Sugammadex: Implications for Future Clinical Practice

Kari Bentley CRNA MSN

Sothida Berry CRNA MSN

Heather Rawlings CRNA MSN

Major Peter Strube CRNA MSNA APNP ARNP

Rosalind Franklin University

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Objectives

Describe the mechanism of action of sugammadex.

Discuss the effectiveness of various dosages of sugammadex for reversing rocuronium and vecuronium induced neuromuscular blockade.

Describe the efficacy of sugammadex following maintenance of anesthesia with inhalation and intravenous anesthesia.

Discuss the potential for residual blockade following administration of sugammadex

Describe the various clinical scenarios in which sugammadex may provide favorable surgical or intubating conditions.

List the potential advantages and disadvantages for the future use of sugammadex.

Discuss the use of sugammadex in specific patient populations such as elderly, renal failure, and pediatric patients.

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Abstract

Sugammadex, a new selective muscle relaxant-binding drug, is used to rapidly

reverse muscle relaxation, regardless of the depth of neuromuscular blockade. The ability

of sugammadex to reverse both shallow or moderate vecuronium and rocuronium

induced neuromuscular blockade may greatly impact the future clinical practice of

anesthesia. Dose finding studies have demonstrated the effectiveness of sugammadex at

reversing deep neuromuscular blockade. Sugammadex is effective when used in

conjunction with either inhalational or intravenous anesthesia. Studies have been

conducted to demonstrate its use in different clinical scenarios and patient populations.

Scenarios such as a potential difficult airway, short duration procedures, and scenarios

where succinylcholine is contraindicated have been examined. Use of sugammadex in

morbidly obese patients, obstetrics, pediatrics, and geriatrics has proven to be safe and

effective. This review highlights the current research surrounding the use of sugammadex

and its potential implications for the future practice of anesthesia.

Keywords: sugammadex, neuromuscular block, reversal, rocuronium, neostigmine

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Neuromuscular-blocking agents (NMBAs) are frequently used in patients

undergoing surgical procedures to facilitate endotracheal intubation, provide patient

immobility, and enhance surgical exposure. Commonly used agents in clinical practice

are rocuronium and vecuronium, both aminosteroid non-depolarizing NMBAs and

succinylcholine, a depolarizing NMBA. Since succinylcholine is metabolized quickly by

the enzyme pseudocholinesterase, a reversal medication is not necessary to reverse

muscle paralysis. Recovery from aminosteroid non-depolarizing NMBAs can take place

spontaneously through hepatic and renal metabolism and elimination, but this process is

slow and may result in residual muscle paralysis.

Reversal of NMBAs is currently accomplished using acetylcholinesterase

inhibitors, most commonly neostigmine, to decrease the risk of residual postoperative

muscle weakness. The suppression of the breakdown of acetylcholine, allows it to

accumulate and displace neuromuscular blockade (NMB) molecules from binding sites

on the nicotinic receptors.1 Acetylcholinesterase inhibitors have a significant side effect

profile due to undesired stimulation of muscarinic receptors, which can cause

cardiovascular, gastrointestinal, and respiratory adverse events.1 Co-administration of

muscarinic antagonists is necessary to counteract these adverse effects. Anticholinergic

agents cause additional side effects, such as tachycardia, sedation, confusion, and blurry

vision.2 A major disadvantage of acetylcholinesterase inhibitors is the inability to

adequately displace enough neuromuscular blocking molecules to reverse a profound

depth of neuromuscular block.1 A reversal agent with improved clinical utility and safety

is desirable to eliminate the routine use of acetylcholinesterase inhibitors.

An alternative to indirect reversal of NMBAs with acetylcholinesterase

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inhibitors is sugammadex, a selective relaxant-binding agent, which directly encapsulates

aminosteroid non-depolarizing NMBAs.1 Sugammadex, a modified gamma cyclodextrin,

is capable of rapid reversal of muscle relaxation, regardless of the depth of

neuromuscular blockade.1 Sugammadex forms a tight complex with unbound steroidal

NMBAs.1 The interaction of the two agents decreases the amount of NMBA in the

plasma, which leads to a shift of NMBA from the tissue into the plasma and reduces the

level of free NMBA at the neuromuscular junction.3 Studies in surgical patients have

