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Neuromuscular Blocking Agents
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Neuromuscular blocking agents are responsible for up to 70% of anaphylactic reactions during general anesthesia.33 In France in 1996, the incidence of anaphylaxis was estimated at 1 in 6500 anesthetics involving a muscle relaxant9 and occurred whether or not the agents cause chemically mediated reactions. In most series, succinylcholine appears to be most frequently involved, although variations in practice patterns account for some differences. In the most recent French series, rocuronium, a steroidal relaxant devoid of chemically mediated histamine release, was the primary drug responsible for reactions.10 Because the main antigenic determinants in the generation of specific IgE antibodies are substituted ammonium ions,34 an 80% cross-reactivity between the different muscle relaxants is observed by skin tests. Cross-reactivity explains why many patients may exhibit allergic symptoms on first exposure to a neuromuscular blocking agent.35 Details for skin testing of these agents are included in a recent article by Laxenaire et al10 (Fig. 106-3).
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Although allergic reactions to β lactams are the most common cause of anaphylactic reactions in the population at large, they occur far less frequently in the operating room (12% of events). These reactions, classifiable as immediate or nonimmediate, can be produced by the four classes of β lactams (penicillins, cephalosporins, carbapenems, and monobactams), which share a common β-lactam ring structure. Cross-reactivity among cephalosporins and between cephalosporins and penicillins can occur.36
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Immediate reactions (type I or mediated by IgE), usually within the first hour after drug administration, are characterized by diffuse erythema, pruritus, urticaria, angioedema, rhinitis, bronchospasm, hyperperistalsis, hypotension, cardiac arrhythmias, and anaphylactic shock alone or in combination. Anaphylaxis occurs in about 0.004% to 0.015% of penicillin37 and 0.001% to 0.1% of cephalosporin36 treatments. The fatality rate from shock after administration of penicillin is 0.0015% to 0.002%. Despite the fact that penicillin-induced anaphylaxis is rare, this drug remains the most common cause of anaphylaxis in human beings, accounting for approximately 75% of anaphylactic deaths in the United States each year.38,39
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In many cases, a detailed history of a patient's reaction to penicillin may allow clinicians to exclude true penicillin allergy, thus allowing these patients to receive the drug.40 Skin tests are the quickest and most reliable method for demonstrating the presence of β-lactam–specific IgE antibodies. Using the suspected β lactams themselves (in particular cephalosporins) in addition to penicillin major and minor determinants as test agents is highly desirable. Patients with a compelling history of type I penicillin allergy who require penicillin should undergo skin testing. Those with a negative skin test result can take penicillin without serious sequelae.41 Only 10% to 20% of patients reporting a history of penicillin allergy are truly allergic when skin testing is performed. Conversely, many patients with positive skin tests have only vague penicillin allergy histories.42
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Although serum-specific IgE assays can be used as complementary tests, negative test results should be interpreted in light of the time elapsed from the last exposure to the suspected β lactam because in vivo and in vitro test sensitivity decreases over time. In some diagnostic workups, patients with a strong history of type I β-lactam allergy and negative skin and in vitro tests undergo a controlled administration of the suspected β lactam.41
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Strategies for dealing with penicillin-allergic patients are evolving and are institution specific. Patients who are allergic to penicillin have been reported to have a 5% to 30% incidence of cross-reactivity to cephalosporins. The recent trend in the United States is to use cephalosporins without a convincing history of penicillin allergy36,41 because alternative antibiotics can cause severe anaphylactoid reactions. For example, chemically mediated red-man syndrome manifested as hypotension and flushing3,43 occurs with rapid vancomycin administration.44
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The incidence of anaphylactoid reactions with thiopental is estimated to be 1 in 30,000.33 Most of the generalized reactions are linked to direct leukocyte histamine release. However, there is evidence for IgE-mediated anaphylactic reactions based on skin tests and specific IgE assay.45
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Ever since Cremophor EL has been discontinued as a solvent for some non-barbiturate hypnotics, many previously reported anaphylactoid reactions have disappeared. Although less frequent, anaphylaxis to all induction agents has been observed.46,47 However, in recent studies, induction agents caused only 3.7% of all anaphylactic cases during anesthesia.10
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Although patients often relate anaphylactic reactions to opiates, immunologically mediated reactions to morphine, codeine phosphate, meperidine, fentanyl and its derivatives are quite rare, occurring only once in 100,000 to 200,000 anesthetics.33 Because of the direct histamine-releasing properties and frequent non–histamine-related cutaneous manifestations, there is significant over-reporting of allergy to opiates. Most opioids (with the possible exception of the fentanyl family) may cause direct release of histamine, urticaria along the vein of administration, and vasodilation. Bronchospasm and angioedema have not been reported, even when large doses of these agents were used for anesthesia before cardiac procedures.48 Codeine has been implicated in several cases of anaphylactoid reactions, but in all of the reported instances, more than one drug was used simultaneously. An anaphylactoid reaction to morphine and an inordinate sensitivity to histamine release have been reported, but skin testing in this patient produced negative results.49