Clinical Anesthesia

Chapter 12

Immune Function and Allergic Response

Jerrold H. Levy

Key Points

1. Anesthesiologists routinely manage patients during their perioperative medical care during which they are exposed to foreign substances, including drugs (antibiotics, anesthetic agents, neuromuscular-blocking agents [NMBAs], sedative/hypnotics), polypeptides (e.g., protamine, aprotinin), blood products, and environmental antigens (e.g., latex).

2. Antibodies are specific proteins called immunoglobulins that can recognize and bind to a specific antigen.

3. Cytokines are inflammatory cell activators that are synthesized to act as secondary messengers and activate endothelial cells and white cells.

4. Immune competence during surgery can be affected by direct and hormonal effects of anesthetic drugs, by immunologic effects of other drugs used, by the surgery, by coincident infection, and by transfused blood products.

5. More than 90% of the allergic reactions evoked by intravenous drugs occur within 5 minutes of administration. In the anesthetized patient, the most common life-threatening manifestation of an allergic reaction is circulatory collapse, reflecting vasodilation with resulting decreased venous return.

6. Many diverse molecules administered during the perioperative period release histamine in a dose-dependent, nonimmunologic fashion.

7. A plan for treating anaphylactic reactions must be established before the event. Airway maintenance, 100% oxygen administration, intravascular volume expansion, and epinephrine are essential to treat the hypotension and hypoxia that result from vasodilation, increased capillary permeability, and bronchospasm. Vasopressin should be considered for refractory shock.

8. After an anaphylactic reaction, it is important to identify the causative agent to prevent readministration.

9. Health care workers and children with spina bifida, urogenital abnormalities, or certain food allergies have been recognized as people at increased risk for anaphylaxis to latex.

10.     NMBAs have several unique molecular features that make them potential antigens.

Allergic reactions represent an important cause of perioperative complications. Anesthesiologists routinely manage patients during their perioperative medical care during which they are exposed to foreign substances, including drugs (i.e., antibiotics, anesthetic agents, neuromuscular-blocking agents [NMBAs], sedative hypnotics), polypeptides (protamine, aprotinin), blood products, and environmental antigens (i.e., latex). Anesthesiologists must be able to rapidly recognize and treat anaphylaxis, the most life-threatening form of an allergic reaction.1

The allergic response represents just one limb of the pathologic response that the immune system can mount against foreign substances. As part of normal host surveillance mechanisms, a series of cellular and humoral elements oversees foreign structures called antigens to provide host defense. These foreign substances (antigens) consist of molecular arrangements found on cells, bacteria, viruses, proteins, or complex macromolecules.1,2,3,4 Immunologic mechanisms (1) involve antigen interaction with antibodies or specific effector cells; (2) are reproducible; and (3) are specific and adaptive, distinguishing foreign substances and amplifying reactivity through a series of inflammatory cells and proteins. The immune system serves to protect the body against external micro-organisms and toxins, as well as internal threats from neoplastic cells; however, it can respond inappropriately to cause hypersensitive (allergic) reactions. Life-threatening allergic reactions to drugs and other foreign substances observed perioperatively may represent different expressions of the immune response.1,2

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Basic Immunologic Principles

Host defense can be divided into cellular and humoral elements.1,2,3,4 The humoral system includes antibodies, complement, cytokines, and other circulating proteins, whereas cellular immunity is mediated by specific lymphocytes of the T-cell series. Lymphocytes have receptors that distinguish between antigens of host and foreign origin. When lymphocytes react with foreign antigens, they respond to orchestrate immunosurveillance, regulate immunospecific antibody synthesis, and destroy foreign invaders. Individual aspects of the immune response and their importance are considered separately.

Antigens

Molecules stimulating an immune response (antibody production or lymphocyte stimulation) are called antigens.4 Only a few drugs used by anesthesiologists, such as polypeptides (protamine) and other large macromolecules (dextrans), are complete antigens (Table 12-1). Most commonly used drugs are simple organic compounds of low molecular weight (around 1,000 daltons). For such a small molecule to become immunogenic, it must form a stable bond with circulating proteins or tissue micromolecules to result in an antigen (hapten-macromolecular complex). Small-molecular-weight substances such as drugs or drug metabolites that bind to host proteins or cell membranes to sensitize patients are calledhaptens. Haptens are not antigenic by themselves. Often, a reactive drug metabolite (e.g., penicilloyl derivative of penicillin) is believed to bind with macromolecules to become antigens, but for most drugs this phenomenon has not been proved.

Thymus-Derived (T-Cell) and Bursa-Derived (B-Cell) Lymphocytes

The thymus of the fetus differentiates immature lymphocytes into thymus-derived cells (T cells). T cells have receptors that are activated by binding with foreign antigens and secrete mediators that regulate the immune response. The subpopulations of T cells that exist in humans include helper, suppressor, cytotoxic, and killer cells.5 The two types of regulatory T cells are helper cells (OKT4) and suppressor cells (OKT8). Helper cells are important for key effector cell responses, whereas suppressor cells inhibit immune function. Infection of helper T cells with a retrovirus, the human immunodeficiency virus, produces a specific increase in the number of suppressor cells. Cytotoxic T cells destroy mycobacteria, fungi, and viruses. Other lymphocytes, called natural killer cells, do not need specific antigen stimulation to set up their role. Both the cytotoxic T cells and natural killer cells take part in defense against tumor cells and in transplant rejection. T cells produce mediators that influence the response of other cell types involved in the recognition and destruction of foreign substances.

Figure 12-1. Basic structural configuration of the antibody molecule representing human immunoglobulin G. Immunoglobulins are composed of two heavy chains and two light chains bound by disulfide linkages (represented by crossbars). Papain cleaves the molecule into two Fab fragments and one Fc fragment. Antigen binding occurs on the Fab fragments, whereas the Fc segment is responsible for membrane binding or complement activation. (Reprinted with permission from Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, 2nd edition. Boston, Butterworth-Heinemann, 1992.)

B cells represent a specific lymphocyte cell line that can differentiate into specific plasma cells that synthesize antibodies, a step controlled by both helper and suppressor T-cell lymphocytes.5 B cells are also called bursa-derived cells because in birds, the bursa of Fabricius is important in producing cells responsible for antibody synthesis.

Antibodies

Antibodies are specific proteins called immunoglobulins (Ig) that can recognize and bind to a specific antigen.6 The basic structure of the antibody molecule is illustrated in Figure 12-1. Each antibody has at least two heavy chains and two light chains that are bound together by disulfide bonds. The Fab fragment has the ability to bind antigen, and the Fc, or crystallizable, fragment is responsible for the unique biological properties of the different classes of immunoglobulins (cell binding and complement activation). Antibodies function as specific receptor molecules for immune cells and proteins. When antigen binds covalently to the Fab fragments, the antibody undergoes

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conformational changes to activate the Fc receptor. The results of antigen-antibody binding depend on the cell type, which causes a specific type of activation (e.g., lymphocyte proliferation and differentiation into antibody-secreting cells, mast cell degranulation, and complement activation).

Table 12-1 Agents Administered During Anesthesia That Act as Antigens

HAPTENS

MACROMOLECULES

Penicillin and its derivatives

Aprotinin
Blood products

Anesthetic drugs (?)

