Department of Anaesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75235, USA*Corresponding author
Accepted for publication: February 29, 2000
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Br J Anaesth 2000; 85: 24650
Keywords: neuromuscular block, rapacuronium; neuromuscular block, rocuronium; anaesthetics i.v., propofol; anaesthetics volatile, sevoflurane; intubation, tracheal
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This study was designed to test the hypothesis that standard intubating doses of rapacuronium and rocuronium differ with regard to their onset/offset of action and tracheal intubating conditions. In addition, we compared the initial recovery profiles of the two non-depolarizing neuromuscular blocking drugs during propofol- or sevoflurane-based anaesthesia.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
On arrival in the operating room, the electrocardiogram (ECG), haemoglobin oxygen saturation (SpO2), and non-invasive arterial pressure were monitored. After premedication with midazolam 2 mg i.v., anaesthesia was induced with propofol 2.5 mg kg1 and fentanyl 1.5 µg kg1 i.v., followed 2 min later by either rapacuronium 1.5 mg kg1 (n=30) or rocuronium 0.6 mg kg1 (n=30) according to a computer-generated randomization sequence. One minute after administration of the neuromuscular blocking drug, direct laryngoscopy was initiated followed by tracheal intubation. Intubating conditions were assessed using a three-point scale (Table 1)6 by an experienced anaesthetist who was blinded to which neuromuscular blocking drug was administered. A 20-s interval was allowed for the first attempt at intubation, and in the event of failure, a second attempt was made at 90 s.
|
Neuromuscular monitoring was performed using the Datex Relaxograph (Helsinki, Finland) to record the EMG response of the adductor pollicis to supramaximal square-wave train-of-four (TOF) stimulation of the ulnar nerve at the wrist for 0.2 ms every 10 s during the onset period, and every 20 s following tracheal intubation. The EMG recording apparatus was connected to the patient before induction of anaesthesia, and the baseline calibration sequence (which required 4560 s to complete) performed as soon as the patient lost consciousness. This was followed 1 min later by a bolus dose of either rapacuronium or rocuronium, administered over 5 s into a rapidly flowing i.v. infusion line positioned in the contralateral forearm from that used for neuromuscular monitoring. Neuromuscular blockade was allowed to recover spontaneously until the first response to TOF stimulation (T1) achieved at least 25% of the baseline value.
Clinically significant cardiovascular events (i.e. changes in arterial pressure or heart rate 30% above or below baseline values) occurring within 10 min of administration of the study drug and any possible histamine release-related signs (e.g. flushing, cutaneous erythema, bronchospasm) were recorded. An adverse event was defined as an unusual or unexpected clinical sign, which manifested itself or worsened during the intraoperative study period, irrespective of whether it was thought to be study drug related.
The following parameters were measured or calculated from the EMG recordings: (i) the time from the end of study drug injection until first depression T1 (lag time); (ii) the time from the end of study drug injection until 95% depression T1 (onset time); (iii) the degree of block at 60 s; (iv) the extent of maximum block; and (v) the time from the end of study drug injection until spontaneous recovery of T1/T0 to 25%. The time to 25% recovery T1/T0 was calculated by using the final EMG T1/T0 value as a reference.7
The sample size was determined by performing an a priori power analysis to detect a difference of 30% or more in the onset time between the two neuromuscular blocking drugs (0.05 two-sided significance level, 80% power) based on previously published data.1 5 Analysis of variance (ANOVA) was used for analysing physical characteristics, and Fishers exact test was utilized for assessing intubating conditions and adverse effects. Students t-test or MannWhitney U-test was used for analysing onset and offset times between the two neuromuscular blocking drugs and the two anaesthetic techniques as appropriate. Differences between groups were considered statistically significant when the P-value was <0.05.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The doseresponse relationship for rapacuronium has not been well established. In their preliminary investigation, Wierda and colleagues2 reported an ED90 of 1.15 mg kg1 for rapacuronium. However, the dosage used was based on the bromide salt of rapacuronium, whereas the dosage calculation in the more recent studies was based on the free base (100 mg=113.4 mg of the bromide salt). Thus, a dose of rapacuronium 1.5 mg kg1 in our study would represent 1.5xED90 (recalculated for the free base). Our study demonstrated that even at this lower dose (1.5xED90 vs 2xED90), the onset of action was more rapid and the degree of blockade at 60 s greater with rapacuronium compared to rocuronium.
