Anaesthesia, 1992, Volume 47, pages 832-834
A comparison of the pharmacodynamics of rocuronium and vecuronium during halothane anaesthesia
M. G. BOOTH, B. MARSH, F. M.M. BRYDEN, E. N. ROBERTSON
W.L. M. BAIRD
Summary Thirty healthy patients were randomised to receive either a single bolus dose of rocuronium 0.6 mg.kg-' or vecuronium 0.1 mg.kg-' during halothane anaesthesia. Onset time, duration 25, duration 75 and train-offour 70 were measured. The onset of neuromuscular blockade following rocuronium was more rapid than vecuronium ( p = 0.0001). AN other pharmacodynamic parameters were similar. During the first minutefollowing injection of the neuromuscular blocking agent, the heart rate increased by 36% in the rocuronium group but remained stable in those patients who received vecuronium ( p = 0.oooS).No adverse effects were noted in either group.
Key words Neuromuscular relaxants; rocuronium, vecuronium. Anaesthetics, volatile; halothane.
A new nondepolarising neuromuscular blocking drug, rocuronium, (laboratory code, Org 9426), currently undergoing evaluation in man, is a monoquaternary aminosteroid compound, the 2-morpholino, 3-hydroxy 16N-ally1 pyrrolidino analogue of vecuronium. Animal studies have shown that, when equipotent doses are compared, rocuronium has an onset of neuromuscular blockade which is twice as rapid as vecuronium, although the duration of action is similar. In these studies, the cardiovascular effects of rocuronium were, in general, slight [ 11, substantiated by initial clinical studies [2-81. The neuromuscular blocking potency of rocuronium was shown to be approximately 20% that of vecuronium in anaesthetised cats and pigs [l]. In patients anaesthetised with nitrous oxide and narcotic, the ED, dose of rocuronium was reported to be somewhere within the range 0.25 mg.kg-' to 0.3 mg.kg-l [7,9, 101. This study compared the pharmacodynamic profile of a single bolus dose (2 x ED,) of rocuronium 0.6 mg.kg-' with vecuronium 0.1 mg.kg-', in 30 healthy patients anaesthetised with nitrous oxide and halothane. Method
The prospective, randomised study was approved by the Hospital Ethics Committee. Written, informed consent was
obtained from 30 healthy patients (ASA 1 or 2), aged 18 to 65 years, who were scheduled for elective nonabdominal surgery. Patients who had had anaesthesia within the previous 3 months or received medication during the past 7 days that could affect neuromuscular function were not studied. Body weight limits were imposed, calculated on the basis of Feight (cm)-1001 kg+25% or - 15%. Additional exclusion criteria included pregnancy and those patients whose serum electrolyte and urea levels and/or liver function tests were outside normal limits. Patients were premedicated with papaveretum and hyoscine on a body weight basis,' administered intramuscularly approximately 1 h before induction of anaesthesia. Morphine was substituted for papaveretum, following the recommendation by the Committee on the Safety of Medicines (June 1991) [l 11. Anaesthesia was induced with thiopentone (3-5 mg.kg-l) and maintained with nitrous oxide 67% and halothane 0.5-1% (end-tidal) in oxygen. Spontaneous ventilation was retained at this stage. Supramaximal stimuli, duration 0.2 ms and frequency 2 Hz,were delivered in a train-of-four (TOF) sequence at 10s intervals to the ulnar nerve at the wrist via surface electrodes, and the evoked responses of the adductor pollicis were transduced and recorded by a Myograph 2000 Neuromuscular Transmission Analyser (Biometer, ,
M.G. Booth, MB, ChB, FRCAnaes, Registrar, B. Marsh, MB, ChB, FFARCSI, Registrar, F.M.M. Bryden, MB, ChB, DRCOG, FFARCSI, Registrar, E.N. Robertson,* BSc, MB, ChB, FFARCS, Consultant, W.L.M. Baird, MB, ChB, FFARCS, FRCP (Glasg), Consultant, Division of Anaesthesia, Royal Infirmary, Glasgow G3 1 3ER. Correspondence should be addressed to Dr Bryden. *Present address: Department of Anaesthesia, Academisch Ziekenhaus, Nijmegen, The Netherlands. Accepted 4 April 1992. 0003-2409/92/010832 + 03 %08.00/0
@ 1992 The Association of Anaesthetists of Gt Britain and Ireland
