Handbook of Clinical Anesthesia

Chapter 12

Immune Function and Allergic Response

Allergic reactions during anesthesia represent an important cause of perioperative complications (Levy JH: Immune function and allergic response. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams & Wilkins, 2009, pp 256–270). Anesthesiologists routinely manage patients during the perioperative period, during which exposure to foreign substances (drugs, including injected anesthetics, antibiotics, neuromuscular blocking drugs, protamine, blood products) and environmental antigens (latex) occurs.

  1. Basic Immunologic Principles

Host defense systems can be divided into cellular (T-cell lymphocytes) and humoral (antibodies, complement, cytokines) elements.

  1. Antigensare molecules capable of stimulating an immune response (antibody production or lymphocyte stimulation) (Table 12-1).
  2. Thymus-Derived Lymphocytes and Bursa-Derived Lymphocytes
  3. Thymus-derived (T-cell) lymphocytescontain receptors that are activated by binding with antigens and subsequently secrete mediators that regulate the immune response (e.g., acquired immunodeficiency syndrome is caused by infection of helper T lymphocytes with a retrovirus known as the immunodeficiency virus).
  4. Bursa-derived (B-cell) lymphocytesdifferentiate into plasma cells that synthesize antibodies.
  5. Antibodiesare specific proteins (immunoglobulins) that can recognize and bind to a specific antigen (see Table 12-1). Antibodies function as specific receptor molecules for immune cells and proteins.


Table 12-1 Biologic Characteristics of Immunoglobulins







Molecular weight






Serum concentration (mg/dL)




<0.5 × 103


Complement activation

All but IgG4


Placental transfer


Serum half-time (days)






Cell binding

Mast cells, neutrophils, lymphocytes mononuclear cells, platelets


Mast cells, basophils, lymphocytes,

Neutrophils, lympho cytes

  1. Effector Cells and Proteins of the Immune Response Cells(Table 12-2)
  2. Monocytes, neutrophils (polymorphonuclear leukocytes), and eosinophils are effector cells that migrate into areas of inflammation in response to chemotactic factors.
  3. Opsonizationis deposition of antibody or complement fragments on surfaces of foreign cells with subsequent facilitation of the process that allows the effector cells to destroy the foreign cell.

Table 12-2 Cells That Participate in the Immune Response

Macrophages (ingest antigens)
Polymorphonuclear leukocytes (neutrophils; first cells to appear in an acute inflammatory reaction)
Eosinophils (function unknown)
Basophils (granulocytes in blood; cell surfaces contain IgE receptors)
Mast cells (located in perivascular spaces of skin, lungs, and intestine; cell surfaces contain IgE receptors)

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Table 12-3 Symptoms Produced by Release of Cytokines

Myocardial depression

  1. Proteins
  2. Cytokines and Interleukins
  3. Cytokines (interleukin-1, tumor necrosis factor)are inflammatory cell activators that are synthesized by macrophages to act as secondary messengers that activate endothelial cells and white blood cells (produce an inflammatory response) (Table 12-3).
  4. T-cell lymphocytes produce interleukins.
  5. Complement
  6. The primary humoral response to antigen and antibody binding is activation of the complement system (about 20 different proteins that are activated by antigen–antibody interactions, plasmin, and endotoxins).
  7. A series of inhibitors regulates the complement system (e.g., angioneurotic edema, which may be activated by surgery manifesting as laryngeal obstruction, is caused by a deficiency of an inhibitor of the C1 complement system).
  8. Effects of Anesthesia on Immune Function.Anesthesia and surgery depress both T- and B-cell responsiveness as well as nonspecific host resistance mechanisms, including phagocytosis. The significance, if any, of these responses is not known. (It is probably of minor importance compared with the hormonal aspects of the stress response.)
  9. Hypersensitivity Responses (Allergy) (Table 12-4 and Fig. 12-1)
  10. Intraoperative Allergic Reactions
  11. More than 90% of the allergic reactions evoked by drugs administered intravenously occur within 3 minutes of administration. (It is estimated that allergic reactions occur once in every 5000 to 25,000 anesthetics administered.)
  12. The only manifestation of an intraoperative allergic reaction may be refractory hypotension(Table 12-5 and Fig. 12-2).


Table 12-4 Classification of Hypersensitivity

Type I Reaction: Immediate-type hypersensitivity reaction (anaphylaxis) with release of chemical mediators (see Table 12-6) from mast cells and basophils in response to binding of IgE antibodies to the surfaces of these cells
Type II Reaction: Mediated by IgG or IgM antibodies directed against antigens on surfaces of foreign cells (e.g., ABO incompatibility reactions)
Type III Reaction: Antigen–antibody complexes that form insoluble complexes that deposit in the microvasculature (e.g., poststreptococcal infections)
Type IV Reaction: Delayed hypersensitivity reaction of cell-mediated immunity (e.g., tissue rejection, tuberculin immunity)

III. Anaphylactic Reactions

  1. IgE-Mediated Pathophysiology.Antigen binding to IgE antibodies, which reflects prior exposure to the antigen, initiates anaphylaxis. The antigen binds by bridging two immunospecific antibodies located on the surfaces of mast cells and basophils, resulting in the release of histamine and other chemicals.
  2. Chemical Mediators of Anaphylaxis(Table 12-6)
  3. Recognition of Anaphylaxis(see Table 12-5)
  4. Individuals vary greatly in their manifestations and course of anaphylaxis (spectrum ranges from minor clinical significance to death).

