Rocuronium, a recently introduced aminosteroidal, non-depolarizing muscle relaxant having a molecular structure quite similar to that of vecuronium, is undergoing extensive clinical evaluation. A comparison of the time course of action of rocuronium with the intermediate duration relaxant atracurium in paediatric patients has, however, not as yet been published.
The various neuromuscular blocking drugs exhibit some differences depending on age. It has been reported that the clinical duration and the recovery time following vecuronium are shorter in young children compared with other age groups [1,2,3], whereas atracurium shows no significant difference in neuromuscular effects in children and adolescents [4,5].
In the present study the time course of neuromuscular blockade in young children following the application of standard doses of rocuronium and atracurium (i.e. approximately twice the ED95) was determined under identical anaesthetic conditions.
After obtaining approval by the Ethics Commitee of the University Hospital Essen and informed consent from the parents, 30 paediatric patients between 18 and 72 months of age and of ASA physical status I or II were enrolled in the study. The children were undergoing a variety of elective surgical procedures requiring general anaesthesia. Patients were excluded if they or their family had a history of neuromuscular disease, malignant hyperthermia, paralysis or muscle atrophia and if they received antibiotics before anaesthesia.
Children were premedicated orally with midazolam 0.5 mg kg−1 and a local anaesthetic cream (EMLA®, Astra Chemicals, Wedel, Germany) was applied to the intended injection site 1 h before beginning anaesthesia. After arrival in the operating room, an intravenous (i.v.) cannula was sited on the dorsum of the hand or on the forearm. Anaesthesia was induced with etomidate 0.2-0.4 mg kg−1, atropine 0.01 mg kg−1 and fentanyl 0.001-0.002 mg kg−1 i.v. and manual ventilation of the lungs was carried out with 50% nitrous oxide in oxygen via a facemask. After induction, the electromyographic response (EMG) of the adductor pollicis muscle was monitored using a Relaxograph™ NMT-100 monitor (Datex, Helsinki, Finland).
Recording and evaluation of the EMG values was performed by an experienced observer who was unaware of which muscle relaxant was being used. The ulnar nerve was stimulated supramaximally at the elbow with repetitive train-of-four (TOF) stimuli (2 Hz for 2 s) at 20-s intervals using the nerve stimulator unit incorporated into the Relaxograph. The test hand was supinated and immobilized by attachment to an arm board. Skin temperature at the test area was monitored continously by means of a surface thermometer and kept at 35°C within a range of ±0.5°C.
Following calibration and stable baseline recording for at least 2 min, patients, randomly assigned to one of two study groups, received a bolus of either rocuronium 0.6 mg kg−1 (group R) or atracurium 0.5 mg kg−1 (group A) administered into a rapidly running i.v. infusion. The electrocardiogram, oscillometric blood pressure (Dinamap®, Critikon Ltd, Hamburg, Germany), pulse oximetry, end-tidal carbon dioxide, endtidal isoflurane (Gas Monitor 2500, Nellcor Inc., Harward, CA, USA) and nasopharyngeal temperature were monitored. Intubation was performed when the response to the first twitch (T1) was less than 10% of control. Thereafter anaesthesia was maintained in all patients with 70% nitrous oxide in oxygen and isoflurane 0.5% end-tidal concentration and continued until recovery from neuromuscular blockade was complete. Supplementary increments of fentanyl were given as necessary. End-expiratory carbon dioxide concentration was maintained between 4.0 and 4.7 kPa.
Onset time was defined from time of injection of the muscle relaxant until a neuromuscular block of 95% or more was achieved. The level of complete restoration in T1 recovery, when no change in four successive twitch heights could be observed, was used as a reference for the recovery measurements in order to eliminate baseline drift. Only the first recovery data were included in the calculations. The times elapsing between injection of muscle relaxant and T1 recovery to 25, 50, 75 and 90% as well as the time until a TOF ratio of 0.7 were recorded. The recovery index was calculated from the time needed for T1 to recover from the 25% to the 75% level.