Comparison of rocuronium and vecuronium Denmark). Control responses were recorded for at least 10 min to allow stabilisation and skin temperature over the thenar eminence was monitored throughout and surface cooling minimised by application of wool gauze pads. The neuromuscular blocking drug was injected into a fast flowing intravenous infusion of 0.9% saline sited in a vein on the contralateral hand and the times were measured from completion of injection. The parameters measured were: onset (time from injection to 100% depression of the first response, T1) duration 25 (time from injection to 25% recovery of Tl), duration 75 (time from injection to 75% recovery of Tl), and TOF 70 (time from injection to a T4/T1 ratio of 70%). Arterial pressure (indirect), heart rate, electrocardiograph (ECG), oxygen saturation, end-tidal CO, and endtidal halothane concentration were monitored continuously throughout the study. Patients were randomly allocated to receive rocuronium 0.6 mg.kg-l (group 1: n = 15) or vecuronium 0.1 mg.kg-I (group 2: n = 15). Following administration of the neuromuscular blocking drug, when the T1 response was ablated, the trachea was intubated and mechanical intermittent positive pressure ventilation (IPPV) instituted. The demographic data from the two groups were analysed by the Wilcoxon 2 sample test, and with respect to sex, using the Chi-squared test. The pharmacodynamic and haemodynamic data were compared by the Wilcoxon 2 sample test; p < 0.05 was considered to be significant.
The demographic data are shown in Table 1. There were no singificant differences between the two groups with regard to sex, age, body weight or height. The pharmacodynamic data are shown in Table 2. The onset of neuromuscular block following rocuronium was 1.0 (0.2) min and 1.6 (0.5) min after vecuronium, the difference being highly significant (p = 0.0001). In all patients depression of T1 was 100%. Duration 25 was 42.7 (11.2) rnin and 43.3 (6.7) min, following rocuronium and vecuronium respectively. The corresponding duration 75 measurements were 66.5 (27.7) min and 65.9 (13.6) min respectively. Duration TOF 70 was 71.2 (21.8) rnin and 76.6 (15.1) min in groups 1 and 2, respectively. In two patients, one in each group, the residual neuromuscular block was reversed before the TOF ratio returned to 70%, to avoid unacceptable delay in the progress of the operating list. There was no statistical difference between the recovery parameters measured in either group of patients. The heart rate and mean arterial pressure recordings made immediately before and 1 rnin after injection of the
Table 2. Mean (SD) onset time of initial dose of neuromuscular blocking agent, duration 25, duration 75 and duration 0.7 in min in the study groups.
Onset time Duration 25 Duration 75 Duration TOF 70
n = 15 Vecuronium
n = 15 Rocuronium
1.6 (0.5)* 43.3 (6.7) 65.9 (13.6) 76.6 (15.1)
1.0 (0.2) 42.7 (11.2) 66.5 (27.7) 71.2 (21.8)
*Significant difference between groups p = 0.0001
neuromuscular blocking agents, but before laryngoscopy, are shown in Table 3. The mean baseline heart rates of patients in group 1 and group 2 were not statistically different. However, 1 min following injection of rocuronium the mean heart rate in group 1 patients increased, whereas in group 2, after vecuronium, the mean heart rate decreased, the difference being statistically significant (p = 0.0022). The change in heart rate, expressed as a percentage of the baseline recordings, was +36.3% (30.76) in group 1 patients and -5.5% (13.18) in group 2 (p = 0.0008). The baseline mean arterial pressure in both groups was similar and the subsequent changes noted 1 rnin after injection of either neuromuscular blocking agent were not significantly different. No untoward sequelae, such as arrhythmias or evidence of histamine release, were observed. Discussion This study has demonstrated that in patients anaesthetised with nitrous oxide and halothane, the onset of neuromuscular blockade following rocuronium is approximately 40% more rapid than that of vecuronium when equipotent doses (2xED,) are compared. This finding is in close agreement with work previously published . However, in our study, the mean time from injection to 100% depression of twitch height (1.O min) following rocuronium 0.6 mg.kg-l was substantially faster than the onset time (1.6 min) reported by Nagashima and his colleagues, who studied the same dose [lo]. Similarly, we recorded an onset time of 1.6 rnin following vecuronium 0.1 mg.kg-' whereas other investigators, for example Rsrvik et al. , have reported the onset to be 2.8 rnin at Table 3. Haemodynamic data, mean (SD) in the study groups.
