Anaesthesia and Allergic Drug Reactions G

400

Anaesthesia and allergic drug reactions G. C. Moudgil MB M SC FFARCSFRCPC

An allergic drug reaction, by definition, is an Compounds of low molecular weight (500-1000) untoward physiologic response produced by an are incapable ofeliciting antibody formation, and as immunologically mediated reaction. Although a such are incomplete antigens or haptens. wide variety of factors such as physico-chemical Most drugs, their metabolites, and preservatives interaction, enzyme induction or inhibition, drug such as methyl paraben are incomplete antigens. overdose or toxicity, may all contribute toward Only after conjugation with a protein called a adverse drug reactions, these should be distin- "carrier" do they become allergenic or immuno- guished from immunologically mediated allergic genic. 3 For this to occur a stable covalent bond is drug reactions that occur capriciously and explo- essential.4 The commonly observed pharmacologic sively, with little or no warning. Contrary to binding of drugs to the serum proteins is too weak to the common belief, allergic reactions are not rare. render them immunogenic. Immunogenicity may In the United States of America, approximately be accomplished when a drug contains a chemically 200,000 patients suffer an allergic drug reaction reactive group such as an anhydride or a quinone. each year during their stay in the hospital. Another Alternatively, a spontaneous or enzymatic conver- one million people probably experience milder sion of the drug in the body may also create reactions that do not require hospital treatment. 1 It chemically reactive groups that are likely to render has been estimated that one of every six patients it immunogenic. requiring medical treatment has suffered a true or Exposure to such drugs or chemically similar suspected allergic reaction to a drug at some time. J substances results in the production of antibodies The use of a greater number of drugs in the such as immunoglobulin E (IgE), immunoglobulin perioperative period has resulted in an enhanced G (IgG), and immunoglobulin M (IgM), by the incidence of allergic drug reactions during anaes- plasma cells. Subsequent exposures to these drugs thesia, z Since allergic drug reactions are potentially may cause an antigen-antibody reaction which life threatening, their prompt recognition and treat- releases pharmacologically active mediators re- ment are essential for the patient's survival and well sponsible for the ultimate adverse effects. Previous being. Therefore, an understanding of the patho- uneventful single or repeated exposures to the same genesis, clinical manifestation, diagnosis, treat- or similar drugs do not negate the possibility of a ment and prevention of allergic drug reactions is severe allergic response on subsequent exposures. 5 essential for better patient care and management. In addition to immune system mediated allergic reactions, where a previous exposure to the drug is Pathogenesis of allergic drug reactions mandatory, drug reactions may also occur by a The ability of the body to recognize and respond to direct effect of the drugs on the effector ceils. These the "non self" forms the basis of the immune non-immunologic drug reactions have been classed response. Following exposure to a foreign sub- as anaphylactoid reactions and their clinical mani- stance (an antigen), the body may either develop festations are indistinguishable from the immune specific serum protein molecules called antibodies, mediated allergic reactions. or produce immunologically sensitized lymphocytes. The production of antibodies and the subsequent antigen-antibody reaction forms the basis of From the Department of Anaesthesia, McMaster Univer- humoral immunity, whereas the induction of sensi- sity Medical Centre, 1200 Main Street West, tized lymphocytes is called cellular immunity. Hamilton, Ontario, LSN 3Z5.

CAN ANAESTH SOC J 1986 / 33: 3 I pp400-14 Moudgil: ANAESTHESIA AND ALLERGIC DRUG REACTIONS 401

Classification of allergic reactions by the dose and the affinity of the drug for the lgE Allergic drug reactions may be subdivided into antibodies, the number of cell-bound IgE antibodies immune system mediated "anaphylactic reactions" and the intracellular concentration of cyclic nucleo- and non-immune direct responses called "anaphyl- tides. ~o Degranulation and the subsequent release actoid reactions." of chemical mediators is an energy dependent process which results in a substantial fall of the Immune system mediated drug reactions intracellular ATP levels. The clinical expressions of More than twenty years ago Gell and Coombs type I hypersensitivity include anaphylaxis, extrin- described the following four basic types of allergic sic asthma and extrinsic rhinitis. reactions that are mediated by immune processes. 6 TYPE I1 - CYTOTOXICHYPERSENSITIVITY TYPE I - ANAPHYLACTICOR IMMEDIATE This reaction is caused by an IgG or IgM antibody HYPERSENSITIVITY that is directed at the cell surface antigen. The A previous exposure to the same, or a similar antigens may be an integral part of the cell mem- pharmacologic agent is necessary for this type of brane, e.g., A or B blood group antigens or they reaction to occur. The earlier exposure to the may be surface adsorbed haptens which stimulate pharmacologic agent results in the production of an antihapten antibody production. Following anti- antibody of the IgE immunoglobin class. The gen-antibody interaction, contact with phagocytes principal site of IgE synthesis is in the lymphatic is enhanced by a reduction in surface charge, and by tissue of the respiratory and gastrointestinal sys- opsonic or immune adherence through the mem- tems, with tonsils and adenoids being particularly brane bound complement protein C3. As a result of rich in IgE forming plasma cells. The IgE antibody this increased cell adherence, cell death is enhanced because of its specific affinity, binds on to the by phagocytosis. Cell damage may also result surface receptors of basophils and mast ceils. The following the complete activation of the comple- IgE receptor is a glycoprotein with molecular ment system. The classical complement system weight of approximately 50,000. 7 The receptor is consists of nine separate components numbered C1 an integral component of the cell membrane of to C9, that on activation interact sequentially with basophils and mast cells and is not seen on any other one another in a cascade fashion (Figure). The types of leucocytes, s It has been estimated that between 40,000 and 100,000 IgE receptors are present on human basophils. The binding of IgE C1 Ab-Ag with its receptor is temperature dependent, quite CT specific, and not affected by immunoglobulins of C4 + C2 ) C~ + Fragments with kinin-like activity other classes. 