Data are presented as mean ± standard deviation and/or range. Statistical analysis was performed by a one way analysis of variance (ANOVA) and a pairwise multiple comparison test (Student-Newman-Keuls) or the Kruskal-Wallis analysis of variance on ranks if normality test was failed. P-values less than 0.05 were considered to be statistically significant.
There were no statistically significant differences in age, weight, and height between the groups (Table 1). In Fig. 1 the time course of neuromuscular blockade is presented with rocuronium and with atracurium. All patients attained a neuromuscular block of 95% or more, following administration of the muscle relaxant investigated. The onset time from injection to 95% blockade was found to be significantly faster after rocuronium (86.3 ± 44.9 s/mean ± SD) than after atracurium (126.3 ± 61.0 s).
Following rocuronium, time to recovery of T1 to 25% (i.e. clinical duration) and to 75% was 22.8 ± 5.31 min and 32.0 ± 8.15 min, respectively. However, in the atracurium group the recovery of T1 to 25% and to 75% was 31.5 ± 6.01 min and 42.4 ± 7.07 min, respectively, and thus was significantly longer compared with the rocuronium group. The time taken to a TOF ratio of 0.7 was significantly shorter in the rocuronium group (37.9 ± 10.3 min) compared with the atracurium group (48.5 ± 7.31 min). Nevertheless, the calculated recovery index was not statistically different between the two groups. More detailed data of the neuromuscular effects are presented in Table 2.
The particular attribute of rocuronium is its rapid onset, which is nearly twice as fast as vecuronium and atracurium in adults . In the present study with young children, the mean onset time of rocuronium was significantly faster compared with that of atracurium following normal doses, as had been expected. The broad standard deviations of mean onset values indicate a pronounced variability in individual sensitivity to neuromuscular blocking agents, already well known for non-depolarizing muscle relaxants in children. The onset times measured in this study agree well with those of previous investigations using the same doses of either rocuronium  or atracurium  in children of the same age group.
Following atracurium the duration of action was significantly longer than with rocuronium. No other direct comparison between rocuronium and atracurium in children has yet been published, but our results are similar to those of a recent study comparing atracurium and rocuronium in adults . Furthermore, in children of the same age group significant differences in clinical duration and recovery parameters had already been found for atracurium vs. vecuronium, which has a very similar molecular structure to rocuronium [10,11]. In a review of other studies, which investigated separately either atracurium or rocuronium in young children, results can be found in clinical duration and recovery very similar to our own [4,5,7,8].
One possible reason for the observed differences in neuromuscular effects of rocuronium and atracurium might be a different affinity of these substances for the pre- and postsynaptic receptors. Another explanation could be the different elimation pathways of the muscle relaxants; however, the clearance of atracurium in children has been determined to be even faster than that of rocuronium [12,13]. It is therefore most probable that a difference in distribution volumes is the main reason for the longer duration of action of atracurium in children. Volume of distribution in children at the steady state (Vdss) was found to be 224 mL kg−1 for rocuronium , 204 mL kg−1 for vecuronium  but only 129 mL kg−1 for atracurium . Kalli and Meretoja  have recently pointed out that the speed of spontaneous recovery after a single dose of vecuronium depends upon redistribution as well as upon elimination. Recovery occurring mainly during the redistribution and early elimination phases will clearly be shorter than recovery depending exclusively on the elimination of the drug.
Assuming that similar mechanisms are valid for atracurium and rocuronuim, the redistribution phase of atracurium would be exhausted earlier compared with that of rocuronium and vecuronium because of atracurium's smaller distribution volume. Thus, elimination, which is slower than redistribution, would become more important during spontaneous recovery from atracurium blockade, therefore prolonging its duration of action in comparison with rocuronium. This view is supported by our finding that the recovery index, describing mainly the final recovery phase of a muscle relaxant, was comparable for the substances investigated.
Summarizing, the onset time of rocuronium in young children is clearly faster than that of atracurium. In this age group the duration of action following the administration of a single dose of atracurium is significantly longer than that following rocuronium. We suggest that these factors may help to confirm the use of rocuronium in young children to be superior to atracurium, especially for short duration surgical procedures.
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