Editorial II

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surgery procedures on outpatients requiring tracheal intubation, and might facilitate the early recovery process. (e.g. fast-tracking) after ambulatory surgery.
Editorial II

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for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. The SYMPHONY Investigators. Sibra®ban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes. Lancet 2000; 355: 337±45 Memon MA, Blankenship JC, Wood GC, Frey CM, Menapace FJ. Incidence of intracranial hemorrhage complicating treatment with glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis of major clinical trials. Am J Med 2000; 109: 213±7 EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med 1994; 330: 956±61 EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. The EPILOG Investigators. N Engl J Med 1997; 336: 1689±96 Kereiakes DJ, Berkowitz SD, Lincoff AM, et al. Clinical correlates and course of thrombocytopenia during percutaneous coronary intervention in the era of abciximab platelet glycoprotein IIb/IIIa blockade. Am Heart J 2000; 140: 74±80 Alvarez JM. Emergency coronary bypass grafting for failed percutaneous coronary artery stenting: increased costs and platelet transfusion requirements after the use of abciximab. J Thorac Cardiovasc Surg 1998; 115: 472±3. Gammie JS, Zenati M, Kormos RL, et al. Abciximab and excessive

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bleeding in patients undergoing emergency cardiac operations. Ann Thorac Surg 1998; 65: 465±9. Lemmer JH Jr. Clinical experience in coronary bypass surgery for abciximab-treated patients. Ann Thorac Surg 2000; 70: S33±7. George JN, Pickett EB, Saucerman S, et al. Platelet surface glycoproteins. Studies on resting and activated platelets and platelet membrane microparticles in normal subjects, and observations in patients during adult respiratory distress syndrome and cardiac surgery. J Clin Invest 1986; 78: 340±8 Coller BS. GPIIb/IIIa antagonists: pathophysiologic and therapeutic insights from studies of c7E3 Fab. Thromb Haemost 1997; 78: 730±5. Tcheng JE, Harrington RA, Kottke-Marchant K, et al. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrelin in elective coronary intervention. IMPACT Investigators. Circulation 1995; 91: 2151±7 Tardiff BE, Califf RM, Tcheng JE, et al. Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention. IMPACT-II Investigators. Integrilin (epti®batide) to Minimize Platelet Aggregation and Coronary Thrombosis-II. J Am Coll Cardiol 1999; 33: 88±96 Steinhubl SR, Kottke-Marchant K, Moliterno DJ, et al. Attainment and maintenance of platelet inhibition through standard dosing of abciximab in diabetic and nondiabetic patients undergoing percutaneous coronary intervention. Circulation 1999; 100: 1977±82.

Editorial II Rapacuronium: why did it fail as a replacement for succinylcholine? The demise of succinylcholine has been predicted after the introduction of each new short-acting non-depolarizing neuromuscular blocking agent (NMBA). The availability of a rapid- and short-acting non-depolarizing NMBA would clearly enhance the ability of anaesthetists to perform daysurgery procedures on outpatients requiring tracheal intubation, and might facilitate the early recovery process (e.g. fast-tracking) after ambulatory surgery. After its introduction in the USA, rapacuronium (Raplon; Organon Akzo Nobel, Orange, NJ, USA) was subjected to intense scrutiny because of the current cost-conscious health-care environment and the increasing concern regarding patient safety with all new drugs.1 2 The challenge facing all anaesthesiologists is to continue to deliver the same high-quality patient care while consuming fewer resources (so-called value-based anaesthesia care). Even though the costs of drugs used for anaesthesia constitute less than 6% of the total cost of perioperative care,3 they are highly visible and represent an easy target for scrutiny by pharmacy cost-control programmes. As both mivacurium and rocuronium failed to eliminate the use of succinylcholine because of perceived de®ciencies in their onset and/or recovery characteristics,4 rapacuronium was viewed as a potential replacement for succinyl-

choline when it was ®rst introduced into clinical practice in 2000. However, as predicted in a 1999 editorial in the British Journal of Anaesthesia by Goulden and Hunter,5 `succinylcholine has still not reached the end of its active life'. It is now clear that rapacuronium has failed as a `replacement for succinylcholine' and was recently withdrawn from the US market. This article will discuss some of the possible reasons why this new muscle relaxant failed to achieve acceptance in the US anaesthesia community.

