James Harper

Why are muscle relaxants used?Facilitation of tracheal intubation

Rapid sequence inductionParalysis important for certain types of surgery

E.g. abdominalPrevents patient movement during delicate surgery

E.g. Neuro or ocularAllows patient’s ventilation to be controlled

ITU

Muscle RelaxantsDepolarising

SuxamethoniumRapid onset and offsetNot pharmacologically reversibleNumerous s/e and c/i

Non-depolarisingCompete with ACh for binding at the α subunit of the

nAChRBlockade 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.

ACh eACh

NDMB

Neostig.

Neuromuscular monitoringAllows indirect determination of neuromuscular

transmissionShould 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 nerveResponse in adductor policis measured

(acceleromyography)NDMB causes fade in the amplitude of the twitches4th twitch affected first then 3nd, 2nd and 1st Ratio of amplitude of 4th:1st twitch = TOF ratio

Train-of-fourTOF ratio for safe

extubation is 0.9 (Viby-Mogensen 2000)

2nd twitch must be visible for anticholinesterase reversal to be effective (van Miert et al. 1997) Atracurium

Current problemsSux. has rapid 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 possiblePORC vs inadequate blockade

Lack NM monitoring despite recommendation → unrecognised PORC (Grayling 2007, Eriksson 2003)

Reversal with neostigmine/edrophonium + parasympatholytic cumbersome. CVS effects and PONV.

The answer – sugammadex?A γ cyclodextrin molecule composed of 8 glucose mols

forming a ringDesigned 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)

Modifed from Naguib 2007

Sugammadex – mechanism of actionSugammadex has its action in the plasma, not at the NMJRocuronium is encapsulated in the plasmaConcentration gradient between free rocuronium in the

plasma and rocuronium at the NMJRocuronium diffuses away from the NMJ into the plasma

where it is chelated by sugammadexnAChRs become free at the NMJ allowing neuromuscular

transmission to resumeGijsenbergh et al. 2005

Better than anticholinesterase?Flockton et 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)

Reversal of profound blockStandard anticholinesterases only effective after

appearance of T2

Sparr et al. 200798 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

Better than suxamethonium?Naguib et 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)

Is sugammadex safe?No serious 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)

ApplicationsMore rapid reversal than anticholinesterases with fewer

s/eMore rapid turnaround of surgical patients

Ability to antagonise a profound blockLarger doses of rocuronium can be used with confidenceLess PORC in the absence of neuromuscular monitoring

Rapid onset-offset of rocuronium/sugammadexCould replace suxamethonium for R.S.I

ConsiderationsEthical

Rocuronium and sugammadex manufactured by Organon Temptation to rely on rocuronium

Consider the patientAdvancement for advancement’s sake or real benefits?

EconomicPotential to use larger doses of rocuroniumPrice of sugammadex??

ConclusionsSugammadex is a more efficacious reversal agent of

rocuronium than anticholinesterasesReplacement of anticholinesterases → benefits for the

patient, anaesthetist and surgeonSuxamethonium may be replaced for R.S.I

Fewer s/e and c/i with rocuronium/sugammadexMore rapid onset-offset profile?

Routine use of sugammadex will depend upon economic considerations

References Aitkenhead A.R., Smith G.m Rowbotham D.J. Textbook of Anaesthesia. 5 th 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 .

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.