J. Watkins

Adverse anaesthetic reactions. An update from a proposed national reporting and advisory service.

Adverse reactions to intravenous anaesthetic drugs occur at a distressingly high frequency throughout the United Kingdom and the Western world in general. In the UK alone the figure for immediate, anaphylactoid, reactions may be as high as 5000-1 0 000 per annum. Their clinical severity ranges from the trivial to life threatening situations and to death. Despite the magnitude of the problem, the UK lacks a coherent policy for the reporting, investigation and follow-up of the reactions and the yellow card reporting system to the Committee on Safety of Medicines (CSM) is clearly inadequate in this context. An ad hoc service has in the past been supplied from centres in Bristol, Edinburgh and Sheffield. A national advisory service to anaesthetists flourishes in Nancy, France,’ and it was to this end that the setting up of a similar system in the UK was proposed early last year, a t an informal meeting of interested parties. As from October I984 the DHSS Supraregional Protein Reference Unit, Royal Hallamshire Hospital, Sheffield, remains a contact centre but advice is supplied by a consortium comprising Professor R.S.J. Clarke (Belfast), Professor G. Gowland (Leeds), Dr J.N. Lunn (Cardiff), Professor W.S. Nimmo (Sheffield), Dr J. Watkins (Sheffield), and Professor J. Whitwam (London). The service is partially funded by subscriptions from the pharmaceutical industry and we gratefully acknowledge their cooperation. Report from Sheffield

Second report from an anaesthetic reactions advisory service

The continued work of the advisory service is reported; this now amounts to at least 300 enquiries about clinically severe adverse reactions each year. Thiopentone is still the most commonly associated intravenous induction agent with adverse reactions (76%), particularly when it is used with suxamethonium. Local anaesthetics account for between 5 and 10% reports.

Etomidate: an 'immunologically safe' anaesthetic agent.

A review of the important aspects of immunity and its disturbance by drugs is given, together with a resume of the various immunological pathways involved in adverse anaesthetic reactions. Etomidate is unique amongst anaesthetic drugs in that it does not release plasma histamine. Between 1978 and 1982, five cases of possible reactions involving the use of etomidate were investigated. All involved only immediate widespread cutaneous flushing or urticaria, which was followed in two cases by extensive perioperative vomiting. The direct involvement of etomidate was uncertain. In 1982 two further cases were investigated which also involved hypotension. In both, suxamethonium and/or alcuronium had been used. The first case was repeated uneventfully when etomidate was used with pancuronium. The second case is as yet unresolved but the reaction was again probably caused by the muscle relaxants. The absence of severe reactions, and particularly cardiovascular effects, to etomidate leads the author to recommend its use in high risk patients, such as those with allergy or atopy and in those who have previously exhibited severe anaphylactoid responses.

Evaluation of mast cell activation (tryptase) in two patients suffering from drug-induced hypotensoid reactions

Tryptase is predominantly found in mast cells, where it resides in secretory granules, and is released with other mediators during mast cell degranulation. By using a newly developed commercial assay for measurements of tryptase levels we have investigated two cases of suspected drug-induced anaphylaxis. Each patient had a similar clinical presentation, consisting of hypotension and cyanosis after administration of thiopentone and suxamethonium. One of the patients showed a highly elevated serum level of tryptase reaching 26 μg/l 30 min after the initial reaction. In addition, slightly elevated levels of specific IgE antibodies to thiopentone were detected. The other patient with similar symptoms showed no increase in the level of tryptase, nor any specific IgE to thiopentone or suxamethonium. These data indicate the patient I suffered from true anaphylaxis, whereas the reaction of patient II occurred by a different mechanism.

Plasma histamine levels following atracurium

Plasma histamine levels were determined in 41 patients, 1.5 and 4 minutes after the intravenous administration of 0.6 mg/kg of atracurium. Clinical features of histamine release were sought at the time of blood sampling. Sixteen patients had elevation of plasma histamine 2.6 (SD 1.2) ng/ml 1.5 minutes after the injection of atracurium. Plasma histamine had returned to control levels at 4 minutes. There was a poor correlation between plasma histamine levels and the clinical manifestations observed. We conclude that atracurium has a low plasma histamine release potential and that cutaneous reactions after atracurium do not always indicate that plasma histamine levels are elevated.

Immunological and non-immunological mechanisms involved in adverse reactions to drugs

