Sugammadex Clinical Advantages in Neuromuscular Reversal Geoff Muller Puerto Vallarta Feb 2018 Conflicts of Interest

Sugammadex Clinical advantages in neuromuscular reversal Geoff Muller Puerto Vallarta Feb 2018 Conflicts of Interest

• None to declare NMB + Anticholinesterase + Anticholinergic NMB + Anticholinesterase + Anticholinergic

Poison + Antidote + Antidote-to-the- antidote NMB + Anticholinesterase + Anticholinergic

Poison + Antidote + Antidote-to-the- antidote

Learning objectives

• Review the use of neuromuscular blockers • Problems with traditional neuromuscular reversal • Pharmacology of sugammadex • Clinical advantages • Practical considerations Residual Curarization and its Incidence at Tracheal Extubation): Canada

Fortier LP, McKeen D, Turner K, de Médicis É, Warriner B, Jones PM, Chaput A, Pouliot JF, Galarneau A. The RECITE Study: A Canadian Prospective, Multicenter Study of the Incidence and Severity of Residual Neuromuscular Blockade. Anesth Analg. 2015 Aug;121(2):366-72. Recite study: Canada Learning objectives

• Review of usage neuromuscular blockers • Problems with traditional neuromuscular reversal • Pharmacology of sugammadex • Clinical advantages • Practical considerations Why are we so bad at NMB reversal? Bertrand Debaene, Benoît Plaud, Marie-Pierre Dilly, François Donati. 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 Bertrand Debaene, Benoît Plaud, Marie-Pierre Dilly, François Donati. 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 TOF>0.9

TOF 0.9 TOF 0.8-0.9 TOF 0.8 TOF 0.7

TOF 0.7-0.8

TOF<0.7

Kirkegaard H, Heier T, Caldwell JE: Efficacy of tactile guided reversal from cisatracurium-induced neuromuscular block. Anesthesiology 2002; 96:45–50 Kirkegaard H, Heier T, Caldwell JE: Efficacy of tactile guided reversal from cisatracurium-induced neuromuscular block. Anesthesiology 2002; 96:45–50 Why are we so bad at NMB reversal?

• Insufficient monitoring • Wide interindividual variation in pharmacokinetics • Low sensitivity of detecting residual block • Time to recovery to TOF ratio >0.9

So what? Residual Neuromuscular block (RNMB) - Airway

• 6/14 with residual block aspirated (TOF ratio <0.9)

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 Nov;87(5):1035-43. RNMB - Airway • 6/14 with residual block aspirated (TOF ratio <0.9) • Normal • Volunteers • Young (22-44yrs) • No reflux or airway disease • No surgery • No other drugs (vecuronium)

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 Nov;87(5):1035-43. RNMB - Airway • TOF ratio 0.5 • 8/12 - Upper airway obstruction • TOF ratio 0.8 • 4/12 - Upper airway obstruction

• Forced inspiratory flow at 53% of max

Eikermann M, Groeben H, Husing J, Peters J. Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Anesthesiology 2003; 98:1333–1337. Resp events in PACU

Murphy GS, Szokol JW, Marymont JH, et al. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg 2008; 107:130–137. Resp events in PACU

Murphy GS, Szokol JW, Marymont JH, et al. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg 2008; 107:130–137. Is there a better way? Learning objectives

• Review of usage neuromuscular blockers • Problems with traditional neuromuscular reversal • Pharmacology of sugammadex • Clinical advantages • Practical considerations Cyclodextrins

• Cyclic oligosaccharide • 6-α,7-β, 8-γ • Febreze – beta cyclodextrin, traps odor molecules • Emulsifier, cholesterol free products, sweeteners, medications Sugammadex

• EU 2009 • Japan 2010 • FDA approval Dec 2015 Sugammadex (Sugar gamma cyclodextrin)

• Synthetic modified cyclodextrin • γ cyclodextrin – 8 monomer ring structure • 6-glucopyranoside units • Side chain to fit rocuronium Sugammadex

