A case report: intravenous provocation testing clears rocuronium after sugammadex-rocuronium complex-induced anaphylaxis

Perioperative anaphylaxis is a life-threatening condition, of which the neuromuscular blocking agents (NMBAs) are the causative agent in 40–60% of perioperative immediate hypersensitivity reactions, especially rocuronium.¹ Sugammadex is the reversal agent of rocuronium, which acts by forming a high-affinity complex (S-R-Cx) with rocuronium in plasma and reduces the amount of available rocuronium. Hypersensitivity reactions to sugammadex have been reported, but its determination as a causative agent may be difficult, as not only the sugammadex, but also S-R-Cx may be the culprit.² We report a case in which identification of the causative agent was inconclusive based on skin prick testing alone and subsequent drug provocation testing was required to rule out rocuronium hypersensitivity.

We obtained informed consent from the patient to publish the case report.

Case report

We report a case of a 65-yr-old man with a medical history of allergic asthma and NSAID allergy who received general anaesthesia for treatment of a perianal abscess. Anaesthesia was induced with propofol 400 mg, fentanyl 300 mcg, and rocuronium 50 mg. Concomitantly, 4 mg dexamethasone was administered. The surgical procedure lasted 47 min and anaesthesia was uneventful until 160 mg sugammadex was administered. Immediately after administration, hypotension (60/40 mm Hg), tachycardia (140 beats min⁻¹), and bronchospasm were noticed. Perioperative anaphylaxis was suspected, and the patient recovered after administration of 500 ml 0.9% natriumchloride, 4 mg clemastine, 0.5 mg epinephrine, 0.6 mg phenylephrine, 25 mg prednisone, and 2.5/0.5 ml inhaled salbutamol/ipratropium. The patient was discharged home the following day and referred to the allergology department.

An allergological workup occurred 3 months later. Tryptase levels during the reaction were not assessed but basal tryptase was 9.3 μg L⁻¹ (reference value, 2.1–10.9 μg L⁻¹). Skin prick tests (SPTs) for latex and chlorhexidine were negative. Moreover, SPT and intracutaneous tests (ICTs) were negative for propofol (10 mg ml⁻¹; SPT 1:1, ICT 1:100 and 1:10), fentanyl (50 mcg ml⁻¹; SPT 1:1 and ICT 1:10), dexamethasone (4 mg ml⁻¹; SPT 1:1, ICT 1:100 and 1:10), and rocuronium (10 mg ml⁻¹; SPT 1:1, ICT 1:2000 and 1:200). Interestingly, the SPT with sugammadex (100 mg ml⁻¹; 1:1) was negative but the ICTs (100 mg ml⁻¹; ICT 1:100 and 1:10) showed aspecific erythema without a wheal. Finally, SPT with a mixture of sugammadex and rocuronium (35.7 mg sugammadex and 10 mg ml⁻¹ rocuronium) was positive. Taken together, immunoglobulin E (IgE)-mediated allergy to S-R-Cx was diagnosed.

To specifically rule out a false-negative result of the skin testing for rocuronium, an i.v. drug provocation test at the ICU was performed, based on previous study protocols.^3,4 To preclude the presence of a rocuronium allergy, the patient received incremental i.v. doses of manually diluted rocuronium 2.5 mg ml⁻¹ with NaCl 0.9% (2.5 mg–5 mg–10 mg) with an interval of 30 min, based on previous studies.³ The patient showed expected signs related to rocuronium pharmacological properties, including a dose-dependent weakness of the facial muscles and perioral paraesthesia for several minutes after each dose, but no signs of anaphylaxis. Thus, an IgE-mediated rocuronium allergy was ruled out.

Discussion

Skin tests are recommended as the first step in assessing an NMBA allergy. However, their diagnostic value in IgE-mediated drug allergies remains limited. NMBAs, especially benzylisoquinolines, may directly stimulate histamine release which will lead into false positive results.⁵ Drug provocation tests remain the gold standard in the diagnosis of suspected NMBA allergy, as false-positive skin tests may lead to unnecessary drug avoidance. Alternatively, false-negative results may occur as well, albeit rare. In this case, further testing after a negative SPT was required to exclude a rocuronium allergy with more certainty.

For NMBAs, the major drawback of drug provocation is the muscle paralysis. To limit the extent of muscle paralysis, testing with the maximum therapeutic dose is not routinely performed with NMBA drug provocation.⁶ Instead, a graded dose approach with low doses is often used, although this may carry a risk of drug desensitisation. There are centres examining whether a full-dose provocation should be used; however, variation exists in the approach to NMBA challenge testing.⁷ Overall, awake i.v. NMBA drug provocation should be performed in allergy centres where allergologists and anaesthesiologists collaborate in high-care units.

In this case, an IgE-mediated allergy to S-R-Cx led to perioperative anaphylaxis, a relatively rare occurrence.^2,8 However, sugammadex is a relatively new drug and its use is increasing, making it possible that the incidence of anaphylaxis may increase over time. Allergy occurs either from an IgE-mediated reaction to sugammadex or to the drug neoantigen formed by the S-R-Cx molecule.⁹ For this reason, it is important to perform skin testing not only with the suspected perioperative drugs separately, but also with a sugammadex-rocuronium mixture. This is highlighted in this case report, as skin testing with sugammadex was nonspecific, but skin testing with S-R-Cx was clearly positive.

Data on potential cross-reactivity with solely rocuronium in cases of S-R-Cx allergy are lacking.^8,9 As skin testing with rocuronium was negative, awake i.v. drug provocation with rocuronium was performed to exclude concomitant rocuronium allergy. We hereby report a unique case where drug provocation with rocuronium was safe and well tolerated in the background of a S-R-Cx allergy. However, the doses for the provocation test, and the proportion of the rocuronium and sugammadex concentration used for SPT and ICT, have not been thoroughly investigated.⁶ Further research into safe and appropriate dosages is warranted.

In conclusion, allergological workup after perioperative anaphylaxis should include skin testing with all suspected perioperative drugs separately. If rocuronium and sugammadex were administered, additional skin testing with the sugammadex and rocuronium mixture is essential to diagnose S-R-Cx IgE-mediated allergy. We have shown that i.v. awake drug provocation was safe and well tolerated. Therefore, rocuronium can be used safely, but cannot be antagonised with sugammadex. Collaboration of allergologists and anaesthesiologists is indispensable in such cases to rule out rocuronium allergy and to ensure safe use of NMBAs in future general anaesthesia.

Declarations of interest

The authors declare that they have no conflicts of interest.

Handling Editor: Susan M. Goobie