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Allergic reactions occurring during anaesthesia

Mertes, P. M.; Laxenaire, M.-C.

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European Journal of Anaesthesiology: April 2002 - Volume 19 - Issue 4 - p 240-262



Although our understanding of allergic reactions during anaesthesia has substantially increased over the past 30 yr, they remain a major cause of concern to anaesthetists. Anaphylaxis is an acute allergic reaction resulting primarily from the rapid antigen-induced, usually IgE-dependent release of potent, pharmacologically active mediators from tissue mast cells and peripheral blood basophils. Anaphylactic reactions may be exacerbated in severity or prolonged in duration by mediators derived from these cells or from other secondary recruited inflammatory cells. These reactions differ from 'anaphylactoid reactions' that are clinically indistinguishable from anaphylaxis but are triggered independently of IgE antibody.

Since the initial report describing an anaphylactic reaction to succinylcholine [1], followed by clinical observations reported by Fisher [2], Sigiel and colleagues [3] and Vervloet and colleagues [4], increasing interest has focused on immune-mediated reactions occurring during anaesthesia. Moreover, in light of the increasing number of anaesthetic drugs, the need for confirmation and quantitative risk assessment of suspected rare serious adverse reactions requiring precise epidemiological studies [5] has continually been reinforced. In addition, awareness of the constant changes in anaesthetic practice has led to elaboration of a growing number of practice guidelines concerning the diagnosis, high-risk group identification and management of anaphylaxis [6-11].


The term 'anaphylaxis' was introduced in 1902 by Charles Richet and Paul Portier to describe the hypersensitivity reactions they observed in dogs after repeated injections of sea anemone toxin [12]. In immunological terms, anaphylaxis is an example of an immediate Type 1 hypersensitivity reaction. Most cases are IgE or rarely IgG mediated. The typical sequence of events in immediate hypersensitivity begins with the production of IgE by B-cells in response to initial exposure to an antigen. These antibodies bind to specific Fc receptors on the surface of effector cells such as mast cells and basophils. The interaction of reintroduced antigen with the bound IgE leads to activation of these cells and the release of various mediators [13]. The mediators are usually classified as preformed or newly synthesized. They include histamine from mast cells and basophils, and tryptase from mast cells [14-16]. The substances are responsible for the clinical manifestations of immediate hypersensitivity. Release is produced by cellular activation and transduction triggered by the bridging of IgE-receptor complexes with allergens. The magnitude of degranulation is influenced by the affinity of a given drug for cell-bound IgE antibodies as well as by their number on the cell surface. It is estimated that the human basophil contains 40 000-100 000 IgE antibody receptors. Basophils and mast cells bind IgE via a high-affinity receptor (FcεRI), whereas lymphocytes, eosinophils and platelets bind them via a low-affinity receptors (FcεRII) triggering the release of further mediators including kinins, prostaglandins, leukotrienes, serotonin or eosinophil cationic protein [17].

Most anaesthetic drugs such as muscle relaxants or opioid derivatives are low molecular weight molecules and are considered as haptens. As such, they are incapable of inducing the production of drug-specific antibodies by themselves. Consequently, previous conjugation of the native drug or one of its degradation products with some protein carrier and processing by professional antigen-presenting cells such as dendritic cells before presentation of peptides on the cell surface in close association with a Class I or II histocompatibility molecule, is usually regarded as the initial step of sensitization [18-20]. Direct interaction with proteins present on the surface of the dendritic cell, as reported for sensitizing metal and some antibiotics, and Class II histocompatibility molecular interactions, should also be given consideration [21-23].

Although antigen presentation by dendritic cells is regarded as an essential step for induction of an immune response in modern immunology, the elicitation of an immediate IgE-mediated reaction to the same drug is influenced by different immunochemical requirements. In anaphylaxis, mast cells and basophils are activated by the cross-linking of FcεRI molecules. This is thought to occur by the binding of multivalent antigens to the attached molecules. This could be a possible explanation for the increased number of anaphylactic reactions to neuromuscular-blocking agents, in comparison with other drugs used during anaesthesia. With respect to muscle relaxants, the main antigenic determinants involved in the generation of specific IgE antibodies are substituted ammonium ions. This was initially demonstrated by Baldo and Fisher [24]. As a result, it has been hypothesized that most neuromuscular blocking agents that bear two similar quaternary ammonium ions per molecule are capable of bridging IgE antibodies and eliciting anaphylaxis. In this regard, the flexibility of the chain between the ammonium ions as well as the distance between the quaternary ammonium ions might be of importance during the elicitation phase of anaphylaxis [25,26]. Flexible molecules such as succinylcholine can stimulate sensitized cells more strongly than rigid molecules (e.g. pancuronium). The relative affinities of the various muscle relaxants to their corresponding IgEs may also play a role. This also explains the cross-reactivity between the different muscle relaxants observed with IgE antibodies of most patients, and initially evidenced by skin testing [27,28]. This cross-reactivity, however, was only observed in 70% of patients presenting with anaphylaxis to muscle relaxants [29]. In addition to the above-mentioned steric considerations, which could explain why two muscle relaxants do not necessarily behave similarly, further hypotheses have been proposed. In some cases, the antigenic determinant may either correspond to the quaternary ammonium epitope or extend to an adjacent part of the molecule. Another rare possibility might be that IgE antibodies could be complementary to structures other than the ammonium group [30].

The main antigenic determinants involved in the generation of specific IgE antibody towards other anaesthetic drugs has also been defined. Two antigenic determinants have been identified in the thiopental molecule: the secondary pentyl and ethyl groups attached in position 5 of the pyrimidine ring nucleus and the thiol region on the opposite side [30,31]. 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 [32].

Finally, 240 potentially allergenic proteins have been identified in processed latex products. Seven sensitizing proteins have been identified or cloned and assigned allergen designation Hev b1-b7 [33-36]. A 14-kD protein (rubber elongation factor) is one of the major allergens responsible for allergic reactions among healthcare workers, and a 27-kD protein has been implicated among several vulnerable patient populations [37,38]. Hevein [39], pro-hevein [40], latex lysosome and rubber elongation factor [41] are other potent implicated allergens.

In some instances, IgE-mediated anaphylactic reactions have been reported at the first known contact with an incriminated drug. 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 quaternary ammonium group [21]. The latter is the case of neuromuscular blocking agents [24]. Such a hypothesis has been proposed for adverse reactions to neuromuscular blockers and IgE antibodies generated towards acetylcholine, different membrane phospholipids or food lecithins from soy or egg [42]. Similar observations have been made concerning anaphylactic reactions to latex in patients with a history of food allergy to different fruits (avocado, kiwi, banana, fig, chestnut, hazelnut, sweet pepper, melon, pineapple, papaya). They contain several proteins similar or identical to those found in latex [43-58].


