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Abstract

Since its first human use in 2005, the γ-cyclodextrin sugammadex (Org 25969) has had the potential to become the reversal agent of choice, for rocuronium- or vecuronium-induced neuromuscular blockade. Sugammadex binds to the aminosteroid neuromuscular blocker, encapsulating it and extracting it from the neuromuscular junction, effectively ceasing activity and allowing neuromuscular transmission to recover rapidly. Phases I–III and subsequent trials have found sugammadex to be safe and effective in a wide range of doses and for the reversal of a range of depth of muscle relaxation in healthy volunteers and a variety of disease states. Sugammadex use may allow refinement of anesthetic practice and improvement in surgical conditions, through the maintenance of deep neuromuscular blockade right to the end of surgery, with subsequent rapid reversal. Debate remains about the use of sugammadex in the treatment of rocuronium anaphylaxis and airway emergencies. The high price of sugammadex currently prohibits its routine use, but if the price falls, after expiry of its patent, it may become cost-effective as a readily available agent in certain specific clinical situations. Serious adverse reactions have occurred in less than 1% of patients and are most commonly because of hypersensitivity. No deaths have been reported, but caution is advised in neonates, pediatrics, and pregnancy where data are lacking.

Keywords

sugammadex Bridion safety efficacy rocuronium cyclodextrin

Introduction

Ever since the introduction of curare to anesthesia in the 1940s, neuromuscular blockade has played a pivotal role in facilitating anesthetic, surgical, and critical care practice–- a role that still holds true today.¹

The depolarizing relaxant suxamethonium was first introduced in the early 1950s and was noted to produce rapid profound muscle relaxation within 30 seconds that lasted only a few minutes in the majority of patients.¹ This quick acting, short duration relaxant proved useful for induction of anesthesia by rapid-sequence induction (RSI), where swift placement of an endotracheal tube protects the respiratory tract from gastric content aspiration. Additionally, the short duration of action of suxamethonium gives the anesthetist the option of allowing the patient to recover spontaneous ventilation relatively quickly, should difficulty in securing the airway arise. Unfortunately, suxamethonium is associated with a number of unwanted side-effects, some of which can be fatal such as anaphylaxis, arrhythmias, and malignant hyperthermia. Despite these potential side-effects, no other muscle relaxant possesses properties comparable to suxamethonium for RSI, resulting in its continued use.²

In 1988, rocuronium was found to achieve intubating conditions almost as rapidly as suxamethonium (within 60 seconds) if administered in a sufficiently large dose (1.2 mg/kg). It has therefore become popular as an alternative neuromuscular blocker for RSI.³ However, the intermediate duration of action of the intubating dose of rocuronium (60–90 minutes) is an obvious disadvantage for short surgical procedures and can create serious problems should there be unexpected difficulty in securing the airway.

The acetylcholinesterase inhibitor, neostigmine increases the availability of acetylcholine at the neuromuscular junction. It is used in combination with glycopyrrolate (which in turn antagonizes the muscarinic side-effects of neostigmine) to reverse the action of competitive non-depolarizing muscle relaxants such as rocuronium. However, it is only effective once recovery from the non-depolarizing agent has been established, at least the second twitch (T2) on train-of-four (TOF).⁴ Neostigmine as a reversal agent is slow (increasing risk of residual neuromuscular block post-operatively) and not able to immediately reverse a non-depolarizing muscle relaxant.^5–7 As a consequence, research continued for the ideal reversal agent, one that is rapid without residual neuromuscular blockade, can completely reverse any depth of neuromuscular block, and is free from muscarinic effects.

In 2001, a modified γ-cyclodextrin, sugammadex (Org 25969) was discovered by Bom et al.^8,9 This bound to rocuronium in a 1:1 ratio decreasing its plasma concentration to zero.^8–11 Sugammadex quickly inactivated rocuronium by encapsulation, reversing its neuromuscular blocking effects. A number of animal studies followed, which confirmed the effectiveness of sugammadex at reversing aminosteroid muscle relaxants (with the greatest effect on rocuronium followed by vecuronium and pancuronium).^12–19 In 2005, the first exposure of sugammadex to human volunteers was reported to be safe and effective.²⁰ In 2008, the European Medicines Agency (EMEA) approved sugammadex for clinical use with many other countries throughout the world following suite. The American Food and Drug Administration (FDA), however, did not approve sugammadex because of concerns over hypersensitivity in some subjects, and sugammadex remains currently unavailable in the United States (US).¹⁰

This review discusses the safety and efficacy of sugammadex.

Metabolism and Pharmacokinetic Profile

Sugammadex (Org 25969) is chemically described as per-6-(2-carboxyethylthio)-per-6-deoxy-γ-cyclodextrin sodium and belongs to the γ-cyclodextrin family.^13,21 It is licensed worldwide (except the US) to reverse any depth of neuromuscular block, induced by rocuronium or vecuronium in adults and children greater than two years of age.²² It is manufactured by the drug company Merck Sharp and Dohme (MSD)–-N.V. Organon in the Netherlands and Organon Ltd in Ireland.^8,19 The trade name for sugammadex is Bridion (100 mg/mL), and it can be obtained in 2 mL (200 mg) and 5 mL (500 mg) vials. The vial solution can be diluted further with 0.9% saline, which can be particularly useful in pediatrics. The molecular weight of sugammadex is 2178 Da, and 9.7 mg of sodium is present per milliliter. It is administered intravenously over 10 seconds as a single bolus injection. The pH of solution is 7–8 and the osmolality 300–500 mOsm/kg. Sugammadex is highly water soluble, with a volume of distribution of approximately 11–14 L in adults with normal renal function. Sugammadex and the sugammadex–-rocuronium complex bind negligibly to plasma proteins and erythrocytes.²² Physical incompatibility between sugammadex and verapamil, ondansetron, and ranitidine has been reported and requires a saline flush between administrations if the same intravenous access is to be used.

When administered as an intravenous bolus dose, sugammadex exhibits linear pharmacokinetics in the dose range 0.22–16 mg/kg. Many dose–-response studies have investigated a variety of dosage permutations of sugammadex (0.5–96 mg/kg) with rocuronium (0.6, 0.9, 1.0, 1.2 mg/kg) or vecuronium (0.1 mg/kg) with and without maintenance doses.^5,22–40 For routine reversal of neuromuscular blockade with rocuronium or vecuronium, a dose of 4 mg/kg is recommended if recovery reaches one to two post-tetanic counts and 2 mg/kg if there is spontaneous recovery to at least T2. The median time to recovery of the T4/T1 ratio to 0.9 is about three minutes.²² For immediate reversal of rocuronium-induced blockade, 16 mg/kg of sugammadex is recommended. If this is given three minutes after a bolus of 1.2 mg/kg rocuronium for RSI, the median time to recovery of the T4/T1 ratio to 0.9 is approximately 1.5 minutes.^41,42 In the exceptional event of post-operative recurrence of neuromuscular block, a repeat dose of 4 mg/kg of sugammadex is recommended, with close patient monitoring, after an initial 2 or 4 mg/kg dose. There is currently no data to recommend sugammadex for the immediate reversal of vecuronium.^22,43

It is possible that clinical circumstances might require further relaxation with rocuronium after the initial reversal of neuromuscular blockade with sugammadex. If reversal had been done with up to 4 mg/kg sugammadex, it is recommended to wait five minutes before re-administering a dose of 1.2 mg/kg of rocuronium or to wait four hours, after which a dose of 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium may be used to achieve blockade.⁴⁴ If the initial reversal with sugammadex was with a dose of 16 mg/kg, then the recommendation is to wait 24 hours before reusing rocuronium or vecuronium. If repeat relaxation is required urgently, an alternative non-aminosteroid neuromuscular blocking agent may be used instead; delay is not necessary.

