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ANAPHYLACTOID REACTIONS TO I.V. SUBSTANCES
Br.jf. Anaesih. (1979), 51, 51
ANAPHYLACTOID REACTIONS TO I.V. SUBSTANCES J. WATKINS
J. WATKINS, PH.D., Protein Reference Unit, Department of Immunology, Hallamshire Hospital Medical School, Sheffield S10 2RX. 007-0912/79/010051-10 $01.00
HYPERSENSITIVITY REACTIONS
Before proceeding further with the action of specific i.v. substances it is worth summarizing the four major reaction mechanisms which comprise the hypersensitivity response scheme. These are designated Types I to IV and are admirably described in detail in a number of textbooks (Barrett, 1977; Roitt, 1977). The Type I reaction most resembles that exhibited by patients showing anaphylactoid response to i.v. substances since it is, by definition, immediate. This immunological reaction is for the most part restricted to a genetically prone individual who produces a specific type of antibody, termed a reagin (generally IgE), in response to antigens or allergens which are well tolerated by the population as a whole. In order to produce anaphylaxis these unfortunate patients still require previous antigenic challenge in order to achieve a passive sensitization state. If we are considering allergies which result from natural oral or respiratory immunizations then it is not usually necessary to speculate on the mechanism but only on the specific allergen, but reactions which occur to compounds that the individual has never seen before are most unlikely to be Type I hypersensitivity reactions. Unlikely, but not impossible, since some administered i.v. substances may closely resemble natural antigens such as bacterial proteins and polysaccharides, so that immunological cross-reactions may occur. Once produced, the reaginic antibodies adhere to mast cells. Subsequent antigen challenge causes a physico-chemical reaction upon the surface of the cell which leads to degranulation. The resulting histamine release causes either local cutaneous phenomena or systemic anaphylaxis. The reaginic antibodies are for the most part the IgE class of immunoglobulins. However, IgG reagins are also known (Parish, 1970; Berrens, Koers and Bruynzeel, 1977); these, unlike IgE, may involve complement proteins for the release of histamine. The patient with high IgE concentrations (> 400 iu ml"1) in the plasma is frequently described as atopic: such concentrations are frequently observed in the patient with atopic asthma and in well-defined allergy © Macmillan Journals Ltd 1979
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Although i.v. therapy offers numerous advantages to the clinician, a wide variety of complications of i.v. therapy exists (Jaeger and Rubin, 1970; D'Arcy and Thomson, 1974; Woods and Marston, 1977). It-is important to realize that anaphylactoid or "hypersensitivity" reactions occupy only a small part of this range of complications. Nevertheless, the majority of reactions can be avoided, for example microbial contamination of infusion sets, or the interactions of solutions of unsuitable pH or inorganic salt content, and it is the anaphylactoid response which is of increasing interest and importance since there are at present no ways of satisfactorily predicting such reactions. I have purposely refrained from the term "allergic" to describe these reactions since that automatically implies an immune-mediated response. The clinical manifestations, cutaneous (for example flushing or urticaria), pulmonary (such as bronchospasm) and cardiovascular (such as hypotension) do indeed resemble those produced by the immediate, immunemediated, hypersensitivity response since the chemical mediators of such reactions, predominantly histamine, are identical. Nevertheless, in the absence of laboratory tests to confirm the mechanism, clinical manifestations alone cannot be used to distinguish between antibody-mediated reactions, complementmediated reactions and reactions occurring by the release of histamine from mast cells by the direct action of the injected substance. On the basis of clinical observation alone, hypersensitivity-type reactions are best described as anaphylactoid, the term anaphylactic or allergic being reserved for those reactions in which evidence for definite antibody involvement exists. This terminology was accepted at the Symposium on Adverse Response held in Sheffield, 1978 (Watkins and Clarke, 1978). A second descriptive term, "histaminoid", may be used to describe chemical reactions restricted to cutaneous phenomena such as flushing or urticaria.
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FIG. 1. Fixed drug reactions on the arm of a patient who exhibited a marked anaphylactoid reaction to thiopentone. The flared areas correspond to the precipitation of specific antibody-drug complexes on the sites of previous venipunctures and not to the site of administration of the anaesthetic (dorsum of hand). The patient had received a previous exposure to the drug uneventfully. Photograph by kind permission of Dr P. Latto, Anaesthetic Department, University Hospital of Wales, Cardiff.
incorporation of the protein into Freund's adjuvant. This raises interesting possibilities regarding the use of detergents or solubilizers for several anaesthetic drugs (for example propanidid, Althesin, etomidate). The effector mechanism is essentially the T lymphocyte. It should be clear to the reader that these hypersensitivity reactions do not represent abnormal mechanisms. In themselves they are extremely important in the control of numerous disease processes. It is the magnitude of their involvement in a particular reaction which defines their abnormality. Perhaps not so obvious is the fact that few, if any, hypersensitivity reactions involve specifically one particular mechanism. A Type I reaction may act as a trigger for a Type III, the influence of the former being hidden by the magnitude of the secondary response. Likewise, an apparently insignificant immune reaction may trigger complement nonclassically, producing large quantities of anaphylatoxin and systemic anaphylaxis. Complement
Only the Type I and Type IV reactions may proceed directly without the involvement of the complex system of complement proteins. These proteins, which comprise nine major components, represent nearly 10% of the globulins in the human so it is not surprising that complement participates in several important biological functions (Schur and Austen, 1968; Ruddy, Gigli and Austen, 1972).
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states. It must be observed, however, that this is still a somewhat crude classification, since we should be considering specific IgE antibodies and normal or even decreased concentrations of plasma total IgE may conceal important allergies. Finally, it is the cellbound IgE which is of importance in the Type I reaction: the parallelism between humoral antibody and cell-bound antibody may not hold for certain individuals. Type II reactions also are described as antibodydependent cytotoxic hypersensitivity responses. Again, the patient requires previous antigenic challenge to produce antibodies, but the antigens in this case are present on the surface of either host or foreign cells. Combination of antibody with cellular antigens encourages demise of that cell either by phagocytosis or by activation of the full classical complement pathway up to C8 and C9, producing lysis. Adverse reactions invoking this type of mechanism include transfusion reaction, rhesus incompatibility and long-standing organ transplants. Autoimmune conditions such as Hashimoto's thyroiditis and Goodpasture's syndrome proceed through this mechanism and so may certain types of drug reaction. In the latter, drugs with simple molecular structure may be bound to cell membranes, thus undergoing conversion from haptens to full antigens. The resulting complex may then evoke autoantibodies, for example haemolytic anaemias to phenacetin. However, the majority of small-molecule drugs are more likely to couple to plasma proteins, giving rise to complex-mediated (Type III) reactions. The formation of excessive amounts of soluble complexes of antigen and antibody may fix complement, releasing anaphylatoxins which cause histamine release, vascular permeability changes and an influx of polymorphs which in turn release further factors contributing to the inflammatory response. Two types of complexes may be found, those with antibody excess and those with antigen excess. In antibody excess (Arthus-type) the complexes are rapidly precipitated and tend to be localized in the site of antigen introduction. This type of reaction is illustrated in figure I—an anaphylactic response to thiopentone. This particular reaction, however, also produced a systemic response resulting in hypotension. The final hypersensitivity scheme, Type IV, cellmediated (delayed), is encountered in allergic reactions to bacteria and the like and in the rejection of transplanted tissues. Comparable reactions to soluble proteins are obtained when sensitization is induced by
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C3-
C3a (anaphylatoxin) + C3b
These normally inactivate C3b, producing a large inactive molecule C3c, while the tissue can comfortably absorb the small amount of histamine produced by the anaphylatoxin. However, if by blocking of the C3b inactivator, or by sudden excessive breakdown of C3 itself, the highly active C3b molecule exceeds some predetermined threshold, then a feedback mechanism takes place through C3 proactivator, activating more and more C3 with subsequent massive histamine release. Some i.v. substances, such as Althesin and propanidid, have a particular tendency to this type of non-immunological activation: with others such as dextrans, alternate pathway activation is uncommon, In the laboratory, complement C3 conversion can be readily demonstrated in sequential samples of patients' plasma taken after reaction (Watkins, Udnoon et al., 1976), either by conventional single-dimension immunoelectrophoresis (fig. 2) or by the two-dimensional Laurell technique (Laurell, 1965) which display C3 and its reaction product C3c in the form of peaks of precipitin, the relative areas indicating the degree of conversion (fig. 3). Chemical mediators of anaphylaxis
Several important pharmacologically active compounds are discharged from cells during anaphylaxis. Histamine is the most important of these and the only one proven to be essential to the anaphylactic response (Lorenz et al., 1972,1976, 1977). The other
FIG. 2. Conventional agar immunoelectrophoresis of sequential plasma samples taken over 24 h following anaesthesia with Althesin. Protein migration is towards the left of the photographs, the "troughs" contain anti-C3 antiserum. (A) Samples from a patient who exhibited a marked anaphylactoid response. The first sample (1 h) shows marked C3 conversion (>50%) with the C3C conversion product very evident. Conversion products are gradually removed over 24 h (sample 4). (B) C3 electrophoresis patterns from a patient who had an uneventful induction of anaesthesia. The time sequences of the samples are comparable to samples 1-4 of (A). C3 conversion is minimal.