revealed that sugammadex provides well-tolerated and dose-dependent rapid reversal of

shallow and profound rocuronium-induced neuromuscular block.4 Sugammadex is also

capable of encapsulating vecuronium molecules, but to a lesser extent.2 Sugammadex is

regarded as an ideal reversal agent that will likely change the future practice of

anesthesia.5  

Impact on Clinical Practice

Sugammadex has been evaluated at various doses in many clinical scenarios,

primarily related to the timing of administration in relation to when the NMBA was given

and the depth of the neuromuscular block. Level of blockade is most commonly

monitored using a peripheral nerve stimulator to assess the train-of-four (TOF) ratio.

TOF consists of 4 electrical impulses delivered at 2 Hz over a 1.5 second interval. The

ratio is determined by comparing the height of the fourth twitch (T4) to the height of the

first twitch (T1). When T4 is no longer present, 70-75% of the nicotinic acetylcholine

receptors have been occupied by NMBA. If twitches are absent, a tetanus stimulus is

applied and a post-tetanic count (PTC) is assessed to determine the depth of blockade.

Shallow or moderate block relates to the reappearance of the second twitch (T2) or

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approximately 30 min after the administration of rocuronium or vecuronium.6 Deep block

is associated with absence of TOF twitches with a PTC of 1-2 or an average of 10-15 min

after administration of rocuronium or vecuronium.6

Dose-finding studies have demonstrated the effectiveness of sugammadex at

rapidly reversing aminosteroid-induced neuromuscular blockade, including profound

blockade.1, 3-5 Sugammadex will have important clinical implications in surgical patients

requiring maintenance of deep neuromuscular block throughout the entire surgical

procedure. This will also be a beneficial drug in cases where surgery ends earlier than

expected and a dose of an aminosteroid neuromuscular blocking agent was recently

administered. The incidence of residual paralysis and associated post-operative

complications is reduced with administration of sugammadex compared to

acetylcholinesterase inhibitors.17 Sugammadex is also advantageous in patients requiring

rapid sequence induction, in procedures that require a very short duration of muscle

paralysis, and in situations where succinylcholine is contraindicated.

Reversal of Shallow / Moderate Block

Schaller et al.7 researched shallow residual rocuronium-induced blockade (TOF

ratio 0.4-0.7) since this is a common depth of blockade encountered in the clinical

setting.  This study used sugammadex at doses of 0.0625, 0.125, 0.25, 0.5 or 1 mg/kg and

was compared with the use of neostigmine at doses of 5, 8, 15, 25, or 40 mcg/kg to

reverse a shallow block once TOF ratio reached 0.5 -0.9.7 Results from this study found

that sugammadex 0.22 mg/kg is able to reverse a TOF ratio > 0.5 in an average of 2 min,

while neostigmine 34 mcg/kg reverses the same level of blockade within 5 min.7

A study by Suy et al.8 investigated the dose response relationship of sugammadex

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as a single dose reversal agent for a rocuronium or vecuronium-induced block after the

reappearance of T2. Results of the study concluded that when compared to those in the

placebo group, a decrease in the mean time to recovery was found for all TOF ratios with

both rocuronium and vecuronium.8 Patients who received rocuronium were found to have

a mean recovery time of 31.8 min with placebo, 3.7 min with 0.5 mg/kg sugammadex,

and 1.1 min with 4 mg/kg sugammadex.8 Vecuronium-induced patients had a recovery

time of 48.8 min with placebo, 2.5 min with 1 mg/kg sugammadex, and 1.4 min with 8

mg/kg sugammadex.8

Khuenl-Brady et al.2 compared the use of neostigmine versus sugammadex in the

reversal of 0.1 mg/kg vecuronium.  The results indicated that time to recovery of TOF

ratio to 0.9 averaged 2-3 min after administration of 2 mg/kg sugammadex compared to