Chymopapain
Colloid volume expanders
Neuromuscular blocking agents
Protamine
Latex

Table 12-2 Biological Characteristics of Immunoglobulins (Igs)

 

IgG

IgM

IgA

IgE

IgD

Heavy chain

γ

µ

A

ε

δ

Molecular weight

160,000

900,000

170,000

188,000

184,000

Subclasses

1, 2, 3, 4

1, 2

1, 2

   

Serum concentration (mg/dL)

6–14

0.5–1.5

1–3

<-0.5 × 103

<0.1

Complement activation

All but IgG4

+

-

-

-

Placental transfer

+

-

-

-

-

Serum half-life (days)

23

5

6

1–5

2–8

Cell binding

Mast cells (IgG4) Neutrophils Lymphocytes Mononuclear cells Platelets

Lymphocytes

 

Mast cells Basophils

Neutrophils Lymphocytes

Modified from Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, 2nd edition. Boston, Butterworth-Heinemann, 1992.

Five major classes of antibodies occur in humans: IgG, IgA, IgM, IgD, and IgE. The heavy chain determines the structure and the function of each molecule. The basic properties of each antibody are listed in Table 12-2.

Effector Cells and Proteins of the Immune Response Cells

Monocytes, neutrophils (polymorphonuclear leukocytes [PMNs]), and eosinophils represent important effector cells that migrate into areas of inflammation in response to specific chemotactic factors, including lymphokines, cytokines, and complement-derived mediators. The deposition of antibody or complement fragments on the surface of foreign cells is called opsonization, a process that promotes killing foreign cells by effector cells. In addition, lymphokines and cytokines produce chemotaxis of other inflammatory cells in a manner described in the following sections.

Monocytes and Macrophages

Macrophages regulate immune responses by processing and presenting antigens to effect inflammatory, tumoricidal, and microbicidal functions. Macrophages arise from circulating monocytes or may be confined to specific organs such as the lung. They are recruited and activated in response to micro-organisms or tissue injury. Macrophages ingest antigens before they interact with receptors on the lymphocyte surface to regulate their action. Macrophages synthesize mediators to facilitate both B-lymphocyte and T-lymphocyte responses.

Polymorphonuclear Leukocytes (Neutrophils)

The first cells to appear in acute inflammatory reaction are neutrophils that contain acid hydrolases, neutral proteases, and lysosomes. Once activated, they produce hydroxyl radicals, superoxide, and hydrogen peroxide, which aid in microbial killing.

Eosinophils

The exact function of the eosinophil in host defense is unclear; however, inflammatory cells recruit eosinophils to collect at sites of parasitic infections, tumors, and allergic reactions.1

Basophils

Basophils comprise 0.5 to 1% of circulating granulocytes in the blood.1 The surface of basophils contain IgE receptors, which function similarly to those on mast cells.

Mast Cells

Mast cells are important cells for immediate hypersensitivity responses. They are tissue fixed and located in the perivascular spaces of the skin, lung, and intestine.1 The surface of mast cells contain IgE receptors, which bind to specific antigens. Once activated, these cells release physiologically active mediators important to immediate hypersensitivity responses (see “IgE-Mediated Pathophysiology”). Mast cells can be activated by a series of both immune and nonimmune stimuli.

Proteins

Cytokines/Interleukins

Cytokines are inflammatory cell activators that are synthesized by macrophages to act as secondary messengers and activate endothelial cells and white cells.7 Interleukin-1 and tumor necrosis factor are examples of cytokines considered to be important mediators of the biological responses to infection and other inflammatory reactions. Liberation of interleukin-1 and tumor necrosis factor produces fever, neuropeptide release, endothelial cell activation, increased adhesion molecule expression, neutrophil priming, hypotension, myocardial suppression, and a catabolic state.7 The term interleukin was coined for a group of cytokines that promotes communication between and among (“inter”) leukocytes (“leukin”). Interleukins are a group of different regulatory proteins that act to control many aspects of the immune and inflammatory responses. The interleukins are polypeptides synthesized in response to cellular activation; they produce their inflammatory effects by activating specific receptors on inflammatory cells and vasculature. T-cell lymphocytes influence the activity of other immunologic and nonimmunologic cells by producing an array of interleukins that they secrete. Different interleukins of this class have been isolated and characterized; they function as short-range or intracellular soluble mediators of the immune and inflammatory responses. The interleukin family of cytokines has been rapidly growing in number because of advances in gene cloning.

Complement

The primary humoral response to antigen and antibody binding is activation of the complement system.8 The complement system consists of around 20 different proteins that bind to activated antibodies, other complement proteins, and cell membranes. The complement system is an important effector system of inflammation. Complement activation can be initiated

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by IgG or IgM binding to antigen, by plasmin through the classic pathway, by endotoxin, or by drugs through the alternate (properdin) pathway8 (Fig. 12-2). Specific fragments released during complement activation include C3a, C4a, and C5a, which have important humoral and chemotactic properties (see “Non–IgE-Mediated Reactions”). The major function of the complement system is to recognize bacteria both directly and indirectly by attracting phagocytes (chemotaxis), as well as the increased adhesion of phagocytes to antigens (opsonization), and cell lysis by activation of the complete cascade.

Figure 12-2. Diagram of complement activation. Complement system can be activated by either the classic pathway (immunoglobulin [Ig] G, IgM–antigen interaction) or the alternate pathway (endotoxin, drug interaction). Small peptide fragments of C3 and C5 called anaphylatoxins (C3a, C5a) that are released during activation are potent vasoactive mediators. Formation of the complete complement cascade produces a membrane attack unit that lyses cell walls and membranes. An inhibitor of the complement cascade, the C1 esterase inhibitor, ensures the complement system is turned off most of the time.

A series of inhibitors regulates activation to ensure regulation of the complement system. Hereditary (autosomal dominant) or acquired (associated with lymphoma, lymphosarcoma, chronic lymphocytic leukemia, and macroglobulinemia) angioneurotic edema is an example of a deficiency in an inhibitor of the C1 complement system (C1 esterase deficiency). This syndrome is characterized by recurrent increased vascular permeability of specific subcutaneous and serosal tissues (angioedema), which produces laryngeal obstruction and respiratory and cardiovascular abnormalities after tissue trauma and surgery, or even without any obvious precipitating factor.9 One of the important pathologic manifestations of complement activation is acute pulmonary vasoconstriction associated with protamine administration.1

Effects of Anesthesia on Immune Function

Anesthesia and surgery depress nonspecific host resistance mechanisms, including lymphocyte activation and phagocytosis.6 Immune competence during surgery can be affected by direct and hormonal effects of anesthetic drugs, by immunologic effects of other drugs used, by the surgery, by coincident infections, and by transfused blood products. Blood represents a complex of humoral and cellular elements that may alter immunomodulation to various antigens. Although multiple studies demonstrate in vitro changes of immune function, no studies have ever proved their importance.6

Besides, such changes are likely of minor importance compared with the hormonal aspects of stress responses.

Hypersensitivity Responses (Allergy)

Gell et al.3 first described a scheme for classifying immune responses to understand specific diseases mediated by immunologic processes. The immune pathway functions as a protective mechanism, but can also react inappropriately to produce a hypersensitivity or allergic response. They defined four basic types of hypersensitivity, types I to IV. It is useful first to review all four mechanisms to understand the different immune reactions that occur in humans.

Figure 12-3. Type I immediate hypersensitivity reactions (anaphylaxis) involve immunoglobulin E (IgE) antibodies binding to mast cells or basophils by way of their Fc receptors. On encountering immunospecific antigens, the IgE becomes cross-linked, inducing degranulation, intracellular activation, and release of mediators. This reaction is independent of complement.