SummaryThis communication reviews the mechanisms involved in anaphylactic and anaphylactoid reactions to intravenous drugs used in anaesthesia. Although the mechanisms involved are pertinent to other drugs and substances used in clinical practice, the use of the intravenous route makes this a particularly worrying problem in anaesthetic practice. Despite the similarity of the clinical manifestations to those expected from immediate immunological hypersensitivity (anaphylaxis), relatively few reactions involve antibodies. Instead, a variety of mechanisms occur where activation of the blood inflammatory response systems, particularly complement, may be either primary or secondary to activation of the coagulation or fibrinolytic cascades of the blood clotting mechanisms. Immediate anaphylactoid reactions, manifest in the release of vasoactive substances such as histamine, may therefore pose very minor problems compared with coagulation problems arising in the periand post-operative period.It is important to discover the mechanism of all adverse reactions not only if these are to be avoided in the reactants in the future but also because of the necessity for devising suitable prophylactic and therapeutic measures for general use. The practical problems of such investigations are explored with particular reference to the laboratory investigation of subclinical reactions in terms of plasma histamine release and changes in blood leucocyte distribution.ZusammenfassungDieser Beitrag referiert über die beteiligten Mechanismen bei anaphylaktischen und anaphylaktoiden Reaktionen nach intravenöser Gabe von in der Anästhesie verwendeten Arzneimitteln. Obwohl die in Frage kommenden Mechanismen auch auf andere Arzneimittel und Substanzen in der klinischen Praxis zutreffen, macht gerade der Gebrauch der intravenösen Gabe dies zu einem speziellen und beunruhigenden Problem in der praktischen Anästhesie. Trotz der Ähnlichkeit in der klinischen Manifestation im Vergleich zum Soforttyp der immunologischen Reaktion (Anaphylaxie) sind hier nur bei relativ wenigen Reaktionen Antikörper beteiligt. Stattdessen tritt eine Fülle von Mechanismen auf, wobei die Aktivierung der Effektorsysteme des Blutes, speziell des Komplements, entweder primär oder sekundär zur Aktivierung der gerinnungs- oder fibrinolytischen Kaskaden der Blutkoagulationsmechanismen führt. Direkte anaphylaktoide Reaktionen, die sich durch die Freisetzung von vasoaktiven Substanzen wie Histamin manifestieren, stellen sich daher als geringe Probleme dar, verglichen mit den Koagulationsproblemen, die in der peri- und postoperativen Periode auftreten.Es ist wichtig, die Mechanismen all dieser Nebenreaktionen aufzuklären, nicht nur, damit diese bei Reaktanten in der Zukunft vermieden werden können, sondern auch wegen der Notwendigkeit, geeignete prophylaktische und therapeutische Maßnahmen für den allgemeinen Gebrauch zu erarbeiten.Die praktischen Probleme solcher Untersuchungen werden unter besonderer Berücksichtigung von Laboruntersu-chungen subklinischer Reaktionen durch Bestimmung von Plasmahistaminfreisetzung und der Veränderungen der Leukozytenverteilung im Blut erforscht.

Bronchospasm following the use of vecuronium

A case history is presented which records bronchospasm due to vecuronium. Immunological investigations, including basophil degranulation tests, indicated that the bronchospasm was not caused by direct histamine release and was not IgE mediated. It was of interest that intradermal testing gave a positive whealresponse against neuromuscular agents other than those involved in the anaesthetic procedure under investigation. A positive reaction to vecuronium was only obtained when given in a high concentration and accords with the general belief that vecuronium has extremely low potential for histamine release.

Tryptase release and clinical severity of anaesthetic reactions

Plasma tryptase measurements provide a convenient measure of mast cell degranulation and are being increasingly used in the investigation of drug induced anaphylactoid reactions. A study involving 30 patients exhibiting life threatening response to anaesthetic drugs was carried out to explore the limitations of this diagnostic assay. The patients divided into two roughly equal groups “tryptase releasers” and “non-tryptase releasers”, despite having comparable clinical severity. The tryptase releasers showed the more typical manifestations of the anaphylactoid response, predominantly hypotension, and a relationship was apparent between the measured tryptase level and systolic blood pressure (BP). Tryptase levels of>25 ng/ml were associated with unmeasurable BP. In contrast, the non-releasers exhibited acute bronchospasm, either alone or as the initial and predominant clinical manifestation. However, urinary methylhistamine assays indicated that, despite normal plasma tryptase levels, some of these patients had undergone mast cell or basophil degranulation. The importance of measuring both plasma tryptase and urinary methylhistamine to obtain further discrimination of non-tryptase releasing reactions is illustrated by reference to thein vivo behaviour of a mast cell tumour.

The early diagnosis of impending coagulopathies following surgery and multiple trauma

SummaryBlood coagulation problems, either disseminated intravascular coagulation (DIC) or adult respiratory distress syndrome (ARDS) are frequent complications during the recovery of the polytraumatized surgical patient or accident victims. The key to their successful control lies in prompt recognition and aggressive treatment of the disease as soon as it appears. Unfortunately their onset is not usually well defined clinically and success in handling usually depends upon clinical expertise in recognising “high risk” situations coupled with measurements in the haematological laboratory of changes in plasma coagulation factors.It is suggested in this communication that a relatively simple examination of plasma complement profiles in the high risk, intensive care patient, may not only provide early warning of the onset of a coagulopathy but also distinguish the type. Simple tests are described, based on the assessment of plasma complement C5 levels, which have a high predictive value for the onset of ARDS, a disease with few early clinical manifestations and notably lacking in early changes in haematological parameters.In prospective trials complement tests correctly identified 18 patients who later developed ARDS but were no more effective than haematological tests in the identification of 24 patients who subsequently developed DIC.

Report of the symposium

SummaryThe past decades have seen considerable shifts of emphasis in surgical care. The recognition that pus was not laudable, was followed by a realisation that not all complications were inevitable and that prophylaxis could effectively reduce the incidence of most common problems in the post-operative period. As anaesthesia has become safer, it has been possible to embark on more intricate and prolonged procedures and for sufficient time to be available to ensure adequate intraoperative care.These two phenomena have firstly increased the complexity of management in the post-operative period, and have brought this aspect of surgical care more obviously to the limelight. However, many separate disciplines are involved in the care of the patient post-operatively, and the Symposium was organised1 to bring the different groups together to identify the areas of recent development in the different specialities and to integrate the overall care of the individual patient.