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Mitigation of rocuronium-induced anaphylaxis by sugammadex: the great unknown

Last post 15 Dec 2011, 2:34 AM by Brian Baldo. 0 replies.
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  •  15 Dec 2011, 2:34 AM 1009

    Mitigation of rocuronium-induced anaphylaxis by sugammadex: the great unknown

    Gamma-cyclodextrin is a cyclic oligosaccharide of eight glucopyranose units linked α(1-4) in a circular arrangement that forms a toroidal shape around a central cavity.  The hydrophobic nature of the central cavity endows γ-cyclodextrin with the capacity to encapsulate and form stable inclusion complexes with a range of different so-called guest molecules and such host-guest cyclodextrin complexes are widely used to improve drug solubility and stability [1].  In an attempt to improve the delivery of the neuromuscular blocking drug (NMBD) rocuronium, the cavity of γ-cyclodextrin was chemically modified by extending it to permit the encapsulation of the whole rocuronium molecule [2].  The extent, efficiency and specificity of the encapsulation led to the successful employment of the modified cyclodextrin, named sugammadex, to reverse rocuronium-induced neuromuscular blockade by removing the drug from the plasma and creating a concentration gradient that moves the rocuronium from the neuromuscular junction to the plasma [2].

     

    Neuromuscular blocking drugs are easily the most common cause of drug-induced anaphylaxis during the perioperative period [3] and, coincident with the popularity of rocuronium for neuromuscular blockade, there has been an increase in reports of anaphylaxis to the drug.  In early 2010, Jones and Turkstra [4] suggested that in cases where traditional management has failed, “there may be sufficient pharmacologic and pathophysiologic rationale to consider administration of sugammadex” as a novel treatment for the rapid reversal of rocuronium-induced anaphylaxis.  Attention was also drawn to the possibility that the allergenic ammonium groups of rocuronium in the inclusion complex might still be accessible for binding to complementary IgE antibody molecules in the sera of a rocuronium-allergic patient. Soon after, some published case reports described the apparent reversal of difficult to manage anaphylactic responses to rocuronium during anaesthesia [5-7] but, since it is ethically not possible to conduct a clinical trial of the effectiveness or otherwise of sugammadex in the treatment of rocuronium-induced anaphylaxis, recommendation or rejection of this application of the specific cyclodextrin must await the further gathering of reports of individual cases.  In the meantime, less direct and invasive investigations such as carefully planned skin tests and in vitro studies designed to detect the accessibility of sugammadex-bound rocuronium allergenic determinants can, and are, being pursued (for references see [8]).  Before sugammadex can be universally accepted for the management of rocuronium-induced anaphylaxis, two important relevant questions need to be answered: Are the rocuronium allergenic structures on the rocuronium-sugammadex complex accessible to IgE antibody binding and can sugammadex compete with the IgE antibodies for free, antibody-bound and cell-bound rocuronium molecules? 

     

    The signs and symptoms of a type I IgE antibody-mediated allergic reaction are elicited by cross-linking of high affinity receptor (FcεRI)-bound IgE antibodies on mast cells and basophils by allergen molecules reacting with the bivalent antibody combining sites via the complementary allergenic determinant structures.  The IgE antibody-FcεRI receptor complex is known to be both long-lasting and to dissociate exceptionally slowly with the rate of antibody dissociation easily compensated for by the rate of local IgE antibody synthesis [9].  Removal of allergen, either in its free or antibody-bound state, will therefore interfere with the sequence of events leading ultimately to the allergic cascade including the release of the allergic and inflammatory mediators of anaphylaxis.  Given this, it is difficult to understand how sugammadex could so quickly alleviate anaphylactic symptoms in the recently reported cases.  Such a rapid reversal of anaphylaxis would require not only the removal of free rocuronium in the plasma but also the stripping and removal of the antibody-bound drug cross-linking the cell-bound anti-rocuronium IgE antibodies.

     

