Allergy to Anaesthetic Agents

The occurrence of anaphylaxis during general anaesthesia is a major concern, because there is a lack of relevant information on which to base strategies for diagnosing and preventing anaphylaxis and its recurrence. All of the anaesthetic drugs currently used during anaesthesia are able to trigger allergic reactions.

Early studies on the mechanisms of anaphylaxis during general anaesthesia focused on the nonspecific release of histamine as a pharmacological effect of hypnotic agents. Only during the 1970s did attention begin to be paid to immunological mechanisms, such as IgE-dependent allergic reactions, and the role of neuromuscular blocking agents (NMBAs) in perioperative anaphylaxis. It is important to be able to determine the cause of the reaction and to determine the appropriate measures for treatment and subsequent prevention.

Epidemiology

Allergic and nonallergic anaphylaxis that occurs under anaesthesia is a significant cause of perioperative morbidity and mortality. These may be allergic or immunologic (IgE, IgG, and immune-complex mediated) or nonallergic (chemically mediated or nonimmunologic) reactions. Most allergic reactions are IgE mediated.

Relatively more anaphylactic reactions occur during general anaesthesia in France, Australia, New Zealand and the United Kingdom (UK) than in most other countries, including Sweden, Denmark and the USA. It is therefore natural that researchers in France, Australia, New Zealand and the UK have been pioneers in this field of research, and that diagnostic centers and networks for this specific purpose, where anaesthesiologists and allergologists cooperate on follow-up examinations, have primarily been established in these high-prevalence countries.

Studies from Australia, France and the UK indicate that, when all mechanisms are included, the incidence of adverse perioperative reactions to anaesthesia is about 1/3,500 procedures. Anaphylactic reactions to anaesthesia and associated agents used during the perioperative period have been variably recorded depending on the country and the mechanisms involved. The estimated incidence of anaphylaxis is 1/10,000 to 1/20,000 in Australia and 1/13,000 in France. The incidence of anaphylaxis to NMBAs is 1/6500 anaesthetic episodes. Although rare, these episodes may lead to death even when appropriately treated. In Japan between 1952 and 1990, 4.7% of the 105 reported cases of anaphylaxis to anaesthesia resulted in death. Perianaesthetic anaphylactic reactions continue to account for non-negligible mortality rates ranging between 3% and 5%; the morbidity rates have not yet been assessed. The latest French national epidemiological survey (conducted from January 2001 to December 2002) reported that, of patients who experienced anaphylaxis, 69% were diagnosed with allergic anaphylaxis and 31% with nonallergic anaphylaxis. In Norway, the results of a 6-year study showed that 1 allergic reaction to NMBAs occurred per 5,200 anaesthesias performed where NMBAs had been administered, and that allergic reactions to NMBAs accounted for 66.2% of all allergic reactions to anaesthesia recorded. For rocuronium, the Norwegian Medicines Agency in 2001 estimated a frequency of 1 in 5,000, a rate more than 20-fold higher than in the rest of Scandinavia. This disparity may be due to previous exposure to pholcodine, an ingredient in cough syrups that is widely used in France, Norway, the UK, New Zealand and Australia, but not in Sweden, Germany, the USA and Denmark. The mechanism by which pholcodine use may predispose to anaphylactic reactions to NMBAs will be discussed further below.

Physiopathology

IgE-mediated anaphylaxis
The epitope of NMBAs recognized by IgE antibodies is the quaternary or tertiary ammonium ion. Cross-sensitization between NMBAs is seen in up to 70% of patients allergic to one NMBA, primarily between NMBAs including at least two quaternary ammonium ions. In addition, this cross-allergy most often occurs between NMBAs of the same chemical group, for example, between aminosteroids (pancuronium, vecuronium, rocuronium), between benzylisoquinones (atracurium, mivacurium, cisatracurium), or between suxamethonium and other NMBAs. Several explanations could account for these non systematic cross-reactions: the antigen recognized by the IgE antibodies may not be strictly identical, and in some cases not only the quaternary ammonium but also the phenyl groups surrounding it may be involved; the affinity between the IgE antibodies and the quaternary ammonium may differ from one NMBA to another; and the flexibility and the length of the chain linking the 2 quaternary ammonium ions may also play a triggering role in an allergic reaction. An NMBA with a rigid backbone between the two ammonium ions (e.g., pancuronium and vecuronium) appears to be less likely to initiate anaphylaxis than a flexible NMBA molecule such as suxamethonium. Furthermore, the distance between the two quaternary ammonium epitopes has to be between 6.2 Å and 10.4 Å to induce binding. Thus, any two NMBAs will not necessarily behave in the same way with regard to inducing reactions.

