Allergy to Anesthetic Agents
Updated: May 2013
Originally posted: October 2007
Reviewed by: Mario Sánchez-Borges, MD
Mertes Paul Michel, MD, PhD. Pôle Anesthésie, Réanimations Chirurgicales, SAMU, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (Prof. Mertes is the Corresponding Author)
Demoly Pascal, MD, PhD. University Hospital of Montpellier, Département de Pneumologie, INSERM U657, Hôpital Arnaud de Villeneuve, France
Stenger Rodolphe, University Hospital of Strasbourg, Service d'Allergologie, Nouvel Hôpital Civil, France
Anesthesia represents a pharmacologically unique situation, during which patients are exposed to multiple foreign substances including anesthetics, analgesics, antibiotics, antiseptics, blood products, heparin, polypeptides, and intravascular volume expanders, which can produce immediate hypersensitivity reactions or anaphylaxis.
Since no preemptive therapeutic strategies exist, both vigilance of the attending clinicians to rapidly recognize and treat these reactions and subsequent allergological investigations to identify the offending agent and prevent recurrences, are of critical importance.
Immediate hypersensitivity reactions can be either immune mediated (allergic) or non-immune mediated (pseudoallergic or anaphylactoid reactions)1. They have been recognized as one of the most common causes of morbidity and death in anesthesiology practice.
Several variations have been reported regarding the incidence of these reactions between countries, probably reflecting differences in clinical practice and reporting systems, but also because of the possible influence of multiple environmental factors2,3.
Nevertheless, over the last decades, a long term policy of systematic clinical and/or biological investigation of immediate hypersensitivity reactions carried out in France, the United Kingdom, New Zealand and Australia, Denmark and Norway has produced a relatively coherent view of the epidemiology of these reactions.
The estimated incidence of immediate hypersensitivity reactions from all mechanisms ranges from one in every 1,250 to 10,000 anesthetics4.
In most series, allergic reactions represent at least 60% of all hypersensitivity reactions observed within the perioperative period. Recently, a combined analysis of 3 different French databases, using a capture-recapture method has allowed a nationally based estimate of the incidence of immediate IgE-mediated allergic reactions occurring during anesthesia, stratified according to sex, age, and causal substance. This report has confirmed the general view that immediate-type hypersensitivity reactions are largely underreported, with the incidence of allergic reactions being estimated at 100.6 [76.2-125.3] per million procedures5. A significant female predominance is also usually observed, the estimated incidence reaching 154.9 (117.2-193.1). The expected mortality rate ranges between 3 to 9%, whereas overall morbidity remains unknown6, 7.
Structure-activity studies designed to explore the molecular basis of specific IgE binding of neuromuscular blocking agents have established that quaternary and tertiary ammonium ions were the main component of the allergenic sites on the reactive drugs 8.
However, differences have been observed regarding the risk of allergic reactions with the different NMBAs. In addition, cross-sensitization among the different agents has been reported to be frequent, but not constant, varying between 60 and 70 % of patients allergic to neuromuscular blocking agents. The patterns of cross-reactivity vary considerably between patients. Cross-reactivity to all NMBAs is relatively unusual, but seems to be more frequent with aminosteroid neuromuscular blocking agents than with benzylisoquinoline-derived neuromuscular blocking agents4, 9.
To explain these differences it has been suggested that the flexibility of the chain between the ammonium ions as well as the distance between the substituted ammonium ions might be of importance during the elicitation phase of IgE-mediated reactions. Flexible molecules, such as succinylcholine, were considered more potent in stimulating sensitized cells than more rigid molecules. Another possible hypothesis is that the antigenic determinant may extend to the adjacent part of the molecule. IgE antibodies could also be complementary to structures other than the ammonium group.
This can be the case for the propenyl ammonium groups present in rocuronium and alcuronium4, 9. Epitopes other than ammonium have been implicated in IgE-mediated anaphylaxis to other general anesthetics. Two antigenic determinants have been identified in the thiopentone molecule. These are the secondary pentyl and ethyl groups attached in position 5 of the pyrimidine ring nucleus and the thiol region, on the opposite side. Thiopentone-reactive IgE has been found in the sera of some subjects allergic to muscle relaxants, but not to thiopentone. The antigenic determinants on propofol are the two isopropyl groups. The antigenic determinant on morphine comprises the methyl-substitute attached to the N-atom and the cyclohexenyl ring with a hydroxyl group at carbon-6. Cross-reactivity between morphine, codeine and other narcotics has been reported.
