Standardised Drug Provocation Testing in Perioperative Hypersensitivity

The goal of this clinical trial is to evaluate the safety and outcome of systematic drug provocation testing with anaesthetics at therapeutic doses in adult patients undergoing diagnostic work-up for 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. Workflow: Negative in vitro (sIgE, BAT) and negative in vivo (skintests) tests for all index products NAP 1-3: provocation tests for all index drugs NAP 4: confirmation by elimination: provocation with index products in order of ascending likelihood so as to clear drugs unlikely to be the culprit and 'confirm' the likely culprits such as NMBA without administering them Positive in vitro (sIgE, BAT) and/or positive in vivo (skintests) test for one or more index products For the positive index products: sIgE, BAT and skintests for alternatives in same drug class NAP 1-4: Provocation test for one safe alternative after negative tests For the negative index products: NAP 1-4: provocation test for index products Concurrently with the work-up for anaesthetics, possible non-anaesthetic triggers (antibiotics, antiseptics, latex, …) are investigated in the same sequence (first in vitro and in vivo tests, followed by DPT) with provocations taking place in the allergology day hospital using the regular standardized protocols. DPT with anaesthetics take place in the OR or PACU under supervision of an anaesthetist. In a first session hypnotics, benzodiazepines, opiates and/or NMBA's are administered in the PACU. In this first session up to 1/10th of a therapeutic dose of NMBA's is administered while for all other drugs we use a full therapeutic dose. In a second session that takes places in the OR NMBA's are given up to a full therapeutic dose after induction -with anaesthetics that have previously been deemed safe- and intubation. Both in the OR and PACU all patients will receive standard monitoring according to the American Society of Anesthesiologists which includes pulse oximetry, 5-lead electrocardiography and non-invasive blood pressure measurements. During spontaneous ventilation oxygen will be supplemented through a nasal cannula equipped with a gas sampling line for capnography. Quantitative neuromuscular monitoring will be available in all cases where NMBA are administered. All drugs for emergent treatment of any hypersensitivity reaction (including adrenaline and vasopressors) and equipment for respiratory support will be present for any provocation. Before the procedure is started baseline parameters are established, the skin is investigated for rashes and the patient is asked whether they have any respiratory or cutaneous complaints to establish a baseline. During the DPT the circulatory and respiratory system as well as the skin and mucosa will be actively monitored for signs of POH. If symptoms develop caused by a hypersensitivity reaction, the DPT is suspended, prompt treatment according to current recommendations is initiated and tryptase is sampled within the appropriate timeframe. The DPT is then considered positive. If no reaction occurs, the DPT is considered negative. Therapeutic doses are listed in the table below. In the first session doses are administered in a stepwise approach every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose, 3/10th of the dose and ultimately 6/10th of the dose. After the last administration of a drug a 60 minute interval is observed before moving on to the next drug. After the last administration of the last drug the patient is observed for at least 60 minutes and until the usual PACU discharge criteria are met. For NMBA's the first session ends after 1/10th of the therapeutic dose. If the provocation is negative, the patient is planned for a second session under general anaesthesia where the NMBA will be administered at 3/10th of the therapeutic dose followed 15 minutes later by 7/10th of the therapeutic dose. For each provocation a checklist will be available containing all information regarding the drugs to be administered and their doses as well as drugs to be used in case of anaphylaxis or need for emergency intubation. Therapeutic dosis of anaesthetic drugs: full dose (1/100th-1/10th-3/10th-6/10th) (for NMBA: 1/100th-1/10th-3/10th-7/10th) Hypnotics Propofol 2mg/kg (0.02-0.2-0.6-1.2mg/kg) Ketamine 1mg/kg (0.01-0.1-0.3-0.6mg/kg) Etomidate 0.2mg/kg (0.002-0.02-0.06-1.2mg/kg) Benzodiazepines Midazolam 0.05mg/kg (0.0005-0.005-0.015-0.03mg/kg) Analgesics Fentanyl 1µg/kg (0.01-0.1-0.3-0.6µg/kg) Sufentanil 0.1µg/kg (0.001-0.01-0.03-0.06µg/kg) Remifentanil 0.5µg/kg (0.005-0.05-0.15-0.3µg/kg) Alfentanil 10µg/kg (0.1-1-3-6µg/kg) NMBA Rocuronium 0.6mg/kg (0.006-0.06-0.18-0.42mg/kg) Atracurium 0.5mg/kg (0.005-0.05-0.15-0.35mg/kg) Cisatracurium 0.15mg/kg (0.0015-0.015-0.045-0.105mg/kg) Succinylcholine 1mg/kg (0.01-0.1-0.3-0.7mg/kg)

