The search for a rapid-acting non-depolarizing neuromuscular blocking agents has continued in view of the numerous side-effects of succinylcholine. Although mivacurium was the first short-acting non-depolarizing neuromuscular blocking agent to be introduced into clinical practice, it is slow-acting, liberates histamine and lacks early reversibility. While rocuronium provides a reliably rapid onset of block and acceptable intubating conditions within 60–90 s, it is an intermediate duration agent. The development of rapacuronium has been an attempt to provide anaesthetists with a non-depolarizing relaxant with a rapid onset and short duration of action. The aim was to design a low-potency compound, as there is strong evidence of low potency being associated with a rapid onset of action [1,2]. The first use in human beings was described by Wierda and colleagues in 1993 .
Rapacuronium (Org 9487) is the 16-N-allyl-17-β-propionate analogue of vecuronium (Figure 1) and like vecuronium and rocuronium is a monoquaternary compound. The compound was shown to have low potency in several animal species . These also showed the onset of block to be rapid when compared to an equipotent dose of vecuronium, and that the block could be antagonized with neostigmine from relatively deep levels.
The estimated ED95 in human beings was originally suggested to be over 1.0 mg kg−1 , but more recently it has been estimated to be about 0.75 mg kg−1 . The reasons for this may be the use of the bromide salt in the previous studies compared to the estimates being based on the active moiety (100 mg active moiety = 113.4 mg bromide salt), and also the use of a cumulative dose method of estimation of potency.
Onset and duration of action
Initial studies with rapacuronium showed it to have a rapid onset of action, similar to that of succinylcholine under stable and established anaesthesia, a dose of 1.5 mg kg−1 producing an average block of 93% at 60 s and 100% at 83 s compared to a 100% block with succinylcholine 1.0 mg kg−1 in 67 s . Rapid onset of block with rapacuronium has been confirmed in several subsequent studies using a variety of anaesthetic, nerve stimulation and recording techniques [7–11]. While in some of these reports the onset times of rapacuronium in a dose of 1.5 mg kg−1 were similar to those after succinylcholine 1.0 mg kg−1, in others the onset time was significantly slower. However, the onset time of rapacuronium 1.5 mg kg−1 is significantly faster than that of mivacurium 0.25 mg kg−1, vecuronium 0.07 mg kg−1 and rocuronium 0.6 mg kg−1 (Table 1) [9,10,12].
The onset of block at the laryngeal muscles was reported to be faster than at the adductor pollicis muscle, although the degree of maximum block was less . The reasons for rapid onset of action of rapacuronium are discussed fully elsewhere in this issue of the journal .
A clinical duration (i.e. recovery to T1 of 25% of control) of 8–9 min following rapacuronium 1.5 mg kg−1 was reported in the first study in human beings . However, this study was performed using the earlier preparation of rapacuronium and the dose was based on the bromide salt. More recent studies based on the active moiety have reported clinical durations of 14–20 min following a 1.5 mg kg−1 dose [7,10,11,14,15].
As with other neuromuscular blocking agents, the duration of action of rapacuronium increases in a dose-related manner, increasing from 14 to 16 min with 1.5 mg kg−1 to 23–25 min with 2.5 mg kg−1 doses (Table 1) [14,15]. The spontaneous recovery to a train-of-four ratio of 0.7 in these studies increased significantly from 30 to 38 min to 54–57 min with these doses. The duration of action, measured to a train-of-four ratio of 0.7, is longer when anaesthesia is maintained with potent inhalational agents such as isoflurane, sevoflurane and desflurane, when this time may be approximately an hour or even longer [16–18].
The clinical duration of rapacuronium 1.5 mg kg−1 is shorter than that of mivacurium 0.25 mg kg−1 and equipotent doses of vecuronium and rocuronium, although recovery to a train-of-four ratio of 0.7 is slightly longer for rapacuronium (Table 1) [9,10,12]. Repeated or continuous administration may lead to prolonged recovery after rapacuronium (see below).