17-18 min after 50 mcg/kg neostigmine.2

Research by Duvaldestin et al.9 evaluated the use of sugammadex in reversing

rocuronium and vecuronium-induced NMB under sevoflurane anesthesia. One group

received vecuronium 0.1 mg/kg and mean time to recovery to TOF ratio of 0.9 was 68.4

min when sugammadex was administered at 0.5 mg/kg, 9.1 min (2 mg/kg), 3.3 min (4

mg/kg), and 1.7 min (8 mg/kg).9 Another group received 0.6 mg/kg rocuronium and

mean time to recovery of TOF ratio of 0.9 was 79.8 min when sugammadex was

administered at 0.5 mg/kg, 3.2 min (2 mg/kg), 1.7 min (4 mg/kg), and 1.1 min (8

mg/kg).9

Flockton et al.10 compared reversal of 0.6 mg/kg rocuronium with 2 mg/kg

sugammadex to reversal of 0.15 mg/kg cisatracurium with 50 mcg/kg neostigmine.  The

efficacy variable measured in this study was the time to TOF ratio of 0.9 after reversal

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agent administration at reappearance of T2.10 The time to recovery of TOF ratio to 0.9

was almost five times faster with sugammadex, 1.4 min with sugammadex versus 17.6

min with neostigmine.10

Research by Sorgenfrei et al.11 studied the use of sugammadex, administered at

reappearance of T2, to reverse a NMB induced by 0.6 mg/kg rocuronium in a group of

patients anesthetized with fentanyl and propofol. Patients in the placebo group recovered

from NMB at 21 min, while those in the sugammadex group with doses greater than or

equal to 2 mg/kg recovered in 3 min.11

Reversal of Deep / Profound Block

When the level of NMBA is profound, the increase in acetylcholine concentration

following administration of acetylcholinesterase inhibitors is inadequate to displace

enough NMBA molecules to reverse NMB.1 Studies have been conducted to examine the

effects of sugammadex used in reversal of deep NMB produced by aminosteroid non-

depolarizing NMBAs.  Some studies investigated a single dose of sugammadex, while

others trialed various doses to determine optimal dosing to achieve a T4/T1 ratio of

0.9.1,3,5,12-14 Recovery from deep neuromuscular blockade, defined as 1-2 PTCs, is

considerably faster with sugammadex versus neostigmine.1,3,5,12-14

Jones et al.1 conducted a study using sugammadex at a dose of 4 mg/kg to reverse

a deep rocuronium-induced block, which resulted in a recovery time that was 17 times

faster than neostigmine at a dose of 70 mcg/kg. Sugammadex or neostigmine was

administered at reappearance of 1-2 PTCs.1 Recovery to TOF ratio of 0.9 occurred within

3 min in 70% of sugammadex patients and all except one recovered within 5 min.1 In the

neostigmine group, 73% of the patients achieved a TOF ratio of 0.9 in 30-60 min and

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23% of the patients required more than 60 min to reach this recovery parameter.1

Research by Pavoni et al.5 found that 16 mg/kg sugammadex administered 3 min

after 1.2 mg/kg rocuronium resulted in a mean recovery time to TOF ratio of 0.9 in 114

+/- 75 sec. A second group in this study received 4 mg/kg sugammadex 15 min after 0.6

mg/kg rocuronium was given, which resulted in a mean time to TOF ratio of 0.9 in 186

+/- 105 sec.5

Puhringer et al.3 studied sugammadex at doses of 2, 4, 8, 12, or 16 mg/kg

administered at either 3 or 15 min following 1.0-1.2 mg/kg rocuronium. This research

concluded that the encapsulation of rocuronium by sugammadex allows for significantly

faster, in a dose-dependent manner, reversal of high dose rocuronium.3 There were no

occurrences of residual neuromuscular blockade in any of the dosing groups.3 There were

no differences in recovery time at the two different time points of administration, with the

exception of the 2 mg/kg and 4 mg/kg doses.3 A plateau effect existed in the time to

recovery at doses of 8 mg/kg or greater.3 Sugammadex 16 mg/kg given at 3 or 15 min

after rocuronium was significantly faster in reversing high-dose rocuronium (1.6 and 0.9

min vs. placebo at 111 and 91 min).3

Boer et al.14 revealed a dose-dependent relationship for reversal of rocuronium-

induced neuromuscular blockade following administration of sugammadex at 2, 4, 8, 12,

and 16 mg/kg.  Sugammadex was administered 5 min after a dose of 1.2 mg/kg

rocuronium. Patients who recovered spontaneously required an average of 122 min,

while those who received sugammadex recovered in less than 2 min.14

Additional clinical studies have supported the dose-dependence of sugammadex

to speed of recovery.12-13 A study by Sparr et al.12 consisting of 98 subjects found that