The effective half-life of sugammadex in adults with normal renal function is approximately 2.5 hours, and the estimated plasma clearance is about 75 mL/minute (using a three-compartment model). Metabolism of sugammadex in preclinical studies was found to be minimal, with renal excretion of the unchanged molecule being the predominant route of elimination.

Pharmacokinetic parameters can be calculated from the total sum of non-complex-bound and complex-bound concentrations of sugammadex. Parameters such as clearance and volume of distribution are assumed to be the same for non-complex-bound and complex-bound sugammadex in anesthetized subjects.²² A number of pharmacokinetic and pharmacodynamic models have been developed for sugammadex in an attempt to predict more accurate dosing and aminosteroid neuromuscular block reversal.^45,46

Special Populations

Renal failure

In patients with normal renal function, more than 90% of the sugammadex given is excreted within 48 hours, with 96% of the dose being excreted in the urine.^34,47 At least 95% of the excreted dose is unchanged sugammadex.⁴⁷ Excretion via feces and via expired air is negligible (<0.02% of the dose).⁴⁷ Normally, rocuronium is predominantly eliminated via biliary excretion (75%) and to a lesser extent by renal and fecal routes.³ However, when sugammadex is given to patients who have received rocuronium, there is increased renal elimination of rocuronium in complex with sugammadex. Urinary excretion is the major route of elimination of the sugammadex–-rocuronium complex.³⁰ Sugammadex is not currently recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/minute) as elimination can be significantly delayed and result in a prolonged duration of action (.24 hours), which may be problematic if further doses of aminosteroid are to be given.^22,48,49 There is also data suggesting that neuromuscular block reversal is slower with sugammadex in severe renal impairment, although no firm conclusions have yet been made and warrant further investigation.^50,51 Despite this, sugammadex use in end-stage renal failure appears to be safe and effective at reversing rocuronium blockade, with a number of cases reporting successful clinical use without adverse effects (AE).^50,52,53 For mild to moderate renal impairment (creatinine clearance >30 and <80 mL/minute), the recommended dosage of sugammadex is the same for patients as those with normal renal function.²² Hemodialysis using a high flux dialysis membrane (sustained low-efficiency daily dialysis (SLEDD)) was found in one study to be effective at removing sugammadex and sugammadex–-rocuronium complex.⁵¹

Gender/race

No gender differences have been observed with sugammadex use. No clinically different pharmacokinetic parameters have been found between Japanese and Caucasian subjects. Limited data indicate no difference in parameters in Black or African Americans.²²

Polymyositis/dermatomyositis

One report has suggested that polymyositis delays sugammadex onset and reversal of rocuronium blockade.⁵⁴ However, in another report, sugammadex (4 mg/kg) was used in a patient with Sjögren's syndrome and polymyositis, to reverse deep neuromuscular blockade, successfully and without delay, following laparoscopic anterior resection.⁵⁵ The authors of this report argue that polymyositis does not affect the neuromuscular junction itself and therefore should not affect the onset of rocuronium action or indeed its reversal with sugammadex. It was postulated that the delayed effect of sugammadex in the first report was because of diminished cardiac output in the elderly patient involved.

Neurological disorders

There are a number of case reports of sugammadex use in patients with various neurological disorders, where recovery from neuromuscular blockade can be variable and blockade prolonged. Sugammadex (2–3 mg/kg) has been used in myasthenia gravis to reverse both rocuronium and vecuronium neuromuscular blockade successfully and rapidly.^56–58 This simplifies anesthetic management and reduces uncertainty of inadequate reversal, which is often seen when anticholinesterases are considered in such patients.^57–62 Patients with myotonic dystrophy show myotonic responses to suxamethonium and neostigmine as well as increased sensitivity to non-depolarizing muscle relaxants.^63–65 One case report describes a patient with myotonic dystrophy who, in 2009, underwent caesarean section where rocuronium (1 mg/kg) was used for RSI.⁶⁶ Owing to depth of blockade at the end of surgery (TOF at T0), neostigmine had been contraindicated. Muscle strength recovered much later, on intensive care, two and half hours post-induction. In 2011, the same patient presented for caesarean section at 38 weeks gestation. Rocuronium (1 mg/kg) was again used as the muscle relaxant for RSI. At the end of surgery, with TOF at T0, sugammadex was used successfully (4 mg/kg) achieving TOF of 0.9 at two minutes allowing uneventful extubation and subsequent recovery. Sugammadex has also been used safely, at recommended doses, for reversal of rocuronium-induced neuromuscular blockade in cases of amyotrophic lateral sclerosis and Huntington's disease.⁶⁷ ⁶⁸

Cardiopulmonary disease

The safety and efficacy of sugammadex for reversal of rocuronium-induced blockade in 77 patients with pulmonary disease was evaluated by Amao et al in 2012.⁶⁹ Doses of 2–4 mg/kg were well tolerated and effective. Bronchospasm occurred in two patients, who received desflurane for anesthesia maintenance. Bronchospasm is a well-known complication of desflurane use particularly in asthmatic patients, and hence, although sugammadex may have been associated with bronchospasm, it is difficult to ascertain blame.⁷⁰ Sugammadex has been used successfully for reversal of rocuronium in a patient with cystic fibrosis and severe bronchiectasis undergoing percutaneous endoscopic gastrostomy.⁷¹ In patients with cardiovascular disease or heart failure, 2–4 mg/kg of sugammadex was found to be safe and effective.^72,73 Effects on blood pressure and heart rate are variable and not clinically significant. Cammu et al showed that in patients with heart failure who received 2 mg/kg of sugammadex to reverse rocuronium (0.6 mg/kg) and maintenance doses of 0.1 mg/kg, neuromuscular function was adequately restored, but longer reversal times were seen (time to TOF ratio of 0.9 was 2.78 ± 0.67 minutes) compared to healthy young patients.⁷³ This delay in recovery may be related to reduced cardiac output effecting sugammadex delivery and action as all patients had an ejection fraction of 25% or less. Sugammadex use in cardiac surgical patients has not been formally evaluated to date but is recommended by some authors.⁷⁴ No significant QT interval (QTc) prolongation was found with sugammadex (4–32 mg/kg).^75–77 Sugammadex has been used successfully in heart transplant recipients.⁷⁸

