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Sugammadex - a revolution in anaesthesia?
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- 2. Why are musclerelaxants used? Facilitation of tracheal intubation Rapid sequence induction Paralysis important for certain types of surgery E.g. abdominal Prevents patient movement during delicate surgery E.g. Neuro or ocular Allows patient’s ventilation to be controlled ITU
- 3. Muscle Relaxants Depolarising Suxamethonium Rapid onsetand offset Not pharmacologically reversible Numerous s/e and c/i Non-depolarising Compete with ACh for binding at the α subunit of the nAChR Blockade can be reversed with anticholinesterase Drug Onset (s) Offset (min) Suxamethonium 60 10 Atracurium 110 43 Mivacurium 170 16 Rocuronium 75 33 Vecuronium 180 33 Modified from Aitkenhead et al.
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- 5. Neuromuscular monitoring Allows indirectdetermination of neuromuscular transmission Should be performed whenever a NMB is used (Eriksson et al. 2003) Train-of-four (TOF) twitch response Electric current applied in bursts of 4 to the ulnar nerve Response in adductor policis measured (acceleromyography) NDMB causes fade in the amplitude of the twitches 4th twitch affected first then 3nd , 2nd and 1st Ratio of amplitude of 4th :1st twitch = TOF ratio
- 6. Train-of-four TOF ratio forsafe extubation is 0.9 (Viby- Mogensen 2000) 2nd twitch must be visible for anticholinesterase reversal to be effective (van Miert et al. 1997) Atracurium
- 7. Current problems Sux. hasrapid onset and offset but many s/e and often c/i What would the alternative be for R.S.I? Rocuronium has rapid onset but in a ‘cannot intubate cannot ventilate’ situation return to spontaneous breathing is too slow Reversal of profound ND blockade is not possible PORC vs inadequate blockade Lack NM monitoring despite recommendation → unrecognised PORC (Grayling 2007, Eriksson 2003) Reversal with neostigmine/edrophonium + parasympatholytic cumbersome. CVS effects and PONV.
- 8. The answer –sugammadex? A γ cyclodextrin molecule composed of 8 glucose mols forming a ring Designed to encapsulate aminosteroid NDMBs, especially rocuronium (rocuronium>vecuronium>>pancuronium) Sugammadex binds rocuronium v tightly and irreversibly in a 1:1 ratio forming an H2O soluble complex (Hunter et al. 2006) (Naguib 2007)
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- 10. Sugammadex – mechanismof action Sugammadex has its action in the plasma, not at the NMJ Rocuronium is encapsulated in the plasma Concentration gradient between free rocuronium in the plasma and rocuronium at the NMJ Rocuronium diffuses away from the NMJ into the plasma where it is chelated by sugammadex nAChRs become free at the NMJ allowing neuromuscular transmission to resume Gijsenbergh et al. 2005
- 11. Better than anticholinesterase? Flocktonet al. 2008 Compared time to recovery of TOF 0.9 Rocuronium 0.6mgkg-1 followed by sugammadex 2mgkg-1 Cisatracurium 0.15mgkg-1 followed by neostigmine 50μgkg-1 Reversal given at appearance of T2 Mean time to recovery Rocuronium/sugammadex 1.9 min Cisatracurium/neostigmine 9.0 min (p<0.0001) Greater change in HR in neostigmine group (glycopyrrolate)
- 12. Reversal of profoundblock Standard anticholinesterases only effective after appearance of T2 Sparr et al. 2007 98 anaesthetised patients given rocuronium 0.6mgkg-1 Randomised to varying doses of sugammadex or placebo 3, 5 or 15 mins after rocuronium Recovery to 0.9 TOF reduced from 52.1 mins to 1.8 mins when 8mgkg-1 sugammadex given 3mins after rocuronium
- 13. Better than suxamethonium? Naguibet al. 2007 Compare speed of recovery from 1.2mgkg-1 rocuronium followed 3 mins later by 16mgkg-1 sugammadex with spontaneous recovery from 1mgkg-1 suxmaethonium Total onset-offest time is faster for rocuronium/sugammadex (4min 47) than suxamethonium (9min 23) Suxamethonium produces superior intubating conditions compared to rocuronium (Karcioglu et al. 2006)
- 14. Is sugammadex safe? Noserious adverse effects have been reported to date QT ↑ (Gijsenbergh et al.), transient BP↓ (de Boer et al.) and ↑ urinary N-acetyl glucosaminidase (Flockton et al.) Rocuronium/sugammadex excreted mainly in the urine (Gijsenbergh et al.) – renal failure? No known effect on any receptor system, no need for anti-muscarinic – cardiovascular stability Equally effective under maintenance anaesthesia with propofol as sevoflurane (unlike neostigmine) (Vanacker et al. 2007)
- 15. Applications More rapid reversalthan anticholinesterases with fewer s/e More rapid turnaround of surgical patients Ability to antagonise a profound block Larger doses of rocuronium can be used with confidence Less PORC in the absence of neuromuscular monitoring Rapid onset-offset of rocuronium/sugammadex Could replace suxamethonium for R.S.I
- 16. Considerations Ethical Rocuronium and sugammadexmanufactured by Organon Temptation to rely on rocuronium Consider the patient Advancement for advancement’s sake or real benefits? Economic Potential to use larger doses of rocuronium Price of sugammadex??
