sample sizes especially for the later recovery variables (due to the difficulty in accurately predicting the need for further muscle relaxation); (ii) the widespread disagreement in regard to comparative measurements with acceleromyography versus MMG or electromyography (EMG); and (iii) the inherent variability resulting from the fact that 20 patients were enrolled at each of four different medical centres. Most importantly, complete equilibration (steady-state conditions) for the anaesthetic agents10 and rapacuronium between the muscle and plasma compartments may not have been achieved during the 45–60 min study period.

In conclusion, when potent inhalation agents are administered in clinically relevant concentrations for maintenance of anaesthesia, the neuromuscular blocking activity, recovery profile and infusion requirements for rapacuronium (administered as a variable-rate infusion) were similar to those observed during a propofol-based anaesthetic technique. Further studies are needed to validate these results using other neuromuscular monitoring techniques, a more tightly controlled propofol infusion rate and fixed ET concentrations of the inhaled agents.

Acknowledgement

This study was supported in part by Organon, West Orange, NJ, USA.

References

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