Type I Reactions

Type I reactions are anaphylactic or immediate-type hypersensitivity reactions (Fig. 12-3). Physiologically active mediators are released from mast cells and basophils after antigen binding to IgE antibodies on the membranes of these cells. Type I hypersensitivity reactions include anaphylaxis, extrinsic asthma, and allergic rhinitis.

Type II Reactions

Type II reactions are also known as antibody-dependent cell-mediated cytotoxic hypersensitivity or cytotoxic reactions (antibody-dependent cell-mediated cytotoxic; Fig. 12-4). These reactions are mediated by either IgG or IgM antibodies directed

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against antigens on the surface of foreign cells. These antigens may be either integral cell membrane components (A or B blood group antigens in ABO incompatibility reactions) or haptens that absorb to the surface of a cell, stimulating the production of antihapten antibodies (autoimmune hemolytic anemia). The cell damage in type II reactions is produced by (1) direct cell lysis after complete complement cascade activation, (2) increased phagocytosis by macrophages, or (3) killer T-cell lymphocytes producing antibody-dependent cell-mediated cytotoxic effects. Examples of type II reactions in humans are ABO-incompatible transfusion reactions, drug-induced immune hemolytic anemia, and heparin-induced thrombocytopenia.

Figure 12-4. Type II or cytotoxic reactions. Antibody of an immunoglobulin (Ig) G or IgM class is directed against antigens on an individual's own cells (target cell). The antigens may be integral membrane components or foreign molecules that have been absorbed. This physiologic choice may lead to complement activation, including cell lysis (upper figure) or to cytotoxic action by killer T-cell lymphocytes (lower figure).

Figure 12-5. Type III immune complex reactions. Antibodies of an immunoglobulin (Ig) G or IgM type bind to the antigen in the soluble base and are subsequently deposited in the microvasculature. Complement is activated, resulting in chemotaxis and activation of polymorphonuclear leukocytes at the site of antigen-antibody complexes and subsequent tissue injury.

Type III Reactions (Immune Complex Reactions)

Type III reactions result from circulating soluble antigens and antibodies that bind to form insoluble complexes that deposit in the microvasculature (Fig. 12-5). Complement is activated, and neutrophils are localized to the site of complement deposition to produce tissue damage. Type III reactions include classic serum sickness observed after snake antisera or antithymocyte globulin, and immune complex vascular injury, and may occur through mechanisms of protamine-mediated pulmonary vasoconstriction.1

Type IV Reactions (Delayed Hypersensitivity Reactions)

Type IV reactions result from the interactions of sensitized lymphocytes with specific antigens (Fig. 12-6). Delayed hypersensitivity reactions are mainly mononuclear, manifest in 18 to 24 hours, peak at 40 to 80 hours, and disappear in 72 to 96 hours. Antigen-lymphocyte binding produces lymphokine synthesis, lymphocyte proliferation, generation of cytotoxic T cells, and attracts macrophages and other inflammatory cells. Cytotoxic T cells are produced specifically to kill target cells that bear antigens identical with those that triggered the reaction. This form of immunity is important in tissue rejection, graft-versus-host reactions, contact dermatitis (e.g., poison ivy), and tuberculin immunity.

Figure 12-6. Type IV immune complex reactions (delayed hypersensitivity or cell-mediated immunity). Antigen binds to sensitized T-cell lymphocytes to release lymphokines after a second contact with the same antigen. This reaction is independent of circulating antibody or complement activation. Lymphokines induce inflammatory reactions and activate, as well as attract, macrophages and other mononuclear cells to produce delayed tissue injury.

Intraoperative Allergic Reactions

Intraoperative allergic reactions occur once in every 5,000 to 25,000 anesthetics, with a 3.4% mortality rate.10,11 More than 90% of the allergic reactions evoked by intravenous drugs occur within 5 minutes of administration. In the anesthetized patient, the most common life-threatening manifestation of an allergic reaction is circulatory collapse, reflecting vasodilation with resulting decreased venous return (Table 12-3). The only manifestation of an allergic reaction may be refractory hypotension.12 Portier and Richet13 first used the word anaphylaxis (from ana, “against,” and prophylaxis, “protection”) to describe the profound shock and resulting death that sometimes occurred in dogs immediately after a second challenge with a foreign antigen. When life-threatening allergic reactions mediated by antibodies occur, they are defined as anaphylactic. Although the term anaphylactoidhas been used in the past to describe nonimmunologic reactions, this term is now rarely used.14

Anaphylactic Reactions

IgE-Mediated Pathophysiology

Antigen binding to IgE antibodies initiates anaphylaxis (Fig. 12-7). Prior exposure to the antigen or to a substance of similar structure is needed to produce sensitization, although an allergic history may be unknown to the patient. On re-exposure, binding of the antigen to bridge two immunospecific IgE antibodies found on the surfaces of mast cells and basophils releases stored mediators, including histamine, tryptase, and chemotactic factors.15,16,17 Arachidonic acid metabolites (leukotrienes and prostaglandins), kinins, and cytokines are subsequently synthesized and released in response to cellular activation.18 The released mediators produce a symptom complex of bronchospasm and upper airway edema in the respiratory system, vasodilation and increased capillary permeability in the cardiovascular system, and urticaria in the cutaneous system. Different mediators are released from mast cells and basophils after activation.

Chemical Mediators of Anaphylaxis

Histamine stimulates H1, H2, and H3 receptors. H1 receptor activation releases endothelium-derived relaxing factor (nitric oxide) from vascular endothelium, increases capillary permeability, and contracts airway and vascular smooth

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muscle.1,19,20 H2 receptor activation causes gastric secretion, inhibits mast cell activation, and contributes to vasodilation.19 When injected into skin, histamine produces the classic wheal (increased capillary permeability producing tissue edema) and flare (cutaneous vasodilation) response in humans.21 Histamine undergoes rapid metabolism in humans by the enzymes histamine N-methyltransferase and diamine oxidase found in endothelial cells.1

Table 12-3 Recognition of Anaphylaxis During Regional and General Anesthesia

SYSTEMS

SYMPTOMS

SIGNS

Respiratory

Dyspnea

Coughing

Chest discomfort

Wheezing

Sneezing

Laryngeal edema

Decreased pulmonary compliance

Fulminant pulmonary edema

Acute respiratory failure

Cardiovascular

Dizziness

Disorientation

Malaise

Diaphoresis

Retrosternal oppression

Loss of consciousness

Hypotension

Tachycardia

Dysrhythmias

Decreased systemic vascular resistance

Cardiac arrest

Pulmonary hypertension

Cutaneous

Itching

Urticaria (hives)

Burning

Flushing

Tingling

Periorbital edema

 

Perioral edema

Reprinted with permission from Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, 2nd edition. Boston, Butterworth-Heinemann, 1992.

Figure 12-7. During anaphylaxis (type I immediate hypersensitivity reaction), (1) antigen enters a patient during anesthesia through a parenteral route. (2) It bridges two immunoglobulin E antibodies on the surface of mast cells or basophils. In a calcium-dependent and energy-dependent process, cells release various substances—histamine, eosinophilic chemotactic factor of anaphylaxis (ECF-A), leukotrienes, prostaglandins, and kinins. (3) These released mediators produce the characteristic effects in the pulmonary, cardiovascular, and cutaneous systems. The most severe and life-threatening effects of the vasoactive mediators occur in the respiratory and cardiovascular systems. I.V., intravenous; I.M., intramuscular. (Reprinted with permission from Levy JH: Identification and Treatment of Anaphylaxis: Mechanisms of Action and Strategies for Treatment Under General Anesthesia. Chicago, Smith Laboratories, 1983.)

