Published on October 2nd, 2012 | by Daniel Jolley0
If sugammadex is the answer what is the question?
Sugammadex is a modified γ-cyclodextrin and the first ‘selective relaxant binding agent’ (SRBA). The addition of eight carboxyl-thio-ether groups at the C6 positions extends the size of the lipophilic cavity, enabling encapsulation of the NMBD rocuronium bromide. The high binding affinity for the aminosteroid rocuronium effectively prevents biological interaction of rocuronium.
As rocuronium in plasma binds within sugammadex, rocuronium molecules in the neuromuscular junction move down their concentration gradient into the circulation where they too are selectively bound to sugammadex in a 1:1 ratio. Rocuronium is strongly bound to sugammadex by electrostatic forces between the positively charged rocuronium quaternary ammonium ion and the negatively charged sugammadex side-chains. The rate of molecular binding to dissociation is approximately 25 million to 1 for rocuronium and 10 million to 1 for vecuronium.
Sugammadex (Bridion®) is a remarkable drug. It also has a cool name. The anaesthesia community has moved very quickly to embrace the potential of this first and only ‘selective relaxant binding agent’ (SRBA), despite it’s considerable cost.
“Sugammadex is likely the most exciting drug in clinical neuromuscular pharmacology since the introduction of atracurium and vecuronium in the middle 1980s.” – Miller RD 1
Novel pharmacology and a cool name are however insufficient reasons alone to alter our practice. There is a certain lack of clarity in the community and literature as to where sugammadex fits into anaesthesia practice and to what extent it should alter how we currently manage muscle relaxation and reversal. There has also been very limited discussion of the unintended consequences of a shift to rocuronium-sugammadex based techniques over other neuromuscular drugs.
There is no doubt that sugammadex offers a new and improved way of reversing aminosteroid muscle relaxation, in particular that from rocuronium. The speed at which it reverses even profound neuromuscular blockade is incredible and potentially life saving. Sugammadex’s onset is 10 times faster than neostigmine and three times faster than edrophonium. 2
A Cochrane review by Abrishami et al. 3 of 18 RCTs totalling 1,300 patients supported the superiority of sugammadex over neostigmine at all studied levels of blockade (see below in the sidebar). Importantly there were no more adverse events compared with neostigmine (< 1%) – though it is worth highlighting that these are still relatively small numbers and we cannot ascertain the true level of safety until a significant period of market surveillance passes. 4 Reminding us that very little in life or medicine is risk-free, there have been at least three cases of hypersensitivity to sugammadex reported from Japan. 5
Neville Gibbs and Peter Kam very nicely outlined the three current indications for use of sugammadex 6 even at it’s current high cost:
- Pre-planned early reversal of rocuronium when suxamethonium is contraindicated. The most obvious example is electroconvulsive therapy in patients with a pseudocholinesterase deficiency or neuromuscular denervation conditions.
- Pre-planned reversal of rocuronium by sugammadex rather than neostigmine in situations where even very mild residual neuromuscular block carries significant risk to the patient. Examples fall into two groups: patients with neuromuscular disorders such as myotonic dystrophy or myasthenia gravis; and patients with severe pulmonary disease with limited reserve. The editors extended this to also include “…patients in whom reversal with anticholinesterases may be only partially effective (e.g. patients with poor renal function, hypothermia, acidosis)…”.
- Unplanned early reversal of rocuronium in patients with an unexpectedly difficult intubation where rapid reversal may allow awakening of the patient. Given the professional fear we have of the ‘Can’t Intubate Can’t Ventilate’ scenario it is unsurprising that it is this indication, likely the most rare of the three, that has captured anaesthesia community’s greatest interest.
Cochrane 2009 / Abrishami A, et al.
- 2 mg/kg reversal at TOF 2 appearance.
- 4 mg/kg reversal at PTC 1-2.
- 16 mg/kg reversal 3-5 min post-induction.
Since sugammadex’s appearance in clinical practice, case reports covering examples of use from all three groups have been widely published. I would add a fourth indication:
- Rescue from residual curarisation in those patients whom despite ‘reversal’ with neostigmine still have identifiable neuromuscular blockade. 7 Incomplete reversal and residual curarisation is likely a lot more common in the PACU than we appreciate, although the clinical consequences (ie. possible increased pulmonary complications) are still poorly defined. 8
Should sugammadex then replace neostigmine for all aminosteroid reversal?
