Sugammadex (Bridion) is a unique reversal agent of aminosteroid-induced neuromuscular blockade. It is the first agent in its class. Initial human trials in 20051 found sugammadex to be safe and effective. Further studies followed, resulting in its approved for clinical use in Europe and Australia in 2008.2,3
In December 2015, the US Food and Drug Administration (FDA) approved Bridion® Injection 100 mg/mL for the reversal of neuromuscular blockade (NMB) induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery.
Sugammadex is an alternative to anticholinesterases in anaesthesia. It allows the use of rocuronium as a substitute for suxamethonium for rapid sequence induction (RSI) and has many potential uses in clinical practice.
Mechanism of action
Sugammadex is a direct reversal agent for aminosteroid neuromuscular blocking drugs (NMBDs). It is a modified gamma-cyclodextrin with a hydrophilic exterior and lipophilic centre, allowing it to encapsulate all aminosteroid NMBDs, with greatest affinity for rocuronium, followed by vecuronium and then pancuronium.2 Each molecule of sugammadex encapsulates one molecule of rocuronium.
Sugammadex works by two mechanisms; firstly, it encapsulates the circulating aminosteroid, rendering it inactive in the plasma; secondly, it promotes dissociation of the aminosteroid from the neuromuscular junction (NMJ) by creating a concentration gradient from the NMJ to the plasma, where it is also encapsulated. This encapsulation of the NMBD allows the return of neuromuscular function.
Mechanism of action video
The pharmacokinetics of sugammadex is linear in the dose range 0.1-32 mg/kg.2,4 One safety study has suggested that this linear relationship extends up to 96 mg/kg.5 In the healthy adult population, sugammadex has an estimated volume of distribution of 11-14 L, an elimination half-life of around 2 hours and a clearance of 88 ml/min.4 Sugammadex is not metabolised and is excreted almost exclusively unchanged by the kidneys, with more than 90% being renally excreted within 24 hours.4,5 Administration of sugammadex alters the pharmacokinetics of rocuronium, with the rocuronium-sugammadex complex behaving in a similar manner to sugammadex, and elimination of rocuronium being shifted away from the biliary system to predominant renal excretion.1,4,5
Sugammadex has the ability to reverse any depth of rocuronium-induced neuromuscular blockade. The dose of sugammadex required to ensure complete reversal is dependent upon the depth of block, the timing and the dose of rocuronium.4,6 Depth of block is described as "routine", "moderate" and "profound". It is defined by response to neuromuscular monitoring, train-of-four (TOF) and post-tetanic count (PTC). Routine block is represented by a TOF of 2 or more. Moderate block represents a deeper level of block and corresponds to a TOF of 0 and PTC of 1-2. Profound block is the deepest level of neuromuscular block and occurs 3-5 minutes post-NMBDs, when there is no response on neuromuscular monitoring to TOF or PTC. Adequate reversal is determined by a TOF of >0.9, where the height of the fourth twitch is 90% of the height of the first twitch.
