Sugammadex – What Price Are We Willing To Pay?

It is rare for a drug to polarise opinions as much as Sugammadex. There are anaesthetists adamant they’ll see out their careers without administering it, while others cancel operations because of its lack of availability. There are also those who keep supplies in their bags at the expense of the institution it’s taken from.

Much of the difference of opinion stems from it’s cost. To the best of our knowledge the cost of a 200mg vial of Sugammadex varies from A$45 to 195 depending on contract agreements between the supplier MSD and different hospitals. This compares with $10 to 20 for the combination of neostigmine and glycopyrollate.

None of us like feeling held to ransom by a pharmaceutical company and yet even those fiercely opposed to Sugammadex know it’s a better drug than its competitor neostigmine.

The popularity of Sugammadex has seen hospitals spending a large budget on this single drug. This has lead departments to reduce costs by restricting access to it, some institutions not purchasing it at all.

Any restriction of access:
1. Prolongs the time to obtain Sugammadex in a time critical airway rescue.
2. Alters the way we provide anaesthesia.
3. Sends a message to staff that neostigmine should be used for routine reversal.

1. Prolongs the time to obtain sugammadex in a time critical airway rescue.

A manikin based simulation published in Anaesthesia (1) found the mean time to Sugammadex administration was 6.7 minutes. They noted: ‘costly time was lost because Sugammadex was not directly available in the operating theatre. This decision was made at a managerial level because Sugammadex is an expensive drug.

Further an editorial of the Difficult Airway Society guidelines (2) states: ‘No longer should Sugammadex be kept hidden away centrally in some locked cupboard, but available immediately to hand in the anaesthetic/operating room.

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There’s been several case reports of successful airway rescue using Sugammadex across all age groups (3,4,5,6,7,8,9).

There are also airway rescue case reports where Sugammadex has been unsuccessful. (10,11) Several factors appear to contribute – mechanical (as opposed to functional) airway obstruction, residual anaesthetic agents (opioids, hypnotics, volatiles, induction agents), and time delays to obtaining and under-dosing of Sugammadex.

It’s important that clinicians are aware that Sugammadex will not rescue all failed airway events and each case is assessed individually. Relying on the reversibility of rocuronium with Sugammadex as a difficult airway plan may impair patient safety if it decreases the likelihood of other more appropriate strategies.

2. Alters the way we provide anaesthesia.

Times have changed. The ready availability of Sugammadex has enabled us to provide anaesthesia differently, often in the best interests of our patients.

By more confidently administering larger doses of rocuronium on induction we can gift ourselves with rapid optimal mask ventilation and intubation conditions.  It’s intuitive that this has the potential to reduce airway trauma. Some institutions now advocate the combination of rocuronium and Sugammadex over suxamethonium for rapid sequence induction. This has received support from the latest update of the Difficult Airway Society Guidelines. (12)

There are instances where we have difficulty overcoming functional airway obstruction, as perhaps witnessed in the Elaine Bromiley case (see here). With Sugammadex immediately available we are more likely to paralyse with rocuronium to rapidly provide optimal airway conditions. Without available Sugammadex we likely elect to deepen anaesthesia with poorer effect, deferring paralysis with suxamethonium to avoid its unwanted adverse effects.

With available Sugammadex we are more likely to provide muscle relaxation to our patients, confident we can completely reverse muscle relaxation rapidly. In turn we often provide muscle relaxation throughout the duration of an operation. This has lead to us providing better conditions for our surgeons. Patients are less likely to move, less likely to have sudden rises in intracranial, intraocular, and intra-abdominal pressure (herniation of abdominal contents, or damage to bowel with laparoscopic instruments). We are more likely to keep our patients paralysed until the end of surgery, not needing to wait for the second twitch on the train-of-four.

3. Sends a message to staff that neostigmine should be used for routine reversal.

There are anaesthetists who believe that Sugammadex is overused, administered when they believe no reversal agent is indicated, and given when neostigmine would do just as well.

Increasing numbers of anaesthetists, on the other hand, feel uncomfortable denying patients the benefits of Sugammadex. In a study carried out at Royal Perth Hospital in 2014, 45% of colleagues reported that they would feel professionally impaired without the unrestricted availability of Sugammadex. (13)

We should question:
– Should we routinely reverse when we’ve given a single muscle relaxant dose 2 hours prior?
– Does Sugammadex provide better reversal than neostigmine?
– How do Sugammadex and neostigmine’s side effect profiles compare?
– Is the routine use of Sugammadex over neostigmine cost effective?

