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

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

Ideal muscle relaxant Onset Duration Metabolite/accumulation Safety Reversibility Cost

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

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

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

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 ” Anesthesiology 1997; 86:765-71

relationship between receptor occupancy and neuromuscular monitoring

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

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. Eikerman M, et al. Anesthesiology 2003; 98: 1333-7. Eriksson LI, et al. Anesthesiology 1993;78: 693-9.

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

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

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

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

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

Pancuronium in cardiac surgery Increase duration of weaning and tracheal extubation Significant muscle weakness after 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

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

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

Claudius C, et al. Anesthesiology 2008;8(6):1117-40

Claudius C, et al. Anesthesiology 2008;8(6):1117-40

Neuromuscular blockade reversal

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

Sugammadex

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

Hydrophilic exterior : polar hydroxyl group Hydrophobic cavity

Carboxyethyl group Quaternary nitrogen

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

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

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

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

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

Clinical studies

Randomized, placebo-controlled, assessor-blinded trial Reversal of Rocuronium-induced Neuromuscular Block by the Selective Relaxant Binding Agent Sugammadex : A Dose-finding and Safety Study Sorgenfrei IF. Anesthesiology 2006; 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

5-min reversal after rocuronium Reversal of Rocuronium-induced (1.2 mg/kg) Profound Neuromuscular Block by Sugammadex A Multicenter, Dose-finding and Safety Study de 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

After rocuronium 0.6 mg/kg. Early Reversal of Profound Rocuronium-induced Neuromuscular Blockade by Sugammadex in a Randomized Multicenter Study Efficacy, Safety, and Pharmacokinetics Sparr 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

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

Sugammadex 3 times more rapid than edrophonium 10 times more rapid than neostigmine

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

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

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

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

Approval of Sugammadex   11-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

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.

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