This finding is consistent with the inverse relationship between potency of non-depolarizing neuromuscular blocking drugs and the speed of onset of effect.8 With less potent drugs like rapacuronium, more drug molecules are administered, thereby increasing the concentration gradient between the plasma and the motor end-plate.9 10 An alternative explanation for the rapid onset of rapacuronium relates to its rapid equilibration between the plasma and effect sites.11 The equilibration rate constant (Keo) of rapacuronium (0.41 min1) is more than twice that of rocuronium (0.17 min1)12 and 3.4 times that of vecuronium (0.12 min1).13 Additionally, in animal studies rapacuronium has been shown to possess calcium channel blocking effects that produce vasodilatation 2550 times greater than vecuronium.14 Increased blood flow to skeletal muscle may also contribute to the rapid onset of neuromuscular blockade with rapacuronium.
The fast onset of neuromuscular blocking effect after rapacuronium coincides with the achievement of clinically acceptable (good-to-excellent) intubating conditions in the majority of patients at 60 s. Kahwaji and colleagues15 reported good-to-excellent intubating conditions in 86% of young adults and 84% of elderly patients within 90 s after rapacuronium 1.5 mg kg1. However, our findings differed from those of Wierda and colleagues1 who reported good-to-excellent intubating conditions at 60 s in 100% of patients. A possible explanation for this difference relates to the fact that tracheal intubation was performed 510 min after inhalation of isoflurane (1.0%) in combination with nitrous oxide in the earlier study. The onset time of rapacuronium 1.5 mg kg1 in the laryngeal adductor muscles is 1.0 (0.2) min,4 shorter than rocuronium 0.5 mg kg1 at 1.4 (0.3) min16 and approaching succinylcholine 0.5 mg kg1 at 0.9 (0.1) min.17 At the time of intubation, rapacuronium-induced neuromuscular block at the larynx would be nearly maximum, thereby facilitating tracheal intubation.
The 25% recovery time of rapacuronium was found to be longer in the present investigation compared to two previous studies by Wierda and colleagues.1 2 These investigators reported that 25% T1/T0 recovery of rapacuronium was 8.0 (1.9) min and 8.9 (2.0) min during 1.0% isoflurane1 and 1.0% halothane2 anaesthesia, respectively. However, our results are consistent with those of Kahwaji and colleagues (14 (6) min for young adults and 17 (5) min for elderly adults) 15 and Purdy and colleagues (16.2 (4.0 min)).18 The discrepancies are probably accounted for by the different drug moieties. A dose of 1.5 mg kg1 in the present study is equivalent to 1.7 mg kg1 in Wierdas studies, at least partially explaining the difference in 25% T1/T0 recovery time. Recovery time of T1/T0 to 25% after rapacuronium during either propofol- or sevoflurane-based anaesthesia was found to be significantly shorter than after rocuronium. The more rapid plasma clearance of rapacuronium contributes to its shorter duration of action (7.3 ml kg1 min1 vs 4.0 ml kg1 min1 for rocuronium).19
Recovery of T1/T0 to 25% with both neuromuscular blocking drugs was similar during propofol and sevoflurane anaesthesia. This finding may be related to the time-dependent potentiating effects of potent inhaled agents on non-depolarizing neuromuscular blocking drugs.20 Although data for sevoflurane are not available, full isoflurane-induced potentiation of muscle relaxant activity requires 3045 min of steady-state anaesthesia.21 It is possible that the 25% recovery of T1/T0 after both rapacuronium and rocuronium would have been prolonged during sevoflurane (vs propofol) anaesthesia had the exposure occurred over a longer time interval. Xue and colleagues22 have reported that recovery of T1/T0 to 25% after rocuronium 0.4 mg kg1 was longer during sevoflurane anaesthesia (1.75%) compared to a propofol-based technique. However, in their study the patients received the volatile anaesthetic for ~40 min before the neuromuscular blocking drug was administered. The experimental design used by these investigators bears little relevance to the usual clinical situation; we therefore allowed for a much shorter stabilization period of ~1 min.
A shortcoming of the current study lies in the use of the Datex Relaxograph for monitoring neuromuscular function. As a result of the downward drift of the EMG amplitude over time, it is not uncommon for T1/T0 to regain only 7080% of its baseline value despite a TOF ratio exceeding 0.9.23 In the present study, the final T1/T0 values recovered to 81 (SD 9)% of baseline values, corresponding to TOF ratios of 0.85. To compensate for this phenomenon, the values for 25% T1/T0 recovery times were determined by using proportional recalculation based on the final EMG T1/T0 value.7
In conclusion, rapacuronium 1.5 mg kg1 exhibited a more rapid onset of action than rocuronium 0.6 mg kg1 and provided good-to-excellent intubating conditions in the majority of patients at 60 s. The initial recovery time of rapacuronium was ~50% shorter than that of rocuronium, and was not significantly altered by the maintenance anaesthetic. These data suggest that rapacuronium is a useful addition to the armamentarium of currently available non-depolarizing neuromuscular blocking drugs for facilitating tracheal intubation in patients undergoing short surgical procedures.
