Sugammadex and rocuronium anaphylaxis

I have been intrigued since the first case reports appeared describing the use of sugammadex in rocuronium anaphylaxis. It sounds beautiful and elegant. A drug that magically mops up the offending molecule, removing it from circulation; quickly reversing the cardiovascular collapse as rapidly as it reverses muscle relaxation.

Unfortunately the truth is not quite as clear. Case reports showing impressive recovery of rocuronium anaphylaxis minutes after giving sugammadex are tempered by in vitro and in vivoimmunological studies suggesting an inability of sugammadex to modify a type 1 hypersensitivity reaction. The reality is likely somewhere in between, highlighting our limited understanding of anaphylaxis and our tendency to rush to over-simplified models of disease processes.

The story so far...

Jones and Turkstra first raised the possibility of using sugammadex to treat rocuronium anaphylaxis in 2010.¹ One year later Nolan McDonnell and team published the first case report of a remarkable use of sugammadex to manage rocuronium anaphylaxis.² McDonnell described a 33 year old having an elective diagnostic laparoscopy suffering anaphylaxis to rocuronium. After 19 min of conventional resuscitation, involving CPR, 3500 mL of intravenous fluids and 4 mg of epinephrine/adrenaline - 500 mg of sugammadex was given with remarkable effect:

"A dose of 500 mg (6.5 mg kg21) was given while chest compressions were in progress. The last dose of epinephrine had been given 4 min previously. Approximately 45 s after administration and while chest compressions were in progress, the patient suddenly opened her eyes and reached for her tracheal tube.

"Her next recorded arterial pressure and SpO2 (which had been unrecordable on administration of the sugammadex) were 111/56 mm Hg and 97%, respectively, with a heart rate of 126 beats/min. This was recorded 2 min after she had exhibited spontaneous movement."

It is difficult not to be impressed. McDonnel was apropriately cautious when discussing possible mechanisms for the effect:

"...it may be that the binding of the rocuronium molecule by sugammadex prevented further vasoactive mediator release and allowed the previously administered epinephrine to have increased efficacy. ... it may be that the associated increase in muscle tone assisted with the restoration of venous return and cardiac output. It is also possible that the effect was purely by coincidence and that the reversal in her clinical condition was secondary to the epinephrine and fluid resuscitation that had been instituted. Other as yet unidentified processes may also have played a role."

Since that first Australian case report there has been a steady trickle of others.³ Funnell, Griffiths and Hodzovic published a report from the UK of a 47 year old woman undergoing a laparoscopic cholecystectomy with confirmed rocuronium anaphylaxis. Sugammadex 400 mg was given after 1 hour of conventional therapy with remarkable results:⁴

"Within 2.5 min, the patient awoke and resumed spontaneous respiration, airway pressures improved, and it was possible to half the epinephrine infusion to 0.09 mg/kg."

Motamed, Baguenard and Bourgain from the Institut Gustave Roussy in France described management of rocuronium anaphylaxis in a 61 year old woman with 4 mg/kg sugammadex 14 min after intubation.⁵ Also from France, Barthel and team successfully managed anaphylaxis in a 44 year old woman with sugammadex 16 mg/kg, and suggested a dose-related effect.⁶ There are other case reports, now from a total of five countries, with likely many more unpublished.⁷ Notably there are not yet any case reports of confirmed rocuronium anaphylaxis where sugammadex was not beneficial.⁸

In healthy contrast Wordsworth reports a 50 year old lady experiencing rocuronium anaphylaxis with spontenaous recovery after 18 minutes of conventional resuscitation in the absence of sugammadex. This should give us pause.⁹ Admittedly this case was much less severe anaphylaxis than the sugammadex case reports, but could the reported 'sugammadex rescues' be the result of spontaneous recovery? The natural cessation of mast cell degranulation and the effectiveness of conventional resuscitation, helped along by improvements in venous return with recovery of skeletal muscle tone - and with a little wishful thinking and confirmation bias thrown in?