Clearly sugammadex offers faster and more complete NMBD reversal than either neostigmine or edrophonium. In fact sugammadex given at an appropriate dose at almost any level of neuromuscular blockade has a faster onset of action than neostigmine even at much more advanced levels of neuromuscular recovery (Geldner et al. 9)
Additionally, use of sugammadex leads to less increase of heart-rate than when using neostigmine-glycopyrrolate or edrophonium-atropine and almost total avoidance of the dry-mouth associated with the later (5% vs 85-95%).2
There is however a degree of breathless excitement among anaesthetists proposing undemonstrated benefits of sugammadex that may lead to ill-considered changes in our practice.
“If large doses of rocuronium can be given, the surgeons may be presented with better surgical conditions with a more intense neuromuscular block, and reversal can still be accomplished…”
– Miller RD 1
(The degree of muscle relaxation provided by our current titrated-use of modern NMBDs provides excellent surgical conditions – to suggest that a greater, more profound degree of relaxation will give an unspecified benefit to surgeon and patient stretches the likely benefits of sugammadex too far.)
“Will sugammadex’s increased effectiveness, in comparison to neostigmine, lessen the need for or use of monitoring neuromuscular function?” – Miller RD 1
Surprisingly, while approved for use in Europe, UK and Australia, sugammadex’s application for approval was rejected by the FDA in 2008. At the time sugammadex was owned by Schering-Plough (now owned by Merck) having bought the original intellectual property owner Organon BioSciences for $14 billion in 2007 – thought to be driven by the opportunity to control sugammadex. The primary reason for the FDA rejection is concern over hypersensitivity reactions.
Dr Ronald Miller presented on the company’s behalf at the FDA meeting, “It was extremely surprising and disappointing, and bordering on unbelievable … It’s really a very regrettable situation … Time may prove the FDA to be correct, but I don’t think so.”
It is one thing to identify the clear advantages of sugammadex over anti-cholinesterase inhibitors – but it is quite another to rush to change our practice before a clear outcome benefit has been shown. A study from White et al. 10 highlighted the wide variability in time to return to a TOF ratio of 0.9 among patients after reversal with sugammadex. While 80% of patients reached TOFR 0.9 ≤ 5 min the wide variability included one patient for whom reversal took 22 minutes. Clearly it is not yet time to throw out our neuromuscular monitors.
There are three major reasons why sugammadex should not yet be our first reversal choice in most surgical cases:
1. Sugammadex: Cost
The current open-market price for sugammadex is an order of magnitude greater than for anti-cholinesterase inhibitor / anti-cholinergic combinations. Until the cost of sugammadex falls it is difficult to justify its use as a standard reversal agent.
Several reports have attempted to identify the effects of giving anaesthetists unrestricted access to sugammadex as a reversal agent. These have been conducted in the setting of hospitals fortunate enough to negotiate (confidential) reduced pricing for the drug. Ledowski et al. 11 demonstrated an increase of about AUS$85 per case (using the list price of sugammadex) for muscle relaxation and reversal costs. While this appears a small amount, as a colleague pointed-out, multiply by tens-of-thousands of cases and this quickly becomes a significant new drain on a hospital budget.
An economic study of the cost effectiveness of sugammadex 12 suggested that it may be cost effective if there are significant time savings in the operating theatre but not if the savings are instead in the PACU. However even then it is unlikely that time savings achieved through faster reversal will translate directly into theatre savings given that there are many factors determining case turn-over.
2. Sugammadex: Unproven outcome benefit
The pharmacological advantages of sugammadex are undeniable. But outside the few edge cases discussed (‘Can’t Intubate Can’t Ventilate’ being the most prominent) no outcome benefit has been shown for most surgical cases. Over the past two decades the definition of residual neuromuscular blockade has progressively risen from a TOF ratio (T4/T1) of 0.7 to a TOF ratio of 0.9. Residual blockade even with intermediate agents rocuronium and atracurium is more common than most anaesthetists would like to admit. 13 Though pharyngeal tone dysfunction has been demonstrated to occur at a TOFR < 0.9, possibly increasing the risk of aspiration, the clinical significance for most patients remains uncertain. 14 15
Audit data suggesting modest shortening of hospital stay when sugammadex is used is intriguing, though far from definitive or consistent between studies.11, 16 It is conceivable that a reduction in post-operative pulmonary complications due to a decrease in residual blockade incidence could have this benefit.
3. Sugammadex: Unintended consequences of a shift to rocuronium
Hospitals that provided unrestricted access to sugammadex11 saw a dramatic increase in the consumption of rocuronium if they were not already a predominate rocuronium consumer. The consequences of this shift to rocuronium have not been properly discussed.
In parts of Europe, notably France and Norway, rocuronium is a disproportionate cause of anaphylaxis. However in the US the incidence of anaphylaxis to rocuronium is quite low. The reason for this incongruity are best discussed elsewhere (see: Pholcodine: significance for anesthesia?) but may lead to an increase in perioperative anaphylaxis in regions where rocuronium sensitivity is more common. The situation in Australia is less clear; some unpublished reports claim that the incidence of rocuronium anaphylaxis is similar to that of suxamethonium, while older published-reports suggest that it instead merely tracks market share.