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time to TOF ratio of 0.9 was less than 3 min following 6 mg/kg sugammadex. When

sugammadex was given at 2 mg/kg, recovery to TOF ratio of 0.9 was 15 min.12 Research

by Groudine et al.13 supported that reversal with sugammadex at higher doses resulted in

faster recovery times. Sugammadex administered at a dose of 4- 8mg/kg to reverse a

profound neuromuscular blockade resulted in a mean recovery time of 1.7 min compared

with 44.2 min in the group that received 0.5 mg/kg sugammadex.13

Use with Inhalation Anesthesia vs. Intravenous Anesthesia

  Volatile anesthetics potentiate the duration of action of NMBAs. Vanacker et

al.15 studied the effects of sugammadex administration following maintenance anesthesia

with either propofol or sevoflurane. The study found that sevoflurane does not reduce the

efficacy of sugammadex in reversing rocuronium-induced NMB.15 Time from

administration of 0.6 mg/kg rocuronium to reappearance of T2 was 33 min in the

propofol group and 51.8 min in the sevoflurane group.15 The mean time from

administration of 2 mg/kg sugammadex to TOF ratio of 0.9 was 1.8 min in both the

propofol and sevoflurane groups.15 The results confirm that sevoflurane enhances NMB,

but it does not reduce the efficacy of sugammadex in reversing NMB.15

Rex et al.16 concluded that a single dose of sugammadex after continuous

rocuronium infusion is equally effective in maintenance anesthesia with sevoflurane or

propofol. The study of 52 subjects found the type of maintenance anesthesia had a

significant effect on plasma rocuronium concentration measured prior to administration

of sugammadex.16 The propofol group had 33% lower rocuronium plasma concentration

than the sevoflurane group.16 Both groups received a continuous infusion of rocuronium

at 7 mcg/kg/min, which was adjusted to maintain a depth of zero twitches with no more

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than 10 PTC.16 Following rocuronium infusion discontinuation, subjects received a dose

of 4 mg/kg sugammadex at T1 of 3-10%.16 Mean recovery time from administration of

sugammadex to a TOF ratio of 0.9 was 1.4 min in the sevoflurane group and 1.3 min in

the propofol group.16

Residual Blockade

Peripheral nerve stimulation (PNS) is the most widely used monitor to assess the

depth of neuromuscular blockade and to determine adequacy of NMBA reversal.17 A

TOF ratio of 0.9 or greater is the desired parameter to achieve prior to tracheal

extubation.  Despite utilizing the TOF as an assessment tool to determine the level of

block, many patients will be extubated prior to full return of pharyngeal and respiratory

muscle function.17 The consequences of residual neuromuscular blockade in the early

postoperative period include hypoventilation, hypoxia, airway obstruction, pulmonary

complications, aspiration, and increased mortality.1,17

        The use of subjective visual assessment for determination of twitch response may

lead to overestimation of the level of neuromuscular recovery.  Illman et al.17 conducted

research to determine if sugammadex is able to reduce the potentially unsafe period of

neuromuscular recovery.  The time gap between loss of visual fade by using a PNS until

TOF ratio > 0.9 using objective monitoring equipment is considered to be a potential

period of unsafe recovery.17 This trial demonstrated that reversal of a moderate

rocuronium-induced block with sugammadex reduces the potentially unsafe recovery

period to less than 20 sec as compared to neostigmine, which averaged 10 min.17 The use

of sugammadex to antagonize NMBA will decrease the incidence of critical respiratory

events associated with residual blockade.17

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Clinical Scenarios & Patient Populations

Procedures of short duration requiring muscle relaxation

Kadoi et al.18 researched three different doses of sugammadex to determine

optimal dosing to produce equal recovery time from rocuronium-induced muscle

relaxation compared with spontaneous recovery from succinylcholine in patients

undergoing electroconvulsive therapy (ECT).  Neuromuscular recovery of T1 to 90% and

time to first spontaneous breath with sugammadex at a dose of 16 mg/kg was

significantly shorter than with 1 mg/kg succinylcholine.18 Sugammadex 4 mg/kg resulted

in a longer time to recovery of T1 to 10% and 90% and longer time to first spontaneous

breath compared to succinylcholine.18 Comparable recovery times were seen with

succinylcholine and sugammadex at a dose of 8 mg/kg.18 Sugammadex used to reverse

rocuronium is an efficacious alternative to succinylcholine in short duration procedures

requiring muscle relaxation.

