REVIEW ARTICLE Anaphylaxis During the Perioperative Period David L. Hepner, MD*, and Mariana C. Castells, MD, PhD† *Department of Anesthesiology, Perioperative and Pain Medicine, and †Allergy and Clinical Immunology Training Program, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts Anesthesiologists use a myriad of drugs during the provi- perioperative period. Symptoms may include all organ sion of an anesthetic. Many of these drugs have side ef- systems and present with bronchospasm and cardiovas- fects that are dose related, and some lead to severe cular collapse in the most severe cases. Management of immune-mediated adverse reactions. Anaphylaxis is the anaphylaxis includes discontinuation of the presumptive most severe immune-mediated reaction; it generally oc- drug (or latex) and anesthetic, aggressive pulmonary and curs on reexposure to a specific antigen and requires the cardiovascular support, and epinephrine. Although a se- release of proinflammatory mediators. Anaphylactoid re- rum tryptase confirms the diagnosis of an anaphylactic actions occur through a direct non-immunoglobulin reaction, the offending drug can be identified by skin- E-mediated release of mediators from mast cells or from prick, intradermal testing, or serologic testing. Prevention complement activation. Muscle relaxants and latex of recurrences is critical to avoid mortality and morbidity. account for most cases of anaphylaxis during the (Anesth Analg 2003;97:1381–95) he term “anaphylaxis” was coined by Nobel reactions in which immune-complex formation and dep- prize recipients Portier and Richet (1) in 1902, osition leads to tissue damage (3). Anaphylactoid reac- T when they described a dog that had tolerated a tions occur through a direct nonimmune-mediated re- previous injection of actinotoxin, a jellyfish toxin, but lease of mediators from mast cells and/or basophils or reacted with bronchial spasm, cardiorespiratory ar- result from direct complement activation, but they rest, and death to a smaller dose 14 days later. present with clinical symptoms similar to those of ana- Whereas prophylaxis in Greek means “protection,” phylaxis (3,4). anaphylaxis means “opposite protection” or “against Anaphylaxis is generally an unanticipated severe protection” (2). Anaphylaxis generally occurs on reex- allergic reaction, often explosive in onset, that can posure to a specific antigen and requires the release of occur perioperatively, especially during a surgical procedure when multiple drugs are administered dur- proinflammatory mediators, but it can also occur on ing the conduction of an anesthetic. Because patients first exposure, because there is cross-reactivity among are under drapes and mostly unconscious or sedated, many commercial products and drugs. the early cutaneous signs of anaphylaxis are often Immune-mediated allergic reactions are classified, ac- unrecognized, leaving bronchospasm and cardiovas- cording to their mechanism, on the basis of the Gell and cular collapse as the first recognized signs of anaphy- Coombs classification. Whereas anaphylaxis is a Type I laxis. A survey of anaphylaxis during anesthesia dem- immunoglobulin (Ig)E-mediated hypersensitivity reac- onstrated that cardiovascular symptoms (73.6%), tion involving mast cells and basophils, contact derma- cutaneous symptoms (69.6%), and bronchospasm titis is a Type IV T-lymphocyte cell-mediated delayed- (44.2%) were the most common clinical features (5). type hypersensitivity reaction. Other immune-mediated The incidence of anaphylaxis and anaphylactoid reac- reactions include Type II reactions in which IgG, IgM, tions during anesthesia is very difficult to estimate but and complement mediate cytotoxicity and Type III has been calculated to range from 1 in 3,500 to 1 in 13,000 cases (6,7). Another report from Australia estimated the Supported by the Department of Anesthesiology, Perioperative incidence to be between 1 in 10,000 and 1 in 20,000 (8), and Pain Medicine and by the Department of Medicine, Brigham whereas the most recent report, from Norway, estimated and Women’s Hospital, Harvard Medical School. the incidence to be 1 in 6,000 (9). Muscle relaxants are Accepted for publication June 6, 2003. associated with the most frequent incidence of anaphy- Address correspondence and reprint requests to David L. Hepner, MD, Department of Anesthesiology, Perioperative and Pain Medicine, laxis, and over the last two decades, natural rubber latex Brigham and Women’s Hospital, Harvard Medical School, 75 Francis (NRL, or cis-1,4-polyisoprene) has emerged as the sec- St., Boston, MA 02115. Address e-mail to [email protected]. ond most common cause of anaphylaxis (5,10). How- DOI: 10.1213/01.ANE.0000082993.84883.7D ever, one report (5) found