Epitopes other than ammonium have been implicated in IgE-mediated anaphylaxis to other general anaesthetics. The antigenic determinants on thiopental are the pentyl and ethyl groups attached to position 5 on the pyrimidine ring nucleus and the secondary region of the ring, encompassing and including the attached hetero atom. The antigenic determinants on propofol are the two isopropyl groups; propofol induces true allergy in few patients, and the previously high incidence of adverse reactions decreased greatly when other solvents were substituted for cremophor EL, suggesting that it was the solvent rather than propofol itself that caused the reactions. Other hypnotics such as etomidate or ketamine have been reported to cause perioperative allergic reactions only rarely. Allergenic determinants identified on morphine encompass the N-methyl group and the cyclohexenyl ring with a hydroxyl at C6. Cross-reactivity between morphine, codeine and other narcotics has been alleged.

Nonallergic anaphylaxis
Whereas NMBAs, opiates and hypnotics may all cause an immunologic reaction shortly after induction, chemically mediated histamine release is far more likely to occur. It may be impossible to distinguish a true allergic event from chemically mediated release, as some drugs can cause reactions via both mechanisms. Nonspecific histamine release may also be facilitated by the presence of an atopic disease or the speed at which the product is injected. The symptoms in response to a nonspecific histamine release are generally less severe than when an allergic reaction is involved.

Clinical Manifestations

The clinical manifestations of anaphylaxis are classified into five grades of severity: Grade I: mild, self-limiting reactions, e.g., isolated skin symptoms; Grade II: moderate reaction quickly responding to therapy, e.g., hypotension or bronchospasm or multivisceral symptoms; Grade III: severe reactions requiring prolonged treatment, e.g., anaphylactic shock; Grade IV: cardiac and respiratory arrest; Grade V: death. These signs can occur at any time; however, in 80% to 90% of cases, they occur at the induction of general anaesthesia, 5 to 10 minutes after the drugs have been injected. There are often very few clinical symptoms; the fact that the anaphylactic reaction can consist of a single symptom often results in anaphylaxis being overlooked as a diagnosis. The absence of cutaneomucosal signs does not necessarily make it possible to rule out the diagnosis of anaphylaxis; however, the clinical manifestations of immunological reactions are more serious and long-lasting than those of pharmacological reactions. The results of the last epidemiological study (a 2-year survey, 2001-2002) on the incidence of anaphylaxis during anaesthesia, conducted by Laxenaire in France, confirmed the particular severity of allergic adverse reactions compared to non-allergic reactions (p<0.001).

In the milder cases, spontaneous improvement can occur without any specific treatment. However, when in doubt, the anaphylactic reaction should be treated with appropriate doses of epinephrine based on its severity. In cases where the diagnosis has not been properly made and appropriate allergological tests have not been carried out, subsequent exposure is liable to have serious or even lethal consequences. It is up to the anaesthesiologist and the surgeon, depending on the risk/benefit of proceeding with surgery, as to whether it should be continued or discontinued.

