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Optimal Neuromuscular Blockade Management J. Ross Renew, MD, FASA, FASE Assistant Professor of Anesthesiology Mayo Clinic Jacksonville, FL

Nomenclature Level of Objective Subjective Evaluation Depth Blockade Measurement at AP With PNS at AP 5 Complete block No PTC No PTC PTC ≥ 1, no TOFC 4 Deep block PTC > 1, no TOFC 3 Moderate block TOFC = 1-3 TOFC = 1-3 2b Shallow block TOFR < 0.4 TOFC = 4 with fade detected 2a Minimal block TOFR = 0.4-0.9 TOFC = 4 with no fade detected TOFR ≥ 0.9 1 Acceptable recovery Unable to detect AP = adductor pollicis muscle; PTC = post-tetanic count; TOFC = train-of-four count; TOFR = train-of-four ratio. Adapted from: Naguib M, et al. Anesth Analg . 2018;127(1):71-80.

Nomenclature Clinical assessment: Inability to smile, swallow, speak; PPV = 0.47 • General weakness; PPV= 0.51 • • Inability to lift head for 5 seconds; PPV= 0.51 • Inability to lift leg for 5 seconds; PPV= 0.50 Inability to sustain hand grip for 5 seconds; PPV= 0.51 • Inability to perform sustained tongue depressor test 5 seconds; PPV= 0.52 • PPV = positive predictive value. Cammu G, et al. Anesth Analg . 2006;102(2):426-429.

Nomenclature Peripheral nerve stimulator: • Tactile assessment slightly more sensitive than visual Inexperienced anesthesiologists cannot detect fade when TOFR > 0.3 • Majority cannot detect fade when TOFR > 0.4 • Viby-Mogensen J, et al. Anesthesiology . 1985;63(4):440-443.

Objective Monitoring • Hand-held versus monitoring incorporated into anesthesia workstation • Monitors: – Acceleromyography (AMG) – Kinemyography (KMG) – Electromyography (EMG) Murphy GS, et al. Anesthesiology . 2008;109(3):389-398.

Neostigmine • Acetylcholinesterase inhibitor that prevents breakdown of ACh to overwhelm postsynaptic nicotinic receptors • Requires co-administration with antimuscarinic agent • 0.2 mg glycopyrrolate IV for each 1 mg neostigmine IV (similar onset time) • Edrophonium (0.5 to 1 mg/kg) + atropine (7 to 14 µg/kg IV) ACh = acetylcholine; IV = intravenous. Neostigmine methylsulfate. Product information. American Reagent. 2017.

Neostigmine (cont’d) • TOFC > 2 Recommend 70 µg/kg • TOFC = 4 Recommend 20-50 µg/kg • Ceiling effect at 5 mg Naguib M, et al. Anaesthesia . 2017;72(Suppl 1):16-37.

Neostigmine (cont’d) • Recommend administration with at least TOFC = 3 • Median time to recovery with TOFC = 3 is 15.6 minutes (7.3 to 43.9) • Median time to recovery with TOFC = 4 is 9.7 minutes (5.1 to 26.4) • Can be prolonged with inhalation anesthesia, hypothermia, acidosis, electrolyte disturbances, hypercarbia, and patient age Kim KS, et al. Anesth Analg . 2004;99(4):1080-1085.

Spontaneous Recovery • Unpredictable response to NMBA • 37% of patients had residual weakness 2 hours after intubating dose of intermediate-acting NMBA • Do not omit NMBA antagonism if one cannot demonstrate adequate recovery (quantitative monitoring) • Neostigmine administered in the absence of NMB can cause paradoxical reduction in TOFR • 40 µg/kg after spontaneous recovery had no increase in adverse events (it actually had less diplopia) NMBA = neuromuscular blocking agent. Debaene B, et al. Anesthesiology . 2003;98(5):1042-1048; Goldhill DR, el al. Anaesthesia . 1989;44(4):293-299; Murphy G, et al. Anesthesiology . 2018;128(1):27-37.

Residual Neuromuscular Blockade • Subjective feelings of weakness • Oropharyngeal dysfunction • Prolonged PACU stay • Postoperative pulmonary complications • Respiratory collapse requiring reintubation/ICU care ICU = intensive care unit; PACU = post-anesthesia care unit. Berg H, et al. Acta Anaesthesiol Scan . 1997;41(9):1095-1103. Murphy GS. Minerva Anesthesiol . 2006;72(3):97-109. Murphy GS, et al. Anesth Analg . 2008;107(1):130-137.

Strategies to Avoid RNMB • Use of short- or intermediate-acting NMBA • Use quantitative monitoring to guide redosing and confirm adequate recovery • Administer NMBA antagonists at appropriate depth of blockade • Extubate the trachea once adequate recovery has been confirmed RNMB = residual neuromuscular block. Brull SJ, et al. Anesthesiology . 2017;126(1):173-190.

