Rapacuronium has been used in clinical practice in the United States since its introduction in 1999. The lessons learned from this experience and the reasons why it is used are the focus of this review. In general rapacuronium has been used for procedures of short duration which require tracheal intubation. The rapid onset of action is an obvious advantage. Examples of these are outpatient laparoscopic, dental and oral procedures such as tonsillectomy. The other class of procedures where the use of rapacuronium is advantageous is where rapid termination of action is important. Examples of these are procedures that require neural monitoring. The surgeon often uses motor function monitors when the procedure can impinge on critical neural systems. These include procedures near the facial nerve, nerves of speech or spinal cord.
The characteristics of rapacuronium that cause it to be selected in clinical practice are a rapid onset and a rapid recovery. The onset of rapacuronium is said to approach that of succinylcholine . It is also said to be comparable to that of rocuronium . Witkowski and colleagues and Miguel and colleagues [3,4] compared the onset of action of clinically appropriate doses of rapacuronium and rocuronium in 24 patients after a propofol induction. The results of this comparison as recorded on a train-of-four myographic monitor are shown in Figure 1. As can be seen, the onset of action of rapacuronium is slightly more rapid than that of rocuronium. Both the higher and lower doses of rapacuronium have a faster onset than either dose of rocuronium. While these doses are not exactly equipotent, they are clinically comparable being the recommended doses in the United States. The recommended intubating dose of rapacuronium, 1.5 mg kg−1, has a somewhat faster onset than the recommended intubating dose of rocuronium (0.6 mg kg−1). While these few seconds do not make much difference in the usual clinical practice, they can be helpful when rapid intubation is important. In fact, this rapid onset approaches that of succinylcholine , a finding reported by others in this supplement [5–7].
Possible use during rapid-sequence induction
The arrival on the market of a rapid-onset, short-duration drug whose characteristics can approach those of succinylcholine raises the question of its suitability for use in rapid-sequence induction. While rapacuronium does not have official labelling for this use in the United States, it is also true that no drug has specific official labelling in the United States for rapid-sequence induction. One of the reasons for this is a lack of standards in this area. A search of textbooks and the current literature failed to uncover any adopted standard or widely accepted definition of rapid-sequence induction. There are also no officially adopted standards for indications as to when this is appropriate. In practice and in the literature there are multiple drug regimens and techniques that have been used or suggested over the years for rapid-sequence induction. While we speak of ‘rapid-sequence induction’ as if it is a single issue, it has many variations to meet differing situations. The extreme example is a patient with acute trauma when the patient may be unstable and/or have some airway compromise. Another example of rapid-sequence induction is for patients undergoing Caesarean section. Here, a patient is likely to be healthy with the complications of pregnancy, such a slow gastric emptying and airway oedema. Rapid-sequence induction has also been discussed for relatively healthy patients undergoing elective surgery but with some risk of gastric aspiration. It is hard to imagine a single drug regimen or technique that can cover all of these circumstances. However, all of these share a common characteristic in that there is strong desire to secure the airway rapidly without harm to the patient.
Rapid recovery is the second and more important characteristic that distinguishes rapacuronium from previous non-depolarizing neuromuscular blocking drugs. The spontaneous recovery to 25% twitch height (clinical duration) after a dose of 1.5 mg kg−1 is about 16 min (Organon Inc. Package Insert. West Orange, NJ, USA). This is significantly faster than any other non-depolarizing relaxant we have available in the United States. Recovery can be accelerated even further by the administration of neostigmine . Several studies have shown that neostigmine given just 2 min after the administration of rapacuronium can lead to accelerated recovery. In this situation, neostigmine is actually given during complete blockade when no response to nerve stimulation can be elicited. Another value of this technique is the concept of rescue recovery. If circumstances require bringing back neuromuscular function in a rapid manner, reversal of block with neostigmine can be carried out immediately. There is no need to wait for return of some function. Recovery has been shown to take place rapidly after rescue, neostigmine reducing the offset by half the time of spontaneous recovery. A study confirmed that there is a significant acceleration to several endpoints of recovery by neostigmine administration . Our experience in 20 patients who received 1.5 or 2.0 mg kg−1 of rapacuronium after a thiopental induction is presented in Figure 2. This figure shows that the recovery of the twitch to 25% of full control took approximately 9 min when neostigmine (50 µg kg−1) was given 2 min after the administration of rapacuronium. This is similar to the time to 25% recovery for succinylcholine [1,10]. This comparison suggests that rapacuronium can be used in places where only succinylcholine could provide early recovery in the past. Rapacuronium, however, has an advantage in that rapid recovery can be selected if and when needed. In this way, its duration can be made flexible in comparison to succinylcholine.