The precise mechanisms of non-immune-mediated reactions remain difficult to establish. They are usually considered to result from a direct pharmacological stimulation of mast cells and basophils, causing release of inflammatory mediators. However, other mechanisms may be involved 10,11. Non-allergic anaphylaxis does not entail an immunological mechanism and, therefore, previous contact with the culprit substance is not necessary. Nonspecific histamine release may 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 show striking variations of intensity in different patients (Table 1). The onset and severity of the reaction relate to the mediator’s specific end organ effects. The difference between immune or non-immune-mediated reactions cannot be made on clinical grounds alone. Antigenic challenge in a sensitized individual usually produces immediate clinical manifestations of anaphylaxis, but onset may be delayed especially when dyes are concerned.
Table 1: Grade of severity for quantification of immediate hypersensitivity reactions
Anaphylactic reactions commonly involve the skin, cardiovascular and respiratory systems, and virtually any system, including the gastrointestinal, central nervous and genitourinary systems. However, these features may occur as a single condition. Therefore, an anaphylactic reaction restricted to a single clinical symptom (e.g. bronchospasm, tachycardia) can easily be misdiagnosed because many other pathophysiological conditions may have identical clinical manifestations. Under such circumstances, in the absence of appropriate allergologic assessment, subsequent re-exposure is liable to have serious or even lethal consequences.
There is a wide array of reaction severity and responsiveness to treatment. The cornerstones of treatment are epinephrine and fluid therapy12. In grade I reactions, spontaneous improvement can occur without any specific treatment. In more severe cases, the anaphylactic reaction should be treated with appropriate doses of epinephrine and fluid infusion based on its severity and on clinical response.
The use of a large diversity of vasopressors and inotropes such as noradrenaline, vasopressin, methylene blue or glucagon has been proposed when initial resuscitation with epinephrine and fluids are not successful13.
Several recent case reports suggest that administration of sugammadex, a chemically modified gamma-cyclodextrin used for rapid reversal of rocuronium-induced neuromuscular blockade might be useful in mitigating rocuronium-induced anaphylaxis14, 15. However, several theoretical and experimental objections to the likelihood of an allergen-binding agent being able to attenuate the immunological cascade of anaphylaxis have been raised16-18. On the contrary, allergic reactions to sugammadex have also been reported19.
If the efficacy of sugammadex is further confirmed, the possibility of encapsulating and removing other allergenic drugs should be considered as a new therapeutic approach in cases of intractable anaphylaxis.
Substances responsible for IgE-mediated anaphylaxis.
Every agent used during the perioperative period may be involved. Neuromuscular blocking agents (NMBAs) represent the most frequently incriminated substances ranging from 50 to 70% 2. Among NMBAs, 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 into account the market shares of these drugs. 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.
The frequency of allergic reactions to latex largely depends on the local prevention policy applied in each institution. Reactions involving antibiotics have rapidly increased in the last decade, reflecting the increasing prevalence of allergy to these drugs in the general population as well as their increased use in perioperative antibiotic prophylaxis. Hypnotic agents, opioids, colloids, aprotinin, protamine are less frequently incriminated, whereas cases involving dyes, chlorhexidine, have been reported with increasing frequency. Allergy to local anesthetics is rarely reported.
Substances responsible for non-allergic anaphylaxis
It is difficult to definitively identify the drugs responsible for non-IgE mediated reactions because there are no specific tests available. Among the NMBAs, atracurium and mivacurium are histamine-releasing drugs, whereas cisatracurium seems to be practically devoided of histamine-releasing effects at the doses usually administered. Nonspecific histamine-release has been observed with thiopental, morphine and vancomycine in response to the injection of rapid high concentrations of these substances. An increased number of reactions involving non-steroidal anti-inflammatory drugs (NSAIDs) used during multimodal analgesia are also reported.
Sex and age
A significant female predominance has been reported in all series. However, in children, the various incriminated substances differ significantly from those for adult patients, with a sex/ratio of 15. This provides a very attractive hypothesis to explain the female predominance in adults. The similar incidence of allergic and non-allergic reactions according to gender before adolescence strongly suggests a role for sex hormones in the increase of immediate hypersensitivity reactions to low-molecular-weight compounds observed in women after puberty.
