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We present a case of early skin and challenge testing in a patient following severe anaphylaxis to rocuronium. The patient presented for semi-elective laparoscopic cholecystectomy and developed anaphylaxis with severe cardiovascular collapse after induction of anaesthesia. Surgery was cancelled but was considered necessary before the recommended four to six weeks for formal allergy testing. Limited skin and challenge testing was performed to rocuronium and cisatracurium while the patient was in the intensive care unit to identify a safe neuromuscular blocking drug for subsequent early surgery. The subsequent surgery, 48 hours after the initial reaction, was uneventful. The case highlights the difficulties when anaesthetising patients with recent anaphylaxis who have not yet had formal allergy testing and presents a potential management strategy involving early skin testing.

We present a case of anaphylaxis to suxamethonium and/or vecuronium in a patient who had previously suffered an anaphylactic reaction, presumably to rocuronium. The patient had not been referred for formal allergy testing after the first anaphylactic reaction. Subsequent formal allergy testing revealed sensitivities to suxamethonium, rocuronium and vecuronium. Her next anaesthetic, using cisatracurium, was uneventful. It is recommended that all patients with suspected perioperative anaphylaxis are referred for testing. This is the responsibility of the anaesthetist. Particular caution should be used with suspected neuromuscular blocking drug allergy as cross-reactivity is common and not predictable by drug structure.

Rocuronium, a non-depolarizing neuromuscular blocking drug has a rapid onset of action, a comparatively low potency and, with a more favourable side effects profile than succinylcholine, it has become a popular alternative to that drug for rapid sequence inductions in anaesthesia. The rocuronium-binding cyclodextrin derivative sugammadex, prepared by per-6 substitution of the primary hydroxyls of γ-cyclodextrin with thiol ether-linked propionic acid side chains to extend the hydrophobic cavity to accommodate rocuronium, is used to reverse neuromuscular blockade by encapsulating the drug as an inclusion complex and removing it from the neuromuscular junction to the plasma. It has recently been suggested that sugammadex might also be of value in the management of rocuronium-induced anaphylaxis and this has been potentially supported by recent case reports. However, before sugammadex can be recommended for this purpose, it is important to establish whether or not the allergenic substituted ammonium groups at each end of the rocuronium molecule in the inclusion complex are masked within the cavity or left exposed for interaction with rocuronium-reactive IgE antibodies in the sera of rocuronium-allergic patients. Detailed experimental strategies and experimental protocols to investigate the allergenic potential of the sugammadex-rocuronium inclusion complex are presented and a possible explanation of the apparently rapid and successful reversal of anaphylaxis by administration of sugammadex is advanced and discussed.

Cyclodextrins, oligosaccharides linked in a circular arrangement around a central cavity, are used extensively in the pharmaceutical industry to improve drug delivery. Their usefulness depends on their capacity to form a drug inclusion, or host-guest, complex within the cavity. In an attempt to improve the delivery of the widely used neuromuscular blocking drug (NMBD) rocuronium, a rocuronium inclusion complex was formed with a chemically modified γ-cyclodextrin. The high binding affinity and specificity of the modified carrier (named sugammadex) for rocuronium (and other aminosteroid NMBDs) led to its use in anaesthesia as an innovative and useful agent for rapid reversal of rocuronium-induced neuromuscular block by sequestering the drug as an inclusion complex. This, in turn, led to the suggestion that sugammadex might be useful to remove the NMBD from the circulation of patients experiencing rocuronium-induced anaphylaxis, a suggestion subsequently supported in case reports where traditional treatment had failed. Successful resuscitations suggested that sugammadex might be a valuable new treatment for such intractable cases but, given the inappropriateness of clinical trials, confirmation or refutation will have to await the slow accumulation of results of individual case reports. Important questions related to antibody accessibility of drug allergenic structures on the rocuronium-sugammadex inclusion complex, and the competition between sugammadex and IgE antibodies (both free and cell bound) for rocuronium, also remain and can be investigated in vitro. The sugammadex findings indicate that the use of carrier molecules such as the cyclodextrins to improve drug delivery will sometimes give rise to changed immunologic and allergenic behaviour of some drugs and this will have to be taken into account in preclinical drug safety assessments of drug-carrier complexes. The possibility of encapsulating and removing other allergenic drugs, e.g., penicillins and cephalosporins, in cases of difficult-to-reverse anaphylaxis to these drugs is discussed., (© 2011 Blackwell Publishing Ltd.)