The observation of possible non-specific histamine release triggered by compounds having a simple chemical structure [59] has led to intense debate about the real nature of adverse reactions associated with anaesthesia during symposia organized in France, the UK and Germany [60-66]. The concept of shock related to non-specific histamine release by various anaesthetic substances was supported by many studies carried out by Lorenz and colleagues [67,68]. However, since the first report of an anaphylactic reaction to succinylcholine [1], followed by clinical observations reported by Fisher [2], Sigiel and colleagues [3] and Vervloet and colleagues [4], increasing interest has been focused on immune-mediated reactions occurring during anaesthesia. The development of skin tests [69-71] and the identification by Baldo and Fisher [24] of the particular role played by quaternary ammonium ions on specific IgE production led to the recognition of the frequent implication of muscle relaxants in anaphylaxis during anaesthesia [72].

Most reports on the incidence of anaphylaxis originate in France [29,73-76], Australia [2,77-79], the UK [80-84] and New Zealand [69,85]. They reflect an active policy of systematic clinical and/or laboratory investigation of anaphylactoid reactions suspected to be mediated by an immune mechanism. Anaphylactic reactions have also been reported for smaller series in the USA [86,87]. Nevertheless, the true incidence of anaphylactic reactions and their associated morbidity/mortality remain poorly defined. This is due to uncertainties over reporting accuracy and exhaustiveness. This is illustrated by the differences observed between reports from various developed countries. First, the clinical reaction must be recognized and it should be emphasized that patients experiencing anaphylaxis during anaesthesia present with a variety of signs and that these may not appear all at once. In addition, some debate remains about the interpretation and significance of skin and laboratory tests usually required to distinguish between anaphylactic and anaphylactoid reactions. Finally, there are often difficulties in obtaining valid data on the number of patients exposed to the risk in the population from which reactions are reported. With these limits in mind, the estimated incidence of anaphylaxis was 1:10 000-20 000 in Australia in 1993 [78] and 1:13 000 in France in 1996 [29]. Although rare, these may lead to death, even when appropriately treated [29,88], with a mortality rate ranging from 3.5% [89] to 4.7% [90].

The prevalence of the risk of anaesthetic anaphylaxis in the overall population, which corresponds to the proportion of patients who would respond, if exposed to antigenic anaesthetic substances remains poorly defined. Skin tests and/or specific IgE assays performed on the general population could estimate it. However, their clinical significance is questionable. If positive, they reflect an IgE-dependent sensitivity but do not necessarily indicate that an allergic reaction will occur. Nevertheless, the prevalence of allergy to anaesthetic drugs is probably higher than the incidence of reactions, because patients undergoing anaesthesia do not necessarily receive the drug to which they are allergic.

The prevalence of muscle relaxant sensitivity, based on skin test positivity and/or detection of specific IgE to quaternary ammonium ions, shows wide variation. A positive reaction in 9.3% of the general population has been reported [91], with extremes ranging from 1.6% in patients with no history of atopy and/or drug allergy to 16% in patients presenting these risk factors [92,93]. This contrasts with the incidence of anaphylaxis to neuromuscular blocking agents, which has been estimated as 1:6500 for anaesthesia where a muscle relaxant is included in the anaesthetic protocol [29].

The prevalence of latex sensitization, a major cause of anaphylaxis during anaesthesia, varies depending on the population studied. As with all allergy-causing substances, the greater the exposure in a given population, the greater the number of sensitized individuals. Nevertheless, significant differences have been reported. The prevalence of latex sensitization in the literature has been reported to vary from approximately 1 to 6.6% [94,95], reaching 15.8% in anaesthesiology staff [96]. However, as previously mentioned, this IgE-dependent sensitivity does not necessarily indicate that an allergic reaction will occur in case of exposure to latex.

Causative agents


Muscle relaxants. Among the drugs and other agents involved in anaphylaxis, muscle relaxants are most frequently involved, with a range of 50-70% [29,84,86,87,97-99](Fig. 1). In France the incidence of anaphylaxis to muscle relaxants was estimated at 1:6500 anaesthetic procedures involving a muscle relaxant in 1996 [29]. Anaphylactic reactions have been reported for all neuromuscular blocking agents, even with recently commercialized substances [29,99-111]. In most series, succinylcholine appears to be more frequently involved [74,76,112], with some differences reflecting variations in anaesthesiological practices from one country to another [13,99]. In the French survey conducted between 1 January 1997 and 31 December 1998, the percentage of anaphylactic reactions observed with each drug was compared with the estimated number of patients who effectively received these drugs over the study period [99]. The results derived from such estimates should, however, be carefully contemplated. However, they indicate that succinylcholine and rocuronium seemed to be more frequently involved. Vecuronium and pancuronium followed them whereas atracurium was the least frequently involved (Fig. 2). It should also be noted that in this series, anaphylaxis to a neuromuscular blocking agent was observed in 48 patients (14.7%) with no history of anaesthesia, and, as a consequence, no previous administration of any muscle relaxant.

Figure 1
Figure 1:
Agents involved (%) in anaphylaxis during anaesthesia in France (n = 477) from January 1997 to December 1998.
Figure 2
Figure 2:
Neuromuscular-blocking agents (%) responsible for anaphylaxis in France (n = 336) from January 1997 to December 1998.

Hypnotics. The estimated incidence of anaphylactoid reactions with thiopental was estimated as 1:30 000 [80]. It was suggested that most of the generalized reactions were related to its ability to elicit direct leukocyte histamine release [113]. However, there is evidence for IgE-mediated anaphylactic reactions based on skin tests and a specific IgE assay [114-117]. Although the radioimmunoassay developed for the detection of antibodies that react with thiopental is a valuable aid in confirming the diagnosis of Type I allergy to this drug, its use requires some specific consideration. IgE antibody formed in patients who react to a neuromuscular blocking agent could cross-react in vitro with the thiopental solid phase. In this case, however, thiopental does not inhibit the binding of these antibodies to the thiopental solid phase but inhibition is observed with the neuromuscular blocking agent. This allows one to distinguish between sensitization to thiopental and neuromuscular blocking drugs [30,31,118,119].

Ever since Cremophor EL (used as a solvent for some non-barbiturate hypnotics) has been avoided, many previously reported anaphylactoid reactions have disappeared. Although less frequent, anaphylaxis to all induction agents has been observed [13,120]. In the last French survey, five cases to thiopental, 10 to propofol and three to midazolam were recorded [99](Fig. 1), whereas no anaphylactic reaction to etomidate and ketamine was observed.