A. Should we routinely reverse when we’ve given a single muscle relaxant dose 2 hours prior?

After a single dose of intermediate-duration muscle relaxant and no reversal, residual paralysis is common, even more than 2 h after the administration of muscle relaxant. Post-operative residual curarisation (PORC) is common, with a wide range of inter-patient variability for modern, intermediate-duration muscle relaxants. (14)

Most anaesthetists incorrectly estimate the incidence of PORC to be less than 1%. (15)

Residual paralysis is common at tracheal extubation and PACU arrival, despite qualitative neuromuscular monitoring and the use of neostigmine. (16)

Partial paralysis with TOFR < 0.9 causes pharyngeal dysfunction and misdirected swallowing, increasing the risk of aspiration. (17)

PORC is associated with a greater incidence of desaturation in the post-anaesthesia care unit. (18)

Our methods of assessment of residual neuromuscular blockade are poor. Although DBS is more sensitive than TOFC, manual assessment of DBS fade can only detect residual paralysis at TOF ratio < 0.7. (19)

B. Does Sugammadex provide better reversal than neostigmine

In a randomised controlled trial of 150 patients undergoing abdominal surgery on admission to recovery no patients having received Sugammadex demonstrated residual paralysis, however 43% of patients reversed with neostigmine had TOF-ratio < 0.9. (20)

Sugammadex is superior to neostigmine for reversal of rocuronium neuromuscular blockade (Cochrane Database). (21)

Reversal with Sugammadex may reduce the incidence of post-operative residual paralysis and consequent morbidity. Patients receiving Sugammadex are also less likely to desaturate in recovery and have fewer post-operative chest x-ray changes. (22)

Reversal with Sugammadex produces better recovery of diaphragm function than neostigmine reversal. (23)

C. How do Sugammadex and neostigmine’s side effect profiles compare?

Increased availability and use of Sugammadex understandably leads to increased use of rocuronium. There are concerns that the incidence of anaphylaxis to rocuronium may be greater than with other muscle relaxants. Discerning the incidence of anaphylaxis to different neuromuscular blocking drugs is difficult – perhaps the best estimate so far puts the incidence to rocuronium at 8, atracurium at 4, and vecuronium at 2.8 per 100,000 exposures. (24)

There have been case reports of hypersensitivity reactions to Sugammadex. (25) Other recognised side effects appear to be related to under dosing or to the fast recovery of muscle function provided by Sugammadex.(26) The product information states ‘Sugammadex is not recommended for use in patients with severe renal impairment, including those requiring dialysis’. However several studies have demonstrated the safety of administering Sugammadex to reverse rocuronium in this patient population. (27,28,29) There are potential interactions with oral contraceptives – patients should be advised to manage as if they have missed one daily dose, while those using non-oral contraceptives should use an additional non hormonal contraceptive method for the next 7 days.

Neostigmine is not free from adverse effects. There is good evidence to support an increased risk of postoperative nausea or vomiting (30), bradycardia, dizziness and increased salivation.

D. Is the routine use of Sugammadex over neostigmine cost effective?

The price of Sugammadex has reduced since it was originally brought to market. Even at its high cost in 2010 there were strong economic arguments made for using Sugammadex for routine reversal. (31)

Statistically significant decreases in median time from surgery to hospital discharge (0.2 days shorter) have been demonstrated in one study after introduction of Sugammadex. (32) A retrospective audit identified an association between the introduction of unrestricted access to sugammadex and a fall in ‘anaesthetic theatre time’. Mean hospital stay was also observed to be 0.8 days shorter. (33)

Determining the anaesthesia costs per hour or case is extremely difficult due to huge differences in health care systems between countries, states, and even hospitals. The best estimate in Australia in 2014 puts theatre cost per minute at $42. (see here)

In a single centre retrospective analysis performed in Italy and presented in 2016 a cost saving of €2.9/case was found when Sugammadex was used as first-choice reversal drug. (34)

As the evidence-base increases and the cost falls, we will shift our practice to using Sugammadex and its successors. We will recognise larger groups of patients for whom residual paralysis is detrimental (everyone?) while simultaneously appreciating how common the problem truly is. (35)

There are numerous anecdotes demonstrating the impact of Sugammadex on our practice. They demonstrate the frailties in trying to put cases into a trial. They also reveal there are unforeseen costs in having limited access to sugammadex. The reports below are de-identified cases:

1. A patient develops hives post induction. The decision is made not to proceed with surgery. The patient is reversed with Sugammadex saving approximately 30 minutes of theatre time.

2. Post induction of an obese renal patient for AV fistula formation in the groin (atracurium used for muscle relaxation), the surgeon lifts the fat apron to note candidal growth in the groin. He decides not to proceed with surgery. 40 minutes later the patient is reversed with neostigmine and glycopyrollate. The patient has respiratory distress in recovery potentially related to a time pressured and incomplete reversal. The patient is eventually reintubated and transferred to ICU.