substances of putative significance are serotonin, bradykinin and other kinins, slow reacting substanceanaphylaxis (SRS-A), and prostaglandins. The function of the last may well be the modulation of histamine release (Engineer et al., 1978), since prostaglandins are known to cause granule reabsorption by mast cells. It is worth noting that the systemic anaphylactic response not only shows striking variation according to the species studied, but also varies in its intensity in different individuals. This is attributed to species differences in susceptibility of different tissues (the shock organ), to histamine liberated in the course of the reaction, and also to variations in the individual distribution of the sensitized mast cells. FREQUENCY OF ANAPHYLACTOID REACTIONS
The definition of frequency implies that the adverse response can be quantitated in some simple and universally adopted manner. This is not so, and it is evident from table I that, particularly for Althesin, much of the variability must lie in what is regarded as a significant anaphylactoid response by the observer. Laboratory investigations (Lorenz, 1975; Watkins, Clark et al., 1976) indicate that subclinical anaphylactoid reactions occur in many people following the administration of i.v. hypnotic agents. These reactions presumably do not exceed a genetically
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Traditionally, the combination of antigen and antibody gives rise to a cascade activation of complements Cl to C9, somewhat analogous to clotting mechanisms. The scission products of complement activation have specific biological functions. The products C3a and C5a are known as anaphylatoxins. Not only are they responsible for histamine release, but they also intrude into the blood clotting system, causing aggregation of platelets. Complements C3 and C4 exist in plasma in relatively high concentration, C3 in excess of 1 g litre" 1 and C4 perhaps 0.5 g litre"1. They are easily measurable by conventional immunochemical techniques (Mancini, Carbonara and Heremans, 1965). Complement C3 is of particular interest to the immunologist, since it can be directly activated without a specific antigen-antibody reaction; this is the basis of the so-called alternate pathway mechanism. Like most potentially "active" plasma proteins, complement C3 is held in a dynamic state by specific protease inhibitors:
53
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DF
23hrs
6hrs
FIG. 3. Laurell immunoelectrophoresis patterns of C3 components in plasma taken from patients D. P. and C. V. showing anaphylactoid response after induction with Althesin for identical minor surgical procedures. Sample times after injection are indicated. Note the initial high degree of conversion (twin peaks): the C3c inactive products are indicated by the arrows. The surgical procedure had to be abandoned in the case of patient C. V. in whom significant conversion persisted for 24 h. Patient D. P. exhibited a lower degree of conversion and it was possible to continue surgery (reproduced by permission from Watkins, Udnoon and Taussig (1978). TABLE I. Reported frequency of anaphylactoid response to i.v. ant reaction mechanisms from the literature, the hypnotics (reproduced by permission from Clarke, Fee and absence of a measure of reaction severity presents the Dundee (1978))
first stumbling block.
Propanidid Dannemann and Lubke (1970) Kay (1972) Doenicke (1974) Methohexitone Driggs and O'Day (1972) Althesin Clarke et al. (1975) Watt (1975) Fisher (1976) Evans and Keogh (1977) Thiopentone Evans and Keogh (1977)
lin
750
1 in 1700 540 1 in lin
7 000
l i n 11 000 lin 900 1 in 900 1 in 930
1 in 14 000
denned threshold for the individual. Measurement of histamine release is theoretically ideal for defining reactions, but the experimental requirements are totally unsuited for clinically severe cases under theatre conditions. In trying to assess the predomin-
Intravenous hypnotics The work of Clarke, Dundee and their colleagues (Clarke et al., 1975) has clearly indicated that clinical features include skin changes, hypotension, bronchospasm and abdominal symptoms, in that order of frequency. Their work demonstrates the fallacy of adverse response reporting in the absence of a measure of severity. In spite of some 90 reactions to Althesin reported in the literature only one death has occurred, whereas there have been six deaths reported in 45 reactions following thiopentone. The data can be interpreted to indicate that although the patient is more likely to have a reaction to Althesin than to thiopentone, any reaction to the former is unlikely to be fatal. Fisher (1977a) considers a general frequency of 1 in 5000 for i.v. hypnotics with increasing frequency attributed to cross-sensitivity and the
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CV
30min
ANAPHYLACTOID REACTIONS
55
investigations into predisposing factors will be of limited value. Based on our experiences, we suggest that four basic mechanisms are involved, although more than one mechanism may be involved in a given reaction. These reaction mechanisms may be conveniently summarized as follows: (1) Type I hypersensitivity response. These require previous exposure and involve IgE antibodies. There is direct histamine release from mast cells without the involvement of complement. (2) Immune reactions. The class of immunoglobulin involved may be in doubt, but histamine release occurs by the classical complement pathway. Contrast media Immunochemically, serial samples show complement Adverse reactions to intravascular radiological C4 and C3 consumption with varying degrees of C3 contrast media, essentially tri-iodo substituted de- conversion, generally less than 30%. (3) Alternate pathway activation of C3. These rivatives of benzoic acid, are probably more frequent than with any other i.v. substance. The large dose involve direct activation of C3 and consequently high (perhaps 140 g injected intravascularly within 30 min) levels of C3 conversion may be observed in plasma gives rise to adverse reactions predominantly as a samples. Complement C4 shows no significant result of the osmolarity of the injected solution consumption or conversion in the reaction. This (x 5 to x 8 plasma). Mild reactions occur in 1 in 2000 group appears to contain both individuals apparently administrations, severe 1 in 20 000, and fatal 1 in sensitized by previous exposure to the substance and first time responders. 40 000 administrations (Witten, 1975). (4) Pharmacological or chemical release of histamine. Plasma substitutes The injected substance causes histamine release Modern plasma substitutes include plasma protein directly from the mast cell without antibody or preparations, modified gelatins, dextrans and starches. complement involvement. This may reflect drug Anaphylactoid manifestations resemble those of the concentration, speed of injection, the distribution of i.v. hypnotics, with cutaneous effects, bronchospasm mast cells in the vascular system, or a combination of and hypotension as predominant features. In spite of these. a large number of case reports published during the past decade the frequency of reactions to plasma Table II shows the analysis of reactions reported to substitutes has been uncertain (Ring et al., 1975). this laboratory between 1974 and 1977, predominantly Recent work by Ring and Messmer (1977) suggested a to Althesin and thiopentone. Although there are frequency of anaphylactoid reactions of 1 in 10 000 no clinical differences in the adverse responses to for plasma protein preparations, 1 in 1000 for gelatine, these drugs (Garrett, 1978) it is quite clear that two 3 in 10 000 for dextran and 8 in 10 000 for hydroxy- very different mechanisms predominate. Althesin ethyl starch. However, L orenz andDoenicke (personal reactions generally involve excessive (alternate pathcommunication) suggest that the total number of way) activation of complement C3, leading to histareactions is considerably greater. mine release, and are not reagin-antibody mediated. In contrast, barbiturate reactions generally represent MECHANISMS AND PREDISPOSING FACTORS immediate immune-mediated, hypersensitivity reThis laboratory has previously suggested simple tests actions. The latter, of course, will have required (Watkins, Udnoon et al., 1976) involving measure- previous exposure to the agent in order to produce ment of the consumption and conversion of comple- immune sensitization. This is in contrast to complement C3 and C4 and immunoglobulin IgE on serial ment-mediated reactions, which can occur on first samples of the patient's plasma taken over the 24 h exposure without previous sensitization. We would following reaction. These tests, considered in relation therefore expect atopic individuals to be at higher to the clinical features of the case, afford a useful tool risk than the normal population with substances in distinguishing the mechanism of the adverse tending to produce antibody response. This is well response. If such tests are not undertaken then illustrated in table III, a survey by Clarke, Fee and greater number of drugs used per anaesthetic (Fisher, 1975). Muscle relaxants, particularly suxamethonium and gallamine, also appear to be frequently involved in anaphylactoid response (Fisher, 1975). For several years the relaxant tubocurarine has been known to release histamine (Comroe and Dripps, 1946) and it has also been suggested that this drug causes bronchospasm (Bennett et al., 1970). There is little doubt that some reported reactions to i.v. hypnotic agents involve the muscle relaxant, but no valid figures exist for the frequency of reactions to these drugs.
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TABLE II. Analysis of reactions reported between 1974 and 1977 Complement involved
Cases reported
Mechanism analysis possible
Classical
Alternate
1974 Althesin Thiopentone Methohexitone
19 1 1
5 0 1
1 0 0
4 0 1
2/5 0 1/1
0/5 0 0/1
1975 Althesin Propanidid Thiopentone
16 1 1
7 0 1
3 0 0
4 0 0
2/7 0 0/1
0/7 0 0/1
1976 Althesin Propanidid Thiopentone
15 2 2
12 2 2
4 0 1
6 2 1
1/10 0/2 2/2
2/12 0/2 0/2
1977 Althesin Thiopentone Thiopentone/dextran* Dextran
12 6 2 2
11 5 1 1
1 3 0 0
5 1 1 1
0/11 4/5 0/1 0/1
5/11 0/5 0/1 0/1
IgE involved
Probably pharmacological
TABLE III. Percentage frequency of a history of atopy, allergies and previous anaesthesia (from Clarke, Fee and Dundee, 1978)
Number of surgical patients Number questioned Eczema, hay fever or asthma Drug or food allergies Previous anaesthesia Same anaesthetic previously
Dundee (1978) of allergy and hypersensitivity conditions in a group of random surgical patients and in a group of "adverse responders". It is clear that previous exposure to the agent is an important factor predisposing to anaphylactoid response and indicates that the same drugs should not be used repeatedly in patients with known atopy. The necessity for laboratory investigations is now more obvious because there is little point in excluding a patient from say, Althesin, if in fact the muscle relaxant is the causative factor. In theory, since many reactions to Althesin occur on first exposure by complement C3 activation, there seems little point in excluding this drug from atopic patients. However, Althesin is a steroid drug and the action of steroids on the immune system overall are complex and not fully understood. We find it
Patients reacting (Clarke et al., 1975)
5500
86
9 14 66 0
14 19 61 47
surprising that antibodies to the Althesin formulation do appear to be produced and we have previously speculated on the role of the surfactant, Cremophor EL, as an adjuvant in this respect. Complement C3 activation appears to be a frequent feature of the anaphylactoid response to i.v. hypnotic agents and to radio-contrast media (Heideman, Jacobsson and Lindhokn, 1976; Lang, Lasser and Kolb, 1976), but not to plasma substitutes. The latter may predominantly involve "aggregate anaphylaxis" (Becker and Austen, 1976). However, it is often far from clear as to what constitutes direct complement activation and what constitutes "feedback" following an initial immune-mediated event. It is becoming evident that some individuals have an inherent (genetic) instability of complement C3 while in others the instability may arise as a result of underlying
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* Reaction time relative to drug administration suggests these were dextran reactions
ANAPHYLACTOID REACTIONS
Mechanisms specific to plasma substitutes
Unlike the hypnotic and muscle relaxant drugs which are haptenic at best, plasma substitutes are potentially antigenic compounds in their own right.