Opioids. Reactions to morphine, codeine phosphate, meperidine, fentanyl and its derivatives are uncommon [32]. Because of their direct histamine-releasing properties, distinction between anaphylaxis and non-immune-mediated histamine release is not always easy [121,122]. Hapten inhibition studies performed in the serum of a subject who experienced an anaphylactic reaction following the administration of papaveretum [123] has led to the identification of the allergic determinant (cyclohexenyl ring with a hydroxyl group at C-6 and methyl substituent attached to the N atom) involved in IgE binding [30]. Only seven cases were recorded in the last 2-yr epidemiologic survey in France (morphine = 1, fentanyl = 4, sufentanil = 2) [99](Fig. 1.).

Local anaesthetics. Allergic reactions to local anaesthetics are rare despite their frequent use. It is estimated that <1% of all reactions to local anaesthetics have an allergic mechanism [76,124,125]. Inadvertent intravascular injection leading to excessive blood concentrations of the local anaesthetic, or systemic absorption of epinephrine that was combined with the local anaesthetic, are by far the most common causes of adverse reactions produced by these drugs. In a series by Fisher and Bowey [125] that reports the results of an investigation conducted in 208 patients with a history of allergy to local anaesthetics over 20 yr, four patients were reported to have had an immediate allergy, and four patients had delayed allergic reactions.

Although severe anaphylactic reactions have been reported with both types of local anaesthetics [126-129], ester local anaesthetics, having a benzoic acid ring in their structure and the capability of producing metabolites related to para-aminobenzoic acid [130-132], are more likely than amide local anaesthetics to provoke an allergic reaction. Allergy to local anaesthetics may also be due to methyl-paraben [130-133], paraben [134] or metabisulphites [135,136] used as preservatives in commercial preparations.

Non anaesthetic drugs. Antibiotics are commonly administered perioperatively and can cause allergic reactions. A discussion of allergic reactions to antibiotics is beyond the scope of this review. However, their frequency has increased over the last 20 yr. They account for between 2 and 8% of reported anaphylactic reactions [99,112], cephalosporin being most commonly incriminated in Australia, whereas penicillins remain most frequently involved in France. Vancomycin, which is increasingly used for prophylaxis, has also been incriminated in some instances [137]. However, in most cases, the adverse reactions observed are related to the chemically mediated red-man syndrome associated with rapid vancomycin administration [138-140].

Protamine, whose use to reverse heparin anticoagulation has increased over the last two decades, has also been incriminated [76,103,141]. Reactions may involve a number of mechanisms including IgE, IgG and complement [142-145].

Aprotinin, a naturally occurring serine protease inhibitor, has found widespread applications either by the i.v. route or as a component of biological sealants, because of its ability to decrease blood loss and, as a consequence, transfusion requirements. Anaphylactic reactions are mediated by IgG and IgE antibodies [146]. The risk of anaphylactic reactions has been estimated as between 0.5 and 5.8%. Patients previously treated with this drug present an increased risk [147-149].

Perioperative exposures to agent other than to drugs

Latex. Allergy to natural rubber latex, which contains a complex mixture of water-soluble plant proteins, has become a major source of concern in clinical practice. It is the second most common cause of anaphylaxis during anaesthesia in the general population. However, in children subjected to numerous operations, particularly those suffering from spina bifida, it is the primary cause of anaphylaxis [150,151]. Most patients are sensitized to proteins originating from rubber tree sap (Hevea brasiliensis) present in products made from latex, such as gloves, catheters and various medical or non-medical products containing natural rubber. Latex exposure can occur as a result of contact with the skin or mucous membranes, with inhalation, ingestion and parenteral injection or with wound inoculation. The incidence of allergy to latex has rapidly increased, rising from 0.5% before 1980 to 19% in 1994 in France [76]. However, in the last French survey, latex sensitization was held responsible for 12.1% of recorded cases [99](Fig. 1). These results appear to be somewhat encouraging. They seem to indicate that increasing awareness of the risk of latex sensitization in children with spina bifida [152,153] or healthcare workers [154,155], combined with the efficacy of surgery in a latex-safe environment [156,157], could be responsible for the decrease of anaphylaxis to latex we observed.

Colloids. All synthetic colloids have been shown to produce clinical anaphylaxis. The overall incidence of reactions has been estimated to range between 0.033% [158] and 0.22% [75]. Although direct release of histamine has been reported with urealinked gelatin [159], evidence for IgE-mediated adverse reactions to gelatin has been reported [75]. In addition, adverse reactions to urea-linked gelatin (0.852%) seem to be more frequent than with modified fluid gelatin (0.338%) [75], whereas IgG-mediated adverse reactions to hydroxyethyl starch are uncommon [160-163]. Adverse reactions to dextrans were estimated as 0.275%, when it was 0.099% for albumin and 0.058% for hydroxyethyl starch solutions [75]. Eleven anaphylactic reactions to gelatin and two reactions to hydroxyethyl starch solutions were reported in the last French survey of anaphylaxis during anaesthesia [99](Fig. 1).

Clinical features

The intensities of allergic reactions show striking variation from one patient to another. Manifestations may range from mild non-life-threatening anaphylaxis to severe anaphylactic shock and death [13,78,99,164].

The onset and severity of the reaction are related to the mediator's specific end organ effects. Consequently, the difference between anaphylactoid and true anaphylactic reactions cannot be made on clinical grounds alone. IgE-dependent anaphylaxis was evident in 53% of cases [29] in a recent study involving patients investigated for an anaphylactoid reaction during anaesthesia. Clinical symptoms reported in patients with a true anaphylactic reaction and in those presenting with non-IgE-mediated anaphylactoid reactions were similar. However, when a classification based on symptom severity was applied (Table 1)[158], clinical manifestations were more severe in patients with documented anaphylaxis. Nevertheless, some cases corresponding to true IgE-mediated anaphylactic reactions were classified as Grade I or II. As a result, any suspected anaphylactoid reaction occurring during anaesthesia should be thoroughly investigated to establish a precise diagnosis and appropriate recommendations.

Table 1
Table 1:
Grade of severity for quantification of the anaphylactoid reaction.

Anaphylaxis may occur at any time during anaesthesia and may progress slowly or rapidly. Ninety per cent of reactions appear within minutes after the i.v. injection of anaesthetic products or antibiotics. Alertness is essential because reactions may be well established before they are noticed. The most commonly reported initial features are pulselessness, a difficulty in lung inflation and desaturation [103]. In our experience, a decreased end-tidal CO2 expiration is also of valuable diagnostic interest. If the signs appear later during the maintenance of anaesthesia, they suggest an allergy to latex or volume expanders [75,165,166]. Latex allergy should also be considered when gynaecological procedures are performed. Particles from obstetricians' gloves, which accumulate in the uterus during obstetrical manoeuvres, could suddenly be released into the systemic blood flow following oxytocin injection [29,167]. Anaphylactic reactions to antibiotics have also been reported following removal of a tourniquet during orthopaedic surgery [168,169].