• Toroidal shape Sugammadex

• Toroidal shape • Donut shape • Encapsulates aminosteroid NMB Sugammadex

• Toroidal shape • Donut shape • Encapsulates aminosteroid NMB – Pancuronium – Vecuronium – Rocuronium – Pipecuronium

Lipophilic core

Water solubility

Pharmacodynamics

• No receptor effects Pharmacodynamics

• No receptor effects • No muscarinic (cholinergic) effects Pharmacokinetics

• Terminal Elimination half life 100-136mins • Clearance approaches GFR • Administered dose excreted in urine over 24hrs • Increases Rocuronium renal excretion from 26 to 76% • No plasma protein binding Interactions – hormonal contraception • Binds to progestogens • Women taking hormonal contraceptives: – continue taking hormonal contraceptive – alternate non-hormonal contraceptive for 7 days

• Toremifene (Fareston) SERM – – Can displace NMB – Recovery from NMB may be delayed Interactions

• Also binds: – Cortisone – Atropine – Remifentanil – Verapamil – Fusidic acid – Flucloxacillin Interactions

• Also binds: – Cortisone – Atropine – Remifentanil – Verapamil – Fusidic acid – Flucloxacillin - ≥500 mg should be avoided for 6 h after sugammadex Variable Dosing

• Rocuronium and Vecuronium: • TOF 0 and ≥ PTC 1-2 twitches 4mg/kg • TOF ≥ 2/4 twitches 2mg/kg

• Rocuronium RSI (1.2mg/kg) 16mg/kg Side effects

• Marked bradycardia, asystole • Dysgeusia – distortion of taste • Allergic reactions • Erythematous rash Learning objectives

• Review of usage neuromuscular blockers • Problems with traditional neuromuscular reversal • Pharmacology of sugammadex • Clinical advantages • Disadvantages Clinical scenarios • Preplanned early reversal in short procedures where succinyl choline is contraindicated • Instead of neostigmine in neuromuscular or resp disease • Unplanned early reversal – CICO • Instead of neostigmine for time saving • Instead of neostigmine for side effect avoidance

Gibbs NM, KAm PCA. Anaesthesia and Intensive Care, Vol. 40, No. 2, March 2012 Sugammadex vs Neostigmine

Brueckmann B, Sasaki N, Grobara P, Li MK, Woo T, de Bie J, Maktabi M, Lee J, Kwo J, Pino R, Sabouri AS, McGovern F, Staehr-Rye AK, Eikermann M. Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study. Br J Anaesth. 2015 Nov;115(5):743-51. Sugammadex vs Neostigmine

• Twitch = 2 • 2mg/kg sugammadex vs 50mcg/kg neostigmine – 1.96 vs 12.86 mins • PTC 1-5 • 4mg/kg sugammadex vs 70mcg/kg neostigmine – 2.9 vs 48.8 mins

Hristovska AM, Duch P, Allingstrup M, Afshari A. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. Cochrane Database Syst Rev. 2017 Aug 14;8:CD012763. RSI recovery vs succinyl choline

• T1 recovery to 90% - 6.2 vs 10.9 mins • T4:T1 90% recovery 2.2 mins after sugammadex

Lee C, Jahr JS, Candiotti KA, Warriner B, Zornow MH, Naguib M. Reversal of profound neuromuscular block by Sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from suxamethonium. Anesthesiology 2009; 110: 1020–5.

Case reports – Rescue reversal

Airway risk factors Airway pathology Sugammadex use: Outcome Planned vs Unplanned

Paton et al. Y Y Planned Spontaneous ventilation Desforges et al. Y N Unplanned Spontaneous ventilation Barbosa et al. ? N Unplanned Spontaneous ventilation Curtis et al. Y Y Planned Needle cric + trache Kyle et al. N Y (undiagnosed) Unplanned Trache

Uzawa et al. ? Y (undiagnosed) Unplanned Spontaneous ventilation CICO

Mohamed Naguib, Lara Brewer, Cristen LaPierre, Aaron F. Kopman, Ken B. Johnson. The Myth of Rescue Reversal in Can’t Intubate, Can’t Ventilate” Scenarios. Anesth Analg. 2016 Jul;123(1):82-92 CICO Practical considerations for CICO • Availability – In OR – Quantity • Dosage • Multiply X 16 • Draw up and administer • (Manikin simulation study - 6.7mins)

