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Rapacuronium Bromide

A Review of its Use in Anaesthetic Practice

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Summary

Abstract

Rapacuronium bromide (rapacuronium) is an aminosteroid, nondepolarising neuromuscular blocking agent (NMBA). At the recommended dose for endotracheal intubation (1.5 mg/kg), an intravenous bolus of rapacuronium has a rapid onset (≈1.2 to 1.8 minutes) and short duration of action (10.2 to 16.5 minutes) in adults undergoing elective surgery. Rapacuronium 1.5 mg/kg produced clinically acceptable intubating conditions in 68 to 89% of these patients at about 1 minute after administration. The onset, extent and duration of action and clinical efficacy of an intubating dose of rapacuronium appeared to be similar in the general adult population, adult patients with renal or hepatic dysfunction, patients undergoing Caesarean section, and elderly, paediatric or obese adult patients.

Onset time with rapacuronium 1.3 to 2.5 mg/kg (0.9 to 1.8 minutes) was similar to or slower than that with a 1 mg/kg dose of the depolarising NMBA suxamethonium chloride (0.8 to 1.2 minutes). Intubating conditions were clinically acceptable about 1 minute after administration in 86 to 100% of patients with rapacuronium 1.3 to 2.5 mg/kg compared with in 88 to 97% of patients with suxamethonium chloride 1 or 1.5 mg/kg. Spontaneous recovery was slower with rapacuronium than with suxamethonium chloride, but neostigmine 0.04 or 0.05 mg/kg administered 2 or 5 minutes after rapacuronium 1.3 or 1.5 mg/kg acceler-ated recovery.

In the few available comparative clinical trials, rapacuronium 1.5 mg/kg appeared to have a more rapid onset of action than the nondepolarising NMBAs mivacurium chloride 0.25 mg/kg, rocuronium bromide 0.45 or 0.6 mg/kg or vecuronium bromide 0.07 mg/kg, and a shorter duration of action than rocuronium bromide 0.45 or 0.6 mg/kg or vecuronium bromide 0.07 mg/kg.

Additional boluses (≤3) of rapacuronium 0.5 or 0.55 mg/kg after an intubating bolus of 1.5 mg/kg provided continued skeletal muscle relaxation during short surgical procedures in adult patients. However, these patients may recover more slowly than those who receive a single bolus of the drug.

Bronchospasm was the most common treatment-related adverse event with rapacuronium 0.3 to 3 mg/kg (3.4% of adult patients). Tachycardia, injection site reaction and hypotension were also reported in small proportions of patients (1.6, 1.1 and 0.9%). The overall incidence of drug-related adverse events was similar with rapacuronium 1.5 or 2.5 mg/kg or suxamethonium chloride 1 mg/kg (8 vs 6%) but bronchospasm, tachycardia and injection site reaction tended to occur more often with rapacuronium.

Conclusions: At the recommended dose of 1.5 mg/kg, the nondepolarising NMB A rapacuronium has a rapid onset and short duration of action. It may provide a nondepolarising alternative to suxamethonium chloride for endotracheal intubation. Rapacuronium may be preferred over rocuronium bromide, vecuronium bromide or mivacurium chloride in this indication.

Pharmacodynamic Properties

Neuromuscular block. At the dose recommended for endotracheal intubation (1.5 mg/kg), rapacuronium bromide (rapacuronium) administered as a single intravenous bolus dose has a rapid onset of action. Onset time (time to maximum twitch suppression) is ≈1.2 to 1.8 minutes with rapacuronium 1.5 mg/kg and is inversely correlated with doses in the range 0.3 to 2.5 mg/kg. With rapacuronium 2.5 mg/kg, onset time is ≈1 or 1.3 minutes.

The duration of action is short with rapacuronium 1.5 mg/kg but intermediate with rapacuronium 2.5 mg/kg. Clinical duration (time to recovery of twitch response to 25% of baseline) is 10.2 to 16.5 minutes with the 1.5 mg/kg dose versus 18.6 to 25.4 minutes with the 2.5 mg/kg dose. Recovery from neuromuscular block is accelerated about 40 to 50% by administration of an anticholinesterase agent (usually neostigmine 0.04 to 0.07 mg/kg) 2 or 5 minutes after a bolus dose of rapacuronium 1.5 mg/kg in adult patients.

