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Neuromuscular Blocking Drugs
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Muscle relaxants are a common cause of anaphylactic reactions during anesthesia, with IgE-mediated mechanisms including positive Prausnitz-Kustner tests, basophil–histamine release studies, inhibition of basophil–histamine release after desensitization to anti-IgE, and demonstration of drug-specific IgE antibodies are observed in sera from patients with adverse reactions to muscle relaxants.20,54-58
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Extensive in vitro cross-reactivity has been reported between muscle relaxants and other compounds that contain quaternary and tertiary ammonium ions.59-61 Insofar as these compounds are found in many drugs, foods, cosmetics, disinfectants, and industrial materials, patients may become sensitized through environmental contact. Sensitization to ammonium ion epitopes in cosmetics has been postulated to explain the predominance of reactions in women.61 Although the exact incidence of allergic reactions caused by muscle relaxants is unknown, reactions to muscle relaxants are less common in the United States than in France and Australia.
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Acute allergic reactions have been reported after administration of thiobarbiturates, especially thiopental. Proposed mechanisms for thiobarbiturate reactions include nonimmunologically induced mediator release and IgE-mediated reactions. A thiopental RAST has been developed,62 and mast cell histamine release to thiopental in vitro has been described.63,64
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Anaphylaxis to propofol with laboratory confirmation has been reported in only 2 patients,65,66 without laboratory confirmation (therefore a presumptive diagnosis) in an infant with egg and peanut allergy,67 and in 2 adult patients, one of whom had a pruritic maculopapular rash around the eyes (for 3 months)68 and one of whom died from cardiovascular collapse with increased serum tryptase and methylhistamine levels at postmortem.69 Although warnings about administration of propofol to patients with egg allergy can be strident, the lecithin in the propofol emulsion containing ethylenediaminetetraacetic acid (EDTA) as a preservative is derived from egg yolk, not egg albumin found in egg white. In most patients with egg allergies, egg albumin is the sensitizing protein. In the propofol emulsion using metabisulfite as the preservative, metabisulfite may be the allergenic component. Because the propofol emulsion also contains soybean oil, patients with soybean oil allergy should not receive propofol.
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Despite patients commonly reporting "allergic reactions" to local anesthetics, true allergic reactions to injected local anesthetics are exceedingly rare. Adverse reactions to local anesthetics often are the result of vasovagal reactions, toxic reactions (probably caused by accidental intravenous injection), side effects from epinephrine, or psychomotor responses such as hyperventilation. Toxic symptoms often involve the central nervous and cardiovascular systems and may produce slurred speech, euphoria, dizziness, excitement, nausea, emesis, disorientation, or convulsions. Vasovagal reactions are usually associated with bradycardia, sweating, pallor, and rapid improvement in symptoms when the patient is supine. Sympathetic stimulation, either from epinephrine or anxiety, may result in tremors, diaphoresis, tachycardia, and hypertension. Rarely, signs of reactions to local anesthetics are consistent with IgE-mediated mechanisms such as urticaria, bronchospasm, and anaphylactic shock.70 IgE-mediated sensitivity has, on rare occasions, been reported to parabens, preservatives used in local anesthetics.
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Local anesthetics are divided into 2 general chemical classes, the esters and the amide compounds (Box 86-5). Ester local anesthetics are metabolized to para-aminobenzoic acid (PABA); therefore, ester local anesthetics cross-react and patients may present with allergic or hypersensitivity reactions. In addition, individuals allergic to other drugs metabolized to PABA, such as sunscreens and methylparaben preservatives, may experience a cross-reaction. There is no cross-reaction with the amide compounds. Epinephrine-containing local anesthetics with the antioxidant metabisulfite may be allergenic because of the metabisulfite component.71,72
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Evaluation of the patient with a history of adverse reactions to local anesthetics should include a complete history of the episode, skin testing, and incremental drug challenge. The local anesthetic tested should be appropriate for the proposed procedure and not expected to cross-react with the drug implicated in the previous reaction. If the previous drug is unknown, an amide-type local anesthetic should be chosen. In a patient with a history suggestive of an IgE-mediated reaction or possible paraben sensitivity, preparations without paraben should be used for testing, challenge, and treatment. Preparations with epinephrine should not be used for skin testing because they may mask a positive skin test and induce toxic effects.
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Narcotics typically cause nonimmunologically mediated histamine release from skin mast cells rather than anaphylaxis. In vitro studies suggest that skin mast cells are uniquely sensitive to narcotics, whereas gastrointestinal and lung mast cells and circulating basophils do not release histamine when exposed to narcotics.13,14,73 Most opiate-induced reactions are self-limited, cutaneous, and restricted to hives and pruritus or mild hypotension treated by fluid administration. This nonimmunologic release of mediators is a far more common clinical occurrence than are the rare reactions induced by morphine-specific IgE antibody.