Bisschops MMA, Holleman C, Huitink JM. Can sugammadex save a patient in a simulated “cannot intubate, cannot ventilate” situation? Anaesthesia 2010; 65:936-941. Short procedures – deep paralysis Sugammadex vs Neostigmine Sugammadex vs Neostigmine PONV

Palabiyik O, Orhan M, Sonbahar T, Sayhan H, Tomak Y. Does Sugammadex Administration Affect Postoperative Nausea and Vomiting After Laparoscopic Cholecystectomy: A Prospective, Double-Blind, Randomized Study. Surg Laparosc Endosc Percutan Tech. 2017 Aug;27(4):237-240 Carron M, Zarantonello F, Tellaroli P, Ori CA. Efficacy and safety of sugammadex compared to neostigmine for reversal of neuromuscular blockade: a meta-analysis of randomized controlled trials. J Clin Anesth. 2016 Dec;35:1-12. Hristovska AM, Duch P, Allingstrup M, Afshari A. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. Cochrane Database Syst Rev. 2017 Aug 14;8:CD012763. Learning objectives

• Review of usage neuromuscular blockers • Problems with traditional neuromuscular reversal • Pharmacology of sugammadex • Clinical advantages • Practical considerations Residual block after sugammadex

• Incidence TOFR <0.9 – No reversal - 13.0% – Neostigmine - 23.9% – Sugammadex - 4.3% (1.7-9.4%)

• TOFR <0.9 – No reversal - 13.0% – Neostigmine - 23.9% – Sugammadex - 4.3% (1.7-9.4%)

Kotake Y, Ochiai R, Suzuki T, Ogawa S, Takagi S, Ozaki M, Nakatsuka I, Takeda J. Reversal with sugammadex in the absence of monitoring did not preclude residual neuromuscular block. Anesth Analg 2013;117:345–51. Residual block after sugammadex • 6 cases in literature • Issues: – Under-dosing – Not using TOF guidance – Larger doses (infusions) – Hypothermia • 1 case appeared to be a genuine outlier

Le Corre F, Nejmeddine S, Fatahine C, et al. Recurarization after sugammadex reversal in an obese patient. CanJ Anesth2011;58:944–947. Murata T, Kubodera T, Ohbayashi M, et al. Recurarization after sugammadex following a prolonged rocuronium infusion for induced hypothermia. Can J Anesth 2013; 60:508–9. Özel F, Altunkan AA, Azizoğlu M. Postoperative Respiratory Failure in a Patient with Undiagnosed Myastenia Gravis. Turk J Anaesthesiol Reanim. 2016 Apr;44(2):108-10. Ortiz-Gómez JR, Palacio-Abizanda FJ, Fornet-Ruiz I. Failure of sugammadex to reverse rocuronium-induced neuromuscular blockade. Eur J Anaesthesiol 2014; 31:708–721 Bellod A, March X, Hernandez C, Villalonga A. Delayed recurarisation after sugammadex reversal. Eur J Anaesthesiol 2014; 31:710–712. Delayed Residual block after sugammadex Delayed Residual block after sugammadex Sugammadex to treat anaphylaxis to rocuronium • NMBs are the most common causal agents in anesthesia (55-69%) • Allergen is the quarternary ammonium ion • Sugammadex encapsulates free allergen • Slows/halts immunologic process

Treatment for Roc anaphylaxis - not so simple • Some of the epitope might protrude from complex • Incorrect causative agent in 1/3 of cases • Sugammadex vs IgE – which has great affinity for rocuronium

Jones PM, Turkstra TP. Mitigation of rocuronium-induced anaphylaxis by sugammadex: the great unknown. Anaesthesia 2010; 65:89-90. Platt PR, Clarke RC, Johnson GH, Sadleir PH. Efficacy of sugammadex in rocuronium-induced or antibiotic-induced anaphylaxis. A case- control study. Anaesthesia. 2015 Nov;70(11):1264-7.

