Recovery from NMBA : problems and solutions

1. Recovery from NMBA : problems and solutions Wirat Wasinwong Anesthesia department Faculty of Medicine Prince of Songkla University

2. Muscle relaxant • 1912 : curare • 1970s : pancuronium • 1980s : vecuronium, cisatracurium, mivacurium, rocuronium • rapacuronium

3. Ideal muscle relaxant • Onset • Duration • Metabolite/accumulation • Safety • Reversibility • Cost

4. Rocuronium • Dose 0.6-0.9 mg/kg • Onset 60-90 sec. • Duration 20-40 min. • Minimal cardiovascular effect • Hepatorenal excretion

5. Dam and Goldman “ Today, the most common cause of postoperative respiratory inadequacy is the use and misuse of muscle relaxant drugs” Anesthesiology 1961; 22:699-707

6. Postoperative residual curarization (PORC) • 1979 • Residual postoperative weakness • Incomplete recovery • Ventilatory complications

7. Anesthesiology 1997; 86:765-71 • Kopman, Yee and Neuman “ normal vital muscle function, including normal pharyngeal function, requires the TOF ratio at the adductor pollicis to recover to > 0.9 ”

8. relationship between receptor occupancy and neuromuscular monitoring

9. no neuromuscular block block A.H. Bom , Dept. Pharmacology, Organon Newhouse, Scotland, UK

10. Minimal residual paralysis • Impair pharyngeal muscle function • Reduce lower esophageal sphincter tone • Increase risk • Aspiration • Upper airway obstruction • Impair hypoxic ventilatory response Eriksson LI, et al. Anesthesiology 1997;87: 1035-43. EikermanM, et al. Anesthesiology 2003; 98: 1333-7. Eriksson LI, et al. Anesthesiology 1993;78: 693-9.

11. Incidence of residual block Study year n TOF NDMR PORC reverse Cammu G 2002 30 <O.7 cisatracurium 40 % Y rocuronium 47 Gatke MR 2002 120 <0.8 roc with TOF 3 without TOF 16.7 Hayes AH 2001 150 <0.8 vecuronium 64 atracurium 52 rocuronium 47 Baillaed C 2000 568 <O.7 vecuronium 42 N Berg H 1997 691 <0.7 pancuronium 26 atr, vec 5.3 Shorten GD 1992 panc with TOF 15 wthout TOF 47

12. Debeane B,et al. Anesthesiology,2003;98(5):1042-8

13. Naguib M, et al. Br J Anaesth 2007;98(3):302-16.

14. Murphy GS,et al.Anesth Analg 2004,98:193-200

15. Berg H,et al. Acta Anaesthesiol Scand 1997;41:1095

16. Pancuronium in cardiac surgery • Increase duration of weaning and tracheal extubation • Significant muscle weaknessafter tracheal extubation Murphy GS, et al. Anesth Analg 2002;95:1534-9 Murphy GS, et al. Anesth Analg 2003;96:1301-7 Thomas R, et al. Anaesthsia 2003;58:265-70

17. How to avoid PORC • Avoid long acting NMBA • Avoid unnecessary deep block • Antagonize block at the end • Do not initiate reversal before • Spontaneous muscle activity presents • 3 or 4 response of TOF • Use reliable clinical evaluation • Objective neuromuscular monitoring

18. Objective neuromuscular monitoring is evidence based practice Ericksson LI. Anesthesiology 2003;98:1037-9.

19. Neuromuscular blockade reversal

20. Disadvantages of anticholinesterases • Inability to antagonize profound block • Relatively slow onset of action to peak1 • neostigmine (7–11 min) • pyridostigmine (15–20 min) • Muscarinic effects • bradycardia and hypotension • bronchoconstriction and excessive secretions • nausea and vomiting 1. Bevan DR et al. Anesthesiology. 1992; 77:785–805

21. Sugammadex

22. top / bottom view side view a-cyclodextrin 6 glucose units b-cyclodextrin 7 glucose units g-cyclodextrin 8 glucose units

23. Hydrophilic exterior : polar hydroxyl group Hydrophobic cavity

24. Carboxyethyl group Quaternary nitrogen

25. Sugammadex • Water-soluble complex formation 1:1 ratio with steroidal muscle relaxants • rocuronium > vecuronium >> pancuronium