Peptide Mediators of Anaphylaxis

Factors are released from mast cells and basophils that cause granulocyte migration (chemotaxis) and collection at the site of the inflammatory stimulus.18 Eosinophilic chemotactic factor of anaphylaxis (ECF-A) is a small-molecular-weight peptide chemotactic for eosinophils.22 Although the exact role of ECF-A or the eosinophil in acute allergic response is unclear,

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eosinophils release enzymes that can inactivate histamine and leukotrienes.18 In addition, a neutrophilic chemotactic factor is released that causes chemotaxis and activation.18,23Neutrophil activation may be responsible for recurrent manifestations of anaphylaxis.

Table 12-4 Biological Effects of Anaphylatoxins

Biological Effects

C32

C52

Histamine release

+

+

Smooth muscle contraction

+

+

Increased vascular permeability

+

+

Chemotaxis

 

+

Leukocyte and platelet aggregation

 

+

Interleukin release

+

+

Arachidonic Acid Metabolites

Leukotrienes and prostaglandins are both synthesized after mast cell activation from arachidonic acid metabolism of phospholipid cell membranes through either lipoxygenase or cyclo-oxygenase pathways.24,25 The classic slow-reacting substance of anaphylaxis is a combination of leukotrienes C4, D4, and E4.25 Leukotrienes produce bronchoconstriction (more intense than that produced by histamine), increased capillary permeability, vasodilation, coronary vasoconstriction, and myocardial depression.25 Prostaglandins are potent mast cell mediators that produce vasodilation, bronchospasm, pulmonary hypertension, and increased capillary permeability.18,25 Prostaglandin D2, the major metabolite of mast cells, produces bronchospasm and vasodilation.25 Elevated plasma levels of thromboxane B2 (the metabolite of thromboxane A2), also a prostaglandin synthesized by mast cells as well as by PMNs, have been demonstrated after protamine reactions associated with pulmonary hypertension.26,27

Kinins

Small peptides called kinins are synthesized in mast cells and basophils to produce vasodilation, increased capillary permeability, and bronchoconstriction.18,28 Kinins can stimulate vascular endothelium to release vasoactive factors, including prostacyclin, and endothelial-derived relaxing factors such as nitric oxide.1

Platelet-Activating Factor

Platelet-activating factor (PAF), an unstored lipid synthesized in activated human mast cells, is a potent biological material, producing physiologic effects at concentrations as low as 10-10 M.18 PAF aggregates and activates human platelets, and perhaps leukocytes, to release inflammatory products. PAF causes an intense wheal-and-flare response, smooth muscle contraction, and increased capillary permeability.18

Recognition of Anaphylaxis

The onset and severity of the reaction relate to the mediator's specific end-organ effects. Antigenic challenge in a sensitized individual usually produces immediate clinical manifestations of anaphylaxis, but the onset may be delayed 2 to 20 minutes.29,30 The reaction may include some or all the symptoms and signs listed in Table 12-3. Individuals vary in their manifestations and course of anaphylaxis.31,32 A spectrum of reactions exists, ranging from minor clinical changes to the full-blown syndrome leading to death.31,33 The enigma of anaphylaxis lies in the unpredictability of when it happens, the severity of the attack, and the lack of a prior allergic history.

Non–IgE-Mediated Reactions

Other immunologic and nonimmunologic mechanisms release many of the mediators previously discussed, independent of IgE, creating a clinical syndrome identical with anaphylaxis. Specific pathways important in producing the same clinical manifestations are considered later.

Complement Activation

Complement activation follows both immunologic (antibody-mediated; i.e., classic pathway) or nonimmunologic (alternative) pathways to include a series of multimolecular, self-assembling proteins that release biologically active complement fragments of C3 and C5.10,34 C3a and C5a are called anaphylatoxins because they release histamine from mast cells and basophils, contract smooth muscle, increase capillary permeability, and cause interleukin synthesis (Table 12-4). C5a interacts with specific high-affinity receptors on PMNs and platelets, causing leukocyte chemotaxis, aggregation, and activation.35 Aggregated leukocytes embolize to various organs, producing microvascular occlusion and liberation of inflammatory products such as arachidonic acid metabolites, oxygen free radicals, and lysosomal enzymes (Fig. 12-8). Antibodies of the IgG class directed against antigenic determinants or granulocyte surfaces can also produce leukocyte aggregation.36 These

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antibodies are called leukoagglutinins. Investigators have associated complement activation and PMN aggregation in producing the clinical expression of transfusion reactions,36,37pulmonary vasoconstriction after protamine reactions,27 adult respiratory distress syndrome,36 and septic shock.38

Table 12-5 Drugs Capable of Nonimmunologic Histamine Release

Antibiotics (vancomycin, pentamidine)
Basic compounds
Hyperosmotic agents
Muscle relaxants (d-tubocurarine, metocurine, atracurium, mivacurium, doxacurium)
Opioids (morphine, meperidine, codeine)
Thiobarbiturates

Figure 12-8. Sequence of events producing granulocyte aggregation, pulmonary leukostasis, and cardiopulmonary dysfunction. (Reprinted from Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, 2nd edition. Boston, Butterworth-Heinemann, 1992.)

Nonimmunologic Release of Histamine

Many diverse molecules administered during the perioperative period release histamine in a dose-dependent, nonimmunologic fashion39,40,41,42,43 (Table 12-5 and Fig. 12-9). The mechanisms involved in nonimmunologic histamine release are not well understood, but represent selective mast cell and not basophil activation.43,44 (Fig. 12-10). Human cutaneous mast cells are the only cell population that releases histamine in response to both drugs and endogenous stimuli (neuropeptides).1 Nonimmunologic histamine release may involve mast cell activation through specific cell-signaling activation.40 (Fig. 12-11). Different molecular structures release histamine in humans, which suggests that different mechanisms are involved. Histamine release does not depend on the µ receptor because fentanyl and sufentanil, the most potent µ receptor agonists clinically available, do not release histamine in human skin.39 Although the newer muscle relaxants may be more potent at the neuromuscular junction, drugs that are mast cell degranulators are equally capable of releasing histamine.39,40 On an equimolar basis, atracurium is as potent as d-tubocurarine or metocurine in its ability to degranulate mast cells.40 At clinically recommended doses, newer aminosteroidal agents (such as rocuronium and rapacuronium) have minimal effects on histamine release.44,45

Figure 12-9. Example of an anaphylactic reaction after rapid vancomycin administration in a patient. Hypotension is associated with an increased cardiac output and decreased calculated systemic vascular resistance. Plasma histamine levels 1 minute after the vancomycin administration were 2.4 ng/mL and subsequently decreased to zero. The patient was given ephedrine, 5 mg, and blood pressure returned to baseline values. AP, arterial pressure; PAP, pulmonary arterial pressure; CO, cardiac output; HR, heart rate; CVP, central venous pressure; SVR, systemic vascular resistance. (Reprinted from Levy JH, Kettlekamp N, Goertz P, Hermens J, Hirshman CA: Histamine release by vancomycin: A mechanism for hypotension in man. Anesthesiology 1987; 67: 122–125.)