The onset and extent of action of rapacuronium was similar in adult (aged 18 to 64 years) and elderly patients (aged 65 to 85 years) and appeared to be similar in healthy adults and in adult patients with renal or hepatic dysfunction. Spontaneous recovery may be slower in elderly patients and more rapid in adult patients with hepatic dysfunction than in other adult patients, but the difference was not significant or statistics were not reported. There was no significant difference in duration of recovery between patients with and without renal dysfunction, but data are limited. The onset and duration of action of rapacuronium in paediatric patients (aged ≤13 years) appeared to be within the ranges observed in adults.

The onset of action (based on onset time) appeared to be more rapid with rapacuronium 1.5 mg/kg than with rocuronium bromide 0.45 or 0.6 mg/kg, vecuronium bromide 0.07 mg/kg or mivacurium chloride 0.25 mg/kg in the few available comparative trials, but was similar to or slower than that of the fast-acting depolarising NMBA suxamethonium chloride 1 mg/kg. Onset time was 0.9 to 1.8 minutes with rapacuronium 1.3 to 2.5 mg/kg versus 0.8 to 1.2 minutes with suxamethonium chloride 1 mg/kg. Twitch suppression at 1 minute varied, but did not differ significantly between rapacuronium (70 to 93%) and suxamethonium chloride (80 or 95%).

Duration of action (based on clinical duration) with rapacuronium 1.5 mg/kg tended to be shorter than that with rocuronium bromide 0.45 or 0.6 mg/kg or vecuronium bromide 0.07 mg/kg but did not differ significantly from that with mivacurium chloride 0.25 mg/kg. However, clinical duration was similar with the 2.5 mg/kg dose of rapacuronium and with mivacurium chloride 0.25 mg/kg or rocuronium bromide 0.45 mg/kg. Clinical duration was longer with rapacuronium 1.5 mg/kg or 2.5 mg/kg than with suxamethonium chloride 1 or 1.5 mg/kg. The duration of recovery from neuromuscular block induced with rapacuronium 1.3 or 1.5 mg/kg and accelerated by an anticholinesterase agent relative to that with suxamethonium chloride 1 mg/kg alone varied in different clinical trials.

Neuromuscular block induced with a single bolus of rapacuronium 1.5 mg/kg can be maintained (twitch response ≤25% of baseline) with ≤3 additional boluses of rapacuronium 0.5 or 0.55 mg/kg. The duration of neuromuscular block can increase with each successive maintenance bolus of rapacuronium 0.5 or 0.55 mg/kg, suggesting that accumulation of the drug may occur.

Other Effects. Plasma histamine levels did not increase in the 5 minutes after administration of a single bolus of rapacuronium 1 mg/kg but increased transiently after a 2 or 3 mg/kg dose. Similar to other NMBAs, rapacuronium tended to decrease blood pressure (by 0 to 30% from baseline) and increase heart rate (by 10 to 24% from baseline) in the first few minutes after administration; these changes generally resolved within 15 minutes. These effects of rapacuronium were not correlated with plasma histamine levels in a dose-ranging trial.

Heart rate increased more in patients who received rapacuronium than in those who received suxamethonium chloride and the difference was significant in 2 of 3 trials. The extent of the decrease in blood pressure with rapacuronium was similar to that with mivacurium chloride or vecuronium bromide and was variable relative to that with suxamethonium chloride.

Pharmacokinetic Properties

Data collected in studies of the pharmacokinetic properties of rapacuronium were analysed by traditional or population approaches, and were analysed using 2- or 3-compartmental models in different trials. After administration of a single intravenous bolus of 0.5 to 2.5 mg/kg or a short infusion of 1 mg/kg of rapacuronium, the plasma concentration declined rapidly over time. The apparent volume of distribution at steady state (Vss) was 0.316 to 0.457 L/kg with a single bolus of rapacuronium 1.5 mg/kg. The first-order rate constant (ke0) for equilibration of the drug between the central compartment (plasma) and the effect compartment (neuromuscular junction) was 0.38 to 0.42 per minute, and tended to be higher than that reported for rocuronium bromide or vecuronium bromide. This suggests that rapacuronium reaches the neuromuscular junction more rapidly than these other nondepolarising NMBAs, consistent with its more rapid onset of action.

