Sugammadex: Pharmacology, Safety, and Associated Anesthetic Implications

LESSON 24 L. Harold Barnwell, DNAP, CRNA Volume 39* Staff Anesthetist and Affiliate Faculty 4/06/2017 Department of Anesthesiology and Nurse Anesthesia Virginia Commonwealth University and Medical Center Richmond, Virginia

*The use of this volume for Class A CE credits will expire 05/31/2018. *The use of this volume for Class A CE Credits will expire 05/31/2018 Copyright© 2017 by Current Reviews for Nurse Anesthetists®, Ft. Lauderdale, Florida Publisher And Editor-in-Chief FRANK MOYA, MD Coral Gables, Florida

EDITORIAL BOARD ADVISORY BOARD

John Aker, CRNA, DNAP Monte Lichtiger, MD Charles Barton, MSN, MEd David Lott, CRNA Coralville, IA Coral Gables, Florida Akron, Ohio Hollywood, Florida

Chuck Biddle, CRNA, PhD Mary Jeanette Mannino, Carol G. Elliott, CRNA, MPA, Frank T. Maziarski, CRNA Richmond, Virginia CRNA, JD PhD Seattle, Washington Laguna Niguel, California Kansas City, Kansas Linda Callahan, CRNA, PhD Charles Moss, CRNA, MS Klamath Falls, Oregon Maria Garcia-Otero, CRNA, Linda J. Kovitch, CRNA, Westcliffe, Colorado PhD MSN Nancy Gaskey-Spears, Coral Gables, Florida Bedford, Massachusetts Laura Wild, CRNA, MSN CRNA, PhD Pennington, New Jersey Gastonbury, Connecticut Sandra Ouellette, CRNA Winston-Salem, North Carolina Joseph A. Joyce, CRNA, BS Winston-Salem, North Carolina

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Current Reviews® is intended to provide it’s subscribers with information that is relevant to anesthesia providers. However, the information published herein reflects the opinions of it’s authors and does not represent the views of Current Reviews in Clinical Anesthesia®, Current Reviews for Nurse Anesthetists®, or Frank Moya Continuing Education Programs, LLC. Anesthesia practitioners must utilize their knowledge, training and experience in their clinical practice of anesthesiology. No single publication should be relied upon as the proper way to care for patients. The information presented herein does not guarantee competency or proficiency in the performance of procedures discussed.

Copyright 2017 by Current Reviews®. Reproduction in whole or in part prohibited except by written permission. All rights reserved. Information has been obtained from sources believed to be reliable, but it’s accuracy and completeness, and that of the opinions based therein are not guaranteed. Printed in U.S.A. Current Reviews® is published biweekly by Current Reviews®, 1828 S.E. First Avenue, Ft. Lauderdale, FL 33316. POSTMASTER: Send address changes to Current Reviews®, 1828 S.E. First Avenue, Ft. Lauderdale, FL 33316 or email [email protected]. Sugammadex: Pharmacology, Safety, and Associated Anesthetic Implications

L. Harold Barnwell, DNAP, CRNA Staff Anesthetist and Affiliate Faculty Department of Anesthesiology and Nurse Anesthesia Virginia Commonwealth University and Medical Center Richmond, Virginia

LESSON OBJECTIVES 6. Define residual neuromuscular blockade. Upon completion of this lesson, the reader should 7. Discuss the pharmacokinetics of sugamma- be able to: dex, including its primary method of elimina- 1. Identify the indication for sugammadex use tion. in clinical anesthesia practice. 8. Discuss the drug interactions that should be 2. Describe the evolution of neuromuscular considered prior to sugammadex adminis- blockade in clinical anesthesia since the first tration. report on the use of curare. 9. Discuss the warnings and precautions re- 3. Explain the mechanism of action of sugam- lated to the use of sugammadex, including madex reversal. the drug’s effect on coagulation. 4. Describe the chemical structure of sugam- 10. Identify the minimum waiting interval for re- madex. administration of rocuronium or vecuronium 5. State the manufacturer’s recommended dos- following reversal with sugammadex. ing of sugammadex.

® Current Reviews for Nurse Anesthetists designates this lesson for 1 CE contact hour in Clinical pharmacology/therapeutics.