Antihistamine pretreatment before administration of drugs that are known to release histamine in humans does not inhibit histamine release; rather, the antihistamines compete with histamine at the receptor and may attenuate decreases in systemic vascular resistance.1 However, the effect of any drug on systemic vascular resistance may depend on other factors in addition to histamine release.46,47

Treatment Plan

A plan for treating anaphylactic reactions must be established before the event. Airway maintenance, 100% oxygen administration, intravascular volume expansion, and epinephrine are essential to treat the hypotension and hypoxia that result from vasodilation, increased capillary permeability, and bronchospasm.1 Table 12-6 lists a protocol for managing anaphylaxis during general anesthesia, with representative doses for a 70-kg adult. The treatment plan is the same for life-threatening anaphylactic or anaphylactoid reactions. Therapy must be titrated to needed effects with careful monitoring.1 Severe reactions need aggressive therapy and may be protracted, with persistent hypotension, pulmonary hypertension, lower respiratory obstruction, or laryngeal obstruction that may persist 5 to 32 hours despite vigorous therapy.48 All patients who have experienced an anaphylactic reaction should be admitted to an intensive care unit for 24 hours of monitoring because manifestations may recur after successful treatment.

Figure 12-10. Electron micrograph of human cutaneous mast cell after injection of dynorphin, a κ opioid agonist. The cell outline is rounded and most of the cytoplasmic granules are swollen, exhibiting varying degrees of decreased electron density and flocculence consistent with ongoing degranulation. The perigranular membranes of the adjacent granules at the periphery of the cell are fused to each other and to plasma membrane. Original magnification ×72,000. (Reprinted with permission from Casale TB, Bowman S, Kaliner M: Induction of human cutaneous mast cell degranulation by opiates and endogenous opioid peptides: Evidence for opiate and nonopiate receptor participation. J Allergy Clin Immunol 1984; 73: 778–781.)

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Initial Therapy

Although it may not be possible to stop the administration of antigen, limiting antigen administration may prevent further mast cell and basophil activation.

Maintain Airway and Administer 100% Oxygen

Profound ventilation–perfusion abnormalities producing hypoxemia can occur with anaphylactic reactions.49 Always administer 100% oxygen, with ventilatory support as needed. Arterial blood gas values may be useful to follow during resuscitation (see Chapter 59).

Figure 12-11. Different mechanisms of mediator release from human cutaneous mast cells stimulated immunologically by anti-immunoglobulin (Ig) E and by nonimmunologic stimuli with substance P. Anti-IgE stimulation, like antigen stimulation, initiates the release of histamine, prostaglandin D2 (PGD2), or leukotriene C4 (LTC4) by a mechanism that takes 5 minutes to reach completion and requires the influx of intracellular calcium. Nonimmunologic activation with drugs or substance P releases histamine but not PGD2 or LTC4 by a mechanism that is complete within 15 seconds and uses calcium mobilized from intracellular sources. (Reprinted with permission from Caulfield JP, El-Lati S, Thomas G, Church MK: Dissociated human foreskin mast cells degranulate in response to anti-IgE and substance P. Lab Invest 1990; 63: 502–510.)

Discontinue All Anesthetic Drugs

Inhalational anesthetic drugs are not the bronchodilators of choice to treat bronchospasm during anaphylaxis, especially if the patient is hypotensive.

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These drugs interfere with the body's compensatory response to cardiovascular collapse, and halothane sensitizes the myocardium to epinephrine.

Table 12-6 Management of Anaphylaxis During General Anesthesia

INITIAL THERAPY

1.    Stop administration of antigen.

2.    Maintain airway and administer 100% O2.

3.    Discontinue all anesthetic agents.

4.    Start intravascular volume expansion (2–4 L of crystalloid/colloid with hypotension).

5.    Give epinephrine (5–10 µg IV bolus with hypotension, titrate as needed; 0.1–1.0 mg IV with cardiovascular collapse).

SECONDARY TREATMENT

1.    Antihistamines (0.5–1 mg/kg diphenhydramine)

2.    Catecholamine infusions (starting doses: epinephrine, 4–8 µg/min; norepinephrine, 4–8 µg/min; or isoproterenol, 0.5–1 µg/min as an infusion; titrated to desired effects)

3.    Bronchodilators: inhaled albuterol, terbutaline, and/or anticholinergic agents with persistent bronchospasm)

4.    Corticosteroids (0.25–1 g hydrocortisone; alternatively, 1–2 g methylprednisolone)a

5.    Sodium bicarbonate (0.5–1 mEq/kg with persistent hypotension or acidosis)

6.    Airway evaluation (before extubation)

7.    Vasopressin for refractory shock

IV, intravenous(ly).
aMethylprednisolone may be the drug of choice if the reaction is suspected to be mediated by complement.
Reprinted with permission from Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, 2nd edition, Boston, Butterworth-Heinemann, 1992; p 162.

Provide Volume Expansion

Hypovolemia rapidly develops during anaphylactic shock.50 Fisher50 reported up to 40% loss of intravascular fluid into the interstitial space during reactions. Therefore, volume expansion and epinephrine are important in correcting the acute hypotension. Initially, 2 to 4 L of lactated Ringer solution, colloid, or normal saline should be administered, keeping in mind that an additional 25 to 50 mL/kg may be necessary if hypotension persists. Refractory hypotension after intravascular volume and epinephrine administration requires additional hemodynamic monitoring. The use of transesophageal echocardiography for rapid assessment of intraventricular volume and ventricular function, and to determine other occult causes of acute cardiovascular dysfunction, can be important for accurate assessment of intravascular volume and guidance of rational therapeutic interventions.51 Fulminant noncardiogenic pulmonary edema with loss of intravascular volume can occur after anaphylaxis. This condition requires intravascular volume repletion with careful hemodynamic monitoring until the capillary defect improves. Colloid volume expansion has not proved to be more effective than crystalloid volume expansion for treating anaphylactic shock.

Administer Epinephrine

Epinephrine is the drug of choice when resuscitating patients during anaphylactic shock. Epinephrine's α-adrenergic effects vasoconstrict to reverse hypotension; β2 receptor stimulation bronchodilates and inhibits mediator release by increasing cyclic adenosine monophosphate in mast cells and basophils.52,53,54 The route of epinephrine administration and the dose depend on the patient's condition. Rapid and timely intervention is important when treating anaphylaxis. Furthermore, patients under general anesthesia may have altered sympathoadrenergic responses to acute anaphylactic shock, whereas patients under spinal or epidural anesthesia may not be able to mount the appropriate vasoconstrictive sympathetic response and may need even larger doses of catecholamines.

In hypotensive patients, 5- to 10-µg intravenous doses of epinephrine should be administered incrementally to restore blood pressure. Additional volume and incrementally increased doses of epinephrine should be administered until hypotension is corrected. Infusion is an ideal method of administering epinephrine; it is best to infuse epinephrine through central intravenous access lines during acute volume resuscitation. If cardiovascular collapse ensues, intravenous cardiopulmonary resuscitative doses of epinephrine, 0.1 to 1.0 mg, should be administered and repeated until hemodynamic stability resumes. Patients with laryngeal edema without hypotension should receive subcutaneous epinephrine. Intravenous epinephrine should not be administered to patients with normal blood pressures.

