Identification and Quantitation of Hypersensitivity Reactions to Intravenous Anaesthetic Agents

Abstract

SUMMARYIt is not possible to distinguish between direct pharmacological effects and immune-mediated hypersensitivity reactions by clinical observation alone and errors may occur in the absence of laboratory tests. A convenient and simple test is the measurement of plasma complement C3 consumption and conversion in sequential blood samples taken at intervals over the 24 h following an adverse response.Interest in adverse reactions to i.v. anaesthetic agents, particularly those appearing to be related to hypersensitivity, has increased in recent years (Clarke et al., 1975). Reports of reactions to propanidid (Epontol) attributed to hypersensitivity are frequent (Clarke, 1974). Reports of hypersensitivity to thiopentone (Dundee and Wyant, 1974) and methohexitone (Driggs and O'Day, 1972), although fewer than those associated with propanidid, are similar in character. The new steroid anaesthetic, Althesin, has caused a significant number of adverse reactions of the hypersensitivity type (Sutton, Garrett and McArdle, 1974). Unfortunately it is not possible to distinguish readily between direct pharmacological effects and immunemediated hypersensitivity reactions, the latter implying previous sensitization of the patient either to the anaesthetic agent itself or to a cross-reacting antigen. It is important to distinguish the mechanism of the adverse response because (a) the patient may require further anaesthesia at some later date, (b) it affords a critical assessment of the advantages and disadvantages of any new anaesthetic drug and (c) there may be legal implications of death during anaesthesia.Recent investigations have suggested that certain transient changes may occur in the blood of patients who suffer an adverse reaction following the administration of an i.v. anaesthetic agent. Alterations in the concentrations of certain circulating components of the complement system, of immunoglobulin IgE and of white cell numbers have been apparent from serial sampling of blood from such patients (Watkins, Appleyard and Ward, 1975). These changes may be quantitated by simple laboratory techniques. The measurement of consumption and conversion of complement component C3 in sequential blood samples taken over 24 h following an adverse response provides a convenient laboratory assay of the adverse reactions. METHODS Blood samplesVenous blood (5 ml) was collected into a heparinized tube as soon as possible after the onset of the reaction and the time, relative to onset, was noted. Three further heparinized blood samples (5 ml) were collected at convenient times over the next 24 h. A further sample was taken not sooner than 5 days after the event to provide a "base-line" profile of the patient. The plasma was separated from these samples by centrifugation and stored at -20 to -25 °C pending analysis.

Intradermal Testing in the Diagnosis of Acute Anaphylaxis during Anaesthesia — Results of Five Years Experience

“…Leucocyte challenge tests (Dundee et al 1974) and basophil degranulation tests (Fox, Wilson and Rabow 1971) have been used but require special expertise and may also be susceptible to error due to direct histamine release. Changes in serum complement have been used to identify the nature of the reaction Thornton 1976) but these changes give no help as to the drug responsible.…”

Immune-Mediated Reactions to Althesin (Alphaxalone)

“…Subsequently, these antibodies liberate histamine in immune-mediated immediate hypersensitivity reactions without the intervention of complement. However, complement conversion is a feature of the observed anaphylactic responses to Althesin (Watkins et al, 1976). This may be explained by the production of non-IgE anaphylactic antibodies which utilize complement (Parish, 1970), or by a secondary mechanism involving complement directly.…”

“…Total complement C3 and C4 was assayed immunochemically. The degree of C3 conversion in samples was assessed by two-dimensional immuno-electrophoresis (Laurell, 1965;Watkins et al, 1976).…”

“…Of 30 patients who had exhibited a hypersensitivity type of reaction to i.v. anaesthesia and who were referred to us for investigation, only nine could be characterized as showing immune-mediated responses, and only one a pharmacological response (Watkins et al, 1976). It seemed that an understanding of the mechanisms of the adverse reaction was more likely to arise from detailed experiments with Althesin on a single healthy volunteer than from a random study of patients examined retrospectively.…”

Histamine in Anaesthesia and Surgery: Causality Analysis

“…The two predominant features of his studies were the classification of reaction mechanisms underlying the adverse reactions (four practical "baskets" into which the reactions could be "distributed" after analysis of blood cells, antibodies, complement factors and sometimes plasma histamine) and the development of a nationwide analysis and advice system for hospitals and pharmaceutical companies (NAARAS, National Adverse Anaesthetic Reactions Advisory Service) (WATKINS and LEVY 1988). The work started with a year-by-year analysis of all cases and blood samples sent to the Hallamshire Hospital by doctors in the Midlands of England (WATKINS et al 1976a(WATKINS et al ,b, 1978(WATKINS et al , 1981WATKINS 1979WATKINS , 1981aWATKINS ,b, 1982WATKINS and THORNTON 1982). It was enlarged by a carefully conceived network between these adverse reactions and other neural, humoral and immunological responses during anaesthesia and trauma including such common and severe diseases as disseminated intravascular coagulopathy (DIC) , adult respiratory distress syndrome (ARDS), thromboembolism and tissue oedema (WATKINS 1981a,b;WATKINS and THORNTON 1982;WATKINS and SALO 1982;.…”