Pregnancy

The effect of sugammadex in both mother and fetus before delivery time remains unknown, with no robust clinical data in pregnancy available.²² Sugammadex (2–4 mg/kg) has been used successfully after Caesarian section.^79,80 These studies, however, do not confirm safety of sugammadex use and fetal well-being.⁸¹ Sugammadex should therefore be used with extreme caution in pregnancy and only if circumstances make it absolutely necessary. Sugammadex is found in animal breast milk, but it is unknown whether breast milk excretion occurs in humans. MSD states that cyclodextrin absorption is low when administered orally; hence, after a single dose to a breast feeding woman, no effect on the suckling child is anticipated.²²

Elderly

The efficacy and safety of sugammadex (2–4 mg/kg) in the elderly has been investigated in a number of trials.^26,82,83 Recovery time following rocuronium-induced neuromuscular block in two studies was found to be longer in elderly patients (.75 years) than in younger patients (time to TOF ratio of 0.9 was 3.6 vs. 1.3 minutes⁸³ and 3.6 vs. 2.3 minutes,⁸² respectively). It is hypothesized that differences in recovery time seen in the elderly may be because of reduced cardiac output and altered perfusion within tissue compartments, influencing the distribution and redistribution rates of rocuronium and/or sugammadex.^82,83 The onset of rocuronium in the elderly is slower and duration of action prolonged compared with younger patients if renal dysfunction is present. The prolonged action of rocuronium observed in the elderly may be because of slower release from receptors at the neuromuscular junction.⁸⁴ Despite slow recovery to a TOF ratio of 0.9, reversal of rocuronium or vecuronium with sugammadex (2–4 mg/kg) is still much more rapid in the elderly, when compared to neostigmine (50 μg/kg) reversal (3.6 vs. 18.6 minutes, respectively).^85,86 It is currently recommended that the same dose of sugammadex should be used in the elderly as that for healthy adults.²²

Neonates/pediatrics

Data for the infant (.28 days) and pediatric population are limited, with only one study and few cases reported.^26,87–89 No studies have been undertaken in neonates. The pharmacokinetic and pharmacodynamic profile for rocuronium differs not only between children and adults but also between infants and children.⁹⁰ The duration of rocuronium has been found to be prolonged in infants compared to children, with greater potency in infants and less in children, compared to adults.^91–93 For example, Plaud et al found that when 2 mg/kg of sugammadex was given at reappearance of T2 on TOF, to an infant (28 days–23 months, n = 1), children (2–11 years, n = 4), adolescents (12–17 years, n = 6), and adults (18–65 years, n = 5), recovery of TOF ratio to 0.9 was at 0.6, 1.2, 1.9, and 1.3 minutes, respectively.²⁶ Based on this study, sugammadex (2 mg/kg) can be recommended for routine reversal of rocuronium-induced blockade at reappearance of T2 on TOF, in children aged more than two years.²² No recommendation for infants was made because of the low number of participants in this study. Immediate reversal (16 mg/kg of sugammadex) in children or adolescents has not been studied and is not currently recommended.

Liver disease

Studies of sugammadex use in hepatic impairment have not been conducted. Caution is advised in severe liver disease or coagulopathy, as there is potential for sugammadex to cause further derangement in clotting parameters in patients at increased risk of bleeding.²² In patients with mild to moderate liver dysfunction, no sugammadex dose adjustment is advised, as sugammadex excretion is predominantly via the renal route.

Obesity

In morbidly obese patients, sugammadex has been shown to be hugely beneficial in reducing the risk of possible prolonged and residual neuromuscular blockade and associated morbidity.^56,94 It is recommended that dosage is based on actual body weight as generally applied to adults.²² However, this has recently been challenged.^95,96 One study found no significant clinical difference between ideal body weight and actual body weight to calculate sugammadex dosage.⁹⁷

Mechanism of Action

Three naturally occurring cyclodextrins exist, alpha, beta, and gamma, that are composed of six, seven, and eight glucose molecules, respectively. These glucose molecules are linked by alpha-(1–4) bonds in a circular arrangement or truncated cone.⁹⁸ Hydroxyl groups point outward and aid water solubility, whereas the alpha-(1–4) linkages are directed inward creating a lipophilic cavity.^12,19,98 It is this cavity, which allows lipophilic molecules to fit and interact within the cyclodextrin forming an inclusion complex. Cyclodextrins can be used to improve water solubility of insoluble drugs, and to increase drug stability and compatibility. More recently attention has been directed toward drug encapsulation.

Sugammadex is a modified gamma cyclodextrin that has a high affinity for the lipophilic compound rocuronium and other aminosteroids.^9,11 Calorimetry and X-ray crystallography have confirmed that sugammadex forms a complex with rocuronium by binding the rocuronium within the cyclodextrin ring cavity.⁸ Other compounds, eg, exogenous (hydrocortisone) and endogenous steroids (aldosterone) and drugs such as atropine and verapamil, can form complexes with sugammadex, but with significantly less affinity (100–700x weaker), and they are thought not to be clinically significant.^12,99

Sugammadex acts through two mechanisms. On intravenous injection, sugammadex remains in the plasma and rapidly encapsulates any free aminosteroid neuromuscular blocking agent, such as rocuronium within its lipophilic cavity in a 1:1 ratio, drastically reducing the effective plasma concentration of the blocker. This is the first mechanism. Molecules of blocker agent then move down the concentration gradient out of the tissue compartment, of which the neuromuscular junction is a part, and into the central compartment, the plasma. This leads to a rapid decrease in the occupation of nicotinic acetylcholine at the neuromuscular junction. It is this second mechanism of mass extraction from the nicotinic junction into the plasma that results in recovery of neuromuscular function.²² The diffusion gradient between compartments is maintained until either all the rocuronium is held in sugammadex–-rocuronium complex in the plasma or until all the sugammadex molecules are saturated. Assays cannot distinguish between free rocuronium and its complex with sugammadex; hence, the movement of rocuronium from the tissue compartment to the plasma appears as an increase in total plasma rocuronium concentration. Renal clearance of rocuronium is limited. However, the sugammadex–- rocuronium complex is eliminated predominantly by renal excretion; hence after treatment with sugammadex, there is an increase in the proportion of the original rocuronium dose recovered in the urine.^30,100

Clinical Studies and Efficacy

Since 2002, multiple Phase I–-III studies have been undertaken to assess the safety and efficacy of sugammadex.^12,74

Phase I (safety and efficacy)

Following animal studies, the first documented human study of sugammadex was undertaken by Gijsenbergh in 2005.^20,101 A total of 29 healthy male volunteers were given sugammadex (0.1–8 mg/kg) as part of a randomized trial without any serious adverse effects (SAE) (see Safety section). In all, 19 subjects were given sugammadex or placebo only, during one to three treatment periods each. The remaining 10 volunteers underwent total intravenous general anesthesia with propofol, remifentanil, and rocuronium (0.6 mg/kg) on two separate occasions. Three minutes following administration of rocuronium, each patient received either placebo or a single dose of sugammadex (0.1–8 mg/kg). Neuromuscular monitoring was continued until full recovery from anesthesia (at least 90 minutes after sugammadex or until TOF ratio of 0.9 was achieved). Sugammadex was found in all 29 patients to be well tolerated and effective in reversing rocuronium-induced neuromuscular blockade. When 8 mg/kg of sugammadex was given, the TOF returned to 0.9 within two minutes.