Despite the clinical similarity of adverse reactions produced both by the hypnotics and by plasma substitutes, it would not be surprising if the predominant mechanism of response differed. Richter and his colleagues (1978) produced convincing evidence for the involvement of soluble aggregates or immune complexes in patients reacting to all types of plasma substitute. Among plasma protein solutions human serum albumin (HSA) is most widely employed. Here aggregates may form as a result of polymerization upon storage (Ring, 1976) and these may give rise to "early" reactions. Late reactions in patients, 3 or more days after administration may represent the immunological consequences of the genetic polymorphism of albumin (Weitkamp et al., 1973). Dextrans and gelatins may react specifically with antibodies or non-specifically with euglobulins present in the plasma of many patients (Richter, Hedin and Ring, 1977). In the case of the dextrans, preformed antibodies (Hedin, Richter and Ring, 1976) may exist from the body's experience of crossreacting bacterial polysaccharides. Despite their apparent involvement in adverse clinical reactions, the activation pathway of these complexes remains far from clear although complement C3 activation does not appear to be an important factor. This again may reflect the problem of not reporting severity of reaction. In man, most plasma substitute reactions to dextrans, gelatins and starches involve urticaria and gut reactions rather than vascular changes; it is possible that these represent stimulation of the axon reflex. In contrast, the author has seen excessive C3 activation in two fatal reactions to dextran so that the latter may represent a fortunately rare mechanism for response to dextrans (see also Johnson and Laurell, 1974). In man, plasma histamine release to plasma expanders is relatively uncommon (Lorenz et al., 1973, 1975). Factors predisposing to anaphylactoid response
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immunopathological conditions involving circulatory immune complexes (Type III reaction). Such conditions may include auto-immune disease such as systemic lupus erythematosis (SLE) and rheumatoid arthritis or even chronic infection (Watkins, Ward and Appleyard, 1977). It is worth noting that these conditions do not presuppose antibodies directed against the drug or drug complex, but merely "immune complexes". Such reactions can be readily demonstrated in vitro using either heat-aggregated IgG preparations or IgG anti-albumin-albumin complexes to convert plasma C3. Thus we may have the curious situation in which the patient may have reacted against the drug rather than the drug reacting specifically with the patient. Such reactions may be triggered non-specifically by any substance which, exacerbates an underlying primary (genetic) or secondary (induced) immunopathological condition and may explain why the patient later reacts adversely to a drug totally different from that which was implicated in the first reaction (Watkins, Padfield and Alderson, 1978). A further, apparently genetic, factor involves complement C2 (Ruddy et al., 1970). Activation of this second component of complement gives rise to angioeurotic oedema without C3 intervention. On the subject of possible genetic effects and response to i.v. hypnotics, there is a curious situation with regard to certain patients receiving more than one exposure to Althesin. In addition to patients in whom reaginic antibodies appear to be involved, there is a second group in whom anaphylactoid response follows a second exposure to Althesin, 1-4 weeks after the first administration. Preliminary studies show that either the patients themselves or their families have increased IgD concentrations, with one or more of the family displaying atopic concentrations of IgE (Watkins, Allen and Ward, 1978). IgD is a lymphocyte receptor and may have memory characteristics for short-term response (Rowe et al., 1973; Bargellesi et al., 1978). An analogous situation in the miniature pig model has been reported in detail by Glen and others (1978). Here, although Cremophor EL also elicited a short-term response, alphaxalone itself was definitely implicated (reported at the Sheffield Symposium, 1978). Perhaps we have here a hybrid Type I/Type IV reaction.
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In summary, the principal factors predisposing to anaphylactoid response include (a) genetic features such as atopy (IgE), possibly increased IgD and primary complement anomalies; (b) frequency of exposure to the agents, with anomalous behaviour to Althesin; (c) underlying immune or auto-immune processes leading to complement C3 instability and probably activation of other secondary immune effectors such as prostaglandins; (d) pharmacological effects and (e) stress. The last, we have not considered previously, but there is no doubt that anaesthetic and surgical trauma combine to produce marked
58 alterations in hormone concentrations in the patient, mediated through various centres of the brain. This gives rise to specific changes in protein chemistry, cell metabolism and both the cellular and the humoral "limbs" of specific immune response. MANAGEMENT OF THE ANAPHYLACTOID RESPONSE
Treatment A common manifestation of anaphylactic reaction is hypotension accompanied by extravasation of fluid into extracellular tissues (Fisher, 1977a). This is usually mediated by histamine which induces peripheral vasodilatation and venous pooling, although other plasma factors may produce similar effects. Clearly, the lost fluid should be restored, preferably using a colloid plasma expander. Fluid should be transfused rapidly up to a volume of 1-2 litre (Fisher, 1977a), but the volume must be continuously monitored by the central venous pressure. In contrast to i.v. hypnotic agents and muscle relaxants, anaphylactic reactions to plasma substitutes are relatively slow in onset. In the event of reaction the infusion should preferably be changed to HSA, which is the colloid least likely to cause trouble. In acute hypotension the most favoured drug is adrenaline (Kelly and Patterson, 1974). Isoprenaline is also effective, but may be undesirable because of pre-existing tachycardia and in this case a-adrenergic stimulators such as metaraminol would seem to be specifically indicated. However, a-adrenergic and cholinergic drugs reduce the cell content of cyclic AMP and may enhance histamine release. On balance,
a drug which has a direct effect on smooth muscle would appear to be indicated, such as angiotension amide (Whitwam, 1978). Bronchospasm is the most life-threatening feature of anaphylactoid response (Fisher, 1977b) and can only be treated by tracheal intubation and administration of oxygen, adrenaline and aminophylline. CONCLUSIONS
Relatively few anaphylactoid reactions to i.v. substances are antibody-mediated. Many involve secondary effectors of the immune response directly. Although it is possible to define at least four basic mechanisms, it is obvious that these overlap and more than one may occur in any given reaction. It is not possible to assign a particular reaction mechanism to a particular i.v. substance, although most drugs have a preferred mode of response. Thus, reactions to thiopentone generally require multiple exposure to that drug and frequently represent Type I hypersensitivity reactions. In contrast, some 40% of Althesin reactions involve first exposure to the drug and result from complement activation. True anaphylaxis is dangerous, particularly with "long-lived" drugs like the barbiturate hypnotics and this is probably the reason why the less frequent reactions to thiopentone cause more deaths than those to Althesin. Radiological contrast media have probably the highest potential risk with a fatality rate of 1 in 40 000 patients injected: here complement C3 activation appears to be the harmful factor. The position is further complicated by the way in which individual patients respond to a specific substance. This may be at complete variance with its expected adverse response mode and presumably reflects genetic factors influencing responsiveness. Although we cannot pinpoint the patient at risk we can at least take simple and practical steps to reduce the possibility of response in high-risk patients. REFERENCES
Altounyan, R. E. C. (1969). Disodium cromoglycate: development and clinical pharmacology; in Progress in Bronchial Asthma, p. 15. Proceedings of a symposium on DSCG. Sydney, Australia: Fisons Ltd. Bargellesi, A., Corte, G., Cosulich, E., Ferrarini, M., Sitia, R., and Viale, G. (1978). Recent trends in IgD. La Ricerca Clin. Lab., 8, 195. Barrett, J. T. (1978). Textbook of Immunology, p. 309. St Louis, Missouri: C. V. Mosby Co. Becker, E. L. and Austen, K. F. (1976). Textbook of Immunopathology (eds P. A. Miescher and H. J. MiillerEberhard), p. 117, New York: Grune and Stratum.
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Prevention Active prevention may lie in two types of drug, disodium cromoglycate and H1 and H 2 receptor antagonists. Disodium cromoglycate has not been sufficiently studied in pre-anaesthetic medication (Watkins, Clark et al., 1976), but it may be particularly effective in preventing bronchospasm in susceptible individuals (see review by Altounyan, 1969; Orr, 1975). Unfortunately, it is of no value in treatment of an established reaction. Since histamine release is the cause of all the tissue-damaging and life-threatening reactions, pretreatment with anti-histamine is a logical measure, particularly in atopic patients. However, both H x and H 2 actions should probably be antagonized (Lorenz et al., 1977) using a combination of drugs (for example promethazine with cimetidine). The potential toxicity of steroids make their use for prophylactic therapy undesirable (Munroe-Ford, 1977).