Table 1: Table showing dose of sugammadex required to reverse different levels of rocuronium neuromuscular blockade.4
| Type of block
|| Dose of sugammadex
|| Time to TOF >0.9 |
| Routine– TOF count 2
|| 2 mg/kg
|| 2 minutes |
| Moderate– Post tetanic count 1-2
|| 4 mg/kg
|| 3 minutes |
| Profound– 3-5 minutes post NMBDs
|| 4 mg/kg
|| 3 minutes |
For reversal of routine and moderate rocuronium and also vecuronium-induced blockade, similar doses of sugammadex are required.4,6 However, the dose of sugammadex for reversal of profound vecuronium-induced block has not been studied and therefore has not been formally determined.4,6
There is great variability in recovery times after administration of sugammadex at all depths of block, hence neuromuscular monitoring is recommended until complete reversal is clinically achieved.3,4,6 Reduced doses of sugammadex (<2 mg/kg) are associated with prolonged recovery times and incomplete reversal, and are therefore not recommended.1,3,4,6
Repeat use of NMBDIf the patient requires repeat neuromuscular blockade after receiving a dose of sugammadex, the recommendation is to utilise an alternative NMBD - for example, suxamethonium or a benzylisoquinolinium - in the first instance. However, it is sometimes possible to re-paralyse the patient with rocuronium, although the dose required depends on the sugammadex dose given and the time since administration. Paralysis onset with rocuronium in this situation is often delayed, with duration of action being shorter than normal.4
Table 2: Table showing the dose of rocuronium required after administration of sugammadex.4
| Time since 4 mg/kg sugammadex administration
|| Dose of NMBD |
| 5 minutes
|| 1.2 mg/kg rocuronium |
| 4 hours
|| 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium |
Bridion versus neostigmine
Following the administration of a non-depolarising NMBD, reversal often occurs spontaneously over a set duration of time or can, in most cases, be expedited through the administration of an anticholinesterase such as neostigmine in combination with glycopyrrolate. Neostigmine has well-recognised undesirable effects and can result in variable reversal of neuromuscular blockade.2 It also has the disadvantage of not being able to reverse profound depth of blockade. If given during a profound or moderate level of neuromuscular blockade, neostigmine can potentially exacerbate neuromuscular block by a direct action on open nicotinic receptors. Early studies established that sugammadex compared with neostigmine was superior in producing complete reversal of neuromuscular blockade from both routine and moderate levels of block, occurring up to 17 times faster with sugammadex.6 These results have been consistent in subsequent studies, along with recognition of a reduced risk of postoperative residual blockade with sugammadex compared with neostigmine.1-3
Bridion/rocuronium versus suxamethonium
Suxamethonium has been the muscle relaxant of choice in RSI due to its rapid onset and offset of action.2 However, it is associated with numerous and potentially life-threatening adverse effects.2 Rocuronium 1.2 mg/kg can emulate the intubating conditions of suxamethonium for RSI, but with the consequence of a prolonged duration of action, 35-75 minutes compared with less than 10 minutes.2 Administration of sugammadex after high-dose rocuronium 1.2 mg/kg, profound blockade, can result in a quicker return of NMF when compared with spontaneous resolution of suxamethonium-induced blockade.1,6 Sugammadex at a dose of 16 mg/kg will reverse profound neuromuscular blockade within 1.3-1.9 minutes post-administration.6 However, time taken to locate, calculate the dose and administer sugammadex may significantly delay the time to reversal. It must be recognised that return of NMF does not necessarily equate to return of spontaneous ventilation in a ‘can’t intubate, can’t ventilate’ (CICV) situation.3 However, there are some case reports of successful use of sugammadex in CICV situations, warranting its inclusion on a departmental difficult airway trolley.1,3
The Difficult Airway Society includes the use of sugammadex as an option in step B of their CICV guideline in children aged 1 to 8 years.
Compared with suxamethonium, the use of rocuronium and sugammadex to facilitate electroconvulsive therapy (ECT) has been associated with shorter recovery times and reduced postoperative complaints such as myalgia and headache.3
The recommended dose of sugammadex for the elderly (>75 years) is the same as in younger adult patients.4 However, the onset of action may be slower, which is possibly attributed to a reduced cardiac output in the elderly population.1
Routine reversal of a TOF count of 2 with sugammadex 2 mg/kg in children age 2 to 17 years is recommended. However, despite safe use in a small number of case reports, sugammadex use is not endorsed in neonates or infants.1,4
Pregnancy and breastfeeding
There are no documented cases of sugammadex being used during pregnancy, and is not recommended,4 despite minimal placental transfer.2 There are, however, multiple case reports of administration to women post-Caesarean section, which may allow rocuronium to become an acceptable alternative NMBD to suxamethonium for emergency obstetric intubation.1,3
There is an ongoing debate surrounding the dosing of sugammadex in obese patients, as currently dosing is based on actual body weight.4 However, a dose based on ideal body weight (IBW) plus 40% appears to be safe. Dosing based on IBW alone has been associated with slower recovery times and may lead to an increased risk of inadequate reversal.3
