DA Drug allergy Background Allergy testing for perioperative drug re- ELISpot Enzyme-linked immunospot actions poses a particular diagnostic challenge. Neu- IgE Immunoglobulin E romuscular blocking agents (NMBA) and antibiotics NMBA Neuromuscular blocking agents are among the most common triggers. In principle, NSAID Non-steroidal anti-inﬂammatory drugs however, any drug administered perioperatively is ca- PODR Perioperative drug reaction pable of causing a hypersensitivity reaction. Methods This article is an overview of selected sci- entiﬁc articles and is based on research in PubMed, Introduction specialist databases, and guidelines. Results Besides patient’s history and laboratory tests Perioperative drug reactions (PODR) are deﬁned as (the latter being feasible to only a limited extent), skin hypersensitivity reactions to drugs administered in tests play a particularly important role. To obtain clin- immediate temporal relation to—i. e., before, during, ical relevant results, profound knowledge on the best or after—a surgical procedure. According to various point in time for testing, the drug concentrations to studies, reactions of this kind have an incidence of be used, how to perform tests correctly, and the as- approximately 1:10,000 procedures, with the number sessment criteria is of special importance. of unknown cases estimated to be much higher. They Conclusion Final outcomes of the diagnostic proce- are generally immediate reactions (onset less than dures should be providing thorough information of 1 h following administration of the triggering drug); the patient about the ﬁndings, drugs that should be around two thirds are immunoglobulin E (IgE)-medi- avoided in the future as well as alternative prepara- ated and one third is non-allergic in nature. T-cell- tions, and, if necessary, preventive measures to be mediated delayed-type reactions are rare. Due to taken in the event of further surgical interventions. patient history-related limitations (patient’s unaware- ness of reactions under general anesthesia, anesthetic Keywords Drug allergy · Perioperative · Neuro- log often not available or difﬁcult to read), the multi- muscular blocking agents · Anesthetics · Prophylaxis tude of different drugs administered, and the limited possibilities to test some preparations (see below), allergy testing in PODR poses a particular challenge. Clinical symptoms Prof. Dr. W. Pfützner () Department of Dermatology and Allergology, University Skin, cardiovascular, and respiratory symptoms are Hospital Marburg, Baldingerstraße, 35043 Marburg, among those most commonly seen. Skin reactions Germany firstname.lastname@example.org are described less frequently in this context than in other forms of anaphylaxis. However, skin rashes such K. Brockow as urticaria or ﬂushing may be concealed by surgical Department of Dermatology and Allergology am drapes. Cardiac symptoms such as hypotension and Biederstein, Technical University of Munich, Munich, Germany tachycardia can be misinterpreted as pharmacologi- 126 Perioperative drug reactions – practical recommendations for allergy testing and patient management K mini-review Table 1 Elicitors of perioperative drug reactions cal side effects and mechanical respiratory difﬁculties may be attributed to insufﬁcient sedation. Unusual Substance group Examples reactions such as myocardial ischemia due to cardio- Neuromuscular blocking Polarizing: atracurium, cisatracurium, agents mivacurium, pancuronium, rocuronium, vascular spasms or paradoxical bradycardia are also vecuronium possible. Delayed reactions are seen hours to days Depolarizing: suxamethonium following the surgical procedure in the form of locally Antibiotics Systemic: penicillins, cephalosporins, indurated plaques at the injection site (e.g., delayed- quinolones type reactions to heparins), delayed urticaria and/or Local: gentamicin angioedema (e. g., as a manifestation of analgesic hy- Analgesics (NSAID) Paracetamol, ibuprofen, metamizole persensitivity to cyclooxygenase inhibitors), as well as delayed-type hypersensitivity rashes (particularly if Natural rubber latex (Powdered) natural rubber latex gloves drug administration is ongoing following the proce- Disinfectant Chlorhexidine, povidone-iodine dure, e. g., continued antibiotic or analgesic adminis- Colloids Dextrans, Gelafundin (alpha-Gal) tration). Radiocontrast agents Iotrolan, iodixanol Opioids Fentanyl, remifentanil, alfentanil, sufentanil, Triggers morphine General anesthetics Propofol, ketamine, thiopental, etomidate Neuromuscular blocking agents (NMBA), which can Heparins Heparin, low-molecular-weight heparins elicit both