Allergic Reaction, Hypersensitivity, Perioperative Complication, Anaphylaxis, Anaphylactic Reaction, Immediate Hypersensitivity, Hypersensitivity, Drug

Incremental administration of propofol up to a cummulative full therapeutic dose (2mg/kg) in POH patients investigated for propofol. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose, 3/10th of the dose and ultimately 6/10th of the dose (0.02mg/kg-0.2 mg/kg -0.6 mg/kg -1.2mg/kg).

Incremental administration of ketamine up to a cummulative full therapeutic dose (1mg/kg) in POH patients investigated for ketamine. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose, 3/10th of the dose and ultimately 6/10th of the dose (0.01 mg/kg -0.1 mg/kg -0.3 mg/kg -0.6mg/kg).

Incremental administration of etomidate up to a cummulative full therapeutic dose (0.2mg/kg) in POH patients investigated for etomidate. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose, 3/10th of the dose and ultimately 6/10th of the dose (0.002 mg/kg -0.02 mg/kg -0.06 mg/kg -1.2mg/kg).

Incremental administration of midazolam up to a cummulative full therapeutic dose (0.05mg/kg) in POH patients investigated for midazolam. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose, 3/10th of the dose and ultimately 6/10th of the dose (0.0005 mg/kg -0.005 mg/kg -0.015 mg/kg -0.03mg/kg).

Incremental administration of fentanyl up to a cummulative full therapeutic dose (1mcg/kg) in POH patients investigated for fentanyl. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose, 3/10th of the dose and ultimately 6/10th of the dose (0.01 mcg/kg -0.1 mcg/kg -0.3 mcg/kg -0.6mcg/kg).

Incremental administration of sufentanyl up to a cummulative full therapeutic dose (0.1mcg/kg) in POH patients investigated for sufentanyl. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose, 3/10th of the dose and ultimately 6/10th of the dose (0.001 mcg/kg -0.01 mcg/kg -0.03 mcg/kg -0.06µg/kg).

Incremental administration of alfentanil up to a cummulative full therapeutic dose (10mcg/kg) in POH patients investigated for alfentanil. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose, 3/10th of the dose and ultimately 6/10th of the dose (0.1 mcg/kg -1 mcg/kg -3 mcg/kg -6µg/kg).

Incremental administration of remifentanil up to a cummulative full therapeutic dose (0.5mcg/kg) in POH patients investigated for remifentanil. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose, 3/10th of the dose and ultimately 6/10th of the dose (0.005 mcg/kg -0.05 mcg/kg -0.15 mcg/kg -0.3µg/kg).

Incremental administration of rocuronium up to a cummulative full therapeutic dose (0.6mg/kg) in POH patients investigated for rocuronium. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose (0.006 mg/kg -0.06 mg/kg ). In a second session 3/10th of the dose and ultimately 7/10th of the dose (0.18 mg/kg -0.42mg/kg) are administerd under general anesthesia.

Incremental administration of atracurium up to a cummulative full therapeutic dose (0.5mg/kg) in POH patients investigated for atracurium. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose (0.005 mg/kg -0.05 mg/kg ). In a second session 3/10th of the dose and ultimately 7/10th of the dose (0.15 mg/kg -0.35mg/kg) are administered under general anesthesia .

Incremental administration of cisatracurium up to a cummulative full therapeutic dose (0.15mg/kg) in POH patients investigated for cisatracurium. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose (0.0015 mg/kg -0.015 mg/kg ). In a second session 3/10th of the dose and ultimately 7/10th of the dose (0.045 mg/kg -0.105mg/kg) are administered under general anesthesia .

Incremental administration of succinylcholine up to a cummulative full therapeutic dose (1mg/kg) in POH patients investigated for succinylcholine. Doses will be administered every 15 minutes starting at 1/100th of the dose, followed by 1/10th of the dose (0.01 mg/kg -0.1 mg/kg). In a second session 3/10th of the dose and ultimately 7/10th of the dose (0.3 mg/kg -0.7mg/kg) are administered under general anesthesia.

Prevalence of hypersensitivity during direct provocation for drugs that tested negatively in conventional tests.

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