Sugammadex: when should we be giving it?

Sugammadex is a modified γ-cyclodextrin used for the reversal of neuromuscular blockade caused by the aminosteroid rocuronium and, to a lesser extent, vecuronium. It was introduced into UK practice in 2008 and, since the review by Mirakhur eight years ago 1, it has enjoyed an increase in popularity. As well as reversing routine neuromuscular blockade, its use has been described in the treatment of rocuronium allergy as well as in the ‘cannot intubate, cannot oxygenate’ scenario following administration of high-dose rocuronium. This editorial will examine whether we should be giving the drug more often in clinical practice. At the end of surgery, incomplete neuromuscular recovery is common. Not only are the intercostal muscles functionally impaired, but respiratory control is affected, and residual paralysis may result in incoordination of the pharyngeal muscles, affecting the integrity of the upper airway 2. Clinical evaluation of muscle strength, such as head-lift or hand-grip, and respiratory parameters, such as tidal volume or vital capacity, are not sensitive for detecting neuromuscular weakness. The use of a peripheral nerve stimulator is therefore essential when any neuromuscular blocking drug is administered, yet a recent survey from Singapore 3 revealed that monitoring was used routinely by only 13% of anaesthetists, despite its widespread availability. The objective, quantitative assessment of a train-of-four (TOF) response to ulnar nerve stimulation of the adductor pollicis muscle is the gold standard, and attaining a TOF ratio of 0.9 is generally accepted to indicate adequate recovery of neuromuscular function. Monitoring the TOF ratio is the only method to accurately determine when it is appropriate to administer reversal agents and attempt tracheal extubation. Although monitoring the facial nerve is common, it is less accurate than the ulnar because the facial nerve is more resistant to neuromuscular blocking agents 4. A quantitative monitor such as the TOF-Watch™ (Mainline Medical Inc., Norcross, Georgia, USA) costs approximately £975 (Euro 1165, $1250) compared with £395 (Euro 472, $506) for a qualitative device such as an RS8™ peripheral nerve stimulator (Blue Box Medical Ltd., New Forest Enterprise Centre, Chapel Lane, Totton, UK). I personally believe the extra cost is worth investing in, but most anaesthetic departments still only possess qualitative monitors, even though the AAGBI recommends use of a quantitative peripheral nerve stimulator 5. If a qualitative monitor is used, the first twitch following a train-of-four stimulus appears at approximately 10% recovery, the second at 20%, the third at 30% and the fourth at 40%. The detection of fade, either by tactile or visual methods, is not possible once the TOF ratio is 0.5 or more. This means that there is a window between 50% and 100% recovery of neuromuscular function when a reversal agent is often given. Song et al. 6 found that, following cisatracurium administration, if neostigmine was given when the fourth twitch in a TOF appeared (i.e. 40% recovery), it took between 9.0 and 15.5 min to attain a TOF ratio of 0.9. If neostigmine was given when there was no detection of fade (i.e. 50% recovery or more) then this was reduced to between 4.0 min and 13.5 min. In addition, Choi et al. 7 demonstrated that, after administration of rocuronium, if the TOF ratio was 0.5 and neostigmine 40 μg.kg−1 was given, then it only took a median of 3.8 min to attain a TOF ratio of 1.0. When there is moderate spontaneous recovery of neuromuscular function (the presence of three or more twitches in a TOF), then the issue of whether to give neostigmine or sugammadex probably does not arise; neostigmine can be given in an appropriate dose and a suitable time allowed before its effects become apparent and tracheal extubation performed. A pragmatic approach to interpretation of the response to a TOF stimulus and administration of either neostigmine or sugammadex is shown in Table 1. It is at deeper levels of neuromuscular blockade where sugammadex comes into its own. Laryngeal microsurgery is an example of a short procedure that requires deep levels of anaesthesia and neuromuscular blockade. The laryngeal muscles are relatively resistant to neuromuscular blockade and if sugammadex is available, because rapid reversal from a deep level of block is possible, anaesthetists may have no hesitation in administering