Clinical experience with rapacuronium Rapacuronium was a non-depolarizing NMBA of the aminosteroid class. In early clinical studies,6±8 it was alleged to have both a rapid onset and a rapid offset of action, and its effect was also reported to be easily reversible even when the degree of neuromuscular block was still profound. The onset time for block of the laryngeal adductor muscles after an intubating dose of rapacuronium 1.5 mg kg±1 was 1.0 (SD 0.2) min,7 and compared favourably with that of succinylcholine 1.5 mg kg±1 [0.9 (0.1) min)] and rocuronium 0.5 mg kg±1 [1.4 (0.3) min].4 Furthermore, rapacuronium was reported to provide good to excellent intubating conditions in 60±90 s,7 8 which would theoretic-

Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2002

Editorial II

ally allow the drug to be used for rapid-sequence intubation of patients considered to be at risk of aspiration during induction of anaesthesia. However, Blobner and colleagues9 cautioned that succinylcholine clearly provided better intubating conditions than rapacuronium for rapid-sequence induction. The clinical duration of action of rapacuronium after an intubating dose (1.5 mg kg±1) was 14 (6) min,8 comparable to those of succinylcholine and mivacurium [10 (2) min and 20 (6) min respectively].4 Moreover, the time for the train of four (TOF) to return to 0.7 (i.e. to achieve clinical recovery) after rapacuronium was similar to that for mivacurium, and clearly longer than that for succinylcholine.4 8 Depending on the primary maintenance anaesthetic,10 muscle relaxant activity after an intubating dose of rapacuronium typically persisted for 30±60 min. While rapacuronium was found to produce more rapid spontaneous recovery of neuromuscular function than other NMBAs of the aminosteroid class11 and its duration of action could be reduced by reversal with anticholinesterase drugs,6 12 13 it was still not really comparable to succinylcholine.4 For example, Purdy and colleagues12 reported that the neostigmine-assisted recovery time of rapacuronium to a TOF of 0.7 required almost 20 min, signi®cantly longer than the spontaneous recovery time of succinylcholine.4 6 12 14 It was also unclear whether the spontaneous and/or anticholinesterase-assisted reversal of rapacuronium's relaxant effects facilitated, or actually impeded, the fast-tracking recovery process.15 Furthermore, spontaneous recovery after a 1 h infusion (or multiple top-up doses) of rapacuronium can be prolonged,16 analogous to the timecourse of an intermediate-acting NMBA. By replacing succinylcholine in the ambulatory setting, the well-known side-effects of the latter drug could be avoided.4 5 However, the side-effects of succinylcholine (e.g. myalgias, hyperkalaemia, malignant hyperthermia) should not be replaced by other potentially serious sideeffects (e.g. bronchospasm).17 Although the overall incidence of bronchospasm was allegedly to be `only' 3.4% in the 2000 patients receiving rapacuronium for intubation during the registration process,18 Sparr and colleagues19 reported an 11% incidence of pulmonary side-effects (e.g. bronchospasm, increased airway pressure) after administration of an intubating dose of rapacuronium. Blobner and colleagues9 subsequently reported an 18% incidence of respiratory complications during intubation with rapacuronium. After the introduction of rapacuronium into clinical practice, it became apparent that rapacuronium could induce severe (even life-threatening) bronchospasm in children and young adults.20±22 In the early clinical reports of rapacuronium-associated bronchospasm,19 23 a majority of the cases occurred in patients with well-known predisposing factors (e.g. asthma, chronic bronchitis, history of smoking). Although it was suggested that histamine or leukotriene release may be responsible for rapacuronium-induced bronchospasm,5 8 Levy and colleagues24 failed to ®nd a