Reversal of rapacuronium block
Initial enthusiasm for rapacuronium was based not only on its rapid onset of action but also for the ability to antagonize its effects even in the presence of deep block. It was in fact shown that a train-of four ratio of 0.7 could be attained within approximately 11 min when neostigmine 50 µg kg−1 was given 2 min after rapacuronium administration . This time was similar to the time for 90% recovery following succinylcholine 1.0 mg kg−1. While subsequent studies also confirmed the rapid reversibility of the effects of rapacuronium, the times taken to achieve adequate antagonism were generally somewhat longer, particularly with higher doses; this may have been due to the dosage of the drug administered being based on the active moiety. In general, administration of anticholinesterase agents reduces the recovery time to a train-of-four ratio of 0.7 by about half (from 35 to 18 min after rapacuronium 1.5 mg kg−1 and from approximately 54 to 30 min after the 2.5 mg kg−1 dose) irrespective of the time of administration of the reversal agents [7,15]. This is in contrast to mivacurium, where administration of an antagonist shortens the recovery time only slightly and insignificantly . Antagonism of rapacuronium block may be slow and unpredictable when anaesthesia has been maintained with sevoflurane . Edrophonium and neostigmine are equally effective at early reversal of rapacuronium block following a single bolus of 1.5 mg kg−1.
The reduction of dose for maintenance of constant block and the prolonged recovery after a 1-h infusion of rapacuronium suggested the presence of cumulative properties with rapacuronium . Even the administration of only three successive increments of rapacuronium results in a significant increase in the duration of action compared to a single dose [11,22]. The study by McCourt and colleagues  also showed that spontaneous recovery was slow after a 30-min infusion; however, antagonism with neostigmine was still reasonably prompt. It is believed that Org 9488, a 3-hydroxy metabolite of rapacuronium, may be the reason for delayed recovery after rapacuronium. Org 9488 itself has potent and longer lasting neuromuscular blocking effects .
As rapacuronium was developed originally as a potential replacement for succinylcholine, intubating conditions following its administration have been compared mainly with that agent. Wierda and colleagues reported no significant difference in intubating conditions at 60 s following rapacuronium 1.5 mg kg−1 and succinylcholine 1.0 mg kg−1, with more than 90% of intubations being graded as clinically acceptable . Although Hayes and colleagues  reported similar results in a relatively small study, Fleming and colleagues, in a larger study, reported the conditions to be significantly better after succinylcholine (93 vs. 85%) . Intubating conditions in these studies were evaluated under relatively deep and stable anaesthesia.
As expected, the intubating conditions with rapacuronium improve with increasing doses, being reported as ‘excellent’ or ‘good’ at 60 s in 30, 60, 68, 90 and 100% of adults following doses of 0.5, 1.0, 1.5, 2.0 and 2.5 mg kg−1, respectively . The relatively low rate of acceptable conditions following 1.5 mg kg−1 may have been due to relatively light anaesthesia in this study. The intubating conditions at 90 s are significantly better with rapacuronium 1.5 mg kg−1 compared with mivacurium 0.2 mg kg−1 and rocuronium 0.3 mg kg−1 .
The use of rapacuronium for facilitating intubation during rapid-sequence induction of anaesthesia is discussed by Sparr elsewhere in this issue .
Wierda and colleagues described the results of first pharmacokinetic studies in human beings  and suggested a three-exponential decline in the plasma concentrations of rapacuronium. They reported a rate of clearance of 11.1 mL kg −1min−1, a Vdss of 457 mL kg−1 and initial (T½π), redistribution (T½α) and terminal (T½β) half-lives of 2.8, 14.5 and 88 min, respectively. These data suggest that the termination of neuromuscular block after a single bolus of rapacuronium is by redistribution, rather than by elimination. The drug is taken up mainly by the liver. Only 10–12% of an administered dose was recovered from the urine .
The main metabolite of rapacuronium is Org 9488, which has been shown to be more potent, with a longer clinical duration and a slower recovery than rapacuronium . It has been suggested that Org 9488 is likely to be responsible for the slow recovery seen after repeated or prolonged administration of Org 9487.
Since only small amounts of rapacuronium are recovered from urine, it would be expected that its time course of action would be unaffected by renal dysfunction. Although this was confirmed by Szenohradszky and colleagues, they also showed a decreased plasma clearance of rapacuronium in patients with renal failure . A markedly reduced rate of clearance of Org 9488 was also shown by them in patients with renal failure, due to the fact that Org 9488 is dependent primarily on renal excretion. It is therefore highly likely that the duration of action will be prolonged, particularly if repeated doses of rapacuronium are administered in this situation.