Atopy has long been considered as a risk factor for sensitization to muscle relaxants, in light of the high number of atopic patients found in early studies of anaphylactic shock during anesthesia. However, when investigating atopy as a risk factor using specific immunological tests, it does not appear to be a significant risk factor for muscle relaxant sensitivity. Nevertheless, one should keep in mind that basophils of atopic patients release histamine more readily. Therefore, it could be a risk factor for histamine release in case of administration of known histamine-releasing drugs. In addition, atopic patients with asthma or allergic rhinitis to grass or weed pollens could have a cross-sensitivity to latex, and a significant number of atopic patients are reported in series examining latex sensitization. Therefore, atopy is usually considered as a risk factor for peranesthetic allergic reactions to latex.
Drug allergy and food allergy
Allergies to drugs not related to anesthesia are not risk factors for anaphylaxis. On the contrary, any unexplained life-threatening reaction during a previous anesthesia might be an allergic reaction, and as such is a major risk factor for another reaction if the responsible drug is re-administered.
Food allergies have not been recognized as a risk factor with the exception of patients allergic to tropical fruit (especially avocado, banana, and kiwi) because of the cross-allergy with latex.
More than half of patients who have perioperative anaphylactic reactions to NMBAs had never previously received NMBAs9. This suggests a possible cross-reaction with IgE antibodies generated by previous contact with apparently unrelated chemicals. This is a particularly attractive hypothesis in cases where patients react to relatively small and ubiquitous epitopes such as a substituted ammonium group. Indeed, these structures occur widely in many drugs but also in foods, cosmetics, disinfectants and industrial materials. Hence, there would seem to be ample opportunity for sensitive individuals to come into contact with and synthesize IgE antibodies to these unusual, and previously unsuspected, antigenic determinants. However, the hypothesis of the theory of environmental sensitization remains as yet unproven9.
Recently, Florvaag et al. pointed out that anaphylaxis to NMBA was 6 times more common in Norway than in Sweden. They suggested that this difference could be due to differences in preoperative sensitization in relation to pholcodine consumption3. They reported that during the 1970s and 1980s cough syrup containing this drug was available in Sweden whereas IgE antibodies to pholcodine were present in 5 to 6% of sera collected during the same time period. No positive sera were found since 2005 following its withdrawal from the market. They also reported that the number of cases of anaphylaxis to NMBAs was high in the 1970s in Sweden, whereas no case was reported after 1990.
They later demonstrated that pholcodine exposure in patients having experienced an allergic reaction to a NMBA was responsible for a significant increase in specific IgEs to NMBAs in patients having experienced an allergic reaction to one of these drugs. This led to the hypothesis that pholcodine exposure could either lead to IgE-sensitization to this drug and other quaternary ammonium ions or increase the titer of specific IgEs to quaternary ammonium ions and thereby increase the risk of allergic reaction to NMBAs. This hypothesis was further supported by the results of an international prevalence study, showing a statistically significant association between pholcodine consumption and prevalence of IgE-sensitization to this drug and to succinylcholine. However, the results also indicate that other, yet unknown, substances may be involved in IgE-sensitization towards NMBAs. Withdrawal of pholcodine from the Norwegian market resulted in the decrease of IgEs to quaternary ammonium ions in the population and in the number of reports of allergic reactions to NMBA20. These results strongly support the need for further epidemiological studies designed to investigate the possible link between pholcodine exposure and hypersensitivity reactions to NMBAs.
Any suspected hypersensitivity reaction during anesthesia must be extensively investigated using combined pre- and postoperative testing. It is important to confirm the nature of the reaction, to identify the responsible drug, to detect possible cross-reactivity in cases of anaphylaxis to a neuromuscular blocking agent and to provide recommendations for future anesthetic procedures. Whenever possible, confirmation of the incriminated allergen should be based on immunological assessment using more than one test. In the event of discrepancies between different tests, an alternative compound that tested completely negative is advocated.
The diagnostic strategy is based on a detailed history including concurrent morbidity, previous anesthetic history and any known allergies, and on a series of investigations performed both immediately and 4 to 6 to weeks later.
Immediate investigations include circulatory serum tryptase and plasma histamine determinations, and specific IgE assays.
The probability that symptoms are linked to an immediate hypersensitivity reaction is increased in the presence of elevated levels of markers such as serum tryptase and plasma histamine. However, normal levels do not absolutely exclude the diagnosis. High tryptase levels strongly suggest an immunological mechanism.
The search for specific IgE in serum is based mainly on quaternary ammonium ions (reflecting IgE to neuromuscular blocking agents), thiopental, latex, chlorhexidine, and occasionally ß-lactams, according to the drugs administered to the patient. Assays can alternatively be performed at the time of the reaction, or at the time of delayed skin test investigation.