Factors that influence allergic reaction symptom severity in the sensitized individual include the distribution and reactivity of sensitized mast cells and basophils, individual organ susceptibility, released mediators and the endogenous response they elicit [170]. Anaphylaxis commonly involves the skin, cardiovascular and respiratory systems, as well as virtually any system, including the gastrointestinal, central nervous and genitourinary systems. The most recent French epidemiological survey, conducted between January 1997 and December 1998, involved 477 patients having experienced a true anaphylactic reaction during anaesthesia and most adverse reactions were of Grades II (22.9%) or III (62.6%), whereas only 10.1% of Grade I and 4.4% of Grade IV cases were recorded. Interestingly, in this series, reactions to neuromuscular blocking agents were more severe than those to latex. Cutaneous symptoms were present in 69.6% of cases (n = 332), angio-oedema in 11.7% (n = 56), bronchospasm in 44.2% (n = 211), arterial hypotension in 17.8% (n = 85), cardiovascular collapse in 53.7% (n = 256), bradycardia in 2.1% (n = 10) and cardiac arrest in 4% (n = 19) [99]. No difference in the severity of clinical symptoms was observed with regards to gender, history of atopy, asthma and food or drug intolerance. However, a significant association between the onset of clinical bronchospasm and a history of atopy or asthma was observed.

Clinical features may occur as an isolated condition [29,78,99,171]. Therefore, an anaphylactic reaction restricted to a single clinical symptom (e.g. bronchospasm, tachycardia with hypotension) can easily be misdiagnosed because many other pathological conditions may present identical clinical manifestations [13]. In mild cases restricted to a single symptom, spontaneous recovery may be observed even in the absence of any specific treatment. However, it should be kept in mind that under such circumstances, the lack of a proper diagnosis and appropriate allergologic assessment could lead to fatal re-exposure [172]. In our last survey, cardiovascular symptoms (hypotension or cardiovascular collapse) were the sole features in 10.5% (n = 50), bronchospasm in 3.2% (n = 15) and cutaneous symptoms in 7.8% (n = 37) of cases [99].

In most cases, after adequate treatment, clinical signs regress within 1 h without sequelae. However, in some cases, bronchospasm can be particularly severe and resistant to treatment, with a risk of cerebral anoxia. Prolonged inotropic support might also be required in some patients. Moreover, previous treatment by β-adrenoreceptor blocking agents is a potential risk factor explaining a lack of tachycardia, as well as resistance of arterial hypotension to adrenaline [164].

Risk factors

The potential severity of anaphylaxis during anaesthesia underscores the interest of developing a rational approach to reduce its incidence by identifying potential risk factors before surgery. With respect to drug allergy, different items such as gender, previous general anaesthesia, atopy and other drug allergies should be taken into account. Special attention should also be paid in case of allergy to latex.


A female predominance has been demonstrated in perioperative anaphylactic reactions, particularly those concerning allergic reactions to muscle relaxants with a female: male ratio ranging from 8:1 to 4:1 in some series [78,173]. In the last French epidemiological survey, it was 2.7:1 [99]. This difference was not related to an increase in female exposure to neuromuscular blocking agents. It persists even if the gender ratio (1.1 female:1.0 male) of anaesthetized patients as established by the French survey of anaesthesia is taken into account [174]. Similarly, a female predominance was observed with respects to latex sensitization. This does not, however, imply any need for systematic allergy investigation in females before anaesthesia.


Children who have undergone many operations, in particular those suffering from spina bifida, are considered at an increased risk for latex sensitization [6,10,150-152,175]. This increased risk has not been confirmed in adult patients repeatedly exposed to latex [176,177]. In addition, in the last French epidemiological survey of anaphylaxis during anaesthesia, a significant difference was observed regarding the distribution of anaphylaxis to latex according to age ranges. It was significantly different from those observed with neuromuscular blocking agents, with a higher incidence in the younger age ranges [99]. On the contrary, although the peak incidence of anaphylaxis to neuromuscular blocking agents was observed in the fourth decade in females and in the fifth decade in males, anaphylaxis was reported both in young and in elderly patients.


Atopy is a hereditary predisposition in which subjects synthesize IgE antibodies to various allergens introduced into the body via natural routes. It has long been considered 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 anaesthesia, when atopy was defined on clinical grounds alone. However, when confirmed by specific immunological tests, atopy does not appear to be a significant risk factor for muscle relaxant sensitivity [91,93,178]. A history of atopy and/or asthma has a very low specificity and sensitivity is a predictor of anaphylactic reactions. Moreover, it is considered to have an unacceptably high false-alarm rate [103,179]. Nevertheless, one should bear in mind the fact that basophils of atopic patients release histamine more readily [180,181]. As a consequence, it could be a risk factor for histamine release in case of administration of known histamine-releasing drugs such as atracurium, mivacurium, propofol or gelatin [182,183].

History of drug allergy

Allergy to anaesthetic agents is the first factor to consider. Any unexplained life-threatening reaction during a previous anaesthetic might be an allergic reaction, and as such is a major risk factor for a future reaction if the responsible drug is administered again [13]. Moreover, because of the difficulties inherent in the clinical assessment of anaphylaxis and possible cross-reactions, determination of the patient's allergic status should be performed in case of any unexplained reaction to general or local anaesthetics [184].

Previous exposure does not seem to be a risk factor for reaction to muscle relaxants, and anaphylaxis to neuromuscular blocking agents has been observed in the absence of any prior general anaesthesia and, consequently, in the absence of prior administration of any of these agents [99]. However, a documented anaphylactic reaction to a muscle relaxant is a positive risk factor for a renewed shock if a muscle relaxant, even if a recent muscle relaxant to which the patient has never been exposed, is administered. The high incidence of cross-anaphylaxis implies that no other muscle relaxant should be administered without prior testing [185]. Usually, the muscle relaxant for which skin testing is negative should be used [79,102,186,187]. One should bear in mind, however, that even these recommendations do not guarantee absolute prevention of further adverse reactions [188], and that the safest approach is to avoid the drug class whenever possible.

As far as anaphylactic reactions to other drugs than anaesthetics are concerned, no data indicate the need for a particular procedure in the choice of anaesthetic agents. Obviously, the drug to which the patient is allergic must be avoided.