Substances Responsible

Substances responsible for anaphylaxis
Since 1980, more than 4,500 cases of perianaesthetic anaphylaxis have been reported by French and English authors. The drugs most frequently responsible for anaphylactic reactions in the French epidemiological survey were NMBAs (54%), latex (22.3%), antibiotics (14.7%), opioid agents (2.4%), hypnotic agents (0.8%), colloids (2.8%) and others (3%). Thus, although NMBAs are responsible for most cases, hypnotic agents or an antibiotic administered for preventive purposes have occasionally been implicated. When the reactions occurring during anaesthesia have not been due to the drugs injected, latex has almost always been to blame. Other substances such as aprotinin, protamine, ethylene oxide, and chlorhexidine have sometimes also been incriminated. Very few truly allergic accidents have been caused by local anaesthetics. Among the cases of anaphylaxis attributed to NMBAs in the literature, the following substances have been incriminated, in decreasing order of importance: suxamethonium, vecuronium, atracurium, pancuronium, rocuronium, mivacurium and cisatracurium. When interpreting these data, it is necessary, however, to take changes in the market shares of each of the products in question into account. If one expresses the number of reactions observed in terms of the number of subjects exposed to NMBAs, the drugs can be divided into 3 groups: those associated with a high frequency of allergic reactions, including suxamethonium and rocuronium; those associated with an intermediate frequency of allergy, including vecuronium and pancuronium; and those associated with a low frequency of allergy, including atracurium, mivacurium and cisatracurium.

Table 1: Clinical signs: grade of severity

Substances responsible for non-allergic anaphylaxis
It is difficult to definitively identify the drugs responsible for nonspecific histamine release because there are no specific tests available. Among the NMBAs, atracurium and mivacurium are histamine-releasing drugs, whereas cisatracurium seems to be practically devoid of histamine-releasing effects at the doses usually administered. Nonspecific histamine-releasing effects have been observed with thiopental and propofol in response to the injection of high concentrations of these substances. Reactions to opioids (morphine, pethidine and codeine) are usually caused by a direct mast cell mediator rather than by IgE-dependent mechanisms.

Risk Factors

Sex and age
A significant female predominance has been reported, with a range from 8 females:1 male for NMBAs to 2.7 females:1 male for thiopental. Although it remains to be determined why female sex is a risk factor for an allergic reaction, a hypothesis has been put forward to explain why this occurs with NMBAs. The quaternary ammonium responsible for this particular allergy is present not only in NMBAs but also in cosmetics and some household cleaning products. The fact that women come into contact with these products more frequently than men or children might explain why women are more likely to have anaphylactic reactions. The preponderance of women is the same for all NMBAs, and age does not affect the incidence of reactions to NMBAs. Perioperative allergic reactions rarely occur in children, and most that do occur are caused by latex.

Atopy
It has been generally agreed that atopy is a risk factor for allergic reactions because case reports of perioperative allergic reactions have reported a high prevalence of atopy. However, these studies used many definitions of atopy, including a range of symptoms from urticaria and contact dermatitis to asthma, making the use of the term “atopy” unreliable. The authors of more recent studies have defined atopy more exactly, using criteria such as the presence of at least one positive skin test and/or the presence of IgE antibodies against at least one aeroallergen. With this definition, the prevalence of atopy was identical between subjects who experienced at least one allergic perioperative reaction due to NMBA and control subjects. Similar findings were obtained for other anaesthetic agents. Although atopic asthma does not seem to constitute a risk factor for anaesthetic allergy, the presence of asthma in childhood is twice as frequent among patients who have had perioperative allergic reactions as those who have not.

Drug allergy and food allergy
Food allergies and allergies to drugs not related to anaesthesia are not risk factors for anaphylaxis.

Previous anaesthesias
There is no evidence that multiple anaesthesias promote sensitization to a given anaesthetic. However, if an allergy has developed during a previous anaesthesia, anaphylaxis is bound to occur if a subsequent anaesthesia is performed using the same product.

More than half of patients who have perioperative anaphylactic reactions to NMBAs had never previously received NMBAs, suggesting that they had been sensitized by some other substance containing quaternary ammonium epitopes. One study showed that cough syrups containing pholcodine induce the production of specific IgE antibodies against the quaternary ammonium ions that are responsible for subsequent anaphylactic reactions to NMBAs. Previous exposure to pholcodine might therefore explain why the patterns of sensitization differ so greatly between the populations of various countries: pholcodine is widely used in France, Norway, the UK, New Zealand and Australia, where many allergic reactions involving NMBAs have been recorded, whereas little use is made of this substance in Sweden, Germany, the USA and Denmark, where very few allergic reactions of this kind have been reported to occur.

