Standardised Drug Provocation Testing in Perioperative Hypersensitivity

Perioperative hypersensitivity reactions (POH) pose a risk for major morbidity and mortality in the perioperative period. After resolution of the initial reaction it is crucial to determine the culprit drug to allow safe anaesthetics for future procedures.However this is not easy, as many drugs are administered near simultaneously and both anaesthesia and surgery may provoke or mask many of the symptoms of a hypersensitivity reaction. Conventional testing seems to offer good predictive value based on the low incidence of POH in subsequent re-exposures after negative work-up. Despite negative work-up anaesthetists often chose not to re-administer an neuromuscular blocking agent (NMBA) used in the index reaction, especially if no other culprit was found. This introduces an important bias as this group (no culprit found, NMBA not re-exposed) might be at the highest risk of containing false negatives as NMBA are the most frequent cause of POH in our region.The same remark can be made regarding earlier attempts by our group and others at establishing the negative predictive value (NPV) of conventional testing through retrospective analysis of subsequent re-exposures.To truly establish the NPV for conventional testing and thus the need for DPT, a prospective approach is needed where all patients are challenged with index drugs after negative conventional testing.

Adult patients that are referred for diagnostic work-up for POH will be included if they have a clinical history fitting with POH.

All patients will first receive a full diagnostic work-up for all index products consisting of in vivo (skin tests) and in vitro (specific IgE and -for drugs in which it is available- basophil activation tests). Clinical reactions (both index reactions and any reactions during DPT) will be classified according to the National Audit Program (NAP-6) classification which separates non-fatal POH in 4 grades:

• NAP 1 (only cutaneous/mucosal signs)
• NAP 2 (circulatory or respiratory symptoms which don't require treatment)
• NAP 3 (circulatory or respiratory symptoms which require treatment or potential airway compromise)
• NAP 4 (fulfilling indications for cardiopulmonary resuscitation)

Skin tests will be performed at the allergology day clinic following the protocols of the French Society for Anaesthesia and Intensive Care and the French Society of Allergology. Based on these results we make a distinction between patients with an identified culprit and those without an identified culprit.

If a culprit has been found, all other index drugs are challenged at therapeutic doses. The standard testing is performed for alternatives for the culprit drug in the same drug class (such as NMBA) and one drug from this class that tests negative is also used in a challenge at a therapeutic dose.

If no culprit has been found after the initial work-up of skin tests and in vitro tests the next step is determined by the severity of the initial reaction. In NAP-6 grade 1-3 reactions all index drugs are challenged at therapeutic doses. As the benefits of DPT have yet to be fully quantified the risk-benefit analysis in the most severe reactions (NAP 4) is difficult to make. Hence, we use an 'confirmation by elimination' principle in these cases in which we only challenge with the drugs that do not carry the highest likelihood of being the culprit. This likelihood is based on both timing and epidemiology as NMBA are a much more common cause of POH in our region than all other anaesthetics combined. By eliminating all other drugs we 'clear' them for future use and gain confidence in our suspicion of the most likely culprit without having to administer them in this population.

Inclusion criteria

• patients consulting the allergology department of the Antwerp University hospital medical with a history consistent with perioperative hypersensitivity
• Indication for diagnostic work-up as determined at an interdisciplinary meeting between allergologists and anaesthetists
• willing to sign separate informed consent forms for both general anaesthesia and the Drug Provocation Test.

Exclusion criteria

• patient refusal
• incomplete diagnostic work-up
• history inconsistent with perioperative hypersensitivity