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Heideman, M., Jacobsson, B., and Lindholm, N. (1976). Activation of the complement system, by water-soluble contrast media. Acta Radio!. (Diagn.) (JStockh.), 17, 733. Jaeger, R. J., and Rubin, R. J. (1970). Plasticizers from plastic devices: extraction, metabolism and accumulation by biological systems. Science, 170, 460. Johnson, U., and Laurell, A. B. (1974). Activation of complement in anaphylactoid reactions in connection with infusion of dextran. Scand.J. Immunol, 3, 673. Kay, B. (1972). Brietal sodium in children's surgery; in Das Ultrakurznarkoticum Methohexital (ed. C. Lehmann), p. 149. Berlin: Springer-Verlag. Kelly, J. F., and Patterson, R. (1974). Anaphylaxis. J.A.M.A., 227,1431. Lang, J. H., Lasser, E. C , and Kolb, W. P. (1976). Activation of serum complement by contrast media. Invest. Radiol, 2, 303. Laurell, C. B. (1965). Antigen-antibody crossed electrophoresis. Analyt. Biochem., 10, 358. Lorenz, W. (1975). Histamine release in man. Agents Actions, 5, 402. Doenicke, A., Dittmann, I., Hug, P., and Schwarz, B. (1977). Anaphylactoid Reaktionen nach Applikation von Blutersatzmitteln beim Menschen. Anaesthesist, 26, 644. Freundt, M., Schmal, A., Dormann, P., Praetorius, B., and Schusle-Bulich, M. (1975). Plasmahistaminspeigel beim Menschen nach rascher Infusion von Hydroxyathylstarke. Anaesthesist, 24, 228. Messmer, K., Reimann, H. J., Thermann, M., Lahn, W., Beer, J., Schmal, A., Dormann, P., Regenfuss, P., and Hamelmann, H. (1976). Histamine release in human subjects by modified gelatin (Haemaccel) and dextran. Br.J. Anaesth., 48,151. Meyer, R., Reimann, H. J., Kushe, J., Barth, H., Geesing, H., Hutzel, M., and Weissenbacher, B. (1972). Histamine release in man by propanidid and thiopentone: pharmacological effects and clinical consequences. Br.J. Anaesth., 44,355. Reimann, H. J., Thermann, M., Tauber, R., Schmal, A., Dormann, P., Hensel, H., Hamelmann, H., and Werle, E. (1973). Plasma histamine determinations in man and dog following the infusion of plasma substitutes. Agents Actions, 3,183. Mancini, G., Carbonara, A. O., and Heremans, J. F. (1965). Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry, 2, 235. Munroe-Ford, R. (1977). The management of anaphylaxis. Med. J.Aust., 1,222. Orr, T. S. C. (1975). Recent developments concerning the mast cell and the mode of action of disodium cromoglycate. Acta AllergoL, 30 (Suppl. 12), 13. Parish, W. E. (1970). Short-term anaphylactic IgG antibodies in human sera. Lancet, 2, 591. Richter, W., Hedin, H., and Ring, J. (1977). Immunological findings in infusions of colloid solutions. Med. Welt., 28, 1717. Messmer, K., Hedin, H., and Ring, J. (1978). Adverse reactions to plasma substitutes: incidence and pathomechanisms; in Adverse Response to Intravenous Drugs (eds J. Watkins and A. M. Ward), p. 49. London and New York: Academic Press.
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Bennett, D. J., Torda, T. A., Horton, D. A., and Wright, J. S. (r970). Severe bronchospasm complicating thoracotomy. Arch. Surg., 101, 555. Berrens, L., Koers, W. J., and Bruynzeel, P. L. B. (1977). IgE and IgG4 antibodies in specific allergies. Lancet, 2, 92. Clarke, R. S. J., Dundee, J. W., Garrett, R. T., McArdle, G. K., and Sutton, J. A. (1975). Adverse reactions to intravenous anaesthetics. Br. J. Anaesth., 47, 575. Fee, J. H., and Dundee, J. W. (1978). Hypersensitivity reactions to intravenous anaesthetics; in Adverse Response to Intravenous Drugs (eds J. Watkins and A. M. Ward), p. 41. London and New York: Academic Press. Comroe, J. H., and Dripps, R. D. (1946). The histamineHke action of curare and tubocurarine injected intravenously and intra-arterially in man. Anesthesiology, 7, 260. Danneman, H., and Lubke, P. (1970). Complications during anaesthesia with Epontol. 2. Prakt. Anaesth. Wiederbeleb., 5, 237. D'Arcy, P. F., and Thompson, K. M. (1974). Drug additives to intravenous infusions: a survey of 10 hospitals in Ulster. Pharm. J., 213, 172. Doenicke, A. (1974). Propanidid; in Proceedings of the IV European Congress of Anaesthesiology, Madrid, p. 107. Amsterdam: Excerpta Medica. Driggs, R. L., and O'Day, R. A. (1972). Acute allergic reaction associated with methohexital anaesthesia: report of six cases. J. Oral Surg., 30, 906. Engineer, D. M., Neiderhauser, V., Piper, P. J., and Sirois, P. (1978). Release of mediators of anaphylaxis: inhibition of prostaglandin synthesis and the modification of release of slow reacting substances of anaphylaxis and histamine. Br. J. Pharmacol, 62, 61. Evans, J. M., and Keogh, J. A. M. (1977). Adverse reactions to intravenous anaesthetic induction agents. Br. Med. J., 2, 735. Fisher, M. McD. (1975). Severe histamine-mediated reactions to intravenous drugs used in anaesthesia. Anaesth. Intens. Care, 3, 180. (1976). Intradermal testing after severe histamine reactions to intravenous drugs used in anaesthesia. Anaesth. Intens. Care, 4, 97. (1977a). Blood volume replacement in acute anaphylactic cardiovascular collapse related to anaesthesia. Br.J. Anaesth., 49,1023. (1977b). The management of anaphylaxis. Med. J. Austral, 1, 793. Garrett, R. T. (1978). The clinical manifestations of adverse reactions following Althesin and thiopentone; in Adverse Response to Intravenous Drugs (eds J. Watkins and A. M. Ward), p. 37. London and New York: Academic Press. Glen, J. B., Davies, G. E., Thomson, D. S., Scarth, S. C , and Thompson, A. V. (1978). Adverse reactions to intravenous anaesthetics in animals; in Adverse Response to Intravenous drugs (eds J. Watkins and A. M. Ward), p. 129. London and New York: Academic Press. Hedin, H., Richter, W., and Ring, J. (1976). Dextraninduced anaphylactoid reactions in man. Role of dextran reactive antibodies. Int. Arch. Allerg. Appl. Immunol, 52, 145.
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Watkins, J., Clarke, R. S. J. (1978). Report of a Symposium. Adverse responses to intravenous agents. Br. J. Anaesth., 50, 1159. Padfield, A., and Alderson, J. D. (1978). Underlying immunopathology as a cause of adverse responses to two intravenous anaesthetic agents. Br. Med.J., 1, 1180. Udnoon, S., Appleyard, T. N., and Thornton, J. A. (1976). Identification and quantitation of hypersensitivity reactions to intravenous anaesthetic agents. Br. J. Anaesth., 48, 457. Taussig, P. E. (1978). Mechanisms of adverse response to intravenous agents in man; in Adverse Response to Intravenous Drugs (eds J. Watkins and A. M. Ward), p. 71. London, New York: Academic Press. Ward, A. M., and Appleyard, T. N. (1977). Adverse reactions to intravenous anaesthetic induction agents. Br. Med.J., 2,1084. Watt, J. M. (1975). Anaphylactic reactions after use of CT1341 (Althesin). Br. Med.J., 3, 205. Weitkamp, L. R., Salzano, F. M., Neel, J. V., Porta, F., Geerdinf, R. A., and Tarnoky, A. L. (1973). Human serum albumin: twenty-three genetic variants and their population distribution. Ann. Hum. Genet., 36, 381. Whitwam, J. G. (1978). Appropriate therapeutic measures. Abstract: Symposium, Adverse responses to intravenous agents, Sheffield, 1978. Witten, D. M. (1975). Reactions to urographic contrast media. J.A.M.A., 231, 974. Woods, H. F., and Marston, A. (1977). Metabolic interactions during intravenous feeding; in Drug Interactions (ed. D. J. Grahame-Smith), p. 251. London and New York: Macmillan Press.
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Ring, J. (1976). Habilitationsschrift, Univ. Munchen. Messmer, K. (1977). Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet, 1, 466. Seifert, J., Messmer, K., and Brendel, W. (1975). Untersuchungen zur Frage der Nebenwirkungen bei Anwendung von Plasmaersatzmitteln; in Indication, Wirkung und Nebenwirkung Kolloidaler Volumenersatzmittel (eds F. W. Ahnefeld, H. Bergmann, C. Burn, W. Dick, M. Halmagui and E. Rugheimer), p. 58. Berlin: Springer-Verlag. Roitt, I. M. (1977). Essential Immunology, p. 151. Oxford: Blackwell Scientific Publications. Rowe, D. S., Hug, K., Forni, L., and Pernis, B. (1973). Immunoglobulin D as a lymphocyte receptor. J. Exp. Med., 138, 965. Ruddy, S., Gigli, I., and Austen, K. F. (1972). The complement system of man. N. Engl.J. Med., 287, 489, 545, 592, 642. Klemperer, M. R., Rosen, F. S., Austen, K. F., and Kumate, J. (1970). Hereditary deficiency of the second component of complement in man: correlation of C2 haemolytic activity with immunochemical measurement of C2 protein. Immunology, 18, 943. Schur, P. H., and Austen, K. F. (1968). Complement in human disease. Ann. Rev. Med., 19,1. Watkins, J., Allen, R., and Ward, A. M. (1978). Adverse response to alphadolone/alphaxalone: the possible role of immunoglobulin IgD. Lancet, 2, 736. Clark A., Appleyard, T. N., and Padfield, A. (1976). Immune-mediated reactions to Althesin (Alphaxalone). Br.J. Anaesth., 48, 881.