The above study did, however, raise some concerns over possible QTc prolongation. The International Conference on Harmonization (ICH) E14 set a lower and upper safety margin (5 and 10 milliseconds) for mean difference in corrected QTc interval change (QTcl). De Kam et al evaluated the effect of placebo, moxifloxacin (positive control), and sugammadex alone (4 and 32 mg/kg) as well as in combination with rocuronium (1.2 mg/kg) and in combination with vecuronium (0.1 mg/kg).^20,77,102 The QTcl prolonged to 20.8 milliseconds after moxifloxacin (positive control) but was not found to exceed the upper limit of 10 milliseconds after sugammadex alone or in combination with either relaxant. A further study by the same authors in 2013 reported no significant QTc prolongation with sugammadex use, under general anesthesia with either sevoflurane or propofol.¹⁰³

Cammu et al. anesthetized 12 healthy subjects and found sugammadex to be safe and well tolerated following single doses of sugammadex (16, 20, or 32 mg/kg) in combination with 1.2 mg/kg of rocuronium and 0.1 mg/kg of vecuronium.⁷⁶ No serious adverse events were reported although some patients complained of minor effects such as headache, tiredness, feeling cold, dry mouth, and nausea (see Safety section).

Peeters et al randomized 13 healthy adults to receive three intravenous doses of sugammadex (in ascending order 32, 64, and 96 mg/kg) and placebo (interspersed between sugammadex doses), each separated by a one-week washout period.³⁴ High doses of sugammadex (up to 96 mg/kg) were well tolerated in 12 out of 13 subjects. One male patient had a suspected hypersensitivity reaction to sugammadex.

Phase II (dose-finding)

A number of phase II studies, which included more than 800 patients, were undertaken in both Europe and the US to investigate dose-related effectiveness and safety of sugammadex. In 2005, the first results of phase II findings were presented at the European Society of Anaesthesia Congress, Vienna, Austria.¹² From these studies, sugammadex in doses of 4–16 mg/kg was found to be very effective at reversing both rocuronium-induced (0.6, 0.9, and 1.2 mg/kg) and vecuronium-induced (0.1 mg/kg) neuromuscular blockade.^{24,25,30,33,35,36,43,104–106} Aminosteroid dosage, time of sugammadex administration dependent on TOF recovery, or time since neuromuscular blockade administration were all varied, with numerous permutations investigated. Sugammadex (4 mg/kg) given at reappearance of T2 on TOF, after rocuronium (0.6 mg/kg) blockade, reduced the time of reversal to TOF ratio of 0.9, from 21–32 minutes with placebo, to 1.1 minutes.³⁰ With vecuronium-induced (0.1 mg/kg) blockade, TOF ratio of 0.9 was reduced from 49 minutes with placebo to 1.4 minutes with sugammadex (4 mg/kg).²⁴ After profound/deep rocuronium blockade (1.2 mg/kg), sugammadex (16 mg/kg) reduced recovery time to TOF ratio of 0.9 from 124.3 to 1.3 minutes, when administered three minutes after the initial rocuronium dose.¹⁰⁶

There was evidence of block recurrence when low doses of sugammadex (<2 mg/kg) were used indicating sub-optimal dosing.³⁵ In one study, the lowest dose group (0.5–1 mg/kg) in several patients could not adequately reverse rocuronium-induced blockade.²⁵ At 2 mg/kg, all patients were reversed with sugammadex but with marked variability (1.8–15.2 minutes).

Phase III (post-dose-finding studies/further data on safety and efficacy)

The efficacy and safety of sugammadex was further investigated in a number of trials in a variety of different clinical settings and patient groups (see Special Populations section). A Cochrane review in 2008 concluded, from 18 randomized controlled trials (RCTs) comprising more than 1321 adult patients (18 years and older), that sugammadex (2, 4, and 16 mg/kg) compared to placebo or neostigmine was effective in rapidly reversing rocuronium-induced neuromuscular blockade regardless of the depth of block.⁵ No difference in the incidence of unwanted effects between sugammadex, placebo, and neostigmine was found. Serious adverse events occurred in less than 1% of patients who received sugammadex. Further phase III studies were undertaken since this Cochrane review, some of which are discussed below:

•

Reversal of profound neuromuscular block (rocuronium/vecuronium) (TOF ratio zero or <T2, post-tetanic count 1–2): Lee et al compared time to sugammadex (16 mg/kg) reversal of profound rocuronium-induced neuromuscular block (1.2 mg/kg) with time to spontaneous recovery from succinylcholine (suxamethonium) (1 mg/kg).⁴¹ Reversal to 90% T1 with sugammadex was found to be significantly faster than spontaneous recovery from succinylcholine (6.2 vs. 10.9 minutes, P < 0.001). In another study, sugammadex doses of 4 mg/kg or higher were found to provide rapid reversal of deep rocuronium-induced (0.9 mg/kg) and vecuronium-induced (0.1 mg/kg) neuromuscular blockade under sevoflurane maintenance anesthesia.²³ Lemmens et al found recovery from profound vecuronium-induced (0.1 mg/kg) blockade was significantly faster when sugammadex (4 mg/kg) was given, at 1–2 post-tetanic counts, compared to neostigmine (70 μg/kg) or glycopyrrolate (14 μg/kg), with mean recovery time to TOF ratio of 0.9 being 4.2 and 66.2 minutes, respectively.¹⁰⁷ Rex et al investigated the effectiveness of sugammadex following continuous infusion of rocuronium (7 μg/kg/minute after an initial bolus of 0.6 mg/kg), under both propofol or sevoflurane anesthesia.³⁷ The infusion was adjusted to maintain a profound block of zero on TOF response and no more than 10 responses on post-tetanic stimulation. A single dose of 4 mg/kg sugammadex administered at the first twitch (T1) effectively reversed profound rocuronium blockade to TOF ratio of 0.9 within a mean time of 1.25 minutes.