9 Once the antibodies have been bound to mast cells and basophils, these cells are C3b + C3a ready to participate in the immediate hypersensi- Enhanced Anaphylatoxin tivity reaction upon appropriate antigenic stimula- phagocytosis Chemotactic tion. Such an allergenic stimulus is provided by a C5 C,.,.2.} C~b + C5, re-exposure to the same or similar drug. The drug Anaphylatoxin forms a bridge across the two cell-bound lgE Chemotactic antibody molecules and cross-links them. The Csb cross-linking induces a membrane change which C~ + C7 ) C5,6.7 results in an influx of calcium ions and changes in Chemotactic cyclic nucleotide levels. A fall in cyclic 3',5'- C8 + C9 C$'6'7 i, C$.6,7,8,9 adenosine monophosphate (cAMP) or a rise in Cytolysis cyclic 3',5'-guanosine monophosphate (cGMP) fa- CL-C_.9= Components of complement system. vours mast cell degranulation and mediator release, Ab-Ag = Antibody-antigen complex, whereas high concentrations of cAMP stabilize the Bars above numbers indicate activated complementcomponents. mast cell granules. The extent of cellular degranulation is influenced FIGURE Flowdiagram of complement cascade 402 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL complement system, once activated is probably the observed in response to bacteria, viruses, and in most important source of vasoactive mediators. For rejection of transplanted tissues. However, a wide example, activated complement proteins C3a and range of drugs, cosmetics, soaps and dyes, may Csa are potent anaphylatoxins and leucocyte chemo- cause dermal sensitivity by the mechanisms of attractants.tl The anaphylatoxins Can and C5, re- delayed hypersensitivity. Initially the antigen is lease histamine and other vasoactive substances processed and presented by maerophages to a small from mast cells which produce arteriolar dilatation number of T-lymphocytes which become sensitized and increased vascular permeability. The actual to the antigen. On subsequent contact with antigen damage in Type II reactions results from cell lysis these lymphocytes undergo mitosis, proliferate and either by phagocytosis or through complement produce soluble mediators called lymphokines. system activation. The most common examples of There is also a generation of cytotoxic T-cells. Type II reactions in man are transfusion reactions Temporally the production of the lymphokines is and penicillin induced haemolytic anaemia. the first step to occur and their liberation in vitro can be detected within four hours after the binding of the TYPE III -- IMMUNE COMPLEX-MEDIATED REACTIONS antigen to the previously sensitized T-cells. Lym- Type HI allergic reactions are also lgG and lgM phokines influence the functions of macrophages, mediated reactions and can be subdivided into local polymorphonuclear leucocytes, lymphocytes and (Arthus) or generalized (serum sickness) reactions. other cells. Some of the important lymphokine These reactions involve soluble rather than particu- mediated activities include the liberation of macro- late antigens. The formation of antigen-antibody phage migration inhibition factor (MIF), macro- complexes cause an activation of complement sys- phage activation factor (MAF), and monocytes and tem with subsequent neutrophil chemotaxis and polymorphonuclear leucocytes chemotactic fac- proteolytic enzyme liberations. Also there is plate- tors. It is the collective activity of these mediators let aggregation and microthrombi formation with which is responsible for delayed hypersensitivity. ischaemia, which provide yet a further source of These reactions develop slowly, first appearing in vasoactive amine liberation and subsequent tissue 18-24 hours, reaching their peak at about 48 hours, damage. Presence of large amounts of circulating and gradually disappearing by 72-96 hours. The complexes ultimately leads to their deposition in the examples of type IV reactions include graft vs. host basement membranes and blood vessels of the skin, reactions, the tuberculin reactions and contact kidneys, and the central nervous system. When the dermatitis. circulating antibody levels are high, the antigen gets precipitated near the site of entry into the body. The Non-immune allergic reactions reaction in the skin is characterized by polymorph infiltration, oedema and erythema and forms the ANAPHYLACTOID REACTIONS essentials of the Arthus reaction. In contrast, when Clinical manifestations of drug induced, non-im- there is an antigen excess soluble complexes are mune anaphylactoid reactionsare indistinguishable formed and deposited in the kidney glomerulii, the from those of an immune-mediated anaphylactic joints, skin and the choroid plexus. Complement is drug reaction. However, in the anaphylactoid reac- subsequently fixed and produces cellular damage. tions the immune mediated mechanisms are either Well known examples of type III generalized or absent or their involvementcannot be proven. Since systemic reactions include serum sickness and there is no immunologic-basis for anaphylactoid immune complex nephritis. reactions, previous exposure to the drug is not necessary and the reaction may occur on the very TYPE IV -- DELAYEDHYPERSENSITIVITY first "virgin" exposure. Primarily basic drugs, e.g., Delayed hypersensitivity reactions occur without d-tubocurarine, succinylcholin~, thiopentone, tri- the involvement of antibodies or the complement metaphan and polymyxin are capable of displacing system and are entirely cell-mediated responses. directly another basic molecule such as histamine The reactions result from the interaction between from mast cells and basophils and this forms the specificially sensitized T-lymphocytes and the spe- basis of directly mediated anaphylactoid drug reac- cific antigens. Delayed hypersensitivity has been tions in susceptible persons, l~ The susceptibility Moudgil: ANAESTHESIA AND ALLERGIC DRUG REACTIONS 403 towards these reactions is enhanced by genetic mediate hypersensitivity reactions. The term "eosi- features such as atopy, abnormalities of the comple- nophil chemotactic factor of anaphylaxis" was first ment system, and frequency of prior exposure to the used in 1971 to describe a mediator that specifically drug. The severity of the adverse reaction is related attracted eosinophils. 