Contraindications to Succinylcholine

Succinylcholine is associated with many adverse effects and contraindications,

including history of neuroleptic malignant syndrome, severe osteoporosis, amyotrophic

lateral sclerosis, pseudocholinesterase deficiency, and malignant hyperthermia.19 Clinical

scenarios in which succinylcholine is contraindicated poses challenges for anesthesia

providers. An alternate agent that will quickly induce muscle relaxation and expedite fast

recovery time is necessary in many clinical situations.

        Sugammadex used to reverse a deep rocuronium-induced block has been

compared with spontaneous neuromuscular recovery time following succinylcholine.

Lee et al.26 studied reversal of profound high-dose rocuronium (1.2 mg/kg) with 16 mg/kg

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sugammadex and found significantly faster recovery compared to spontaneous recovery

from 1 mg/kg succinylcholine.4 Efficacy parameter, T1 to 90%, was achieved in 6.2 min

in the sugammadex-rocuronium group compared with 10.9 min in the succinylcholine

group.4

Difficult Airway

Succinylcholine has been the preferred medication utilized in patients with a

potential difficult airway. Recent studies indicate that succinylcholine may no longer be

the drug of choice due to the limited time available for successful intubation.20 If the

airway is not secured within the timeframe of maximum effect of succinylcholine,

intubating conditions can be suboptimal and lead to prolonged time of hypoxia.

Sugammadex can potentially reverse neuromuscular blockade faster than spontaneous

recovery from succinylcholine.21

Mcternan et al.22 describes an advantage for the use of sugammadex in a difficult

airway caused by a large infraglottic polyp. Unlike many scenarios where neuromuscular

blockers are avoided in a potentially difficult airway, the effectiveness of sugammadex in

reversing rocuronium may be useful in cases where complete muscle relaxation is

required to surgically operate on a threatened airway.  Mcternan et al.22 reports a surgical

case in which 60-80% of the airway circumference was occupied by a large pedunculated

polyp located underneath the right vocal cord.  Jet ventilation was utilized to facilitate

laser ablation of the tumor. Sugammadex 4 mg/kg was used to reverse the patient with a

TOF of 0 and a PTC of 5.22 Return of TOF >0.9 was achieved in 1 min 45 sec and

extubation proceeded without complications.22 The ability of sugammadex to fully

antagonize the actions of rocuronium in a deep neuromuscular blockade scenario is

13

advantageous for operations involving the airway.

Morbidly Obese

Reversal from neuromuscular blockers and the ability to protect the upper airway

reflexes is one critical goal following general anesthesia with the use of NMBAs.

Avoiding residual paralysis decreases the risk of aspiration and other respiratory

complications.  Similar to other drugs used to induce general anesthesia such as

rocuronium, pharmacokinetic studies indicate that weakly lipophilic drugs are dosed on

ideal body weight rather than actual body weight.23 The dosing of sugammadex has

commonly been calculated based on total body weight.23 Van Lanker et al.23 suggests the

ideal formula that should be used when calculating an appropriate sugammadex dose for

a morbidly obese patient to be 2 mg/kg IBW + 40%.

Desforges and McDonnell 24 describe a case scenario in which sugammadex was

administered to reverse rocuronium in a failed intubation attempt in a morbidly obese

patient weighing 110 kg. After multiple unsuccessful attempts for securing an airway, the

researchers attempted ventilation through a laryngeal mask airway (LMA).24 The oxygen

saturation continued to drop and attempts at ventilation were unsuccessful, so the

researchers administered 700 mg of sugammadex approximately 5 min after the

administration of rocuronium.24 Within 45 sec, the patient made strong respiratory effort

through the LMA.24 This case report demonstrates a successful outcome of using

sugammadex in an unanticipated difficult airway emergency in a morbidly obese patient.

Gaszynski et al.25 investigated the outcome of sugammadex versus neostigmine

for reversal of NMB in severely morbidly obese patients scheduled for bariatric surgery.