Secondary Treatment

Antihistamines

Because H1 receptors mediate many of the adverse effects of histamine, the intravenous administration of 0.5 to 1 mg/kg of an H1 antagonist such as diphenhydramine may be useful in treating acute anaphylaxis. Antihistamines do not inhibit anaphylactic reactions or histamine release, but compete with histamine at receptor sites after it is released. H1antagonists are indicated in all forms of anaphylaxis. The H1 antagonists available for parenteral administration may have antidopaminergic effects and should be given slowly to prevent precipitous hypotension in potentially hypovolemic patients.1 The indications for administering an H2 antagonist once anaphylaxis has occurred remain unclear.

Catecholamines

Epinephrine infusions may be useful in patients with persistent hypotension or bronchospasm after initial resuscitation.1 Epinephrine infusions should be started at 0.05 to 0.1 µg/kg/min (5 to 10 µg/min) and titrated to correct hypotension. Norepinephrine infusions may be needed in patients with refractory hypotension due to decreased systemic vascular resistance. It may be started at 0.05 to 0.1 µg/kg/min and adjusted to correct hypotension.51

Bronchodilators

Inhaled β-adrenergic agents, including inhaled albuterol or terbutaline, if bronchospasm is a major feature.54 Inhaled ipratropium may be especially useful for treatment of bronchospasm in patients receiving β-adrenergic blockers.54 Special adapters allow administration of bronchodilators through the endotracheal tube (see Chapter 2).

Corticosteroids

Corticosteroids have a series of anti-inflammatory effects mediated by multiple mechanisms, including altering the activation and migration of other inflammatory cells (e.g., PMNs) after an acute reaction.53,54 One should consider infusing high-dose corticosteroids early in the course of therapy, although beneficial effects are delayed at least 4 to 6 hours.54Despite their unproven usefulness in treating acute reactions, corticosteroids are often administered as adjuncts to therapy when refractory bronchospasm or refractory shock occurs after resuscitative therapy.55 Although the exact corticosteroid dose and preparation are unclear, investigators have recommended 0.25 to 1 g intravenously of hydrocortisone in IgE-mediated reactions. Alternately, 1 to 2 g of methylprednisolone (30 to 35 mg/kg) intravenously may be useful in reactions believed to be complement-mediated, such as catastrophic pulmonary vasoconstriction after protamine transfusion reactions.56 Administering corticosteroids after an anaphylactic reaction may also be important in attenuating the late-phase reactions reported to occur 12 to 24 hours after anaphylaxis.48

Bicarbonate

Acidosis develops rapidly in patients with persistent hypotension. This acidemia reduces the effect of epinephrine on the heart and systemic vasculature. Therefore, with refractory hypotension or acidemia, sodium bicarbonate, 0.5 to 1 mEq/kg, may be given and repeated every 5 minutes or as dictated by arterial blood gas values.

Airway Evaluation

Because profound laryngeal edema can occur, the airway should be evaluated before extubation of the trachea.29 Persistent facial edema suggests airway edema. The trachea of these patients should remain intubated until the edema subsides. Developing a significant air leak after endotracheal tube cuff deflation and before extubation of the trachea is useful in assessing airway patency. If there is any question of airway edema, direct laryngoscopy should be performed before the trachea is extubated.

Refractory Hypotension—Vasopressin

Vasopressin is an important drug for refractory shock, including vasodilatory shock associated with anaphylaxis. Vasodilatory shock is characterized by hypotension association with a high cardiac output, and is thought to be due to the multiple activation of vasodilator mechanisms and the inability of α-adrenergic mechanisms to compensate.51 Starting doses to consider are 0.01 units/min as an infusion, although bolus administration is part of Advanced Cardiopulmonary Life Support guidelines. Vasopressin may attenuate pathologic-induced vasodilation. Further, additional monitoring, including echocardiography and preferably transesophageal, should be considered in patients with refractory hypotension to better evaluate cardiac function or hypovolemia.

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Perioperative Management of the Patient with Allergies

Allergic drug reactions account for 6 to 10% of all adverse reactions.57 DeSwarte58 suggested that the risk of an allergic drug reaction occurring is approximately 1 to 3% for most drugs, and that around 5% of adults in the United States may be allergic to one or more drugs. Unfortunately, patients often refer to adverse drug effects as being allergic in nature. For example, opioid administration can produce nausea, vomiting, or even local release of histamine along the vein of administration. Patients will say they are “allergic” to a specific drug when, in fact, their adverse reaction is independent of allergy. Nearly 15% of adults in the United States believe they are allergic to specific medication(s) and therefore may be denied treatment with an indicated drug. To understand allergic reactions, the spectrum of adverse reactions to drugs needs to be considered.

Predictable adverse drug reactions account for about 80% of adverse drug effects. They are often dose-dependent, related to known pharmacologic actions of the drug, and typically occur in normal patients. Most serious, predictable adverse drug reactions are toxic and are directly related to the drug in the body (overdosage) or to an unintentional route of administration (e.g., unintended intravenous bupivacaine-induced seizures and cardiovascular collapse). Side effects are the most common adverse drug reactions and are undesirable pharmacologic actions of the drugs occurring at usual prescribed dosages. Most anesthetic drugs present multiple side effects that can produce precipitous hypotension. For example, morphine dilates the venous capacitance bed, thereby decreasing preload; releases histamine from cutaneous mast cells, thereby producing arterial and venous dilation; slows the heart rate; and decreases sympathetic tone. However, the net effects of morphine on blood pressure and myocardial function depend on the patient's blood volume, sympathetic tone, and ventricular function. Hypotension rapidly develops in a volume-depleted trauma patient in pain who is given morphine. Drug interactions also represent important predictable adverse drug reactions. Intravenous fentanyl administration to a patient who has just received intravenous benzodiazepines or other sedative-hypnotic drugs may produce precipitous hypotension that results from decreased sympathetic tone or direct vasodilation from propofol administration.59 This phenomenon represents a dose-dependent, predictable adverse drug reaction that is independent of allergy.

Unpredictable adverse drug reactions are usually dose-independent and usually not related to the drug's pharmacologic actions, but are often related to the immunologic response (allergy) of the individual. On occasion, adverse reactions can be related to genetic differences (i.e., idiosyncratic) in a susceptible individual who has an isolated genetic enzyme deficiency. In most allergic drug reactions, an immunologic mechanism is present or, more often, presumed. Providing that the causal event involves a reaction between the drug or drug metabolites with drug-specific antibodies or sensitized T lymphocytes is often impractical. Without direct immunologic evidence, attributes that may be helpful in distinguishing an allergic reaction from other adverse reactions include (1) allergic reactions occur in only a small percentage of patients receiving the drug, and (2) the clinical manifestations do not resemble known pharmacologic actions. In the absence of prior drug exposure, allergic symptoms rarely appear after <1 week of continuous treatment. After sensitization, the reaction develops rapidly on re-exposure to the drug. In general, drugs that have been administered without complications for several months or longer are rarely responsible for producing drug allergy. The time span between exposure to the drug and noticed manifestations is often the most vital information in deciding which drugs administered were the cause of a suspected allergic reaction.

Although the reaction may produce a life-threatening response in the cardiopulmonary system (anaphylaxis), various cutaneous manifestations, fever, and pulmonary reactions have been attributed to drug hypersensitivity. Usually, the reaction may be reproduced by small doses of the suspected drug or other agents having similar or cross-reacting chemical structures. On occasion, drug-specific antibodies or lymphocytes have been identified that react with the suspected drug, although the relationship is seldom diagnostically useful in practice. Even when an immune response to a drug is demonstrated, it may not be associated with a clinical allergic reaction. As with adverse drug reactions in general, the reaction usually subsides within several days of discontinuation of the drug.