BRITISH JOURNAL OF ANAESTHESIA
ANAPHYLACTOID REACTIONS TO I.V. SUBSTANCES J. WATKINS
J. WATKINS, PH.D., Protein Reference Unit, Department of Immunology, Hallamshire Hospital Medical School, Sheffield S10 2RX. 007-0912/79/010051-10 $01.00
HYPERSENSITIVITY REACTIONS
Before proceeding further with the action of specific i.v. substances it is worth summarizing the four major reaction mechanisms which comprise the hypersensitivity response scheme. These are designated Types I to IV and are admirably described in detail in a number of textbooks (Barrett, 1977; Roitt, 1977). The Type I reaction most resembles that exhibited by patients showing anaphylactoid response to i.v. substances since it is, by definition, immediate. This immunological reaction is for the most part restricted to a genetically prone individual who produces a specific type of antibody, termed a reagin (generally IgE), in response to antigens or allergens which are well tolerated by the population as a whole. In order to produce anaphylaxis these unfortunate patients still require previous antigenic challenge in order to achieve a passive sensitization state. If we are considering allergies which result from natural oral or respiratory immunizations then it is not usually necessary to speculate on the mechanism but only on the specific allergen, but reactions which occur to compounds that the individual has never seen before are most unlikely to be Type I hypersensitivity reactions. Unlikely, but not impossible, since some administered i.v. substances may closely resemble natural antigens such as bacterial proteins and polysaccharides, so that immunological cross-reactions may occur. Once produced, the reaginic antibodies adhere to mast cells. Subsequent antigen challenge causes a physico-chemical reaction upon the surface of the cell which leads to degranulation. The resulting histamine release causes either local cutaneous phenomena or systemic anaphylaxis. The reaginic antibodies are for the most part the IgE class of immunoglobulins. However, IgG reagins are also known (Parish, 1970; Berrens, Koers and Bruynzeel, 1977); these, unlike IgE, may involve complement proteins for the release of histamine. The patient with high IgE concentrations (> 400 iu ml"1) in the plasma is frequently described as atopic: such concentrations are frequently observed in the patient with atopic asthma and in well-defined allergy © Macmillan Journals Ltd 1979
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Although i.v. therapy offers numerous advantages to the clinician, a wide variety of complications of i.v. therapy exists (Jaeger and Rubin, 1970; D'Arcy and Thomson, 1974; Woods and Marston, 1977). It-is important to realize that anaphylactoid or "hypersensitivity" reactions occupy only a small part of this range of complications. Nevertheless, the majority of reactions can be avoided, for example microbial contamination of infusion sets, or the interactions of solutions of unsuitable pH or inorganic salt content, and it is the anaphylactoid response which is of increasing interest and importance since there are at present no ways of satisfactorily predicting such reactions. I have purposely refrained from the term "allergic" to describe these reactions since that automatically implies an immune-mediated response. The clinical manifestations, cutaneous (for example flushing or urticaria), pulmonary (such as bronchospasm) and cardiovascular (such as hypotension) do indeed resemble those produced by the immediate, immunemediated, hypersensitivity response since the chemical mediators of such reactions, predominantly histamine, are identical. Nevertheless, in the absence of laboratory tests to confirm the mechanism, clinical manifestations alone cannot be used to distinguish between antibody-mediated reactions, complementmediated reactions and reactions occurring by the release of histamine from mast cells by the direct action of the injected substance. On the basis of clinical observation alone, hypersensitivity-type reactions are best described as anaphylactoid, the term anaphylactic or allergic being reserved for those reactions in which evidence for definite antibody involvement exists. This terminology was accepted at the Symposium on Adverse Response held in Sheffield, 1978 (Watkins and Clarke, 1978). A second descriptive term, "histaminoid", may be used to describe chemical reactions restricted to cutaneous phenomena such as flushing or urticaria.
52
FIG. 1. Fixed drug reactions on the arm of a patient who exhibited a marked anaphylactoid reaction to thiopentone. The flared areas correspond to the precipitation of specific antibody-drug complexes on the sites of previous venipunctures and not to the site of administration of the anaesthetic (dorsum of hand). The patient had received a previous exposure to the drug uneventfully. Photograph by kind permission of Dr P. Latto, Anaesthetic Department, University Hospital of Wales, Cardiff.
incorporation of the protein into Freund's adjuvant. This raises interesting possibilities regarding the use of detergents or solubilizers for several anaesthetic drugs (for example propanidid, Althesin, etomidate). The effector mechanism is essentially the T lymphocyte. It should be clear to the reader that these hypersensitivity reactions do not represent abnormal mechanisms. In themselves they are extremely important in the control of numerous disease processes. It is the magnitude of their involvement in a particular reaction which defines their abnormality. Perhaps not so obvious is the fact that few, if any, hypersensitivity reactions involve specifically one particular mechanism. A Type I reaction may act as a trigger for a Type III, the influence of the former being hidden by the magnitude of the secondary response. Likewise, an apparently insignificant immune reaction may trigger complement nonclassically, producing large quantities of anaphylatoxin and systemic anaphylaxis. Complement
Only the Type I and Type IV reactions may proceed directly without the involvement of the complex system of complement proteins. These proteins, which comprise nine major components, represent nearly 10% of the globulins in the human so it is not surprising that complement participates in several important biological functions (Schur and Austen, 1968; Ruddy, Gigli and Austen, 1972).
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states. It must be observed, however, that this is still a somewhat crude classification, since we should be considering specific IgE antibodies and normal or even decreased concentrations of plasma total IgE may conceal important allergies. Finally, it is the cellbound IgE which is of importance in the Type I reaction: the parallelism between humoral antibody and cell-bound antibody may not hold for certain individuals. Type II reactions also are described as antibodydependent cytotoxic hypersensitivity responses. Again, the patient requires previous antigenic challenge to produce antibodies, but the antigens in this case are present on the surface of either host or foreign cells. Combination of antibody with cellular antigens encourages demise of that cell either by phagocytosis or by activation of the full classical complement pathway up to C8 and C9, producing lysis. Adverse reactions invoking this type of mechanism include transfusion reaction, rhesus incompatibility and long-standing organ transplants. Autoimmune conditions such as Hashimoto's thyroiditis and Goodpasture's syndrome proceed through this mechanism and so may certain types of drug reaction. In the latter, drugs with simple molecular structure may be bound to cell membranes, thus undergoing conversion from haptens to full antigens. The resulting complex may then evoke autoantibodies, for example haemolytic anaemias to phenacetin. However, the majority of small-molecule drugs are more likely to couple to plasma proteins, giving rise to complex-mediated (Type III) reactions. The formation of excessive amounts of soluble complexes of antigen and antibody may fix complement, releasing anaphylatoxins which cause histamine release, vascular permeability changes and an influx of polymorphs which in turn release further factors contributing to the inflammatory response. Two types of complexes may be found, those with antibody excess and those with antigen excess. In antibody excess (Arthus-type) the complexes are rapidly precipitated and tend to be localized in the site of antigen introduction. This type of reaction is illustrated in figure I—an anaphylactic response to thiopentone. This particular reaction, however, also produced a systemic response resulting in hypotension. The final hypersensitivity scheme, Type IV, cellmediated (delayed), is encountered in allergic reactions to bacteria and the like and in the rejection of transplanted tissues. Comparable reactions to soluble proteins are obtained when sensitization is induced by
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ANAPHYLACTOID REACTIONS
C3-
C3a (anaphylatoxin) + C3b
These normally inactivate C3b, producing a large inactive molecule C3c, while the tissue can comfortably absorb the small amount of histamine produced by the anaphylatoxin. However, if by blocking of the C3b inactivator, or by sudden excessive breakdown of C3 itself, the highly active C3b molecule exceeds some predetermined threshold, then a feedback mechanism takes place through C3 proactivator, activating more and more C3 with subsequent massive histamine release. Some i.v. substances, such as Althesin and propanidid, have a particular tendency to this type of non-immunological activation: with others such as dextrans, alternate pathway activation is uncommon, In the laboratory, complement C3 conversion can be readily demonstrated in sequential samples of patients' plasma taken after reaction (Watkins, Udnoon et al., 1976), either by conventional single-dimension immunoelectrophoresis (fig. 2) or by the two-dimensional Laurell technique (Laurell, 1965) which display C3 and its reaction product C3c in the form of peaks of precipitin, the relative areas indicating the degree of conversion (fig. 3). Chemical mediators of anaphylaxis
Several important pharmacologically active compounds are discharged from cells during anaphylaxis. Histamine is the most important of these and the only one proven to be essential to the anaphylactic response (Lorenz et al., 1972,1976, 1977). The other
FIG. 2. Conventional agar immunoelectrophoresis of sequential plasma samples taken over 24 h following anaesthesia with Althesin. Protein migration is towards the left of the photographs, the "troughs" contain anti-C3 antiserum. (A) Samples from a patient who exhibited a marked anaphylactoid response. The first sample (1 h) shows marked C3 conversion (>50%) with the C3C conversion product very evident. Conversion products are gradually removed over 24 h (sample 4). (B) C3 electrophoresis patterns from a patient who had an uneventful induction of anaesthesia. The time sequences of the samples are comparable to samples 1-4 of (A). C3 conversion is minimal.