Sugammadex offers a unique and supremely effective reversal of aminosteroid muscle relaxation. It is a revolutionary and potentially life saving drug, but likely only for very specific anaesthetic scenarios. Only time will tell if its usefulness lives up to the hype for the majority of relaxant cases.
What do you think? Leave a reply below.
Next week, in part two I will discuss the merits of replacing suxamethonium with rocuronium/sugammadex for rapid sequence induction; and in part three explore evidence for and against using sugammadex to manage rocuronium anaphylaxis.
- Miller RD. Sugammadex: an opportunity to change the practice of anesthesiology? Anesth Analg. 2007 Mar;104(3):477-8. ↩
- Sacan O, White PF, Tufanogullari B, Klein K. Sugammadex reversal of rocuronium-induced neuromuscular blockade: a comparison with neostigmine-glycopyrrolate and edrophonium-atropine. Anesth Analg. 2007 Mar;104(3):569-74. ↩
- 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 Oct 7;(4):CD007362. ↩
- Additionally, avoid giving under the 2 mg/kg minimum recommended dose. Eleveld and team showed that there is a limited clinical range of inadequate sugammadex dosing which can lead to recurarisation. Eleveld DJ, Kuizenga K, Proost JH, Wierda JM. A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex. Anesth Analg. 2007 Mar;104(3):582-4. ↩
- Godai K, et al. Three cases of suspected sugammadex-induced hypersensitivity reactions. Br J Anaesth. 2012 Aug;109(2):216-8. Epub 2012 May 22. ↩
- Gibbs NM, Kam PC. Sugammadex: restricted vs unrestricted or selective vs non-selective? Anaesth Intensive Care. 2012 Mar;40(2):213-5. ↩
- A case report of this situation was recently published by de Menezes – though one could extend this argument to then include all reversal so as to avoid residual paralysis in the first place: de Menezes CC, Peceguini LA, Silva ED, Simões CM. Use of sugammadex after neostigmine incomplete reversal of rocuronium-induced neuromuscular blockade. Rev Bras Anestesiol. 2012 Jul;62(4):543-7. ↩
- Fink H, Hollmann MW. Myths and facts in neuromuscular pharmacology. New developments in reversing neuromuscular blockade. Minerva Anestesiol. 2012 Apr;78(4):473-82. ↩
- Geldner G, et al. A randomised controlled trial comparing sugammadex and neostigmine at different depths of neuromuscular blockade in patients undergoing laparoscopic surgery. Anaesthesia. 2012 Sep;67(9):991-998. ↩
- White and colleagues were primarily investigating whether the degree of residual block at the time of sugammadex administration translated to a longer time to achieve reversal, when using sugammadex 4 mg/kg at least 15 min after the last dose of rocuronium: “…times to achieve a TOF of 0.9 varied from 0.8 to 22.3 and 0.7 to 8.5 min in the 0 twitch and > or = 1 twitch groups, respectively.” White PF, et al. The effect of residual neuromuscular blockade on the speed of reversal with sugammadex. Anesth Analg. 2009 Mar;108(3):846-51. ↩
- Ledowski T, et al. Unrestricted access to sugammadex: impact on neuromuscular blocking agent choice, reversal practice and associated healthcare costs. Anaesth Intensive Care. 2012 Mar;40(2):340-3. ↩
- Paton F, et al. Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a systematic review and economic evaluation. Br J Anaesth. 2010 Nov;105(5):558-67. ↩
- Possibly as high as 27% for surgery up to 90 min duration. Schreiber JU, Mucha E, Fuchs-Buder T. Residual paralysis following a single dose of atracurium: results from a quality assurance trial. Eur J Anaesthesiol. 2010 Nov;27(11):993-4. ↩
- Eriksson LI, et al. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology. 1997 Nov;87(5):1035-43. ↩
- An audit by Ledowski et al. showed over 50% reduction in post-operative desaturations with sugammadex, though it was unclear whether the comparison was to neostigmine or to a combined ‘neostigmine or no-reversal group’. T. Ledowski, et al. Introduction of sugammadex: influence on the incidence of residual paralysis at a tertiary teaching hospital. Anaesth Intensive Care. 2012 Sep;39(5):963. ↩
- Watts RW, London JA, van Wijk RM, Lui YL. The influence of unrestricted use of sugammadex on clinical anaesthetic practice in a tertiary teaching hospital. Anaesth Intensive Care. 2012 Mar;40(2):333-9. ↩