Adverse reactions to neuromuscular blocking agents

Neuromuscular blocking agents (NMBAs) play a predominant role in the incidence of severe adverse reactions occurring during anesthesia. Most hypersensitivity reactions are of immunologic origin (IgE-mediated) or are related to direct stimulation of histamine release. The incidence of IgEmediated hypersensitivity or anaphylaxis is estimated between 1 in 10,000 and 1 in 20,000 anesthesias, and NMBAs represent the most frequently involved substances, with a range of 50% to 70%. Any suspected anaphylactic reaction must be extensively investigated using combined perioperative and postoperative testing. Because of the frequent cross-reactivity observed with muscle relaxants, every available NMBA should be tested. This should help provide documented advice for future administration of anesthesia. There is no demonstrated evidence for systematic preoperative screening in the general population at this time. Other well-known adverse effects have been described, such as the succinylcholine-triggered cytotoxic effects on muscle cells, but these are responsible for characteristic clinical symptoms, which are usually easy to distinguish from anaphylactic reactions     

Anaphylaxis to muscle relaxants: rational for skin tests

IgE-dependent allergy to muscle relaxants (MR) has an estimated prevalence of 1 out of 6500 General Anesthesias (GA). 62% of anaphylaxis during surgery are due to MR anaphylaxis. All the molecules are divalent, carrying two NH4+ epitopes (quaternary ammonium ions), either structurally or after rapid in vivo protonization (vecuronium). The excellent overall performance of skin test makes them the golden standard for the diagnosis of anaphylactoid reactions. Techniques include intradermal tests and prick-tests. The current localizations are the forearm and the back. Positivity criteria are 3 mm for prick-tests. For IDTs, the criterium is the doubling of the size of the injection papula, when 0.02 to 0.04 ml is injected: 8 mm. The recommended concentrations are not falsely negative. Commercial concentrations can be tested by prick tests, except for mivacurium and atracurium tested of 1:10 dilution. A scale of concentrations is advised for IDT starting with 1:10,000, up to a normally non reactive concentration that is: 100 micrograms/ml (succinylcholine), 200 micrograms/ml (gallamine), 10 micrograms/ml (atracurium), 2 micrograms/ml (mivacurium), 200 micrograms/ml (pancuronium), 400 micrograms/ml (vecuronium), 1,000 micrograms/ml (rocuronium), 200 micrograms/ml (cis atracurium). The specificity and sensitivity of the skin tests to MRs are greater than 95%. The reproducibility over years is 88%. The overall concordance of PT and IDR is 97%. Both types of tests can be used for the diagnosis. IDT have to be carried out for the search of the cross sensitization. 84% of patients do have cross sensitization to MRs but only 16% react to all MRs. The further use of MRs selected by negative IDTs has been proved to be safe.     

β内酰胺类抗生素超敏反应的诊断和治疗

β内酰胺类抗生素超敏反应,是由免疫机制介导的药物不良反应,包括速发型和非速发型变态反应,两者判断的依据是症状发生和用药时间间隔。诊断β内酰胺类药物过敏需要详尽的病史、合适的皮肤试验及体外实验室检查,必要时需进行药物激发试验。     

L’allergie aux vaccins associés chez l’enfant. Une étude de 30 cas fondée sur les tests cutanés à lecture immédiate,semi-retardée et retardée,sur les dosages des anticorps spécifiques et sur les injections de rappel

Skin tests (prick and intradermal) were performed with vaccines containing diphtheria, pertussis, tetanus, polio and Haemophilus influenzae type b antigens (D.P.T.Pol.Hib), and with selected components of the vaccines in 30 children reporting reactions suggestive of allergy to these vaccines. Serum-specific IgE and IgG against components of the vaccines were also studied. Immediate responses in skin tests and specific IgE determinations strongly suggested the diagnosis of immediate-type hypersensitivity to tetanus or diphtheria toxoids in ten children (33.3%), including four of the six children with anaphylaxis, and six of the 16 children with urticaria and angioedema. In the other 20 children, immediate, semi-late and late responses in skin tests and specific IgE determinations were negative. Booster immunizations were given with monovalent or bivalent vaccines in 14 of these children, and were well tolerated. Our results suggest that most large local reactions and mild to moderately severe generalized skin reactions to multivalent vaccines are not allergic, but instead result from a nonspecific inflammatory reaction. However, our results show that toxoids may induce immediate-type hypersensitivity reactions in children, and suggest that skin tests with vaccines and vaccine components, and the determination of specific IgE against vaccine components, are of diagnostic value in children with anaphylaxis, and immediate and accelerated urticaria and angioedema induced by booster injections of multivalent vaccines.     

Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy.

Anti-IgE therapy with omalizumab, a recombinant humanized monoclonal antibody, has anti-inflammatory effects in allergic asthma and rhinitis. Although omalizumab has been exceptionally safe, reactions after its administration have been reported. The goal of this study was to assess two patients who experienced apparent anaphylaxis after omalizumab administration. Two cases of apparent anaphylaxis after omalizumab administration are reported with diagnostic evaluation using skin testing and unique IgE and IgG anti-omalizumab serological assays. At the time of evaluation, both atopic asthmatic patients had total (free and bound) serum IgE levels of 199 kIU/L (100% free) and 200 kIU/L (80% free and 20% bound), respectively. Epicutaneous skin tests to omalizumab were negative at 150 mg/mL of omalizumab in both subjects and the nonexposed negative control subject. Intradermal skin tests were positive at 0.15 mg/mL in subject 1 and negative at 1.5 mg/mL of omalizumab in subject 2 and the control subject. Intradermal testing to polysorbate produced significant wheal/flare reaction in subject 2 but not in the negative control subject. Serological assays for IgE or IgG antibodies reactive with omalizumab were negative. The in vitro and in vivo immunologic data support the conclusion that the adverse reactions experienced by two patients after omalizumab administration after more than a year of successful omalizumab therapy for asthma were likely anaphylactoid in nature. Polysorbate, an excipient in omalizumab, is known to cause similar reactivity to other medicines and is the most likely cause of these reactions.     

IgE-mediated metamizol allergy and the usefulness of the cellular allergen stimulation test

Metamizol is a pyrazolone-derivative nonsteroidal anti-inflammatory drug that is commonly associated with hypersensitivity reactions. Some of these reactions are IgE-mediated and potentially severe, which limits the diagnosis based on oral drug challenge. We describe 6 selective metamizol hypersensitivity cases, regarding clinical evaluation and diagnosis management, with focus on the usefulness of skin tests and the cellular allergen stimulation test (CAST). All patients were female, aged 27 to 50 years old. All had immediate reactions after metamizol administration: 3 had anaphylaxis and 3 had urticaria and angioedema. Skin prick tests with metamizol were positive in 2 patients. Intradermal tests were positive in the remaining, all with 1/100 dilution, and elicited systemic reactions in 2 of them. CAST to metamizol was negative in all cases. The patients tolerated other nonsteroidal anti-inflammatory drugs. Skin tests proved to be a good diagnostic method to identify IgE-mediated metamizol allergy, although skin tests elicited systemic symptoms in some cases. Despite this being a small sample, our results showed a very low sensitivity for CAST which differs from data previously reported in the literature.     

Perioperative anaphylaxis in a 44-year-old man.

This article presents a case report of perioperative anaphylaxis in a previously nonallergic 44-year-old man undergoing cervical spine surgery. After receiving general anesthesia with midazolam, propofol, lidocaine, fentanyl, rocuronium, and sevoflurane and cefazolin for prophylaxis, the patient developed hypotension, tachycardia, bronchospasm, and generalized erythema. A serum tryptase concentration was markedly elevated 2 hours after the anaphylactic episode. Initial prick and intradermal skin tests (excluding skin testing for unavailable benzylpenicilloyl polylysine) and IgE immunoassays for penicillin and cefazolin were negative. However, repeat prick skin testing for cefazolin 6 weeks after anaphylaxis was positive. Although anaphylaxis to cephalosporins is rare, it remains a potential cause of perioperative anaphylaxis. All cases of perioperative anaphylaxis require a workup to identify the offending agent and to avoid future reactions. Skin testing regimens for several commonly implicated drugs used for general anesthesia are available and are described.     

The use of in vivo and in vitro tests in children with beta lactam allergy

BackgroundDrug allergies are reactions within the context of drug hypersensitivity reactions, which are caused by immunological mechanisms due to a previously sensitising drug. Beta-lactam antibiotics (BLA) are the leading agents causing drug hypersensitivity reactions in children.The aim of this study is to evaluate the diagnostic importance of in vivo and in vitro diagnostic tests in children with suspected immediate-type BLA hypersensitivity and to investigate the frequency of their use for the final diagnosis.MethodsPatients admitted to the Outpatient Clinic of Division of Paediatric Allergy and Immunology with suspicion of immediate-type BLA hypersensitivity between December 2014 and December 2018 were investigated. Patients with a history of immediate reactions to BLA were examined by performing drug specific IgE, skin prick tests, intradermal tests and drug provocation tests (DPT).ResultsDuring the study period, 148 patients were admitted to our clinic with suspected immediate-type BLA hypersensitivity. Forty-eight patients completed all assessment steps and were enrolled in the study. It has been shown that 27 patients did not have drug allergy. BLA hypersensitivity was proven in 21 patients by using in vivo test algorithm. More than half of the patients were diagnosed via skin tests with culprit drug.ConclusionAllergy work-up should be performed in patients with immediate reactions to BLA. A skin test can demonstrate BLA hypersensitivity in most patients. Thus, skin tests should be performed prior to the drug provocation test.     