correlation between plasma histamine levels and the occurrence of bronchospasm. Recent experiments suggest that the most likely mechanism of rapacuronium-induced bronchospasm may relate to its antagonistic activity at the muscarinic (M2) receptor (Emala CW, Hirshman CA. A mechanism for bronchospasm induced by rapacuronium: M2 muscarinic receptor antagonism. Anesthesiology 2001; 95: A1360). On the basis of recent case reports,20±22 it would appear that another important factor contributing to the occurrence of bronchospasm relates to early stimulation of the airway (e.g. rapidsequence induction). It has been suggested by Meakin and colleagues22 that rapacuronium can enhance the increase in pulmonary resistance induced by vagus nerve stimulation by blocking prejunctional M2 receptors that physiologically inhibit vagally mediated increases in pulmonary resistance. By ensuring an adequate depth of anaesthesia before instrumenting the airway and/or administering a drug which could block the effects of rapacuronium at the M2 receptor, it might be possible to decrease the risk of bronchospasm in patients receiving rapacuronium for tracheal intubation. Nevertheless, further laboratory and clinical studies would be required to demonstrate that a reliable method exists for preventing bronchospasm before rapacuronium could be considered safe for widespread use by anaesthesia practitioners. The increasing popularity of the laryngeal mask airway for super®cial, `non-cavitary' surgical procedures has clearly reduced the need for muscle relaxants during ambulatory anaesthesia. However, for brief procedures requiring muscle relaxation without tracheal intubation (e.g. electroconvulsive therapy), rapacuronium was viewed as a potentially useful alternative to succinylcholine in situations where the latter drug was contraindicated.25 By supplanting the use of intermediate and long-acting NMBAs with shorter-acting muscle relaxants, the risk of residual paralysis after short ambulatory procedures and the attendant morbidity could be reduced. Furthermore, by minimizing the need for reversal agents (e.g. neostigmine, glycopyrrolate), it might be possible to reduce the sideeffects related to the use of reversal drugs in the ambulatory setting (e.g. dry mouth, postoperative nausea and vomiting, arrhythmias). While rapacuronium may provide a faster onset and/or more rapid recovery than other available non-depolarizing NMBAs,11 the higher cost (per unit dose) and lack of a stable, water-soluble formulation also contributed to its failure to gain widespread acceptance in the anaesthesia community. In assessing the ®nancial consequences associated with the introduction of any new drug, it is important to examine the drug's impact on the total costs of surgical and anesthetic care.1 Although anesthetic practices have advanced to the point where cost savings from variations in drug use are less important than the cost reductions achieved by system-wide improvements in the ef®ciency of resource utilization, the pharmacoeconomic impact of rapacuronium

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was not studied before its introduction into clinical practice.2 If the introduction of a new non-depolarizing muscle relaxant could facilitate the fast-tracking recovery process after ambulatory surgery and/or potentially reduce recovery care costs, it might well prove to be a costeffective alternative to a less expensive generic drug (e.g. succinylcholine) in the ambulatory setting.

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Conclusions The failure of rapacuronium to replace succinylcholine, mivacurium and the intermediate-acting muscle relaxants for ambulatory surgery procedures requiring tracheal intubation was related to several factors. Although concerns regarding the occurrence of severe bronchospasm led the manufacturer to withdraw this drug from the US market, unrealistic expectations, such as a `succinylcholine replacement,' lack of a conveniently administered formulation, the declining use of tracheal intubation in the ambulatory setting, and the failure to demonstrate its cost-effectiveness in clinical practice, were other factors contributing to its failure to gain widespread acceptance in ambulatory anaesthesia. Nevertheless, the availability of a safe and cost-effective fast-onset, short-duration non-depolarizing NMBA would ®ll a long-standing void in the anaesthetist's armamentarium. P. F. White Department of Anesthesiology & Pain Management University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas TX 75390-9068 USA

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References 1 Watcha MF, White PF. Is the introduction of new anesthetic drugs and techniques economically justi®ed? Curr Opin Anaesth 1997; 10: 158±62 2 Chiu JW, White PF: The pharmacoeconomics of neuromuscular blocking drugs. Anesth Analg 2000; 90: S19±23 3 Macario A, Vitez TS, Dunn B, McDonald T. Where are the costs in perioperative care? Analysis of hospital costs and charges for inpatient surgical care. Anesthesiology 1995; 83: 1138±44 4 Tang J, Joshi GP, White PF. Comparison of rocuronium and mivacurium to succinylcholine during outpatient laparoscopic surgery. Anesth Analg 1996; 82: 994±8 5 Goulden MR, Hunter JM. Rapacuronium (Org 9487): do we have a replacement for succinylcholine? [editorial]. Br J Anaesth 1999; 82: 489±92 6 Wierda JM, van den Broek L, Proost JH, Verbaan BW, Hennis PJ. Time course of action and endotracheal intubating conditions of ORG 9487, a new short-acting steroidal muscle relaxant; a comparison with succinylcholine. Anesth Analg 1993; 77: 579±84 7 Debaene B, Lieutaud T, Billard V, Meistelman C. ORG 9487