Latex allergy

The reported prevalence of latex allergy varies greatly depending upon the population studied and the methods used to detect sensitization. As is the case with all substances causing allergy, the greater the exposure in a population, the greater the number of sensitized individuals. The potentially life-threatening risk of anaphylactic shock during surgery in patients allergic to, or belonging to 'at-risk' groups for latex allergy, has recently been emphasized [165,189-191]. The initial signs suggesting allergy include pruritus, urticaria or contact angio-oedema. Conjunctivitis, rhinitis and asthma in subjects wearing gloves containing natural latex, or confined to an area in which the air is polluted by latex particles, has also been observed. Patients at risk must be routinely screened. High levels of latex-specific IgE antibodies can lead to anaphylactic shock during surgery if it is not performed in a latex-safe environment. 'At-risk' groups could be defined as follows [10,192]:

• Children, such as those with spina bifida, who have been operated on several times, and/or with prolonged use of indwelling urinary catheters, present a 40-50% risk of sensitization to latex. Controversy remains between authors who favour a positive relation between the number of operations and the frequency of latex allergy [193,194], and those who do not [175]

• These recommendations have recently been extended to patients with a history of multiple surgical procedures [10]. However, this also remains subject to controversy. In a recent study, we could not detect any increase in sensitization in spinal cord-injured adult patients [177]. This is also the case for chronic renal failure patients having a high degree of latex exposure [176]

• Healthcare workers who wear latex gloves or work in areas having a high concentration of latex particles, such as operating rooms. The risk of sensitization increases with increased exposure. The prevalence of sensitivity is 10%, and can reach 15.8% in anaesthetic staff [96]. Dental school students also present a particular risk, and sensitization increased from 0 to 10% in first- and fourth-year students, respectively [195]

• Other individuals with occupational exposure such as rubber industry workers [196]

• Patients allergic to several fruit (avocado, kiwi, banana, fig, chestnut, hazelnut, sweet pepper, melon, pineapple, papaya) due to cross-allergy with latex [197]

• Individuals with severe hand dermatitis who wear latex gloves. It has been suggested that dermatitis disrupts skin integrity and facilitates absorption of latex allergen

• Patients with a history of hay fever, rhinitis, asthma or eczema (atopy) are considered as being at risk in some recommendations [10], but not in others [11]. A significant number of atopic patients are reported in several series concerning latex sensitization [45,96,198,199], with an increased risk for latex allergy of 36%, compared with 9.4% in non-atopic patients [45]. In addition, atopic patients with asthma or allergic rhinitis to grass or weed pollens could have a cross-sensitivity to latex [200]. However, in the absence of well-defined positive and negative predictive values of systematic screening for latex sensitization in atopic patients before anaesthesia, this has not been recommended as standard clinical practice in France [11].

Investigation of an allergic reaction

Every patient who experiences an anaphylactoid reaction should benefit from immediate and delayed investigations to confirm an eventual IgE-mediated allergic reaction, to identify the responsible drug and to detect possible cross-reactivity in cases of anaphylaxis to a neuromuscular blocking agent [11]. The anaesthetist administering the drugs associated with the suspected anaphylactic reaction must be responsible for ensuring that these tests are performed and interpreted adequately. The investigation should be conducted in concert with an allergologist or a clinical immunologist. However, the anaesthetist remains responsible for providing further advice to the patient, informing the patient's primary care physician and recording all pertinent data in the patient medical record.

A detailed clinical history remains the single most important source of information when working up a prior allergic reaction. All drugs given before and during the anaesthesia, as well as their timing in relation to the reaction, must be noted. Diagnosis of most drug allergies is, in fact, presumptive and based on a temporal relation with the injection of the incriminated drug. After patient recovery, a detailed history including concurrent morbidity, previous anaesthetic history and any known allergies should be taken. The diagnostic strategy for a suspected anaphylactic reaction is based on laboratory tests, on samples taken during and shortly after the reaction, and on tests carried out days to weeks later. Early tests are essentially designed to determine whether an immunological mechanism is involved. Delayed testing attempts to identify the responsible drug. Whenever possible, confirmation of the incriminated allergen should be based on immunological assessment using more than one test.

Intraoperative testing

Tryptase. Tryptase is released from activated mast cells but not from basophils. Although elevated tryptase levels can be observed in different situations [201], an elevated serum tryptase concentration >25 μg L−1 is strongly in favour of an anaphylactic mechanism [11]. However, a negative test does not completely rule out anaphylaxis. Tryptase concentration should be determined approximately 1 h after the start of the reaction. Tryptase, whose half-life appears to be longer than that of histamine, can still be detected for 1-6 h or more after the onset of anaphylaxis [14,88,112,202]. Moreover, the potential interest and medico-legal value of mast cell tryptase measurement, even at autopsy, has been previously emphasized [88,203].

Histamine. Early increased plasma histamine and increased urinary methylhistamine concentrations may help to confirm the reality of in vivo histamine release [14-16,204]. A conference of European experts rigorously examined the most appropriate techniques for assaying histamine [205]. Histamine should be assayed within the first hour of a suspected anaphylactic reaction, and in mild cases, only early measurements may be increased [206]. Histamine assay should be avoided during pregnancy (particularly near term) and in patients receiving high doses of heparin because of a high rate of false-negativity [11,206,207]. Urinary methylhistamine assays are no longer recommended in view of their low sensitivity in comparison with tryptase and histamine assays.

Specific IgE assay. Radioimmunoassay for the detection of drug-reactive IgE antibody may provide important information for identification of the causative agent of anaphylaxis [13]. Although classically performed several weeks after the reaction, they can be carried out on blood drawn at the time of the reaction. As a result, the presence of specific IgE against the suspected drug at the time of the reaction can be substantiated [15]. Satisfactory correlation with subsequent immunological investigation has been reported when neuromuscular blocking agents are incriminated [15]. They can also help to confirm the diagnosis by identifying the responsible drug in patients in whom skin tests could either not been performed or were negative. These assays test for specific circulating IgE based on the assumption that they reflect IgE bound to mast cells.

Baldo and Fisher initially demonstrated the presence of neuromuscular blocking agent-specific IgE in serum [24] using muscle relaxant coupled to epoxy-Sepharose. Specific IgE adsorbed to the solid phase was detected using radiolabelled anti-IgE. Inhibition of IgE binding was obtained by preincubation of the sera with either soluble muscle relaxants or structurally related compounds. They concluded that the quaternary and tertiary ammonium ions were involved in the allergenic site. This explained the cross-reactivity between different muscle relaxants observed by skin testing, in vitro leukocyte histamine release and serum IgE-RIA [185,208]. The value of radioallergosorbent tests (RAST) for IgE antibodies to muscle relaxants and thiopental is well-established [209]. Although the sensitivity of the CAP-RAST® assay (Pharmacia and Upjohn) is limited (succinylcholine 66%, alcuronium 40%), several teams have improved the sensitivity of specific serum IgE detection up to 90-97% by coupling an analogue of choline to Sepharose (SAQ) [210,211], or p-aminophenylphosphoryl-choline on agarose beads (PAPPC) [211,212]. Recently, specific IgE detection based on morphine in solid-phase form has been proposed [213]. Placing the tested serum in the presence of the offending molecule in its soluble form controls inhibition of specific IgE binding [211]. The concordance rate with skin tests is good (about 83%) in most cases [214,215]. However, a limit to the generalized use of these assays for neuromuscular blocking agents is that, due to the preparation of the materials required for the test, they are usually only possible in specialized laboratories.