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See references 74 and 75.
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Penicillin Antibiotics
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Outside of the operating room, but also within our sphere of responsibility during resuscitation or perioperative care, penicillin antibiotics are the most common medications causing allergic drug reactions (0.7%-8% of treatment cases).76,77 From 0.004% to 0.015% of penicillin treatment courses end in anaphylaxis, resulting in 400 to 800 deaths per year in the United States. Only 10% to 20% of patients who claim an allergy to penicillin react to skin testing with the major and minor determinants.
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A low-molecular-weight chemical, penicillin must covalently combine with tissue macromolecules to produce multivalent hapten–protein complexes. The β-lactam ring, which opens spontaneously under physiologic conditions, forms the penicilloyl group. Other metabolic pathways result in additional antigenic determinants, known as the "minor determinants." Anaphylactic reactions to penicillin usually are mediated by IgE antibodies directed against minor determinants, although some anaphylactic reactions have occurred in patients with only penicilloyl-specific IgE antibodies.
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Individuals with a history of penicillin reactions have a 4- to 6-fold increased risk for subsequent reactions to penicillin compared to those without previous reactions.78 However, most serious and fatal allergic reactions to penicillin and β-lactam antibiotics occur in individuals who have never had a previous allergic reaction. Sensitization of these individuals may have occurred from their last therapeutic course of penicillin or (less likely) by occult environmental exposures. Approximately 10% to 20% of hospitalized patients claim a history of penicillin allergy; however, many of these patients either have been incorrectly labeled as allergic to penicillin or have lost their sensitivity. The most useful single piece of information in assessing an individual's potential for an immediate IgE-mediated reaction is the skin test response to major and minor penicillin determinants.
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Negative skin tests indicate that penicillin antibiotics can be given safely. A limited number of patients with positive skin tests have been treated with therapeutic doses of penicillin. The risk of an anaphylactic or accelerated allergic reaction ranges from 50% to 70% in such patients.79 Therefore, if skin tests are positive, equally effective non–cross-reacting antibiotics should be substituted when available. If alternative drugs fail, induce unacceptable side effects, or clearly are less effective, then administration of penicillin using a desensitization protocol to reduce the risk of anaphylaxis should be considered.
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Like penicillins, cephalosporins possess a β-lactam ring (Box 86-6), and allergic reactions were reported shortly after cephalosporins came into clinical use. Cross-reactivity between penicillins and cephalosporins is about 10% because of this common β-lactam ring structure,80 and standard teaching was to avoid treatment with cephalosporins for those with possible penicillin anaphylaxis. However, evidence has accumulated that the side chain rather than the β-lactam ring is the antigen in cephalosporin allergic reactions. Because first-generation cephalosporins as well as cefamandole have similarities in their side chains, in general, patients with positive skin tests to any penicillin reagent or a history compatible with immediate hypersensitivity should not receive first-generation cephalosporin antibiotics unless alternative drugs are clearly less desirable.37 For the most part, later-generation cephalosporins have significantly greater gram-negative antimicrobial properties, with decreased activity against gram-positive organisms. The fourth-generation cephalosporins have broad-spectrum activity.
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The carbapenems and monobactams (aztreonam) are 2 additional classes of β-lactam antibiotics. Cross-reactivity between penicillin and carbapenems would be expected on the basis of the structure of the drugs. There are no published data on allergy to meropenem in patients who are allergic to carbapenem or penicillins. Allergic reactions to the monobactam aztreonam are thought to involve the side chain, so cross-reactivity with other β-lactams should be rare.
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Although anaphylaxis to vancomycin is rare, hypotension is a serious immediate adverse effect associated with intravenous administration. Direct myocardial depression81 and nonimmunologically mediated histamine release82 have been reported as mechanisms of vancomycin-induced hypotension, and not IgE-mediated anaphylaxis. The hypotension occurs most commonly when the drug is rapidly infused or is administered in a concentrated solution. Vancomycin-associated hypotension may be exacerbated by the concurrent use of other drugs (eg, anesthetics) that cause vasodilatation and/or have a negative inotropic effect.81 In addition to hypotension, vancomycin can produce the "red neck" or "red man" syndrome, an intense erythematous discoloration of the upper trunk, arms, and neck that may be associated with pruritus in conscious patients. Vancomycin also has been associated with the sudden development of throbbing pain or spasm in the chest or parasternal muscles in conscious patients, without evidence of myocardial ischemia. To minimize the risk of reactions, vancomycin should be infused over a period of at least 60 minutes and in a dilute solution (500 mg/100 mL). Reactions should be treated by discontinuation of the infusion, administration of an antihistamine for pruritus, and the use of vasopressors and other interventions (eg, fluids) that counteract the hypotension.