Anaphylaxis to sugammadex

• Japanese study: Hypersensitivity 0.22%; Anaphylaxis 0.039% (n=15479) – Same rate as rocuronium or succinylcholine • Skin prick testing • No commercially available IgE assays • Average person consumes 4g of gamma-cyclodextrin daily • Oral sensitization resulting in anaphylaxis to “first” exposure • Symptoms might develop after extubation – Reintubation

Ue KL, Kasternow B, Wagner A, Rutkowski R, Rutkowski K. Sugammadex: An emerging trigger of intraoperative anaphylaxis. Ann Allergy Asthma Immunol. 2016 Dec;117(6):714-716. Miyazaki Y, Sunaga H, Kida K, Hobo S, Inoue N, Muto M, Uezono S. Incidence of Anaphylaxis Associated With Sugammadex. Anesth Analg. 2017 Oct 19. Anaphylaxis to sugammadex-rocuronium complex • Allergies to: – Rocuronium – Sugammadex – Complex • 2 cases in literature

Yamaoka M, Deguchi M, Ninomiya K, Kurasako T, Matsumoto M. A suspected case of rocuronium-sugammadex complex-induced anaphylactic shock after cesarean section. J Anesth. 2017 Feb;31(1):148-151. Ho G, Clarke RC, Sadleir PH, Platt PR. The First Case Report of Anaphylaxis Caused by the Inclusion Complex of Rocuronium and Sugammadex. A Case Rep. 2016 Nov 1;7(9):190-192. Renal failure

• Sugammadex is entirely renally excreted • Hepatic elimination of rocuronium eliminated once bound to sugammadex • Plasma clearance complex = GFR (120 ml/min). • High-flux dialysis effective in removing

Kopman AF. Sugammadex: A Revolutionary Approach to Anesthesiology 2006; 104:631–2 Pharmacokinetics in renal failure

Staals LM, Snoeck MM, Driessen JJ, van Hamersvelt HW, Flockton EA, van den Heuvel MW, Hunter JM. Reduced clearance of rocuronium and sugammadex in patients with severe to end-stage renal failure: a pharmacokinetic study. Br J Anaesth. 2010 Jan;104(1):31-9. Renal failure

Panhuizen IF, Gold SJ, Buerkle C, Snoeck MM, Harper NJ, Kaspers MJ, van den Heuvel M, Hollmann MW. Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment. Br J Anaesth. 2015 May;114(5):777-84. Renal failure

• No adverse effects related to sugammadex • Six renal patients had measurable rocuronium concentrations at Day7 • No recurrence of NMB • Prolonged sugammadex exposure in renal failure – • current safety data insufficient • recommend against using sugammadex in renal failure

• Reappearance of T1: • 49.1 mins (liver dysfunction) • 33.3 mins (controls) • P=0.016

Fujita A, Ishibe N, Yoshihara T, Ohashi J, Makino H, Ikeda M, Setoguchi H. Rapid reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Acta Anaesthesiol Taiwan. 2014 Jun;52(2):54-8. Hepatic disease

• Roc and sugammadex IBW dosing • Further 2mg/kg if TOFR <0.9 in 3mins • 2nd dose in: – 39.5% with PTC 0-2 – 23.4% in ≥2 twitches • Recommended real body weight dosing

Llauradó S, Sabaté A, Ferreres E, Camprubí I, Cabrera A. Sugammadex ideal body weight dose adjusted by level of neuromuscular blockade in laparoscopic bariatric surgery. Anesthesiology. 2012 Jul;117(1):93-8. Dosing in obesity

• Pooled data from 27 trials • 1418 patients • BMI >30 • All dosed according to actual body weight • No correlation between recovery time and BMI (average 1.9 mins)

Monk TG, Rietbergen H, Woo T, Fennema H. Use of Sugammadex in Patients With Obesity: A Pooled Analysis. Am J Ther. 2017 Sep/Oct;24(5):e507-e516. Sugammadex and magnesium