Sugammadex at a dose of 2 mg/kg resulted in a mean recovery time to TOF ratio of 0.9

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that was 3.5 times shorter than neostigmine at a dose of 0.05 mg/kg.25

Obstetrics

The obstetric population is well known for having a potential difficult airway. The

use of NMBAs has been a topic of controversy in this patient population, as advantages

and disadvantages must be weighed when using muscle relaxation for a cesarean section.

General anesthesia in the obstetric population involves rapid sequence induction (RSI)

with succinylcholine. Succinylcholine has a significant side-effect profile, however no

NMB exists that has as favorable onset and offset characteristics needed to perform

tracheal intubation in this patient population. Rocuronium is typically avoided as its

duration of action is much longer than the time required to perform a cesarean section.

Recent data showing the effectiveness of sugammadex has piqued interest of providers to

the possibility of using rocuronium in the obstetric population as opposed to

succinylcholine. A large dose of rocuronium (1.2 mg/kg) has been shown to have a mean

onset time of 55 sec in comparison to 50 sec when succinylcholine is used.26

A study by Williamson et al.26 examined the use of sugammadex to reverse a

profound rocuronium-induced NMB at the end of obstetric procedures. A group of 18

patients received 4 mg/kg sugammadex to reverse 1.2 mg/kg rocuronium, which resulted

in a mean time to TOF ratio > 0.9 in 62 sec.26 Results also revealed a more rapid return of

neuromuscular function than the spontaneous offset of succinylcholine.26

Pediatrics

The use of sugammadex in the pediatric population has proven to be safe and

effective in clinical trials.27 Pharmacologic treatment differs in the pediatric population in

comparison to the adult population in clinical effect, duration, metabolism and excretion.

15

The clinical duration of rocuronium is prolonged in infants when compared to children.27

Rocuronium potency is greater in infants and less in children compared to adults. Plaud

et al.27 examined the safety and efficacy of sugammadex in 8 infants (28 days-23 mo.), 24

children (2-11 yr.), 31 adolescents (12-17 yr.) and 28 adults (18-65 yr.). The study found

the mean time from administration of rocuronium to the appearance of T2 was 29 min in

the infant group, 21.8 min in the children group, 26 min in the adolescent group, and 32.9

min in the adult group.27 Time to a TOF ratio of 0.9 decreased with increased doses of

sugammadex in all age groups.27 Recovery times to TOF ratio of 0.9 after sugammadex

administration were 0.6-3.7 min (infants), 0.6-3.7 min (children), 1.1-4.6 min

(adolescents) and 1.2-4.2 min (adults) in a dose-dependent manner.27 At a dose of 2

mg/kg sugammadex, recovery of TOF to 0.9 in all age groups occurred with a median

time of 1.1-1.2 min.27 No formal dose-response relation was achieved in the infant group

because of the small number of subjects in each dose group.27 Results indicated that

sugammadex dosing based on body weight had similar plasma sugammadex levels

independent of age group.27 No clinical differences were seen in regards to dose and age

groups with the incidence of adverse effects.27

Elderly

Postoperative morbidity and mortality in the elderly population is higher than in

the adult population. Several factors that contribute to this are physiologic changes in

cardiovascular, respiratory and renal function. Pharmacokinetics and pharmacodynamics

of drugs can vary in clinical effect, duration, metabolism and elimination among the

elderly population. Volume of distribution, albumin levels, and organ function in the

elderly also contribute to unpredictable responses to medications. Renal function declines

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rapidly after the fourth decade of life and the onset, duration, metabolism and elimination

time of drugs are prolonged.28

McDonagh et al.28 studied the efficacy, safety, and pharmacokinetics of

sugammadex in moderate rocuronium-induced neuromuscular blockade in adults (18-64

yr.), elderly (65-74 yr.), and old-elderly (75 yr. or older) patients. The mean time from

administration of sugammadex (2 mg/kg) to recovery of TOF ratio to 0.9 increased

slightly in the elderly and the old-elderly groups.28 The mean time to recovery was 2.3

min in the adult group, 2.6 min in the elderly group and 3.6 min in the old-elderly

group.28 All patients recovered within 10 min, although fewer patients in the elderly or

