Hypersensitivity (or allergic) reactions are exaggerated immunological responses to antigenic stimulation in previously sensitized persons. The antigen, or allergen, may be a protein, polypeptide, or smaller molecule. Moreover, the allergen may be the substance itself, a metabolite, or a breakdown product. Patients may be exposed to antigens through the respiratory tract, gastrointestinal tract, eyes, skin and from previous intravenous, intramuscular, or peritoneal exposure.
Anaphylaxis occurs when inflammatory agents are released from basophils and mast cells as a result of an antigen interacting with immunoglobulin (Ig) E. Anaphylactoid reactions manifest themselves in the same manner as anaphylactic reactions, but are not the result of an interaction with IgE. Direct activation of complement and IgG-mediated complement activation can result in similar inflammatory mediator release and activity.
Depending on the antigen and the immune system components involved, hypersensitivity reactions are classically divided into four types (Table 54–5). In many cases, an allergen (eg, latex) may cause more than one type of hypersensitivity reaction. Type I reactions involve antigens that cross-link IgE antibodies, triggering the release of inflammatory mediators from mast cells. In type II reactions, complement-fixing (C1-binding) IgG antibodies bind to antigens on cell surfaces, activating the classic complement pathway and lysing the cells. Examples of type II reactions include hemolytic transfusion reactions and heparin-induced thrombocytopenia. Type III reactions occur when antigen–antibody (IgG or IgM) immune complexes are deposited in tissues, activating complement and generating chemotactic factors that attract neutrophils to the area. The activated neutrophils cause tissue injury by releasing lysosomal enzymes and toxic products. Type III reactions include serum sickness reactions and acute hypersensitivity pneumonitis. Type IV reactions, often referred to as delayed hypersensitivity reactions, are mediated by CD4+ T lymphocytes that have been sensitized to a specific antigen by prior exposure. Examples of type IV reactions are those associated with tuberculosis, histoplasmosis, schistosomiasis, hypersensitivity pneumonitis, and some autoimmune disorders.
TABLE 54–5Hypersensitivity reactions. ||Download (.pdf) TABLE 54–5 Hypersensitivity reactions.
Type I (immediate)
Type II (cytotoxic)
Hemolytic transfusion reactions
Autoimmune hemolytic anemia
Type III (immune complex)
Acute hypersensitivity pneumonitis
Type IV (delayed, cell-mediated)
Chronic hypersensitivity pneumonitis
1. Immediate Hypersensitivity Reactions
Initial exposure of a susceptible person to an antigen induces CD4+ T cells to lymphokines that activate and transform specific B lymphocytes into plasma cells, producing allergen-specific IgE antibodies (Figure 54–7). The Fc portion of these antibodies then associates with high affinity receptors on the cell surface of tissue mast cells and circulating basophils. During subsequent reexposure to the antigen, it binds the Fab portion of adjacent IgE antibodies on the mast cell surface, inducing degranulation and release of inflammatory lipid mediators and additional cytokines from the mast cell. The end result is the release of histamine, tryptase, proteoglycans (heparin and chondroitin sulfate), and carboxypeptidases. An elevated tryptase concentration in the setting of clinical signs of hypersensitivity signals mast cell activation and is the diagnostic test of choice for anaphylactic reactions. The combined effects of these mediators can produce arteriolar vasodilation, increased vascular permeability, increased mucus secretion, smooth muscle contraction, and other clinical manifestations of type I reactions.
A: Induction of IgE-mediated allergic sensitivity to drugs and other allergens. B: Response of IgE-sensitized cells to subsequent exposure to allergens. Ig, immunoglobulin. (Reproduced with permission from Katzung BG, ed. Basic & Clinical Pharmacology. 8th ed. New York, NY: McGraw-Hill; 2001.)