The major metabolite of rapacuronium, ORG-9488, is formed by hydrolysis at the 3-position of the steroid nucleus. The plasma concentration of this metabolite is approximately 10% of that of the parent drug shortly after administration of a bolus of rapacuronium 1.1 mg/kg.

Clearance of rapacuronium from plasma is rapid (0.422 to 0.666 L/h/kg) and clearance from blood is not consistently related to age or haemoglobin level. Plasma clearance of ORG-9488 is markedly slower than that of the parent drug (0.077 or 0.066 vs 0.437 L/h/kg). Although plasma clearance of rapacuronium was slower in patients with renal dysfunction than in those with normal renal function, the fraction of the administered dose recovered in urine from patients with normal renal function as parent compound and metabolites was low (6.2 to 22%). It was suggested that excretion of the drug is both renal and hepatic. The terminal elimination half-life was approximately 1 to 3 hours and was not affected by renal function.

Clinical Efficacy

Intubating conditions were clinically acceptable in 68 to 89% of adult patients at about 1 minute after administration of a single bolus of rapacuronium 1.5 mg/kg. Intubating conditions did not vary with bodyweight in adults or between adult and elderly patients, and appeared to be similar in the general adult population and in pregnant women undergoing Caesarean section. Clinically acceptable in-tubating conditions were provided by the recommended dose of rapacuronium 2 mg/kg in 100% of infants (aged 2 to 11 months) and children (aged 1 to 12 years) in 2 different studies.

Intubating conditions at about 1 minute after administration were clinically acceptable in 86 to 100% of patients who received rapacuronium 1.3 to 2.5 mg/kg versus in 88 to 97% of those who received suxamethonium chloride 1 or 1.5 mg/kg in 4 clinical trials. In the largest of these trials, intubating conditions were clinically acceptable significantly less often with rapacuronium 1.5 mg/kg than with suxamethonium chloride 1 mg/kg (n = 316; 89 vs 97% of patients).

Tolerability

The overall incidence of treatment-related adverse events with rapacuronium 0.3 to 3 mg/kg was 8% in clinical trials in a total of 1893 adult, elderly and paediatric patients, according to an unpublished summary of clinical trials of rapacuronium. Serious adverse events occurred in 0.3% of these patients.

The most common adverse events in 1300 adult rapacuronium recipients were bronchospasm (3.4% of patients), tachycardia (1.6%), injection site reaction (1.1%), hypotension (0.9%), increased airway pressure (0.6%) and erythematous rash (0.5%). Hypertension, fever, nausea and vomiting each occurred in <0.1% of patients. Bronchospasm was considered a serious adverse event in 2 and tachycardia, hypotension and upper airway obstruction each in 1 patient who received rapacuronium. There was no relationship between histamine levels and the incidence of adverse events which have been associated with histamine release induced with other NMBAs (e.g. hypotension, erythematous rash and bronchospasm).

In comparison with other nondepolarising NMBAs, the overall incidence of adverse events with rapacuronium 0.3 to 3 mg/kg (8%, n = 1893) appeared to be similar to that with mivacurium chloride 0.2 or 0.25 mg/kg (11%, n = 55) but may have been higher than that with vecuronium bromide 0.07 or 0.1 mg/kg (1%, n = 68). Additional data comparing rapacuronium and other nondepolarising NMBAs are limited.

The overall incidence of adverse events was similar with rapacuronium 1.5 or 2.5 mg/kg (8%, n = 630) or suxamethonium chloride 1 mg/kg (6%, n = 572) in adult patients. In patients who received rapacuronium, the incidence of bronchospasm (3.2 vs 1% of patients), tachycardia (2.5 vs 0%) and injection site reaction (2.2 vs 0.5%) tended to be higher, that of erythematous rash (1.4 vs 2.1%) or myalgia (0 vs 0.7%) tended to be lower, and that of hypotension (2.5 vs 2.1%) similar compared with in patients who received suxamethonium chloride.