Anaphylactoid reactions and late skin reactions to iodinated contrast media: present state of the question--idea development]

PURPOSE: Adverse reactions to iodinated contrast media (ICM) share various mechanisms. Anaphylactoid reactions are among the most serious reactions when they are characterized by the elevation of seric tryptase. Pretreatment with corticosteroids and anti-H1 or the use of non-ionic contrast media do not prevent anaphylaxis. Late skin reactions could be mostly related to delayed hypersensitivity. Previous reactions to contrast media, cardiovascular disorders, beta-blockers, asthma, and atopy are risk factors. Female gender and age increase the severity. CURRENT KNOWLEDGE AND KEY POINTS: Anaphylaxis can be demonstrated by intradermal tests and the identification of specific IgEs. Delayed hypersensitivity is shown by the results of epicutaneous tests and the immunohistology of the skin. FUTURE PROSPECTS AND PROJECTS: Allergologic tests are advised in the case of previous reactions. In case of emergency, gadopentetate dimeglumine can be alternatively used. The other risk factors lead to the combination of pretreatment and use of non-ionic monomeric contrast media. Immediate hypersensitivity to iodinated media might increase in the near future with the use of divalent molecules.     

Les réactions allergiques et pseudoallergiques aux antalgiques,antipyrétiques et anti-inflammatoires non stéroïdiens

Antalgics, antipyretics and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used, but suspected allergic reactions to these drugs are rare, especially in children. Most frequent reactions are cutaneous (urticaria, angioedema) and respiratory (rhinitis, asthma). Other reactions (anaphylaxis or anaphylactoid reactions, potentially harmful toxidermias) are rare. In a few patients, reactions may result from a specific (allergic) hypersensitivity (HS), with positive responses in prick and intradermal tests (anaphylaxis, immediate urticaria and/or angioedema) and in intradermal and patch tests (non-immediate reactions). However, most reactions result from a non-specific (non-allergic) HS (intolerance), with a frequent cross-reactivity between the various families of antalgics, antipyretics and NSAIDs, including acetaminophen (paracetamol). Based on a convincing clinical history and/or positive responses in challenge tests, intolerance to antalgics, antipyretics and NSAIDs has been diagnosed in 13 to 50% of the patients with allergic-like reactions to these drugs. Risk factors for HS to antalgics, antipyretics and NSAIDs are a personal atopy and age. In our experience, 50% of the children with allergic-like reactions to antipyretics, antalgics and NSAIDs were diagnosed intolerant to these drugs. Risk was high in children reporting reactions to NSAIDs (aspirin, ibuprofen) and lower in children reporting reactions to paracetamol. All the children intolerant to paracetamol were also intolerant to NSAIDs. In contrast, most children with NSAID intolerance were tolerant to paracetamol. A personal history of atopy and a mean age ≥ 8 years were significant risk factors for intolerance to antalgics, antipyretics and NSAIDs.     

药物过敏发病机制及体内外检测

药物过敏是指免疫介导的药物超敏反应,其机制为IgE介导或非IgE介导。小分子药物主要通过药物原形或代谢产物与载体蛋白结合激活免疫应答,或药物直接与T细胞抗原受体结合激活CD4+T细胞、CD8+T细胞等途径引起体内免疫应答。药物被免疫系统识别后可引发I～IV型超敏反应。目前药物过敏的检测主要包括皮肤试验、实验室检查及药物激发试验。     

The problem of anaphylaxis and mastocytosis

Mastocytosis is a rare disease characterized by an elevated whole body mast cell number. Anaphylaxis is a severe, generalized hypersensitivity reaction with rapid onset. The problem of anaphylaxis and mastocytosis is due to strongly increased mediator release from the elevated mast cell number during allergic reactions. This explains the much higher prevalence of anaphylaxis in mastocytosis than in the general population and its severe and sometimes fatal course. Because of the increased risk of anaphylaxis in mastocytosis, all patients with severe or recurrent anaphylaxis should be analyzed for underlying mastocytosis by estimation of baseline serum tryptase. If this is elevated, patients also should be tested via skin examination for cutaneous mastocytosis and with a bone marrow biopsy. All patients with mastocytosis and anaphylaxis must be instructed about avoiding the responsible elicitors and should carry an emergency kit with adrenaline for self-application. In mastocytosis patients with anaphylaxis due to Hymenoptera stings, venom immunotherapy is recommended for life.     