Immunologic Mechanisms of Drug Allergy

Different immunologic responses to any antigen can occur. Drugs have been associated with all the immunologic mechanisms proposed by Gell et al.3 Although more than one mechanism may contribute to a particular reaction, any one can occur. Penicillin may produce different reactions in different patients or a spectrum of reactions in the same patient. In one patient, penicillin can produce anaphylaxis (type I reaction), hemolytic anemia (type II reaction), serum sickness (type III reaction), and contact dermatitis (type IV reaction).58Therefore, any one antigen has the ability to produce a diffuse spectrum of allergic responses in humans. Why some patients have localized rashes or angioneurotic edema in response to penicillin whereas others suffer complete cardiopulmonary collapse is unknown. Most anesthetic drugs and agents administered perioperatively have been reported to produce anaphylactic reactions.31,39,40,41,42,43,44,45,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81 Muscle relaxants are the most common drugs responsible for evoking intraoperative allergic reactions.67 In this regard, there is cross-sensitivity between succinylcholine and the nondepolarizing muscle relaxants. Unexplained intraoperative cardiovascular collapse has been attributed to anaphylaxis triggered by latex (natural rubber), and certain patients, including those with a history of spina bifida, are at a greater risk for reactions.1,68 Even vascular graft material has been reported as a cause of intraoperative allergic reactions.69

Life-threatening allergic reactions are more likely to occur in patients with a history of allergy, atopy, or asthma. Nevertheless, because the incidence is low, the history is not a reliable predictor that an allergic reaction will occur and does not mandate that such patients should be investigated or pretreated, or that specific drugs be selected or avoided.60Although different mechanisms have been proposed, no one theory has been proved.1 The drugs and foreign substances listed in Table 12-7 may have both immunologic and nonimmunologic mechanisms for adverse drug reactions in humans.

Evaluation of Patients With Allergic Reactions

Identifying the drug responsible for a suspected allergic reaction still depends on circumstantial evidence, suggesting the temporal sequence of drug administration. Conventional in vivo and in vitro methods of diagnosing allergic reactions to most anesthetic drugs are unavailable or not applicable. The

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most important factor in diagnosis is the awareness of the physician that an untoward event may be related to a drug the patient received. The physician must always be aware of the capacity of any drug to produce an allergic reaction. The history is important when evaluating whether an adverse drug reaction is allergic and whether the drug can be readministered. Although a prior allergic reaction to the drug in question is important, it will rarely be conclusive. Direct challenge of a patient with a test dose of drug is the only way to prove a reaction, but this is potentially dangerous and not recommended. Although the anesthesiologist commonly gives small test doses of anesthetic drugs, these are pharmacologic test doses and have nothing to do with immunologic dosages. The demonstration of drug-specific IgE antibodies is accepted as evidence the patient may be at risk for anaphylaxis if the drug is administered.58 Different clinical tests are available to confirm or diagnose drug allergy; several are considered in the following section.

Table 12-7 Agents Implicated in Allergic Reactions During Anesthesia

ANESTHETIC AGENTS
Induction agents (cremophor-solubilized drugs, barbiturates, etomidate, propofol)
Local anesthetics (para-aminobenzoic ester agents)
Muscle relaxants (succinylcholine, gallamine, pancuronium, d-tubocurarine, metocurine, atracurium, vecuronium, mivacurium, doxacurium)
Opioids (meperidine, morphine, fentanyl)
OTHER AGENTS
Antibiotics (cephalosporins, penicillin, sulfonamides, vancomycin)
Aprotinin
Blood products (whole blood, packed cells, fresh-frozen plasma, platelets, cryoprecipitate, fibrin glue, γ-globulin)
Bone cement
Chymopapain
Corticosteroids
Cyclosporin
Drug additives (preservatives)
Furosemide
Insulin
Mannitol
Methylmethacrylate
Nonsteroidal anti-inflammatory drugs
Protamine
Radiocontrast dye
Latex (natural rubber)
Streptokinase
Vascular graft material
Vitamin K
Colloid volume expanders (dextrans, protein fractions, albumin, hydroxyethyl starch)

Reprinted with permission from Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, 2nd edition. Boston, Butterworth-Heinemann, 1992.

Testing for Allergy

After an anaphylactoid reaction, it is important to identify the causative agent to prevent readministration. When one particular drug has been administered and there is a clear correlation between the time of administration and the occurrence of a reaction, testing may be unnecessary, and general avoidance of the drug should be instituted. However, when patients have simultaneously received multiple drugs (e.g., an opioid, muscle relaxant, hypnotic, and antibiotic), it is often difficult to prove which particular drug caused the reaction. Further, the reaction might have been caused by the vehicle or by one of the preservatives. For patients who want to know which drug was responsible and for patients scheduled for subsequent procedures, some degree of allergy evaluation should be undertaken to evaluate the drug at risk. Unfortunately, few laboratory tests exist for anesthetic drugs; therefore, the available allergy tests are discussed.

Leukocyte Histamine Release

Leukocyte histamine release is performed by incubating the patient's leukocytes with the offending drug and measuring histamine release as a marker for basophil activation, although false-positive results can occur.31 This test is not easy to perform, although variations allow the use of whole blood instead of isolated PMNs, and is generally not available.76,82

Radioallergosorbent Test

The radioallergosorbent test (RAST) allows laboratory detection of specific IgE directed toward particular antigens.83 In this test, antigens are linked to insoluble material to make an immunoabsorbent.83,84 When incubated with the serum in question, antibodies of different classes directed toward the antigen bind to it. After washing, the antigen-antibody complex on the immunoabsorbent is incubated with radiolabeled antibodies directed against human IgE and counted in a scintillation counter. The concentration of specific IgE in the patient's serum directed toward the allergen is measured. The RAST is more quantitative than skin tests and avoids the potential of reexposure.84 RAST testing has been used to detect the presence of antibodies to meperidine,49 succinylcholine,85 and thiopental.86 Two major

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limitations to this test include the commercial availability of the drug prepared as an antigen and false-positive test results in patients with high IgE levels.87

Enzyme-Linked Immunosorbent Assay

The enzyme-linked immunosorbent assay (ELISA) measures antigen-specific antibodies. The basis of the ELISA is similar to that of the RAST; however, immunospecific IgE directed against the antigen in question is determined by adding an anti-IgE coupled to an enzyme such as peroxidase that acts as a chromogen.5 A colorless substrate is acted on by peroxidase to produce a colored byproduct. The ELISA has been used to prove IgE antibodies to chymopapain and protamine, and has been developed to screen for other antibodies to diverse agents.

Intradermal Testing (Skin Testing)

Skin testing is the method most often used in patients after anaphylactic reaction to anesthetic drugs after the history has suggested the relevant antigens for testing.88,89 Within minutes after antigen introduction, histamine released from cutaneous mast cells causes vasodilation (flare) and localized edema from increased vascular permeability (wheal). Fisher and Munro67 and Fisher88 suggested that this is a simple, safe, and useful method of establishing a diagnosis in most cases of anaphylactic reactions occurring in the perioperative period. If the strict protocols established by Fisher88 are used, intradermal reactions are helpful. Intradermal testing is of no value in reactions to contrast media or colloid volume expanders. Cross-sensitivity between drugs of similar structures can often be evaluated based on skin testing. Skin testing to local anesthetics is considered a direct challenge or provocative dose testing.90 Local anesthetic drugs are injected in increasing quantities under controlled circumstances. This testing decides if the person can safely receive amide derivatives (e.g., lidocaine) and can also be used to decide if the person is sensitive to the paraaminobenzoic ester agents (e.g., procaine, tetracaine).