- 17. Conclusions Sugammadex is amore efficacious reversal agent of rocuronium than anticholinesterases Replacement of anticholinesterases → benefits for the patient, anaesthetist and surgeon Suxamethonium may be replaced for R.S.I Fewer s/e and c/i with rocuronium/sugammadex More rapid onset-offset profile? Routine use of sugammadex will depend upon economic considerations
- 19. References Aitkenhead A.R.,Smith G.m Rowbotham D.J. Textbook of Anaesthesia. 5th ed. 2007. Churchill Livingstone Elsevier. Bettelli G. Which muscle relaxants should be used in day surgery and when. Curr Opin Anaesthesiol 2006; 19(6):600-605. de Boer HD, Driessen JJ, Marcus MA, Kerkkamp H, Heeringa M, Klimek M. Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugammadex: a multicenter, dose-finding and safety study. Anesthesiology 2007; 107(2):239-244. Donati F. Sugammadex: an opportunity for more thinking or more cookbook medicine? Can J Anaesth 2007; 54(9):689-695. Epemolu O, Bom A, Hope F, Mason R. Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969. Anesthesiology 2003; 99(3):632-637. Eriksson LI. Evidence-based practice and neuromuscular monitoring: it's time for routine quantitative assessment. Anesthesiology 2003; 98(5):1037-1039. Fields AM, Vadivelu N. Sugammadex: a novel neuromuscular blocker binding agent. Curr Opin Anaesthesiol 2007; 20(4):307- 310. Flockton EA, Mastronardi P, Hunter JM, Gomar C, Mirakhur RK, Aguilera L et al. Reversal of rocuronium-induced neuromuscular block with sugammadex is faster than reversal of cisatracurium-induced block with neostigmine. Br J Anaesth 2008; 100(5):622-630. Gijsenbergh F, Ramael S, Houwing N, van Iersel T. First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology 2005; 103(4):695-703. Grayling M, Sweeney BP. Recovery from neuromuscular blockade: a survey of practice. Anaesthesia 2007; 62(8):806-809. Hunter JM, Flockton EA. The doughnut and the hole: a new pharmacological concept for anaesthetists. Br J Anaesth 2006; 97(2):123-126. Karcioglu O, Arnold J, Topacoglu H, Ozucelik DN, Kiran S, Sonmez N. Succinylcholine or rocuronium? A meta-analysis of the effects on intubation conditions. Int J Clin Pract 2006; 60(12):1638-1646. Kopman AF. Sugammadex: a revolutionary approach to neuromuscular antagonism. Anesthesiology 2006; 104(4):631-633.
- 20. References Miller RD.Sugammadex: an opportunity to change the practice of anesthesiology? Anesth Analg 2007; 104(3):477-478. Naguib M. Sugammadex: another milestone in clinical neuromuscular pharmacology. Anesth Analg 2007; 104(3):575-581. Shields M, Giovannelli M, Mirakhur RK, Moppett I, Adams J, Hermens Y. Org 25969 (sugammadex), a selective relaxant binding agent for antagonism of prolonged rocuronium-induced neuromuscular block. Br J Anaesth 2006; 96(1):36-43. Sorgenfrei IF, Norrild K, Larsen PB, Stensballe J, Ostergaard D, Prins ME et al. Reversal of rocuronium- induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study. Anesthesiology 2006; 104(4):667-674. Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V et al. Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics. Anesthesiology 2007; 106(5):935-943. van Miert MM, Eastwood NB, Boyd AH, Parker CJ, Hunter JM. The pharmacokinetics and pharmacodynamics of rocuronium in patients with hepatic cirrhosis. Br J Clin Pharmacol 1997; 44(2):139- 144. Vanacker BF, Vermeyen KM, Struys MM, Rietbergen H, Vandermeersch E, Saldien V et al. Reversal of rocuronium-induced neuromuscular block with the novel drug sugammadex is equally effective under maintenance anesthesia with propofol or sevoflurane. Anesth Analg 2007; 104(3):563-568. Viby-Mogensen J. Postoperative residual curarization and evidence-based anaesthesia. Br J Anaesth 2000; 84(3):301-303.