![]() |
Acknowledgement |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Wierda JM, Beaufort AM, Kleef UW, Smeulers NJ, Agoston S. Preliminary investigations of the clinical pharmacology of three short-acting non-depolarizing neuromuscular blocking agents, Org 9453, Org 9489 and Org 9487. Can J Anaesth 1994; 41: 21320[Abstract]
3 van den Broek L, Wierda JM, Smeulers NJ, Proost JH. Pharmacodynamics and pharmacokinetics of an infusion of Org 9487, a new short-acting steroidal neuromuscular blocking agent. Br J Anaesth 1994; 73: 3315[Abstract]
4 Debaene B, Lieutaud T, Billard V, Meistelman C. ORG 9487 neuromuscular block at the adductor pollicis and the laryngeal adductor muscles in humans. Anesthesiology 1997; 86: 13005[ISI][Medline]
5 Kopman AF, Klewicka MM, Kopman DJ, Neuman GG. Molar potency is predictive of the speed of onset of neuromuscular block for agents of intermediate, short, and ultrashort duration. Anesthesiology 1999; 90: 42531[ISI][Medline]
6 Viby-Mogensen J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996; 40: 5974[ISI][Medline]
7 Meretoja OA, Theroux M. Can final EMG baseline be used as a reference to calculate neuromuscular recovery. Acta Anaesthesiol Scand 1997; 41: 4926[ISI][Medline]
8 Bowman WC, Rodger IW, Houston J, Marshall RJ, McIndewar I. Structure: action relationships among some desacetoxy analogues of pancuronium and vecuronium in the anesthetized cat. Anesthesiology 1988; 69: 5762[ISI][Medline]
9 Min JC, Bekavac I, Glavinovic MI, Donati F, Bevan DR. Iontophoretic study of speed of action of various muscle relaxants. Anesthesiology 1992; 77: 3516[ISI][Medline]
10 Kopman AF. Gallamine, pancuronium and d-tubocurarine compared: is onset time related to drug potency? Anesthesiology 1989; 70: 91520[ISI][Medline]
11 Wright P, Brown R, Lau M, Fisher DM. A pharmacodynamic explanation for the rapid onset/offset of rapacuronium bromide. Anesthesiology 1999; 90: 1623[ISI][Medline]
12 Plaud B, Proost JH, Wierda JM, Barre J, Debaene B, Meistelman C. Pharmacokinetics and pharmacodynamics of rocuronium at the vocal cords and the adductor pollicis in humans. Clin Pharmacol Ther 1995; 58: 18591[ISI][Medline]
13 Fisher DM, Wright PM. Are plasma concentration values necessary for pharmacodynamic modeling of muscle relaxants? Anesthesiology 1997; 86: 56775[ISI][Medline]
14 Muir AW, Sleigh T, Marshall RJ, et al. Neuromuscular blocking and cardiovascular effects of Org 9487, a new short-acting aminosteroidal blocking agent, in anaesthetized animals and in isolated muscle preparations. Eur J Anaesthesiol 1998; 15: 46779[ISI][Medline]
15 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: 10118[Abstract]
16 Meistelman C, Plaud B, Donati F. Rocuronium (ORG 9426) neuromuscular blockade at the adductor muscles of the larynx and adductor pollicis in humans. Can J Anaesth 1992; 39: 6659[Abstract]
17 Meistelman C, Plaud B, Donati F. Neuromuscular effects of succinylcholine on the vocal cords and adductor pollicis muscles. Anesth Analg 1991; 73: 27882[Abstract]
18 Purdy R, Bevan DR, Donati F, Lichtor JL. Early reversal of rapacuronium with neostigmine. Anesthesiology 1999; 91: 517[ISI][Medline]
19 Schiere S, Proost JH, Schuringa M, Wierda JM. Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488). Anesth Analg 1999; 88: 6407
20 Withington DE, Donati F, Bevan DR, Varin F. Potentiation of atracurium neuromuscular blockade by enflurane: time-course of effect. Anesth Analg 1991; 72: 46973[Abstract]
21 Lambalk LM, de Wit APM, Wierda JM, Hennis PJ, Agoston S. Doseresponse relationship and time course of action of Org 9426; a new muscle relaxant of intermediate duration evaluated under various anaesthetic techniques. Anaesthesia 1991; 46: 90711[ISI][Medline]
22 Xue FS, Liao X, Tong SY, Liu JH, An G, Luo LK. Doseresponse and time-course of the effect of rocuronium bromide during sevoflurane anaesthesia. Anaesthesia 1998; 53: 2530[ISI][Medline]
23 Kopman AF, Justo MD, Mallhi MU, Abara CE, Neuman GG. The influence of changes in hand temperature on the indirectly evoked electromyogram of the first dorsal interosseous muscle. Can J Anaesth 1995; 42: 10905[Abstract]