The types of adverse events were generally similar in the general adult population and in elderly (n = 209) and paediatric (total of 168 infants and 177 children) patients who received rapacuronium. The most common adverse event was hypotension (5.3% of patients) in the older patients and tachycardia in infants (4.8%) and children (7.9%).

Dosage and Administration

Rapacuronium is indicated for endotracheal intubation and for maintenance of skeletal muscle relaxation in patients who are undergoing surgical procedures of short duration. Rapacuronium must be administered in conjunction with general anaesthesia and neuromuscular function should be continuously monitored during its use. Administration of rapacuronium by continuous infusion or to provide long term skeletal muscle relaxation is not recommended.

In adult patients, rapacuronium 1.5 mg/kg administered as a rapid intravenous bolus after anaesthetic induction is recommended to facilitate endotracheal intubation at about 1 minute after administration. Neostigmine 0.05 mg/kg can be used after rapacuronium to reduce the duration of action of rapacuronium, provided that ventilatory support is continued until the patient resumes normal res-piration.

No dosage adjustments are recommended in elderly patients or in adult patients with obesity or renal or hepatic dysfunction. The recommended dose in patients undergoing Caesarean section is an intravenous bolus of rapacuronium 2.5 mg/kg after anaesthetic induction with thiopental sodium. In paediatric patients (aged 1 month to 12 years), an intravenous bolus of rapacuronium 2 mg/kg in conjunction with halothane anaesthesia is recommended for endotracheal intubation.

In patients aged 13 to 17 years, the dose of rapacuronium should be individualised. Rapacuronium is not currently recommended for infants aged <1 month.

In adult patients, neuromuscular block is effectively maintained by ≤3 successive intravenous boluses of rapacuronium 0.5 mg/kg following an intravenous bolus of rapacuronium 1.5 mg/kg for endotracheal intubation. Additional boluses should not be administered until there is some recovery from neuromuscular block. There is evidence that rapacuronium can accumulate, causing a slower recovery, when multiple boluses are administered. This use of rapacuronium is not currently recommended in elderly or paediatric patients or in patients who receive an intubating dose of rapacuronium >1.5 mg/kg.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Susan V. Onrust & Rachel H. Foster

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  1. Susan V. Onrust
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  2. Rachel H. Foster
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Correspondence to Susan V. Onrust.

Additional information

Various sections of the manuscript reviewed by: D.P.L. Atherton, Department of Anaesthesia, University of Liverpool, Liverpool, England; D.R. Bevan, Department of Anaesthesia, Vancouver Hospital, Vancouver, British Columbia, Canada; J.E. Caldwell, Departments of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA; D.M. Fisher, Department of Anesthesia, University of California, San Francisco, California, USA; M.E. Goldberg, Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, Camden, New Jersey, USA; A.F. Kopman, Department of Anesthesiology, St Vincents Hospital and Medical Center, New York, New York, USA; G.E. Larijani, Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, Camden, New Jersey, USA; C. Meistelman, Department of Anaesthesia and Intensive Care Medicine, Centre Hospitalier Régional de Nancy, Vandoevre, France; J.J. Savarese, Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, USA; H.J. Sparr, Department of Anaesthesia and Intensive Care Medicine, University of Innsbruck, Innsbruck, Austria.

Data Selection

Sources: Medical literature published in any language since 1966 on rapacuronium bromide, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘rapacuronium-bromide’ or ‘ORG-9487’. Medline search terms were ‘rapacuronium-bromide’ or ‘ORG 9487’. EMBASE search terms were ‘rapacuronium-bromide’ or ‘ORG 9487’. Searches were last updated 15 October 1999.

Selection: Studies in patients undergoing endotracheal intubation who received rapacuronium bromide. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Rapacuronium bromide, intubation, neuromuscular blocking agent, pharmacodynamics, pharmacokinetics, therapeutic use, adverse events.

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Onrust, S.V., Foster, R.H. Rapacuronium Bromide. Drugs 58, 887–918 (1999). https://doi.org/10.2165/00003495-199958050-00011

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