In the case of an ultimately fatal reaction, blood samples taken for the determination of tryptase and specific IgE associated with the suspected allergen should preferably be taken before abandoning resuscitation rather than after death. Sampling should be from the femoral area.
Skin tests carried out 4 to 6 weeks after a reaction, combined with history, remain the mainstay of the diagnosis of an IgE-mediated reaction. If necessary, skin tests can be performed earlier, but if the results are negative, they will require subsequent confirmation. They should be performed, when available, with all the drugs used in the anesthetic procedure, as well as with latex and any other drugs or products administered during the anesthesia, apart from agents administered by inhalation. Skin prick-tests (SPT) and intradermal tests (IDT) with dilutions of commercially available drug preparations are advised. Although highly reliable, skin tests are not infallible. Standardized procedures and dilutions have been defined for most agents tested in order to avoid false positive results (Table 2)12. Control tests using saline (negative control) and codeine (positive control) must accompany skin tests. Skin tests are interpreted after 15 to 20 min. A prick test is considered positive when the diameter of the wheal is at least equal to half of that produced by the positive control test and at least 3 mm greater than the negative control. Intradermal tests are considered positive when the diameter of the wheal is twice or more the diameter of the injection wheal.
Table 2: Concentrations of anesthetic agents normally non-reactive in practice of skin tests.
The estimated sensitivity of skin tests for muscle relaxants is approximately 94 to 97 %. Skin test sensitivity for other substances varies. It is optimal for synthetic gelatins, but poor for barbiturates, opioids and benzodiazepines. Latex sensitization must be investigated by prick-tests. Both prick and intradermal tests have been proposed in the literature for the diagnosis of sensitization to blue dyes. However, false negative prick tests have been occasionally reported.
Flow-assisted allergy diagnosis relies on quantification of shifts in expression of basophilic activation markers after challenge with a specific allergen using specific antibodies conjugated with a fluorochrome or a dye. This technique has been clinically validated for several classical IgE-mediated allergies including indoor and outdoor inhalational allergies, primary and secondary food allergies, natural rubber latex allergy, hymenoptera venom allergy and some drug allergies. Although it does not allow differentiating between IgE-dependent and IgE-independent basophil activation, it is anticipated that it might constitute a unique tool in the diagnosis of IgE-independent hypersensitivity reactions as well as for the diagnosis of IgE-mediated anaphylaxis when a specific IgE assay is unavailable.
Although, several methodological issues remain to be addressed, once fully validated, the basophil activation test using flow cytometry will probably represent an interesting diagnostic tool for NMBA anaphylaxis and for cross sensitization studies.
Indications for these tests are limited. They are restricted to local anesthetics, ß-lactams and latex. They should only be performed in case of negative skin tests. Local anesthetics can be tested by subcutaneously injecting 0.5 to 2 mL of undiluted anesthetic solution (without epinephrine). The test is considered negative if no adverse reaction occurs within 30 minutes after injection. Oral provocation tests are useful for the diagnosis of beta-lactam hypersensitivity.
Presently, no data are available to confirm the predictive value of skin tests for anaphylactic reactions, therefore systematic screening of the general population is not recommended, except for patients in recognized risk groups. Group at risk have been identified as follows: (i) Patients who have had an unexplained reaction to an unidentified allergen during previous anesthesia, (ii) Individuals known to be allergic to drug classes that will be used during the anesthetic period and patients at a risk of latex allergy.
Advice to patients
Since the purpose of investigations is to identify the drug or substance responsible and the mechanism behind the reaction, in order to make subsequent anesthesia as safe as possible, a close collaboration between allergologist and anesthesiologist is highly desirable. In view of the constantly evolving anesthesiology practices, and of the relative complexity of allergy investigation, establishing specialized allergo-anesthesia centers should be promoted. At the end of the allergic work-up, the patient should be warned against any substance which has tested positive, and a warning card or bracelet should be issued. A detailed letter containing information on the reaction, on the drugs given, on the results of follow-up investigations and advice for future anesthetics should be issued to the patient, the referring anesthesiologist and the patient’s general practitioner.
Allergy to anesthetics remains an important cause of morbidity and mortality during anesthesia. NMBAs are the most frequently incriminated drugs, although other drugs used during the perioperative period might be involved. Any suspected hypersensitivity reaction must be extensively investigated using combined peri- and postoperative testing, according to well established guidelines.
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