Introduction sugammadex for consideration prior to adoption of

In light of evidence supporting the reality and danger the drug into the armamentarium. of residual neuromuscular blockade, every anesthetist has wished at times that he or she might be able Historical Perspective to produce rapid and complete reversal of muscle “Every anesthetist has wished at times that he might relaxation without the unfortunate side effects of the be able to produce rapid and complete muscular anticholinesterase reversal agents. On December 17, relaxation in resistant patients under general anes- 2015 Merck received approval from the United 1 States Food and Drug Administration (FDA) for thesia.” With those words, Griffith and Johnson’s sugammadex (BRIDION©), the first cyclodextrin 1942 preliminary report on purified curare (d-tubo- introduced into anesthesia practice. Sugammadex is curarine (dTc)) introduced neuromuscular block- indicated as a reversal agent for neuromuscular ade into clinical anesthesia practice. Griffith and blockade induced by the aminosteriod-based, non- Johnson further described dTc as “a drug which depolarizing agents rocuronium bromide and vec- will give us this kind of relaxation, temporarily 1 uronium bromide in adult surgical patients. This and apparently quite harmlessly.” Throughout the lesson will review the clinical pharmacology, safety 1940s, neuromuscular blocking drugs (NMBDs) were profile, and associated anesthetic implications of rapidly accepted into practice. However, the inher-

Curr Rev Nurs Anesth 39(24):309-320, 2017 311 ent safety hazard associated with these drugs was Residual not fully appreciated until a decade later. Neuromuscular Blockade Following a decade of rapid expansion in the use of dTc, Beecher and Todd published “A Study of Definition Deaths Associated with Anesthesia and Surgery” Residual neuromuscular blockade is defined as in 1954. An analysis of approximately 600,000 a train of four ratio (TOFR) of less than 0.9 at anesthetics across ten institutions demonstrated a the adductor pollicis muscle. The adductor pollicis six-fold increase in mortality in patients receiving muscle is the muscle of the hand used to adduct NMBDs. The rise in mortality was attributable the thumb. The TOFR assesses the degree of fade to a clinical knowledge deficit of a new class of between the first twitch (T1) and the fourth twitch pharmacologic agents and the drug’s physio- (T4). (TOFR = the height of the fourth twitch divided logical target receptors. by the height of the first twitch.) Muscle weak- In an attempt to combat the associated rise in ness with associated respiratory impairment mortality related to residual neuromuscular block- has been observed with a TOFR up to 0.9. The ade, short and intermediate acting NMBDs as well clinical characteristics of residual neuromuscular as reversal agents were introduced. Thesleff and blockade are “reduced upper airway tone and diam- Foldes introduced succinylcholine in the early 1950s eters, upper airway obstruction, pharyngeal dysfunc- as the first depolarizing NMBD. Succinylcholine, an tion with impaired airway integrity, decreased upper ultra short-acting NMBD (duration of action < 10 esophageal tone with an increased risk of aspiration, minutes), was originally understood to have a rela- impaired hypoxic ventilatory control, and unpleasant tive sparing effect on respiration, a lack of unwanted symptoms of muscle weakness.”2 The potential haz- side effects, and initial reports stated that the ard to patient safety is clear, but how frequently does disadvantages of succinylcholine were not serious. residual muscle weakness occur with intermediate- Large-scale clinical use of the drug allowed clinicians to successfully identify succinylcholine-associated acting NMBDs? complications (i.e., hyperkalemia, cardiovascular effects, phase II block, malignant hyperthermia, Incidence increased intra-ocular pressure, myalgia, etc.). The Naguib et al published a meta-analysis of 24 3 introduction of succinylcholine may serve to caution trials (3,375 patients) from 1979 to 2005. The clinicians on the importance of vigilance with the authors identified the pooled incidence of residual adoption of new pharmacologic agents. neuromuscular weakness (TOFR < 0.9) in the postoperative care unit (PACU) to be remarkably high. Following intraoperative use of long-acting NMBDs, Muscle weakness with associated respiratory 72% of patients demonstrated residual neuromus- impairment has been observed with a TOFR cular blockade in the PACU. When an intermediate- up to 0.9. acting NMBD was used, 41% of patients demonstrated residual blockade in the PACU. Several