Agents Implicated in Allergic Reactions

Multiple agents—including antibiotics, induction agents, muscle relaxants, nonsteroidal anti-inflammatory drugs, protamine, colloid volume expanders, and blood products—are the etiologic agents often responsible for anaphylaxis in surgical patients.1 However, any agent the patient receives as an injection, infusion, or environmental antigen has the potential to produce an allergic reaction.1 Almost everything has been reported to produce an allergic reaction at some time, but usually from a case report or small series. The agents most often implicated include antibiotics, blood products, colloid volume expanders, latex, polypeptides, and NMBAs. If patients are allergic to a muscle relaxant, there is a potential for cross-reactivity because of the similarity of the active site, a quaternary ammonium molecule, among the different types of relaxants, and alternatives cannot be chosen without some degree of immunologic testing. Because of the ubiquity of latex as a perioperative environmental antigen, latex allergy is considered separately.

Latex Allergy

For the anesthesiologist, latex represents an environmental agent often implicated as an important cause of perioperative anaphylaxis.91,92,93,94,95,96,97,98,99 Latex is the milky sap derived from the tree Hevea brasiliensis to which multiple agents, including preservatives, accelerators, and antioxidants are added to make the final rubber product. Latex is present in a variety of different products. In March 1991, the U.S. Food and Drug Administration alerted health care professionals about the potential of severe allergic reactions to medical devices made of latex. The first case of an allergic reaction because of latex was reported in 1979 and was manifested by contact urticaria. In 1989, the first reports of intraoperative anaphylaxis because of latex were reported.

Health care workers and children with spina bifida, urogenital abnormalities, or certain food allergies have also been recognized as people at increased risk for anaphylaxis to latex.91,92,93,94,95,96,97,98,99 Brown et al.95 reported a 24% incidence of irritant or contact dermatitis and a 12.5% incidence of latex-specific IgE positivity in anesthesiologists. Of this group, 10% were clinically asymptomatic, although IgE-positive. A history of atopy was also a significant risk factor for latex sensitization. Brown et al.95 suggested that these people are in their early stages of sensitization and their progression to symptomatic disease may be prevented by avoiding latex exposure. Patients allergic to bananas, avocados, and kiwis have also been reported to have antibodies that cross-react with latex.96,97 Multiple attempts are being made to reduce latex exposure to both health care workers and patients. If latex allergy occurs, then strict avoidance of latex from gloves and other sources needs to be considered, following recommendations as reported by Holzman.91 Because latex is such a common environmental antigen, this represents a daunting task.

More important, anesthesiologists must be prepared to treat the life-threatening cardiopulmonary collapse that occurs after anaphylaxis, as previously discussed. The most important preventive therapy is to avoid antigen exposure; although clinicians have used pretreatment with antihistamine (diphenhydramine and cimetidine) and corticosteroids, there are no data in the literature to suggest that pretreatment prevents anaphylaxis or decreases its severity.1 Two patients in a series reported by Gold et al.93 were pretreated, yet still had life-threatening reactions to latex. Patients in whom latex allergy is suspected should be referred to an allergist for proper evaluation and potential in vitro testing (RAST) for definitive diagnosis. When this is not possible, patients should be treated as if they were latex-allergic, and the antigen avoided. Patients with a documented history of latex allergy should wear Medic Alert bracelets.

Muscle Relaxants

NMBAs have several unique molecular features that make them potential allergens. All NMBAs are functionally divalent and are thus capable of cross-linking cell-surface IgE and causing mediator release from mast cells and basophils without binding or haptenating to larger carrier molecules. NMBAs have also been implicated in epidemiologic studies of anesthetic drug-induced anaphylaxis. Epidemiologic data from France suggest that NMBAs are responsible for 62 to 81% of reactions, depending on the period evaluated.100,101,102,103,104,105

In more recent years, NMBAs, especially steroid-derived agents, have been reported as potential causative agents of anaphylactic reactions during anesthesia. The data associating NMBAs in the most recent reports from France are mainly based on skin testing; however, studies have previously reported the steroidal-derived NMBAs and other molecules produce false-positive skin tests (i.e., wheal and flare). One of the major problems is that anaphylaxis to NMBAs is rare in the United States, but has been reported more often in Europe.105,106,107 Although suggestions have been made that this is because of underreporting, the severity of anaphylaxis and its sequelae to produce adverse outcomes clearly make this unlikely based on the current medicolegal climate that exists in the United States. One of the only ways to explain this widely divergent perspective is to understand how the diagnosis is made because the recommended threshold test concentrations have not been defined, resulting in unreliable results.

We previously reported in several studies that steroid-derived agents could induce positive wheal and flare responses

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independent of mast cell degranulation, even at low concentrations, following intradermal injection. This effect is likely because of a direct effect on the cutaneous vasculature that occurs for most NMBAs at concentrations as low as 10-5 M using intradermal skin tests in 30 volunteers.106 A positive cutaneous reaction without evidence of mast cell degranulation was noted at low concentrations (100 µg/mL) of rocuronium in almost all the volunteers. Levy et al.106 have used intradermal injections to compare cutaneous effects of anesthetic and other agents.

Other investigators have also reported similar results. Because prick tests are often used for authenticating NMBAs as causative drugs, Dhonneur et al.105 evaluated 30 volunteers, using prick testing. Each subject received 10 prick tests (50 µL) on both forearms. The investigators studied the wheal and flare responses to prick tests with rocuronium and vecuronium, using four dilutions (1/1,000, 1/100, 1/10, and 1) and two controls, and measured wheal and flare immediately after and at 15 minutes. They noted 50 and 40% of the subjects had a positive skin reaction to undiluted rocuronium and vecuronium, respectively.105 To avoid false-positive results, they suggested that prick testing with rocuronium and vecuronium should be performed in subjects who have experienced a hypersensitivity reaction during anesthesia, with concentrations below that commonly inducing positive reactions in anesthesia-naive, healthy subjects (i.e., for men in a dilution of 1/10 and for women in a dilution of 1/100). Guidelines for prick testing that are internationally agreed on need to be established. Many of these differences may explain the various incidences of allergy to NMBAs among countries. Concentration–skin response curves to rocuronium and vecuronium have showed that prick tests should be performed with dilution of the commercially available preparation. Female volunteers significantly (p <01) reacted to lower vecuronium and rocuronium concentrations than male volunteers. In female subjects, positive skin reactions were reported with dilutions of 1/100 of both relaxants. In male subjects, positive skin reactions were noted with the undiluted concentration, except for one volunteer who reacted to rocuronium (1/10 dilution).

Summary

Although the immune system functions to provide host defense, it can respond inappropriately to produce hypersensitivity or allergic reactions. A spectrum of life-threatening allergic reactions to any drug or agent can occur in the perioperative period.100 The enigma of these reactions lies in their unpredictable nature. Certain patients undergoing high risk procedures with mulitple blood product exposures are also at higher risk.52 However, a high index of suspicion, prompt recognition, and appropriate and aggressive therapy can help avoid a disastrous outcome.

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Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine