Every effort should be made to evaluate the anesthesia log. Approximately 90% of PODR occur during or shortly after the induction of anesthesia, but only from the anesthesia protocol is one able to determine which drugs were previously administered and in which time sequence. The surgical report can also be helpful by including, e. g., disinfectants, dyes, or materials applied locally during implantation procedures, such as gentamicin, in the diagnostic work-up. Intravenously administered triggers generally elicit clinical reactions within a few minutes, whereas topically or percutaneously administered drugs usually cause reactions with a 1- to 2‑h delay.
Skin prick tests are performed in a first step to diagnose anaphylactic reactions; if negative, and to the extent that intravenous (i. v.) solutions of the drugs are available, intradermal tests are performed and readings taken after 20 min each time. Successive tests using increasing concentrations are recommended particularly for the diagnosis of more severe PODR, whereby the maximum concentrations used in skin prick tests generally correspond to undiluted drug solutions and a 1:10 dilution in intradermal tests. Exceptions are made primarily for drugs applied during induction of anesthesia, since particularly NMBA and morphine can cause false-positive test results due to their histamine-releasing properties (Table 2). A wheal diameter of at least 3 mm is regarded a positive skin prick test, while in intradermal testing, a diameter 3 mm larger than the intracutaneously administered depot of the drug solution compared with negative controls following 15–20 min is considered positive. Due to the high cross-reactivity of NMBA and the limited possibility to test these substances in provocation tests, skin testing with all preparations is recommended for this substance class in order to identify a skin test-negative NMBA as a potential alternative if the drug originally used tests positive.
To test for delayed-type reactions (e. g., local injection reaction to heparins, rash to antibiotics), a reading is generally taken of the 1:10 diluted intradermaly, as well as the undiluted epicutaneously, applied drug solutions after (1 to) 2 and 3 days (see ). In the case of high suspicion but negative results, further readings at 96 h and later can be helpful.
Some preparations, such as inhalation anesthetics and sterilant gases, cannot be used for skin testing.
Although IgE diagnostic tests are commercially available for individual beta-lactams (penicillin G and V, amoxicillin, ampicillin, and cefaclor), natural latex, chlorhexidine, suxamethonium, morphine, gelatin, and alpha-1,3-galactosidase (found, for example, in Gelafundin®), their sensitivity is moderate (<60%). The detection of IgE sensitization to pholcodine as an indication of cross-reactivity due to a corresponding sensitization to NMBA or opioids is currently the subject of controversy. Cellular in vitro tests, such as the basophil activation test or the lymphocyte transformation test and the enzyme-linked immunospot (ELISpot) assay to investigate either immediate or delayed-type sensitization to possible triggers, respectively, can be helpful in some cases; however, their sensitivity and specificity are to be viewed critically .
Provocation tests are the gold standard of diagnostic allergy testing and every effort should be made to use them in the case of negative or equivocal laboratory and skin test results (e. g., in suspected non-allergic hypersensitivity to NSAID or local anesthetics) in order to determine drug tolerability. However, various groups of substances, such as general and inhalational anesthetics as well as NMBA, are not amenable to provocation testing due to their pharmacological activity profile. Given the potential for severe hypersensitivity reactions, these tests should generally be carried out in centers with appropriate experience in monitoring and emergency treatment.