limitations challenge the anesthetist in identifying Pancuronium (the first synthetic aminosteroid- residual neuromuscular weakness prior to extuba- based NMBD) was introduced in 1967 by Baird and Reid and approved by the FDA in 1972. Atracurium, tion and PACU transfer. the first intermediate-acting NMBD (duration of action 25-50 minutes), attained FDA approval in Assessment 1983. Vecuronium, an aminosteroid-based inter- Anesthesia providers utilize a combination of mediate-acting NMBD soon followed with FDA clinical tools and assessment parameters to deter- approval in 1984. Rocuronium joined the inter- mine a patient’s recovery and strength prior to mediate-acting aminosteroid family with FDA appro- extubation and transfer to PACU. A pre-extubation val in 1994. One year later the FDA approved the physical assessment for signs of residual muscle use of cisatracurium, an intermediate-acting benzyl- weakness is the most common approach for deter- isoquinolinium, which had the distinct advantage of mining the adequacy of the patient’s recovery from not causing histamine release. NMBDs. Some providers utilize qualitative neuro- Reversal of NMBDs with the use of acetylcho- muscular monitors in addition to physical assess- linesterase inhibitors (e.g., neostigmine) has re- ment, but few employ a quantitative neuromuscular mained controversial since first suggested in 1945. monitoring device. Some anesthetists routinely administer a reversal Pre-extubation physical assessment for residual agent while others contend that in the absence of muscle weakness examines the patient for a regular clinically observable muscle weakness, the side respiratory rate, adequate tidal volumes, and signs effects of reversal outweigh the risk of residual of strength (e.g., thumbs up, hand squeeze, or head neuromuscular blockade. A growing consensus of lift). These assessments have been shown to have clinical studies contests the dogma that clin- poor sensitivity for detecting residual neuromuscular ically undetectable residual neuromuscular blockade. Tidal volume, for example, is shown to be blockade is of little concern to patient safety. well preserved despite residual neuromuscular block-

® 312 Current Reviews for Nurse Anesthetists ade when an endotracheal tube is maintaining air- rocuronium or vecuronium molecule and way patency. However, as TOFR decreases, swallow- prevents the neuromuscular blocking agent ing impairment, airway obstruction, and pulmonary from binding nicotinic cholinergic receptors. aspiration are shown to increase markedly. Anes- Sugammadex has a high affinity for rocuronium. thesia providers routinely rely on these signs of The sugammadex:rocuronium association-dissocia- muscle strength, but a growing body of literature has tion rate is 25,000,000:1. This means the binding emerged demonstrating the poor reliability of such affinity of sugammadex for rocuronium is so high tests in identifying residual neuromuscular blockade. that sugammadex encapsulates rocuronium 25 Qualitative neuromuscular monitoring refers to million times for each instance the complex separ- use of the peripheral nerve stimulator for train of ates. The result is a rapid and reliable reversal of four (TOF) assessment. This modality is considered neuromuscular blockade. qualitative because its findings are subject to the provider’s interpretation. Residual neuromuscular blockade is defined as a TOFR of less than 0.9 at the The 1:1 complex prevents rocuronium from adductor pollicis muscle. However, providers are agonizing nicotinic cholinergic post junctional receptors at the neuromuscular junction. unable to subjectively (visually or tactually) detect fade when the TOFR exceeds 0.4-0.6. Quantitative neuromuscular monitoring refers to Medicinal Chemistry a device capable of both peripheral nerve stimulation and objective quantification (numeric valuation) of The name sugammadex is derived from the drug’s the muscle response. Clinically available quantita- chemical structure. “Su” is representative of the tive monitors work via acceleromyography (AMG) to drug being a sugar-based compound. “Gammadex” measure a muscle’s force of contraction following is derived from the drug’s gamma-cyclodextrin ((- nerve stimulation. Murphy et al concluded, “At the cyclodextrin) chemical structure. Naturally occur- present time, quantitative neuromuscular monitor- ring cyclodextrins contain 6, 7, or 8 cyclic oligo- ing is the only method of determining whether full saccharides (dextrose units) and are respectively recovery of muscular function has occurred and referred to as ", $, or (-cyclodextrins. The molecular reversal drugs safely avoided.”4 Residual neuromus- structure of a cyclodextrin consists of a circular ring cular blockade is an important patient safety con- of dextrose molecules (Figure 1) viewed as a three- sideration. To avert its occurrence, anesthetists may dimensional structure; the configuration appears benefit from a drug capable of rapid and complete as a short, hollow cone. Because sugammadex is a reversal of muscle relaxation that is devoid of ad- sugar-based, short, hollow cone, the drug is regularly verse side effects. referred to in the literature as a doughnut. The doughnut has a hydrophobic (water repel- A Novel Addition ling) inner core and a hydrophilic (water loving) exterior. Sugammadex is a modified (-cyclodextrin. to the Armamentarium The naturally occurring (-cyclodextrin molecule has