Background: The significance of IgE antibodies to neuromuscular blocking agent (NMBA)-induced anaphylactic reactions during anaesthesia is unclear. We investigated the relevance of IgE to rocuronium using an in vitro technique., Methods: Serum samples from 61 patients with anaphylactic reactions during anaesthesia were investigated. On the basis of clinical history, allergy to NMBA was considered likely in 48 patients, further assessed using intradermal skin tests for several commonly used NMBAs, including rocuronium, vecuronium, and succinylcholine. To determine the presence of rocuronium IgE in human serum, a rocuronium-human serum albumin (rocHSA) conjugate was coupled to a solid phase and a radioallergosorbent test performed. The biological effects of patient serum NMBA-IgE on histamine release were investigated using in vitro sensitized basophils from healthy blood donors., Results: IgE to rocuronium was found in 23 of 48 serum samples (48%) with NMBA allergy, although only two of these were able to sensitize basophils to release histamine in response to rocHSA. IgE-responsiveness in the basophil test was only observed with conjugated rocHSA and not with unconjugated rocuronium or the other NMBAs evaluated. However, unconjugated rocuronium inhibited the histamine release induced by rocHSA. Correlation between skin-test reactivity to rocuronium and IgE to rocHSA was low (P>0.1). In contrast, striking correlation between IgE to rocuronium and skin-test reactivity to succinylcholine was found (P<0.001)., Conclusions: Our results indicate that NMBA-related anaphylaxis requires not only IgE NMBA reactivity, but also altered cellular reactivity in the patient. The latter may be demonstrable by testing basophils from the patient, a skin test with (steroidal) NMBA, or both.

Background: Diagnosis of allergy from neuromuscular blocking agents is not always straightforward. The objectives of the current study were to investigate the value of quantification of immunoglobulin E (IgE) by ImmunoCAP (Phadia AB, Uppsala, Sweden) in the diagnosis of rocuronium allergy and to study whether IgE inhibition tests can predict clinical cross-reactivity between neuromuscular blocking agents., Methods: Twenty-five rocuronium-allergic patients and 30 control individuals exposed to rocuronium during uneventful anesthesia were included. Thirty-two sera (total IgE > 1,500 kU/l) were analyzed for potential interference of elevated total IgE titers. Results were compared with quantification of IgE for suxamethonium, morphine, and pholcodine. Cross-reactivity between drugs was assessed by IgE inhibition and skin tests., Results: Sensitivity of IgE for rocuronium, suxamethonium, morphine, and pholcodine was 68, 60, 88, and 86%, respectively. Specificity was 100% for suxamethonium, morphine, and pholcodine IgE and 93% for rocuronium IgE. ROC analysis between patients and control individuals changed the threshold to 0.13 kUa/l for rocuronium, 0.11 kUa/l for suxamethonium, 0.36 kUa/l for morphine, and 0.43 kUa/l for pholcodine. Corresponding sensitivity was 92, 72, 88, and 86%, respectively. Specificity was unaltered. Interference of elevated total IgE with quantification of IgE was demonstrated by the analysis in sera with a total IgE greater than 1,500 kU/l. IgE inhibition did not predict clinical relevant cross-reactivity., Conclusions: The rocuronium ImmunoCAP constitutes a reliable technique to diagnose rocuronium allergy, provided an assay-specific decision threshold is applied. IgE assays based on compounds bearing ammonium epitopes are confirmed to represent reliable tools to diagnose rocuronium allergy. High total IgE titers were observed to affect specificity of the assays.

Background: Diagnosis of anaphylaxis from neuromuscular blocking agents (NMBA) is not always straightforward., Objectives: To assess flow cytometric analysis of activated basophils (BAT) as a diagnostic instrument in anaphylaxis from rocuronium. To investigate whether the technique might help to identify cross-reactive and safe alternative compounds., Methods: For validation of the BAT, 14 patients with perioperative anaphylaxis demonstrating a positive skin test (ST) for rocuronium and eight individuals that tolerated rocuronium and a negative ST for this drug were enrolled. To confirm specificity of the BAT, five patients that tolerated atracurium or cisatracurium with a negative ST for rocuronium were tested. Basophil activation with rocuronium, vecuronium, atracurium, cisatracurium and suxamethonium was analysed flow cytometrically by labelling with anti-CD123/anti-HLADR/anti-CD63., Results: Sensitivity of BAT for rocuronium was 91.7% and specificity 100%. However, in two patients the BAT was lost as a diagnostic tool, as their cells were nonresponsive to positive control stimulation and allergen. Seven from the 12 responsive patients also demonstrated a clear basophilic activation for vecuronium. Moreover, according to ST and/or BAT cross-reactivity between rocuronium and vecuronium was suspected in 10/14 patients. Except one patient, all patients had negative BAT and ST investigations for atracurium and cisatracurium. Currently, five patients tolerated administration of cisatracurium. All control individuals demonstrated negative ST and BAT for all tested NMBA., Conclusions: The BAT constitutes a reliable instrument to diagnose anaphylaxis from rocuronium. The technique also allows quick and simultaneous testing of different potential cross-reactive NMBA and to tailor a safe alternative.