substances of putative significance are serotonin, bradykinin and other kinins, slow reacting substanceanaphylaxis (SRS-A), and prostaglandins. The function of the last may well be the modulation of histamine release (Engineer et al., 1978), since prostaglandins are known to cause granule reabsorption by mast cells. It is worth noting that the systemic anaphylactic response not only shows striking variation according to the species studied, but also varies in its intensity in different individuals. This is attributed to species differences in susceptibility of different tissues (the shock organ), to histamine liberated in the course of the reaction, and also to variations in the individual distribution of the sensitized mast cells. FREQUENCY OF ANAPHYLACTOID REACTIONS
The definition of frequency implies that the adverse response can be quantitated in some simple and universally adopted manner. This is not so, and it is evident from table I that, particularly for Althesin, much of the variability must lie in what is regarded as a significant anaphylactoid response by the observer. Laboratory investigations (Lorenz, 1975; Watkins, Clark et al., 1976) indicate that subclinical anaphylactoid reactions occur in many people following the administration of i.v. hypnotic agents. These reactions presumably do not exceed a genetically
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Traditionally, the combination of antigen and antibody gives rise to a cascade activation of complements Cl to C9, somewhat analogous to clotting mechanisms. The scission products of complement activation have specific biological functions. The products C3a and C5a are known as anaphylatoxins. Not only are they responsible for histamine release, but they also intrude into the blood clotting system, causing aggregation of platelets. Complements C3 and C4 exist in plasma in relatively high concentration, C3 in excess of 1 g litre" 1 and C4 perhaps 0.5 g litre"1. They are easily measurable by conventional immunochemical techniques (Mancini, Carbonara and Heremans, 1965). Complement C3 is of particular interest to the immunologist, since it can be directly activated without a specific antigen-antibody reaction; this is the basis of the so-called alternate pathway mechanism. Like most potentially "active" plasma proteins, complement C3 is held in a dynamic state by specific protease inhibitors:
53
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DF
23hrs
6hrs
FIG. 3. Laurell immunoelectrophoresis patterns of C3 components in plasma taken from patients D. P. and C. V. showing anaphylactoid response after induction with Althesin for identical minor surgical procedures. Sample times after injection are indicated. Note the initial high degree of conversion (twin peaks): the C3c inactive products are indicated by the arrows. The surgical procedure had to be abandoned in the case of patient C. V. in whom significant conversion persisted for 24 h. Patient D. P. exhibited a lower degree of conversion and it was possible to continue surgery (reproduced by permission from Watkins, Udnoon and Taussig (1978). TABLE I. Reported frequency of anaphylactoid response to i.v. ant reaction mechanisms from the literature, the hypnotics (reproduced by permission from Clarke, Fee and absence of a measure of reaction severity presents the Dundee (1978))
first stumbling block.
Propanidid Dannemann and Lubke (1970) Kay (1972) Doenicke (1974) Methohexitone Driggs and O'Day (1972) Althesin Clarke et al. (1975) Watt (1975) Fisher (1976) Evans and Keogh (1977) Thiopentone Evans and Keogh (1977)
lin
750
1 in 1700 540 1 in lin
7 000
l i n 11 000 lin 900 1 in 900 1 in 930
1 in 14 000
denned threshold for the individual. Measurement of histamine release is theoretically ideal for defining reactions, but the experimental requirements are totally unsuited for clinically severe cases under theatre conditions. In trying to assess the predomin-
Intravenous hypnotics The work of Clarke, Dundee and their colleagues (Clarke et al., 1975) has clearly indicated that clinical features include skin changes, hypotension, bronchospasm and abdominal symptoms, in that order of frequency. Their work demonstrates the fallacy of adverse response reporting in the absence of a measure of severity. In spite of some 90 reactions to Althesin reported in the literature only one death has occurred, whereas there have been six deaths reported in 45 reactions following thiopentone. The data can be interpreted to indicate that although the patient is more likely to have a reaction to Althesin than to thiopentone, any reaction to the former is unlikely to be fatal. Fisher (1977a) considers a general frequency of 1 in 5000 for i.v. hypnotics with increasing frequency attributed to cross-sensitivity and the
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CV
30min
ANAPHYLACTOID REACTIONS
55
investigations into predisposing factors will be of limited value. Based on our experiences, we suggest that four basic mechanisms are involved, although more than one mechanism may be involved in a given reaction. These reaction mechanisms may be conveniently summarized as follows: (1) Type I hypersensitivity response. These require previous exposure and involve IgE antibodies. There is direct histamine release from mast cells without the involvement of complement. (2) Immune reactions. The class of immunoglobulin involved may be in doubt, but histamine release occurs by the classical complement pathway. Contrast media Immunochemically, serial samples show complement Adverse reactions to intravascular radiological C4 and C3 consumption with varying degrees of C3 contrast media, essentially tri-iodo substituted de- conversion, generally less than 30%. (3) Alternate pathway activation of C3. These rivatives of benzoic acid, are probably more frequent than with any other i.v. substance. The large dose involve direct activation of C3 and consequently high (perhaps 140 g injected intravascularly within 30 min) levels of C3 conversion may be observed in plasma gives rise to adverse reactions predominantly as a samples. Complement C4 shows no significant result of the osmolarity of the injected solution consumption or conversion in the reaction. This (x 5 to x 8 plasma). Mild reactions occur in 1 in 2000 group appears to contain both individuals apparently administrations, severe 1 in 20 000, and fatal 1 in sensitized by previous exposure to the substance and first time responders. 40 000 administrations (Witten, 1975). (4) Pharmacological or chemical release of histamine. Plasma substitutes The injected substance causes histamine release Modern plasma substitutes include plasma protein directly from the mast cell without antibody or preparations, modified gelatins, dextrans and starches. complement involvement. This may reflect drug Anaphylactoid manifestations resemble those of the concentration, speed of injection, the distribution of i.v. hypnotics, with cutaneous effects, bronchospasm mast cells in the vascular system, or a combination of and hypotension as predominant features. In spite of these. a large number of case reports published during the past decade the frequency of reactions to plasma Table II shows the analysis of reactions reported to substitutes has been uncertain (Ring et al., 1975). this laboratory between 1974 and 1977, predominantly Recent work by Ring and Messmer (1977) suggested a to Althesin and thiopentone. Although there are frequency of anaphylactoid reactions of 1 in 10 000 no clinical differences in the adverse responses to for plasma protein preparations, 1 in 1000 for gelatine, these drugs (Garrett, 1978) it is quite clear that two 3 in 10 000 for dextran and 8 in 10 000 for hydroxy- very different mechanisms predominate. Althesin ethyl starch. However, L orenz andDoenicke (personal reactions generally involve excessive (alternate pathcommunication) suggest that the total number of way) activation of complement C3, leading to histareactions is considerably greater. mine release, and are not reagin-antibody mediated. In contrast, barbiturate reactions generally represent MECHANISMS AND PREDISPOSING FACTORS immediate immune-mediated, hypersensitivity reThis laboratory has previously suggested simple tests actions. The latter, of course, will have required (Watkins, Udnoon et al., 1976) involving measure- previous exposure to the agent in order to produce ment of the consumption and conversion of comple- immune sensitization. This is in contrast to complement C3 and C4 and immunoglobulin IgE on serial ment-mediated reactions, which can occur on first samples of the patient's plasma taken over the 24 h exposure without previous sensitization. We would following reaction. These tests, considered in relation therefore expect atopic individuals to be at higher to the clinical features of the case, afford a useful tool risk than the normal population with substances in distinguishing the mechanism of the adverse tending to produce antibody response. This is well response. If such tests are not undertaken then illustrated in table III, a survey by Clarke, Fee and greater number of drugs used per anaesthetic (Fisher, 1975). Muscle relaxants, particularly suxamethonium and gallamine, also appear to be frequently involved in anaphylactoid response (Fisher, 1975). For several years the relaxant tubocurarine has been known to release histamine (Comroe and Dripps, 1946) and it has also been suggested that this drug causes bronchospasm (Bennett et al., 1970). There is little doubt that some reported reactions to i.v. hypnotic agents involve the muscle relaxant, but no valid figures exist for the frequency of reactions to these drugs.
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56
TABLE II. Analysis of reactions reported between 1974 and 1977 Complement involved
Cases reported
Mechanism analysis possible
Classical
Alternate
1974 Althesin Thiopentone Methohexitone
19 1 1
5 0 1
1 0 0
4 0 1
2/5 0 1/1
0/5 0 0/1
1975 Althesin Propanidid Thiopentone
16 1 1
7 0 1
3 0 0
4 0 0
2/7 0 0/1
0/7 0 0/1
1976 Althesin Propanidid Thiopentone
15 2 2
12 2 2
4 0 1
6 2 1
1/10 0/2 2/2
2/12 0/2 0/2
1977 Althesin Thiopentone Thiopentone/dextran* Dextran
12 6 2 2
11 5 1 1
1 3 0 0
5 1 1 1
0/11 4/5 0/1 0/1
5/11 0/5 0/1 0/1
IgE involved
Probably pharmacological
TABLE III. Percentage frequency of a history of atopy, allergies and previous anaesthesia (from Clarke, Fee and Dundee, 1978)
Number of surgical patients Number questioned Eczema, hay fever or asthma Drug or food allergies Previous anaesthesia Same anaesthetic previously
Dundee (1978) of allergy and hypersensitivity conditions in a group of random surgical patients and in a group of "adverse responders". It is clear that previous exposure to the agent is an important factor predisposing to anaphylactoid response and indicates that the same drugs should not be used repeatedly in patients with known atopy. The necessity for laboratory investigations is now more obvious because there is little point in excluding a patient from say, Althesin, if in fact the muscle relaxant is the causative factor. In theory, since many reactions to Althesin occur on first exposure by complement C3 activation, there seems little point in excluding this drug from atopic patients. However, Althesin is a steroid drug and the action of steroids on the immune system overall are complex and not fully understood. We find it
Patients reacting (Clarke et al., 1975)
5500
86
9 14 66 0
14 19 61 47
surprising that antibodies to the Althesin formulation do appear to be produced and we have previously speculated on the role of the surfactant, Cremophor EL, as an adjuvant in this respect. Complement C3 activation appears to be a frequent feature of the anaphylactoid response to i.v. hypnotic agents and to radio-contrast media (Heideman, Jacobsson and Lindhokn, 1976; Lang, Lasser and Kolb, 1976), but not to plasma substitutes. The latter may predominantly involve "aggregate anaphylaxis" (Becker and Austen, 1976). However, it is often far from clear as to what constitutes direct complement activation and what constitutes "feedback" following an initial immune-mediated event. It is becoming evident that some individuals have an inherent (genetic) instability of complement C3 while in others the instability may arise as a result of underlying
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* Reaction time relative to drug administration suggests these were dextran reactions
ANAPHYLACTOID REACTIONS
Mechanisms specific to plasma substitutes
Unlike the hypnotic and muscle relaxant drugs which are haptenic at best, plasma substitutes are potentially antigenic compounds in their own right.