3. On induction a patient could not be ‘test ventilated’, so muscle relaxation was avoided. There was no evidence of mechanical airway obstruction, the inability to ventilate likely being functional. The patient was woken and an awake fibre optic intubation performed. Surgery eventually commenced 2 hours after the patient had arrived in theatre. The ready availability of Sugammadex may have enabled confidence to administer muscle relaxation at the start of this case – patients may often in turn become easy to ventilate quickly.

4. A renal transplant donor is reversed with neostigmine and glycopyrollate. While still intubated she is transferred on to her recovery bed in theatre. She starts ‘breath holding’ and cannot be ventilated. This does not respond to a bolus dose of propofol. She becomes hypoxic and cyanosed. Suxamethonium is administered and she can be ventilated again, however the neostigmine given prior prolongs the duration of suxamethonium. The patient remains in theatre for another hour until sufficient muscle strength has returned for extubation. This also impacts on the transplant kidney ischaemic time.

5. Towards the end of a tunnelled Vas Cath insertion procedure the intubated patient starts ‘breathing up’. A decision is made not to re paralyse the patient as the surgeon has almost finished. Suddenly the capnograph trace disappears and the surgeon mentions hearing a sucking sound. Despite best efforts the patient cannot be resuscitated. Autopsy reveals gas in the cardiac chambers consistent with air embolus. Ready access to sugammadex may have influenced the decision to administer a muscle relaxant towards the end of the case.

What price are we willing to pay to allow unrestricted access to Sugammadex?

The cost of Sugammadex restricts its availability.

It’s intuitive, that in rare airway rescue cases, if rapid reversal with Sugammadex will be of benefit it needs to be immediately available in sufficient dose at the point of care.

We present a tiered approach to Sugammadex restriction which can limit its use but ensures its immediate availability. A full box of 10 vials of 200mg Sugammadex ensures a 16mg/kg dose will be available for patients weighing up to 125kg.

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We hope that healthcare institutions might adopt this approach so that front line staff are able to provide optimal patient safety allowing for cost constraints.

In the meantime we should collectively put pressure on Merck so that we may all benefit from unrestricted Sugamadex access. This is after all their mantra:

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We ask that Merck do the right thing – the healthcare community won’t forget their decisions – we can only hope that Merck remember ‘medicine is for the people‘.

Sign the petition requesting Merck reduce the price.

Please note we have no financial interest with Sugammadex, MSD, or any of the other products or systems discussed on this website. We appreciate your comments and feedback.

References:

1. Can sugammadex save a patient in a simulated ‘cannot intubate, cannot ventilate’ situation? Anaesthesia, 2010, 65, pages 936–941

2. Radical evolution: the 2015 Difficult Airway Society guidelines for managing unanticipated difficult or failed tracheal intubation. Anaesthesia. 2016 Feb;71(2):131-7.

3. Sugammadex in the management of a failed intubation in a morbidly obese patient. Anaesthesia and Intensive Care, Vol. 39, No. 4, July 2011. 763-4.

4. Reversal of Profound Neuromuscular Blockade with Sugammadex after Failure of Rapid Sequence Endotracheal Intubation: a Case Report. Rev Bras Anestesiol. 2012; 62: 2: 281-284.

5. ‘Can’t intubate, can’t ventilate’: the use of sugammadex as a rescue technique – a case report. Calixto L., Almeida A. Centro Hospitalar do Porto – Hospital Santo António, Department of Anaesthesiology, Porto, Portugal. Airway Management page 234.

6. Successful use of sugammadex in a ‘can’t ventilate’ scenario. L. Paton, S. Gupta and D. Blacoe. Anaesthesia 2013, 68, 861–864.

7. Two cases of the “cannot ventilate, cannot intubate” scenario in children in view of recent recommendations. Anaesthesiology Intensive Therapy 2014, vol. 46, no 2, 88–91.

8. Case report: sugammadex used to successfully reverse vecuronium-induced neuromuscular blockade in a 7-month-old infant. Pediatric Anesthesia 21 (2011) 1073–1088.

9. Sugammadex rescue in a ‘can intubate but can’t ventilate scenario’. Anaesthesia Cases / 2014-0225 / ISSN 2396-8397.

10. Use of sugammadex in a ‘can’t intubate, can’t ventilate’ situation. R. Curtis, S. Lomax and B. Patel. British Journal of Anaesthesia 108 (4): 612–14 (2012).