    The term antibody ‘affinity’ denotes the intrinsic association constant (Ka) between antibody and its complementary univalent determinant and when the antigen contains multiple determinants the association between antigen and antibodies is made up of the sum of the affinities of all the antigenic determinants involved.  Hence, the overall binding affinity of a multideterminant, multivalent antigen with its complementary polyclonal population of antibodies may be many orders of magnitude greater than the binding between an antigen-antibody interaction involving only one or two reactive sites. The average association constants for the interaction of allergens such as those from pollens which are usually multideterminant and multivalent with respect to their allergenic (IgE antibody-binding) determinants are often high, for example, in the range 1010 – 1011 M-1 [10,11].  This contrasts with the allergenicity of NMBDs which are probably monodeterminant or, at most, bideterminant (consisting of quaternary and sometimes tertiary ammonium ion allergenic determinants) and bivalent [12] and therefore one might expect lower average affinities (in terms of the average association constants) and avidities (the overall stability or strength of the complex) for rocuronium-serum IgE antibody interactions.  There is no information available on the affinities and dissociation constants of NMBD-IgE antibody complexes but, in the recent cases where sugammadex proved rapidly effective in managing the rocuronium-induced anaphylaxis, one explanation might be that the relative affinities and avidities of the sugammadex-rocuronium (Ka = 1.8 x 107 M-1) and IgE-rocuronium interactions were higher in the former case thus leading to preferential binding of the drug to, and removal by, the cyclodextrin.  An additional factor may also lead to lower than expected average affinities and avidities for NMBD-IgE antibody complexes.  The origin of NMBD-reactive IgE antibodies in the sera of allergic patients is generally unknown and it is clear that most, if not all, patients who experience anaphylaxis to a NMBD are not sensitized by a NMBD in the first place [12].  It can be assumed, therefore, that the NMBD provoking the allergic response in the patients is not exactly the same structure as the sensitizing agent.  This, in turn, probably results in antigen-antibody combining site complexes of poorer complementarity or‘fit’ and of lower affinity and avidity than interactions where the IgE antibodies were formed in direct response to the original complementary antigen, that is, the antigen that stimulated the antibody response in the first place.

     

    Affinities for antibodies reacting with the same hapten can differ by up to a factor of 105.  It would therefore be instructive to measure the average association constants for rocuronium- IgE antibody complexes using sera from a number of different rocuronium-allergic patients, particularly those given sugammadex in an attempt to reverse anaphylaxis to rocuronium, and compare the values with the association constant for the sugammadex-rocuronium interaction.  Higher affinities for the IgE antibody complexes than for the rocuronium-sugammadex complex are predicted to correlate with the failure of sugammadex to alleviate on-going rocuronium-induced anaphylaxis while mitigation of rocuronium-induced anaphylaxis would occur in patients if the association constant for the sugammadex-rocuronium complex was higher than the affinities of the rocuronium-antibody complexes.  This prediction can be readily tested.

    BA Baldo

    Lindfield

    New South Wales

    Australia

    Email: babaldo@iinet.net.au

    No external funding and no competing interests declared.

    References

    1        Szejtli J. Introduction and general overview of cyclodextrin chemistry. Chemical Reviews 1998; 98: 1743-54.

    2        Bom A, Bradley M, Cameron K et al. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angewandte Chemie International Edition 2002; 41: 266-70.

    3        Fisher MM, Baldo BA. Anaphylaxis during anaesthesia: current aspects of diagnosis and prevention. European Journal of Anaesthesiology 1994; 11: 263-84.

    4        Jones PM, Turkstra TP. Mitigation of rocuronium-induced anaphylaxis by sugammadex: the great unknown.  Anaesthesia 2010; 65: 89-90.

    5        Pedersen NA, Findsen L, Olsen KS. Should sugammadex be used for the treatment of anaphylaxis induced by rocuronium? In: American Society of Anesthesiologists 2010 Meeting Abstracts. Available at: http:/www.asaabstracts.com Neuromuscular Transmission abstract number A539. Accessed March 9, 2011.

    6        McDonnell NJ, Pavy TJG Green LK, Platt PR. Sugammadex in the management of rocuronium-induced anaphylaxis. British Journal of Anaesthesia 2011; 106: 199-201.

    7        Funnell AE, Griffiths J, Hodzovic I.  A further case of rocuronium-induced anaphylaxis treated with sugammadex. British Journal of Anaesthesia 2011; 107: 275-6.

    8        Baldo BA, McDonnell NJ, Pham NH.  Drug-specific cyclodextrins with emphasis on sugammadex, the neuromuscular blocker rocuronium and perioperative anaphylaxis: implications for drug allergy. Clinical and Experimental Allergy 2011; 41: 1663-78.

    9        Gould HJ, Sutton BJ, Beavil AJ et al. The biology of IgE and the basis of allergic disease. Annual Review of Immunology 2003; 21: 579-628.

    10    Kim K-E, Rosenberg A, Roberts S, Blumenthal MN.  The affinity of allergen specific IgE and the competition between IgE and IgG for the allergen in Amb a V sensitive individuals. Molecular Immunology 1996; 33: 873-80.

    11    Hantusch B, Scholl I, Harwanegg C et al.  Affinity determinations of purified IgE and IgG antibodies against the major pollen allergen Phl p 5a and Bet v 1a: Discrepancy between IgE and IgG binding strength. Immunology Letters 2005: 97: 81-9.

    12    Baldo BA, Fisher MM, Pham NH.  On the origin and specificity of antibodies to neuromuscular blocking (muscle relaxant) drugs: an immunochemical perspective. Clinical and Experimental Allergy 2009: 39: 325-44.

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