that the incidence of cases of ©2003 by the International Anesthesia Research Society 0003-2999/03 Anesth Analg 2003;97:1381–95 1381 1382 REVIEW ARTICLE HEPNER AND CASTELLS ANESTH ANALG PERIOPERATIVE ANAPHYLAXIS 2003;97:1381–95 latex anaphylaxis is decreasing as a result of identifica- their cytoplasmic immune tyrosine activation motifs tion of at-risk patients and preventive measures. Antibi- by Lyn and Syk tyrosine kinases. This initiates a otics and anesthesia induction drugs account for the next signal-transduction cascade, which culminates in the group of drugs more likely to lead to an anaphylactic increase of intracellular calcium and the release of reaction (5,10). Table 1 outlines the common drugs in- preformed mediators such as histamine, proteases volved in perioperative anaphylaxis in France (5). (tryptases), proteoglycans, and platelet-activating fac- Serious problems are unusual during surgery (0.4% tor (3,17). Phospholipid metabolism then leads to the of cases), but anesthesia contributes to a third of these generation of potent inflammatory leukotrienes (LTC4, cases (9). Allergic reactions are among the major fac- LTE4, and LTD4) and prostaglandins (PGD2). Hista- tors that contribute to morbidity and mortality during mine, PGD2, and LTC4 are potent vasoactive media- an anesthetic and to changes in postoperative care (9). tors implicated in vascular permeability changes, A recent review of serious intraoperative problems flushing, urticaria, angioedema, hypotension, and highlighted a case of fatal anaphylactic shock and bronchoconstriction (Fig. 1). suggested that preventive strategies are needed for Histamine receptors are present in the skin, gastro- anaphylaxis (9). Because anaphylaxis is a rare event intestinal tract, heart, vascular bed, and bronchial that is not the first consideration for the anesthesiolo- smooth muscle. Whereas histamine 1 receptors are gist, its management in a full-scale anesthesia simula- responsible for increases in mucous production, heart tor has been suggested (11). In one study, none of 42 rate, and flushing, histamine 2 receptors lead to an anesthesiologists tested on a simulator made the cor- increase in vascular permeability, gastric acid secre- rect diagnosis during the first 10 min of anaphylaxis, tion, and airway mucus production. PGD2 and LTC4 and most of them failed to have a structured plan for receptors are present in the skin, bronchial smooth its treatment (11). muscle, and vascular bed and cause bronchoconstric- Earlier review articles focused on the definition, tion, a wheal and flare response, and increased vascu- diagnosis, and management of anaphylaxis (12,13). lar permeability. Proteases prevent local coagulation Other review articles highlight drugs involved in ana- and degrade bronchodilating peptides. Heparin and phylactic and anaphylactoid reactions but concentrate platelet-activating factor can produce local and sys- only on the most common causative drugs (14). Even temic anticoagulation. recent reviews on anaphylaxis during anesthesia de- Anaphylactoid reactions are derived from the acti- vote a limited portion to drugs likely to induce ana- vation of the complement and/or bradykinin cascade phylaxis (15). This review will identify most drugs and the direct activation of mast cells and/or ba- implicated in anaphylaxis and will discuss its diagno- sophils (Fig. 1). Clinical manifestations of anaphylac- sis and management. A MEDLINE literature search toid reactions are indistinguishable from anaphylactic with the key words “anesthesia” plus “anaphylaxis” reactions. These reactions are rapid in onset and start or “hypersensitivity” or “allergy” produced 491 arti- within seconds to minutes of exposure to the allergen. cles from 1966 until October 2002. These articles were Symptoms progress rapidly and can affect most organ reviewed, and the common drugs associated with systems, including the skin (pruritus, flushing, urti- perioperative anaphylaxis were identified. Then a caria, and angioedema) and eyes (conjunctivitis), the search of each specific drug and the key words “ana- upper (rhinitis and angioedema) and lower (broncho- phylaxis,”“hypersensitivity,” or “allergy” was con- constriction with wheezing and dyspnea, and cyano- ducted. In addition, the references of relevant articles sis) airway, the intestinal tract (abdominal pain, nau- were reviewed to identify other articles missed in the sea, vomiting, and diarrhea), and the cardiovascular original search. Finally, additional references were system (tachycardia, hypotension, and shock), and can identified from the book Drug Allergy (16) and from lead to cardiovascular collapse and death (4) (Table 2). the most recent survey of anaphylaxis during anesthe- The onset