Patients with myasthenia gravis pose particular challenges regarding NMBDs, as they require reduced doses, which have a variable duration of action, increasing the risk of postoperative residual blockade.10 Cholinesterase inhibitors such as neostigmine can result in inadequate reversal of NMBDs, especially in patients who are taking pyridostigmine.10 A case series of 21 patients demonstrated that sugammadex was a safe and an effective alternative to neostigmine in patients with myasthenia gravis.10 De Boer et al also showed that recovery times were similar to those in patients without neuromuscular diseases for reversal of both routine and moderate block to a TOF >0.9.10 There are case reports of safe sugammadex use in other neurological conditions, including myotonic dystrophy, amyotrophic lateral sclerosis, Duchenne muscular dystrophy and Huntington’s disease.1,3
Sugammadex is safe for use in patients with pulmonary diseases such as bronchiectasis and cystic fibrosis. Bronchospasm has been documented following administration in a small number of patients.1,4 Sugammadex has also been used effectively in patients with cardiac failure and those who have received a heart transplant, but with a prolonged recovery time compared with the adult population.1,3 It is postulated again that this delayed recovery is due to reduced cardiac output as with the elderly population.1,4
Sugammadex use in patients with a creatinine clearance <30 ml/min is not recommended.4 However, a recent safety and efficacy study comparing reversal of moderate block with sugammadex 4 mg/kg in patients with a creatinine clearance <30 ml/min to >80 ml/min demonstrated complete reversal in those with severe renal impairment.11 Sugammadex was significantly slower at achieving a TOF >0.9 in the renally impaired compared with the normal population group: 3.1 minutes versus 1.9 minutes.11 Sugammadex-rocuronium clearance was significantly reduced and remained detectable in a number of subjects 7 days post-administration.11 Using a high flux filter, haemodialysis can be used to remove sugammadex.1,4,11
Evidence for the use of sugammadex in liver dysfunction is limited. However, as sugammadex is almost solely excreted renally, no dose reduction is necessary in patients with mild to moderate hepatic dysfunction.4 More studies are needed in this area.
Co-administration of sugammadex is not recommended with ondansetron, verapamil and ranitidine due to physical incompatibility.1 The effect of sugammadex is not altered by administration of magnesium and appears to be equally effective with both volatile and intravenous anaesthesia.3 The main drug interactions associated with sugammadex are displacement and capture reactions. Displacement reaction occurs when a drug displaces rocuronium from its sugammadex-rocuronium complex, causing a theoretical risk of recurisation. Potential drugs causing displacement include toremifene, fusidic acid, flucloxacillin and diclofenac.1,2,4 However, such reactions have not been correlated into clinical practice.1 It should also be noted that rocuronium-sugammadex has an extremely high association constant and very low dissociation constant.2 Capturing reactions reduce the efficacy of other drugs when sugammadex encapsulates them. The most significant risk is with hormonal contraceptives, which may be less effective. Any woman who has received sugammadex should be counselled accordingly. They should obey the 7-day contraceptive rule and use extra contraceptive precautions for 7 days following administration of sugammadex.1,2,4
Hypersensitivity, although rare, is by far the most concerning adverse effect of sugammadex, with a literature review highlighting that this can be severe and rapid in nature (anaphylaxis), with most cases presenting within 5 minutes of sugammadex exposure.12 It is important to note that none of the patients in the literature review died.12 It is not clear why sugammadex exposure may result in hypersensitivity, but previous food and pharmaceutical cyclodextrin exposure may be to blame.1,5,12 The incidence of hypersensitivity reactions is estimated at <1% after a single dose, and is likely to increase with higher and repeated dosing of sugammadex.2,3 Diagnosis is confirmed via intradermal skin prick testing.12
Despite this, sugammadex is generally well tolerated.5,11 Common side effects include dysgeusia, headache, fatigue, nausea, vomiting, dizziness, urticaria and abdominal pain.4,5 An issue noted in initial studies was symptoms of inadequate depth of anaesthesia following administration of sugammadex, such as grimacing, sucking and coughing.6 Elevated bispectral index levels were also noted after sugammadex administration.1 The FDA raised concerns regarding QTc prolongation, but subsequent studies using doses of sugammadex up to 32 mg/kg have demonstrated that there is no difference in QTc compared with placebo.1,2 A further issue highlighted by the FDA was the effect of sugammadex on coagulation, due to early studies suggesting an increase in activated partial thromboplastin time (aPTT), possibly by the transient inhibition of factor Xa.2,13 A transient increase in aPTT and prothrombin time (PT) at 10 minutes that normalises by 1 hour at doses of 4 mg/kg have not been associated with adverse clinical consequences.13 These results have been mirrored in other studies with sugammadex 4 mg/kg; however, further studies are needed, with higher doses of sugammadex.2
Animal studies have suggested that sugammadex may be neurotoxic, but also highlighted that penetration of sugammadex across the blood-brain barrier is minimal, reducing this potential risk in humans.3
Bridion is an effective and safe agent for reversing aminosteroid neuromuscular blockade - in particular, all depths of rocuronium-induced blockade. Sugammadex provides a real alternative to neostigmine and has been used successfully in many clinical areas and patient populations that would previously have posed great angst to the anaesthetist, including patients with neuromuscular disorders. Sugammadex use has allowed rocuronium to become a comparable alternative to suxamethonium for RSI.
