Book review
2
Book review E. S. K. Assem (ed): Allergic reactions to anaesthetics: clini- cal and basic aspects. Basel: Karger, 1992. 236 pp; (ISBN 3- 8055-5489-3); £ 128.30; DM 353.-; SFr 295.- The incidence of adverse allergic reactions to anaesthetic drugs is probably increasing. The rate varies from country to country, but is around 0.7 % of all anaesthetics, with a mor- tality rate of 0.05 % [Clarke 1985; Laxenaire et al. 1985]. The incidence of major allergic reactions in Australia has been re- ported to be 1:28 000 anaesthetics in 1970 and 1:5000 in 1981 [Fisher 1982]. However, the overall incidence of reactions to anaesthetic drugs may be as high as 1 in 4000 anaesthetics, and higher still if we equate increases in plasma histamine concentrations with the risk of an adverse reaction. The impetus to the assessment and proper management of allergic (either anaphylactic or anaphylactoid) reactions has been highlighted in the United Kingdom by medicolegal arguments following two fatal cases of suxamethonium hypersensitivity [Assem and Ling 1988; Brahams 1989]. The second of these cases occurred in Aberdeen in 1988, and the ensuing debate centred largely on the suggestion of a local law officer that anaesthetists should consider screening all patients on surgical operating lists before elective surgery [Sheriff Kelbie 1989]. This approach (which might appear to be highly sensible) has only recently been made possible through the development of RAST assays for three intrave- nous anaesthetic drugs (thiopentone, alcuronium, and su- xamethonium), although it is not clear how reliable these tests are. Why do we need to worry about allergic reactions? If the rate of anaphylactic reactions in the UK is of the order of 175-800 cases per year, and if the assumed mortality is around 4 %, then a reaction might contribute to between 7 and 32 deaths per year. The editor of this volume, who has long-standing expertise in the pharmacological and immuno- logical evaluation of the aetiology of such reactions, reports a death rate of 2 % among the 130 cases investigated by his de- partment. Allergic reactions to anaesthetic drugs appear to be more common in women. Why might this be? Several suggestions have been proposed. Perhaps we give more anaesthetics (especially with short-acting hypnotics and neuromuscular blocking drugs) to women - but this alone would not explain the female:male ratio of reactions of up to 9:1. Women are subjected to the immunological changes of pregnancy - but are these really significant in the aetiology of this high female incidence? Two more recent explanations are of importance. Women have a high rate of exposure to quaternary ammo- nium compounds, through cosmetics, detergents, and other household chemicals; but if this were the explanation, why do young children get adverse reactions to neuromuscular blocking drugs on first exposure? The second explanation is that quaternary ammonium compounds are widely dis- tributed in nature and that sensitization may therefore occur through exposure to the epitope, leading to 'autosensitiza- tion' and the production of IgG and IgE antibodies. Why do adverse reactions to anaesthetics occur? Al- though their pathogenesis is still not well understood, the clinical features are the results of the release of vasoactive and pro-inflammatory mediators (such as histamine, tryp- tase, leukotrienes, prostaglandin D2) from peripheral blood basophils and tissue mast cells. Marone and Stellato illustrate the three mechanisms by which human peripheral basophils and mast cells can be acti- vated by general anaesthetics, which in turn can induce the synthesis of IgE-specific antibodies against epitopes present on the drug molecule. Anaphylactic reactions can occur by antigen-antibody interactions with high-affinity membrane- bound receptors or by direct activation of mast cells and ba- sophils through non-immunological mechanisms. These may induce the release of vasoactive peptides. A third mechanism is the activation of either classical or alternative complement pathways, with production of the anaphylotoxins C3a, C5a, and C4a. One advance in the evaluation of adverse drug reac- tions has been the assessment of plasma tryptase as a marker of mast cell disruption, rather than the more classical mea- surement of histamine. The latter is difficult to assay and highly labile, in contrast to tryptase, which is stored in cyto- plasmic granules together with histamine. Unlike histamine, tryptase has a longer in vivo half-life (2 h compared with only a few minutes), and it is easier and more reproducible to measure in the laboratory. One area in which the management of allergic adverse re- actions to intravenous anaesthetic agents has progressed is in the development of solid drug phase radioimmunoassays, which allow the detection of specific IgE antibodies to the causative drug in the serum of affected patients. There are several papers in which cross-reactivity between different muscle relaxants and other drugs containing substituted am- monium ions (e.g. neostigmine, promethazine, trimetaphan, and morphine) has been described. However, the