Diagnosis and management of hypersensitivity reactions caused by oxaliplatin.

Hypersensitivity reactions to oxaliplatin have been increasing since its introduction at the end of the 1990s, but allergy tests with antineoplastic drugs are rarely used to aid diagnosis. We describe 5 cases in which hypersensitivity reactions to oxaliplatin after several courses of chemotherapy were managed by allergy testing and desensitization. Skin prick tests were negative at 1 mg/mL in all patients, positive at 10 mg/mL in 2 tested patients, and negative in 10 control subjects. Intradermal tests were positive and not irritant at 0.01 to 0.001 mg/mL concentrations. A desensitization protocol with increasing concentrations and flow rates was successfully completed in all patients. We conclude that prick and intradermal skin tests are useful in the diagnosis of hypersensitivity reactions to oxaliplatin and that the desensitization protocol performed avoided discontinuation of chemotherapy in all patients.     

The mechanisms, causes, and treatment of anaphylaxis.

Anaphylaxis is a severe life-threatening systemic reaction that offers many challenges to the clinician. The incidence of anaphylaxis is significant in the general population and an important cause of morbidity and mortality. While the most common causes of anaphylaxis include drugs, foods, and venoms, other important etiologies must be considered. The etiology of anaphylaxis is classically based on IgE mediated hypersensitivity but multiple mechanisms may be involved. The clinical presentation of anaphylaxis may be extremely variable with a broad differential diagnosis which will be outlined. Although the diagnosis of anaphylaxis can many times be based on a careful history and physical examination, there are laboratory and skin tests which may be helpful in establishing a diagnosis in some cases. The cornerstone of treatment of anaphylaxis remains epinephrine. Other supportive therapies will be discussed.     

Platelet function in anaphylaxis.

Human platelets, following immunological or nonimmunological activation, are capable of releasing a variety of biologically active mediators and are able to actively participate in hypersensitivity reactions, including anaphylaxis. These cells constitutively express functional receptors for the Fc fragment of IgE, both the low affinity receptor (Fc epsilonRII) and the high affinity receptor (Fc epsilonRI), and could be activated via IgE. Alterations in platelet function have been demonstrated in patients with allergy and nonallergic hypersensitivity, including hypersensitivity to acetylsalicylic acid. Moreover, activated platelets may be responsible for anaphylactic transfusion reactions. Various haemostatic disturbances, particularly a drop in platelet number, were observed during anaphylactic shock. The current review summarises the data from human and experimental studies on platelet function in anaphylactic reactions.     

Réactions allergiques et pseudoallergiques aux médicaments et substances biologiques chez l’enfant

Five to 20% of subjects of all ages report suspected allergic reactions to drugs and biological substances. Children may be less affected than adults, but this difference is disputed and probably results from differences in drug exposure. Most frequently suspected drugs are antibiotics, betalactams especially, antipyretics, analgesics and nonsteroidal anti-inflammatory drugs. Most frequent reactions are morbilliform/maculopapular rashs, urticaria and angioedema. Other cutaneous and respiratory reactions, and severe anaphylactic and anaphylactoid reactions, are rare. The results of allergological studies suggest that, except for a few types of reactions (anaphylactic and immediate reactions, potentially harmful toxidermias) and for very specific drugs (i.e. latex and myorelaxants), most reactions to commonly used drugs and biological substances in children do not result from drug hypersensitivity, but are rather a consequence of the infectious and/or inflammatory diseases for which the drugs have been prescribed. The reactions may also result from complex interactions between drugs, immune system and “danger” signals provided or induced by infectious and/or inflammatory diseases. Diagnosis is based above all on a detailed analysis of clinical history, skin tests (if validated) and challenge tests (if indicated). In children with drug allergy or intolerance, prevention of relapse is based on a rigourous avoidance of the responsible drug and cross-reacting drugs.     

Beer-induced anaphylaxis due to barley sensitization: two case reports.

