Anaesthesia and allergic reactions: factors to take into account

By Cristiano Antonino On Sep 19, 2022

Allergic reactions during anaesthesia are rare but have a significant mortality incidence. Allergic reactions generally occur as a single event, but in a percentage of cases the clinical manifestations recur several hours after the primary event or have a prolonged course beyond 24 hours

Commonly, allergic reactions can be of two types: anaphylactic reactions, which are mediated by IgE immunoglobulins, and anaphylactoid reactions, which are triggered by activation of the complement system.

The former involves the exposure of a subject to an exogenous substance (antigen) that can be of various kinds resulting in the production of IgE immunoglobulins.

IgE reacts with specific receptors present in the membranes of mast cells and basophils.

Subsequent exposure of the patient to the antigen results in interaction with at least two IgE molecules and a series of enzymatic and structural modifications leading to the release of mediators.

The second mechanism involves the activation of the complement system by exogenous substances (drugs, contrast media), or by endogenous substances (tryptase) with the formulation of anaphylottoxins that can directly induce the degranulation of effector cells with a clinical picture of very severe anaphylactic shock: anaphylotoxins in fact release huge quantities of histamine.

Finally, there is a third mechanism that is independent of both IgE and complement, whereby substances such as contrast media, hyperosmolar solutions (mannitol, hypertonic glucosates) and general anaesthetics are themselves directly capable of producing the release of the mediators in question.

The central element from a pathogenetic point of view is the activation of mast cells.

These are a very heterogeneous family of cells that contain numerous molecules such as histamine.

Allergic reactions, what is the incidence in anaesthesia?

Allergic reactions during general anaesthesia vary in frequency between 1/10,000 and 1/13,000 in different countries and in different case series; in 3-9% of cases they are fatal.

Mostly affected are adults between 30 and 50 years of age, mostly females (female/male ratio = 3-4:1).

The frequency with which different drugs used in general anaesthesia lead to allergic reactions varies in different cases.

Myorelaxants are responsible for more than half of anaphylactoid reactions (up to 70%) followed by hypnotics, colloidal plasma substitutes, benzodiazepines and opiates.

Latex, which is implicated in more than 10% of cases, is playing an important role in determining these reactions.

Allergic reactions to curare are mostly severe, predominantly affect the female sex, and are the result of both the non-specific release of mediators and the hypersensitivity mechanism induced by quaternary ammonium ions, antigenic determinants shared by all members of this class of drugs.

The frequency and severity of anaphylaxis to curare can be explained by the structural characteristics of the molecule and the ease of contact with quaternary ammonium ions in the environment (latent acquired sensitisation).

Substances containing quaternary ammonium ions are in fact present in eye drops, antiseptics, laundry detergents, food preservatives and cosmetics.

Hence the possibility of a reaction even to the first anaesthesia.

Certain occupational groups (hairdressers, medical and paramedical personnel, chemists, photographers) are at particular risk of sensitisation.

It has been documented that 80% of those sensitised to muscle relaxants have specific IgE for these drugs even 14 years after a shock.

Factors favouring anaphylactoid reactions under general anaesthesia include

age between 30 and 50 years
prevalence of the female sex;
other intolerances or allergies to drugs and foodstuffs: in curaric shock, allergy to penicillin ascertained and confirmed by intradermal testing or the human basophil degranulation test is common;
individuals intolerant to NSAIDs may present an increased risk of anaphylactoid reactions after taking drugs capable of inducing histamine release;
a food allergy (banana, kiwi, avocado, chestnut) may be associated with latex allergy
anxiety prior to anaesthesia has been reported as a risk factor;
atopy: this is a factor on which there is not yet unanimous agreement. Atopy is judged by many to be a conducive terrain for the non-specific release of histamine, but some authors have concluded that the atopic terrain is not a good predictor of true anaphylaxis and that the medico-legal weight given to this factor is unjustified. Adverse reactions to local anaesthetics have an incidence of 6%, but only 1% of these are sustained by the hypersensitivity mechanism.