•

Reversal of moderate (T2 or greater) and shallow (TOF ratio >0.5) neuromuscular block: A number of controlled trials have shown sugammadex to be effective at reversing rapidly rocuronium- or vecuronium-induced neuromuscular blockade, when administered during moderate (T2 or greater) or shallow blockade (TOF ratio >0.5).^5,32,35,108 Sugammadex, 0.22 mg/kg, was found to be the dose required to reverse a TOF ratio of 0.5 residual-shallow block, to 0.9 or higher, in an average time of two minutes.³² In comparison, neostigmine 34 μg/kg was required to reverse a TOF ratio of 0.5–0.9 or higher, within five minutes.

•

Sugammadex versus neostigmine for reversal: A number of studies have been conducted assessing the effectiveness of sugammadex reversal of rocuronium or vecuronium compared to neostigmine (50 μg/kg) with glycopyrrolate (10 μg/kg).^86,109 These studies found that when sugammadex (2 mg/kg) was administered on reappearance of T2 on TOF, time to recovery to TOF ratio of 0.9 was achieved significantly faster with sugammadex compared to neostigmine (1.5–2.7 minutes vs. 17.9–18.6 minutes, P < 0.0001, respectively).

•

Special populations: See Special Populations section for full discussion. Sugammadex has been used in many different patient populations, as well as in pediatrics and in different pathophysiological conditions, including renal failure.^12,22,26,74 Sugammadex use is not recommended in neonates and pregnant women, because of lack of clinical trials and evidence in these populations. To date, sugammadex (4–16 mg/kg) has been found to be effective for reversal of rocuronium-induced blockade in all patient groups that have been studied. Evidence of sugammadex reversal of vecuronium/pancuronium is limited.

Clinical Studies (Post-marketing) and Sugammadex Indications

Post-marketing, many studies have been undertaken worldwide since 2008, with the aim of investigating further the role and indications for sugammadex in clinical practice. From these studies, the clinical indications for sugammadex use have been growing, with potential benefits being applicable to many areas of anesthesia and critical care as discussed below.

Reversal of any depth of rocuronium- or vecuronium-induced neuromuscular blockade

Studies continue to confirm rapid reversal of rocuronium or vecuronium with sugammadex in clinical practice (See Clinical Studies and Efficacy section).¹¹⁰

RSI and airway rescue (can't intubate, can't ventilate (CICV))

An unanticipated difficult or failed airway following RSI is an anesthetic/critical care emergency. Immediate reversal and spontaneous breathing following RSI with propofol (2 mg/kg) and either rocuronium (1 mg/kg) followed later by sugammadex (16 mg/kg) or suxamethonium (1 mg/kg) was assessed.¹¹¹ Median time from tracheal intubation to spontaneous ventilation was 406 seconds with suxamethonium and 216 seconds with rocuronium–-sugammadex complex (P = 0.002). Early re-establishment of spontaneous ventilation and oxygenation may be lifesaving in a CICV situation. In one case report by Paton et al, in which jet ventilation via cricothyroidotomy failed after 0.6 mg/kg of rocuronium had been given, swift administration of sugammadex allowed return of spontaneous ventilation and resolution of the situation, thus avoiding surgical airway rescue.¹¹² In this case, 6 mg/kg of sugammadex was used successfully when the patient had received 0.6 mg/kg of rocuronium. This is significantly less than the recommended 16 mg/kg for these situations. Although other case reports have indicated similar success, failure has been reported. In one case, sugammadex was given following failed intubation, but despite complete reversal of rocuronium, the airway remained unmanageable necessitating rapid surgical intervention.^113–116 Debate on sugammadex use in these clinical situations continues. The emerging consensus is that sugammadex should not be relied on as a “magic bullet” for the management of a difficult airway, but that prevention of airway failure through anticipation of difficulty, preparation and rescue plan should be the focus.^117–121 Although sugammadex should be immediately available for use in these situations, it should be noted that a simulation study showed that the time for drug preparation and administration (mean 6.7 minutes), and drug action to TOF ratio of 0.9 (2.2 minutes) may be too long (8.9 minutes in total) to prevent patient morbidity and mortality.¹¹⁷

Surgery specific benefits

Deep neuromuscular block has been found to improve the quality of surgical conditions compared with moderate block in retroperitoneal laparoscopic procedures.¹²² The ongoing BLISS trial aims to investigate two groups: Group 1–-deep (rocuronium) and Group 2–- moderate (atracurium/mivacurium) neuromuscular block in patients undergoing laparoscopic renal or prostate surgery and reversal with sugammadex (4 mg/kg) in Group 1 or neostigmine/atropine in Group 2.¹²³ Sugammadex use enables rapid reversal of deep neuromuscular block to be feasible, and it is this property that is being utilized in many surgical situations, particularly in day case and fast-track procedures, and bariatric, ophthalmic, laparoscopic general, and intra-operative spinal surgery.^124–127 There is an indication for sugammadex use to reverse rapidly profound rocuronium blockade post-Caesarean section.⁸⁰

Resolution of rocuronium anaphylaxis

There have been a number of case reports of rocuronium-induced anaphylaxis, where sugammadex administration, along with resuscitative efforts, has significantly improved clinical parameters and/or outcome.^128–132 Sugammadex may be a useful adjunct to managing rocuronium-induced anaphylaxis.¹³³,¹³⁴ However, one cutaneous model disputes sugammadex use in this situation, warranting the need for further studies.^135–137

Electroconvulsive therapy

Sugammadex has been used successfully for rocuronium reversal after electroconvulsive therapy (ECT) with lower rates of myalgia and headache reported, as well as faster awakening time, compared to suxamethonium.^138–140

Other studies of interest

•

Sugammadex and bispectral index (BIS): Reversal of rocuronium-induced blockade may spuriously increase the BIS value because of the effect of muscle activity reappearance and should be taken into account when using BIS to prevent awareness under total-intravenous anesthesia.¹⁴¹,¹⁴²

•

Sugammadex and electrolytes (magnesium/potassium): Two clinical trials have been completed recently, but not yet reported. One investigated whether perioperative magnesium sulfate use has any effect on sugammadex efficacy.¹⁴³ The second assessed whether any changes in potassium levels occurred after treatment with rocuronium, sugammadex, or succinylcholine in adults for short surgical procedures.¹⁴⁴