Despite the large worldwide beer consumption, allergic reactions have very rarely been reported. We describe two cases of severe systemic reactions due to beer ingestion: one case of anaphylaxis requiring emergency care and one of generalized urticaria and angioedema. The two patients underwent a detailed diagnostic procedure involving skin testing, oral challenge with additives, detection of specific IgE to the components of beer, and oral challenge with beer in one patient. The results of the tests, in the particular skin tests and IgE assay, allowed us to detect barley as the specific ingredient responsible for the observed allergic reactions to beer. Therefore, such a sensitization should always be taken into account in the case of suspected reactions following beer ingestion.     

Utility of opium seed extract tests in preventing hypersensitivity reactions during surgery

BackgroundAnaphylaxis during anaesthesia is fatal in 3–9% of patients and analgesics, including opioids, and is the second most common medicament-related cause, although the prevalence is underestimated. We recently found that patients may generate IgE antibodies to opium seeds.ObjectivesTo determine the diagnostic accuracy of specific antibodies to morphine, codeine, rocuronium and oil body and aqueous fractions of Papaver somniferum seeds in the diagnosis and prevention of allergy to opioids.MethodsPatients with hypersensitivity reactions during surgery, and severe clinical allergy (pollen, tobacco), and illicit heroin users were selected. The sensitivity, specificity and predictive values of in vivo and in vitro diagnostic techniques including oil body and aqueous fractions of P. somniferum seeds were measured.ResultsWe studied 203 patients, with mean age 35.1 ± 17.1 and 200 healthy controls. Patients sensitised to heroin or with hypersensitivity reactions during surgery responded to P. somniferum seed tests. Of patients not known to be sensitised to opioids, the highest positivity was in patients sensitised to tobacco (p < 0.001). Opium seed skin tests and IgE, especially the oil body fraction, were more sensitive (64.2%) and specific (98.4%) than morphine, codeine and rocuronium tests for opioid sensitivity. Pollen allergy was not a risk factor for sensitisation to morphine.ConclusionsSensitivity to opioids and intraoperative anaphylaxis can be diagnosed by routine tests. IgE and skin tests for the oil body fraction of P. somniferum had the highest sensitivity for sensitisation to opioids.     

Cellular allergen stimulation test (CAST) 2003, a review.

Specific diagnosis of immediate type allergies, such as rhinoconjunctivis, asthma, urticaria/angioedema and anaphylaxis, particularly when IgE-mediated, traditionally rests on prick and/or intradermal skin tests and, since about 30 years, on the determination of allergen specific IgEs. Some cellular tests, i.e. tests determining the reactivity of blood cells in vitro, particularly basophils, to allergens, have been available for many years. The determination of histamine release has been widely used in allergy pathophysiological research but its routine application in allergy diagnosis has been restricted to few groups. Basophil degranulation, as determined by microscopic examination, was promoted by some groups in the 1980's but has been largely abandoned since around 10 years ago; an alternative cellular test, based on the determination of sulfidoleukotrienes (LTC4, LTD4, LTE4) produced by IL-3 primed basophils stimulated by allergens in vitro, has been proposed. This test became available commercially in 1993 under the name of CAST (Bühlmann Laboratories, Allschwil, Switzerland). The CAST assay has been used in allergy diagnosis in a variety of indications, such as inhalation allergies, allergies to insect venoms, foods, occupational allergens and various drugs. A large number of reports on CAST diagnostic value, however, have been anecdotal. A meta-analysis of validated and well controlled studies encompasses 37 studies, 1614 patients and 1145 controls. This should definitely establish the value of this diagnostic test, particularly in instances where other in vitro or in vivo diagnostic tests are not reliable, such as food or drug allergies, as well as in non-IgE-mediated immediate hypersensitivity reactions. However, a number of questions about the CAST diagnostic assay are still open or have not been systematically explored. This may explain, in addition to the practical limitations inherent to all allergy cellular tests, why CAST has not yet become a very widely used assay worldwide, having gained broad acceptance in some countries but not in others.     

Hymenoptera (apid and vespid) allergy: Update in diagnosis and management

Allergic reactions to Hymenoptera stings range from large local reactions to life-threatening anaphylaxis. Over the last 20 years, significant progress has been made using venom extracts in the diagnosis and treatment of Hymenoptera allergy. Despite these advances, there is still room for improvement in increasing the sensitivity of venom allergen skin testing. The venom allergic patient with negative skin tests poses special problems in management. It is important to note their increased risk with a subsequent sting. Guidelines to be used in determining the duration of venom immunotherapy are still evolving. Knowledge of the risks of discontinuing venom immunotherapy and risk factors associated with anaphylaxis with subsequent stings are required to form an individualized approach to treatment.