Requirements for sugammadex to modify anaphylaxis

Take a step back and consider what would sugammadex need to biochemically achieve in order to modify anaphylaxis? Are there other prerequisites?

Conveniently, smarter minds than I have considered this very question. Jones and Turkstra neatly layout five requirements that need to be satisfied:¹

1. Rocuronium must be the cause of anaphylaxis. "This would appear to be self-evident, but the causative agent is incorrectly identified at the time of the reaction in approximately one-third of cases."
2. "Concentration of rocuronium at the effect site (tissue-bound mast cells and circulating basophils) [must] fall rapidly as a result of encapsulation by sugammadex."
3. "The affinity of sugammadex for rocuronium exceeds the affinity of the complementary cell-bound IgE antibodies."¹⁰
4. "Encapsulation [must] hide the epitope responsible for rocuronium-induced anaphylaxis."¹¹
5. "Endogenous and exogenous steroids [need] to be preserved in concentrations that would favour homeostasis."¹²

Unfortunately these neat requirements assume that anaphylaxis is entirely an IgE mediated process. This is not true. We are only just beginning to understand the depths of our ignorance when it comes to anaphylaxis; identifying alternate pathways for mast cell activation (IgG, macrophages, platelet activating factor) and the importance of other mediators in the process, like nitric oxide.¹³

Immunological studies: in vitro and in vivo

Three prospective studies have examined aspects of the immune-modifiying potential of sugammadex.

Clarke, Sadleir and Platt from Sir Charles Gairdner Hospital, Perth, Australia conducted an elegant prospective study of known rocuronium-sensitive individuals using a cutaneous model of anaphylaxis.¹⁴ Using different order, timing and concentrations of rocuronium and sugammadex they investigated its ability to modify the cutaneous immune response to rocuronium. They showed two important results:

1. Sugammadex pre-mixed with rocuronium was successful in preventing a type 1 hypersensitivity reaction, demonstrating that while sugammadex does not completely encapsulate the rocuonium molecule it does prevent the epitope from binding IgE.
2. Sugammadex was however unable to modify the hypersensitivity reaction after it had been triggered by rocuronium - when using a cutaneous model measuring wheal and flare.

They concluded:

"...there is no evidence that sugammadex should be used for the treatment of rocuronium-induced anaphylaxis, and clinical management should follow established protocols ... our main concern is that the use of sugammadex in anaphylaxis may distract the clinician from instituting well-established management protocols for anaphylaxis."

Leysen and team conducted an in vitro experiment using basophils isolated form known rocuronium-sensitive subjects.¹⁵ Their findings were consistent with Clarke's, showing that while sugammadex pre-mixed with rocuronium prevented basophil activation, sugammadex could not prevent ongoing activation after basophils had been triggered by rocuronium, even at very high sugammadex concentrations.

Finally, Tomak et al. investigated the ability of sugammadex to reduce mast cell degranulation in the rat liver.¹⁶ They showed that sugammadex administered five minutes after rocuronium did reduce the tryptase concentration in rat liver. The applicability of this to human physiology and its use as an anaphylaxis model are questionable (obviously these were not rocuronium-sensitive rats!), although it may hint at an alternate mechanism for sugammadex's benefit: directly modifying the rocuronium-mast cell interaction through non-IgE means.¹⁷

So, what are we to believe?

On one hand we have case reports showing dramatic improvement - we do our patients a disservice to dismiss these as coincidence. On the other hand, testing of conventional models of anaphylaxis produce no such dramatic effect.

Sugammadex is again demonstrated to be a unique drug; it is the first time we have had the ability to rapidly remove a drug allergen from the circulation. Our view of anaphylaxis as an irreversible biochemical cascade entirely dependent on IgE is likely inadequate and incomplete. The observed clinically benefits from sugammadex in the setting of rocuronium anaphylaxis may well be due to modifying processes at the fringes of our current understanding of anaphylaxis.