2~ Eosinophils contain a num- to the dose and the speed of administration of the ber of enzymes capable of neutralizing the effect of drug, since the severity of clinical adverse effects is various mediators released during anaphylactic directly related to the quantity of drug-induced reactions. These reactions include inactivation of release of histamine and other chemical medi- histamine, slow reacting substance of anaphylaxis ators.~2'J3 Thus a rapid and high dose intravenous (SRS-A), and platelet activating factor (PAF), by administration of a basic drug is likely to provoke a the eosinophil liberated enzymes histaminase, aryl- more prompt degranulation of mast cells and sulphatase B and phospholipase D, respectively. basophils and thereby influence the severity of an In addition to "turning off" the allergic inflam- anaphylactoid reaction. matory reaction, eosinophils have also been shown to phagocytose antigen-antibody complexes. Mast Chemical mediators released in allergic reaction cells and basophils also release neutrophil chemo- Irrespective of the mechanisms of drug allergy, tactic factor which is selective for stimulating some chemical mediators are released during the chemotactic migration of neutrophils. allergic reactions. Although more than 20 different mediators have been identified, 14 histamine re- Slow-reacting substance of anaphylaxis (SRS-A) mains the principal mediator essential for anaphy- and leukotrienes laxis. The other important mediators which are The comp!ete structure of SRS-A, a potent biologic released include neutrophil and eosinophil chemo- mediator, derived from arachidonic acid, was not tactic factors (NCF-A, ECF-A), slow reacting identified until 1979.12 The name leukotrienes has substance of anaphylaxis (SRS-A), platelet activat- been given to these mediators since they are ing factor (PAF), and prostaglandins. produced by leucocytes and contain a conjugated triene. These mediators have a unique ability to Histamine specifically produce contraction of smooth muscle In man, two distinct classes of histamine receptor in the small airways. They cause dose-dependent sites (HI and H2) have been identified. Stimulation long-lasting contraction of rat and human pulmo- of the H~ receptors results in smooth muscle nary smooth muscle, this effect being exerted contraction of the respiratory and the gastroin- preferentially on the peripheral compared to the testinal tracts, enhanced exocrine gland secretion, central airways. Furthermore, the contraction pro- and increased vascular permeability that promotes duced is 200-to 20,000-fold greater in intensity than oedema formation by opening the gaps between that produced by histamine. These mediators also endothelial cells of the post-capillary vessels. In produce systemic arterial hypotension by increasing contrast, stimulation of the H2 receptors affects capillary permeability. predominantly gastric acidity and cardiac function. The H2 receptors in atrial and ventricular myocardi- Platelet activating factor (PAF) um mediate positive chronotropic and inotropic re- Following IgE dependent activation of mast cells sponses, similar to beta-adrenergic receptors, is- 17 and basophils, this newly synthesized mediator The deleterious cardiovascular effects of histamine (PAF) is released. The platelet activating factor include hypotension secondary to venodilation and causes vasoactive amine release from the platelets a sudden decrease in left ventricular filling, Is in addition to platelet aggregation. coronary vasoconstriction, ~9 increased myocardial oxygen demand from enhanced inotropy, chrono- Prostaglandins tropy and arrhythmias. 2~ These 20-carbon unsaturated hydroxy acids are derived from arachidonic acid. Human mast cells Eosinophil chemotactic factor of anaphylaxis have been shown to produce the prostaglandins D2, (ECF-A) El, Ea and F2. Prostaglandins PGE1 and PGE2 Eosinophils are intimately associated with im- cause bronchodilation whereas PGD2 and PGFza 404 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL produce a bronchoconstriction in the human as histamine. Hypotension and vascular collapse being. 23 These and other chemical mediators are may result from acute reduction in intravascular responsible for the clinical manifestations in ana- fluid volume as a result of histamine-induced phylactic and/or anaphylactoid types of allergic increases in capillary permeability and subsequent responses. extravascular translocation of fluids. Venous pool- ing due to relaxation of vascular smooth muscle Clinical manifestations may further aggravate the hypotension culminating The symptom complex of an allergic reaction may in a vascular collapse. Tachycardia accompanying involve the skin, the cardiovascular system, the hypotension is most likely due to the chronotropic respiratory tract, the eye, and the gastro intestinal effects of endogenous catecholamine release from tract, either singly or in combination. The severity the adrenals and the sympathetic ganglia. 25 In of the symptoms, the onset of the reaction and the addition, localised cardiac histamine release may duration of reaction are extremely variable. The cause myocardial damage, 26 arrhythmias and/or onset of symptoms following intravenous adminis- conduction delay, and epicardial coronary vasocon- tration of an antigen occurs abruptly, within 2 to 11 struction through a stimulation of the Ht receptors. minutes, reaching a peak at 5 to 60 minutes. The oral ingestion of the antigen on the other hand may Respiratory system precipitate symptoms hours later, although afflic- Histamine-mediated respiratory smooth muscle H~ tion within minutes is also possible. 24 The usual receptor stimulation produces bronchoconstriction order of involvement of various organs in an and obstruction, with cough and audible wheeze. allergic reaction is skin changes, hypotension with Presence of laryngeal oedema with or without tachycardia and arrhythmias, bronchospasm and bronchial obstruction may lead to severe arterial laryngeal oedema with resulting arterial hypoxae- hypoxaemia, pulmonary oedema and death. In fatal mia. While skin changes and mild respiratory re- cases with clinical bronchial obstruction, the lungs actions are the most common clinical manifesta- exhibit marked hyperinflation with microscopic tions, severe respiratory distress from bronchial evidence of luminal secretions, peribronchial con- obstruction and/or laryngeal oedema, along with gestion, submucosal oedema, eosinophilic infiltra- severe hypotension are the prominent features in tion, and acute emphysema attributable to intract- fatal episodes. able bronchospasm.