Despite the clinical similarity of adverse reactions produced both by the hypnotics and by plasma substitutes, it would not be surprising if the predominant mechanism of response differed. Richter and his colleagues (1978) produced convincing evidence for the involvement of soluble aggregates or immune complexes in patients reacting to all types of plasma substitute. Among plasma protein solutions human serum albumin (HSA) is most widely employed. Here aggregates may form as a result of polymerization upon storage (Ring, 1976) and these may give rise to "early" reactions. Late reactions in patients, 3 or more days after administration may represent the immunological consequences of the genetic polymorphism of albumin (Weitkamp et al., 1973). Dextrans and gelatins may react specifically with antibodies or non-specifically with euglobulins present in the plasma of many patients (Richter, Hedin and Ring, 1977). In the case of the dextrans, preformed antibodies (Hedin, Richter and Ring, 1976) may exist from the body's experience of crossreacting bacterial polysaccharides. Despite their apparent involvement in adverse clinical reactions, the activation pathway of these complexes remains far from clear although complement C3 activation does not appear to be an important factor. This again may reflect the problem of not reporting severity of reaction. In man, most plasma substitute reactions to dextrans, gelatins and starches involve urticaria and gut reactions rather than vascular changes; it is possible that these represent stimulation of the axon reflex. In contrast, the author has seen excessive C3 activation in two fatal reactions to dextran so that the latter may represent a fortunately rare mechanism for response to dextrans (see also Johnson and Laurell, 1974). In man, plasma histamine release to plasma expanders is relatively uncommon (Lorenz et al., 1973, 1975). Factors predisposing to anaphylactoid response
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immunopathological conditions involving circulatory immune complexes (Type III reaction). Such conditions may include auto-immune disease such as systemic lupus erythematosis (SLE) and rheumatoid arthritis or even chronic infection (Watkins, Ward and Appleyard, 1977). It is worth noting that these conditions do not presuppose antibodies directed against the drug or drug complex, but merely "immune complexes". Such reactions can be readily demonstrated in vitro using either heat-aggregated IgG preparations or IgG anti-albumin-albumin complexes to convert plasma C3. Thus we may have the curious situation in which the patient may have reacted against the drug rather than the drug reacting specifically with the patient. Such reactions may be triggered non-specifically by any substance which, exacerbates an underlying primary (genetic) or secondary (induced) immunopathological condition and may explain why the patient later reacts adversely to a drug totally different from that which was implicated in the first reaction (Watkins, Padfield and Alderson, 1978). A further, apparently genetic, factor involves complement C2 (Ruddy et al., 1970). Activation of this second component of complement gives rise to angioeurotic oedema without C3 intervention. On the subject of possible genetic effects and response to i.v. hypnotics, there is a curious situation with regard to certain patients receiving more than one exposure to Althesin. In addition to patients in whom reaginic antibodies appear to be involved, there is a second group in whom anaphylactoid response follows a second exposure to Althesin, 1-4 weeks after the first administration. Preliminary studies show that either the patients themselves or their families have increased IgD concentrations, with one or more of the family displaying atopic concentrations of IgE (Watkins, Allen and Ward, 1978). IgD is a lymphocyte receptor and may have memory characteristics for short-term response (Rowe et al., 1973; Bargellesi et al., 1978). An analogous situation in the miniature pig model has been reported in detail by Glen and others (1978). Here, although Cremophor EL also elicited a short-term response, alphaxalone itself was definitely implicated (reported at the Sheffield Symposium, 1978). Perhaps we have here a hybrid Type I/Type IV reaction.
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In summary, the principal factors predisposing to anaphylactoid response include (a) genetic features such as atopy (IgE), possibly increased IgD and primary complement anomalies; (b) frequency of exposure to the agents, with anomalous behaviour to Althesin; (c) underlying immune or auto-immune processes leading to complement C3 instability and probably activation of other secondary immune effectors such as prostaglandins; (d) pharmacological effects and (e) stress. The last, we have not considered previously, but there is no doubt that anaesthetic and surgical trauma combine to produce marked
58 alterations in hormone concentrations in the patient, mediated through various centres of the brain. This gives rise to specific changes in protein chemistry, cell metabolism and both the cellular and the humoral "limbs" of specific immune response. MANAGEMENT OF THE ANAPHYLACTOID RESPONSE
Treatment A common manifestation of anaphylactic reaction is hypotension accompanied by extravasation of fluid into extracellular tissues (Fisher, 1977a). This is usually mediated by histamine which induces peripheral vasodilatation and venous pooling, although other plasma factors may produce similar effects. Clearly, the lost fluid should be restored, preferably using a colloid plasma expander. Fluid should be transfused rapidly up to a volume of 1-2 litre (Fisher, 1977a), but the volume must be continuously monitored by the central venous pressure. In contrast to i.v. hypnotic agents and muscle relaxants, anaphylactic reactions to plasma substitutes are relatively slow in onset. In the event of reaction the infusion should preferably be changed to HSA, which is the colloid least likely to cause trouble. In acute hypotension the most favoured drug is adrenaline (Kelly and Patterson, 1974). Isoprenaline is also effective, but may be undesirable because of pre-existing tachycardia and in this case a-adrenergic stimulators such as metaraminol would seem to be specifically indicated. However, a-adrenergic and cholinergic drugs reduce the cell content of cyclic AMP and may enhance histamine release. On balance,
a drug which has a direct effect on smooth muscle would appear to be indicated, such as angiotension amide (Whitwam, 1978). Bronchospasm is the most life-threatening feature of anaphylactoid response (Fisher, 1977b) and can only be treated by tracheal intubation and administration of oxygen, adrenaline and aminophylline. CONCLUSIONS
Relatively few anaphylactoid reactions to i.v. substances are antibody-mediated. Many involve secondary effectors of the immune response directly. Although it is possible to define at least four basic mechanisms, it is obvious that these overlap and more than one may occur in any given reaction. It is not possible to assign a particular reaction mechanism to a particular i.v. substance, although most drugs have a preferred mode of response. Thus, reactions to thiopentone generally require multiple exposure to that drug and frequently represent Type I hypersensitivity reactions. In contrast, some 40% of Althesin reactions involve first exposure to the drug and result from complement activation. True anaphylaxis is dangerous, particularly with "long-lived" drugs like the barbiturate hypnotics and this is probably the reason why the less frequent reactions to thiopentone cause more deaths than those to Althesin. Radiological contrast media have probably the highest potential risk with a fatality rate of 1 in 40 000 patients injected: here complement C3 activation appears to be the harmful factor. The position is further complicated by the way in which individual patients respond to a specific substance. This may be at complete variance with its expected adverse response mode and presumably reflects genetic factors influencing responsiveness. Although we cannot pinpoint the patient at risk we can at least take simple and practical steps to reduce the possibility of response in high-risk patients. REFERENCES
Altounyan, R. E. C. (1969). Disodium cromoglycate: development and clinical pharmacology; in Progress in Bronchial Asthma, p. 15. Proceedings of a symposium on DSCG. Sydney, Australia: Fisons Ltd. Bargellesi, A., Corte, G., Cosulich, E., Ferrarini, M., Sitia, R., and Viale, G. (1978). Recent trends in IgD. La Ricerca Clin. Lab., 8, 195. Barrett, J. T. (1978). Textbook of Immunology, p. 309. St Louis, Missouri: C. V. Mosby Co. Becker, E. L. and Austen, K. F. (1976). Textbook of Immunopathology (eds P. A. Miescher and H. J. MiillerEberhard), p. 117, New York: Grune and Stratum.
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Prevention Active prevention may lie in two types of drug, disodium cromoglycate and H1 and H 2 receptor antagonists. Disodium cromoglycate has not been sufficiently studied in pre-anaesthetic medication (Watkins, Clark et al., 1976), but it may be particularly effective in preventing bronchospasm in susceptible individuals (see review by Altounyan, 1969; Orr, 1975). Unfortunately, it is of no value in treatment of an established reaction. Since histamine release is the cause of all the tissue-damaging and life-threatening reactions, pretreatment with anti-histamine is a logical measure, particularly in atopic patients. However, both H x and H 2 actions should probably be antagonized (Lorenz et al., 1977) using a combination of drugs (for example promethazine with cimetidine). The potential toxicity of steroids make their use for prophylactic therapy undesirable (Munroe-Ford, 1977).
