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Sugammadex: A Revolutionary Approach to Neuromuscular Antagonism

Kopman, Aaron F. M.D.

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IN 1975, an editorial is this journal asked the question, “Does clinical anesthesia need new neuromuscular blocking agents?”1 The reply was in the affirmative, if these new drugs “provide the practitioner with additional clinical options that broaden the scope of services he can safely provide the patient and surgeon.” Ten years later, atracurium and vecuronium met those criteria, and their introduction into clinical practice produced major alterations in the way we administer nondepolarizing relaxants. In this issue of Anesthesiology, articles by de Boer et al.2 and Sorgenfrei et al.3 provide preliminary animal and human data on sugammadex (Org 25969), a new compound that has the potential to produce an even greater change in the way we think about and administer neuromuscular blocking agents. It seems that we may have, for the first time, the ability to rapidly and completely reverse profound nondepolarizing neuromuscular block.
Early reports suggested than residual muscle weakness in postanesthesia care units was much less common after atracurium and vecuronium than after a long-acting drug such as pancuronium.4 However, it has become clear that drugs of intermediate duration are not as trouble free as initially suggested. Reports of postoperative residual curarization continue to appear.5 In part, this is a function of a change in our understanding of what constitutes adequate neuromuscular recovery. For multiple reasons,6–9 there is now general agreement that return to a train-of-four (TOF) ratio of 0.90 or greater at the end of surgery should be our goal after the administration of nondepolarizing relaxants. Unfortunately, there is a limit to the magnitude of block, which can be completely antagonized by anticholinesterases.10 There is abundant evidence that with the tools available to us at present, prompt recovery to a TOF ratio of 0.90 or greater at the end of anesthesia is often an unrealistic goal.11,12 If we wish to achieve that target on a routine basis, a new paradigm is called for.
Sugammadex administration represents an entirely new approach to the reversal of nondepolarizing neuromuscular block. This compound is a modified γ-cyclodextrin and forms very tight 1:1 complexes with aminosteroid-based relaxants. It functions as an irreversible chelating agent for neuromuscular blocking agents such as rocuronium, pancuronium, and vecuronium. When administered in adequate dosage, it very rapidly decreases the concentration of free or unbound neuromuscular blocking agents to values below the threshold necessary to achieve significant receptor occupancy.
Although the data of Sorgenfrei et al.3 are based on a relatively small number of subjects, their observations are nonetheless striking. After 0.60 mg/kg rocuronium, they administered varying doses of sugammadex when the TOF count had returned to two detectable responses. At sugammadex doses of 2.0 mg/kg and greater, the TOF ratio recovered to values of 0.90 and greater in less than 2 min. (In contrast, Kopman et al.,13 reversing rocuronium at a similar degree of block, found that 5 of 30 patients did not reach a TOF ratio of 0.90 within 30 min of neostigmine [0.50 mg/kg] administration.) Even more impressive is a preliminary report by Boer et al.14 These investigators attempted reversal 5 min after a 1.2-mg/kg dose of rocuronium. By increasing the dose of sugammadex to 12 mg/kg they were also able to achieve TOF ratios of 0.90 within 2 min of drug administration.
Several clinical implications logically follow from the above. When sugammadex becomes commercially available, anesthesiologists will be much less reluctant to give incremental doses of relaxant as the end of surgery approaches. A TOF count of 1 during skin closure will no longer be a source of concern. In addition, high-dose rocuronium for rapid-sequence intubation becomes a much more attractive proposition, especially for cases of short duration. Finally, the clinician will be able to rapidly terminate rocuronium’s effects if faced with a “cannot intubate, cannot ventilate” situation. However, questions remain regarding the potential impact of sugammadex on the day-to-day practice of anesthesia.
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Will Sugammadex Replace Anticholinesterase Antagonists?

Sugammadex has no ability to reverse the neuromuscular effects of benzylisoquinolinium-based relaxants such as cisatracurium. Ergo, the availability of neostigmine will still be required when drugs of this class are administered. However, based on currently available evidence, a strong case can be made for abandoning the use of anticholinesterases for the reversal of aminosteroid-based neuromuscular blockers. Sugammadex is simply a more efficacious antagonist of rocuronium- or vecuronium-induced block than neostigmine. Its side effects seem to be minimal, and no concomitant muscarinic blocking agents need to be added to the reversal mixture.
The extent to which sugammadex will actually supplant neostigmine for the routine reversal of aminosteroid relaxants will probably depend at least in part on economic considerations. The cost of administering neostigmine (plus a muscarinic blocking agent) amounts to only a few pennies. We still have no knowledge of how sugammadex will be packaged or what the acquisition cost will be. The balance that will be struck between drug efficacy and pharmacoeconomics will undoubtedly vary from institution to institution.
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In the Future, Will There Still Be a Role for Benzylisoquinolinium-based Blockers?

Sugammadex seems to be entirely dependant on renal elimination. When rocuronium is bound to the molecule, hepatic pathways of elimination are no longer available. Although sugammadex-induced reversal is likely to be sustained in patients with renal disease,15 the fate of the sugammadex–rocuronium complex in these patients is unclear. Until more information is available, atracurium or cisatracurium represents a more conservative choice for patients with impaired kidney function.
Even if aminosteroid relaxants come to dominate the market, benzylisoquinolinium-based drugs will serve a useful backup role. After sugammadex administration, it may be difficult to reestablish block with rocuronium or vecuronium. Certainly, the required dose these agents will be unpredictable. Benzylisoquinolinium-based agents will retain their expected potency in this situation.
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Will Pancuronium Become a Viable Option for Cases of Short Duration?