Sugammadex (Org 25969) was introduced into clin- an inner cavity that is 7.5 to 8.3 Å (one angstrom (Å) ical practice in 2008 and approved by the FDA in equals one ten-billionth of a meter) and is too small December 2015. Sugammadex is indicated as a to accommodate the rocuronium molecule. Chemists selective relaxant-binding reversal agent for neuro- modified the naturally occurring (-cyclodextrin by muscular blockade induced by rocuronium and vecur- adding eight side chains with polarcarboxyl (-COOH) onium in adult surgical patients (Table 1). Sugam- groups to the drug’s inner core. This modification madex forms a tight 1:1 complex with the amino- extends the inner cavity to 11 Å and allows ade- steriod-based NMBDs (rocuronium and vecuronium). quate binding of rocuronium’s four steroidal rings Each sugammadex molecule encapsulates a (Figure 2).

Table 1. Neuromuscular Blocking Drugs

Classification Drug Sugammadex for Reversal? Non-depolarizing Amniosteriods Rocuronium Yes Vecuronium Benzylisoquinoliniums Cisatracurium No Atracurium Depolarizing Succinylcholine No

Curr Rev Nurs Anesth 39(24):309-320, 2017 313 Figure 1. Sugammadex Molecular Structure. The arrow highlights one of eight polar carboxyl side chains added to the drug’s inner core extending the inner cavity to 11Å to facilitate binding of rocuronium’s four steroidal rings; a circle highlights one of eight dextrose units forming a ring.

The addition of negatively charged carboxyl cells or plasma proteins. The drug may collect in groups also increases the inner core’s attraction to bone and teeth; however, non-clinical toxicology the rocuronium molecule’s positively charged quater- studies have yet to demonstrate a clinically signif- nary nitrogen group (Figure 3). A combination of icant effect of this occurrence. intermolecular forces including electrostatic interactions, van der Waals forces, hydrogen bonding, and Elimination hydrophobic interactions result in the formation of Sugammadex does not appear to undergo any a tight sugammadex:rocuronium complex. The 1:1 significant metabolism in vivo (within the body). The complex prevents rocuronium from binding drug is primarily (95%) renally excreted unchanged nicotinic cholinergic receptors at the neuro- in the urine and has an elimination half-life (t1/2) of muscular junction. The hydrophilic exterior then approximately 2 hours in patients with normal renal promotes rapid and nearly complete (95%) renal function. Therefore, the t1/2 of sugammadex may excretion of the biologically inactive complex. increase up to ten-fold in the patient with renal impairment. The drug is not recommended for use in Pharmacokinetics

Pharmacokinetics describes the relationship between a drug dose and the concentration of a drug at the target effect site over time. Absorption, distribution, and elimination (metabolism and excretion) regulate the concentration of a drug in the plasma that is available to interact with target receptors. Since sugammadex is administered intravenously, absorption is bypassed.