Previous exposure to thiopental is a risk factor. Up to 90% of allergic reactions to thiopental occur in patients with previous exposure.

Diagnosis of a Perioperative Anaphylactic Reaction

Patients showing symptoms of an anaphylactic reaction should immediately be given biological tests followed by a secondary check-up in order to determine whether the accident was due to an IgE-dependent immunological mechanism, to identify the agent responsible and to establish whether cross-sensitization is involved in those cases where an NMBA was responsible for the anaphylactic response.

Immediate investigations
The immediate tests include circulatory serum tryptase and plasma histamine determinations in order to establish whether anaphylaxis has occurred, and testing for specific IgE antibodies in order to identify the agent responsible. High tryptase levels strongly suggest that the reaction was immunological. However, normal findings do not necessarily rule out an immunological reaction. The search for IgE antibodies in the patient’s serum focuses mainly on NMBAs, thiopental and latex. The level of determination of IgE antibodies against NMBAs, by CAP-RAST is not very sensitive (with suxamethonium, its sensitivity is only 66%), so other more sensitive methods such as the QAS-RIA (quaternary ammonium sepparose-radioimmunoassay) and PAPPC-RIA (p-aminophenylphosphoryl-choline-radioimmunoassay) methods are usually preferred. Other tests for specific IgE have also been developed, focusing mainly on morphine, phenoperidine and propofol, but these tests are not available for use in clinical practice

Secondary investigations
All of the drugs administered before and during anaesthesia, as well as their time of administration with respect to the reaction, should be noted. The clinical findings provide indispensable information for investigating the causes of anaphylactic reactions, especially if secondary investigations are needed.

Skin tests
All the substances administered during the perioperative period should be assumed to be potentially responsible, and skin tests should be carried out, where possible, with all the drugs used in the anaesthetic procedure, as well as with latex and any other drugs or products administered during the anaesthesia, apart from agents administered by inhalation.
The excellent overall performance of skin tests makes them the gold standard for diagnosis of anaphylactic reactions. These tests, which include intradermal tests and prick-tests, should ideally be performed 5 to 6 weeks after the reaction. If necessary, skin tests can be performed earlier, but if the results are negative, they will require subsequent confirmation. The skin tests are usually performed on the forearm. The concentrations recommended below provide low numbers of false negatives and false positives.

Skin tests for NMBAs:
Prick-tests can use commercially available concentrations of NMBAs, except for mivacurium and atracurium, which must be tested at a 1:10 dilution. For intradermal tests, a dilution series is used starting with a 1:10,000 dilution and increasing the concentration up to the highest level that usually does not produce a reaction in nonallergic individuals (100 µg/ml for succinylcholine, 10 µg/ml for atracurium, 2 µg/ml for mivacurium, 200 µg/ml for pancuronium, 400 µg/ml for vecuronium, 100 µg/ml for rocuronium and 20 µg/ml for cisatracurium). The specificity and the sensitivity of the skin tests are greater than 95%, and the reproducibility over one year is 88%. The overall concordance of prick-tests and intradermal tests is 97%. When the result of a skin test with one NMBA is positive, it is necessary to perform intradermal tests in order to determine whether any cross-sensitization has occurred with other NMBAs available on the market. Eighty-four percent of patients do have cross-sensitization to NMBAs, but only 16% react to all NMBAs.

Skin tests for hypnotics:
True allergic reactions to thiopental have been identified by positive skin tests and by serological detection of specific IgEs by RAST. However, technical difficulties including nonspecific binding, the poor solubility of thiopental at physiologic pH, and the low sensitivity of the test, make the use of RAST in clinical practice inefficient. At high pH, binding of thiopental to the immunoabsorbent material can generate substituted ammonium ions that are normally internalized within the thiopentone molecule. Specific IgEs against quaternary ammonium ions in subjects sensitive to NMBAs can bind these substituted ammonium ions and simulate sensitivity to thiopentone.