Specific IgE against thiopental, morphine, phenoperidine and propofol have also been detected in serum of sensitized patients, using IgE-RIA [31,32]. Two different allergenic determinants have been identified on opposite sides of the thiopental molecule. One of these determinants involves the ring nitrogens in the pyrimidine nucleus and could be responsible for in vitro cross-reactions with sera from patients allergic to muscle relaxants [31,117]. Recently, the presence of hydrophobic IgE reacting non-specifically with propofol has been reported [216]. This renders the interpretation of specific IgE assays to propofol difficult. In some patients, simultaneous presence of anti-quaternary ammonium IgE was observed. This could be a risk factor for an adverse allergic reaction to propofol and may explain the potentiating effect of the association between propofol and muscle relaxants on in vitro leukocyte histamine release performed in patients who reacted against both drugs [17]. With respect to latex, a radioallergosorbent test is available but is less sensitive than the skin prick test, detecting antibodies in only 50-70% of cases [217].

These factors have recently led to limiting the recommended indications for specific IgE assays to the diagnosis of anaphylaxis to neuromuscular blocking agents, thiopental and latex [11].

Postoperative testing

Skin testing. Intradermal skin or prick tests are usually carried out 6 weeks after a reaction, but may remain positive for years later [218-220]. Ideally, testing should be carried out by a professional experienced in performing and interpreting tests with anaesthetic agents [7,11]. Treatments such as antihistamines, known to decrease cutaneous reactivity, should be interrupted. Prick tests and intradermal reactions with dilutions of commercially available drug preparations are advised [25,221-223]. Standardized procedures and dilutions must be precisely defined for each agent tested, to avoid false-positive results due to direct histamine releasing properties. This could be the case for known histamine-releasing compounds (such as mivacurium, atracurium, tubocurarine and morphine). As such, these should be tested with more dilute solutions [26,185,222-224]. Control tests using saline (negative control) and codeine (positive control) must accompany skin tests to determine whether the skin is apt to release histamine and react to it. Although a certain degree of controversy remains about the maximal concentrations to be used [225], detailed recommendations for skin and intradermal test dilutions of anaesthetic drugs have recently been proposed by the French Society of Anaesthesia (SFAR, Société Française d'Anesthésie et de Réanimation) (Table 2)[11].

Table 2
Table 2:
Recommended drug dilution scale for postoperative skin testing following anaphylactoid reaction during anaesthesia.

Any drug administered during the perioperative period should be considered as a potential cause. In addition, because of the frequent but not systematic cross-reactivity observed with muscle relaxants, every available neuromuscular blocking agent should be tested. This should help prevent future adverse reactions and provide documented advice for future administration of anaesthesia. Moreover, any new muscle relaxant should be routinely tested in patients known to be allergic to these agents to detect possible cross-reactivity [26,28,185].

The sensitivity of skin tests for muscle relaxants is approximately 94-97% [97,208]. However, sensitivity for other substances varies. It is good for synthetic gelatins, but poor for barbiturates, opioids and benzodiazepines [13,71,221]. There has been some controversy concerning the advantages of either prick or intradermal testing. Studies comparing both techniques show little differences between them [70,223]. However, reliability over time concerning prick testing has not been assessed [71], and the reliability of prick tests alone in the individual patient has been questioned by some [226]. Consequently, prick testing is advised for the diagnosis of the muscle relaxant responsible for an anaphylactic reaction, but intradermal testing should be preferred when investigating cross-reaction. In this case, dilutions should be increased to 10−1 to test most aminosteroid muscle relaxants [11]. Latex sensitization must be investigated by prick tests using two different commercial extracts, and in particular the recently standardized latex commercial extract (Stallergenes®) [227].

Other biological tests. Specific IgE radioimmunoassays for the detection of drug-reactive IgE antibody can be performed postoperatively if no blood was drawn at the time of the reaction [220], or when IgE assay is negative due to consumption of drug-specific antibodies during the anaphylactic reaction. However, specific IgE assay performed on blood drawn at the time of the reaction or (when available) prior to the reaction is preferable [15].

Several other tests have been proposed to allow for indirect detection of specific IgE to anaesthetic drugs. The Leukocyte Histamine Release test is reliable for muscle relaxants [228]. Its sensitivity is about 71% [210]. When combined with the simultaneous use of skin tests, and IgE-RIA, it allows for detection in the majority of cases [97]. However, it is quite expensive, time consuming, sometimes considered as a research tool [13], and not recommended in routine practice. Nevertheless, it could be useful when specific IgE assays are not available or when cross-reactivity among muscle relaxants in view of future anaesthesia in sensitized patients is investigated.

The study of human basophil activation by detection of altered plasma membrane molecule expression using flow cytometry has also been proposed [229-231]. These tests are based on the changes of membrane molecules such as CD 63 resulting from basophil activation in the presence of a suspected allergen. Its sensitivity in the diagnosis of muscle relaxant allergy is estimated at 64% and its specificity at 93% [230]. Their potential interest in the diagnosis of anaphylactic reactions to neuromuscular blockers requires further evaluation.

Reports concerning the monitoring of serotonin [232], eosinophil cationic protein [233] or LTC4 [234] release have also been published. However, these assays cannot be recommended in routine clinical practice at the present time.

Challenge tests. Indications for these tests are limited. They are restricted to local anaesthetics and latex [11]. They should only be performed in case of negative skin tests. Local anaesthetics can be tested by subcutaneously injecting 0.5-1.0 mL undiluted anaesthetic solution (without epinephrine). The test is considered negative if no adverse reaction occurs within 30 min after injection [125].

Wearing a latex glove on one hand compared with a vinyl glove on the other hand for 15 min can perform a latex glove provocation test [235]. The test is considered negative in the absence of any local symptoms during the 30 min following the glove-wearing period.

Investigation strategy prior to anaesthesia

In the absence of the established predictive value of tests for the occurrence of peroperative anaphylactic reactions [13,91,93,95], there is no demonstrated evidence for systematic preoperative screening in the general population at this time. Similarly, there is no evidence for the need of investigating sensitization against anaesthetic drugs in patients who are either atopic or sensitized to substances they would not be exposed to during anaesthesia.

Whenever possible, preanaesthetic assessment should be carried out in high-risk patients to detect sensitization to anaesthetic agents or latex. In spite of their satisfactory sensitivity, skin tests should be combined with an IgE assay if available [13]. The anaesthetic protocol for the patient depends on the results of this assessment. However, it should be kept in mind that skin tests performed belatedly after an adverse reaction during anaesthesia could be falsely negative. This is due to a possible spontaneous decrease of specific IgE concentration with time. It is always preferable that any investigation be carried out 6 weeks after the adverse reaction.