We report two cases of severe anaphylactic reactions to rocuronium. Diagnosis was confirmed by skin tests and specific IgE assay. Cross-reactivity to all neuromuscular blocking agents was investigated by intradermal tests and leucocyte histamine release test. Intradermal tests and leukocyte histamine release were negative for cisatracurium. The two patients had undergone a subsequent general anaesthesia using cisatracurium and did not present any adverse reaction.

Patients suspected of anaphylaxis during anaesthesia have been referred to the senior author's clinic since 1974 for investigation. Since release of rocuronium on to the worldwide market, concern has been expressed about its propensity to cause anaphylaxis. We identified 24 patients who met clinical and laboratory (intradermal, mast cell tryptase and morphine radioimmunoassay) criteria for anaphylaxis to rocuronium. The incidence of rocuronium allergy in New South Wales, Australia has risen in parallel with sales, while there has been an associated fall in reactions to other neuromuscular blocking drugs. Data from intradermal testing suggested that rocuronium is intermediate in its propensity to cause allergy in known relaxant reactors compared with low-risk agents (e.g. pancuronium, vecuronium) and higher-risk agents (e.g. alcuronium, succinylcholine).

Seventy-five consecutive patients referred to an anaesthetic allergy clinic were intradermally tested with atracurium and cisatracurium. With the exception of one patient the results were identical, suggesting that allergy to either drug is associated with allergy to the stereoisomer. For skin testing for allergy to neuromuscular blocking drugs it is only necessary to use either atracurium or cisatracurium and cisatracurium is the preferred drug.

The allergic history to anaesthetics in general and especially to synthetic myorelaxants, poses few etiological diagnostic problems in practice, because of on one hand the excellent collaboration between Anesthetists and Allergologists in the CHU at Angers and on the other because of the great sensitivity of skin testing. Why then have a predictive history for myorelaxants? The results of a study at the CHU at Angers on 15 patients showed sensitivity to anaesthetics in general (myorelaxants 86%, Diprivan) and/or an antibiotic, latex were very encouraging. One 15 new general anaesthetics a single minor incident was seen: the 15 patients had benefited from a predictive history.

The technique of Flow Cytometry for activation of basophils (TAB), expressed as the marker CD63, is at present one of the pathways of research applied to drug allergy. In this work are reported the results of TAB of Pneumoallergens and Hymenoptera venoms. TAB can define better than total IgE the atopy of the subject: in effect the fluorescence of the basophils is emphasized in comparison with non-atopic subjects. This hypothesis has been confirmed by a study of three groups of subjects. With regard to drug allergy, it is important to study patients in whom the observations have been documented very objectively by clinical history and positive skin tests to the drug, compared with a negative reference to the same drug. So, TAB has been shown to be very useful in diagnosis of allergy to certain drugs, such as the Myorelaxants.

The cross-reactivity of rocuronium with other neuromuscular blocking agents (NMBAs) was studied in 31 patients known to be allergic to a muscle relaxant. Tests for diagnosing cross-reactivity were skin tests (prick tests and intradermal tests: IDTs), detection by RAST assay of IgEs against the quaternary ammonium group (QAS-RIA: quaternary ammonium sepharose radio-immuno-assay), QAS-RIA inhibition test to detect IgE specificity, and leucocyte histamine release test (LHRT). Skin tests were performed with rocuronium, suxamethonium, gallamine, vecuronium, pancuronium, atracurium. The threshold for cross-reactivity was 10(-1) with all the NMBAs except for atracurium (10(-2)). The inhibition test and LHRT were performed with rocuronium and the NMBA responsible for the shock. Ten volunteers made up the control group for prick tests, QAS-RIA, LHRT. Cross-reactivity was found in 30 patients out of 31. Rocuronium did not cross-react in 10 patients out of 31. They had negative cutaneous tests and negative LHRTs. In one of the five patients allergic to all the NMBAs available, rocuronium was the only one which did not cross-react. In those 10 patients, rocuronium may be safely used for subsequent anaesthesia. In terms of allergy, rocuronium appeared to be very close to the other steroidal NMBAs.

The cross-reactivity between muscle relaxants (MRs) is a risk for inducing anaphylaxis in sensitized patients. The preventive use of monovalent haptens (MHs) was studied in 21 cases. Inhibition of the skin reactivity by mixing MRs and MHs was observed, as was the inhibition of leucocyte histamine release to MRs, up to 3 h after infusion of MHs. These results argue for the use of such a protocol, if surgery requires the use of a MR in patients at risk for anaphylaxis.