Commercial concentrations of thiopental can be used in prick-tests. For intradermal tests, using a range of concentrations is advised, starting with a 1:10,000 dilution up to a 1:10 dilution of the commercial concentration, which is not reactive in nonallergic individuals. Skin tests are also used to diagnose anaphylaxis to opioid agents, using the same scale as for hypnotics. The commercial drug concentration of opioids is 10 mg/ml. Intradermal skin tests with morphine are performed from 0.001mg/ml to 0.01mg/ml. If patients are tested with a concentration above 0.01mg/ml (0.1mg/ml for example), a false positive skin test (a non-specific positive test) may be evoked.

Table 2: Concentration of anaesthetic agents normally non-reactive on skin testing

Determination of specific IgE antibodies
IgE antibodies persist over time, and testing for IgE antibodies can be carried out after a delay if it was not done at the time of the reaction, or if the results of skin tests are negative. Determining whether specific IgEs to NMBAs, thiopental and latex are present can be useful for interpreting negative or inconclusive skin tests in patients whose clinical findings suggest that they have had anaphylactic reactions. The most sensitive tests should preferably be used here. Skin tests for NMBAs are more sensitive than specific IgE determinations, but the sensitivity of the latter method can be improved by using the QAS-RIA and PAPPC-RIA methods. Skin tests for hypnotic drugs are more reliable than searching for a specific IgE. Specific IgE antibodies have less specificity for propofol than for the quaternary ammonium present in the lecithins in solution. Specific IgEs to opioids are known, making the identification of specific IgE antibodies a reliable way to diagnose anaphylaxis to opioid agents.

Other tests
The histamine-releasing leucocyte test is an expensive method that is tricky to handle and is not recommended as an initial approach. This method can provide a useful means of looking for a reaction induced by a drug when no specific IgE findings are available, or for studying the cross-reactions between NMBAs when a previously sensitized patient is due to undergo anaesthesia. The clinical value of the flow cytometry basophil activation test still remains to be confirmed in practical clinical settings.

Predictive Tests

In order to predict which patients might experience anaphylaxis, it is essential to be able to determine the risk factors involved. Patients at risk of perioperative anaphylaxis are those who are allergic, as established by performing proper allergological tests, to any of the drugs to be administered during anaesthesia or other products to which they are liable to be exposed, as well as those who have had a reaction during a previous general anaesthesia that remains unexplained. For those who have had a reaction during a previous anaesthesia, the anaesthetic protocol used during that anaesthetic episode will be very helpful for the allergologist in carrying out a thorough assessment. If the protocol cannot be found, the allergologist will have to test the substances that epidemiological studies have found most frequently cause reactions: all the NMBAs and latex. In patients who are allergic to NMBAs, cross-sensitivity to all other NMBAs must be tested, because the patient may not be allergic to all of them. If that is the case, it is important to know which NMBAs can be used in the anaesthetic protocol.

It is impossible at this time to predict anaphylaxis by simply testing all patients with NMBAs prior to anaesthesia. The prevalence of NMBA sensitization evaluated by either a positive prick test or by specific IgE to quaternary ammonium ions in a serological assay has been rated at 9.3% among the general population, and at the same time, there is a 1.4% risk of anaphylaxis occurring among previously sensitized subjects. If the incidence of anaphylaxis to NMBAs is 1/6500 anaesthetic episodes, 6500 patients would have to be tested to be able to detect one allergic patient, while 585 sensitized patients (9%) would be detected who will never develop anaphylaxis.

Presently, no data are available to confirm the predictive value of skin tests for anaphylactic reactions, so systematic screening of the general population is not recommended. It is of no help to carry out an allergologic assessment in patients who are only allergic to a nonanaesthetic drug or who are atopic without having any other risk factor for sensitivity to anaesthetic agents. Furthermore, even if predictive assessments were possible, they would not prevent nonspecific histamine release in response to anaesthetics administered in the future.

References

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