Distribution The gamma cyclodextrin molecule is highly water-soluble as a result of the doughnut’s hydrophilic outer ring. For this reason, sugammadex Figure 2. Rocuronium Molecular Structure. demonstrates a large apparent volume of distribution The arrow highlights rocuronium molecule’s (11-14 liters). Neither the drug, nor the sugamma- positively charged quaternary nitrogen group. dex:rocuronium complex appears to bind red blood

® 314 Current Reviews for Nurse Anesthetists Figure 3. Sugammadex:rocuronium Complex

patients with severe renal dysfunction, including steroid-based NMBDs. For example, the use of dexa- those patients requiring dialysis. However, no dos- methasone as an antiemetic has been considered. age adjustment is required for patients with mild-to- Buonnano et al demonstrated that the use of dexa- moderate renal dysfunction. The drug’s ability to methasone for postoperative nausea and vomiting reverse rocuronium-induced neuromuscular block- (PONV) prophylaxis does not interfere with sugam- ade remains unchanged in patients with mild-to- madex reversal of rocuronium-induced neuromus- moderate renal impairment. A single study in a cular blockade.5 Hormonal contraceptives are the small subset of patients with severe renal impair- primary clinical concern to date. A bolus dose of ment requiring hemodialysis demonstrated that sugammadex is considered to be equivalent to a sugammadex and the sugammadex:rocuronium com- single missed dose of oral contraceptive. Patients plex were removed during high-flux dialysis (modern should be educated to use additional, non- form of dialysis utilizing dialyzers that have large hormonal contraception for one week after pores for removing both uremic toxins and fluid). No receiving sugammadex. pharmacokinetic differences have been identified to date in regard to age, sex, or race. Nevertheless, the safety and efficacy of sugammadex is yet to be Sugammadex is described as biologically established in children, and the drug is not currently inactive. recommended for use in this population.

Dosing Patients should be educated to use additional, Manufacturer dosing recommendations are based on non-hormonal contraception for one week spontaneous recovery of the response to peripheral after receiving sugammadex. nerve stimulation (Table 2). The manufacturer recommends weight-base dosing based on the patient’s actual body weight. Sugammadex (BRIDION©) is Pharmacodynamics supplied as a sterile, clear colorless to slightly yel- Simply stated, pharmacodynamics describes what low-brown aqueous solution for intravenous infu- the drug does to the body. Specifically, pharmaco- sion. The concentration of available preparations is dynamics describes the relationship between drug 100 mg/ml. Both 2 ml (200 mg) and 5 ml (500 mg) dose and pharmacologic effect. The effectiveness of single dose vial preparations are available. sugammadex as a reversal agent has been shown to If the clinical setting demands rapid re- increase as the dose increases. This relationship is versal of a recently administered dose of referred to in pharmacology as dose-dependent effi- rocuronium (i.e., the “cannot intubate, cannot cacy. ventilate” scenario) sugammadex may be con- Sugammadex may bind other endogenous or sidered. The manufacturer recommends a dose of exogenous steroidal complexes in addition to amino- 16 mg/kg if rapid reversal of neuromuscular blockade

Curr Rev Nurs Anesth 39(24):309-320, 2017 315 Table 2. Manufacturer Dosing Recommendations Based on Spontaneous Recovery of Response to Nerve Stimulation

Spontaneous Recovery of Twitch Response Drug Dose 1-2 PTC* Rocuronium & Vecuronium 4 mg/kg & 0/4 on TOF** 2/4 on TOF** Rocuronium & Vecuronium 2 mg/kg Clinical need to reverse neuromuscular blockade Rocuronium ONLY 16 mg/kg 3 minutes after administration of 1.2 mg/kg of rocuronium

*PTC – post-tetanic count **TOF –Train of four

is indicated approximately 3 minutes following the Warnings and Precautions administration of a single injection of high dose (1.2 Sugammadex is described as biologically in- mg/kg) rocuronium. Sugammadex 16 mg/kg has active and neither stimulates nor antagonizes been shown in a single study to reverse rocuronium receptors in vivo. The drug is contraindicated in 1.2 mg/kg to a TOFR of 0.9 within approximately 3 patients with known hypersensitivity to sugam- minutes, compared to approximately 10 minutes for madex or any of its components. Anaphylaxis has spontaneous recovery from succinylcholine. How- been observed in 0.3% of healthy volunteers studied. ever, further studies are needed to confirm the Cases of marked bradycardia progressing to cardiac clinical efficacy of sugammadex for this indication. arrest have been reported. The manufacturer recom-

mends close hemodynamic monitoring during and If the clinical setting demands rapid reversal immediately following reversal with sugammadex. of a recently administered dose of rocuronium (i.e., the “cannot intubate, cannot ventilate” scenario) sugammadex may be considered. Table 3 Sugammadex: Warnings and Precautions