a high dose of rocuronium. In this issue of Anaesthesia, Choi et al. 8 randomly allocated 44 patients undergoing elective laryngeal microsurgery into two groups. A ‘deep’ group received 0.9 mg.kg−1 rocuronium and 4 mg.kg−1 sugammadex reversal, whilst a ‘moderate’ group received 0.45 mg.kg−1 rocuronium and standard reversal with neostigmine. Not surprisingly, intubating and surgical conditions were considered better in patients in the ‘deep’ group but, in addition, recovery times were shorter in the ‘deep’ group that received sugammadex compared with the ‘moderate’ group that received neostigmine. Relatively small numbers of patients were included in the study and the anaesthetist was not blinded to patient grouping, but it does demonstrate that sugammadex is justified in at least some elective surgical situations. It seems that the over-riding reason why sugammadex is limited in availability is cost. Sugammadex is still under patent and is expensive; £59.64 (Euro 69.40, $74.56) for a 200 mg vial and £149.10 (Euro 173.51, $186.40) for a 500 mg vial (source BNF, https://www.bnf.org/) compared with the neostigmine/glycopyrrolate mixture which is £0.91 (Euro 1.07, $1.14). However, sugammadex offers some advantages over neostigmine. Reversal of neuromuscular blockade is quicker with sugammadex and the patient can, theoretically, be moved from the operating room to the recovery room more quickly, thus improving efficiency and reducing the costs of operating lists. This has been demonstrated in patients undergoing bariatric surgery 9. Sugammadex may also result in reduced postoperative nausea and vomiting (PONV) compared with neostigmine 10, thereby facilitating better quality recovery and allowing faster discharge from the recovery room (Table 2). Sugammadex encapsulates rocuronium so, by ‘removing’ rocuronium molecules from the circulation, it might have a role in the treatment of rocuronium anaphylaxis. Spoerl et al. 11 described three patients with reactions to rocuronium that rapidly resolved following administration of sugammadex. Although such use of sugammadex might appear attractive, it is not licensed for this indication and the cases described by Spoerl et al. were in fact anaphylactoid, rather than truly anaphylactic. Indeed, Jones and Turkstra 12 urged caution when considering sugammadex in this context, because when it does encapsulate rocuronium, the portion of the rocuronium molecule that causes IgE cross-linkage (and hence anaphylaxis) may actually protrude and still make contact with circulating IgE. Also, because sugammadex has the potential to bind other steroids 13, it may inhibit the action of hydrocortisone, a key component of anaphylaxis treatment. In truth, the evidence for a beneficial effect of sugammadex in the treatment of rocuronium-induced allergy is weak. Platt et al. 14 reported 13 cases of presumed rocuronium-induced anaphylaxis in which sugammadex was administered, only eight (62%) of which were later confirmed to be type-1 hypersensitivity reactions to rocuronium. Of the three patients in which the treating anaesthetist thought that sugammadex had been beneficial, one patient didn't actually have an allergy to rocuronium, one patient had no improvement in their blood pressure and the third still required a large number of adrenaline boluses even after sugammadex administration. These data suggest that sugammadex does not in fact modify the clinical course of a suspected reaction to rocuronium. Not only that, but sugammadex itself may cause anaphylaxis. Tsur and Kalansky 15 performed a systematic review and found 15 reports of presumed anaphylaxis to Sugammadex, of which 10 patients proved definitely positive. Yamada et al. 16 even reported one patient who was allergic to both rocuronium and sugammadex. To complicate matters even further, in November 2016 anaphylaxis due to the rocuronium-sugammadex complex itself was reported on two occasions by separate investigators. In one case 17, a man developed severe anaphylaxis shortly after administration of sugammadex following an otherwise uneventful laparoscopic appendicectomy. Skin testing proved negative for sugammadex alone but further testing, performed with premixed sugammadex and rocuronium, produced a markedly positive response. In another case report 18, skin tests were again negative for sugammadex but were strongly positive for a pre-mixed rocuronium-sugammadex complex. Until there is more evidence of its