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neuromuscular block at the adductor pollicis and the laryngeal adductor muscles in humans. Anesthesiology 1997; 86: 1300±5 Kahwaji R, Bevan DR, Bikhazi G, et al. Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapidonset, short-duration muscle relaxant. Anesth Analg 1997; 84: 1011±8 Blobner M, Mirakhur RK, Wierda JMKH, et al. Rapacuronium 2.0 or 2.5 mg kg±1 for rapid-sequence induction: comparison with succinylcholine 1.0 mg kg±1. Br J Anaesth 2000; 85: 724±31 Zhou TJ, Coloma M, White PF, et al. Spontaneous recovery pro®le of rapacuronium during des¯urane, sevo¯urane, or propofol anaesthesia for outpatient laparoscopy. Anesth Analg 2000; 91: 596±600 Zhou TJ, White PF, Chiu JW, et al. Onset/offset characteristics and intubating conditions of rapacuronium: a comparison with rocuronium. Br J Anaesth 2000; 85: 246±50 Purdy R, Bevan DR, Donati F, Lichtor JL. Early reversal of rapacuronium with neostigmine. Anesthesiology 1999; 91: 51±7 Zhou TJ, Tang J, White PF, et al. Reversal of rapacuronium block during propofol versus sevo¯urane anaesthesia. Anesth Analg 2000; 90: 689±93 McCourt KC, Mirakhur RK, Lowry DW, et al. Spontaneous or neostigmine-induced recovery after maintenance of neuromuscular block with Org 9487 (rapacuronium) or rocuronium following an initial dose of Org 9487. Br J Anaesth 1999; 82: 755±6 Coloma M, Zhou T, White PF, Forestner JE. Fast-tracking after outpatient laparoscopy: reasons for failure after propofol, sevo¯urane and des¯urane anaesthesia. Anesth Analg 2001; 93; 112±5 Fu W, Klein KW, White PF, et al. Rapacuronium recovery characteristics and infusion requirements during inhalation versus propofol-based anaesthesia. Br J Anaesth 2000; 85: 302±5 Goudsouzian NG. Rapacuronium and bronchospasm. Anesthesiology 2001; 94: 727±8 Onrust SV, Foster RH. Rapacuronium bromide: a review of its use in anaesthetic practice. Drugs 1999; 58: 887±918 Sparr HJ, Mellinghoff H, Blobner M, et al. Comparison of intubating conditions after rapacuronium (Org 9487) and succinylcholine following rapid sequence induction in adult patients. Br J Anaesth 1999; 82: 537±41 Kron SS. Severe bronchospasm and desaturation in a child associated with rapacuronium. Anesthesiology 2001; 94: 923±4 Naguib M. How serious is the bronchospasm induced by rapacuronium? Anesthesiology 2001; 94: 924±5 Meakin GH, Pronske EH, Lerman J, et al. Bronchospasm after rocuronium in infants and children. Anesthesiology 2001; 94: 926±7 Fleming NW, Chung F, Glass PS, et al. Comparison of the intubating conditions provided by rapacuronium (ORG 9487) or succinylcholine in humans during anaesthesia with fentanyl and propofol. Anesthesiology 1999; 91: 1311±7 Levy JH, Pitts M, Thanopoulos A, et al. The effects of rapacuronium on histamine release and hemodynamics in adult patients undergoing general anaesthesia. Anesth Analg 1999; 89: 290±5 Kadar AG, Kramer BA, Barth MC, White PF. Rapacuronium: an alternative to succinylcholine for electroconvulsive therapy? Anesth Analg 2001; 92: 1171±2