Type I hypersensitivity reactions are classified as atopic or nonatopic. Atopic disorders typically affect the skin or respiratory tract and include allergic rhinitis, atopic dermatitis, and allergic asthma. Nonatopic hypersensitivity disorders include urticaria, angioedema, and anaphylaxis; when these reactions are mild, they are confined to the skin (urticaria) or subcutaneous tissue (angioedema), but when they are severe, they become generalized and a life-threatening medical emergency (anaphylaxis). Urticarial lesions are characteristically well-circumscribed skin wheals with raised erythematous borders and blanched centers; they are intensely pruritic. Angioedema presents as deep, nonpitting cutaneous edema from marked vasodilation and increased permeability of subcutaneous blood vessels. When angioedema is extensive, it can be associated with large fluid shifts; when it involves the pharyngeal or laryngeal mucosa, it can rapidly compromise the airway.
Angioedema can lead to airway compromise and is frequently the cause for anesthesiology airway management consultation in the emergency department. Angioedema is secondary to increased capillary permeability secondary either to activation of mast cells or through kinin mediation. Patients taking angiotensin-converting enzyme (ACE) inhibitors may experience kinin-mediated angioedema. Bradykinin is inactivated by ACE and consequently it may accumulate when ACE is inhibited. Hereditary angioedema can occur in patients with ineffective amounts of complement inhibitor (C1-INH). Treatment for angioedema first focuses upon airway management as needed. Fresh frozen plasma can be given to increase ACE if ACE inhibition is thought to be contributing to angioedema. The bradykinin receptor antagonist icatibant can likewise be administered if available. C1-INH replacement protein is also available to inhibit kinin synthesis. The kallikrein inhibitor ecallantide can also be used to decrease bradykinin production (Figure 54–8).
Treatment of acute attacks of angioedema based on underlying etiology. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; C1INHRP, C1 inhibitor replacement protein; FFP, fresh frozen plasma; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug. (Reproduced with permission from Barbara D, Ronan K, Maddox D, et al. Perioperative angioedema; background, diagnosis and management. J Clin Anesth. 2013 Jun;25(4):335-343.)
2. Anaphylactic Reactions
Anaphylaxis is an exaggerated response to an allergen (eg, antibiotic) that is mediated by a type I hypersensitivity reaction. The syndrome appears within minutes of exposure to a specific antigen in a sensitized person and characteristically presents as acute respiratory distress, circulatory shock, or both. Death may occur from asphyxiation or irreversible circulatory shock. The incidence of anaphylactic reactions during anesthesia has been estimated at a rate of 1:3500 to 1:20,000 anesthetics. A study of 789 anaphylactic and anaphylactoid reactions reported that the most common source antigens were neuromuscular blockers (58%), latex (17%), and antibiotics (15%).
The most important mediators of anaphylaxis are histamine, leukotrienes, basophil kallikrein (BK-A), and platelet-activating factor. They increase vascular permeability and contract smooth muscle. H1-receptor activation contracts bronchial smooth muscle, whereas H2-receptor activation causes vasodilation, mucus secretion, tachycardia, and increased myocardial contractility. BK-A cleaves bradykinin from kininogen; bradykinin increases vascular permeability and vasodilation and contracts smooth muscle. Activation of Hageman factor can initiate intravascular coagulation. Eosinophil chemotactic factor of anaphylaxis, neutrophil chemotactic factor, and leukotriene B4 attract inflammatory cells that mediate additional tissue injury. Angioedema of the pharynx, larynx, and trachea produce upper airway obstruction, whereas bronchospasm and mucosal edema result in lower airway obstruction. Transudation of fluid into the skin (angioedema) and viscera produces hypovolemia, whereas arteriolar vasodilation decreases systemic vascular resistance. Coronary hypoperfusion and arterial hypoxemia promote arrhythmias and myocardial ischemia. Leukotriene and prostaglandin mediators may also cause coronary vasospasm. Prolonged circulatory shock leads to progressive lactic acidosis and ischemic damage to vital organs. Table 54–6 summarizes important manifestations of anaphylactic reactions.