Current and Emerging Neuromuscular Blockade (NMB) Reversal Agents Anthony L. Kovac, MD Kasumi Arakawa Professor of Anesthesiology University of Kansas Medical Center Kansas City, KS

Objectives: Agents for Rapid Recovery of Deep Neuromuscular Blockade (NMB) • New class  selective relaxant binding agents (SRBA): – Selectively binds & terminates non-depolarizing NMB relaxants • Sugammadex  efficacy and safety data  benefits and risks • I mpact/ utility of rapid recovery on surgical practice: Reverse deep and intense NMB A. Improves patient safety, intubation time, postop residual curarization, B. muscle recovery, OR efficiency • Preclinical/ clinical data of emerging agents: gantacurium, CW002, and CW0011, calabadion OR = operating room.

I mpact/ Utility of Rapid Recovery on Surgical Practice Deep NMB useful during: 1. Laparoscopy – – Robotic surgery Microscopic surgery – – Bariatric surgery I mprovement of: 2. – Patient safety – Muscle strength Postoperative intubation time – – Risk of respiratory complications Postoperative residual curarization – – OR efficiency: turnover times Slide courtesy of AL Kovac, MD.

Agents for Reversal of Nondepolarizing NMB • Acetylcholinesterase inhibitors  reverse low levels of NMB (neostigmine) • Encapsulating agents  reverse all levels of NMB – Sugammadex  reverses steroid NMB agents – Calabadion  reverses steroid and benzylisoquinoline NMB agents • L-Cysteine adduction  reverses gantacurium and CW002 Heerdt PM, et al. Anesthesiology . 2015;28(4):403-410. Hunter JM. Br J Anaesth . 2017;119(suppl_1):i53-i62.

Levels of Block After a Normal I ntubating Dose of a Non-depolarizing NMB Agent Block Depth: I ntense Deep Moderate Recovery TOF = 0 TOF = 0 TOF = 1-3 TOF = T4/T1 PTC = ≥1 PTC = ≥1 PTC = 0 PTC = post-tetanic count; TOF = train of four. Fuchs-Buder T, et al. Acta Anaesthesiol Scand. 2009;51(7):789-808.

Cyclodextrin Characteristics • Encapsulating agents (sugammadex) • Interior lipophilic (OH) • Interior hydrophobic Exterior hydrophilic (COO) Allows strong binding to hydrophobic molecules to stabilize or solubilize Naguib M. Anesth Analg. 2007:104(3):575-581. Google Patents: Sugammadex sodium. Filed January 23, 2017. Accessed October 9, 2020. https://patents.google.com/patent/WO2018136013A1/en

Rocuronium and Sugammadex Complex Radiograph Crystal Structure + = Rocuronium Sugammadex Gijsenbergh F, et al. Anesthesiology. 2005:103(4);695-703. Reprinted With Permission. https://pubs.asahq.org/anesthesiology

Sugammadex Characteristics • Binds at 1:1 ratio • Reduces amount of NMB agent to bind to nicotinic receptor • Affinity for steroidal non-depolarizing NMB agents • Affinity: rocuronium > vecuronium • No affinity for succinylcholine, cisatracurium • Half life = 100 minutes • Renal excretion; no metabolism • Over 24 hours, 60%-80% excreted in urine Naguib M. Anesth Analg. 2007:104(3);575-581.

Sugammadex Reversal Doses at Different NMB • Light to moderate block: TOF ≥ 1  2 mg/kg • Deep block: TOF = 0, PTC ≥ 1  4 mg/kg • Intense block: TOF = 0, PTC = 0  16 mg/kg Naguib M. Anesth Analg. 2007:104(3):575-581. Hristovska AM, et al. Cochrane Database Syst Review. 2017;8(8):CD012763.

Sugammadex Rapidly Reverses NMB TOF tracings after rocuronium 0.6 mg/kg and placebo Or Sugammadex 4.0 mg/kg; deep NMB TOF=0, PTC=1 Gijsenbergh F, et al. Anesthesiology. 2005:103(4);695-703. Reprinted With Permission. https://pubs.asahq.org/anesthesiology

Kaplan–Meier curves showing time to recovery to train-of-four ratio of 0.9 after study drug administration at reappearance of second twitch (T2), by treatment group and neuromuscular blocking agent (intent-to-treat population). Gray vertical dotted line represents recovery time of 5 minutes. Sugammadex Rocuronium Efficacy for 1.0 + sugammadex Vecuronium + 0.9 Reversal of sugammadex Vecuronium + 0.8 Cumulative Recovery Rate neostigmine Rocuronium + Rocuronium- and neostigmine 0.7 0.6 Vecuronium- Rocuronium + 0.5 placebo induced NMB: Vecuronium + 0.4 placebo Pooled Analysis 0.3 0.2 of 26 Studies 0.1 0.0 0 10 20 30 40 50 60 70 80 90 Time to Recovery (minutes) Adapted from: Herring WJ, et al. J Clin Anesth. 2017;41:84-91.

Sugammadex 16 mg/ kg Dosing After Rocuronium 1.2 mg/ kg I ntense NMB TOF = 0, PTC = 0 Roc = rocuronium. Naguib M. Anesth Analg. 2007:104(3):575-581. Reprinted With Permission. https://journals.lww.com/anesthesia-analgesia