IgE-mediated and non-allergic reactions, Corticosteroids Prednisolone are among the commonest triggers of PODR (approx- Drug excipients Methyl cellulose, polyethylene glycol imately 60%), followed by natural rubber latex (around Sedatives (benzodiazepines) Midazolam 20%), antibiotics (particularly beta-lactams, 15%), and Local anesthetics Lidocaine volume expanders (approximately 3%). However, the Dyes Patent blue, methylene blue relevanceof latex is on thewane given themostly abounded use of powdered latex gloves in the sur- Sterilant gases Ethylene oxide gical setting. Other, to an extent far rarer, triggers NSAID non-steroidal anti-inﬂammatory drug include general anesthetics (e. g., propofol), opioids, non-steroidal anti-inﬂammatory drugs (NSAID), the disinfectant chlorhexidine, heparins, dyes, benzodi- Patient history azepines, and local anesthetics. Corticosteroids can also be causative in very rare cases. The sterilant gas Every effort should be made to evaluate the anesthe- ethylene oxide and drug additives have also been re- sia log. Approximately 90% of PODR occur during ported eliciting PODR (Table 1). or shortly after the induction of anesthesia, but only from the anesthesia protocol is one able to deter- mine which drugs were previously administered and Diagnostic allergy testing in which time sequence. The surgical report can also be helpful by including, e. g., disinfectants, dyes, or At the time of the reaction materials applied locally during implantation proce- In the case of suspected PODR, serum to measure dures, such as gentamicin, in the diagnostic work-up. mast cell tryptase should be taken 1–2 h following on- Intravenously administered triggers generally elicit set of the ﬁrst clinical symptoms (Fig. 1). This is el- clinical reactions within a few minutes, whereas top- evated in up to 80% of anaphylactic reactions com- ically or percutaneously administered drugs usually pared to baseline (thus the absence of elevated levels cause reactions with a 1- to 2-h delay. does not rule out a PODR). Increases of more than 2 ng/ml plus 20% of the basal level, which should be Skin tests measured 24 h following the reaction at the earliest, are considered positive. Skin prick tests are performed in a ﬁrst step to diag- nose anaphylactic reactions; if negative, and to the extent that intravenous (i. v.) solutions of the drugs are Following a reaction available, intradermal tests are performed and read- Skin tests, as well as in vitro and provocation tests ings taken after 20 min each time. Successive tests if necessary, are used to identify the trigger. These using increasing concentrations are recommended should ideally be performed 4 weeks at the earliest, particularly for the diagnosis of more severe PODR, but not later than 6 months, following the PODR whereby the maximum concentrations used in skin (Fig. 1). If earlier testing is required, e. g., in cases prick tests generally correspond to undiluted drug where a surgical procedure interrupted due to a PODR solutions and a 1:10 dilution in intradermal tests. cannot be postponed for such a long period of time, Exceptions are made primarily for drugs applied dur- positive test results are deemed conclusive. However, ing induction of anesthesia, since particularly NMBA negative tests do not reliably exclude sensitization. and morphine can cause false-positive test results K Perioperative drug reactions – practical recommendations for allergy testing and patient management 127 mini-review Allergy Opmal testing me period for OP PODR possible allergy tesng 12–1 h > 24 h 28 days 6 months 1–2 h beforehand Basal Serum Premedicaon serum tryptase b if necessary tryptase Fig. 1 Recommended time sequence for the specialist man- false-negative results. Prophylactic premedication is recom- agement of perioperative drug reactions (PODR). ( If it is mended particularly in cases where potential PODR triggers essential for a further operative procedure (OP) to be car- need to be administered again or in patients with mast cell ried out promptly, skin tests can be performed 1–28 days disease, although the preventive effect is not reliable) after the PODR, taking into consideration the possibility of due to their histamine-releasing properties (Table 2). Provocation tests A wheal diameter of at least 3 mm is regarded a pos- itive skin prick test, while in intradermal testing, Provocation tests are the gold standard of diagnos- a diameter 3 mm larger than the intracutaneously ad- tic allergy testing and every effort should be made to ministered depot of the drug solution compared with use them in the case of negative or equivocal labora- negative