For the reversal of rocuronium and vecuronium, Anaphylaxis the manufacturer recommends a dose of 4 mg/kg if #Reported in 0.3% of healthy volunteers the patient demonstrates a 1 to 2 post-tetanic count #Observe patients for an appropriate period following administration (PTC), but shows a 0 out of 4 twitch response with TOF monitoring. To assess the post-tetanic count, Marked Bradycardia use a peripheral nerve stimulator to apply 50 Hz #Though rare, bradycardia progressing tetany stimulation for 5 seconds, allow a 3-second to cardiac arrest has been reported pause, then stimulate with 1 Hz twitch stimulation #Monitor for hemodynamic changes and count the total number of post-tetanic twitches following administration or repeat the train of four. Sugammadex (4 mg/kg) reversal of rocuronium-induced neuromuscular Respiratory Function blockade to a TOFR of 0.9 has been shown to occur #Even if recovery from neuromuscular 10 times faster than reversal with neostigmine (0.7 blockade is complete, other drugs used mg/kg) and endrophonium (1 mg/kg). Reversal of in anesthesia practice may suppress neuromuscular blockade with sugammadex respirations (4 mg/kg) at a PTC of 1 to 2 has been shown to #Monitor respiratory pattern following occur within 5 minutes in 97% of patients. A administration dose of 2 mg/kg is recommended for the reversal of Prolonged Neuromuscular Blockade rocuronium or vecuronium if the patient exhibits at #A small number of patients have demon- least a 2 out of 4 twitch response on TOF. Sugam- strated delayed or minimal response to madex (2 mg/kg) reverses rocuronium-induced neuro- sugammadex administration muscular blockade five times faster than does #Monitor ventilation and reflex activity neostigmine (0.5 mg/kg), approximately 2 minutes until recovery occurs vs. approximately 9 minutes, respectively.

® 316 Current Reviews for Nurse Anesthetists Table 4. Re-administration of Neuromuscular Blocking Drugs after Reversal with Sugammadex

Sugammadex Reversal Dose NMBD Dose Minimum Waiting Time Up to 4 mg/kg 1.2 mg/kg rocuronium* 5 minutes Up to 4 mg/kg 0.6 mg/kg rocuronium or 4 hours 0.1 mg/kg vecuronium 16 mg/kg or renal impairment 0.6 mg/kg rocuronium or 24 hours 0.1 mg/kg vecuronium

*Onset of rocuronium may be delayed up to 4minutes; duration of action may be shortened up to 15 minutes.