TABLE 54–6Clinical manifestations of anaphylaxis. ||Download (.pdf) TABLE 54–6 Clinical manifestations of anaphylaxis.
|Organ System ||Signs and Symptoms |
|Cardiovascular ||Hypotension,1 tachycardia, arrhythmias |
|Pulmonary ||Bronchospasm,1 cough, dyspnea, pulmonary edema, laryngeal edema, hypoxia |
|Dermatological ||Urticaria,1 facial edema, pruritus |
Anaphylactoid reactions resemble anaphylaxis but do not depend on IgE antibody interaction with antigen. A drug can directly release histamine from mast cells (eg, urticaria following high-dose morphine sulfate) or activate complement. Despite differing mechanisms, anaphylactic and anaphylactoid reactions typically are clinically indistinguishable and equally life threatening. Table 54–7 lists common causes of anaphylactic and anaphylactoid reactions.
TABLE 54–7Causes of anaphylactic and anaphylactoid reactions.1 ||Download (.pdf) TABLE 54–7 Causes of anaphylactic and anaphylactoid reactions.1
|Anaphylactic reactions against polypeptides ||Venoms (Hymenoptera, fire ant, snake, jellyfish) |
|Airborne allergens (pollen, molds, danders) |
|Foods (peanuts, milk, egg, seafood, grain) |
|Enzymes (trypsin, streptokinase, chymopapain, asparaginase) |
|Heterologous serum (tetanus antitoxin, antilymphocyte globulin, antivenin) |
|Human proteins (insulin, corticotropin, vasopressin, serum and seminal proteins) |
|Anaphylactic reactions against hapten carrier ||Antibiotics (penicillin, cephalosporins, sulfonamides) |
|Disinfectants (ethylene oxide, chlorhexidine) |
|Local anesthetics (procaine) |
|Anaphylactoid reactions ||Polyionic solutions (radiocontrast medium, polymyxin B) |
|Opioids (morphine, meperidine) |
|Hypnotics (propofol, thiopental) |
|Muscle relaxants (rocuronium, succinylcholine, cisatracurium) |
|Synthetic membranes (dialysis) |
|Nonsteroidal antiinflammatory drugs |
|Preservatives (sulfites, benzoates) |
Serum tryptase measurement is helpful in confirming the diagnosis of an anaphylactic reaction. Treatment must be immediate and tailored to the severity of the reaction (Table 54–8).
TABLE 54–8Treatment of anaphylactic and anaphylactoid reactions. ||Download (.pdf) TABLE 54–8 Treatment of anaphylactic and anaphylactoid reactions.
3. Allergic Reactions to Anesthetic Agents
True anaphylaxis due to anesthetic agents is rare; anaphylactoid reactions are much more common. Risk factors associated with hypersensitivity to anesthetics include female gender, atopic history, preexisting allergies, and previous anesthetic exposures. An estimated 1 in 6500 patients has an allergic reaction to a muscle relaxant. In many instances, the patient had no previous exposure to the agent. Investigators suggest that over-the-counter drugs, cosmetics, and food products, many of which contain tertiary or quaternary ammonium ions, can sensitize susceptible individuals.
The incidence of anaphylaxis for thiopental and propofol is 1 in 30,000 and 1 in 60,000, respectively. Allergic reactions to etomidate, ketamine, and benzodiazepines are exceedingly rare. True anaphylactic reactions due to opioids are far less common than nonimmune histamine release. Similarly, anaphylactic reactions to local anesthetics are much less common than vasovagal reactions, toxic reactions to accidental intravenous injections, and side effects from absorbed or intravenously injected epinephrine. IgE-mediated reactions to certain ester-type local anesthetics (eg, procaine and benzocaine), however, are well described secondary to reaction to the metabolite, para-aminobenzoic acid. In contrast, true anaphylaxis due to amide-type local anesthetics is very rare; in some instances, the preservative (paraben or methylparaben) was believed to be responsible for an apparent anaphylactoid reaction to a local anesthetic. Moreover, the cross-reactivity between amide-type local anesthetics seems to be low. Volatile anesthetics are not likely to initiate anaphylaxis.
