Rocuronium is an aminosteroidal non-depolarizing muscle relaxant with a speed of onset similar to that of suxamenthonium and an intermediate duration of action similar to vecuronium and atracurium [1,2]. In animal studies and in most clinical studies, minimal cardiovascular effects are associated with the use of rocuronium in doses up to 3-4 × ED95[3-6]. However, Booth reported a 36% increase in heart rate following rocuronium (0.6 mg kg−1) administration to non-elderly adults . Pancuronium, another aminosteroidal non-depolarizing muscle relaxant, can cause tachycardia which may result in myocardial ischaemia in patients with coronary artery disease . The effect of pancuronium on heart rate is due in part to increased release of, and decreased reuptake of catecholamines at the adrenergic nerve terminal . Thus, the haemodynamic and plasma catecholamine effects of rocuronium in the elderly, a population at increased risk of coronary artery disease, warrant investigation. In patients undergoing coronary artery bypass grafting, rocuronium (0.6 mg kg−1) administration was associated with significant increases in cardiac index and stroke volume index, but not with a change in heart rate . However, all the patients in this study were receiving β blockers. The objective of the current study is to compare the haemodynamic effects of, and change in plasma catecholamine concentrations following vecuronium (0.12 mg kg−1) and rocuronium (0.9 mg kg−1) to elderly patients who were not receiving β blockers.
With institutional ethics committee approval, and having obtained verbal informed consent, 30 ASA Class I-III patients, 65 years of age or older, undergoing elective surgical procedures were studied. Patients considered suitable for inclusion in the study were recruited at a preoperative clinic visit by one of the investigators. Only two of the 32 patients who were approached declined to participate. Exclusion criteria were:
- neuromuscular disease or any condition known to influence neuromuscular function;
- recent exposure to any medication known to influence neuromuscular function;
- exposure to β blocking medication within 1 month of the study;
- an indication for rapid sequence induction of anaesthesia.
Sedative premedication was administered as clinically indicated, comprising midazolam (<0.05 mg kg−1) intravenously (i.v.). General anaesthesia was induced with sodium thiopentone (4-5 mg kg−1) and fentanyl (1.5 μg kg−1). Positive pressure ventilation was applied first via facemask and later via the endotracheal tube to maintain normocarbia end-tidal (ET) CO2 = 4.7-6.0 kPa) (Merlin System, Hewlett Packard Co., Waltham, MA, USA) using nitrous oxide (66%) in oxygen. Vecuronium (0.12 mg kg−1) or rocuronium (0.9 mg kg−1), according to a random allocation, was administered over 5 s into a rapid i.v. infusion. Two min after administration of the muscle relaxant, laryngoscopy and tracheal intubation were performed by an investigator unaware of which muscle relaxant had been given.
Blood pressure was measured non-invasively and heart rate recorded from a continuous Lead II electrocardiographic trace (both displayed and recorded using the Merlin System, Hewlett Packard Co., Waltham, MA, USA)
- immediately prior to induction of anaesthesia (Pre-ind.);
- immediately after and 2 min after induction of anaesthesia (Post-ind. #1 and #2, respectively);
- 1 and 2 min after muscle relaxant administration (Post-MR #1 and #2, respectively);
- immediately, 1 and 2 min after tracheal intubation (Post-int. #1, #2 and #3, respectively).
Automatic ST segment analysis was performed on leads II and V5 from before induction of anaesthesia until 5 min after tracheal intubation (Merlin System, Hewlett Packard Co., Waltham, MA). Significant ST-segment depression, measured 60 ms after the J point was defined as: >1 mm depression if downsloping or horizontal, or >2 mm if upsloping. Temperature was measured using a thermistor temperature probe (Merlin System, Hewlett Packard Co., Waltham, MA) placed in the nasopharynx after tracheal intubation and the minimum temperature obtained during the study period recorded.
After induction of anaesthesia, a 16-gauge i.v. cannula was inserted without prior administration of local anaesthetic (and not in the arm containing the intravenous infusion used for drug administration). Blood samples (7 mL each) were withdrawn for estimation of plasma catecholamines immediately prior to, and 1 min after muscle relaxant administration and 1 min after tracheal intubation. Samples were placed immediately on ice, centrifuged and the plasma stored at −70°C. Plasma concentrations were determined using high performance liquid chromatography with electrochemical detection (ESA Plasma Catecholamine Analysis System at Corning Clinical Laboratory, Teterboro, NJ, USA).