A small number of patients have demonstrated turer also cautions that the onset of a depolarizing delayed or minimal response to the administration of neuromuscular blocker (e.g., succinylcholine) may be sugammadex; as always, monitor ventilation and slower than expected. reflex activity until recovery from neuromuscular blockade occurs. In one clinical trial, bronchospasm Summary was reported as a possibly related adverse event. In this trial 77 patients with a past medical history of Evidence supporting the reality and danger of post- pulmonary complications were administered sugam- operative residual neuromuscular blockade encour- madex. Two asthmatic patients demonstrated bron- ages anesthetists to seek to ensure complete rever- chospasm approximately 2 minutes after receiving sal of muscle relaxation. The ideal reversal agent sugammadex. However, no evidence has conclusively would provide rapid and reliable reversal of neuro- linked bronchospasm to the use of sugammadex muscular blockade without side effects. Sugam- (Table 3). madex (BRIDION©), the first cyclodextrin introduced into clinical anesthesia practice, is now FDA approved and can be considered for reversal of Following sugammadex administration, a mini- neuromuscular blockade induced by rocuronium and mum waiting period is required before re- vecuronium in adult surgical patients. After review- administration of rocuronium or vecuronium. ing the pharmacology, safety, and associated anesthetic implications of sugammadex, anesthetists may Sugammadex (16 mg/kg)has been associated consider adopting this new reversal agent into their with up to a 25-50% prolongation in coagulation armamentarium. profiles for up to 1 hour in selected patients. Clinical ——————— trials to date have not demonstrated an increase in blood loss, bleeding events, or transfusion require- L. Harold Barnwell, DNAP, CRNA, Staff Anesthetist ments related to sugammadex use. The manufac- and Affiliate Faculty, Department of Anesthesiology and turer recommends that coagulation parameters be Nurse Anesthesia, Virginia Commonwealth University and carefully monitored in patients with known coagu- Medical Center, Richmond, Virginia. [email protected] lopathies, those being treated with therapeutic anti- coagulation or receiving thromboprophylaxis drugs Suggested Reading other than heparin and low molecular weight heparin, or patients receiving thromboprophylaxis drugs 1. Griffith H, Johnson GE. The use of curare in who then receive a dose of 16 mg/kg sugammadex. general anesthesia. Anesthesiology 1942; 3:418-20. Following sugammadex administration, a 2. Naguib M, Lien C, Meistelman C. Pharmacology of Neuromuscular Blocking Drugs. In: Miller’s minimum waiting period is required before re- Anesthesia 8th Ed. Miller R, ed. Orlando, FL, administration of rocuronium or vecuronium. Churchill Livingstone, 2015: 958-94. Following a reversal dose of sugammadex, 4 mg/kg, 3. Naguib M, Kopman AF, Ensor JE. Neuromuscular should neuromuscular blockade need to be reintro- monitoring and postoperative residual curarisa- duced, the onset of additional rocuronium will be tion: a meta-analysis. Br J Anaesth 2007 Mar; significantly delayed, and the duration will be sig- 98(3):302-16. nificantly abbreviated (Table 4). A nonsteroidal 4. Murphy G, Boer H, Eriksson L, Miller R. Reversal NMBD is recommended if neuromuscular (Antagonism) of Neuromuscular Blockade. In: blockade is required before the minimum rec- Miller’s Anesthesia 8th Ed. Miller R, ed. Orlando, ommended interval has elapsed. The manufac- FL, Churchill Livingstone, 2015: 958-94.

Curr Rev Nurs Anesth 39(24):309-320, 2017 317 5. Buonanno P, Laiola A, Palumbo C, Spinelli G, clinical neuromuscular pharmacology. Anesth Servillo G, Di Minno RM, Cafiero T, Di Iorio C. Analg 2007 Mar; 104(3):575-81. Dexamethasone does not inhibit sugammadex re- 9. Merck Pharmaceuticals. (2015). BRIDION® versal after rocuronium-induced neuromuscular (sugammadex) Injection: Full Prescribing Infor- block. Anesth Analg 2016 Jun; 122(6):1826-30. mation. Retrieved from: http://www.accessdata. 6. Plummer-Roberts AL, Trost C, Collins S, Hewer I. fda.gov/drugsatfda_docs/label/2015/022225 lbl.pdf Residual neuromuscular blockade. AANA J 2016 10. Lee C, Jahr JS, Candiotti KA, et al. Reversal Feb; 84(1):57-65. of profound neuromuscular block by sugamma- 7. Donati F. Residual paralysis: a real problem or dex administered three minutes after rocuron- did we invent a new disease? Can J Anaesth 2013 ium: a comparison with spontaneous recovery Jul; 60(7):714-29. from succinylcholine. Anesthesiology 2009; 110: 8. Naguib M. Sugammadex: another milestone in 1020-25.

Tips for your Clinical Practice: Key Points

#This novel and unique agent encapsulates rocuronium and vecuronium providing for rapid antagonism of neuromuscular blockade. #The cyclodextrin molecular structure that sugammadex is based on was modified, enlarging it so that it can accommodate rocuronium-like molecules. #Sugammadex acts as a guest-host complex, binding the neuromuscular blocking drug, and having no effect on acetylcholinesterase or any other receptors. #Sugammadex is largely excreted in the urine in the first 8 hours but its efficacy as an antagonist does not appear to rely on renal excretion of the guest-host complex. #Sugammadex appears to be biologically inactive, has minimal association with plasma proteins, and appears to be a safe and effective antagonist to rocuronium and vecuroniuim.