old-elderly group recovered to a TOF ratio of 0.9 within 10 min compared to the adult

group (75.5% vs. 85.4%, respectively).28 The study concluded that recovery to a TOF

ratio of 0.9 was 0.7 min faster in the adult group compared with subjects 65 yr. and

older.28 Sugammadex clearance had an inverse relationship with increasing age and was

decreased by half compared with the adult subject.28 Sugammadex half-life was doubled

in the elderly compared with the typical adult subject (4.6 vs. 2.4 hr., respectively).28 The

study found that sugammadex at a dose of 2 mg/kg was safe and effective at reversing

rocuronium-induced NMB in both adult and elderly patients.28

A study comparing reversibility of rocuronium-induced neuromuscular block with

sugammadex in younger (20-50 yr.) and older (≥70 yr.) patients demonstrated adequate

neuromuscular recovery in both groups.29 A dose of 4 mg/kg sugammadex was

administered at a PTC of 1-2 and the time required to achieve a TOF ratio of 0.9 was

measured.29 Results revealed a significant increase in the amount of time required to

achieve a TOF of 0.9 in the older population, 3.6 min in the older group versus 1.3 min in

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the younger group.29 This study confirmed the safety of sugammadex in the elderly

population.

Renal Failure

Mean time to recovery from rocuronium-induced neuromuscular blockade is

significantly prolonged in patients with end-stage renal failure. Staals et al.30 studied the

safety and efficacy of sugammadex in reversal of rocuronium-induced neuromuscular

blockade in patients with normal kidney function compared to patients with severe

kidney impairment.30 The study compared the effects of 2 mg/kg sugammadex in 15

patients with renal impairment (creatinine clearance <30 ml/.min.) and 15 patients with

normal renal function (creatinine clearance >80 ml/min.).30 Time from administration of

rocuronium to reappearance of T2 was 53.8 min in the renal-impaired group compared to

40.6 min in the normal kidney function group.30 Time from sugammadex administration

to TOF ratio 0.9 was 2 min in the renal insufficiency group compared to 1.65 min in the

control group.30 No recurrence of NMB was seen in any subjects in either group.30

Hematology and urine studies were similar between the two groups when comparing

differences that existed at baseline.30 The study concluded that sugammadex at a dose of

2 mg/kg can safely and effectively reverse rocuronium-induced NMB in patients with

renal compromise.30

Conclusion

Reversal of neuromuscular blockade with acetylcholinesterase inhibitors is

associated with significant adverse side effects, inability to reverse profound

neuromuscular blockade, and potential for residual blockade. A reversal agent with

improved clinical utility and safety is desirable to eliminate the routine use of

18

acetylcholinesterase inhibitors. Dose-finding studies have demonstrated the effectiveness

of sugammadex to provide rapid reversal of any depth of neuromuscular block. An

important clinical implication of sugammadex is the reduced incidence of residual

paralysis and associated post-operative complications in comparison to

acetylcholinesterase inhibitors. Sugammadex is also advantageous in patients requiring

rapid sequence induction, in procedures that require a very short duration of muscle

paralysis, and in situations where succinylcholine is contraindicated.

Discussion

Research to date has shown that sugammadex is a safe and effective agent for

reversal of NMB induced by rocuronium or vecuronium. The future of the drug in the

United States will remain to be seen, pending Food and Drug Administration (FDA)

approval.31 In 2008, the FDA did not approve the original new drug application (NDA)

for sugammadex and requested more information regarding hypersensitivity reactions

and coagulation events.31 Merck submitted the requested data with the NDA

resubmission.31 In January 2013, the FDA concluded the NDA on sugammadex is now

complete for review, which is a significant breakthrough in Merck’s efforts to bring

sugammadex to the U.S.31 Merck expects the review of the NDA to be completed by the

FDA by mid-2013.31

Use of sugammadex could ultimately negate the use of succinylcholine in clinical

practice and permit the use of non-depolarizers for rapid sequence intubation.

Sugammadex provides fast reversal of profound NMB and reduces the incidence of post-

operative respiratory complications associated with residual weakness. FDA approval for

use of sugammadex in the U.S. could greatly impact future anesthesia practice.

19

References

1. Jones RK, Caldwell, JE, Brull, SJ, Soto RG. Reversal of profound rocuronium-induced

blockade with sugammadex: a randomized comparison with neostigmine.