Study group Table 1. Mean (SD) age, weight, height and distribution of sex in the study groups.
Age; years Weight; kg Height; cm Females Males
n = 15 Vecuronium
n = 15 Rocuronium
39.9 (12.0) 64.3 (11.7) 166.7 (6.0) 10 5
40.1 (12.4) 73.0 (7.8) 172.1 (7.8) 5
Heart rate, baseline Heart rate at 1 min YOchange MAP, baseline MAP 1 min YOchange
n = 15 Vecuronium
n = 15 Rocuronium
64.27 (I 3.57) 59.93 (12.33). -5.52 (13.18)t 76.73 (11.57) 75.27 (18.95) -1.97 (15.81)
66.47 (20.57) 84.47 (16.89) +36.30 (30.76) 82.71 (14.55) 86.64 (13.01) +3.62 (16.00)
Significant difference between groups *p = 0.0022; t p = 0.0008.
M.G. Booth et al.
the same dose level. It would seem likely that the varying results can be explained by the difference in experimental design employed in these studies. Whilst we measured the onset time of rocuronium and vecuronium when injected during steady state halothane: nitrous oxide anaesthesia, Nagashima er a/. [lo] and Rsrvik etal.  recorded onset time (and recovery) during nitrous oxide: narcotic anaesthesia. The factors which govern the onset of neuromuscular blocking drugs, other than circulation time, have not yet been fully elucidated. After undertaking extensive studies on a large number of pancuronium and vecuronium analogues, Bowman and his colleagues  demonstrated a clear relationship between effective dose and onset time and showed that rapid onset time, coupled with brief duration of action, could only be obtained with compounds of relatively low potency. They suggested that this could be explained, in accordance with the law of mass action, by the need for a high concentration of molecules in the biophase in order to achieve rapid receptor block. This concept has also been addressed recently by Hull . If vecuronium is administered in a large dose, (with the aim of increasing the concentration of molecules in the biophase to hasten the onset of blockade), because of its inherent high drug : receptor affinity, the more rapid onset will only be achieved at the cost of very prolonged duration of action . In contrast, when rocuronium is administered in approximately equipotent doses, it provides an onset of action which is substantially more rapid than vecuronium, without incurring long duration of action. This interesting pharmacodynamic profile of rocuronium, which is a compound with a potency some 6 to 8 times less than that of vecuronium, is in accordance with the hypothesis outlined above. This study was not specifically designed to evaluate possible cardiovascular effects. However, 1 min after the injection of rocuronium, but before the stimulus of laryngoscopy and tracheal intubation, a moderate increase in heart rate was noted although the arterial pressure remained stable. The haemodynamic parameters did not change following vecuronium. Cardiovascular effects have not been reported before in clinical studies of rocuronium. In the cat, the ratio of vagal to neuromuscular blockade was shown to be 7.2 for rocuronium and 76 for vecuronium [l]. These authors drew attention to the fact that, in this respect, vecuronium provides an especially stringent standard. However, since rocuronium is much less potent than vecuronium as a neuromuscular blocking agent, the possibility of unwanted side effects does arise. Although the increase in heart rate noted in this study was not of great clinical significance, a detailed analysis of the cardiovascular effects of rocuronium in patients, at dose levels of 2 x ED, and above, is warranted. In conclusion, this study has confirmed that under halothane :nitrous oxide anaesthesia rocuronium has a significantly faster onset of neuromuscular blocking action than vecuronium when compared at dose levels of approximately 2xED,. In all other respects the pharmacodynamic profile of these two compounds is similar. The
possibility exists that these dose levels of rocuronium may induce a moderate increase in heart rate. Further detailed evaluation of this interesting compound is certainly indicated. Acknowledgments The authors wish to record their gratitude to their surgical and nursing colleagues for their cooperation throughout this study. We also wish to thank Dr G. N. C. Kenny and Staff, University Department of Anaesthesia, for statistical advice, and Organon Teknika for supplies of rocuronium.
