Rocuronium allergy David Spoerl HUG (University Hospital Geneva)
Rocuronium use
Sugammadex (Bridion ) Modified γ-cyclodextrin with 8 sugar molecules Designed to encapsulate rocuronium and antagonize its pharmaceutical effects Several case reports describing reversal of rocuronium-induced anaphylaxis Whether sugammadex is useful for antagonizing IgE-mediated or pseudoallergic reactions due to rocuronium remains a matter of debate
NMBA anaphylaxis (Quizz) Up to 75 % of reactions have been reported upon first known contact with the NMBA Quaternary and tertiary ammonium (QA) ions are thought to be the main allergenic epitopes in NMBAs. The estimated prevalence of cross-reactivity between NMBA is about 65% by skin tests and 80% by radioimmuno assay (RIA) inhibition tests Epitopes other than ammonium have been implicated in IgEmediated anaphylaxis to general anesthetics. Allergic reactions to NMBAs are almost exclusively IgE-mediated
1997-2004 Allergy Clin Immunol. 2011;128:366-73
Acta Anaesthesiol Scand. 2003;47:576-82. Rocuronium and cisatracurium-positive skin tests in non-allergic volunteers: determination of drug concentration thresholds using a dilution titration technique. Berg CM, Heier T, Wilhelmsen V, Florvaag E. CONCLUSION: Nonmast-cell-mediated positive intradermal skin reactions are frequently occurring with rocuronium, even at vial dilution 1 : 1000.
NMBA anaphylaxis Allergic reactions to NMBAs are almost exclusively IgE-mediated?
Case 1 A 36 year old atopic female Fentanyl, lidocaine, propofol, suxamethonium and ceftriaxone, followed by repeated injections of rocuronium for abdominal surgery At the end of the procedure: generalized urticarial rash associated with bronchoconstriction and hypoxemia. She was treated with anti-histaminics, methylprednisolone and nebulized adrenaline, but only after treatment with 400 mg i.v. sugammadex her condition improved rapidly. Tryptase was not measured during the reaction.
Case 1-work up Skin tests for PPL, MD, amoxicillin, ceftriaxone, lidocaine, procaine, fentanyl, suxamethonium, propofol, latex and chlorhexidine: negative. Specific IgE for penicillin G and V, ampicillin, amoxicillin, chlorhexidine, QA, rocuronium, suxamethonium, ethylene oxide and latex were negative. BAT was negative for atracurium, chlorhexidine, rocuronium (concentration 1000, 100 and 10 ng/ml; highest stimulation index 1.5) and the mixture of rocuronium and sugammadex (concentration 1000, 100 and 10 ng/ml; highest stimulation index 0.9). The basal tryptase was within the normal range 6 months later. IDT for rocuronium at a concentration of 10 mg/ml: erythema without papule formation at the 10-3 and 10-2 dilution, clearly positive at 10-1 dilution, which is known to be irritative. The mixture of sugammadex and rocuronium (1:1 molecular) was negative in all tested dilutions (mild erythema at the 10-1 dilution).
Case 2 A 48 year old female scheduled for surgical resection of an unexplained left parietal cerebral mass. Induction with propofol and fentanyl, and 40 mg rocuronium: tachycardia, generalized urticarial rash, profound hypotension (mean arterial pressure between 40 and 50 mmhg). Hydrocortisone and clemastine were administered once. Despite repeated epinephrine injections and intravenous fluids the patient remained hypotensive. 53 minutes after the induction, 200 mg of sugammadex were injected, resulting in rapid hemodynamic normalization, disappearance of the urticarial rash and extubation 15 minutes later. Tryptase level of 36 mg/l (normal value <11.1 mg/l).