Consequently, an allergologic work-up is indicated in the following:

• Patients presenting a documented allergy to an anaesthetic drug or latex. The results of the initial investigations must be taken into account. When muscle relaxants are concerned, recent muscle relaxants should be tested before renewed anaesthesia

• Patients having experienced an unexplained reaction during a previous general anaesthesia, including severe hypotension, bronchospasm or oedema during recovery. It is conceivable that the reaction might have been related to sensitivity to an anaesthetic agent or latex. The list of all injected substances will help guide the allergologist through his assessment. If the anaesthetic protocol is unavailable, the substances that are most often incriminated in epidemiological studies should be tested (i.e. muscle relaxants and latex: skin tests, eventually specific IgE assays)

• Patients who allege an allergy to local anaesthetics, when local anaesthesia is scheduled. The local anaesthetic used at the time of the reaction, otherwise the most commonly reported local anaesthetics (i.e. lidocaine, mepivacaine and bupivacaine) should be tested. If an allergy to local anaesthetics is suspected, but skin tests are negative, progressive challenge testing may be indicated, according to the protocol described by Fisher and Bowey [125]

• Patients belonging to a high-risk group for sensitization to latex (children subjected to multiple operations, those with spina bifida, patients having experienced clinical symptoms of latex allergy in any circumstances, patients allergic to avocado, kiwi, banana, fig, chestnut, hazelnut, sweet pepper, melon, pineapple and papaya) (prick test ± specific IgE assays) [11,175,236,237].

In the case of emergency surgery, the anaesthetic technique used should be based on patient history (whenever possible):

• In case of unexplained reaction during previous general anaesthesia, regional block or general anaesthesia without muscle relaxant in a latex-safe environment is advisable

• In case of allergy to a local anaesthetic, general anaesthesia should be preferred. If regional block is still required, a challenge test must be performed and proved negative

• In case of known allergy to a muscle relaxant, all such drugs must be all avoided

• In case of a high risk of latex sensitization, surgery should be performed in a latex-safe environment.

Prevention and treatment


Primary prevention. Prevention of anaphylaxis has two major objectives. It should be aimed at preventing sensitization of a patient to a particular allergen, or aimed at preventing the occurrence of an anaphylactic reaction to a reintroduced allergen in a presensitized patient. In this regard, prevention of latex allergy in spina bifida patients by primary prevention, which consists in avoiding latex during medical and surgical care of these patients, is very effective [157]. Similarly, the wearing of powderless, low-latex-allergen gloves by healthcare workers has been proposed as a possible means to reduce the levels of latex aeroallergen in the operating room and the rate of sensitization to latex in healthcare workers [6]. On the other hand, in the wake of the relatively high rate of sensitization in the absence of any prior exposure, optimal prevention of sensitization to neuromuscular blocking agents, even if their administration were radically curtailed, is probably unattainable [99].

Secondary prevention. Avoidance of causal agent Prevention of anaphylactic reactions relies mainly on accurate documentation of previous reactions and the avoidance of the incriminated drug. Therefore, during the preanaesthetic consultation, a detailed history should be taken, with special emphasis on atopy, drug allergy, allergy to latex and to tropical fruit. The use of a specific questionnaire is particularly helpful (Table 3)[11,164,192].

Table 3
Table 3:
Preanaesthetic questionnaire.

Latex-sensitive patients should be managed by complete avoidance of potential latex exposure [10,11]. This is most easily achieved if a comprehensive institutional policy exists. Patient care must be carefully co-ordinated among all professionals, including pre- and postoperative nursing teams and theatre staff. Whenever possible, the patient should be scheduled for elective surgery as the first case of the day to reduce patient exposure to aerosolized latex particles. Warnings identifying a risk for latex allergy should be posted inside and outside the operating room and in perioperative care areas, and the patient should wear a medical alert bracelet or necklace. A checklist of recommendations should accompany the patient throughout his/her hospital stay (Table 4). In addition, a list of readily available non-latex product alternatives should be established in collaboration with the facility's central supply area service and should be prominently displayed in patient care locations.

Table 4
Table 4:
Checklist for patient who is allergic to latex.

Pharmacological prophylaxis

Steroids and antihistamines. Pretreatment with corticosteroids or histamine-receptor antagonists, by either H1- or H1- and H2-receptor antagonists remains controversial. No evidence of beneficial effects of prophylactic administration of corticosteroids in anaesthesia has been shown at this time [158]. Pretreatment with H1- and H2-receptor antagonists reduces histamine-mediated adverse effects in various studies [238]. Antihistamine administration was effective in reducing the incidence of opioid-induced anaphylactoid reaction [239], and the adverse effects of non-immune histamine release following muscle relaxant [240,241] or vancomycin [140] administration. H1- and H2-receptor antagonist administration combined with widespread immunologic screening was reported to have beneficial effects on the incidence and severity of chymopapain-induced adverse reactions [242]. It has also been shown that H1- and H2-receptor antagonists have a beneficial effect in the prophylaxis of anaphylactoid reactions provoked by urea-linked gelatin solutions used as volume expanders [239], as well as in a prospective study conducted in patients undergoing standard general anaesthesia [243]. In fact, these beneficial effects have mainly been obtained during clinical manifestations associated with non-immunemediated histamine release.

Moreover, histamine detected during alarming immune-mediated reactions is merely a marker of co-release of more dangerous mediators. In addition, such a prophylactic approach has been found to be ineffective [244,245], or even, in some cases, deleterious [246,247]. Many authors consider that pretreatment with corticosteroids or antihistamines, or both, do not provide for a reliable prevention of immune-mediated reaction [10,42,248,249]. Nevertheless, even in the absence of any well-documented studies concerning anaphylaxis, some authors propose pretreatment with H1 or H1 and H2 antagonists as useful in the management of the patient with a history of anaphylaxis or at risk of non-immune histamine release [42,172,226,238]. In France, the use of these associations remains a matter of controversy. When prescribed, preventive treatment is usually limited to H1-receptor antagonists. However, proven anaphylactic reactions even in the wake of preoperative H1-H2-receptor antagonists and steroids have been documented in epidemiological surveys [29,146].

Monovalent hapten inhibition. Monovalent hapten inhibition with hapten dextran has been shown to significantly reduce but not completely abolish adverse reactions to dextran [250-253]. The use of monovalent haptens, which can occupy antibody sites without bridging specific IgE fixed on sensitized cells, has also been proposed for muscle relaxants. In this respect, any molecule presenting a quaternary ammonium ion could be considered as a potential monovalent hapten. Choline and tiemonium were initially used. Unfortunately, clinical tolerance of the highest doses was poor. As a result, the concentrations obtained were too low to be effective [254,255]. Recently, Moneret-Vautrin and colleagues demonstrated inhibition of skin mast-cell reactivity to muscle relaxants by mixing them with the monovalent haptens cytidylcholine and ethamsylate [256]. Furthermore, they obtained an inhibition of leukocyte histamine release for up to 3 h following the infusion of these monovalent haptens in patients allergic to muscle relaxants. Morphine, with its high affinity to reactive muscle relaxant antibodies, has also been proposed as a possible preventive hapten [13,226]. However, possible prevention of muscle relaxant anaphylaxis by monovalent haptens cannot be recommended in standard clinical practice [11].