Refereaces [I] M m AW, HOUSTON J, GREENKL, MARSHALL RJ, BOWMAN WC, MARSHALL IG. Effects of a new neuromuscular blocking agent (Org 9426) in anaesthetizedcats and pigs and in isolated nerve-muscle preparations. British Journal of Anaesthesia 1989; 63:400-10.  NAGASHIMA H, NGUYENHD, KINSEY A, KOSAM, HOLLINGER I, GOLDINER PL, FOLDIS FF. The human dose response of Org 9426. Anesthesiology 1989; 71: A773. WC, WILKSDH, BRANWMBW, DIANAP, coo^  TULLOCK DR. Org 9426 Single-dose response, onset, and duration with halothane anesthesia. Anesthesiology 1990; 73: A877. LM, KLOPPENBURC  WIERDAJMKH, KLEEFUW, LAMBALK WD, AGOSTON S. The pharmacodynamics and pharmacokinetics of Org 9426, a new non depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. Canadian Journal o/ Anaesthesia 1991; 38.430-5. B, GORBACK MS.  QUILLTJ, BEGINM, GLASSPSA, GINSBERG Clinical responses to Org 9426 during isoflurane anesthesia. Anesthesia and Analgesia 1991; 7 2 203-6. G , DUB~DIS M, LEAD, KATANAB, TRAND. Effects  LAPEYRE of 3 intubating doses of Org 9426 in humans. Anesfhesiology 1990; 73: A906. (1Boou LHDJ, KNAPEHTA. The neuromuscular blocking effect of Org 9426. A new intermediately-actingsteroidal nondepolarizing muscle relaxant in man. Anaesthesia 1991; 46: 341-3.  LAMBALK LM, DE WIT APM, WIERDAJMKH, HENNISPJ, AGOSTONS. Dose-response relationship and time course of action of Org 9426. A new muscle relaxant of intermediate duration evaluated under various anaesthetic techniques. Anaesthesia 9 I; 46: 907- I 1.  WIERDAJMKH, DE WITAPM, KUIZENGA K, AGOSTONS. Clinical observations on the neuromuscular blocking action of Org 9426, a new steroidal non-depolarizing agent. British Journal of Anaesthesia 1990; 64:521-3. [lo] NAGASHIMA H, NGWEN HD, MASONMM, SCHILLER WS, GOLDINER PL. FOLDES FF. Musclar relaxation with Org 9426 under balanced anesthesia. Anesthesiology 1990; 73 A890. [I 11 COMMITIEE ON SAFETY OF MEDICINES. Currenf Problems 1991; 31: No. 7. [I21 RBRVIK K, HUSBY P, GRAMSTAD L, VAMNES Js, ME.Comparison of large dose of BIIXCH-LARSEN L, KOLLER vecuronium with pancuronium for prolonged neuromuscular blockade. British Journal of Anaesthesia 1988; 61: 180-5. [I31 BOWMAN WC, RODGERIW, HOUSTONJ, MARSHALL RJ, MCINDEWAR I. Structure: action relationships among some desacetoxy analogues of pancuronium and vecuronium in the anesthetized cat. Anesthesiology 1988; 69: 57-62. [141 HULL CJ. Pharmacokinefics for anaesthesia. Oxford: Buttenvorth-Heinemann, 1991: 333-6. [I51 GINSBERG B, GLASSPS, QUILLT, SHAFRON D, OSSEYKD. Onset and duration of neuromuscular blockade following high-dose vecuronium administration. Anesthesiology 1989; 71: 201-5.