How do allergic reactions to anaesthesia manifest themselves clinically?

Severe allergic reactions during anaesthesia may manifest clinically with some fairly characteristic clinical signs, which are

shrimp-red coloured erythema, which first affects the upper chest and face and then generalises. Sometimes the erythema is only noticeable at the injection site or along the course of the vein used for the injection;
oedema affecting the larynx, causing dysphonia and breathing difficulties in the awake patient, and the pharynx, causing dysphagia. In addition to the classic facial localisation, it may affect the tongue, airways, hands or may generalise; sometimes it may be appreciated only on awakening, at the level of the eyelids or lips;
hypotension with tachycardia to the point of shock. Rhythm disturbances appear and cardiac arrest is not an exceptional occurrence. Tachycardia may be considered pathognomonic of anaphylactic shock;
violent headache, loss of consciousness, convulsive seizures;
severe bronchospasm to the point of pulmonary oedema. If anaesthesia has already been induced, there is inability to ventilate the patient in a mask or even after intubation;
sialorrhoea, nausea, vomiting, profuse diarrhoea and abdominal pain. All these signs are actually hardly visible in anaesthesiology: sometimes diarrhoea may appear only on awakening.

How can a laboratory diagnosis be made?

Laboratory tests can be helpful in confirming the diagnostic suspicion.

Since histamine has a half-life in the blood of only a few minutes, other substances to look for are

tryptase, a protease contained in mast cells; its concentration in the blood rises from 30 minutes to 4 hours after the anaphylactic reaction, but can also be present up to 12 hours after the allergic event;
assay of C3 and C4;
urinary methyl-histamine (a breakdown product of histamine) assay.

How are allergic reactions to anaesthesia treated?

Discontinue administration of the suspected drug
Administer 100% oxygen
Infuse crystalloid solutions up to 2 – 3 litres
Administer adrenaline
Administer antihistamine drugs
Hydrocortisone
Beta 2 stimulants
Theophylline if refractory bronchospasm appears
Inotropes in case of shock

What to do in patients who have had an allergic reaction?

There are still unresolved issues such as the identification of those at risk, the identification of the drugs involved and the drugs that can be used with relative peace of mind, the type of anaesthesia to be proposed.

The so-called test ointment procedure must always be avoided, which not only gives false positives and false negatives, but also exposes the patient to high risks.

The Italian Society of Allergology and Clinical Immunology has developed a protocol, which is a good operational and scientific reference to follow.

It is essential to collect anamnestic information, which should concern

previous allergic reactions
anaesthesia protocol adopted;
simultaneous use of other substances;
time of onset of symptoms;
detailed description of symptoms;
treatment practised.

Diagnostic tests, to be carried out when really necessary, can be performed in vitro and in vivo.

IN VITRO TESTS

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At present, they present some problems for reliable diagnostics.

For local anaesthetics there is no laboratory kit available for the detection of serum specific IgE towards

these substances.

In contrast, the detection of specific IgE against quaternary ammonium ions of muscle relaxants is currently possible.

The assay of serum tryptase and urinary methylhistamine is a valuable aid in distinguishing between a mast cell degranulation reaction and other pathogenetic mechanisms, but obviously offers no possibility of identifying the molecule responsible for the adverse event.

LIVE TESTS

They comprise a skin test at scalar dilutions which may be followed by a tolerance test characterised by administering increasing amounts of the drug.

There has long been debate about the predictive value of preoperative screening using skin tests to identify individuals at risk of an anaphylactic reaction, particularly with regard to muscle relaxants and latex.

The most recent data seem to suggest that systematic screening for muscle relaxants and latex is not advisable, but that it is meaningful for latex in a selected group of at-risk subjects (spina bifida carriers, particularly exposed healthcare personnel).

The lack of reliable predictive methods, however, suggests in ‘risk’ cases the implementation of prophylactic measures such as the choice of an appropriate anaesthesia protocol and premedication.