Chuck Biddle, CRNA, PhD Richmond, Virginia

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THIS AUTHOR’S AND FMCEP’S SPECIFIC DISCLOSURES: CThe author / faculty has indicated that there is no relevant financial interest or relationship with any commercial interest. CThe author / faculty has indicated that, as appropriate, he/she has disclosed that a product is not labeled for the use under discussion, or is still under investigation. CAs a matter of policy, FMCEP does not have any relevant financial interest or relationship with any commercial interest. In addition, all members of the staff, Governing Board, Editorial Board and CME Committee who may have a role in planning this activity have indicated that there is no relevant financial interest or relationship with any commercial interest. CCurrent Reviews is intended to provide its subscribers with information that is relevant to anesthesia providers. However, the information published herein reflects the opinions of its authors. Anesthesia practitioners must utilize their knowledge, training and experience in their clinical practice of anesthesiology. No single publication should be relied upon as the proper way to care for patients.

DESIGNATON OF SPECIFIC CONTENT AREAS: Current Reviews for Nurse Anesthetists (CRNA) is designed to meet the standards and criteria of the American Association of Nurse Anesthetists (AANA) for the prior-approved continuing medical education activity, Provider-Directed Independent Study, also known as home study. CRNA is an approved program provider. CRNA has designated the lessons which meet specific content areas such as pharmacology, HIV/AIDS, etc. However, only the Board of Nursing of an individual State is the final authority in the determination of whether or not these lessons meet the State’s licensure requirements.

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POST-STUDY QUESTIONS

1. Sugammadex is indicated for reversal of neuro- G C. Ester hydrolysis. muscular blockade induced by which neuromus- G D. Hoffman elimination. cular blocking drug (NMBD)? G A.Cisatracurium. 7. Which of the following drug interactions should be G B. Succinylcholine. considered prior to the administration of sugam- G C.Rocuronium. madex? G D. Curare. G A. The use of dexamethasone for PONV prophylaxis may interfere with the ability of sugam- 2. Griffith and Johnson first reported on the use of madex to reverse neuromuscular blockade. purified curare in: G B. A bolus dose of sugammadex is considered to G A. 1935. be equivalent to a single missed dose of oral G B. 1942. contraceptive. G C. 1957. G C. Angiotensin receptor blockers may interfere with G D. 1963. the ability of sugammadex to reverse neuromuscular blockade. 3. Residual neuromuscular blockade is defined as: G D. Patients taking 81 mg of aspirin daily should not G A. A train of four ratio of less than 0.9 at the receive sugammadex. adductor pollicis muscle. G B. A train of four ratio of less than 0.5 at the 8. The manufacturer recommends which of the fol- adductor pollicis muscle. lowing sugammadex doses if the patient demon- G C. A train of four ratio of less than 0.9 at the strates 2 out of 4 twitches on train of four moni- orbicularis oculi muscle. toring? G D. A train of four ratio of less than 0.5 at the G A. 1 mg/kg. orbicularis oculi muscle. G B. 2 mg/kg. G C. 4 mg/kg. 4. What is the mechanism of action of sugammadex G D. 16 mg/kg. reversal? G A. Antagonism of acetylcholine at muscarinic re- 9. Coagulation parameters should be carefully moni- ceptors. tored in which of the following scenarios? G B. Inhibition of acetylcholinesterase. G A. Patients with known coagulopathies. G C. Potentiation of acetylc holine at the neuromus- G B. Patients being treated with therapeutic anticoag- cular junction. ulation. G D.Encapsulation of rocuronium or vecuronium. G C. Patients receiving thromboprophylaxis drugs and who then receive a dose of 16 mg/kg sugam- 5. The chemical structure of sugammadex can be de- madex. scribed as: G D. All of the above. G A. A modified gamma cyclodextrin. G B. A short, hollow cone resembling a doughnut. 10. When reinstituting neuromuscular blockade after G C. A circle of dextrose molecules. sugammadex reversal, what will be observed with G D. All of the above. additional rocuronium administration? G A.Onset accelerated, duration prolonged. 6. Sugammadex is primarily eliminated via: G B.Onset accelerated, duration abbreviated. G A. Renal excretion. G C.Onset delayed, duration prolonged. G B.Hepatic metabolism. G D.Onset delayed, duration abbreviated.

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