•

Residual neuromuscular block: Residual neuromuscular blockade or post-operative residual curarization (PORC) has been investigated extensively and remains a hot topic. One study found that the incidence of PORC was high at 39%.¹⁴⁵ Illman et al assessed the time gap between loss of visual fade by using peripheral nerve stimulation until objective TOF has returned to >0.90, this being the “potentially unsafe period of recovery,” where the patient may not have full control over pharyngeal and respiratory muscles.⁴⁰ A significant time gap was found with reversal of rocuronium by neostigmine compared to sugammadex, suggesting that sugammadex allows safer reversal and reduced PORC risk. Kotake et al found that monitoring of TOF is crucially important when sugammadex is used for reversal of rocuronium-induced neuromuscular block, as risk of PORC and TOF <0.9 after tracheal extubation remained as high as 9.4% in cases where neuromuscular monitoring was not used.¹⁴⁶ Pongracz et al argue that PORC can still occur with TOF ratio at 0.9 (normally deemed satisfactory recovery). They therefore investigated the time taken from the administration of sugammadex, once rocuronium blockade had recovered spontaneously to fourth twitch on TOF (T4) to TOF 1.0.³¹ 1–2 mg/kg of sugammadex was found to rapidly and effectively reverse rocuronium-induced blockade that had recovered spontaneously to a threshold T4 count within five minutes, significantly reducing the risk of PORC when compared to neostigmine. Pavoni et al used myogenic motor-evoked potentials (mMEPs) to assess sugammadex for reversing rocuronium-induced blockade. They found that sugammadex (16 and 4 mg/kg) provided complete recovery from “profound” (1.2 mg/kg of rocuronium) and “deep” (0.6 mg/kg of rocuronium) blockades.¹⁴⁷

Costs and Economic Evaluation

A small number of studies have evaluated the economics of sugammadex use for rocuronium/vecuronium reversal in clinical practice raising much debate.^10,148–151 No study has yet assessed fully the clinical impact of sugammadex on perioperative and long-term morbidity and mortality. This is largely because of the difficulty in designing such a study.¹⁵² At the time of writing, sugammadex was priced at £29.82 per milliliter (100 mg/mL) in the UK.¹⁵³ The cost of use ranged from £41.75 (2 mg/kg), £83.49 (4 mg/kg), and £333.98 (16 mg/kg) per dose, in a 70 kg patient, depending on how sugammadex was utilized. The higher cost of sugammadex compared to other reversal agents has prevented sugammadex from becoming the routine reversal agent of choice in many countries.¹⁵²

When reversing profound rocuronium blockade, sugammadex has been shown to reduce time to TOF ratio of 0.9 by 47.5 minutes when compared to neostigmine and glycopyrrolate.¹⁴⁹ Reduction in reversal time has the potential to reduce time in theatre, which may translate into a cost saving through increased theatre efficiency and throughput.¹⁴⁹ However, despite potential cost savings with reversal time reduction, when the cost of the sugammadex dose is factored in, most cases make a net loss, particularly if high doses are used (>4 mg/kg). Cost savings in theatre and recovery are dependent on every minute (theatre staff members are estimated to cost £4.44/minute) and thus are influenced by many factors such as theatre set-up, staff efficiency, patient co-morbidity, and not just time to neuromuscular block reversal.

Caldwell et al suggest that sugammadex use may justify the cost, if used in situations where there is no alternative, such as during an airway crisis or to prevent ICU admission.¹⁰ The benefits of profound rocuronium block producing excellent surgical conditions combined with the ability for rapid reversal once surgery has finished may produce a cost saving if the surgeon is able to operate more quickly and effectively when aided by profound blockade.

Kakinuma et al attempted to reduce costs by combining a reduced dose of sugammadex (0.5 mg/kg) and neostigmine/atropine.¹⁵⁴ A total of 40 patients were intubated without relaxant using remifentanil and propofol and then given rocuronium (0.6 mg/kg). Five minutes after rocuronium administration, patients were given either 0.5 mg/kg of sugammadex, 0.04 mg/kg of neostigmine, and 0.02 mg/kg of atropine or 1 mg/kg of sugammadex. Recovery time to TOF ratio of 0.9 was 18.8 and 29.9 minutes, respectively (cost $36.87 vs. $24.76). Despite saving about 10 minutes when using combined sugammadex and neostigmine/atropine, the time to recovery was still long. A dose of 0.5 mg/kg of sugammadex was found in other studies to produce inadequate reversal. Combination in this way may save some time, but the doses used are not recommended because of under-dosing, with the risk of residual neuromuscular blockade and the unnecessary exposure of the patient to the side-effects of both drugs, in particular those associated with anticholinesterase use.

In Perth, Ledowski et al reported the impact of sugammadex and associated healthcare costs by comparing one month of unrestricted sugammadex use in 2011 with restricted access over one month in 2010.¹⁵⁰ Sugammadex use rose by 743% in 2011, with a 48% reduction in glycopyrrolate and neostigmine use, compared to that in 2010. No differences were found in anesthesia duration, operating time, or time spent in the post-anesthesia care unit, despite an increased ($85) cost per case for muscle relaxation and reversal. A significant decrease in time between surgery and discharge (median 2.0 vs. 2.2 days) was found and could not be explained.

Further investigation and economic studies are required to justify the high price of sugammadex in clinical practice. Routine reversal with sugammadex may occur in the future when the drug comes off patent and the price drops. However, until this occurs, access is likely to be restricted, particularly during times of austerity when healthcare budgets are being scrutinized.

Safety

The safety profile for sugammadex remains to be confirmed. Cyclodextrins have various roles: in the food industry as dietary fibers, in the pharmaceutical industry as solubilizing agents, and in the cosmetic industry for reducing odors and fragrances. As a group, they are considered to be relatively inert.^22,155 Sugammadex is one of the first cyclodextrins to be used primarily as a medicinal product. Doses of sugammadex used clinically are low, in comparison to other medicinal products that use cyclodextrins as excipients, such as VFEND^® (voriconazole, Pfizer¹⁵⁶) and SPORANOX^® (Itraconazole, Janssen-Cilag¹⁵⁷), reducing overall cyclodextrin exposure to the patient.

In 2008, the FDA rejected the initial new drug application (NDA) for sugammadex, requesting additional data from MSD, in regards to potential hypersensitivity reactions and an increased risk of bleeding events. MSD resubmitted this application in January 2013, with further rejection in September 2013 because of concerns about operational aspects of a hypersensitivity study. The flaws in this study design have not currently been made public.¹⁵⁸ The NDA included non-clinical safety data, which stated that in rat studies sugammadex had bound to mineralized tissues such as bone and teeth (especially in young rats) but had demonstrated no intrinsic pharmacological activity, genotoxicity, reproductive toxicity, or teratogenicity and therefore did not represent a risk to humans. The risk to bones and teeth was followed up with subsequent studies not demonstrating an increased risk of fractures or risk to bone development in rats. The human clinical trial data submitted compared sugammadex against placebo and neostigmine, as well as being used to reverse rocuronium and vecuronium. These trials demonstrated that sugammadex doses of up to 96 mg/kg were well tolerated.³⁴ The NDA included a case study report of a healthy volunteer, with no history of allergy, developing paresthesia, visual disturbance, rash, stomach discomfort, palpitations, nausea, tachycardia, and flushing while receiving a sugammadex 8.4 mg/kg infusion. The infusion was discontinued, and the symptoms spontaneously resolved. Follow-up skin tests concluded that the subject was probably allergic to sugammadex. MSD completed a follow-up skin test trial with six subjects (healthy volunteers) of previous clinical trials that had shown potential hypersensitivity symptoms to sugammadex (five consented) compared to a control group who had not been exposed to sugammadex. In both groups, one subject showed positive skin test results.¹⁵⁹