Minimum sample size (12<n<15 in each group) was calculated using a power analysis based on the following:
comparison of two groups using an unpaired, one-tailed Student's t-test
α=0.05 and β=0.2 (α and β are the acceptable likelihoods of encountering a Type I or Type II error by chance)
A difference of 20% between groups in heart rate was sought
Effect size (Heart rate) = 61 beats min−1 × 20% = 12 beats min−1
Standardized effect size = Effect size/standard deviation = 12/13.1* = 0.91
*Based on prior data .
Comparisons of heart rate and blood pressure were made based on data from all 30 patients studied (n = 15 in each group). Comparisons of plasma catecholamine concentrations were made based on data from the latter 20 patients enrolled (n = 10 in each group). Randomization was stratified to ensure equal numbers in each group. Data were expressed as mean ± SD. Within group comparison for data obtained at different time points was performed using one-way ANOVA for repeated measures. Between group comparisons were performed using unpaired Student's t-tests. The χ2 test was used for comparison of gender proportions between the two groups. P<0.05 was considered statistically significant.
The two groups were similar in terms of age, gender and weight (Table 1). The minimum nasopharyngeal temperature recorded during the study period was similar in the two groups (Table 1). The dose of midazolam administered to the patients in the vecuronium group (0.6 ± 0.5 mg) was similar to that administered to those in the rocuronium group (0.6 ± 0.4 mg).
No significant changes occurred in heart rate or blood pressure within two minutes of administration of either rocuronium or vecuronium (Table 2). Although induction of anaesthesia was not associated with a change in heart rate in either group, an increase in heart rate of equal magnitude (approximately 10 beats min−1 compared with the post-induction level) occurred in the two groups after tracheal intubation and persisted for at least 2 min. Following induction of anaesthesia, systolic, but not diastolic blood pressure decreased to a similar extent in both groups. Compared with the immediate post-induction level, both systolic and diastolic blood pressures increased to a similar degree (approximately 15 mmHg) in the two groups following tracheal intubation. No patient demonstrated ST segment changes consistent with myocardial ischaemia.
Reference ranges for the supine position were 70-750 pg mL−1 for noradrenaline, and 0-110 pg mL−1 for adrenaline. Plasma noradrenaline and adrenaline concentrations demonstrated marked inter-patient variability, but did not change significantly in either group following either muscle relaxant administration or tracheal intubation (Figs 1 and 2). No significant difference occurred between the two groups before or after administration of the muscle relaxant or after tracheal intubation (Figs 1 and 2). Plasma noradrenaline concentration increased by greater than 25% after muscle relaxant administration in only two patients, one in each group. Plasma noradrenaline concentrations increased from 749 to 1443 pg mL−1 in the patient who received rocuronium and from 474 to 880 pg mL−1 in the patient who received vecuronium. All plasma adrenaline concentrations were within the normal range.
The data obtained in this study (rocuronium group n = 15) indicate that rocuronium (0.9 mg kg−1) does not cause tachycardia or hypertension in elderly patients. This is consistent with previous findings in animals  and non-elderly adult patients [5,6,11] but not with those of Booth et al. who demonstrated a marked tachycardia after administration of rocuronium (0.6 mg kg−1).
In halothane-anaesthetized dogs, five times (but not three times) ED90 of rocuronium resulted in an increase in heart rate, from 109 ± 8.5 to 123 ± 18.7 beats min−1. In Booth's study of patients anaesthetized with thiopentone, nitrous oxide and halothane, heart rate increased from 67 ± 21 to 85 ± 17 beats min−1 within 1 min of administration of rocuronium . The patients who participated in this study breathed spontaneously via facemask for at least 10 min prior to administration of rocuronium. If hypercapnoea resulted (ET CO2 was not reported), this may have augmented a sympathomimetic effect of rocuronium. Premedication in Booth's study included intramuscular (i.m.) hyoscine. The vagolytic effect of hyoscine can augment the tachycardiac effects of subsequently administered pancuronium . In patients anaesthetized with fentanyl (50 μg kg−1), heart rate and blood pressure did not change, but cardiac index (+ 11%), and stroke volume index (+ 15%) increased and pulmonary capillary wedge pressure (−25%) decreased following administration of rocuronium (0.6 mg kg−1) . These changes occurred despite the fact that all the patients in the study were taking β-blocking medication. In contrast, rocuronium has been reported to have no haemodynamic effects in patients anaesthetized with N2O/O2-isoflurane , thiopentone-N2O/O2-fentanyl , or with N2O/O2-sufentanil .