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Heideman, M., Jacobsson, B., and Lindholm, N. (1976). Activation of the complement system, by water-soluble contrast media. Acta Radio!. (Diagn.) (JStockh.), 17, 733. Jaeger, R. J., and Rubin, R. J. (1970). Plasticizers from plastic devices: extraction, metabolism and accumulation by biological systems. Science, 170, 460. Johnson, U., and Laurell, A. B. (1974). Activation of complement in anaphylactoid reactions in connection with infusion of dextran. Scand.J. Immunol, 3, 673. Kay, B. (1972). Brietal sodium in children's surgery; in Das Ultrakurznarkoticum Methohexital (ed. C. Lehmann), p. 149. Berlin: Springer-Verlag. Kelly, J. F., and Patterson, R. (1974). Anaphylaxis. J.A.M.A., 227,1431. Lang, J. H., Lasser, E. C , and Kolb, W. P. (1976). Activation of serum complement by contrast media. Invest. Radiol, 2, 303. Laurell, C. B. (1965). Antigen-antibody crossed electrophoresis. Analyt. Biochem., 10, 358. Lorenz, W. (1975). Histamine release in man. Agents Actions, 5, 402. Doenicke, A., Dittmann, I., Hug, P., and Schwarz, B. (1977). Anaphylactoid Reaktionen nach Applikation von Blutersatzmitteln beim Menschen. Anaesthesist, 26, 644. Freundt, M., Schmal, A., Dormann, P., Praetorius, B., and Schusle-Bulich, M. (1975). Plasmahistaminspeigel beim Menschen nach rascher Infusion von Hydroxyathylstarke. Anaesthesist, 24, 228. Messmer, K., Reimann, H. J., Thermann, M., Lahn, W., Beer, J., Schmal, A., Dormann, P., Regenfuss, P., and Hamelmann, H. (1976). Histamine release in human subjects by modified gelatin (Haemaccel) and dextran. Br.J. Anaesth., 48,151. Meyer, R., Reimann, H. J., Kushe, J., Barth, H., Geesing, H., Hutzel, M., and Weissenbacher, B. (1972). Histamine release in man by propanidid and thiopentone: pharmacological effects and clinical consequences. Br.J. Anaesth., 44,355. Reimann, H. J., Thermann, M., Tauber, R., Schmal, A., Dormann, P., Hensel, H., Hamelmann, H., and Werle, E. (1973). Plasma histamine determinations in man and dog following the infusion of plasma substitutes. Agents Actions, 3,183. Mancini, G., Carbonara, A. O., and Heremans, J. F. (1965). Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry, 2, 235. Munroe-Ford, R. (1977). The management of anaphylaxis. Med. J.Aust., 1,222. Orr, T. S. C. (1975). Recent developments concerning the mast cell and the mode of action of disodium cromoglycate. Acta AllergoL, 30 (Suppl. 12), 13. Parish, W. E. (1970). Short-term anaphylactic IgG antibodies in human sera. Lancet, 2, 591. Richter, W., Hedin, H., and Ring, J. (1977). Immunological findings in infusions of colloid solutions. Med. Welt., 28, 1717. Messmer, K., Hedin, H., and Ring, J. (1978). Adverse reactions to plasma substitutes: incidence and pathomechanisms; in Adverse Response to Intravenous Drugs (eds J. Watkins and A. M. Ward), p. 49. London and New York: Academic Press.
Downloaded from http://bja.oxfordjournals.org/ at Karolinska Institutet on May 25, 2015
Bennett, D. J., Torda, T. A., Horton, D. A., and Wright, J. S. (r970). Severe bronchospasm complicating thoracotomy. Arch. Surg., 101, 555. Berrens, L., Koers, W. J., and Bruynzeel, P. L. B. (1977). IgE and IgG4 antibodies in specific allergies. Lancet, 2, 92. Clarke, R. S. J., Dundee, J. W., Garrett, R. T., McArdle, G. K., and Sutton, J. A. (1975). Adverse reactions to intravenous anaesthetics. Br. J. Anaesth., 47, 575. Fee, J. H., and Dundee, J. W. (1978). Hypersensitivity reactions to intravenous anaesthetics; in Adverse Response to Intravenous Drugs (eds J. Watkins and A. M. Ward), p. 41. London and New York: Academic Press. Comroe, J. H., and Dripps, R. D. (1946). The histamineHke action of curare and tubocurarine injected intravenously and intra-arterially in man. Anesthesiology, 7, 260. Danneman, H., and Lubke, P. (1970). Complications during anaesthesia with Epontol. 2. Prakt. Anaesth. Wiederbeleb., 5, 237. D'Arcy, P. F., and Thompson, K. M. (1974). Drug additives to intravenous infusions: a survey of 10 hospitals in Ulster. Pharm. J., 213, 172. Doenicke, A. (1974). Propanidid; in Proceedings of the IV European Congress of Anaesthesiology, Madrid, p. 107. Amsterdam: Excerpta Medica. Driggs, R. L., and O'Day, R. A. (1972). Acute allergic reaction associated with methohexital anaesthesia: report of six cases. J. Oral Surg., 30, 906. Engineer, D. M., Neiderhauser, V., Piper, P. J., and Sirois, P. (1978). Release of mediators of anaphylaxis: inhibition of prostaglandin synthesis and the modification of release of slow reacting substances of anaphylaxis and histamine. Br. J. Pharmacol, 62, 61. Evans, J. M., and Keogh, J. A. M. (1977). Adverse reactions to intravenous anaesthetic induction agents. Br. Med. J., 2, 735. Fisher, M. McD. (1975). Severe histamine-mediated reactions to intravenous drugs used in anaesthesia. Anaesth. Intens. Care, 3, 180. (1976). Intradermal testing after severe histamine reactions to intravenous drugs used in anaesthesia. Anaesth. Intens. Care, 4, 97. (1977a). Blood volume replacement in acute anaphylactic cardiovascular collapse related to anaesthesia. Br.J. Anaesth., 49,1023. (1977b). The management of anaphylaxis. Med. J. Austral, 1, 793. Garrett, R. T. (1978). The clinical manifestations of adverse reactions following Althesin and thiopentone; in Adverse Response to Intravenous Drugs (eds J. Watkins and A. M. Ward), p. 37. London and New York: Academic Press. Glen, J. B., Davies, G. E., Thomson, D. S., Scarth, S. C , and Thompson, A. V. (1978). Adverse reactions to intravenous anaesthetics in animals; in Adverse Response to Intravenous drugs (eds J. Watkins and A. M. Ward), p. 129. London and New York: Academic Press. Hedin, H., Richter, W., and Ring, J. (1976). Dextraninduced anaphylactoid reactions in man. Role of dextran reactive antibodies. Int. Arch. Allerg. Appl. Immunol, 52, 145.
59
60
Watkins, J., Clarke, R. S. J. (1978). Report of a Symposium. Adverse responses to intravenous agents. Br. J. Anaesth., 50, 1159. Padfield, A., and Alderson, J. D. (1978). Underlying immunopathology as a cause of adverse responses to two intravenous anaesthetic agents. Br. Med.J., 1, 1180. Udnoon, S., Appleyard, T. N., and Thornton, J. A. (1976). Identification and quantitation of hypersensitivity reactions to intravenous anaesthetic agents. Br. J. Anaesth., 48, 457. Taussig, P. E. (1978). Mechanisms of adverse response to intravenous agents in man; in Adverse Response to Intravenous Drugs (eds J. Watkins and A. M. Ward), p. 71. London, New York: Academic Press. Ward, A. M., and Appleyard, T. N. (1977). Adverse reactions to intravenous anaesthetic induction agents. Br. Med.J., 2,1084. Watt, J. M. (1975). Anaphylactic reactions after use of CT1341 (Althesin). Br. Med.J., 3, 205. Weitkamp, L. R., Salzano, F. M., Neel, J. V., Porta, F., Geerdinf, R. A., and Tarnoky, A. L. (1973). Human serum albumin: twenty-three genetic variants and their population distribution. Ann. Hum. Genet., 36, 381. Whitwam, J. G. (1978). Appropriate therapeutic measures. Abstract: Symposium, Adverse responses to intravenous agents, Sheffield, 1978. Witten, D. M. (1975). Reactions to urographic contrast media. J.A.M.A., 231, 974. Woods, H. F., and Marston, A. (1977). Metabolic interactions during intravenous feeding; in Drug Interactions (ed. D. J. Grahame-Smith), p. 251. London and New York: Macmillan Press.
Downloaded from http://bja.oxfordjournals.org/ at Karolinska Institutet on May 25, 2015
Ring, J. (1976). Habilitationsschrift, Univ. Munchen. Messmer, K. (1977). Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet, 1, 466. Seifert, J., Messmer, K., and Brendel, W. (1975). Untersuchungen zur Frage der Nebenwirkungen bei Anwendung von Plasmaersatzmitteln; in Indication, Wirkung und Nebenwirkung Kolloidaler Volumenersatzmittel (eds F. W. Ahnefeld, H. Bergmann, C. Burn, W. Dick, M. Halmagui and E. Rugheimer), p. 58. Berlin: Springer-Verlag. Roitt, I. M. (1977). Essential Immunology, p. 151. Oxford: Blackwell Scientific Publications. Rowe, D. S., Hug, K., Forni, L., and Pernis, B. (1973). Immunoglobulin D as a lymphocyte receptor. J. Exp. Med., 138, 965. Ruddy, S., Gigli, I., and Austen, K. F. (1972). The complement system of man. N. Engl.J. Med., 287, 489, 545, 592, 642. Klemperer, M. R., Rosen, F. S., Austen, K. F., and Kumate, J. (1970). Hereditary deficiency of the second component of complement in man: correlation of C2 haemolytic activity with immunochemical measurement of C2 protein. Immunology, 18, 943. Schur, P. H., and Austen, K. F. (1968). Complement in human disease. Ann. Rev. Med., 19,1. Watkins, J., Allen, R., and Ward, A. M. (1978). Adverse response to alphadolone/alphaxalone: the possible role of immunoglobulin IgD. Lancet, 2, 736. Clark A., Appleyard, T. N., and Padfield, A. (1976). Immune-mediated reactions to Althesin (Alphaxalone). Br.J. Anaesth., 48, 881.
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