controls following 15–20 min is considered tory and skin test results (e. g., in suspected non-al- positive. Due to the high cross-reactivity of NMBA lergic hypersensitivity to NSAID or local anesthetics) and the limited possibility to test these substances in in order to determine drug tolerability. However, vari- provocation tests, skin testing with all preparations ous groups of substances, such as general and inhala- is recommended for this substance class in order tional anesthetics as well as NMBA, are not amenable to identify a skin test-negative NMBA as a potential to provocation testing due to their pharmacological alternative if the drug originally used tests positive. activity proﬁle. Given the potential for severe hyper- To test for delayed-type reactions (e. g., local injec- sensitivity reactions, these tests should generally be tion reaction to heparins, rash to antibiotics), a read- carried out in centers with appropriate experience in ing is generally taken of the 1:10 diluted intradermaly, monitoring and emergency treatment. as well as the undiluted epicutaneously, applied drug solutions after (1 to) 2 and 3 days (see ). In the case Practical recommendations and guidance follow- of high suspicion but negative results, further readings ing testing at 96 h and later can be helpful. Some preparations, such as inhalation anesthetics Drugs that cause reactions in skin or laboratory tests and sterilant gases, cannot be used for skin testing. should be avoided, unless a false-positive test reac- tion (e. g., to histamine liberators) can be proven by a negative provocation test. Positive skin tests or the Laboratory tests detection of speciﬁc IgE antibodies to beta-lactams, Although IgE diagnostic tests are commercially avail- natural rubber latex, chlorhexidine, and pyrazolone able for individual beta-lactams (penicillin G and V, analgesics (in particular metamizole) have high pre- amoxicillin, ampicillin, and cefaclor), natural latex, dictive value. Patient history data, test ﬁndings, drugs chlorhexidine, suxamethonium, morphine, gelatin, to be avoided, and recommended alternative drugs and alpha-1,3-galactosidase (found, for example, in are documented in an allergy passport, which should Gelafundin ), their sensitivity is moderate (<60%). be presented to physicians and pharmacists in the fu- The detection of IgE sensitization to pholcodine as ture. Recommendations on alternative drugs are par- an indication of cross-reactivity due to a correspond- ticularly important when it comes to drugs with po- ing sensitization to NMBA or opioids is currently the tential cross-reactivity to structurally related prepara- subject of controversy. Cellular in vitro tests, such as tions; their possible tolerance needs to be determined the basophil activation test or the lymphocyte trans- by means of negative skin tests (e. g., NMBA) or provo- formation test and the enzyme-linked immunospot cation tests (e. g., antibiotics and analgesics). The pos- (ELISpot) assay to investigate either immediate or de- sibility of an increased risk for PODR to propofol in layed-type sensitization to possible triggers, respec- patients showing IgE-mediated sensitization to poten- tively, can be helpful in some cases; however, their tially cross-reacting food stuff is meanwhile discussed sensitivity and speciﬁcity are to be viewed critically only in relation to children with a previous history of . severe anaphylaxis to hen’s egg, but not in relation to 128 Perioperative drug reactions – practical recommendations for allergy testing and patient management K mini-review Conﬂict of interest W. Pfützner declares the following Table 2 Maximum skin test concentrations of drugs used competing interests: Lectures for Thermo Fisher-Phadia. for anesthetic induction (from Brockow ) K. Brockow declares that he has no competing interests. Drug Skin prick test Intradermal test (concentration) (dilution factor) (dilution factor) Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License Midazolam (5 mg/ml) 5 mg/ml (pure) 0.5 mg/ml (1:10) (http://creativecommons.org/licenses/by/4.0/), which per- Propofol (10 mg/ml) 10 mg/ml (pure) 1 mg/ml (1:10) mits unrestricted use, distribution, and reproduction in any Ketamine (10 mg/ml) 10 mg/ml (pure) 1 mg/ml (1:10) medium, provided you give appropriate credit to the origi- Thiopental (25 mg/ml) 25 mg/ml (pure) 2.5 mg/ml (1:10) nal author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Etomidate (2 mg/ml) 2 mg/ml (pure) 0.2 mg/ml (1:10) Morphine (10 mg/ml) 1 mg/ml (1:10) 0.01 mg/ml (1:1000) Fentanyl (0.05 mg/ml) 0.05 mg/ml (pure) 0.005 mg/ml (1:10) References Remifentanil 0.05 mg/ml (pure) 0.005 mg/ml (1:10) (0.05 mg/ml) Cited Literature Sufentanil 0.005 mg/ml (pure) 0.0005 mg/ml (1:10) (0.005 mg/ml) 1. Brockow K, Garvey LH, Aberer W, Atanaskovic-Markovic M, Alfentanil (0.5 mg/ml) 0.5 mg/ml (pure) 0.05 mg/ml (1:10) Barbaud A, Bilò MB, et al. Skin test concentrations for sys- Atracurium (10 mg/ml) 1 mg/ml (1:10) 0.01 mg/ml (1:1000) temically administered drugs—an ENDA/EAACI drug al- lergyinterestgrouppositionpaper. Allergy. 