Skin The characteristic skin lesions in an allergic reac- Gastrointestinal and other organ systems tion are well circumscribed discrete wheals, with Gastrointestinal manifestations include nausea, erythematous, raised, serpiginous borders and vomiting, abdominal pain of a crampy nature and blanched centres. These urticarial eruptions are blood diarrhoea. In addition, allergic reactions may intensely pruritic, with a diffuse or a localized dis- also cause coagulation defects, leucopenia, and a tribution to the face, chest and upper arms, and may reduction in body temperature. The severity of these coalesce to form giant hives that seldom persist symptoms may be modified by different anaesthetic beyond 48 hours. The oedema of the eyelids may he agents; however, there is no evidence to suggest prominent along with lacrymation, occular itching that either general27 or regional2s anaesthesia may and conjunctivitis. These skin manifestations are afford a protection against occurrence of an allergic due to the release of chemical mediators from mast reaction. On the contrary, it is possible that regional cells. The classic triad of erythema, wheal and analgesia, by producing sympathetic block, may flare response results from the mediator-provoked potentiate histamine-induced hypotension, and thus capillary dilatation, increased vascular permeability enhance morbidity or mortality of an allergic and the stimulation of the axon reflex respectively. reaction.

Cardiovascular system Diagnosis Cardiovascular homeostasis may be severely In most cases the diagnosis of drug allergy is based affected by the release of chemical mediators such upon a temporal association of an adverse reaction Moudgil: ANAESTHESIA AND ALLERGIC DRUG REACTIONS 405 with the administration of a drug. However, such a is later followed by a marked elevation in the diagnosis of allergy is presumptive and "true antibody IgE level. allergy" can be established only after confirmation Previous exposure to the drug(s) is necessary in of an immunological basis. In order to establish the humoral antibody (IgG, IgM) mediated reactions mechanism and the agent responsible for an allergic with classical complement system activation. Serial reaction, several tests should be carried out and plasma samples in this case will reveal complement their results considered in relation to the clinical C3 and C4 consumption of varying degrees, the features. The methods for investigating allergic consumption of C3 generally being less than 30 per reactions include allergy skin test, plasma IgE cent. In contrast, high levels of complement C3 antibody and complement proteins C3 and C4 conversion (30-70 per cent), without C4 conver- levels, plasma histamine levels, leucocyte hista- sion, are observed in reactions following alternative mine release test, IgE inhibition test and radio pathway activation of the complement system. An allergosorbent tests. anaphylactoid reaction may occur following the Measurements of plasma histamine levels pro- first exposure to the drug without any changes in vide a direct measure of the release of effector antibody IgE levels or complement C3 and C4 substance, but fail to elucidate the mechanism levels. responsible for the reaction. Presence of elevated After full recovery, the patient should be referred lgE antibodies along with a positive skin test to an experienced clinical immunologist where demonstrate previous sensitization. The comple- comprehensive details of the adverse incident, ment and histamine measurements at the time of a drugs administered and their sequence, stress, reaction indicate the mechanism of reaction. In atopy and other inherent risk factors can be as- contrast the leucocyte histamine release test and the sessed. On the basis of this evaluation, in vivo, radio allergosorbent test help identify the causative allergy skin tests, as well as the in vitro leucocyte agent. Following a suspected allergic reaction, a histamine release test should be conducted in order detailed clinical history with reference to previous to identify the drug responsible for the reaction. 32 single or multiple exposures to the drug, the patient's immune status and his "degree of stress" Investigation (viral infection, chronic inflammation, preoperative apprehension and fear) should be reviewed and Allergy skin testing serial measurements of plasma IgE, and comple- The allergy skin test is simple, inexpensive, and the ment C3 and C4 should be made. Ideally the first only in vivo test for confirming IgE antibody sample of venous blood should be taken within 30 mediated drug reactions. Despite controversy over minutes of reaction and subsequent samples at 3, 6, its diagnostic value, safety, and ability to elucidate 12 and 24 hours respectively. 29'3~A further sample a mechanism, this test is more valuable than other taken three to five days after the event provides a tests in detecting the agent responsible for a normal baseline for the patient. Where facilities are reaction. 33 available serial plasma histamine levels should also Patients should be tested approximately a month be measured as described by Lorenz et al. 31 after the reaction and should be off all drugs which Fluorimetric techniques allow plasma histamine may modify the response. Drug(s) under investiga- measurements, the normal levels being 0.2-1.0 tion are diluted in normal saline (1:1000 dilution ng.ml-l. Values above 2ng.m1-1 are associated usually) and 0.01 to 0.02 ml are injected intrader- with flushing and urticaria, while plasma levels really to raise a 1-2 mm wheal on the medial aspect above 5.0 ng.ml- 1 are associated with severe clini- of the forearm. Since diluents or preservatives in cal manifestations and profound hypotension. commercial preparations may also act as allergens, In anaphylactic or Type I hypersensitivity re- tests using the diluent or the preservative separately sponse there is usually a history of previous are also required. Since localized histamine release exposure to the drug, and within one hour after an due to the trauma of injection may cause a wheal anaphylactic reaction there is a sudden decrease in through dermographism, a control intradermal in- the plasma IgE levels reflecting a binding of the jection of normal saline must be included in order to antibody to the allergenic drug. This initial decrease avoid a false positive interpretation through der- 406 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL mographism. 