Anesthesiology. 2008;109:816-824. doi: 10.1097/ALN.0b013e31818a3fee.

2. Khuenl-Brady KS, Wattwil M, Vanacker BF, Lora-Tamayo JI, Rietbergen H,

Alvarez-Gomez JA. Sugammadex provides faster reversal of vecuronium-induced

neuromuscular blockade compared with neostigmine: a multicenter, randomized,

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Questions

1. Traditional neuromuscular reversal agents work by______ and may lead to significant side effects due to the blocking of _______receptors which may result in bradycardia.

a. pseudocholinesterase; muscarinicb. pseudocholinesterase; nicotinicc. inhibiting acetylcholinesterase; muscarinicd. inhibiting acetylcholinesterase; nicotinic

Answer: c

2. Sugammadex is a modified gamma cyclodextrin, which directly encapsulates amino- steroid non-depolarizing neuromuscular agents.

a. true b. false

Answer: true

3. Studies have shown that sugammadex can effectively reverse:a. shallow or deep neuromuscular block from non-depolarizing

neuromuscular agentsb. only when one or more twitches are present from non-depolarizing

neuromuscular agentsc. deep block from depolarizing neuromuscular agentsd. only when one or more twitches are present from depolarizing

neuromuscular agents

Answer: a

4. Studies have found there is no dose response relationship with sugammadex and time to adequate neuromuscular recovery.

a. trueb. false

Answer: false

5. Sugammadex is notably less effective following maintenance anesthesia with a volatile agent compared to maintenance anesthesia with propofol.

a. trueb. false

Answer: false

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6. Potential implications for sugammadex use following rocuronium include:a. potential difficult airwayb. short proceduresc. morbidly obesed. all of the abovee. none of the above

Answer: d

7. Sugammadex must be co-administered with:a. anticholinesterase b. muscarinic antagonistc. both A & Bd. none of the above

Answer: d

8. Research has found that rocuronium duration of action in patients with significant renal dysfunction is:

a. slightly increasedb. slightly decreasedc. no change

Answer: a

9. Studies have found that time to full neuromuscular recovery following sugammadex administration in patients with renal failure is not significantly different that patients with normal creatinine function.

a. trueb. false

Answer: true

10. The FDA denied approval of sugammadex during initial drug approval due to:a. morbidity and mortality during initial drug studiesb. increased incidence of perioperative myocardial ischemia/infarctionc. unknown potential hypersensitive reactions and coagulation events

Answer: c

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11. Metabolism and elimination of aminosteroid non-depolarizing agents occur via:a. hepatic and renal routesb. plasma esterasec. 1st pass effectd. diffusion

Answer: a

12. Neostigmine works by suppressing breakdown of acetylcholine and allowing it to accumulate and displace neuromuscular blocking molecules from binding sites on the nicotinic receptors.

a. trueb. false

Answer: true

13. Anticholinergic agents side effects include:a. tachycardiab. bradycardiac. sedationd. blurry visione. a, c, & df. b, c, & d

Answer: e

14. Sugammadex can adequately reverse:a. rocuroniumb. atracurium c. succinylcholine d. all of the above

Answer: a

15. Sugammadex has proven to effectively reverse neuromuscular blocking drugs that are eliminated via Hoffman elimination.

a. trueb. false

Answer: false

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16. Studies have shown that sugammadex is not effective in reversal of shallow neuromuscular blockade

a. trueb. false

Answer: false

17. Succinylcholine is metabolized by:a. acetylcholinesteraseb. pseudocholinesterasec. Hoffman eliminationd. rapid diffusion

Answer: b

18. When T4 is no longer present how many nicotinic receptors are occupied by neuromuscular blocking agent:

a. 0-25%b. 25-50% c. 50-75%d. 70-75%e. 75-100%

Answer: d

19. When assessing level of blockade with a train of four ratio, the ratio is determined by:a. comparing the height of T4 to T1b. comparing the height of T1 to T4c. comparing the height of T4 to T3d. comparing the height of T3 to T4

Answer: a

20. Sugammadex studies indicate a higher incidence of recurization with sugammadex compared to neostigmine

a. trueb. false

Answer: false

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