These conflicting data pose two important questions. First, if a sympathomimetic effect of rocoronium does occur, are harmful effects likely to result from its administration? Second, if rocuronium induced-tachycardia does occur, what is the mechanism? The current study addressed one aspect of the first question by administration of a large (3 × ED95) bolus dose of rocuronium to elderly patients. Coronary artery disease, both symptomatic and non-symptomatic, is most prevalent in the elderly. Therefore they are at increased risk of myocardial ischaemia from sympathomimetic drugs. During high dose fentanyl anaesthesia, the use of pancuronium (compared with metocurine or a metocurine/pancuronium combination) is associated with a higher incidence of myocardial ischaemia . In one study of patients with coronary artery disease, myocardial ischaemia was detected in 50% of patients anaesthetised with high dose fentanyl and pancuronium . The control (post-induction, pre-muscle relaxant) heart rate in our study (70.9 ± 11 beats min−1) was greater than that (61 ± 13.1) in the study by McCoy et al., reflecting the exclusion of patients taking β-blockers and, possibly, less deep anaesthesia. The larger dose of rocuronium, the relatively light depth of anaesthesia, and the exclusion of patients taking β-blockers were employed to increase the likelihood of demonstrating a sympathomimetic effect, if one existed. Despite these conditions, rocuronium administration did not result in increases in heart rate, blood pressure or ECG evidence of myocardial ischaemia.
Potential mechanisms of rocuronium-induced haemodynamic effects have been studied in animals and in man [3,5,11]. In anaesthetized cats, rocuronium has a small degree of vagolytic activity . Plasma histamine concentrations do not increase in association with rocuronium administration [5,11] eliminating either baroreceptor-mediated compensatory tachycardia, or H2-receptor mediated positive chronotropism as a causative mechanism. The tachycardia and hypertension associated with the use of pancuronium, another steroidal non-depolarizing muscle relaxant, has been extensively studied. These cardiovascular changes result from (a) a vagolytic effect , (b) binding to muscarinic receptors which normally inhibit transmission through autonomic ganglia  or (c) augmenting release of and blocking reuptake of catecholamines at adrenergic nerve endings . Plasma adrenaline and noradrenaline concentrations increase when pancuronium is administered to facilitate tracheal intubation  or after administration of pancuronium to ill neonates . In patients anaesthetized with midazolam (0.1 mg kg−1) and fentanyl (15 μg kg−1), plasma noradrenaline concentration decreased significantly less in patients who received pancuronium than in those who received an equipotent dose of pipecuronium . In the current study, no significant change in plasma catecholamine concentrations occurred following either rocuronium or vecuronium administration. This suggests that other catecholamine-related adverse effects, such as arrhythmias or increased myocardial oxygen consumption, are not more likely to occur following rocuronium than vecuronium administration. However, the two-fold elevation (749-1443 pg mL−1) in plasma noradrenaline concentration, prior to tracheal intubation, in one patient who received rocuronium raises the possibility that marked individual variation in response may occur.
Vecuronium bromide was selected for comparison because of its well-established cardiovascular stability [19,20]. The doses selected for comparison (0.9 mg kg−1 for rocuronium and 0.12 mg kg−1 for vecuronium) are approximately equipotent in terms of neuromuscular blocking effects, each being 3 × ED95[21,22]. The short (2 min) interval between administration of the muscle relaxant and tracheal intubation was selected because this interval approximates with that which would occur in clinical practice. This short interval enabled us to assess the potentially sympathomimetic effects of rocuronium in combination with the known sympathomimetic response to laryngoscopy and tracheal intubation. The absence of adverse haemodynamic effects of this combination suggests that use of rocuronium in the clinical setting is unlikely to cause tachycardia or hypertension in elderly patients. One possible weakness of this study is that the sample studied may not typify the elderly population in general. It is possible that, because patients taking β-blockers were excluded, the patients studied represent a healthier subdivision of elderly patients.
Based on the small number of patients studied, bolus administration of rocuronium (0.9 mg kg−1) to elderly patients does not appear to cause a clinically significant change in heart rate, blood pressure or plasma catecholamine concentration. It is unlikely that the use of rocuronium in the elderly population will result in myocardial ischaemia unless other risk factors are present.
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