In patients with cirrhosis there is no difference in onset time, maximal block and duration of block following a single bolus of rapacuronium 1.5 mg kg−1 when compared with normal controls .
Safety and tolerability
Short-lasting decreases in arterial, right atrial, pulmonary artery and pulmonary capillary wedge pressures have been observed in beagle dogs and pigs with rapacuronium . The vagal and ganglionic to neuromuscular blocking dose ratios in the cat were determined to be 3 : 1 and 22–24 : 1, respectively, for rapacuronium. Rapacuronium has also been shown to increase norepinephrine release from human atrial tissue in vitro .
Heart rate increases of 10–15% were reported following rapacuronium 1.5 mg kg−1 by Miguel and his colleagues . However, increases of >30% were observed more often in those patients who received the higher doses, with a tendency towards a decrease in arterial pressure. Detailed studies in human beings showed a decrease in mean arterial pressure and systemic vascular resistance and an increase in heart rate and cardiac output ; these results suggest the possibility of histamine release (see below), although inhibition of voltage activated Ca2+ channels producing vasodilatation has also been suggested .
Histamine concentrations were measured by Levy and colleagues after administration of rapacuronium 1.0, 2.0 or 3.0 mg kg−1 . Although the two higher doses of rapacuronium were associated with significant increases in plasma histamine compared with baseline, sporadic increases also occurred following the lowest dose. The authors were, however, unable to show a correlation between increases in histamine concentrations and the occurrence of cardiovascular effects. There were very few reports of cutaneous flushing or erythema and none occurred in any of the five patients with the highest histamine concentrations. The role of histamine release in pulmonary side-effects (see below) is not clear at this stage.
Although generally low in frequency, one of the consistent untoward effects reported following the use of rapacuronium has been the occurrence of bronchospasm and increased airway pressure. In a review of safety aspects in 1300 patients, the incidence of bronchospasm was determined to be 3.4% with an 8.0% frequency of all side-effects . The incidence of pulmonary side-effects is, however, higher in recent reports in patients undergoing rapid-sequence induction, and appears to be dose-related . An incidence of 11–18% has been reported in these studies after 1.5–2.5 mg kg−1 doses. In addition to the use of higher doses of rapacuronium, factors predisposing to these side-effects include a history of smoking or bronchial hyperreactivity and presence of relatively light anaesthesia at the time of intubation. There have been more recent reports of such serious side-effects in children with extreme difficulties in ventilation and occurrence of arterial hypoxemia . It is possible that histamine release may be responsible for mediating these events, although in the vast majority there were no cutaneous manifestations of histamine release. Evidence of a definite reason is lacking at this stage. Whatever the mechanism, it is a serious problem with rapacuronium, which has led to withdrawal of the drug in the United States with release in other areas of the world very doubtful.
Use of rapacuronium and methods of administration
It appears that the most common indication for the use of rapacuronium would have been for providing muscle relaxation for relatively short surgical procedures (approximately 15–30 min), similar to situations where mivacurium is currently used; these include procedures such as tonsillectomy, laparoscopy, dental procedures and other types of day surgery. Another indication would be for tracheal intubation in procedures around the head and neck region. The advantage of using rapacuronium would be a faster onset of action, more reliable relaxation and better conditions for tracheal intubation within 90–120 s, and the feasibility of early antagonism. The intubating conditions during rapid-sequence induction are not as good as after succinylcholine and may necessitate the use of larger doses. A single bolus dose is perhaps the best method for administration of rapacuronium, repeated or continuous administration resulting in slow spontaneous recovery. Side-effects would preclude the use of a dose greater than 1.5 mg kg−1.
Rapacuronium is perhaps the first non-depolarizing neuromuscular blocking agent with a rapid onset and a short duration of action, whose neuromuscular blocking effects can be shortened further by administration of an anticholinesterase agent even when the block is deep. It provides reliable muscle relaxation of flexible duration. Occurrence of side-effects, particularly pulmonary side-effects has, however, made the introduction of this agent into clinical practice doubtful.
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