34 A wheal greater than 1.0cm, ap- between the specific antibody and the antigenic pea_ring within ten minutes and persisting for at least drug that stimulated the formation of the antibody is 30 minutes, is generally accepted as a positive utilized. The patient's plasma containing the anti- response. However, the following abnormal re- body IgE is incubated with the suspected drug, the sponses also constitute valid and reliable criteria for antigen-antibody complex is formed with the resul- a positive response in a standardized test pro- tant decrease in the IgE levels. Again, this test is not cedure. 33 routinely available, is expensive and difficult to - Wheals greater than 7.0mm, when they persist perform. in serial dilutions and if pseudopod formation is also present. Radioallergosorbent test (RAST) 39'4~ - Large flares which persist 30 minutes in serial This radioimmunoassay estimates the amounts of dilutions. antibodies specific for an antigen or a drug. The - Generalized cutaneous itching in the absence of antibody content of a serum can be assessed by its wheal and flare responses, if they can be shown ability to bind to the antigen which has been to occur only with one drug. rendered insoluble by coupling to an immunoadsor- - Wheals of greater than 0.8 mm arising three to bent. Initially an antigen-antibody complex is four hours after testing. formed by adding commercial antigen to the pa- A false negative intradermal test may occur if tient's plasma. The radioactivity of the antigen- degradation of the drug to an antigen or its conjuga- antibody complex following the addition of anti- tion to a carrier protein were not possible at the IgE will correlate with the in vivo oncentration of injection site. Although relatively minute amounts drug-specific IgE antibodies. Although the test is of drugs are utilized during the intradermal test, specific and sensitive for IgE mediated type I systemic anaphylaxis can still occur and appropriate hypersensitivity, its usefulness as a diagnostic tool resuscitative measures and drugs should always be has been limited by the non-availability of the readily available. specific drugs as a commercially prepared antigen. A variation of the intradermal test (Prausnitz- False positive results may also occur in patients Kustner test 35) utilizes intradermal injection of with high nonspecific serum IgE levels. Despite plasma from an allergic patient into a non-allergic these limitations it is a useful diagnostic test of drug person and subsequently intradermal injection of induced anaphylaxis. the suspected drug at the same site. A wheal and flare response should occur within 20 minutes if Anaesthetic drugs that induce allergic reactions antibodies to the drug were present in the patient's A large spectrum of anaesthetic drugs as well as plasma sample. Because of the possible transmis- other agents such as antibiotics, blood products, sion of viral hepatitis this test has largely been volume expanders, radiocontrast dyes and chymo- abandoned. papain have been known to initiate an allergic response. The clinical manifestations and their Leucocyte histamine release testa6'37 treatments are essentially identical irrespective of This test utilizes the ability of an allergenic drug to the reaction being anaphylactic or anaphylactoid. degranulate and release histamine from leucocytes in vitro. This test is particularly useful in establish- Narcotics ing a diagnosis of anaphylactoid response when the Narcotics may stimulate anaphylactoid reactions evidence for immunologic system involvement is with a direct release of histamine from basophils lacking. The leucocytes obtained from the patient and mast cells. Morphine produces erythema along on incubation with the serial dilutions of the the vein and may cause orthostatic hypotension by suspected drug should cause an increased histamine histamine induced peripheral vasodilation. True release in a dose-dependent manner. The test is anaphylactic type responses are extremely rare with laborious and difficult and at present is mainly a morphine. However, following administration of research instrument. meperidine, anaphylactic reactions with urticaria, bronchospasm, hypoxaemia and hypotension and lgE inhibition testa8 subsequent IgE antibody demonstration, have been In this test the principle of specificity of binding previously reported. 41 Synthetic narcotics such as Moudgil: ANAESTHESIA AND ALLERGIC DRUG REACTIONS 407 fentanyl, sufentanil, and alfentanil can produce incidence of allergic reactions with propanidid has histamine induced bronchospasm and vasodilata- been reported as 1:540. as The higher incidence of tion, but true anaphylaxis or anaphylactoid reac- allergic reactions to these drugs has been attributed tions have not been reported following their admini- to the solvent cremophor EL. 49 A memory me- stration.* diated reaction, involving complement activation by the classical and/or alternate pathways, with the Intravenous induction agents liberation of anaphylatoxin C3a and the resulting granulocyte margination, are an integral part of the BARBITURATES allergic process. There is an initial neutropenia due Both anaphylaetic42 and anaphlactoid type drug to the cremophor-mediated increase in the adher- reactions have been reported following the admini- ence of the granulocytes to vessel walls, which is stration of thiopentone and methohexitone. 43 The subsequently replaced by marked neutrophilia. The incidence of these reactions has been variously role of cremophor in the allergic reactions gains estimated to be 1 in 1400 for thiopentone,4. and I in further credibility when one observes a higher 7000 for methohexitone. .5 However, on critical incidence of drug reactions following diazepam appraisal of the literature, an overall incidence of l administration where the adjuvant cremophor had in 30,000 would appear to be more realistic. 