26. Sugammadex • No effects on acetylcholinesterase or any other receptors (nicotinic, muscarinic) • Acid-base change: no effects on sugammadex efficacy

27. Pharmacokinetics • Elimination half-life ≈100 min • Clearance 120 mL/min • similar to normal glomerular filtration rate • Volume of distribution 18 L • > blood volume, but substantially < the volume of the extracellular space • 59–80% of administered dose excreted in the urine over 24 h Gijsenbergh F et al. Anesthesiology. 2005; 103:695–703

28. Sugammadex increases renal excretion of rocuronium • 14% of an administered rocuronium dose is excreted in the urine within 0–24 h • With concomitant administration of sugammadex (8.0 mg/kg at 3 min) renal excretion of rocuronium within 0–24 h increased to 39–68% Gijsenbergh F et al. Anesthesiology. 2005; 103:695–703

29. Sugammadex • Drugs that potentiate effects of neuromuscular blocking agents (Mg2+, aminoglycosides) may need higher sugammadex dose • Other steroids • Cortisone, atropine, verapamil • 120-700 time < rocuronium • Clinical insignificant

30. Clinical studies

31. Reversal of Rocuronium-induced Neuromuscular Block by the Selective Relaxant Binding Agent Sugammadex : A Dose-finding and Safety StudySorgenfrei IF. Anesthesiology2006; 104:667–74 • Randomized, placebo-controlled, assessor-blinded trial • 27 male patients. • 0.6 mg/kg rocuronium • Sugammadex 0.5, 1, 2, 3 ,4 mg/kg at T2 of TOF

33. Reversal of Rocuronium-induced (1.2 mg/kg) ProfoundNeuromuscular Block by SugammadexA Multicenter, Dose-finding and Safety Studyde Boer, HD, et al. Anesthesiology 2007; 107:239–44 • phase II, multicenter,assessor-blinded, placebo-controlled, parallel study. • 43 patients • 5-min reversal after rocuronium • Adverse effects : diarrhea, light anesthesia

35. Early Reversal of Profound Rocuronium-inducedNeuromuscular Blockade by Sugammadex in aRandomized Multicenter StudyEfficacy, Safety, and PharmacokineticsSparr HJ, et al. Anesthesiology 2007; 106:935–43 • 98 male adult patients • Reversal at 3,5 and 15 min • After rocuronium 0.6 mg/kg. • Adverse effect: sucking, moving, glimace, cough

38. Anesth Analg 2007;104(3):569-74

39. Sugammadex • 3 times more rapid than edrophonium • 10 times more rapid than neostigmine

40. Side effects • Hypotension • Cough • Vomitting • Dry mouth • Abnormal smell • Sensation of a changed temperature • Abnormal level of N-acetyl glucosaminidase in urine

41. Safety • Biologically inactive • Not bind to plasma proteins • Sugammadex well tolerated in studies to date Gijsenbergh F et al. Anesthesiology. 2005; 103:695–703

42. Limitation • succinylcholine, benzylisoquinolinium • Ineffective • After reversing with sugammadex : difficult ,unpredictable dose of rocuronium, vecuronium to re-establish block : more intense block benzylisoquinolinium : decrease dose

43. Limitation • Cost • Sugammadex-rocuronium complex in renal disease : unclear • Reverse profound block with inadequate dose : incomplete recovery

44. Approval of Sugammadex11-Mar-08 07:05 pm • Schering-Plough announces the FDA Advisory Committee unanimously recommends U.S. approval of sugammadex, the first and only selective relaxant binding agent (19.82 +0.17) -Update- Co announced that the U.S. Food and Drug Administration (FDA) Advisory Committee on Anesthetics and Life Support has recommended sugammadex for approval. After reviewing data on the safety

45. Gantacurium • Lack of accumulation • Dose 2.5-3 x ED95 • Maximum block onset within 90 sec. • 25-75% recovery index = 3 min. • 7 min. for mivacurium • 9 min. for rapacuronium • 14 min. for cisatracurium • Clinical duration < 10 min. • Complete recovery to TOF>0.9 within 15 min.

46. Thank you