Czarnetzki C, Tassonyi E, Lysakowski C, Elia N, Tramèr MR. Efficacy of sugammadex for the reversal of moderate and deep rocuronium-induced neuromuscular block in patients pretreated with intravenous magnesium: a randomized controlled trial. Anesthesiology. 2014 Jul;121(1):59-67. Pediatrics • Interaction with dexamethasone N=60 • Effective: 3 trials n=180 vs neostigmine • Open label n=42 (oncology) , n=14 (Congenital cardiac) • Case reports – Neuromyopathic disease – Neonates • Dosing unchanged

Tobias JD. Current evidence for the use of sugammadex in children. Paediatr Anaesth. 2017 Feb;27(2):118-125. Bleeding

• No interaction with platelet function with/without aspirin • aPTT and PT(INR) increase

de Kam PJ, El Galta R, Kruithof AC, Fennema H, van Lierop MJ, Mihara K, Burggraaf J, Moerland M, Peeters P, Troyer MD. No clinically relevant interaction between sugammadex and aspirin on platelet aggregation and coagulation parameters. Int J Clin Pharmacol Ther. 2013 Dec;51(12):976-85. Bleeding

• Hip and knee replacements with thromboprophylaxis • Randomized, blinded to neostigmine / sugammadex • n=1184

Rahe-Meyer N, Fennema H, Schulman S, Klimscha W, Przemeck M, Blobner M, Wulf H, Speek M, McCrary Sisk C, Williams-Herman D, Woo T, Szegedi A. Effect of reversal of neuromuscular blockade with sugammadex versus usual care on bleeding risk in a randomized study of surgical patients. Anesthesiology. 2014 Nov;121(5):969-77.

Safety

• Toxicology seems very safe (food studies) • Kids – Not FDA approved • Pregnancy: – no human data except in cesarean section – Placental transfer - 6% – Almost non-teratogenic in animals • Breast feeding – Present in rat milk – Oral absorption very low • QTc unchanged / normal Economics Economics

$86.96 $217.45

Neo cost (multi-dose vial) – 10ml $56.80 Glycopyrrolate (multi-dose vial) – 5ml $27.75 Economics

• 70kg patient • Sugammadex $86.96 • Neo+Glyco $28.40 + $19.43 =$47.83 Economics • End of surgery to OR discharge: – 9.1 mins - sugammadex – 13.9 - neostigmine • Max: – 22 mins - sugammadex – 72 mins - neostigmine • No difference in PACU stay

Putz L, Dransart C, Jamart J, Marotta ML, Delnooz G, Dubois PE. Operating room discharge after deep neuromuscular block reversed with sugammadex compared with shallow block reversed with neostigmine: a randomized controlled trial. J Clin Anesth. 2016 Dec;35:107-113. Reduces frustration

• Waiting an hour for twitches to return or Remember about 10 minutes • Ventilation in PACU ago when I said we had 3 hrs left … well surprisingly we have finished Dexter F, Coffin S, Tinker JH. Decreases in anesthesia-controlled time cannot permit one additional surgical operation to be reliably scheduled during the workday. Anesth Analg. 1995 Dec;81(6):1263-8.

Economics • Combination reversal: – 4mg/kg sugammadex – vs – 2mg/kg + Neostigmine 50mcg/kg + Glyco 10mcg/kg • 50% reduction in 200mg ampoules for patients 52- 100kg • Non-inferior reversal

Aouad MT, Alfahel WS, Kaddoum RN, Siddik-Sayyid SM. Half dose sugammadex combined with neostigmine is non-inferior to full dose sugammadex for reversal of rocuronium-induced deep neuromuscular blockade: a cost-saving strategy. BMC Anesthesiol. 2017 Apr 11;17(1):57. Outcome benefits

• Cochrane review: 10 studies (n= 959) • Serious adverse events: – RR 0.54; 95%CI 0.13-2.25 GRADE: low quality • No mortality data

Summary

• Sugammadex: – Reverses any depth of block – Variable dosing – Can eliminate postoperative weakness Questions?