There is a wide array in reaction severity and in the efficacy of response to treatment. In addition, no controlled trials of treatment in humans are available. As a result, the ultimate judgement with regards to a particular clinical procedure or treatment scheme must be made by the clinician in light of the clinical presentation and available diagnostic and treatment options. Treatment of anaphylaxis is aimed at interrupting contact with the responsible antigen, modulating the effects of released mediators and inhibiting mediator production and release. It must be initiated as quickly as possible, and relies on widely admitted principles [7,11,164,172,226,248,257,258].

Non-specific measures. Administration of the suspected antigen must be interrupted, and the surgical procedure should be interrupted unless otherwise impossible.

Maintenance of airway patency is imperative and early endotracheal intubation should be considered because of a possible rapid onset of angio-oedema. Oxygen 100% should be administered. Large-bore i.v. access should be available, electrocardiograph and blood pressure monitoring must be started if not already performed, and the patient must lay flat with their lower limb elevated. These measures must be applied in all cases. They are usually sufficient in case of mild Grade I anaphylactoid reaction.

Specific treatment Anaphylactoid reaction of Grades II and III severity. Epinephrine is the drug of choice [259]. It opposes the deleterious systemic adverse effects of released mediators, through its vasoconstricting (α-mediated), positive inotropic (β1-mediated) and bronchodilating (β2-mediated) properties. It also reduces mast cell and basophil mediator release. Ventricular dysrhythmias have been reported in patients with pre-existing heart disease or in those receiving halogenated hydrocarbons [171]. However, this should not preclude administration of epinephrine, but electrocardiographic monitoring is indicated.

There are no data favouring one route of administration over another. Subcutaneous or intramuscular administration at a dose of 0.5-1.0 mg (10 μg kg−1 in children) repeated every 10 min [260], or even inhaled administration is possible [261-264].

When an i.v. route is available, titrated bolus administration according to arterial pressure and pulse is advised (10-20 μg in Grade II reactions, 100-200 μg in Grade III reactions) [7,11,265,266]. Administration should be renewed every 1-2 min until the clinical response is considered satisfactory (i.e. there is a measurable improvement in blood pressure, airway resistance and stabilization or regression of angio-oedema) [172]. Doses must be increased rapidly in case of inefficacy. Continuous infusion may be required in some cases (0.05-0.1 μg kg−1 min−1, titrated as needed).

Central venous and pulmonary artery catheterization for optimal guidance of inotropes and fluid volume administration should be considered in cases refractory to standard therapy. Prolonged monitoring in the intensive care unit is required because of the risk of recurrent reactions. Adjunction of anti-histamines and administration of H2-blocking drugs has also been proposed in some guidelines [258].

Intravascular volume expansion must be associated with vasoactive amines. Fluid infusion should be initiated immediately, while preparing epinephrine for injection. Rapid infusion of crystalloids (10-25 mL kg−1) over 20 min, repeated if necessary must be performed. Colloid infusion, avoiding any potentially incriminated solution, should be started when the volume of crystalloids infused >30 mL kg−1.

Bronchospasm is usually reversible with epinephrine. However, in case of persistent bronchospasm, or in the absence of arterial hypotension, inhaled β2-agonists (salbutamol) is advised. In case of refractory bronchospasm or immediate increased severity, i.v. administration of a bolus dose of 100-200 μg, followed by continuous infusion at 5-25 μg min−1 should be considered. Intravenous infusion can also be performed in non-intubated patients when appropriate inhalation chambers are unavailable.

Norepinephrine may be indicated in conditions where low peripheral perfusion pressure predisposes to intrapulmonary shunting (started at a 4-8 μg min−1, titrated as needed), or in case of persistent vasodilatation in the absence of bronchospasm [172]. Dobutamine can be used in case of pulmonary oedema, a cardiac assist device may be necessary if cardiac failure persists [172,267]. Phosphodiesterase inhibitors and PGE1 may be used in case of severe pulmonary hypertension [268].

In case of sympathetic blockade produced by either β-adrenoreceptor-blocking drugs or regional anaesthesia, symptoms are usually refractory to treatment. Doses of epinephrine should be increased (up to ≥10 mg); high-dose dopamine or other adrenoreceptor agonists may be required. Atropine (1-2 mg i.v.), as well as glucagon (initial dose 1-5 mg, followed by 1.0-2.5 mg h−1 infusion) may be added [269-271].

During pregnancy, hypotension must be initially treated by i.v. ephedrine injection; a 10 mg bolus dose repeated every 1 or 2 min (with cumulative doses up to 7 mg kg−1). Epinephrine administration should be started in case of inefficacy.

Anaphylactoid reaction of Grade IV severity - cardiac arrest. External cardiac massage must be instituted immediately; associated with a 1 mg bolus of epinephrine i.v. repeated every 1-2 min and rapidly increased to 5 mg as of the third injection. Cumulative doses could reach ≥50 mg. This must be associated with recommended practice guidelines concerning management of patient presenting with cardiac arrest.

Secondary therapy. Corticosteroids (hydrocortisone 200 mg i.v. every 6 h) can be administered to prevent delayed manifestations of anaphylaxis [11,272].


Anaphylaxis continues to be a significant adverse event during anaesthesia and is probably under diagnosed. Substances other than anaesthetic agents may cause it. Treatment is aimed at interrupting contact with the responsible antigen, modulating the effects of the released mediators, and inhibiting mediator production and release. It should be initiated immediately with a rapid administration of epinephrine. As for all rare events, detailed diagnostic and therapeutic protocols, as well as emergency drugs, should be available in operating rooms, and management training on the anaesthesia simulator is advised.

Because no premedication can effectively prevent an allergic reaction, it is the anaesthetist's responsibility to ensure that any suspected anaphylactic reaction be thoroughly investigated using combined per- and postoperative testing. In addition, systematic inquiries aimed at identifying patients belonging to an at-risk group must be performed before any anaesthesia. Patients must be fully informed of investigation results and advised to provide a detailed report before any future anaesthesia. The wearing of a warning bracelet or possession of a warning card is strongly indicated.

In view of the constantly evolving anaesthesiological practices and of the relative complexity of allergy investigation, an active policy to identify patients at risk and to provide any necessary support from expert advice to anaesthetists and allergologists through the constitution of allergo-anaesthesia centres should be promoted.


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