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Sulfonamides are generally safe and are often used for chronic prophylaxis. Occasionally, they cause allergic reactions such as minor skin rashes after approximately 1 week of therapy. Life-threatening reactions have been described in HIV-infected infants reexposed to sulfamethoxazole-trimethoprim (SMX-TMP). Stevens-Johnson syndrome and toxic epidermal necrolysis have been associated with SMX-TMP treatment, presumably mediated by an immune reaction similar to graft versus host disease.83 Despite concerns having been raised about other sulfonamide-containing drugs such as diuretics, sulfonylureas, and celecoxib, these antimicrobial agents have an aromatic amine group and a substituted ring not found in the nonantibiotic sulfonamide-containing drugs, so cross-reactivity seems unlikely.84,85
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Other Classes of Antibiotics
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Development of a serious allergic reaction to non–β-lactam antibiotics, such as the aminoglycosides, is rare. Nonurticarial rashes can be treated with antihistamines.
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Multiple Antibiotic Allergy Syndrome
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The multiple antibiotic allergy syndrome, wherein certain individuals are recognized as making "generic" allergic antibody to unrelated antibiotics, is an evolving entity.86 Female gender, a history of multiple antibiotic reactions, and reactions to nonsteroidal anti-inflammatory drugs appear to be the main risk factors.87
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Adverse, allergic-type reactions induced by radiocontrast media (RCM) injections may occur immediately or have a delayed presentation. Most immediate reactions, the event for which an anesthesiologist would likely be summoned, begin 1 to 3 minutes after intravascular administration. Fatal reactions after radiocontrast administration result in an estimated 500 deaths annually in the United States. Patients with a previous reaction to RCM have an approximately 33% (range 17%-60%) chance of a repeat reaction on reexposure.52 Depending on the chemistry of the RCM (Table 86-3), if ionic RCM was administered previously, the use of nonionic RCM will result in a 10-fold decrease in a severe immediate repeat reaction.88
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The exact mechanism of adverse reactions to RCM is unknown. Intravascular injection activates complement, either by the classic or the alternative pathway89; therefore, production of anaphylatoxins with subsequent mast cell and basophil mediator release has been suggested as the cause of these reactions. However, RCM are capable of inducing nonimmunologic histamine release from mast cells and basophils in the absence of complement activation; hypertonicity has been suggested as the cause, as has an IgE-mediated cause based on elevated tryptase levels, particularly with severe or fatal reactions.90-93
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Pretreatment of high-risk patients with oral prednisone (50 mg) and diphenhydramine (50 mg) 1 hour before radiocontrast administration reduces the risk of reactions to 9% (Box 86-4).94 Almost all reactions in pretreated patients are of no clinical importance (eg, mild urticaria). The addition of oral ephedrine (25 mg) 1 hour before radiocontrast administration (in patients without angina, dysrhythmias, or other contraindications for ephedrine administration) further reduces the reaction rate to 3.1%.53 Combining premedication with nonhyperosmolar contrast media may be of additional benefit in preventing reactions in high-risk individuals.51
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Protamine sulfate, a polycationic protein extracted from salmon milt, is used to reverse heparin anticoagulation and slow the absorption of certain insulins (Neutral Protamine Hagedorn, or NPH, and protamine zinc insulin, or PZI). The use of intravenous protamine following cardiopulmonary bypass, cardiac catheterization, hemodialysis, or pheresis has resulted in increasing reports of life-threatening adverse reactions.
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Diabetic patients receiving daily subcutaneous injections of insulins containing protamine have a greatly increased risk for life-threatening reactions when given protamine intravenously.95-97 Another group that may be at increased risk for protamine reactions are men who have undergone vasectomies. After vasectomy, 55% to 73% of men will develop antibodies to sperm antigens, and of this group, 20% to 33% develop autoantibodies to protamine.98 In addition, because protamine is produced from the matured testis of salmon or related species of fish belonging to the family Salmonidae or Clupeidae, it has been suggested that individuals allergic to fish may have serum antibodies directed against protamine.99 Finally, prior exposure to intravenous protamine given for the reversal of heparin anticoagulation may increase the risk for a reaction with subsequent protamine administration.100,101 Following cardiopulmonary bypass, risk factors found to correlate with adverse events following protamine administration included NPH insulin use (odds ratio = 8.18; 95% confidence interval [CI] 2.08-32.2), fish allergy (odds ratio = 24.5; CI 1.24-482.3), and a history of nonprotamine medication allergy (odds ratio = 2.97; CI 1.25-7.07).91
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The exact mechanisms by which acute protamine reactions occur are incompletely understood. Some protamine reactions may be associated with complement activation, either through protamine–heparin complexes or through the interaction of protamine and complement fixing, antiprotamine IgG antibody, leading to pulmonary artery pressure elevation through the generation of thromboxane.102,103
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Cutaneous hypersensitivity and eczema may occur from chronic exposure to topical preparations. Of 50 case reports of chlorhexidine anaphylaxis, one-third occurred during surgery104; however, the risk of development of type I and type IV allergy to chlorhexidine, even with daily occupational exposure of health care workers, is extremely rare.104 The intriguing explanation for allergic reactions lies in the fact that its molecular structure is symmetrical, with 2 identical epitopes. Therefore, it is capable of cross-linking mast and basophil cell surface IgE antibodies, thereby promoting degranulation and allergic reactions in sensitized individuals. This mechanism is similar to other divalent drugs such as succinylcholine. Moreover, sensitization to chlorhexidine is likely because of its presence in numerous consumer products such as cleaning fluids, toothpastes, mouth rinses, etc.
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Concerns are often expressed about allergy to iodine in the context of povidone iodine preparation solutions or in patients with a history of seafood allergy. Similar concerns are voiced about patients with allergy to RCM because of the iodine component. The reaction to povidone iodine is typically allergic contact dermatitis or local irritation. There is, however, 1 case report of anaphylaxis to povidone-iodine applied intravaginally, but because of the lack of follow-up allergy testing, it is unclear if this reaction was caused by the iodine or the povidone.105 Povidone is the carrier molecule for iodine atoms. A 9-year-old child has been confirmed to have eosinophilia, elevated specific IgE level, and a positive skin prick test for povidone iodine.106 Fish allergy is due to protein M and tropomyosin, neither of which contain iodine.107,108
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Transfusion-Related Anaphylaxis
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Transfusion-related anaphylaxis, a serious, life-threatening condition, is discussed in Chapter 83.
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Natural rubber latex present in various materials, especially surgical gloves, is responsible for a dramatic change in the etiology of intraoperative anaphylactic shock, increasing in 1 series from 0.5% of cases in 1989 to 22.3% in 2002.
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Natural rubber latex is a complex suspension of polyisoprene, lipids, phospholipids, and proteins. The proteins are found in 3 physical states: water soluble, starch bound, or latex bound, and there are at least 240 potentially allergenic proteins in the processed latex product. The protein content of latex gloves can vary up to 1000-fold among different lots marketed by the same manufacturer and 3000-fold between gloves from different manufacturers.109 A number of chemicals, including preservatives, accelerators, antioxidants, and vulcanizing compounds, are added during the manufacturing process to yield the final product. Although the chemicals added to latex have long been associated with contact dermatitis and type IV reactions, it was only after the embracing of universal precautions that reports from around the world describing generalized urticaria, angioedema, upper and lower respiratory obstructions, and cardiovascular collapse first appeared. Patients who have suffered severe systemic reactions often have a history of contact urticaria or angioedema to rubber products such as gloves or rubber balloons, or atopy.
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Certain populations are at significantly increased risk for latex allergy. These include health care workers, who have had increased exposure to latex usually in the form of gloves; patients with prolonged or frequent exposure to latex products such as urinary catheters; and latex factory workers.110 A health care worker who is atopic is at increased risk, and the risk is increased if he or she had prior surgery.111 Anesthesiologists have a 12.5% and 2.4% prevalence of latex sensitization and allergy, respectively.112 Patients with meningomyelocele or congenital urologic anomalies seem particularly susceptible, with an estimated incidence of latex allergy averaging 50%.
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IgE antibodies play a major role in the immunopathogenesis of latex-induced allergy and anaphylaxis. The diagnosis of latex allergy is made by a combination of medical history, physical examination, and reliable in vivo or in vitro tests. Although skin prick testing is both sensitive (100%) and specific (99%), this method should be restricted to patients with a compelling history and an inconclusive serologic test result because of possible systemic reactions. The RAST for latex-specific IgE is recommended, although it is less sensitive than skin prick testing.
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Serum tryptase levels in the immediate postanaphylaxis period may be helpful in confirming the diagnosis following a clinical episode. The positive predictive value of tryptase for the diagnosis of anaphylaxis is 92.6%, and the negative predictive value is 54.3%.113 Multiple allergies are often found in latex allergic patients. Cross-reactivity of latex with tropical fruits is not uncommon,114 and such findings in the history can be used to heighten suspicion about a patient's potential for latex allergy.
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Patients who have had serious allergic reactions to latex and patients at high risk (eg, patients with meningomyelocele) should avoid contact with latex products. Because prophylactic drug protocols have proven ineffective, a latex-safe environment is advocated.115,116 Box 86-7 provides a checklist for dealing with the latex-allergic patient. Moreover, patients in high-risk pediatric groups, such as children with urologic birth defects and myelomeningocele, should be offered latex-free exposure in the operating room from birth to avoid subsequent sensitization. The American Society of Anesthesiologists has a brochure available on its website summarizing current recommendations for anesthesiologists caring for latex-allergic patients.117
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