Avoidance of reversal
Because rapacuronium recovers so rapidly, the question arises as to whether we can eliminate reversal in selected cases. While practitioners report that they are doing this in the clinical setting it is not an area that has been well studied. Data from a previous study were re-examined to determine the time to more complete recovery spontaneously. Because the most complete recovery of neuromuscular blockade is usually defined in terms of the train-of-four, the recovery of this parameter along with its standard deviation was calculated for a group of patients who recovered spontaneously under propofol, fentanyl and nitrous oxide anaesthesia. The results for a small group of patients who recovered spontaneously to a train-of-four ratio of 0.8 are shown in Table 1 . Assuming a normal distribution of recovery times, these data would suggest that normal patients have a greater than 99% chance of recovery of train-of-four ratio to >0.8 in 60 min. The data also suggest that a significant percentage of patients may not need reversal of their residual block after rapacuronium. Table 1 shows that approximately one-half of patients have recovered adequate neuromuscular function by 30 min. Other studies  show that recovery is slower under sevoflurane anaesthesia. In these cases, the need for reversal will have to be guided by neuromuscular monitoring and clinical judgement.
Adverse effects reported following rapacuronium are similar to those seen with several other non-depolarizing neuromuscular blocking drugs. These include hypotension, tachycardia, bradycardia and bronchospasm. In general, these effects appear to be dose-related and are probably related to the low potency of rapacuronium, which necessitates a higher-milligram dose. This low potency is also the probable reason for its rapid onset . Studies employing doses greater than 1.5 mg kg−1 show a greater incidence of side-effects than those found with lower doses [12,13]. The recommended dose in the United States, i.e. 1.5 mg kg−1, represents a compromise between rate of onset of action, reasonable duration and minimal side-effects. In fact, the US package insert lists 1.5 mg kg−1 as the only recommended dose for routine circumstances. Overall, there has been a low reported incidence of side-effects in the United States since the approval of rapacuronium in August 1999. Since that time at least one million patients have been treated (data on file with Organon Inc.). The side-effect that has generated the most concern and discussion appears to be bronchospasm. The package insert lists its incidence as 3.2% in the clinical trials prior to approval. Since that time, after the official release of the drug, the reported incidence has been just 0.005% (data on file with Organon Inc.). As is typical of postrelease reporting, the incidence is likely to be underreported. We suspect that most of the short-lived and mild respiratory effects detected as wheezing or increased airway pressure are probably not reported.
In spite of the low reported incidence of bronchospasm, its impact has been profound. Cases have been reported [15–17] where the bronchospasm has been severe and life-threatening, mainly in children. These prompted editorial comment  about the place of rapacuronium, given these adverse events. Further review by the regulatory agencies and manufacturer led to the voluntary withdrawal of rapacuronium from the US marketplace in March 2001, pending revision of the package insert.
What is the place of rapacuronium? Many studies and clinical experience show that rapacuronium can provide reliable intubating conditions after 50–60 s in elective patients. It is difficult to secure an airway much faster than this with any drug. Again, why rapacuronium? There are strong reasons to avoid succinylcholine . Indeed, a review of succinylcholine many years ago concluded with the sentence ‘It is to be hoped that future years see a gradual decline of the use of suxamethonium with accompanying benefit to the patient’ . In fact, succinylcholine appears to have less and less impact as time has passed. It is possible that the introduction of rapacuronium and other rapid-onset non-depolarizing relaxants will speed the transition away from succinylcholine.
In the United States, rapacuronium was used mainly for brief procedures in patients requiring tracheal intubation. Usage was greatest in the outpatient setting where its rapid recovery can be put to the best advantage. Here its acceptance followed a desire to avoid the side-effects and complications associated with succinylcholine. Another advantage in practice was that reversal may often be unnecessary in procedures lasting over 30 min, since muscle strength appears to recover spontaneously by the end of the procedure. This area is largely unexplored in clinical studies to date, but is an area of great importance to practitioners. This area will have to be defined more clearly in the future. For now, the fate of rapacuronium is unclear. While it is undergoing review, clinicians will await an approved non-depolarizing alternative to succinylcholine.
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