Sugammadex does not have an equal affinity with all aminosteroids. Reversal of pancuronium (a bis-quaternary) seems to require larger doses of sugammadex than are needed to antagonize rocuronium. Therefore, the lower initial cost of pancuronium compared with rocuronium may be offset by a higher acquisition price for sugammadex. Will routine monitoring of neuromuscular function still be required?
A recent editorial in this journal opined that it was time to introduce objective neuromuscular monitoring in all operating rooms and that quantitative monitoring should be used whenever a nondepolarizing neuromuscular blocking agent is administered.16 Will the introduction of sugammadex modify this recommendation? Perhaps.
It is the opinion of this author that no drug is “user-proof.” Attempts to reverse profound block with inadequate doses of sugammadex will result in incomplete reversal. Therefore, it will still be important to know the extent of neuromuscular block before sugammadex administration. However, knowledge of the TOF count or the posttetanic count may be sufficient information on which to base sugammadex dosage. Objective measurement of the TOF ratio may be most helpful when determining whether antagonism of residual block is actually required.
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Does Clinical Anesthesia Still Need New Neuromuscular Tools in Addition to Sugammadex?

Although rocuronium at a dose of 1.0 mg/kg or greater followed shortly thereafter by high-dose sugammadex can be made to mimic (or even improve upon) the onset–offset profile of succinylcholine, it is doubtful that this protocol will be adopted on a routine basis. The sequence is likely to be somewhat cumbersome and, of greater importance, probably prohibitively expensive. Therefore, there is still a gap in our armamentarium: a nondepolarizing replacement for succinylcholine. Progress in this direction continues.17
Aaron F. Kopman, M.D.
Department of Anesthesiology (N.R. 408), Saint Vincent’s Hospital Manhattan, New York, New York. akopman@nyc.rr.com or akopman@gmail.com
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References

1. Savarese JJ, Kitz R: Doesclinical anesthesia need new neuromuscular blocking agents? Anesthesiology 1975; 42:236–9

2. de Boer HD, van Egmond J, de Pol F, Bom A, Booji LHDJ: Reversal of profound rocuronium neuromuscular blockade by sugammadex in rhesus monkeys. Anesthesiology 2006; 104:718–23

3. Sorgenfrei IF, Norrild K, Larsen PB, Stensballe J, Østergaard D, Prins ME, Viby-Mogensen J: Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: A dose-finding and safety study. Anesthesiology 2006; 104:667–74

4. Bevan DR, Smith CE, Donati F: Postoperative neuromuscular blockade: A comparison between atracurium, vecuronium, and pancuronium. Anesthesiology 1988; 69:272–6

5. Debaene B, Plaud B, Dilly MP, Donati F: Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003; 98:1042–8

6. Kopman AF, Yee PS, Neuman GG: Correlation of the train-of-four fade ratio with clinical signs and symptoms of residual curarization in awake volunteers. Anesthesiology 1997; 86:765–71

7. Eriksson LI, Sundman E, Olsson R, Nilsson L, Witt H, Ekberg O, Kuylenstierna R: Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: Simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology 1997; 87:1035–43

8. Eriksson LI, Sato M, Severinghaus JW: Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology 1993; 78:693–9

9. Kopman AF, Justo MD, Mallhi MU, Neuman GG: Re-establishment of paralysis using mivacurium following apparent full clinical recovery from mivacurium-induced neuromuscular block. Anaesthesia 1996; 51:41–4

10. Beemer GH, Bjorksten AR, Dawson PJ, Dawson RJ, Heenan PJ, Robertson BA: Determinants of the reversal time of competitive neuromuscular block by anticholinesterases. Br J Anaesth 1991; 66:469–75

11. Kopman AF, Kopman DJ, Ng J, Zank LM: Antagonism of profound cisatracurium and rocuronium block: The role of objective assessment of neuromuscular function. J Clin Anesth 2005; 17:30–5

12. Kirkegaard H, Heier T, Caldwell JE: Efficacy of tactile-guided reversal from cisatracurium-induced neuromuscular block. Anesthesiology 2002; 96:45–50

13. Kopman AF, Zank LM, Ng J, Neuman GG: Antagonism of cisatracurium and rocuronium block at a tactile train-of-four count of 2: Should quantitative assessment of neuromuscular function be mandatory? Anesth Analg 2004; 98:102–6

14. de Boer H, Marcus M, Schouten P, Heeringa M, Driessen J: Reversal of rocuronium-induced (1.2 mg.kg-1) neuromuscular block by Org 25969: A multi center dose finding and safety study (abstract). Anesthesiology 2005; 103:A1117

15. Bom AH, van Egmond J, Hope F, van de Pol F: Rapid reversal of rocuronium-induced neuromuscular block by Org 25969 is independent of renal perfusion (abstract). Anesthesiology 2003; 99:A1158

16. Eriksson LI: Evidence-based practice and neuromuscular monitoring: It’s time for routine quantitative assessment. Anesthesiology 2003; 98:1037–9

17. Belmont MR Lien CA, Tjan J, Bradley E, Stein B, Patel SS Savarese JJ: Clinical pharmacology of GW280430A in humans. Anesthesiology 2004; 100:768–73

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