2013;68:702–12. Cisatracurium 2 mg/ml (pure) 0.02 mg/ml (1:100) (2 mg/ml) 2. Möbs C, Pfützner W. Cellular in vitro diagnostics of adverse drug reactions. Allergo J Int. 2014;23:164–71. Rocuronium (10 mg/ml) 10 mg/ml (pure) 0.05 mg/ml (1:200) Mivacurium (2 mg/ml) 0.2 mg/ml (1:10) 0.002 mg/ml (1:1000) Pancuronium (2 mg/ml) 2 mg/ml (pure) 0.2 mg/ml (1:10) Further Reading Vecuronium (4 mg/ml) 4 mg/ml (pure) 0.4 mg/ml (1:10) Suxamethonium 10 mg/ml (1:5) 0.1 mg/ml (1:500) 3. Asserhøj LL, Mosbech H, Krøigaard M, Garvey LH. No evi- (50 mg/ml) dence for contraindications to the use of propofol in adults allergic to egg, soy or peanut. Br J Anaesth. 2016;116:77–82. 4. Bonadonna P, Pagani M, Aberer W, Bilò MB, Brockow K, adults or individuals allergic to soy and peanut. Sim- Oude Elberink H, et al. Drug hypersensitivity in clonal ilarly, there are no preventive limitations on the pe- mast cell disorders: ENDA/EAACI position paper. Allergy. rioperative administration of other drugs to patients 2015;70:755–63. 5. Dewachter P, Mouton-Faivre C, Hepner DL. Perioperative with mast cell diseases, e. g., mastocytosis, assuming anaphylaxis: what should be known? Curr Allergy Asthma they have no known history of drug hypersensitivity. Rep. 2015;15:21. The administration of morphine is an exception here. 6. Guyer AC, Saff RR, Conroy M, Blumenthal KG, Camargo CA, As a precautionary measure, prophylactic premed- LongAA,etal. Comprehensiveallergyevaluationisusefulin ication can be administered to these patients—as well the subsequent care of patients with drug hypersensitivity as to patients with PODR in whom it has not been reactions during anesthesia. J Allergy Clin Immunol Pract. possible to unequivocally identify, and thus avoid, 2015;3:94–100. 7. Kvisselgaard A, Krøigaard M, Mosbech H, Garvey L. No the trigger—prior to further surgical procedures. Al- cases of perioperative allergy to local anaesthetics in the though this measure is not able to reliably prevent Danish Anaesthesia Allergy Centre. Acta Anaesthesiol a renewed PODR, it might prevent a course as se- Scand. 2017;61:149–55. vere as the original reaction in 90% of cases should 8. Lafuente A, Javaloyes G, Berroa F, Goikoetxea MJ, Moncada a PODR occur. According to the recommendations on R, Núñez-Córdoba JM, et al. Early skin testing is effective their administration in individuals allergic to radio- for diagnosis of hypersensitivity reactions occuring during contrast agents, methylprednisolone 32 mg orally, for anesthesia. Allergy. 2013;68:820–2. 9. MertesPM,MalinovskyJM,JouffroyL,AbererW,Terreehorst instance, can be administered 12 and 2 h prior to elec- I, BrockowK, Demoly P, Working Group oftheSFAR andSFA, tive procedures or 40 mg i. v. 1–4 h prior to emergency ENDA, EAACI Interest Group on Drug Allergy. Reducing procedures, both combined with 4 mg dimetindene the risk of anaphylaxis during anesthesia: 2011 updated i. v. 30 min beforehand. Any future surgical proce- guidelines for clinical practice. J Investig Allergol Clin dures should be performed with emergency response Immunol. 2011;21:442–53. measures in place. 10. Schopp JG, Iyer RS, Wang CL, Petscavage JM, Paladin AM, Bush WH, et al. Allergic reactions to iodinated contrast Although it is often not possible to establish media: premedication considerations for patients at risk. the clinical relevance of positive skin tests to an- Emerg Radiol. 2013;20:299–306. esthetics, including NMBA, thereby unequivocally 11. Trautmann A, Seidl C, Stoevesandt J, Seitz CS. Gen- identifying the cause of PODR, these diagnostic mea- eral anaesthesia-induced anaphylaxis: impact of allergy sures and allergological recommendations are highly testing on subsequent anaesthesia. Clin Exp Allergy. effective in the prevention of repeated anaphylactic 2016;46:125–32. reactions during further surgical interventions. 12. Pfützner W, Wulf H. Perioperative anaphylaxia on drugs. Anasthesiol Intensivmed Notfallmed Schmerzther. 2017;52:704–15. K Perioperative drug reactions – practical recommendations for allergy testing and patient management 129
Allergo Journal International – Springer Journals
Published: Jun 4, 2018
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