References and further reading
- Lobaz S, Clymer M, Sammut M. Safety and efficacy of sugammadex for neuromuscular blockade reversal. Clin Med Insights Ther 2014; 6: 1-14.
- Jahr JS, Miller JE, Hiruma J, Emaus K, You M, Meistelman C. Sugammadex: A scientific review including safety and efficacy, update on regulatory issues, and clinical use in Europe. Am J Ther. 2015; 22(4): 288-97.
- Ledowski T. Sugammadex: what do we know and what do we still need to know? A review of the recent (2013 to 2014) literature. Anaesth Intensive Care 2015;43:14-22.
- eMC. Bridion 100mg/ml solution for injection. .
- Peeters PAM, van den Heuvel MW, van Heumen E, Passier PCCM, Smeets JMW, van Iersel T, Zwiers A. Safety, tolerability and pharmacokinetics of sugammadex using single high doses (up to 96 mg/kg) in healthy adult subjects. Clin Drug Investig 2010;30(12): 867-874.
- Abrishami A, Ho J, Wong J, Yin L, Chung F. Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade. Cochrane Database Syst Rev 2009;4:CD007362.
- Abad-Gurumeta A, Ripollés-Melchor J, Casans-Francés R, Espinosa A, Martínez-Hurtado E, Fernández-Pérez C, Ramírez JM, López-Timoneda F, Calvo-Vecino JM, Evidence Anaesthesia Review Group. A systematic review of sugammadex vs neostigmine for reversal of neuromuscular blockade. Anaesthesia 2015;70:1441-52.
- Kopman AF, Naguib M. Laparoscopic surgery and muscle relaxants: is deep block helpful? Anesth Analg 2015; 120: 51-8.
- Platt PR, Clarke RC, Johnson GH, Sadleir PHM. Efficacy of sugammadex in rocuronium-induced or antibiotic induced anaphylaxis. A case-control study. Anaesthesia 2015;70:1264-7.
- de Boer HD, Shields MO, Booij LHDJ. Reversal of neuromuscular blockade with sugammadex in patients with myasthenia gravis. A case series of 21 patients and review of the literature. Eur J Anaesthesiol 2014; 31: 708- 21.
- Panhuizen IF, Gold SJA, Buerkle C, Snoeck MMJ, Harper NJN, Kaspers MJGH, van den Heuvel MW, Hollmann MW. Efficacy, safety and pharmacokinetics of sugammadex 4mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment. Br J Anaesth 2015; 114(5): 777-84.
- Tsur A, Kalansky A. Hypersensitivity associated with sugammadex administration: a systematic review. Anaesthesia 2014; 69: 1251-7.
- Rahe-Meyer N, Fennema H, Schulman S, Klimscha W, Przemeck M, Blobner M, Wulf H, Speek M, McCrary C, Williams-Herman D, Woo T, Szegedi A. Effect of reversal of neuromuscular blockade with sugammadex versus usual care on bleeding risk in a randomized study of surgical patients. Anesthesiology 2014; 1212: 969-77.