three types of assays available (RAST, Sepharose-drug radioimmunoas- says, and QAS [quaternary ammonium Sepharose] radioim- munoassays) are not specific. Should we use RAST as a screening test before anaesthesia and surgery in the allergic patient (Brahams 1989)? This will only be a useful screen if the rate of biological false positives is low ( < 0.1%); present studies show rates up to about 7 % [Reid et al. 1992]. What should we be measuring if the patient suffers an al- lergic reaction? In describing the work of the group from the University of Sheffield, who investigated over 4000 case re- ports during a 17-year period, Watkins makes the following suggestions. Blood samples should be taken sequentially over the 24 h after the reaction and taken into EDTA tubes together with a 24-h collection of urine. From these, white cell numbers and differential count, platelet count, and haemoglobin can be measured. Other basic tests should in- clude immunoglobulin quantification, complement proteins, albumin, haematocrit, tryptase, and histamine and its metabolites. Skin or intradermal testing (favoured by Fisher and col- leagues) appears to have limitations, with poor specificity and sensitivity for some drugs, but extremely useful in the as- sessment of reactions to muscle relaxants. However its true predictive value still needs to be evaluated (with proper determination of sensitivity and specificity). Other chapters cover the immunology of anaesthetic-re- lated liver disease, statistical aspects of preoperative screen- ing for anaesthetic allergens, and the socio-economics of widespread screening. In the final chapter Newdick (a law-
Transcript of Book review
Book review
E. S. K. Assem (ed): Allergic reactions to anaesthetics: clini- cal and basic aspects. Basel: Karger, 1992. 236 pp; (ISBN 3- 8055-5489-3); £ 128.30; DM 353.-; SFr 295.-
The incidence of adverse allergic reactions to anaesthetic drugs is probably increasing. The rate varies from country to country, but is around 0.7 % of all anaesthetics, with a mor- tality rate of 0.05 % [Clarke 1985; Laxenaire et al. 1985]. The incidence of major allergic reactions in Australia has been re- ported to be 1:28 000 anaesthetics in 1970 and 1:5000 in 1981 [Fisher 1982]. However, the overall incidence of reactions to anaesthetic drugs may be as high as 1 in 4000 anaesthetics, and higher still if we equate increases in plasma histamine concentrations with the risk of an adverse reaction.
The impetus to the assessment and proper management of allergic (either anaphylactic or anaphylactoid) reactions has been highlighted in the United Kingdom by medicolegal arguments following two fatal cases of suxamethonium hypersensitivity [Assem and Ling 1988; Brahams 1989]. The second of these cases occurred in Aberdeen in 1988, and the ensuing debate centred largely on the suggestion of a local law officer that anaesthetists should consider screening all patients on surgical operating lists before elective surgery [Sheriff Kelbie 1989]. This approach (which might appear to be highly sensible) has only recently been made possible through the development of RAST assays for three intrave- nous anaesthetic drugs (thiopentone, alcuronium, and su- xamethonium), although it is not clear how reliable these tests are.
Why do we need to worry about allergic reactions? If the rate of anaphylactic reactions in the UK is of the order of 175-800 cases per year, and if the assumed mortality is around 4 %, then a reaction might contribute to between 7 and 32 deaths per year. The editor of this volume, who has long-standing expertise in the pharmacological and immuno- logical evaluation of the aetiology of such reactions, reports a death rate of 2 % among the 130 cases investigated by his de- partment.
Allergic reactions to anaesthetic drugs appear to be more common in women. Why might this be? Several suggestions have been proposed. Perhaps we give more anaesthetics (especially with short-acting hypnotics and neuromuscular blocking drugs) to women - but this alone would not explain the female:male ratio of reactions of up to 9:1. Women are subjected to the immunological changes of pregnancy - but are these really significant in the aetiology of this high female incidence? Two more recent explanations are of importance. Women have a high rate of exposure to quaternary ammo- nium compounds, through cosmetics, detergents, and other household chemicals; but if this were the explanation, why do young children get adverse reactions to neuromuscular blocking drugs on first exposure? The second explanation is that quaternary ammonium compounds are widely dis- tributed in nature and that sensitization may therefore occur through exposure to the epitope, leading to 'autosensitiza- tion' and the production of IgG and IgE antibodies.
Why do adverse reactions to anaesthetics occur? Al- though their pathogenesis is still not well understood, the clinical features are the results of the release of vasoactive and pro-inflammatory mediators (such as histamine, tryp-
tase, leukotrienes, prostaglandin D2) from peripheral blood basophils and tissue mast cells.