Figure 12-1. Type I immediate hypersensitivity reactions (anaphylaxis) involve IgE antibodies binding to mast cells or basophils at the Fc receptors. On encountering immunospecific antigens, the IgE becomes cross-linked, inducing degranulation, intracellular activation, and release of chemical mediators.

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Table 12-5 Recognition of Anaphylaxis During Regional and General Anesthesia






Laryngeal edema
Decreased pulmonary compliance
Fulminant pulmonary edema
Acute respiratory failure


Retrosternal discomfort

Cardiac dysrhythmias
Decreased systemic resistance
Pulmonary hypertension
Cardiac arrest



Periorbital edema
Perioral edema

  1. The enigma of anaphylaxis lies in the unpredictability of its occurrence, the severity of the attack, and the lack of a prior patient allergic history.
  2. Nonimmunologic Release of Histamine
  3. Many diverse molecules administered during the perioperative period release histamine in a dose-dependent, nonimmunologic fashion (Table 12-7).
  4. Nonimmunologic histamine release differs from antigen-mediated histamine release in that histamine appears to be the only mediator released.
  5. When administered at clinically recommended doses, aminosteroid muscle relaxants (e.g., rocuronium) have minimal effects on histamine release.
  6. Antihistamine pretreatmentdoes not inhibit histamine release but instead competes with histamine at the receptor and attenuates the resulting physiologic effects.
  7. Treatment Plan.The treatment plan is the same for life-threatening anaphylactic or anaphylactoid reactions. All patients who have experienced life-threatening allergic reactions should be admitted to the hospital for 24 hours of monitoring because manifestations may recur even after successful treatment.



Figure 12-2. During a type I allergic reaction, antigen enters a patient during anesthesia via a parenteral route (intravenous [IV] or intramuscular [IM]) (panel 1). The antigen bridges two IgE antibodies on the surface of mast cells or basophils, causing degranulation (panel 2). The released chemical mediators produce the characteristic clinical symptoms of an allergic reaction (panel 3). ECF = extracellular fluid.


Table 12-6 Chemical Mediators of Anaphylaxis

Peptide mediators
Eosinophilic chemotactic factor
Neutrophilic chemotactic factor
Arachidonic acid metabolites (leukotrienes and prostaglandins are synthesized after mast cell activation from arachidonic acid metabolism of phospholipid cell membranes)
Platelet-activating factor

  1. Initial Therapy(Table 12-8)
  2. Epinephrineis the drug of choice for resuscitation of patients experiencing an allergic reaction (α-Adrenergic effects reverse hypotension, and β-adrenergic stimulation produces bronchodilation and inhibits continued release of chemical mediators.)
  3. Arterial blood gases should be monitored during resuscitation.
  4. Up to 40% of intravascular fluid volume may be translocated into the interstitial space during an allergic reaction.
  5. Secondary Treatment(see Table 12-8)
  6. Bronchodilators.Inhaled β-adrenergic agents, including inhaled albuterol and terbutaline, are indicated if bronchospasm is a major feature. Inhaled ipratropium may be especially useful for treatment of bronchospasm.
  7. Airway Evaluation.If there is any evidence of upper airway edema (e.g., facial edema, absence of air leak when the tracheal tube cuff is deflated), direct laryngoscopic examination should be performed before the trachea is extubated.

Table 12-7 Drugs Capable of Nonimmunologic Histamine Release

Antibiotics (vancomycin)
Basic compounds (protamine)
Hyperosmotic agents
Nondepolarizing skeletal muscle relaxants (atracurium > pancuronium, vecuronium, and rocuronium)
Opioids (morphine)
Possibly thiobarbiturates

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Table 12-8 Management of Anaphylaxis During General Anesthesia

Initial Therapy
Stop administration of antigen
Maintain upper airway and administer 100% oxygen
Discontinue all anesthetic drugs
Initiate intravascular volume expansion (2–4 L of crystalloid or colloid solution in the presence of hypotension)
Administer epinephrine (5–10 µg IV with hypotension and titrate as needed; 0.1–1.0 mg IV with cardiovascular collapse)
Secondary Treatment
Antihistamines (0.5–1 mg/kg diphenhydramine IV)
Catecholamine infusions (starting doses: epinephrine, 4–8 µg/min; norepinephrine, 4–8 µg/min; isoproterenol, 0.5 to 1 µg/min as continuous infusion and titrated to effect)
Albuterol (4–8 puffs by metered-dose inhaler)
Corticosteroids (cortisol, 250–1000 mg; methylprednisolone, 1–2 g, especially if complement activation is suspected)
Airway evaluation before extubation
Refractory hypotension (vasopressin to treat refractory vasodilatory shock, 0.01 U/min)