3~ To been substituted for propylene glycol, s~ It is sug- date six deaths have been reported following thio- gested that the detergent properties of the cremo- pentone administration.46 These allergic reactions phor may impart immunogenicity.5j The clinical are more common in patients with atopy, allergies features of the reaction in order of frequency to food, and seasonal allergies. The frequency and include skin changes, hypotension, bronchospasm the time interval between administration of the and abdominal symptoms. The mechanism respon- drugs play an important role in the pathogenesis of sible for these reactions should be established by allergic reactions. In susceptible patients even oral serial measurements of complement C3 and C4, administration of amylbarbitone can produce an along with changes in the antibody and the leuco- allergic response following previous sensitization cyte counts during the reaction. by thiopentone, a7 Both regional and general anaesthesia may potentiate the histamine induced hypo- KETAMINE tension by further vasodilation and impared cate- Anaphylactoid reactions without hypotension or cholamine release, through peripheral sympathetic bronchospasm, but with a macular rash have been nervous system block. Histamine induced broncho- reported following ketamine administration. A spasm may also remain refractory to treatment with negative P-K test, despite prior exposure to keta- a bronchodilator during an allergic response to mine would further suggest an anaphylactoid origin barbiturates .,3 The mechanism underlying the reac- in such reactions. 32 tion is often difficult to elucidate because of the multiplicity of drugs used during clinical anaesthe- ETOMIDATE sia and therefore a thorough history along with a Reactions to etomidate differ from those to the complete physical and laboratory examination is other induction agents in that the symptoms are required to understand the pathogenesis of the drug predominantly cutaneous or gastrointestinal and the reaction. more hazardous cardiovascular and respiratory manifestations are lacking. 53 ALTHESIN AND PROPANIDID The incidence of allergic reactions with althesin is Local anaesthetics much higher (1 in 930) 4a than with thiopentone True allergic reactions to local anaesthetics are rare, although the latter carries a higher mortality. The accounting for less than one per cent of all adverse reactions to these agents. 54 Although an allergic *Since the acceptance of this manuscript an anaphylactic response to the amide group of agents has occa- drug reaction to fentanyl, substantiated by a positive sionally been documented, the incidence of allergy intradermal skin test to serial dilutions of the drug is mostly confined to the ester type local anaesthetics has also been reported. Can Anaesth Soc J 1986, 33: that produce metabolites related to the highly 75-8. antigenic compound para-aminobenzoic acid. 408 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

Local anaesthetic solutions may contain methyl- should be taken into consideration when skin testing paraben, a preservative with bacteriostatic and with the liquid succinylcholine. As with the local fungistatic properties. Methylparaben is an alkyl anaesthetics, an allergic response following suc- ester of parahydroxy benzoic acid and its structural cinylcholine may, in fact, be due to the preservative similarity to para-aminobenzoic acid renders it rather than the drug itself. Also, the bronchospasm antigenic. As a result, hypersensitivity reaction observed may well be due to intubation and light may occur due to prior stimulation of the antibody anaesthesia rather than to an allergic response. A production by the preservative itself. In addition to direct release of histamine from mast cells and methyl paraben, bisulfite sensitivity may also mani- basophils following quaternary ammonium com- fest as allergy to local anaestheticsY Allergic pounds has been shown to occur both systemically reactions to local anaesthetics must be carefully and cutaneously, with all muscle relaxants currently distinguished from the inadvertent intravascular in use.59 injections as well as their cardiotoxic effect, which have generated considerable concern regarding their Antibiotics safety. ~6 Suspected allergic reactions to local Intravenous administration of antibiotics during anaesthetics should be investigated by immunologi- surgery is common and allergic reactions after such cal and skin testing procedures with the pure drug as administration have been reported with different well as the preservative. subclasses of antibiotics. While allergic reactions to penicillin are well established, its cross-sensitivity Muscle relaxants with cephalosporins should also be recognized. 6~ Allergic reactions to muscle relaxants occur more Similarly, adverse reactions and cross-sensitivity commonly than has been previously suspected. 57 between aminoglycosides such as vancomycin and Both anaphylactic and anaphylactoid reactions have other para-amino benzoic acid derivatives should been observed; however, cross-sensitivity between also be bome in mind. Recently both anaphylactic muscle relaxants has not been reported. Patients and anaphylactoid responses have been reported with previous allergy, atopy, asthma, and prior following intravenous vancomycin therapy.65 Even reactions to anaesthesia, have a significantly higher without a true allergic response, rapid intravenous incidence of allergic reactions to muscle relax- infusion of vancomycin may cause up to a 50 per ants. 5s There is also a preponderance of female cent fall in the systolic blood pressure; the mecha- patients having allergic reactions to the muscle nism responsible for this is not clear. 66 relaxants. 59 Patients with allergy to penicillin and cosmetics appear to react to muscle relaxants with Chymopapain greater frequency. ~ The possibility of sensitivity to Chymopapain injections have been shown to be cosmetics predisposing in reactive patients provides effective for the relief of pain from a herniated a possible explanation for preponderance of female lumbar disc. However, allergic reactions of varying patients reacting to muscle relaxants. Sensitivity to severity including cardiovascular collapse and more than one muscle relaxant may occur and has death, with an estimated incidence of 0.82 per cent been shown for alcuronium and d-tubocurarine,61 have been associated with these injections. These and succinylcholine, gallamine, decamethonium, allergic reactions appear to be more common in and fazadinium.62 The mechanism of reaction to women, in patients with multiple allergies, and in muscle relaxants remains unclear, and despite patients with allergies to papaya or papaya deriva- absence of previous exposure to the drug, the tives. 