Marone and Stellato illustrate the three mechanisms by which human peripheral basophils and mast cells can be acti- vated by general anaesthetics, which in turn can induce the synthesis of IgE-specific antibodies against epitopes present on the drug molecule. Anaphylactic reactions can occur by antigen-antibody interactions with high-affinity membrane- bound receptors or by direct activation of mast cells and ba- sophils through non-immunological mechanisms. These may induce the release of vasoactive peptides. A third mechanism is the activation of either classical or alternative complement pathways, with production of the anaphylotoxins C3a, C5a, and C4a. One advance in the evaluation of adverse drug reac- tions has been the assessment of plasma tryptase as a marker of mast cell disruption, rather than the more classical mea- surement of histamine. The latter is difficult to assay and highly labile, in contrast to tryptase, which is stored in cyto- plasmic granules together with histamine. Unlike histamine, tryptase has a longer in vivo half-life (2 h compared with only a few minutes), and it is easier and more reproducible to measure in the laboratory.
One area in which the management of allergic adverse re- actions to intravenous anaesthetic agents has progressed is in the development of solid drug phase radioimmunoassays, which allow the detection of specific IgE antibodies to the causative drug in the serum of affected patients. There are several papers in which cross-reactivity between different muscle relaxants and other drugs containing substituted am- monium ions (e.g. neostigmine, promethazine, trimetaphan, and morphine) has been described. However, the three types of assays available (RAST, Sepharose-drug radioimmunoas- says, and QAS [quaternary ammonium Sepharose] radioim- munoassays) are not specific. Should we use RAST as a screening test before anaesthesia and surgery in the allergic patient (Brahams 1989)? This will only be a useful screen if the rate of biological false positives is low ( < 0.1%); present studies show rates up to about 7 % [Reid et al. 1992].
What should we be measuring if the patient suffers an al- lergic reaction? In describing the work of the group from the University of Sheffield, who investigated over 4000 case re- ports during a 17-year period, Watkins makes the following suggestions. Blood samples should be taken sequentially over the 24 h after the reaction and taken into EDTA tubes together with a 24-h collection of urine. From these, white cell numbers and differential count, platelet count, and haemoglobin can be measured. Other basic tests should in- clude immunoglobulin quantification, complement proteins, albumin, haematocrit, tryptase, and histamine and its metabolites.
Skin or intradermal testing (favoured by Fisher and col- leagues) appears to have limitations, with poor specificity and sensitivity for some drugs, but extremely useful in the as- sessment of reactions to muscle relaxants. However its true predictive value still needs to be evaluated (with proper determination of sensitivity and specificity).
Other chapters cover the immunology of anaesthetic-re- lated liver disease, statistical aspects of preoperative screen- ing for anaesthetic allergens, and the socio-economics of widespread screening. In the final chapter Newdick (a law-
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yer) discusses the legal liability of the anaesthetist towards the patient who suffers an anaphylactic reaction and con- cludes that 'to prove negligence, the plaintiff would need to adduce experts prepared to say not just that they would not have chosen the treatment in question, but that such treat- ment was negligent, i. e. so at variance with the broad cross- section of current medical opinion that n o reasonable doctor ought to have done it'.
In all, this is a useful volume for the interested expert. It should be used as a reference by all clinical anaesthetists.
References
Assem ESK, Ling BY (1988) Fatal anaphyactic reaction to suxamethonium: new screening test suggests possible prevention. Anaesthesia 43:958-961
Brahams D (1989) Fatal reaction to suxamethonium: case for screening by radioallergosorbent test. Lancet I: 1400-1401
Clarke RSJ (1985) Clinical features and changing trends in hypersensitivity reactions. Ann Fr Anesth R~anim 4: 146- 151
Fisher MM (1982) The epidemiology of anaesthetic anaphy- lactoid reactions in Australasia. Klin Wochenschr 60: 1017-1020
Laxenaire MC, Moneret-Vautrin DA, Vervolet D, Alazia M, Francois G (1985) Accidents anaphilactoides graves peri- anesthesiques. Ann Fr Anesth R~anim 4:30-46
Reid TMS, Imray JM, Noble DW (1992) Anaesthetic allergy and prospective radioallergosorbent testing. In: Assem ESK (ed) Allergic reactions to anaesthetics: clinical and basic aspects. Karger, Basel, pp 162-173
Sheriff Kelbie (1989) Sheriffdom of Grampian, Highlands and Islands: determination given on 9 May 1989 at Aber- deen.
John Sear (Oxford)