Serotherapy, an approach currently used to protect humans against animal bites or stings, is often too specific. To broaden antiserum paraspecificity, use of antibodies directed against areas shared by all members of a toxin family was previously proposed. MST2 is a mAb that recognizes all long-chain curaremimetic toxins (Charpentier et al. (1990) J. Mol. Recog. 3, 74-81). It binds to toxin residues that make contact with the toxin's target, e.g., the nicotinic acetylcholine receptor (AcChoR). We now show that MST2 also recognizes (-) nicotine, an agonist of AcChoR. Binding properties of MST2 therefore mimick, at least partially, binding properties of AcChoR. Injection in rabbits of MST2 mixed with adjuvant, elicited anti-idiotypic (anti-Id) antibodies that inhibited binding of the toxin to AcChoR. A proportion of these anti-Id antibodies specifically bound AcChoR and thereby mimicked the toxin. Furthermore, rabbits immunized with MST2 elicited auto-anti-anti-Id antibodies capable of binding the toxin. Our data provide a molecular explanation for the previously reported signs of myasthenia gravis as triggered by antibodies raised against cholinergic antagonists. Implications in the design of antisera to toxic proteins are discussed.

Intradermal skin tests (two dilutions) carried out systematically with 5 muscle-relaxant drugs were used to study the cross-reactivity between these drugs in 131 patients who had suffered from anaphylaxis. The skin tests were positive for at least 2 drugs in 65.6% of the cases. We observed a significant concordance (positive-positive or negative-negative skin tests) between pancuronium and vecuronium (p less than 0.01) and a significant correlation between the skin test diameters obtained with these 2 drugs (p less than 0.02 for wheals and p less than 0.01 for flares). Conversely, the lack of concordance between pancuronium and suxamethonium was significant (p less than 0.05). When comparing all the concordances obtained with each pair of drugs, it appeared that the concordance between pancuronium and vecuronium was significantly higher than all others. For other concordances, 2 main factors seemed to play a role: the N+ of the ammonium ions included in a ring as in pancuronium and the presence of a 'choline-like' side chain as in suxamethonium. But there was no significant correlation between skin test diameters. Altogether, these results suggest that in vivo there is no 'true' cross-reactivity between the drugs except frequently between pancuronium and vecuronium. In all other cases, the patients have probably specific IgE antibodies for each drug, all these antibodies being able to recognize the ammonium determinant; this common property may be insufficient to induce a clinical allergy.

Thirty-four patients (31 female and three male patients) with a previous anaphylactoid shock to muscle relaxants were investigated. The seric antimyorelaxant IgE was detected by radioimmunoassay (RIA), and the results were compared to intradermal test (IDR) reactions to dilutions of the commercial drugs. The RIA was carried out with a Sepharose-myorelaxant solid phase and anti-IgE 125I-labeled IgG. The results corresponded to the percentage of labeled anti-IgE bound on the solid phase. The RIA with Sepharose-alcuronium and Sepharose-choline was estimated positive from determination with normal sera (n = 12) when bound IgE was greater than 1.0% and 1.5%, respectively. The RIA and IDR were positive in 43.5% and 75%, respectively, of the cases, with a concordance of 66%. One test at least was positive in 79.4% of the cases. No correlation was found between IgE seric levels and the RIA nor between the cutaneous sensitivity and the RIA. Cross-reactivity with Sepharose-choline and Sepharose-alcuronium was observed in 50%, and it was demonstrated by IDR in only 34.2%. The RIA demonstrated the specificity of IgE to quaternary ammonium compounds as myorelaxant drugs. The positive IDR revealed the bridging of mast cell-bound specific IgE, depending on structural conditions, such as the flexibility of the molecules or the variable specificity of the antibodies, restricted to quaternary ammonium ions or enlarged to a broader part of the incriminated molecules.

Anaphylaxis to myorelaxants is the main etiology of adverse reactions to anesthetics and adjuvants. The diagnosis relies on skin tests--prick or intradermal tests--radio-immunoassays for series specific IgE, human basophil degranulation tests and leucocyte histamine++ release. 28 patients with an anaphylaxis to myorelaxants have been studied, using the two tests. Skin tests are the more specific and accurate ones. ARIA using a quaternary ammonium hydrated gel, is highly specific and its sensitivity reaches 80%. The leucocyte histamine release may be interest in evaluating anaphylaxis especially when another drug might be involved. The sensitivity of HBDT is low, indicating that HBDT is to be discarded as far as other tests have been developed, for myorelaxants. However, its usefulness for other drugs has to be compared to leucocyte histamine release.