11. A persistant ‘can’t intubate, can’t oxygenate’ crisis despite rocuronium reversal with sugammadex. B.C.Kyle, D.Gaylard, R.H.Riley. Anaesth Intensive Care. 2012 Mar 1;40(2):344-6.

12. Difficult Airway Society 2015 guidelines for management of unanticipated difficult intubation in adults. British Journal of Anaesthesia, 115 (6): 827–48 (2015)

13. Neuromuscular Monitoring, Muscle Relaxant Use, and Reversal at a Tertiary Teaching Hospital 2.5 Years after Introduction of Sugammadex: Changes in Opinions and Clinical Practice. Anesthesiology Research and Practice Volume 2015, Article ID 367937.

14. Residual Paralysis in the PACU after a Single Intubating Dose of Nondepolarizing Muscle Relaxant with an Intermediate Duration of Action. Anesthesiology 2003; 98:1042–8.

15. A Survey of Current Management of Neuromuscular Block in the United States and Europe. (Anesth Analg 2010;111:110–9).

16. The RECITE Study: A Canadian Prospective, Multicenter Study of the Incidence and Severity of Residual Neuromuscular Blockade. Anesthesia & Analgesia Issue: Volume 121(2), August 2015, p 366–372.

17. Incidence and Mechanisms Upper Esophageal Dysfunction Humans of Pharyngeal and in Partially Paralyzed. Pharyngeal Videoradiography and Simultaneous Manometry after Atracurium. Anesthesiology. 2000 Apr 1;92(4):977-84.

18. The influence of residual neuromuscular block on the incidence of critical respiratory events. A randomised, prospective, placebo-controlled trial. Eur J Anaesthesiol. 2011 Dec 1;28(12):842-8.

19. Is the diagnosis of significant residual neuromuscular blockade improved by using double-burst nerve stimulation? Eur J Anaesthesiol. 1991 May 1;8(3):213-8.

20. Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study. British Journal of Anaesthesia, 115 (5): 743–51 (2015).

21.Sugammadex, a selective reversal medication for preventing postoperative residual neuromuscular blockade (Review). Cochrane Db Syst Rev. 2009 Jan 1(4):CD007362

22. Introduction of sugammadex as standard reversal agent: Impact on the incidence of residual neuromuscular blockade and postoperative patient outcome. Indian J Anaesth. 2013 Jan 1;57(1):46-51.

23. Electromyographic activity of the diaphragm during neostigmine or sugammadex-enhanced recovery after neuromuscular blockade with rocuronium: A study in anaesthetised healthy volunteers. Eur J Anaesthesiol. 2015 Jan 1;32(1):49-57.

24. Anaphylaxis to neuromuscular blocking drugs: incidence and cross-reactivity in Western Australia from 2002 to 2011 P. H. M. Sadleir*, R. C. Clarke, D. L. Bunning and P. R. Platt. BJA Advance Access published January 18, 2013.

25. Three cases of suspected sugammadex-induced hypersensitivity reactions. Br J Anaesth. 2012 Aug;109(2):216-8.

26. Sugammadex as a reversal agent for neuromuscular block: an evidence-based review. Core Evid. 2013;8:57-67.

27. Efficacy and safety of sugammadex in the reversal of deep neuromuscular blockade induced by rocuronium in patients with end-stage renal disease.Eur J Anaesthesiol 2015; 32:681–686

28. Multicentre, parallel-group, comparative trial evaluating the efficacy and safety of sugammadex in patients with end-stage renal failure or normal renal function. British Journal of Anaesthesia 101 (4): 492–7 (2008)

29. Dialysability of sugammadex and its complex with rocuronium in intensive care patients with severe renal impairment. British Journal of Anaesthesia 109 (3): 382–90 (2012)

30. Drugs for preventing postoperative nausea and vomiting (Review). Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004125.

31. Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a systematic review and economic evaluation. Br J Anaesth. 2010 Nov 1;105(5):558-67

32. Unrestricted access to sugammadex: impact on neuromuscular blocking agent choice, reversal practice and associated healthcare costs. Anaesth Intensive Care. 2012 Mar 1;40(2):340-3.

33. The influence of unrestricted use of sugammadex on clinical anaesthetic practice in a tertiary teaching hospital. Anaesth Intensive Care. 2012 Mar 1;40(2):333-9.

34. Sugammadex for reversal of neuromuscular blockade: a retrospective analysis of clinical outcomes and cost-effectiveness in a single center. Clinicoecon Outcomes Res. 2016 Feb 18;8:43-52.

35. Sugammadex: restricted vs unrestricted or selective vs non-selective? Anaesth Intensive Care. 2012 Mar 1;40(2):213-5. N M Gibbs and P C A Kam.

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