  1. Refractory Hypotension.Vasopressin may attenuate pathologic refractory vasodilation. Monitoring, including echocardiography, is a consideration in patients with refractory hypotension to better evaluate cardiac function or hypovolemia.
  2. Perioperative Management of the Patient With Allergies

Allergic drug reactions account for 6% to 10% of all adverse drug reactions. It is estimated that 5% of adults in the United States are allergic to one or more drugs.

  1. Immunologic Mechanisms of Drug Allergy
  2. Most drugs administered to patients by anesthesiologists have been reported to produce allergic reactions (Table 12-9).
  3. Muscle relaxants are the drugs that are most commonly responsible for evoking intraoperative allergic reactions. (Cross-sensitivity is present between succinylcholine and nondepolarizing muscle relaxants.)
  4. Unexplained intraoperative cardiovascular collapse has been attributed to anaphylaxis triggered by latex (natural rubber). Patients with spina bifidahave an increased incidence of allergy to latex. Symptoms


caused by latex allergy may not occur until several minutes after exposure and thus may be erroneously attributed to other causes.

Table 12-9 Drugs Implicated in Allergic Reactions During Anesthesia

Anesthetic Drugs
Muscle relaxants (cross-sensitivity among all drugs is possible)
Induction drugs (barbiturates, propofol)
Local anesthetics (para-aminobenzoic acid ester drugs)
Other Drugs
Antibiotics (cephalosporins, penicillin, vancomycin)
Blood products (whole blood, packed cells, platelets, fresh-frozen plasma, fibrinogen, gamma globulin)
Radiocontrast dye
Latex (natural rubber)
Drug preservatives/additives
Colloid volume expanders
Vascular graft material

  1. Life-threatening allergic reactions are more likely to occur in patients with a history of allergy, atopy, or asthma. Because the incidence of allergic reactions is so rare, even this history does not mandate further evaluation or pharmacologic pretreatment.
  2. Evaluation of Patients with Allergic Reactions. Identifying the drug responsible for a suspected allergic reaction depends on circumstantial evidence indicating the temporal sequence of drug administration.
  3. Direct challenge of a patient with a test dose of the suspected offending drug is potentially hazardous and not recommended.
  4. A small test dose of drug given during anesthesia more accurately reflects a pharmacologic test doseand has nothing to do with immunologic dosages.
  5. The demonstration of drug-specific antibodies is generally accepted as evidence that the patient may be at risk for anaphylaxis if the drug is administered.
  6. Testing for Allergy
  7. After an allergic reaction, it is important to identify the offending allergen in order to prevent readministration.


(Patients often have simultaneously received multiple different drugs with or without preservatives.)

Table 12-10 Tests for Drug Allergy

Leukocyte histamine release (incubate patient's leukocytes with the drug in question and measure histamine release as a marker for basophil activation)
Radioallergosorbent test (RAST; commercially available antigens [few anesthetic drugs are available] are incubated with the patient's plasma for detection of specific IgE antibodies)
Enzyme-linked immunosorbent assay (ELISA; measures antigen-specific antibodies; similar to the RAST test)
Intradermal testing (histamine release from mast cells causes vasodilation [flare] and localized edema)

  1. In vitrotests are available for anesthetic drugs (Table 12-10).
  2. Agents Implicated in Allergic Reactions.Any agent a patient received as an injection, infusion, or environmental antigen has the potential to produce an allergic reaction.
  3. Latex Allergy.Health care workers and children with spina bifida and urogenital abnormalities are at increased risk for latex allergy. Patients who are allergic to bananas, avocados, and kiwis may also cross-react with latex. It is a daunting task to create a latex-free environment for care of sensitized patients. (These patients should wear Medic Alert bracelets.)
  4. Muscle Relaxantspossess molecular features that make them potential allergens.
  5. Prick tests are often used for authenticating neuromuscular blocking drugs as causes of allergic reactions. There is the potential for cross-sensitivity between muscle relaxants because of similarity of the active site (quaternary ammonium molecule).
  6. An alternative muscle relaxant cannot be chosen without some degree of immunologic testing.
  7. Summary

A spectrum of unpredictable life-threatening allergic reactions to any drug may occur in the perioperative period. A high index of suspicion, prompt recognition, and appropriate and aggressive therapy can help avoid a disastrous outcome.

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

Title: Handbook of Clinical Anesthesia, 6th Edition

Copyright ©2009 Lippincott Williams & Wilkins

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