The severity of allergic reactions to latex-containing products ranges from mild contact dermatitis to life-threatening anaphylaxis. Latex allergy associated with anaphylaxis during anesthesia is now much rarer due to removal of latex-containing products from the medical environment. Most serious reactions seem to involve a direct IgE-mediated immune response to polypeptides in natural latex, although some cases of contact dermatitis may be due to a type IV sensitivity reaction to chemicals introduced in the manufacturing process. Nonetheless, a relationship between the occurrence of contact dermatitis and the probability of future anaphylaxis has been suggested. Chronic exposure to latex and a history of atopy increases the risk of sensitization. Healthcare workers and patients undergoing frequent procedures with latex items (eg, repeated urinary bladder catheterization, barium enema examinations) should therefore be considered at increased risk. Patients with spina bifida, spinal cord injury, and congenital abnormalities of the genitourinary tract have a markedly increased incidence of latex allergy. The incidence of latex anaphylaxis in children is estimated to be 1 in 10,000. A history of allergic symptoms to latex should be sought in all patients during the preanesthetic interview. Foods that cross-react with latex include mango, kiwi, chestnut, avocado, passion fruit, and banana. Interleukin (IL)-18 and IL-13 single nucleotide polymorphisms may affect the sensitivity of individuals to latex and promote allergic responses.
Anaphylactic reactions to latex may be confused with reactions to other substances (eg, drugs, blood products) because the onset of symptoms can be delayed for more than 1 h after initial exposure. Treatment is the same as for other forms of anaphylactic reactions. Preventing a reaction in sensitized patients includes pharmacological prophylaxis and absolute avoidance of latex. Preoperative administration of H1 and H2 histamine antagonists and steroids may provide some protection, although their use is controversial. Although most pieces of anesthetic equipment are now latex-free, some may still contain latex. Manufacturers of latex-containing medical products must label their products accordingly. Only devices specifically known not to contain latex (eg, polyvinyl or neoprene gloves, silicone endotracheal tubes or laryngeal masks, plastic face masks) can be used in latex-allergic patients.
5. Allergies to Antibiotics
Many true drug allergies in surgical patients are due to antibiotics, mainly β-lactam antibiotics, such as penicillins and cephalosporins. Although 1% to 4% of β-lactam administrations result in allergic reactions, only 0.004% to 0.015% of these reactions result in anaphylaxis. Up to 2% of the general population is allergic to penicillin, but only 0.01% of penicillin administrations result in anaphylaxis. Cephalosporin cross-sensitivity in patients with penicillin allergy is estimated to be 2% to 7%, but a history of an anaphylactic reaction to penicillin increases the cross-reactivity rate up to 50%. Patients with a prior history of an anaphylactic reaction to penicillin should therefore not receive a cephalosporin. Although imipenem exhibits similar cross-sensitivity, aztreonam seems to be antigenically distinct and reportedly does not cross-react with other β-lactams. Sulfonamide allergy is also relatively common in surgical patients. Sulfa drugs include sulfonamide antibiotics, furosemide, hydrochlorothiazide, and captopril. Fortunately, the frequency of cross-reactivity among these agents is low.
Like cephalosporins, vancomycin is commonly used for antibiotic prophylaxis in surgical patients. Vancomycin is associated with a reaction (the “red man” or “red neck” syndrome) that consists of intense pruritus, flushing, and erythema of the head and upper torso in addition to arterial hypotension. Isolated systemic hypotension seems to be primarily mediated by histamine release, because pretreatment with H1 and H2 antihistamines can prevent hypotension, even with rapid rates of vancomycin administration. Vancomycin can also produce true anaphylactic or anaphylactoid reactions. Protamine commonly causes vasodilatory hypotension and less commonly presents as an anaphylactoid reaction with pulmonary hypertension and systemic hypotension.
Immunological mechanisms are associated with other perioperative pathologies. Transfusion-related lung injury may be secondary to the activity of antibodies in the donor plasma, producing a hypersensitivity reaction that leads to lung infiltrates and hypoxemia (see Chapter 51). IgG antibody formation directed at heparin–PF4 complexes results in platelet activation, thrombosis, and heparin-induced thrombocytopenia.