efficacy, sugammadex should not be used for presumed rocuronium allergy and clinical management of anaphylaxis should follow the current AAGBI guidelines 19. In a manikin-based ‘cannot intubate, cannot oxygenate’ (CICO) situation, Bisschops et al. 20 studied the total time taken for anaesthetic teams to prepare and administer sugammadex. The average time from the initial decision to use the drug, administer it and attain a TOF ratio of 0.9 was 8.9 min. They highlighted the fact that sugammadex might not have saved this imaginary patient, although Makris 21 pointed out that this time could be reduced if a syringe pre-loaded with sugammadex was available on the difficult airway trolley. Irrespective of whether or not sugammadex is given in a CICO scenario, adequate ventilation should be restored before oxygen desaturation occurs and this depends on the duration of unresponsiveness and extent of ventilatory depression as well as neuromuscular blockade. Naquib et al. 22 showed that, when 1.2 mg.kg−1 rocuronium was followed 3 min later by 16 mg.kg−1 sugammadex, recovery of neuromuscular function only took 4.5 min. However, if ventilatory rescue is inadequate, oxygen desaturation will occur despite full reversal of neuromuscular blockade, because the duration of ventilatory depression after sugammadex reversal may be as long as 15 min, especially in obese patients. The clinical management of a CICO scenario should therefore focus on restoration of a patent airway and oxygenation rather than relying on pharmacological intervention. Another potential problem with sugammadex has recently been highlighted by McGuire and Dalton 23. They successfully exchanged a tracheal tube for an LMA Classic®* in two patients (performing the so called ‘Bailey manoeuvre’). Both patients then developed what appeared to be upper airway obstruction two minutes after administration of 200 mg sugammadex, having previously demonstrated a patent airway. Positive end-expiratory pressure (PEEP) resolved the problem without oxygen desaturation. In their third patient, they observed similar airway obstruction after sugammadex and inserted a fibrescope, noting that the vocal cords were completely closed. All their subsequent patients who received sugammadex had temporary upper airway obstruction that commenced approximately 2 min after its administration, with adduction of the vocal cords and coinciding with a TOF ratio of > 0.9. It may have been that the anaesthetic depth was too light but the authors concluded that ‘the administration of sugammadex was resulting in a rapid increase in upper airway tone’. The manufacturers’ recommended dosing regimen for sugammadex was originally developed to reverse the effects of vecuronium rather than rocuronium. The dose needed is double that required when rocuronium has been given, and it may be that we are giving too high a dose of sugammadex; Schaller et al. 24 found that if patients had a TOF ratio of 0.5, only 0.22 mg.kg−1 sugammadex was required for 95% of patients to acquire a TOF ratio of 0.9. This is one-twentieth to one-tenth of the dose commonly administered to patients, as the small vial contains 200 mg, all of which is usually administered to a patient as there is no incentive to reduce the dose because the remainder of the vial must be discarded. Could this relative over-dosing with sugammadex possibly be implicated in the findings of McGuire and Dalton? Their research was challenged on the basis of being unethical 25 and generated a lively debate; please go to our website (http://www.respond2articles.com/ana/) to read more on this topic. So when should we be giving sugammadex? In my view, it is not yet time to abandon neostigmine. We have been using it for a long time, it is familiar and can be given to reverse the effects of atracurium as well as rocuronium and vecuronium. Sugammadex is useful when deep neuromuscular blockade with rocuronium is required for Ear, Nose and Throat surgical procedures, thoracic and abdominal surgery. It can be used in conjunction with rescue ventilation techniques in the ‘cannot intubate cannot oxygenate’ scenario but should not be given in suspected rocuronium allergy. When sugammadex becomes cheaper and more widely available, it is possible that rocuronium will become the only non-depolarising neuromuscular blocking agent used and sugammadex the reversal agent of choice. CB is an Editor of Anaesthesia. No other external funding or competing interests declared.