Case 2-work up Prick tests and IDT were negative to all substances used during the procedure as well as to latex, and chlorhexidine. Specific IgE were negative for rocuronium, chlorhexidine, suxamethonium, QA, ethylene oxide, and latex. BAT was negative for rocuronium, rocuronium and sugammadex mixture, and atracurium (same concentrations as in case 1, highest stimulation index for rocuronium 1.9, for rocuronium and sugammadex mixture 0.9). Basal tryptase was within normal range. Prick tests were positive to pure rocuronium 10 mg/ml, and negative for the 1:1 mixture of rocuronium and sugammadex. IDT to rocuronium was positive at 10-2 and 10-1 dilution, which is a presumably irritative dose. IDT using the 1:1 mixture of rocuronium and sugammadex was negative at 10-2 and 10-1 dilution
Case 3 A 69 year old male scheduled for craniotomy for suspected glioblastoma multiforme. Induction with propofol, sufentanyl and injection of 50 mg rocuronium: severe hypotension (mean arterial pressure between 40 and 50 mmhg), requiring intravenous fluids and epinephrine (total dose of 1.5 mg). 60 minutes after the first dose of rocuronium, a second dose of 20 mg was injected to facilitate transoesophageal echocardiography, that did not show signs of cardiogenic shock. 40 minutes after the second dose of rocuronium, 400 mg of sugammadex were injected. The blood pressure stabilized rapidly and the patient was extubated after a second dose of 200 mg of sugammadex, injected 20 minutes later. The patient did not receive corticosteroids or anti-histaminic drugs before extubation. Tryptase was within normal range during the reaction and two hours later
Case 3-work up Because of the necessity to rapidly perform the surgical procedure, skin tests were performed only three days after the reaction and still under corticosteroid treatment, possibly compromising their validity. Skin tests for all substances used during the procedure were negative. No specific IgE were found against rocuronium, chlorhexidine, suxamethonium, QA, and latex. Due to low basophil count (<0.01% of leucocytes), BAT was inconclusive. IDT for rocuronium was weakly positive at a 10-1 dilution, and negative for the 1:1 rocuronium and sugammadex mixture at the same dilution
Summary Two patients received standard treatment for anaphylaxis, including corticosteroids, anti-histaminic drugs and adrenaline, without sufficient apparent response. One patient received only epinephrine. The rapid clinical improvement within minutes after sugammadex in the three patients can thus not be explained by the standard treatment for anaphylaxis. Hypersensitivity to other drugs used during surgery in all three patients could not be identified by skin and specific ige-testing as well as BAT. Rocuronium hypersensitivity could not be demonstrated in the three patients, neither in vivo by skin tests nor in vitro by IgE to QA, IgE to rocuronium or BAT. Sugammadex mixed in a 1:1 ratio with rocuronium was able to neutralize the irritative effect of rocuronium in all performed skin tests.
Your evaluation?
Non-IgE mediated activation: hmrgprx2 Nature. 2015; 519: 237 241.
Your evaluation? Our hypothesis is that rocuronium induced a non-ige (anaphylactoid/ pseudoallergic) reaction in our patients and that sugammadex was able to reverse this reaction
Investigations-HUG
Investigations-HUG
Conclusions We report three cases of probable non-ige mediated (pseudo-allergic, anaphylactoid) reactions to rocuronium, which rapidly resolved after administration of sugammadex. Our study confirmed the specificity of sugammadex for inhibiting rocuronium induced pseudo-allergic reaction, and not other NMBA induced non-ige mediated reactions. Our study speak against an unspecific stabilizing effect of sugammadex on mast cells and support our hypothesis that sugammadex suppresses rocuronium specific, non-ige mediated mast cell activation.
Future perspectives It is possible that the high rate of anaphylactic reactions reported in NMBA naïve patients, as well as the high percentage of cross-reactivity reported in NMBA allergic patients (mostly based on skin test results), might in fact be due to the effects of NMBA on the hmrgprx2 receptor and therefore be pseudo-allergic (anaphylactoid) and not allergic. This mechanism may also explain the irritative reaction in skin tests with NMBAs. Further studies in larger cohorts are needed to clarify the role hmrgprx2 receptor in immediate type reactions to drugs. In the meanwhile, neither the presence of IgE in the serum nor positive skin tests per se allows to affirm that a given anaphylactic reaction is IgE mediated.
Thank you
Investigations-literature Sugammadex is able to prevent basophil activation by rocuronium, provided that sugammadex and rocuronium were pre-incubated prior to basophil stimulation (Anaesthesia 2011;66:526-527. ) These in vitro experiments were consistent with data from skin tests in rocuronium sensitized patients: Clarke et al. showed that these patients were anergic to sugammadex-bound rocuronium and concluded that sugammadex was able to prevent rocuronium from interacting with the immune system, presuming an underlying IgE mediated mechanism. (Anaesthesia 2012;67:266-273).
Mast cell activation Nat Rev Immunol. 2004;4:787-99.
In vitro tests: sige IgE to suxamethonium has repeatedly been reported to be too insensitive to diagnose allergy from NMBAs in general (sensitivity varying between 30 and 60%) IgE QA: Sensitivity 88-97%, specificity 97-100% (Anesthesiology. 2003;99:536-45) IgE Rocuronium: sensitivity 68%, specificity 93% with 0.35kUa/l. Morphine: Sensitivity of 88% and specificity of 100 % 5% of the sera of blood donors and 10% of the sera routinely analysed in two allergy laboratories demonstrated IgE reactivity for morphine (Acta Anaesthesiol Scand 2005;49:437 444). Anesthesiology 2007; 107:253 9
In vitro tests: sige Anesthesiology 2007; 107:253 9
Spec=18/(18+13)=58 Allergy 2011; 66: 1014 1019
RE-exposure
RE-exposure
NMBA anaphylaxis Allergic reactions to NMBAs are almost exclusively IgE-mediated?