67 Allergy skin testing is a reliable way to clinical features of bronchospasm, cardiovascular predict patients likely to develop an allergic reac- collapse, angioneurotic oedema, along with posi- tion to chymopapain. Premedication with Hi and tive evidence of P-K and IgE mediated reaction H2 receptor blockers and high-dose steroids have represent a Type I hypersensitivity or anaphylaxis. also been found to decrease the incidence and The role of preservatives and additives in reac- severity of allergic reactions. Although several tions to succinylcholine has been discussed and anaesthetic techniques have been utilized, invasive speculated upon by Morrow. 63 Since the liquid arterial pressure monitoring along with endotra- form only and not the powder form of succinylcho- cheal anaesthesia may be a prudent precaution in line contains methylparaben, this preservative susceptible patients. 68 Moudgil: ANAESTHESIA AND ALLERGIC DRUG REACTIONS 409 lntravascular contrast media apprehension and hypotension. Plasma protein Approximately five per cent of the radiological fraction preparations may contain prekallikrein studies utilizing intravascular contrast media are activators which may be responsible for activation complicated by adverse systemic reactions of which of kallikrein-kinin system following intravenous one-third are severe. 69 Several factors may in- infusion of these solutions. 74 The high levels of fluence the risk of a reaction. A history of atopic kinin activity may be responsible for these reac- disease, seafood hypersensitivity and asthma, can tions. Sodium acetate in plasma protein solutions increase the risk of a reaction by 10 to 15 per cent. 7o may also cause hypotension by vasodilatation. Low Anaphylactoid reactions have been known to occur molecular weight dextrans cannot induce antibody in all age groups including infants, though the formation, but may react with preformed anti- number of these reactions are disproportionately dextran antibodies following prior exposure m higher in the third and fourth decades of life. There polysaccharides of viral or bacterial origin. These is no gender bias, but the patients with cardiac antibodies belong to the IgG and IgM classes and disease are four to five times more likely to have a there is no evidence of IgE activity. There is systemic reaction. The dose and the manner of the evidence that dextran may activate the alternate dye injection also influence the risk. Distinctly pathway of the complement system with form,don fewer reactions occur at a dose of less than 20 g of cleavage products of C2, C3 and Cs, which in turn iodine which roughly approximates to 50 ml of a produce the symptoms of an allergic reaction. particular contrast compound. 7~ The reaction may These plasma volume expanders should be used manifest as vasomotor, vasovagal, dermal, osmotic with caution in patients susceptible to an allergic and anaphylaetoid. Most severe reactions are idio- reaction. syncratic and the history of reaction to contrast Blood media may not predict the current response. Acqui- Manifestations of an allergic reaction to blood sition of a knowledge of their pathogenesis and transfusion may vary from pruritis, erythema, treatment may help prevent and decrease the mor- urticaria and raised body temperature to an abrupt bidity and mortality of these reactions. 72 onset of pulmonary oedema in the absence of fluid overload or cardiac dysfunction. Incompatible plas- Plasma volume expanders ma proteins may initiate the release of histamine Plasma protein solutions as well as synthetic plasma from mast cells and basophils with manifestations substitutes have been implicated in the initiation of of an allergic reaction. These reactions have oc- anaphylactic or anaphylactoid responses. The inci- curred in three per cent of patients receiving dence of severe reactions was estimated as 0.003 properly typed and cross-matched blood. 75 per cent following administration of plasma protein solutions, while dextran, gelatin and hydroxyethyl Protamine starch solutions respectively produced adverse re- Protamine, a polycationic polypeptide derived from actions in 0.008, 0.038 and 0.006 per cent of the salmon sperm, frequently used for neutralization of patients. 73 The reactions to dextran are more com- heparin during surgery and blood component dona- mon in males, whereas female patients in the tion, may produce an anaphylactic-type reaction. perinatal period are more susceptible to modified Both in dog and in man, protamine causes a gelatin solutions. Increasing volume, concentration decrease in systemic vascular resistance with a fall and the rate of infusion may also increase direct in cardiac output and a concomitant increase in histamine release. Depending on the severity of the pulmonary artery pressure by releasing histamine reaction, the symptoms may be classed as Grade I - and other vasoactive substances from the platelets with skin manifestations alone; Grade II - with and the mast cells as well as by the activation of the moderate hypotension, nausea and respiratory dis- complement system through the classical pathway. tress; Grade HI - with severe hypotension, shock Patients with allergy to fish and seafood are more at and bronchospasm; and Grade IV - cardiac and/or risk of having an anaphylactic reaction on exposure respiratory arrest. to protamine. 76 Similarly, diabetic patients on Rapid infusion of plasma protein fraction can protamine zinc insulin therapy may stimulate the produce flushing, a feeling of fullness in the head, production of IgE antibodies, and subsequent expo- constricting chest pain, abdominal and back pain, sure to protamine can cause an allergic reaction by 410 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL degranulation and release of vasoactive chemicals human anaphylaxis, these drugs should be used in from mast cells and basophils. The vasectomized all forms of anaphylaxis. Although HI receptor patients, theoretically, may also be at an enhanced blocking drugs, such as diphenhydramine, may help risk of sensitivity to protamine due to the sperm to reverse the effects of histamine at HI receptor autoantibody formation. 