The EMEA acknowledged the potential for hypersensitivity reactions to sugammadex, but stated that “sugammadex's benefits outweighed the risks” and approved its market authorization in July 2008.¹⁶⁰

The first published clinical trial in humans was by Gijsenbergh et al in 2005.²⁰ In all 29 subjects, there were no reported SAE. AE were reported with the most significant being paresthesia in the forearm at the site of the cannula, which developed after a sugammadex 8 mg/kg dose and lasted for seven days. Except for the paresthesia, all AE were of mild intensity and required no treatment. QTc prolongation (.450 milliseconds) was also reported in eight cases, six of which occurred when reversing rocuronium anesthesia. Doses up to 8 mg/kg of sugammadex were well tolerated, and the AEs that occurred were not considered clinically relevant.

Following this initial trial, several studies have investigated the safety of different dosage regimens of sugammadex, when used with different anesthetic agents and doses. These included studies by Shields et al who administered 0.5–6 mg/kg of sugammadex two hours after prolonged anesthesia and rocuronium,³³ de Boer et al who used high dose rocuronium (1.2 mg/kg) in anaesthetized patients and then administered 16 mg/kg of sugammadex five minutes later,⁴² and Suy et al who randomized patients following general anesthesia, to receive rocuronium, vecuronium, or placebo, and then administered 4 mg/kg of sugammadex.²⁴ All three papers reported no SAE.

Sacan et al compared the efficacy and safety of sugammadex against alternative neuromuscular blocker antagonists.³⁸ This involved 60 elective surgery patients anaesthetized with desflurane–-remifentanil–-rocuronium combination and then administered either 4 mg/kg of sugammadex, 1 mg/kg of edrophonium with 10 μg/kg of atropine or 70 μg/kg of neostigmine with 14 μg/kg of glycopyrrolate for reversal. The neostigmine/glycopyrrolate group had significantly higher heart rates. The sugammadex group had a significantly lower incidence of dry mouth, when compared against the other two groups.

The summary of product characteristics (SPC) for sugammadex by MSD states that hypersensitivity reactions are the only contraindication to sugammadex use (risk less the 1%).²² Sugammadex hypersensitivity reactions have occurred at low and high doses.¹⁶¹ A case report in 2010 by Menendez-Ozcoidi et al reported a single case study of a 17-year-old male who received 3.2 mg/kg of sugammadex dose.¹⁶¹ Within one minute of administration, he developed intense thoracic erythema, severe lip and palpebral edema, and bilateral wheeze. On allergy testing, he had a positive skin prick test to sugammadex. The patient had a history of mild asthma, and this may have predisposed him to an atopic response to sugammadex. Previous cyclodextrin exposure via food products may have caused prior sensitization.

In 2012, Godai et al reported three case studies of suspected sugammadex-related hypersensitivity reactions.¹⁶² All three cases involved female patients undergoing elective surgery. The dose of sugammadex ranged from 1.9 to 2.2 mg/kg, which is considered a low licensed dose. The reactions all occurred three to four minutes after receiving sugammadex. The reactions varied between cases. Case 1 developed a local reaction, facial erythema and blepharedema; but no systemic reaction. Case 2 developed hypotension, tachycardia, and generalized erythema. Case 3 developed a clinically severe reaction, with respiratory wheeze, associated oxygen desaturation, and localized erythema over her arm. Cases 1 and 2 had positive skin tests to sugammadex, whereas case 3 declined testing. The authors acknowledge that without immunology testing, case 3 could be because of a non-immunological cause. Adverse reactions observed in these three cases could not fully exclude other potential allergens as a cause (eg, opioidmediated histamine release, antibiotics, latex, colloids, and surgical disinfectants).

The FDA rejected the initial NDA for sugammadex because of concerns over possible hemostasis effects. Volunteers who received sugammadex (4 and 16 mg/kg) had a mean prolonged activated partial thromboplastin time (APTT) by 17 and 22% and prolonged prothrombin time to international normalized ratio (PT:INR) by 11 and 22%, respectively. These effects lasted for ≤30 minutes. In trials with patients undergoing joint replacement surgery (with and without anticoagulants), the incidence of bleeding was not clinically significant.¹⁵⁵ No clinically relevant reduction in platelet aggregation was found when 4 mg/kg of sugammadex was used in addition to aspirin.¹⁶³

Reported anesthetic complications associated with sugammadex use include limb movement, coughing, grimacing, sucking on the endotracheal tube, and light anesthesia or awareness. These complications have been attributed to trial design or residual blockade, with sugammadex being administered too soon or sub-optimal dosing after neuromuscular blockade. Awareness or insufficient depth of anesthesia has also been reported with neostigmine, where it has been hypothesized that rapid neuromuscular block reversal, combined with surgical stimulus, can cause increased cerebral stimulation and motor signs.⁵

QT interval (QTc) prolongation had been identified as AE related to sugammadex administration in early clinical trials, and this is acknowledged by MSD in the applications to the FDA and EMEA. One study by Rex et al investigated the use of 16 mg/kg of sugammadex to reverse high dose (1.2 mg/kg) of rocuronium and reported an incidence of QTc prolongation.¹⁶⁴ This was further investigated by Dahl et al who used sugammadex in cardiac patients.¹⁶⁵ The trial recruited 121 patients and used 2–4 mg/kg of sugammadex to reverse rocuronium-induced neuromuscular blockade. There was no evidence of significant QTc prolongation in any patient on electrocardiogram, during this study. In 2013, de Kam et al reported another study investigating any effect of sugammadex (4 mg/kg) on QT/QTc interval prolongation when combined with QTc-prolonging sevoflurane or propofol anesthesia.¹⁰³ Sugammadex (4 mg/kg) was found not to cause any clinically relevant QTc interval prolongation compared to placebo when combined with propofol or sevoflurane.

MSD recommends that the sugammadex dose does not need to be adjusted in patients with mild renal impairment (CrCl from ≥30 mL/minute to <80 mL/minute) but need not be used in patients with severe renal impairment (CrCl <30 mL/minute) or receiving dialysis.¹⁵⁵ The basis for this was a trial consisting of 30 patients by Staals et al where two groups (CrCl <30 mL/minute (15 patients) and CrCl ≥80 mL/minute (15 patients)) each received a 2 mg/kg of sugammadex dose.⁵⁰ The safety profile in the renal impairment group was not appreciably different from the control group, but clearance was reduced 17 fold.

In patients with pulmonary disease, sugammadex was found to be safe and effective. However, Amao et al had two SAE when bronchospasm occurred in two asthmatic patients close to extubation (1 minute and 55 minutes later) and successfully treated each with bronchodilators.⁶⁹ The authors did not attribute the bronchospasm to sugammadex.

The licensed dose of sugammadex for reversal of neuromuscular blockade is 2–16 mg/kg as a single intravenous bolus. Phase I clinical trials used doses up to 96 mg/kg in healthy volunteers in human tolerance tests.¹⁵⁹ During a phase III trial by Molina et al, a single patient was accidentally administered 40 mg/kg of sugammadex when reversing 1.2 mg/kg of rocuronium.¹⁶⁶ In this case, no SAE or AE were observed.

Within pediatric practice, data on sugammadex use are limited. Sari et al conducted a retrospective study of 46 pediatric patients (aged between 28 days and 17 years) who received sugammadex (2 mg/kg) to reverse rocuronium blockade (0.6 mg/kg) in anesthetized patients within their institution.¹⁶⁷ No hypersensitivity or statistically side-effects correlated to sugammadex were observed. Further safety studies are warranted.

Theoretically, molecules with a high affinity for sugammadex (toremifene, fusidic acid) could interact and displace any complexes (rocuronium–-sugammadex) previously formed.^22,168 This could result in free rocuronium for example, being re-released with recurrence of neuromuscular blockade. Disastrous complications with significant patient harm could be seen if this were to occur post-operatively and unnoticed. Studies to date have shown no recurrence of neuromuscular blockade through displacement (flucloxacillin, diclofenac), but vigilance is still advised by MSD.^22,168 Sugammadex could affect the efficacy of other medicinal products through capture interactions and thus lower drug levels. Both progesterone and estrogen levels may be reduced, affecting the efficacy of contraceptive delivery (oral and depot), warranting the patient to use an additional method of contraception at least one week post-sugammadex.²²

Penetration of the blood brain barrier by sugammadex is poor (<3% in rats), and thus, no central nervous system toxicity is expected. However, one safety issue has been raised by Palanca et al who found that clinically relevant sugammadex concentrations in primary culture was associated with cortical neuron necrosis and cell death.¹⁶⁹ This may have potential implications for sugammadex use if used in patients where the blood brain barrier has been disrupted (trauma, ischemia, infections) or immature (neonates) and warrants further investigation.

Currently within the literature, sugammadex use appears to be well tolerated with no deaths associated. Its safety profile continues to be investigated, particularly with fresh concerns regarding hypersensitivity reactions. Hypersensitivity reactions occur in <1% of patients who receive sugammadex, with reactions observed in both healthy volunteers as well as patients undergoing surgery. There is some evidence to show atopic patients may be at higher risk of hypersensitivity reactions. Other adverse effects such as anesthetic complications, insufficient depth of anesthesia, QTc, and clotting time prolongation have been reported, but the evidence base has not proven sugammadex as a definitive cause of these adverse reactions.

Conclusions

Since its first human use in 2005, many studies have shown that, overall, the γ-cyclodextrin sugammadex is safe and effective for the reversal of any depth (T0–T4) of rocuronium-induced neuromuscular blockade (0.6–1.2 mg/kg) and moderate vecuronium blockade (0.6 mg/kg) in doses of 2–16 mg/kg, depending on the clinical situation and the TOF. The indications for use have increased, as efficacy has been proven in many different patient populations including those with renal failure. Sugammadex achieves reversal of neuromuscular blockade at least 15 minutes faster than the standard neostigmine/glycopyrrolate combination and if used with TOF monitoring has the potential to decrease time spent in theatre and time to full recovery. This may allow more efficient utilization of theatre facilities, although so far, this has not been shown in the few economic studies that have been conducted. The ability to maintain deep rocuronium blockade right to the end of surgery with rapid reversal allows more favorable surgical conditions to be precisely controlled. Anesthetic techniques can be tailored to suit day-case, fast-track, bariatric, and retroperitoneal procedures. Such refinements may in themselves produce an economic cost saving. Novel uses of sugammadex in ECT and post-Caesarean section have also reported success. Post-operative residual neuromuscular blockade risk is significantly reduced with sugammadex, and this may translate into improved patient safety. Issues regarding hypersensitivity are yet to be resolved, and although sugammadex has been approved and used safely in many countries worldwide, the FDA has still not granted a license in the US. Occurrence of serious adverse events with sugammadex use is uncommon (<1%), but can occur. Currently, unrestricted sugammadex use is thought not to be cost-effective for routine reversal of neuromuscular blockade, although if tailored toward specific surgical procedures or certain time-critical situations such as a “CICV” airway situation, use may be beneficial with significant cost-savings. Sugammadex is the closest agent we have to an “ideal” reversal agent and is likely to be used more in the future, particularly if prices fall off patent and FDA approval goes ahead. Further studies are warranted to assess safety in neonates, pediatrics (<2 years), and pregnancy where caution is currently advised. The recent study suggesting sugammadex causes neuronal apoptosis in primary cultures, and warrants further study and thorough investigation.

Author Contributions

SL wrote the first full draft excluding the section on safety. MC wrote the draft section on safety, which was then added to and edited by SL. Critical revisions were made jointly by SL and MS. All authors reviewed and approved the final manuscript.

Disclosures and Ethics

As a requirement of publication the authors have provided signed confirmation of their compliance with ethical and legal obligations including but not limited to compliance with ICMJE authorship and competing interests guidelines, that the article is neither under consideration for publication nor published elsewhere, of their compliance with legal and ethical guidelines concerning human and animal research participants (if applicable), and that permission has been obtained for reproduction of any copyrighted material. This article was subject to blind, independent, expert peer review. The reviewers reported no competing interests. Provenance: the authors were invited to submit this paper.

Footnotes

Acknowledgment

The authors wish to thank Ms. Emma Johnson for her support of the lead author and patience during the writing of this review.

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Safety and Efficacy of Sugammadex for Neuromuscular Blockade Reversal

Abstract

Keywords

Introduction

Metabolism and Pharmacokinetic Profile

Special Populations

Renal failure

Gender/race

Polymyositis/dermatomyositis

Neurological disorders

Cardiopulmonary disease

Pregnancy

Elderly

Neonates/pediatrics

Liver disease

Obesity

Mechanism of Action

Clinical Studies and Efficacy

Phase I (safety and efficacy)

Phase II (dose-finding)

Phase III (post-dose-finding studies/further data on safety and efficacy)

Clinical Studies (Post-marketing) and Sugammadex Indications

Reversal of any depth of rocuronium- or vecuronium-induced neuromuscular blockade

RSI and airway rescue (can't intubate, can't ventilate (CICV))

Surgery specific benefits

Resolution of rocuronium anaphylaxis

Electroconvulsive therapy

Other studies of interest

Costs and Economic Evaluation

Safety

Conclusions

Author Contributions

Disclosures and Ethics

Footnotes

Acknowledgment

References