77 In susceptible patients a sites in the smooth muscle of the lungs, vascular test dose of 5-10 mg of intravenous protamine has tree and the gastro-intestinal tract, the H2 receptors been recommended. 7s in the heart and the stomach may also need to be blocked by drugs like cimetidine in the presence of Rationale of drug therapy arrhythmias and hypotension. The objective of the drug therapy in anaphylaxis is Corticosteroids have also been recommended for firstly to prevent and/or attenuate the release of use in acute anaphylaxis. They have neither an chemical mediators from mast cells and basophils, adverse effect, nor are they contraindicated in acute and secondly, to abolish or curtail the severity of the anaphylaxis, and may be useful in persistent hypo- non.physiologic response to these chemical media- tension and bronchospasm. However, there is little tors. The release of chemical mediators is encour- or no evidence that they can act sufficiently rapidly aged by a fall in the intracellular cAMP or a rise in to reverse acute anaphylaxis that may progress cGMP concentrations, whereas high concentrations from onset to death in minutes. of cAMP stabilize the target cells against degranulation. The drugs considered in the treatment of aller- Management of anaphylaxis gic reactions include the adrenergic agents, the The manifestations of anaphylaxis may vary from methylxanthines, the antihistamines, and the corti- mild urticaria and pruritis to a life-threatening costeroids. reaction with bronchospasm and hypotension. The adrenergic drugs with 13-agonist activity, Therapy depends on the severity and manifestations such as epinephrine and isoproterenol, tend to of the reaction. Therapy should be titrated to the stabilize the target cells by increasing the intracellu- desired effects with appropriate monitoring and lar cAMP, and prevent the progression of anaphy- severe reactions may require aggressive therapy laxis by decreasing the release of histamine and with larger doses of medications. An outline of a SRS-A. Furthermore, the 13-adrenergic stimulation protocol for the management of anaphylaxis is also reverses the mediator induced bronchocon- listed in the Table. striction. The a-agonists such as norepinephrine, phenylephrine tend to decrease cAMP and increase Prevention of allergic drug reactions the mediator release, and therefore should only be The factors predisposing to allergic drug reactions used to maintain perfusion pressure in the presence are obviously closely linked to prevention. History of severe refractory hypotension. of chronic atopy, asthma, hay fever, drug allergies The methylxanthines inhibit the degradation of and food sensitivities should be sought at the time of cAMP by phosphodiesterase with the resultant the preoperative visit since their presence will make increase in the intracellular cAMP levels. This a patient more prone to an allergic reaction. In increase in the cAMP causes a decreased release of addition, repeated and multiple exposures to the histamine and SRS-A following an antigenic drug same or similar drugs also enhances the incidence of challenge. These agents are also potent broncho- allergic reactions. Similarly, drugs with adjuvants dilators for antigen or histamine induced broncho- and preservatives have the potential to initiate an spasm; however, it is unknown whether or not the allergic response. The interval between exposures effectiveness of these agents is based on changes in is also important since a time interval of two weeks cAMP. Because of their unpredictable cardiovascu- is deemed optimal for development and expression lar effects and possible potentiation of hypotension, of drug allergy. they should only be used to treat bronchospasm Preoperative preparation of patients who are refractory to epinephrine therapy. susceptible to an allergic response should include an Antihistamines act as competitive inhibitors of HI receptor antagonist (diphenhydramine 0.5-1.0 histamine at the target cell receptors. Since hista- mg.kg -1) and an H2 receptor antagonist (cimetidine mine is the cardinal offending chemical mediator in 4-6 mg.kg -~) PO. Since stress has been known to Moudgil: ANAESTHESIA AND ALLERGIC DRUG REACTIONS 411

TABLE Protocol for management of anaphylaxis

Reaction Immediate treatment Secondary treatmenl

Mild Conjunctivitis Prompt discontinuation of the Diphenhydramine50 mg orally every six hours Urticaria allergenic drug Pruritis Airway maintenance with 100% oxygen Erythema Epinephrine 0.3-0.5 mg IM (0.3-0.5 ml of I: 1000 solution) Diphenhydramine 50 nag IM Monitor BP, pulse and respiration

Severe Laryngeal oedema Stop allergenicdrug DiphenhydramineIV 0.5-1.0 mg.kg- ~. If hypotension Bronchospasm Airway maintenancewith endntracheul present add cimetidine 4 ~g.kg -~ IV. Hypotension intubationif necessary and IV aminophylline(3-5 mg'kg-I) if bronchospasmsevere 100% 02 therapy and persistent Epinephrine 1V 5 Ixg'kg-~ titratedto Sympathomimeticsonly if necessary tn maintain desired effect perfusion pressure Volume expansion with 1-2 litres of Norepinephrine 1-2 v,g'min-' ~ Titrated to crystalloids or colloids Isoproterenol0.5- 1.0 I-~g'min-~ | desired effect Corticnsternids Hydrocortisone I g 1V or methylprednisoloneI-2 g IV if complementactivation is suspected Monitor - EKG - Blood Pressure - Blood Gases - Urinaryoutput - CVP/or pulmonary capillary pressure (rarely required) Bicarbonate to correct acidosis

induce respiratory distress, premedication with sideration of preventive measures is warranted in benzodiazepines may be useful. Administration of order to reduce the morbidity and mortality from disodium cromoglycate is desirable in patients with allergic drug reactions. atopy. Patients with a history of allergic reactions to radiographic contrast media, should receive pred- Acknowledgements nisone 50 nag PO every six hours for one day, with The author thanks Dr. J. Dolovich, Professor of the last dose given one hour prior to the procedure, Paediatrics, and Dr. D. P. Singal, Professor of along with diphenhydramine 50 mg IM. This regi- Pathology, for their valuable critique of the manu- men has been shown to decrease the incidence and script. Also, I wish to thank Mrs. Valerie Cannon the severity of allergic reactions to the radiographic for her expert secretarial assistance. contrast media.

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